16 ON 2020 GI Lower WB

LOWER GASTROINTESTINAL AND PANCREATIC CANCERS
Courtney C. Cavalieri, Pharm.D., BCOP

Clinical Oncology Pharmacist
Huntsman Cancer Institute at the University of Utah
Salt Lake City, Utah
LEARNING OBJECTIVES
At the end of the presentation and after reviewing the accompanying reading materials, the participant
should be able to:
1. Design an appropriate patient-specific treatment, supportive care, and monitoring plan taking
into consideration efficacy and safety outcomes from clinical trials and current treatment
guidelines for patients with lower gastrointestinal (GI) or pancreatic cancers.
2. Discuss short- and long-term treatment goals, including post-therapy and survivorship, with a
patient with lower GI or pancreatic cancers and his or her caregiver.
3. Assess the impact of pharmacogenomics on the efficacy and toxicity of relevant anticancer and
supportive-care agents for a patient with lower GI or pancreatic cancers.
4. Select relevant information and guidance for the public regarding lower GI and pancreatic
cancer-related issues (e.g., risk factors, prevention, screening).
5. Develop an appropriate plan for preventing, monitoring, and treating adverse reactions
associated with pharmacotherapy for lower GI or pancreatic cancers, including chemotherapy-
induced diarrhea, hand-foot syndrome, hand foot skin reaction, neurotoxicity from oxaliplatin,
and dermatologic toxicities from epidermal growth factor receptor inhibitors.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) referenced with permission from the
National Comprehensive Cancer Network® (NCCN®). To view the most recent and complete version of
the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN
GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive
Cancer Network, Inc.
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and
disclaims any responsibility for their application or use in any way.
©2020 American Society of Health-System Pharmacists, Inc. and American College of Clinical Pharmacy. All rights reserved.
1
COLON AND RECTAL CANCER
I. Genomics1
A. Genetic alterations 1-3
1. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch Syndrome
a. Accounts for 2-4% of all colorectal cancers
b. Not characterized by excessive polyps
c. Autosomal dominant trait caused by germline mutations in DNA mismatch repair (MMR) genes
MLH1, MSH2, MSH6, and PMS2
1) Patients’ lifetime risk of colon cancer up to 80%
2) Women have up to 60% risk of endometrial cancer
3) Increased risk (1-13%) for other malignancies such as ovarian, hepatobiliary, genitourinary,
pancreatic, and small intestine
d. Onset of colon cancer occurs around 43 years of age
2. Familial adenomatous polyposis (FAP)
a. Accounts for about 1% of all colorectal cancers
b. Manifested by hundreds to thousands of adenomatous polyps that cover the colon and rectum
c. Autosomal dominant disorder caused by mutation in APC (adenomatous polyposis coli) gene
1) About 30% of patients have a de novo APC germline mutation (no prior family history)
d. If left untreated, 100% will progress to colorectal cancer by early 40’s
3. Other genetic entities include Muir-Torre, Turcot, Gardner, Cowden, Bannayan-Riley-Ruvalcaba,

Peutz-Jeghers, juvenile polyposis, and serrated polyposis syndromes (SPS)
B. Defective DNA mismatch repair (dMMR)2
1. Up to 19% of colorectal cancers develop due to defective function of DNA mismatch repair system
a. Patients with dMMR status are biologically the same as those with high level microsatellite
instability (MSI-H) status though dMMR is determined by immunohistochemistry (IHC) testing
and microsatellite status is determined by next generation sequencing (NGS). This is discussed in
more depth in the Pharmacogenomics module.
2. dMMR/MSI-H status predicts decreased benefit from adjuvant therapy with a fluoropyrimidine in
patients with stage II disease
a. Multiple retrospective reviews have investigated the benefit of using fluorouracil (5-FU)-based
adjuvant chemotherapy versus observation in MSI-H/dMMR patients after curative resection of
stage II or stage III colon cancer
1) Patients with MSI-H/dMMR tumors have significantly increased overall survival (OS),
increased disease-free survival (DFS), and lower rates of tumor recurrence than patients with
MSI-L, MSS, or pMMR who were observed after surgery (IE, no adjuvant therapy)4-6
2
2) In patients with MSI-H/dMMR stage II disease, adjuvant therapy was associated with
decreased OS and higher risk of death compared to observation4, 5; however patients with
MSI-H/dMMR stage III disease still experienced benefit from adjuvant therapy over
observation6
b. Patients with stage II MSI-H/dMMR tumors may have a good prognosis and do not benefit from
adjuvant 5-FU therapy2
c. Patients with stage III MSI-H/dMMR tumors can still benefit from 5-FU-based adjuvant therapy
and therefore should be considered for treatment over observation alone6
3. dMMR/MSI-H status also predicts increased benefit from programmed cell death protein 1 (PD-1)
inhibitors in patients with progressive metastatic disease (further discussed in Treatment of
metastatic colon and rectal cancer)
a. Approximately 3.5-6.5% of stage IV colorectal tumors are dMMR/MSI-H2
b. Both pembrolizumab and nivolumab with or without ipilimumab have shown encouraging
response rates and progression-free survival in heavily pretreated metastatic colorectal cancer
that is dMMR/MSI-H7-9
c. Pembrolizumab and nivolumab with or without ipilimumab have FDA approved indications for
patients with MSI-H or dMMR metastatic colorectal cancer that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
d. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend

pembrolizumab or nivolumab with or without ipilimumab in patients with metastatic
dMMR/MSI-H colorectal cancer in second- or third-line therapy2
C. Enzymatic deficiencies
1. Dihydropyridine dehydrogenase (DPD) deficiency and 5-FU10-12
a. 5-FU is metabolized by 2 routes
1) 20% anabolic
2) 80% catabolic (mainly occurs in liver)
b. DPD is an enzyme that is involved in the initial and rate-limiting step of 5-FU catabolism
1) Varying concentrations of DPD in humans may affect 5-FU bioavailability and account for
varying patient response to 5-FU
c. DPD deficiency
1) Genetic abnormality in the DPYD gene; partial deficiency occurs in 3-5% and complete
deficiency occurs in 0.2% of general population
2) High concentration of DPD = decreased 5-FU activity
3) Low concentration of DPD = increased levels of 5-FU that may result in severe GI toxicities
(mucositis, diarrhea), myelosuppression, neurologic toxicity, and possibly death
4) Screening for DPD deficiency prior to 5-FU exposure is not routinely performed
3
a) There are numerous DPYD variants, and only a few have clearly established relationships
to DPD function
5) Currently, there is no universally used test for DPD deficiency
a) Testing options range from targeted analysis of specific variants to full coding regions
6) The Clinical Pharmacogenetics Implementation Consortium (CPIC®) provides dose

modification recommendations for fluoropyrimidines based on an assigned activity score12:
a) Activity Score 2
i. DPYD normal metabolizer: an individual carrying 2 normal function alleles
ii. No dose modifications recommended
b) Activity Score 1 or 1.5
i. DPYD intermediate metabolizer: an individual carrying 1 normal function allele and

1 no function allele, or 2 decreased function alleles
ii. Reduce starting dose by 25-50%
c) Activity Score 0 or 0.5
i. DPYD poor metabolizer: an individual carrying 2 no function alleles, or 1 no function

allele and 1 decreased function allele
ii. Avoid the use of fluoropyrimidines; if these agents are required, the starting dose
should be significantly decreased and early drug monitoring should be implemented
2. Uridine diphosphate glycosyltransferase 1 family polypeptide A1 (UGT1A1) and irinotecan13, 14
a. Metabolism and pharmacokinetics of irinotecan
1) Irinotecan has a dipiperidino side-chain linked to the captothecin base molecule
2) Carboxylesterases in the liver and gastrointestinal (GI) tract cleave the side chain to form the
metabolite SN-38
a) SN-38 is about 1000-fold more potent inhibitor of topoisomerase I than irinotecan
3) SN-38 is then glucuronidated by UGT1A1 in the liver, creating the inactive SN-38G which is
eliminated via biliary excretion into the GI tract
4) SN-38G can be “reactivated” back to SN-38 via bacterial β-glucuronidase enzymes that
remove the glucuronide group
b. Reduced activity of UGT1A1 can lead to significant toxicities15
1) Patients with a UGT1A1*28 polymorphism, especially a homozygous mutation, are at much

higher risk to develop significant neutropenia, although higher doses are associated with
more toxicity
2) Approximately 10% of US population is homozygous for UGT1A1*28 allele
3) Irinotecan dose reductions are recommended for patients who are UGT1A1*28 homozygous
in the prescribing information16
4
a) A reduction of at least one level from the starting dose is recommended, however
modifications should also consider the specific dosing regimen and individual patient
characteristics
4) FDA-approved test is available to evaluate for UGT1A1 polymorphisms, however there are
no official guidelines for the use of this test in clinical practice
D. Predictive biomarkers17-21
1. Testing does not demonstrate predictive value for response to anti-EGFR monoclonal antibody (MAB)
therapy and therefore routine testing for EGFR is not recommended
2. RAS (KRAS, NRAS, and HRAS)
a. RAS mutations predict lack of response to anti-EGFR MABs
b. Several trials have demonstrated these agents only work in RAS-wild type (WT) disease
c. NCCN Guidelines® and ASCO guidelines recommend testing all patients with metastatic disease
prior to starting an anti-EGFR MAB for treatment
d. ASCO Guideline on Molecular Biomarkers for the Evaluation of Colorectal Cancer21
1) All patients with metastatic colorectal cancer who are candidates for anti-EGFR MAB therapy
should have their tumor tested for the following:
a) KRAS and NRAS
i. Exon 2, codons 12 and 13
ii. Exon 3, codons 59 and 61
iii. Exon 4, codons 117, and 146
iv. RAS mutations in exons 2, 3, or 4 are associated with lack of benefit from anti-EGFR
MAB therapy and may be associated with worse outcomes when added to
chemotherapy
b) Treatment with anti-EGFR MAB therapy should only be considered in patients whose
tumor does not have one of the above mutations (IE, these agents are only appropriate
for wild-type disease)
3. BRAF20
a. BRAF V600E mutation occurs in 5-15% of colorectal cancers and results in poorer prognosis
b. RAS and BRAF mutations are typically mutually exclusive at diagnosis
c. Data suggest lack of activity for anti-EGFR MAB therapy in the presence of V600E mutations
1) The NCCN panel® recommends all patients at diagnosis of stage IV disease undergo
genotyping for BRAF2, 22
2) ASCO recommends BRAF mutational analysis be performed for prognostic stratification21
d. Unlike other disease states with BRAF V600E mutations responsive to BRAF +/- MEK inhibition,
colorectal cancers with these mutations show limited, if any, response to BRAF inhibitors23
5
1) Response rates for single-agent BRAF inhibitors in BRAF V600E-mutated melanomas have
been reported up to 80%, vs <5% seen in BRAF-mutated colorectal cancers
2) The lack of response is hypothesized to be due to feedback activation of EGFR, which leads
to MAPK signaling pathway reactivation, which could in turn result in further progression of
the tumor rather than control
a) Colorectal cancer cells are of epithelial origin and express EGFR; melanoma cells do not
3) In order to overcome this reactivation of the MAPK pathway, BRAF inhibition therapies have
been evaluated with the addition of anti-EGFR MAB therapies
4) This dual inhibition has led to improved response rates, and promising survival outcomes
that are still maturing
e. The NCCN Guidelines® support various regimens containing anti-EGFR MABs and BRAF ± MEK
inhibitors for use in patients with BRAF V600E-mutated metastatic colorectal cancer
1) Colorectal cancer patients with BRAF mutations should not be treated with either an anti-
EGFR MAB alone or a BRAF ± MEK inhibitor alone
II. Prevention and screening
A. Chemoprevention
1. Diet
a. Vitamin supplementation24, 25
1) Observational studies associated increase calcium and vitamin D intake with decreased
colorectal cancer risk
2) Women’s Health Initiative
a) 18,176 participants randomly assigned to receive supplemental calcium and vitamin D,

and 18,106 received placebo
b) After 7 years of follow-up, calcium and vitamin D had no effect on the risk of colorectal
cancer (HR 1.08, 95% CI, 0.86 – 1.34)
3) Baron and colleagues confirmed that calcium and vitamin D supplementation did not have a
significant effect on the risk of adenoma
4) Selenium supplementation has shown mixed results in observational studies
b. High fiber26
1) High fiber diet thought to dilute carcinogens in stool, decrease colon transit time and create
favorable environment in colon
2) Increased fiber intake does not significantly reduce colon cancer risk
2. Cyclooxygenase inhibition27
a. Cyclooxygenase COX-2 expression is enhanced in up to 90% of colorectal carcinomas
1) Data have shown the efficacy of using COX-2 inhibitors to decrease the incidence of
colorectal adenomas,28, 29 however due to the risk of cardiovascular events associated with
6
their use, COX-2 inhibitors are not recommended routinely for prevention of sporadic
adenomas30
b. NSAIDs27
1) Women who regularly used aspirin (≥2 325 mg tablets per week) had a multivariate risk
reduction (RR) for colorectal cancer of 0.77 (95% CI, 0.67-0.88)
2) U.S. Preventive Services Task Force (USPSTF) recommendations on initiating aspirin31
a) Grade B for adults aged 50 to 59 years with a ≥10% 10-year cardiovascular disease (CVD)
risk
b) Grade C for adults aged 60 to 69 years with a ≥10% 10-year CVD risk
c) There is currently insufficient evidence to make a recommendation for adults younger

than 50 years or 70 years or older
3) Chemoprevention in familial adenomatous polyposis (FAP)30
a) Cyclooxygenase-2 (COX-2) inhibition32
i. Primary objective: to determine whether inhibition of COX-2 reduces the extent of

polyposis in patients with FAP
ii. Conclusion: COX-2 inhibition in FAP results in reduction of the number of colorectal
polyps, decreases risk of developing colorectal adenocarcinoma, and may also delay
need for a prophylactic colectomy
iii. Due to lack of phase IV data however, the FDA indication for use of celecoxib in FAP
was removed in 201130
b) NSAIDs
i. The use of sulindac or aspirin has not shown to significantly decrease the
development of colorectal adenomatous polyps in patients with FAP30
ii. There are some data that the use of sulindac in combination with erlotinib can
decrease duodenal polyp burden compared to placebo33
c) Currently, there are no FDA-approved medications for chemoprevention of colorectal

cancer in patients with FAP and the NCCN Panel acknowledges the limited data available
B. Screening
1. Various sources have published recommendations for screening including the NCCN Guidelines®,
American Cancer Society (ACS), U.S. Preventative Services Task Force (USPSTF), and the U.S. Multi-
Society Task Force on Colorectal Cancer (USMSTF)
a. The ACS and USPSTF do not have screening guidelines specifically for people at increased or high
risk of colorectal cancer
7
Colon Cancer Screening Recommendations2, 30, 34-39
NCCN Guidelines®, ACS, USPSTF, & USMSTF
Average Risk Any one of the following options is appropriate
NCCN®, USPSTF, & Colonoscopy every 10 years
USMSTF: Age ≥50 years
ACS: Age ≥45 years Fecal occult blood test OR Fecal immunohistochemical test (FIT) every 1 year
FIT-DNA test every 1 or 3 years#

The decision to screen
between ages 76-85 CT Colonography every 5 years
years should be
individualized Flexible sigmoidoscopy every 5-10 years†
NCCN Guidelines® USMSTF
Increased Risk
IBS (ulcerative colitis, Initiate colonoscopy 8 years after onset of
Crohn’s disease) symptoms, then every 1-3 years
Personal history of Colonoscopy
adenoma or sessile Low-risk polyps: every 5-10 years
serrated polyp found Intermediate-risk polyps: every 5 years
on colonoscopy High-risk polyps: every 3 years
Personal history of CRC Colonoscopy at 1 year post-resection, then 3
years, then every 5 years
Positive family history Colonoscopy
of CRC* ≥1 first-degree relative diagnosed at any age:
initiate at age 40 or 10 years before earliest
diagnosis, then every 5 years
≥1 second-degree relative age <50: initiate at

age 50, then every 5-10 years
High Risk
Positive family history 2 first-degree relatives diagnosed at any age OR 1 first-
of CRC* degree relative diagnosed at <60 years: initiate
colonoscopy 10 years before age of earliest diagnosis
or age 40 (whichever is earlier)
1 first-degree relative diagnosed at ≥60 years: initiate

at age 40; tests and intervals per average-risk
recommendations
Lynch syndrome Initiate colonoscopy at age 20-25, or 2-5 years before earliest diagnosis if ≤25, then every 1-2 years
CRC = colorectal cancer; IBS = inflammatory bowel disease
#
NCCN®, ACS, & USMSTF recommend every 3 years, whereas USPSTF recommends every 1 or 3 years
†NCCN® and USMSTF allow a range of 5-10 years, whereas ACS & USPSTF recommends every 5 years
*Positive family history is considered increased-risk by NCCN and high-risk by USMSTF
2. Other high risk patients include those with classical and attenuated FAP, Cowden syndrome, Li-
Fraumeni syndrome, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile and serrated
polyposis syndrome, and colonic adenomatous polyposis of unknown etiology. Refer to the NCCN
Guidelines® for Genetic/Familial High-Risk Assessment: Colorectal for specific screening
recommendations for these patients.
8
Screening modalities for colorectal cancer 34, 39, 40
Method Procedure Advantages Disadvantages
Fecal occult Checks for occult (hidden) • No bowel preparation • Colonoscopy needed if abnormal
blood test (FOBT) blood in stool • Inexpensive results
• Easy to use; test can be performed • 50% of colorectal cancers go
at home undetected due to no bleeding at the
• Noninvasive and no sedation time of examination
needed • Certain foods and medications may
alter results
Fecal Uses antibodies to detect • No bowel preparation • Colonoscopy needed if abnormal
immunochemical hemoglobin in stool • No drug or food interactions results
test (FIT) • Improved accuracy compared with
FOBT
• Easy to use; test can be performed
at home
• Noninvasive and no sedation
needed
FIT-DNA test Screens stool samples for • No bowel preparation • May miss diagnosis of polyps
(Cologuard®; aka presence of red blood • No pre-test dietary restrictions • May produce false positive results
stool DNA test) cells and DNA mutations • Easy to use; test can be performed • Colonoscopy needed if abnormal
that may indicate at home results
presence of cancer • Noninvasive and no sedation • Limited data on optimal interval
needed between screening
• Insufficient evidence regarding follow-
up after abnormal tests
Flexible Visualizes distal portion • Can be used for biopsy or excision • Views only lower 1/3 of colon and can
sigmoidoscopy of the colon (lower 35- of polyps miss ~50% of lesions if not done past
60%) and rectum via a • Minimal bowel preparation the sigmoid colon
sigmoidscope • Does not require a specialist • Test availability has declined in the
United States
Colonoscopy Visualizes the entire • Provides information on the • Inability to detect small lesions
colon using a mucosa of the entire colon because of mucosa folds, blind
*Preferred due to
colonoscope • Can be used for biopsy or excision corners, and cecum may not be
its superior ability
of polyps reached
to detect lesions
in proximal or • Highly sensitive diagnostic tool • Full bowel preparation, expensive,
right side of the • Best method for screening high- sedation needed
colon risk patients • Risk of bowel tears or infection
CT colonography Examines the entire colon • Views entire colon • Requires full bowel preparation
(aka virtual via series of X-rays used • Does not require sedation • If polyps or other suspicious lesions
colonoscopy) to produce 2-D and 3-D are detected, a colonoscopy is needed
images for biopsy and/or excision
• Can miss small polyps, some false
positive results
• Expensive
• Unclear follow up for potential of
extracolonic findings
9
Patient Case #1 (ARS Question 1):
TG is a 52-year old female who recently underwent her first screening colonoscopy which revealed a sigmoid
mass. Biopsy was consistent with malignancy. Staging scans did not reveal metastatic disease, and therefore she
underwent resection. Pathology revealed moderately differentiated adenocarcinoma, with invasion through the
muscularis propria into the pericolonic tissue, negative margins, and no evidence of perineural or
lymphovascular invasion; 2 of 19 lymph nodes were positive, thus it was staged T3 N1b M0. She presents to the
oncologist for discussion of adjuvant treatment. Her performance status is 1 and she is 6 weeks out from
surgery.
Which of the following is the most appropriate care plan for TG’s stage IIIB colon cancer?
A. Capecitabine
B. FOLFOX
C. FOLFIRI
D. Observation
III. Treatment and symptom management
A. Principles of Surgery 1, 2, 22
1. Treatment of choice in patients with potentially curable disease
2. Palliation or symptom management in metastatic disease
a. Bleeding, obstruction, localized abdominal pain caused by bulky tumor mass
3. Removal of isolated pulmonary or hepatic metastases
a. Curative in 20-25% of patients if all metastatic disease can be resected
b. Complete resection must be feasible based on anatomy
4. 12 lymph nodes necessary for adequate sampling to determine node positive or negative disease
5. Surgical approach for colon cancer
a. Generally involves partial colectomy
1) Complete resection of tumor, adjacent mesentery, and regional lymph nodes
6. Surgical approach for rectal cancer22
a. Transanal excision may be performed for superficial rectal tumors meeting specific criteria
b. Transabdominal resection
1) Abdominoperineal resection (APR) – performed for tumors located in the lower one-third of
the rectum involving the anal sphincter or the levator muscles, and in cases where negative
margin resection of primary tumor results in loss of anal sphincter function and incontinence
a) APR generally removes distal sigmoid colon, rectum, and anus, which requires creation
of a permanent colostomy
10
2) Low anterior resection (LAR) – used for tumors located in the mid to upper rectum, leaves
the anal sphincter intact
a) Generally removes primary tumor and 4-5 cm below distal edge of the tumor using TME
(see below) and creation of colorectal anastomosis
3) Total mesorectal excision (TME) – removal of the mesorectum including vascular and
lymphatic structures, fatty tissue, and mesorectal fascia, sparing autonomic nerves
a) TME is designed to remove surrounded lymphatic structures, which reduces positive

radial margin and local recurrence rates
B. Principles of radiation therapy 1, 2, 22
1. Colon cancer - minimal role as rates of distant recurrences are higher than local recurrences
a. May use radiation for a T4 lesion, perforation, incomplete resection or palliative therapy if
unresectable or inoperable - bleeding, obstruction
2. Rectal cancer
a. Administered prior to or following surgery in patients with curable disease
1) Neoadjuvant for stage II and III disease
a) Utilized to improve resectability of primary tumor (decrease risk for positive margins
and increase opportunity for LAR resection) and to decrease risk of local recurrence
2) Adjuvant for stage II and III disease
a) Used to desurgical approach is used would be helpfulcrease risk of local recurrence
b) Radiation alone after surgery has been found to be inferior to concurrent radiation and
chemotherapy in rectal cancer
3) Metastatic disease
a) Utilized for symptom reduction (pain, bleeding)
3. Complications of radiation to the rectum
a. Acute toxicity
1) Thrombocytopenia/leukopenia, dysuria, diarrhea, abdominal cramping, proctitis, vaginal

stenosis and/or dryness, dyspareunia
b. Chronic toxicity (can persist for months following discontinuation of XRT)
1) Diarrhea, small bowel disease, proctitis, enteritis, pelvic fractures/decreased bone density,
infertility, sexual dysfunction, erectile dysfunction, urinary incontinence/frequency/urgency
C. Principles of chemotherapy2, 22
1. For recommendations on dosing and schedules of chemotherapy regimens, please refer to the NCCN
Guidelines® for Colon Cancer and NCCN Guidelines® for Rectal Cancer for the most up-to-date
information
a. Definitions of common regimens
1) FOLFOX
11
a) There are multiple iterations of FOLFOX. The current standards are mFOLFOX6 and
mFOLFOX7.
b) mFOLFOX6 Q 14 days
i. Bolus 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, and oxaliplatin IV 85 mg/m2 Day
1
ii. Infusional 5-FU continuous IV infusion (CIVI) 1200 mg/m2/day x 2 days (over 46-48
hours)
c) mFOLFOX7 Q 14 days
i. Leucovorin IV 400 mg/m2 and oxaliplatin IV 85 mg/m2 Day 1
ii. Infusional 5-FU continuous IV infusion (CIVI) 1200 mg/m2/day x 2 days (over 46-48
hours)
2) CAPEOX or XELOX Q 21 days
a) Oxaliplatin IV 130 mg/m2 Day 1
b) Capecitabine PO 1000 mg/m2 Days 1-14
i. North American patients may require lower doses of capecitabine based on

tolerance/toxicities
3) FOLFIRI Q 14 days
a) Bolus 5-FU IV 400 mg/m2, leucovorin IV 400 mg/m2, and irinotecan IV 180 mg/m2 Day 1
b) Infusional 5-FU CIVI 1200 mg/m2/day x 2 days (over 46-48 hours)
4) FOLFOXIRI Q 14 days
a) Leucovorin IV 400 mg/m2, irinotecan IV 165 mg/m2, and oxaliplatin IV 85 mg/m2 Day 1
i. NCCN® strongly recommends a starting dose of CIVI 5-FU consistent with the
FOLFIRI or FOLFOX regimens, as the higher dose used in original trials is associated
with poorer tolerance in U.S. patients
2. Neoadjuvant
a. Colon cancer
1) For localized disease, regimens usually contain a fluoropyrimidine with or without oxaliplatin
a) Regimen should be based on expected patient tolerability, and prior chemotherapy if

applicable
2) Can be used for metastatic patients for conversion to resectability
a) Optimal sequencing of neoadjuvant/adjuvant chemotherapy unknown
b) Multiple trials have shown successful conversion with fluoropyrimidine-based

regimens41, adding bevacizumab42-44, or adding cetuximab45-47
b. Rectal cancer
12
1) Used in combination with radiation to increase radiation sensitization and improve systemic
control of disease
2) Fluoropyrimidine-based chemotherapy is recommended, and should be delivered

concurrently with neoadjuvant radiation
3. Adjuvant
a. Decreases risk of disease recurrence by eradicating micrometastatic disease and improving

disease-free survival (DFS) after surgical resection for curative intent
b. Results in a 2 - 5 % absolute risk reduction for recurrence of stage II and a 20 - 25 % absolute risk
reduction for recurrence of stage III
c. Adjuvant therapy typically begins 4 to 8 weeks after surgery and lasts for 6 months
1) Certain patients with stage III, low-risk disease may be eligible for 3 months of therapy (see
below)
d. Fluoropyrimidine-based regimens are standard of care
1) Toxicity profile differs between infusional and bolus 5-FU/leucovorin
a) Infusional 5-FU more commonly associated with hand-foot syndrome and GI toxicity
b) Bolus 5-FU/leucovorin more commonly associated with hematologic toxicity
2) Capecitabine is clinically equivalent to bolus 5-FU/leucovorin in terms of disease-free

survival48
a) Capecitabine associated with significantly lower incidence of grade 3/4 neutropenia and
stomatitis; however also associated with significantly higher incidence of grade 3/4
hand-foot syndrome
3) Addition of oxaliplatin increases benefit for stage III patients
a) The MOSAIC trial compared 5-FU/leucovorin to FOLFOX4 in patients with resected stage
II and stage III colon cancer49, 50
i. FOLFOX4 was superior in overall survival (OS) to 5-FU/leucovorin at 6 years (72.9%

vs. 68.7%; p=0.023) for stage III colon cancer
ii. There was no difference in disease-free survival (DFS) or OS for stage II disease: DFS
HR 0.84 (95% CI, 0.62-1.14) and OS HR 1.00 (95% CI, 0.7-1.41)
b) CAPEOX is considered an acceptable alternative to FOLFOX51, 52
4) Irinotecan is not used in the adjuvant setting for early stage patients
5) No targeted agents are approved for use in the adjuvant setting for early stage patients
4. Metastatic disease
a. Used for palliation of symptoms and to prolong life in patients with unresectable, incurable
disease
b. Can be used in some patients for conversion to resectability
13
c. Includes either a combination of chemotherapy or single agents in sequential, continuous fashion
(see Treatment of metastatic colon and rectal cancer below for detailed discussion)
D. Treatment of early stage colon cancer (stages I, II, III)2
1. Goal of treatment is cure
2. Stage I
a. Surgical excision of primary tumor and removal of regional lymph nodes
b. Observation (no adjuvant chemotherapy) is recommended
3. Stage II53
b. Considerations for adjuvant chemotherapy:
1) Reduces risk of recurrence; 3% survival benefit
2) Evaluation of MSI/MMR status
3) Presence of one or more of the following high-risk features guides therapy per NCCN
Guidelines®:
a) Poorly differentiated histology (exclusive of MSI-H cancers)
b) Lymphovascular invasion
c) Perineural invasion
d) Bowel obstruction
e) Localized perforation
f) Close, indeterminate or positive margins
g) <12 lymph nodes surgically examined
c. Stage II, low-risk and MSI-H/dMMR
1) Observation (no adjuvant chemotherapy) is recommended
d. Stage II, low-risk
1) Observation or clinical trial is recommended
2) Can consider adjuvant chemotherapy with capecitabine or 5-FU/leucovorin
e. Stage II, high-risk features (including T4 tumors)
1) Adjuvant chemotherapy with capecitabine, 5-FU/leucovorin, or clinical trial is recommended
2) Can consider FOLFOX, CAPEOX, or observation
4. Stage III
b. Adjuvant chemotherapy with FOLFOX or CAPEOX is recommended
14
c. Can consider capecitabine or 5-FU/leucovorin for patients in whom oxaliplatin may not be a
suitable option
d. Duration of adjuvant therapy in stage III disease54
1) The IDEA consortium of trials showed that for patients with low-risk stage III disease (T1-3,
N1), 3 months of CAPEOX is non-inferior to 6 months of CAPEOX in terms of disease-free
survival
a) Non-inferiority of 3 vs 6 months of FOLFOX has not been shown
2) NCCN® preferred recommendations:
a) Stage III, low-risk
i. CAPEOX x3 months
ii. FOLFOX x6 months (category 1) or x3 months
b) Stage III, high-risk
i. CAPEOX x6 months (category 1) or x3 months
ii. FOLFOX x6 months (category 1)
Correct answer is B. Patients with stage III disease are recommended to receive adjuvant chemotherapy for 3-6
months with an oxaliplatin-containing regimen. FOLFOX and CAPEOX are the preferred, Category 1 regimens in
the NCCN Guidelines®.
Answer A is incorrect because TG does not have a contraindication to receive an oxaliplatin-containing regimen
Answer C is incorrect as irinotecan-containing regimens have not been shown to provide survival benefit in the
adjuvant setting
Answer D is incorrect because TG has stage III disease with no known contraindications to chemotherapy
KV is a 73-year old male who presents to his PCP with complaints of bleeding with bowel movements. A
colonoscopy reveals a 3 cm fungating mass at the anal verge. Biopsy of the mass displayed moderately
differentiated adenocarcinoma. An MRI of the pelvis revealed a T3 lesion with involvement of the internal anal
sphincter and intersphincteric fat. CT scans were negative for metastatic disease. He has no other pertinent
medical comorbidities and can perform all of his ADLs.
Which of the following is the most appropriate initial therapy for KV’s clinical stage II rectal cancer?
A. Transabdominal resection
B. Radiation alone
C. Radiation plus capecitabine
D. Radiation plus FOLFOX
15
E. Treatment of early stage rectal cancer (stages I, II, III)22
1. Treatment goal is cure
2. The rectum is located 12-15 cm from the anal verge
3. Clinical stage
a. Upon diagnosis, patients are staged clinically by endorectal ultrasound (EUS) or MRI of pelvis
b. This is used to determine whether patients should receive neoadjuvant chemoradiation or

proceed with surgery first for early stage rectal cancer (non-metastatic disease)
4. Pathologic stage / restaging
a. Findings after resection determine the patient’s pathologic stage, which determines appropriate
post-operative therapy
b. Restaging also helps assess treatment response if neoadjuvant treatment was given
5. Post-operative therapy (adjuvant therapy) is indicated in all patients who receive preoperative
(neoadjuvant therapy) regardless of surgical pathology results for non-metastatic disease
a. Adjuvant therapy typically involves sequential regimens of chemotherapy + chemoradiation for 6

months total
6. Chemoradiation (chemoRT)55-57
a. The addition of chemotherapy to radiation either pre- or postoperatively improves local radiation
sensitization and systemic control of disease
b. Preoperative chemoRT also has increased rates of pathologic complete response, leading to
sphincter preservation
c. Despite improvements in local control, most trials have not shown improvements in DFS or OS
d. If a patient is medically fit to receive chemotherapy concurrently with radiation, it would be

preferred over radiation alone
e. The addition of oxaliplatin to fluoropyrimidine-based chemoRT did not improve surgical or

survival outcomes and resulted in patients experiencing more diarrhea58, 59
1) The addition of oxaliplatin to chemoRT for rectal cancer is not supported or recommended
f. Acceptable regimens include:
1) Capecitabine/RT or infusional 5-FU/RT (both preferred)
2) Bolus 5-FU/RT
3) Refer to the NCCN Guidelines® for Rectal Cancer for information on dosing and schedules of
chemoradiation regimens
7. Chemotherapy
a. Acceptable regimens include:
1) FOLFOX or CAPEOX (both preferred)
2) 5-FU/LV or Capecitabine
16
NCCN Guidelines® Treatment Pathways for Early Stage Rectal Cancer22
Pathologic Stage I
without high-risk Observation
features
Transanal
excision (if Transabdominal
appropriate) resection (then Consider
follow algorithm observation
Pathologic Stage I below)
with high risk
features
Transabdominal
ChemoRT resection, then
chemotherapy
Clinical Stage I
Pathologic
Observation Chemotherapy
Stage I
Observation
Transabdominal Pathologic
Resection Stage II
Sequential
regimen Option
1*
Pathologic Sequential
regimen Option 1
Stage III or Option 2*
Transabdominal
Chemotherapy
resection
ChemoRT
OR
Clinical Stage II Radiation alone Systemic therapy
Resection
or III for advanced
contraindicated
OR disease
Locally
unresectable or
medically Transabdominal
Observation
inoperable resection
Chemotherapy  ChemoRT
OR
Radiation alone  Chemotherapy Systemic therapy
Resection
for advanced
contraindicated
disease
*Option 1: Chemoradiation  chemotherapy; Option 2: Chemotherapy  chemoradiation  chemotherapy
17
Correct answer is C. Radiation plus a fluoropyrimidine as neoadjuvant therapy is a preferred, Category 1

recommendation for stage II rectal cancer based on data that show the addition of chemotherapy to
preoperative radiation enhances pathologic response and improves local control
Answer A would only be appropriate if KV had a medical contraindication to combined modality therapy, which
he does not
Answer B could be considered if KV had a contraindication to chemotherapy, however the addition the
chemotherapy to radiation has shown significant decreased tumor size, pathologic TN stage, and lymphatic,
vascular, and perineural invasion rates
Answer D is not correct. Addition of oxaliplatin to chemoRT has been studied, and results show no difference in
pathologic response with greater adverse events. The addition of oxaliplatin to neoadjuvant radiation is not
recommended at this time.
F. Treatment of metastatic colon and rectal cancer (stage IV)2, 22
1. Treatment goal is palliation, although select patients can still be cured
2. Principles
a. Chemotherapy is used for palliation of symptoms and to prolong life in patients with metastatic
disease
1) Refer to the NCCN Guidelines® for Colon Cancer and NCCN Guidelines® for Rectal Cancer for
detailed information on dosing and schedules of chemotherapy regimens
b. Radiation may be used for palliation and/or symptom control
c. Liver-directed therapy may also be considered for liver metastases (refer to Locoregional
Therapy section in the Upper Gastrointestinal and Hepatocellular Carcinomas module for more
detailed information)
d. Surgical resection of the primary tumor may be performed for palliation or symptom
management in patients with bleeding, obstruction, or localized abdominal pain due to large or
bulky primary tumor
1) Removal of isolated pulmonary or hepatic metastases may be performed in select patients
2) Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy

(HIPEC) can be considered for patients with peritoneal carcinomatosis
a) The high morbidity and mortality, as well as conflicting efficacy, make this intervention a
controversial issue
3. First-line systemic treatment options
a. Fluoropyrimdine-based regimens are the standard of care
1) Capecitabine is considered equivalent to 5-FU/LV in terms of clinical outcomes
a) Capecitabine is associated with less stomatitis, alopecia, and neutropenia, and higher
incidence of hand-foot syndrome and grade 3/4 hyperbilirubinemia60
18
2) The addition of oxaliplatin or irinotecan to 5-FU (FOLFOX or FOLFIRI, respectively) was shown
to increase PFS and TTP, and OS for irinotecan, vs 5-FU alone
a) Oxaliplatin associated with more neutropenia, mucositis, diarrhea, and peripheral

neuropathy
b) Irinotecan associated with significantly more diarrhea, neutropenia, and asthenia61, 62
3) CAPEOX is non-inferior to FOLFOX for PFS, OS, and ORR63, 64

a) FOLFOX associated with more neutropenia and febrile neutropenia
b) CAPEOX associated with more diarrhea and hand-foot syndrome
c) Neurotoxicity similar between groups
4) Combining oxaliplatin and irinotecan with 5-FU (FOLFOXIRI) significantly improved RR

(p<0.0001), PFS (p=0.0006), and OS (0.032) over FOLFIRI, while associated with significantly
more neurotoxicity and neutropenia65
a) Concerns about exposing patients to 5-FU, oxaliplatin, and irinotecan in 1st line setting,
leaving limited options beyond 1st progression
5) Either FOLFOX or FOLFIRI may be used 1st line, followed by the other regimen in 2nd line, as
PFS has not been shown to be significantly different; toxicities associated with each regimen
may help determine the sequence66
a) FOLFOX associated with significantly more neurotoxicity, grade 3/4 neutropenia and
thrombocytopenia
b) FOLFIRI associated with significantly more grade 3/4 febrile neutropenia,

nausea/vomiting, mucositis, fatigue
b. Bevacizumab
1) Bevacizumab has demonstrated improved response rates and survival outcomes when
added to fluoropyrimidine-based regimens
2) Bevacizumab is recommended in combination with 5-FU, capecitabine, FOLFOX, CAPEOX64, 67,

68
, FOLFIRI69, 70, and FOLFOXIRI71, 72 for 1st line therapy of metastatic colon and rectal cancer
3) Associated with grade 3/4 toxicities of thromboembolic events, hypertension, bleeding
4) Dose differs based on schedule:
a) Every 14 days: 5 mg/kg IV
b) Every 21 days: 7.5 mg/kg IV
c. Anti-EGFR monoclonal antibodies (MABs)
1) Cetuximab and panitumumab have demonstrated improved response rates and PFS when
added to FOLFOX73-75 or FOLFIRI76, however the addition has not shown to significantly
increase OS
2) The addition of cetuximab or panitumumab to FOLFOX and FOLFIRI for 1st line therapy of
metastatic colon and rectal cancer with RAS wild-type tumors is supported in the NCCN
Guidelines®
19
a) FOLFIRI + panitumumab is listed as an option for first-line therapy in the NCCN
Guidelines® based on extrapolation from data in second-line treatment2, 22
b) Cetuximab + CAPEOX was associated with significant diarrhea and dermatologic

toxicities, therefore is not recommended73
3) Cetuximab is associated with rash, infusion reactions, and diarrhea and panitumumab is
associated with rash, diarrhea, paronychia, low magnesium, and mucositis
4) Dosing
a) Panitumumab IV 6 mg/kg Q 14 days
b) Cetuximab IV 400 mg/m2 for first infusion, then 250 mg/m2 weekly OR 500 mg/m2 Q 14
days
5) Primary tumor sidedness2
a) Right-sided tumors occur from cecum to hepatic flexure, and left-sided tumors occur
from splenic flexure to rectum
b) A growing body of evidence77-80 has shown that patients with right-sided, RAS wild-type
primary tumors confer little to no benefit from cetuximab or panitumumab in first-line
therapy
c) The NCCN panel recommends that only patients whose primary tumors originate on the
left side of the colon with RAS wild-type be offered an anti-EGFR monoclonal antibody
for front-line treatment of metastatic disease
i. Until data are more definitive, cetuximab or panitumumab can still be offered for all
RAS wild-type patients in subsequent line therapy
d. Bevacizumab with chemotherapy vs cetuximab with chemotherapy in the front-line setting has
shown no significant difference in overall survival, therefore either targeted therapy is an
appropriate addition to front-line chemotherapy regimens81
e. Summary of first-line treatment options per NCCN Guidelines®2, 22
1) Patients appropriate for intensive therapy
a) FOLFOX or CAPEOX ± bevacizumab
b) FOLFIRI ± bevacizumab
c) FOLFOXIRI ± bevacizumab
d) FOLFOX or FOLFIRI + cetuximab or panitumumab (KRAS/NRAS/BRAF wild-type and left-

sided tumors only)
e) 5-FU/LV or capecitabine ± bevacizumab

2) Patients not appropriate for intensive therapy
a) 5-FU/LV or capecitabine ± bevacizumab
b) Cetuximab or panitumumab (KRAS/NRAS/BRAF wild-type and left-sided tumors only)

[Category 2B]
20
c) Nivolumab ± ipilimumab; pembrolizumab (dMMR/MSI-H only) [Category 2B]
4. Subsequent-line systemic treatment options
a. Principles2, 22
1) In general, metastatic colorectal cancers are treated continuously with systemic therapy in a
sequential fashion upon progression
a) Therapy is stopped either upon change in level of care (IE, hospice) or patient
preference for a treatment “holiday”
2) Choice of subsequent-line therapy is based on previous therapies received, presence of

predictive biomarkers, patient comorbidities, and adverse effects/tolerance from previous
treatments
a) Patients should at least receive a fluoropyrimidine, oxaliplatin, irinotecan, an anti-

vascular agent, and an anti-EGFR MAB (if KRAS/NRAS/BRAF wild-type) at some point in
their continuum of systemic therapy treatment, if no contraindications or comorbidities
preclude these therapies
3) Please refer to the NCCN Guidelines® for Colon Cancer2 and NCCN Guidelines® for Rectal
Cancer22 sections on Continuum of Care – Systemic Therapy for Advanced or Metastatic
Disease for full algorithm on specific recommendations to sequencing therapy
b. Anti-vascular therapy
1) Continuation of bevacizumab with 2nd-line chemotherapy significantly improved PFS and OS

over chemotherapy alone, in patients who had bevacizumab with their 1st line of treatment82
2) Ziv-aflibercept83 and ramucirumab84, each in combination with FOLFIRI, have shown

improved PFS and OS over FOLFIRI alone in patients with metastatic colorectal cancer that
have progressed following an oxaliplatin-based regimen with and without bevacizumab
a) NCCN Guidelines® also support the use of irinotecan with ziv-aflibercept or

ramucirumab
3) Bevacizumab is the preferred anti-angiogenic agent based on toxicity and cost2, 22
c. Anti-EGFR MABs
1) Cetuximab or panitumumab may be given in combination with irinotecan, FOLFOX, or

FOLFIRI in RAS wild-type metastatic colorectal cancer in the 2nd line setting as this has been
shown to improve PFS over chemotherapy alone85, 86
2) Either agent may also be given alone as monotherapy, as this has shown to improve PFS and
OS compared to best supportive care87, 88
3) If cetuximab or panitumumab is used with initial therapy, then the other agent should not be
used in subsequent lines of therapy. After clinical failure of an anti-EGFR MAB, there are no
data to support the use of the other agent and the NCCN® panel recommends against this
practice2, 22.
d. BRAF-targeted regimens
21
1) Patients with BRAF V600E mutation positive disease have worse outcomes compared to
those without the mutation2, 22
a) Blockade with BRAF inhibitors with or without MEK inhibitors has resulted in feedback
upregulation of EGFR via the MAPK pathway, and therefore these agents have been
utilized with anti-EGFR therapies
2) Irinotecan + vemurafenib + cetuximab OR panitumumab
a) Patients were randomized to irinotecan and cetuximab with or without vemurafenib89
b) The addition of vemurafenib improved PFS (4.4 vs 2.0 months, P<0.001) and response
rates (16% vs 4%, p=0.08)
c) Toxicities were increased in the vemurafenib arm, including neutropenia, anemia, and
nausea
3) Dabrafenib + trametinib + cetuximab OR panitumumab
a) Dabrafenib + trametinib + panitumumab produced a 26% response rate in patients with

BRAF+ metastatic colorectal cancer90
b) No dose-limiting toxicities were observed and the most common side effects were
acneiform rash and diarrhea
4) Encorafenib + binimetinib + cetuximab OR panitumumab
a) A safety lead-in from the BEACON trial91 with encorafenib + binimetinib + cetuximab in
30 patients who had received at least one prior regimen revealed common adverse
effects of diarrhea (77%), acneiform rash (67%), fatigue (63%), and nausea (63%)
b) Dose-limiting toxicities were seen in 5 of 30 patients and included hypersensitivity to

cetuximab, binimetinib-related retinopathy, and binimetinib-related decreased left
ventricular ejection fraction
c) Six patients discontinued as least one study drug due to adverse effects
d) Efficacy was also assessed, and revealed an overall response rate of 48%, progression-
free survival of 8.0 months (95% CI, 5.6 to 9.3 months), and overall survival of 15.3
months (95% CI, 9.6 months to not reached)
e) This combination was granted a breakthrough therapy designation by the FDA in August
201892
5) These regimens are only appropriate in patients with a BRAF V600E mutation and who have
not previously received an anti-EGFR MAB or a BRAF/MEK inhibitor combination
e. HER2-targeted regimens
1) Based on positive outcomes in HER2-amplified breast and gastric cancers, HER2 regimens
are being evaluated in HER2-amplified colorectal cancers
a) Only 2-6% of metastatic colorectal cancers harbor HER2 amplification
2) Trastuzumab + lapatinib
22
a) The HERACLES trial93 included patients with HER2-positive metastatic colorectal cancer
who had progressed on at least one prior standard of care regimen
b) Of the 27 patients included, 8 (30%) achieved an objective response
i. 74% of patients had received four or more prior treatment regimens
c) Median PFS was 21 weeks (95% CI 16-32) and OS was 46 weeks (95% CI 33-68)
d) Toxicities were expected, including diarrhea (78%), rash (48%), fatigue (48%),
paronychia (33%), and conjunctivitis (19%)
3) Trastuzumab + pertuzumab
a) The phase II basket trial MyPathway94 reported on patients with HER2-amplified

metastatic colorectal cancer who were treated with trastuzumab and pertuzumab
i. Patients were included who had received at least 1 standard regimen, and no
previous HER2-directed therapy
b) Of the 57 patients included, 18 (32%) achieved an objective response
i. The majority of patients were heavily pretreated, with the median number of prior
treatments of 4
c) Estimated PFS was 2.9 months (95% CI 1.4-5.3) and OS was 11.5 months (95% CI 7.7
months to not reached)
4) These regimens are recommended for HER2-amplified and RAS wild-type patients who have
not received any previous treatment with HER2-targeted therapy
f. Other oral therapy regimens
1) Regorafenib (CORRECT95)
a) Patients had received fluoropyrimidine-based therapy, irinotecan, oxaliplatin, and

bevacizumab, and an anti-EGFR MAB if RAS wild-type
b) Regorafenib significantly increased OS (6.4 vs 5.0 months; p=0.0052) and PFS (1.9 vs 1.7
months; p<0.0001) compared to best supportive care
c) Dose modifications required in 76% of patients, of which 70% required more than 1
dose interruption due to adverse events
i. Adverse events requiring dose modifications included dermatological,

gastrointestinal, constitutional, and metabolic/laboratory events
d) Regorafenib associated with grade 3/4 adverse events of hand-foot skin reaction (17%),
fatigue (9%), diarrhea (7%), hypertension (7%), and rash or desquamation (6%)
e) Administration
i. 160 mg PO daily days 1-21 of 28-day cycle
(a) Can also titrate dose during 1st cycle to attenuate toxicities per the ReDOS
trial96:
23
• First cycle: 80 mg PO daily days 1-7, then 120 mg PO daily days 8-14, then
160 mg PO daily on days 15-21 as tolerated
• Subsequent cycles: 160 mg PO daily days 1-21 of 28-day cycle
ii. Take following low-fat meal (<30% fat)
2) Trifluridine/tipiracil (TAS-102; RECOURSE97)
a) Patients had received ≥2 prior regimens, including fluoropyrimidine-based therapy,

irinotecan, oxaliplatin, and bevacizumab, and an anti-EGFR MAB if RAS wild-type
b) TAS-102 significantly increased OS (7.1 vs 5.3 months; p<0.001), PFS (p<0.001), and
disease control rate (44% vs 16%; p<0.001) compared to best supportive care
c) In TAS-102 group, 53% of patients had a delay in beginning of next cycle by ≥4 days due
to toxicity
i. Dose reductions due to toxicity were required in 14% of patients
d) Grade 3/4 adverse events: neutropenia (38%), anemia (18%), and thrombocytopenia
(5%)
e) Administration
i. 35 mg/m2/dose (based on trifluiridine-component, max 80 mg) PO twice daily days

1-5 and 8-12 of 28-day cycle
ii. Take within 1 hour after completion of meals
3) Larotrectinib or entrectinib are treatment options for patients with cancers that are NTRK
gene fusion positive98
g. Immunotherapy
1) Pembrolizumab7
a) Investigators evaluated the efficacy of pembrolizumab in colorectal cancer with dMMR

and pMMR, and non-colorectal cancer with dMMR
b) Patients had treatment refractory progressive metastatic cancer (97.5% patients had ≥2
previous lines of therapy)
c) The dMMR cohorts had increased ORR (40% and 71% vs 0%) and PFS at 20 weeks (78%
and 67% vs 11%) than those in the pMMR cohort
d) These data support the hypothesis that tumors with dMMR are more responsive to PD-1
inhibitors than tumors with pMMR
2) Nivolumab ± ipilimumab8, 9
a) Authors evaluated the efficacy of nivolumab ± ipilimumab in patients with MSI-H and
non-MSI-H metastatic colorectal cancer
b) Patients had progressed or were intolerant to ≥1 previous line of therapy
c) Responses were observed in the MSI-H group regardless of PD-L1 expression or BRAF or
KRAS mutation status
24
3) Based on these data, both pembrolizumab and nivolumab ± ipilimumab have gained FDA
approval as well as support from the NCCN Guidelines® for treatment of patients with
metastatic colorectal cancer that is MSI-H/dMMR for subsequent therapy after failure on
standard lines of treatment
4) Patients progressing of either of these immunotherapy regimens should not be offered the
other2, 22
5. Resectable synchronous liver and/or lung only metastases2, 22
a. For patients who are candidates for surgery, options are:
1) Synchronous or staged colectomy with liver or lung resection, followed by adjuvant

chemotherapy
2) Neoadjuvant chemotherapy for 2-3 months, followed by synchronous or staged colectomy

with liver or lung resection
3) Colectomy followed by adjuvant chemotherapy and a staged resection of metastatic disease
b. Conversion to resectability
1) Any active metastatic chemotherapeutic regimen is an appropriate choice for attempted

conversion to resectability41, 65, 99-102
a) Irinotecan is associated with increased risk of steatohepatitis (20.2%, P=0.00001) and

oxaliplatin is associated with increased risk of sinusoidal injury (18.9%, P=0.0001)103.
b) The NCCN Guidelines® consider it acceptable to add bevacizumab to chemotherapy to

convert patients to resectability, however data with oxaliplatin-based regimens are
controversial. Bevacizumab should be discontinued at least 6 weeks prior to surgery,
and re-initiation should be delayed until 6-8 weeks after surgery2, 42-44.
c) It is acceptable practice to add an anti-EGFR MAB (cetuximab or panitumumab) to

planned chemotherapy for conversion to resectability in patients with KRAS WT disease
based on improvement in RR and R0 resection rates45, 47, 104, 105
2) Reevaluate patients for resection every 2 months
3) If patients are deemed resectable, options for post-resection therapy are adjuvant
chemotherapy or observation
c. Perioperative chemotherapy
1) Combined neoadjuvant and adjuvant treatment should not exceed 6 months
2) Chemotherapy used in preoperative setting to increase curative resection rates and to

convert patients from unresectable to resectable disease
3) Pre-operative chemotherapy with oxaliplatin and irinotecan has been associated with
steatosis, steatohepatitis, portal hypertension, and sinusoidal injury, which may affect
outcomes after liver resection103
4) Neoadjuvant chemotherapy options
a) FOLFIRI, FOLFOX, or CAPEOX ± bevacizumab
25
b) FOLFIRI or FOLFOX + panitumumab or cetuximab
5) Adjuvant chemotherapy options
a) FOLFOX or CAPEOX (preferred)
b) FOLFIRI, FOLFOX, or CAPEOX ± bevacizumab
c) FOLFIRI or FOLFOX + panitumumab or cetuximab
6) Possible to achieve long-term survival with this approach
7) The NCCN® panel recommends to limit neoadjuvant chemotherapy for potentially resectable
metastatic disease to 2-3 months, with adjuvant chemotherapy limited to maximum of 3
months (for a total of perioperative chemotherapy of 6 months)
Patient Case #3 (ARS question 3):
EH is a 65-year old male with newly diagnosed, KRAS-mutated metastatic colorectal cancer to his liver. He
presents today to begin treatment with FOLFIRI + bevacizumab. During the irinotecan infusion, he experiences
abdominal cramping and diaphoresis. He also experiences an episode of diarrhea.
What is the most appropriate intervention to alleviate EH’s symptoms?
A. Give atropine, and consider pre-medication with atropine for future cycles
B. Give loperamide, and counsel EH to take loperamide around the clock at home
C. Give octreotide, and consider pre-medication with octreotide for future cycles
D. Give tincture of opium, and counsel EH to take tincture of opium around the clock at home
IV. Supportive care
A. Chemotherapy-Induced Diarrhea (CID)53, 106, 107
1. Any chemotherapeutic agent may cause diarrhea, but higher rates of diarrhea are reported with
irinotecan, 5-FU, methotrexate, cytarabine, tyrosine kinase inhibitors, immune checkpoint inhibitors
and stem cell transplant conditioning
a. 50 - 80% of patients receiving modulated 5-FU regimens, single-agent irinotecan, and

combination regimens of irinotecan and 5-FU experience diarrhea and greater than 30% of these
patients may experience grade 3 to 5 diarrhea
b. If diarrhea is suspected to be caused by an immune checkpoint inhibitor, management differs

from “typical” chemotherapy-induced diarrhea. Refer to the Melanoma and Non-melanoma Skin
Cancers module for management of immune therapy-related diarrhea/colitis.
2. Possible contributing factors include106, 107:
a. Underlying malignancy
b. Infection
c. Radiation
d. Diet (high fiber, dairy products)
26
e. Medications other than chemotherapy (antibiotics, opiate withdrawal, SSRIs)
f. Inflammatory disorders
g. Malabsorption
h. Neuroendocrine factors
i. Psychological factors
3. Assessment
a. Duration and timing of symptoms
b. Constellation of signs and symptoms
c. Severity of symptoms
1) Grading based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0108
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Increase of <4 stools per Increase of 4 - 6 stools per Increase of ≥7 stools per Life-threatening Death
day over baseline; mild day over baseline; day over baseline; consequences; urgent
increase in ostomy output moderate increase in hospitalization indicated; intervention indicated
compared to baseline ostomy output compared severe increase in ostomy
to baseline; output compared to
limiting instrumental ADL baseline; limiting self-care
ADL
d. Patient’s constellation of symptoms should be classified as either uncomplicated or complicated
1) Uncomplicated: Grade 1 or 2 diarrhea with no other complicating signs or symptoms
2) Complicated
a) Grade 1 or 2, but has any of the following risk factors:
i. Moderate to severe cramping
ii. Grade 2 or higher nausea and/or vomiting
iii. Decreased performance status
iv. Fever, sepsis, neutropenia
v. Frank bleeding or dehydration
b) Grade 3 or 4 diarrhea
4. Management53, 106
a. Uncomplicated CID
1) For grade 2, hold chemotherapy until resolution
2) Recommend elimination of all lactose-containing products and alcohol
3) Frequent small meals and oral hydration (e.g., 8-10 glasses of clear fluids such as water,
sport drinks, broth)
27
4) Instruct patients to record number of stools and report any symptoms described above
5) Initiate loperamide 4 mg x 1 followed by 2 mg every 4 hours or after every loose stool (not to
exceed 16 mg/day; 24 mg/day for irinotecan-induced diarrhea)
6) If diarrhea resolves:
a) Continue dietary modifications and gradually add solid foods to diet
b) Patients with chemotherapy-induced diarrhea can discontinue loperamide when

diarrhea-free for at least 12 hours
c) Patients with radiation-induced diarrhea should continue taking loperamide for the
duration of radiation therapy
7) If mild to moderate diarrhea persists >24 hours on loperamide, increase dose of loperamide
to 2 mg every 2 hours and consider starting oral antibiotics as prophylaxis for infection
8) If mild to moderate diarrhea persists for more than 48 hours on loperamide (24 hours after
starting high-dose loperamide):
a) Discontinue loperamide
b) Start a second-line antidiarrheal, such as octreotide 100 to 150 mcg subcutaneously or

other agent (tincture of opium 10 to 15 drops in water every 3-4 hours or budesonide)
c) Patients with chemotherapy-induced diarrhea should undergo complete stool and blood
work-up and replace fluids and electrolytes as needed
d) Patients with radiation-induced diarrhea may continue on high-dose loperamide with

frequent evaluation
b. Complicated CID
1) Admit to hospital and start intravenous hydration and electrolyte replacement
2) Octreotide 100 to 150 mcg subcutaneously TID or continuous infusion (25 to 50 mcg/hour) if
patient severely dehydrated, with dose escalation up to 500 mcg subcutaneously TID until
diarrhea is controlled
a) Upon improvement, titrate off; do not abruptly discontinue
3) Administration of IV antibiotics as indicated
4) Complete stool and blood work-up
5) Discontinue any cytotoxic chemotherapy until all symptoms resolve and consider dose
reductions for future cycles
c. Patients who progress to grade 3 or 4 diarrhea while on loperamide therapy for 24 to 48 hours
should be treated as described above
5. Irinotecan-induced diarrhea13, 14, 106, 109
a. Refer above to Metabolism and Pharmacokinetics of Irinotecan in the Genomics section for
background on irinotecan
b. Two phases of diarrhea:
28
1) Acute phase
a) Occurs during or immediately after irinotecan infusion (within 24 hours)
b) Accompanied with cholinergic symptoms such as cramps, diaphoresis, flushing,

salivation, visual disturbances, and lacrimation
c) Mechanism: Direct inhibition of acetylcholinesterase by irinotecan
2) Delayed phase
a) Dose-limiting toxicity
b) Occurs after 24 hours after irinotecan infusion
i. Median onset reported is day 6 (range 2 to 12)
c) Mechanism: primarily a secretory process with exudative properties, thought to be due

to the reactivated form of SN-38
i. SN-38 may directly cause mucosal damage to intestinal lumen
ii. Luminal environment altered by irinotecan, allowing proliferation of bacteria that

produce β-glucuronidase
iii. Irinotecan itself can cause severe colonic damage or an increase in mucin secretion
c. Management
1) Acute: atropine
a) Suppresses cholinergic effects of irinotecan
b) Start with 0.25 mg IV or subcutaneous to a maximum cumulative dose of 1.2 mg
c) Monitor blood pressure and heart rate
d) May also be given as secondary prophylaxis in a patient with prior acute diarrhea
2) Delayed
a) Loperamide110, 111
i. 4 mg at first sign of diarrhea, followed by 2 mg every 2 hours (4 mg every 4 hours at

night) until 12 hours following last bowel movement up to 24 mg/day
(a) Exceeding the daily limit of 16 mg/day is recommended for treatment of

irinotecan-associated diarrhea in adults
ii. Change to as-needed dosing after 12-hour bowel movement-free period
b) Atropine has no role in management of delayed diarrhea
c) Supportive management
i. Fluids and electrolytes
(a) Dehydration is common with persistent and/or severe diarrhea
(b) Goal: drink 3 or more liters of clear liquids/day, which should consist of
electrolyte-containing fluids (sport drinks, broth, decaffeinated tea, etc.)
29
(c) Route of rehydration (IV or PO) is dependent upon severity of dehydration and
electrolyte abnormalities
ii. Nutrition
(a) Avoid dairy, caffeine, alcohol and concentrated fruit juices
(b) “BRAT” diet (bananas, rice, applesauce, and toast)
(c) Bulk-forming agents
(d) Severe diarrhea may require bowel rest with parenteral nutrition
iii. In addition, follow principles outlined above for treatment based upon severity
Agents for chemotherapy-induced diarrhea (CID)106, 107, 112

Agent Mechanism Dose Place in therapy Comments
Loperamide Decreases intestinal motility 4 mg PO initial dose, First-line for Reduces fecal incontinence,
via direct action on the followed by 2 mg every uncomplicated frequency of bowel
smooth muscle of the 2-4 hours or with every movements and stool weight
intestine loose stool (maximum
daily dose of 16mg; 24mg
if irinotecan-induced)
Tincture of Contains various opioid Deodorized formulation Alternative second Recommended, despite lack
opium alkaloids including morphine, (10 mg/mL) choice for of literature in CID
which is primary agent for persistent,
10-15 drops in water Pay close attention to
mechanism. Decreases uncomplicated
every 3 to 4 hours formulation being used, as
digestive secretions and
concentrations and dosing
increases gastrointestinal Camphorated
differs
muscle tone, resulting in formulation AKA
reduction in intestinal transit paregoric (0.4 mg/mL)
time. 5-10 mL in water 1 to 4
times daily
Octreotide Decreases secretion of 100 to 150 mcg Persistent Patients may also be
various hormones, such as subcutaneous three uncomplicated or transitioned to octreotide
vasoactive intestinal peptide times daily initially, then first-line for LAR
up titrate to symptom complicated
Prolongation of intestinal May be more beneficial for
control
transit time radiation-induced diarrhea vs
oral opioids
Reduced secretion and
increased absorption of fluid Optimal dosage not well
and electrolytes defined
Budesonide Inhibitory effect on mucosal 9 mg PO once daily Second-line for Effective in loperamide-
prostaglandins persistent, refractory diarrhea
uncomplicated
30
Diphenoxylate Decreases intestinal motility 1-2 tablets PO every 6-8 In combination Little published data for CID
via direct action on the hours with loperamide
smooth muscle of the for uncomplicated
intestine
Absorbents Absorbs excess fluid to form 7.5-30 g PO daily Alternative Large volume and abdominal
(psyllium, a gelatinous mass to increase bloating limit use
methylcellulose) density of fecal matter
Probiotics Counteracts disturbances in Not defined In conjunction Patients with severely

normal gut flora with other agents weakened immune system
should avoid
Correct answer is A. Acute irinotecan-associated diarrhea is a cholinergic reaction; therefore atropine is the
most appropriate treatment to alleviate EH’s symptoms.
Answer B is incorrect because loperamide will not alleviate the cholinergic reaction of acute irinotecan diarrhea.
Loperamide can be considered for delayed diarrhea.
Answer C is incorrect because octreotide will not alleviate the cholinergic reaction of acute irinotecan diarrhea.
Octreotide can be considered for complicated delayed diarrhea or diarrhea that is refractory to loperamide.
Answer D is incorrect because tincture of opium will not alleviate the cholinergic reaction of acute irinotecan
diarrhea. Tincture of opium can be considered for use in persistent, uncomplicated diarrhea.
B. Hypersensitivity to monoclonal antibodies used in solid tumors113-116
1. Presentation113, 117
a. Accompanied by flushing, rash, fever, pruritus, dyspnea, bronchospasm, rigors, nausea/vomiting,

and/or hypotension
b. Type I hypersensitivity reaction
1) IgE-mediated drug-immunoglobulin complex binds to mast cells, causing release of

mediators of reaction
2) Usually occurs within the first few minutes of the 1st or 2nd infusion, however 10 to 30% of
reaction are delayed
c. Occurs in up to 20% of patients
1) Severe hypersensitivity reactions are rare with an estimated incidence of <5%
2. Geographic influences on cetuximab reactions118, 119
a. The Southeastern United States has consistently reported higher incidence of cetuximab-related
infusion reactions (up to 27%), vs the rest of the country (1-3%)
31
b. O’Neil and colleagues quantified the rates of hypersensitivity reactions at 3 Southeastern
institutions
1) Out of 88 assessable patients, 22% experienced first infusion grade 3 to 5 hypersensitivity

reaction
2) All patients were pretreated with H1 antagonist, and 65% were given a steroid as an anti-
emetic
3) They reported no significant association between reactions and age, sex, or race
4) There was an association of increase hypersensitivity reactions in lung cancer patients (43%;
P=0.03) and prior significant allergy history (36%; P=0.009)
5) The authors theorized that the increased incidence may be a result of increased exposure to
mouse antigens or other antigens that mimic cetuximab that are regionally based, such as a
particular plant or tree pollen
c. There is currently no way to test patients for hypersensitivity risk
1) Patients with head & neck cancers may be at higher risk
d. As the reaction typically occurs within 30 minutes of infusion, the use of a test dose has been
proposed but is not standard of care
e. Patients who experience a hypersensitivity reaction may be successfully treated with

panitumumab, as it is a fully humanized monoclonal antibody
3. Prevention of hypersensitivity reactions (HSR) and infusion reactions113, 117
a. Recognition of high-risk patients
1) Type of antibody (IE, chimeric, murine, humanized)
2) Ensure appropriate premedication regimen, if indicated, is given
b. Premedication
1) There is no established standard premedication regimen
a) Use prescribing information or guidelines to guide choice of regimen
2) Usually includes acetaminophen, H1 antagonist, H2 antagonist, and/or corticosteroids
3) Premedication with corticosteroids may prevent or dampen non-IgE mediated infusion

reactions
a) Dexamethasone 8-20 mg (commonly used antiemetic doses)
4) Generally given with first dose and continued throughout treatment
4. For detailed management of HSR and infusion reactions, refer to the Gynecologic Malignancies
module
C. Oxaliplatin-induced neurotoxicity120-124
1. Dose-limiting toxicity that is a persistent sensory peripheral neuropathy which has been reported
with all dose levels and schedules of administration
32
2. Development is primarily related to total cumulative dose
3. Up to 97% of patients receiving oxaliplatin will have neurologic symptoms and abnormalities during
treatment
4. Patients can develop delayed onset or worsening of the persistent form of neuropathy even after
treatment discontinuation
5. Two distinct clinical forms of neuropathy: acute and chronic
a. Acute neurotoxicity
1) Transient, sensory disturbance in 85% to 95% of patients
2) Rapid onset of hours to days following treatment
3) May regress between treatment cycles, but frequently reoccurs with further treatment
4) Presents as paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or
throat
5) Paresthesias without pain occur in about 65% patients and paresthesias with pain occur in
approximately 11% of patients
6) Dysesthesias occur in approximately 68% patients and are exacerbated by cold exposure
7) Pharyngolaryngeal dysesthesias are also reported in approximately 38% and are

characterized by subjective sensations of dysphagia or dyspnea and/or jaw spasm without
associated laryngospasm, bronchospasm, or stridor.
a) Disturbing to patients and can be described as a loss of the breathing sensation
b) May be exacerbated by exposure to cold ambient temperature, drinking cold liquids, or

handling cold objects
8) 13% to 28% of patients receiving doses of 85 to 130 mg/m2 experience severe neurosensory
adverse effects with functional impairment
9) Symptoms resolve in about a week, but can recur with subsequent infusions
b. Chronic neurotoxicity
1) Persistent sensory chemotherapy-induced peripheral neuropathy that is gradually

progressive in onset
2) Related to cumulative dose and similar to other forms of platinum- and taxane-induced
neuropathies
a) Incidence is 16% to 21% patients
b) Onset > 14 days after oxaliplatin dose and can become persistent between treatment
cycles with progression in symptom severity
c) Pain and paresthesias can completely resolve in some cases and may only be partially
reversible or permanent in others
i. Numbness and tingling can worsen during the first 3 months after discontinuing
therapy (sometimes called “coasting”), and then begin to resolve125
33
d) Associated with cumulative doses between >540 to 850 mg/m2 or about 6-9 cycles and
it is estimated that 10-15% of patients have moderate neuropathy after a cumulative
dose of 780 to 850 mg/m2121
e) Clinical presentation is subjective, usually progresses gradually, and manifests as pure

sensory symptoms including numbness, paresthesia, and pain in the hands and feet with
symptoms usually appearing in the toes followed by the fingers
i. Sensory findings, such as diminished or absent proprioception, sharp/dull

discrimination, temperature, touch, touch/pain two-point discrimination, and
vibration are typically diminished in the stocking and glove distribution in patients
with symptoms
ii. Longest nerves in extremities are usually the first affected leading to a symmetric,
length-dependent peripheral neuropathy that spreads from distal to proximal
(stocking / glove) distribution
iii. Distribution is usually symmetrical and has a disproportionate degree of sensory

symptoms reported in comparison to the motor symptoms and findings on exam
iv. Paresthesias occur in the lower distal extremities in a stocking-glove distribution

with the most severe symptoms occurring on plantar surfaces
v. Motor weakness symptoms are less commonly reported, and if present are
observed in up to 50% of patients with more persistent and severe sensory findings
6. Pathophysiology120-123
a. Acute toxicity
1) Oxalate metabolite of oxaliplatin chelates calcium and magnesium and interferes with
voltage-gated sodium channels and electrical current
2) Oxaliplatin causes prolonged opening of the sodium channels in sensory nerves that results
in a hyperexcitable state
b. Chronic toxicity
1) Exact mechanism unknown
2) Damage to peripheral nerves by harming microtubules and interfering with microtubule-

based axonal transport
3) Oxaliplatin binds to mitochondrial DNA resulting in oxidative stress
4) Drug accumulation in dorsal root ganglion and sensory nerves
7. Prevention of acute oxaliplatin-induced neuropathy120
a. Prolonging infusion from 2 hours to 6 hours may decrease acute neuropathy
b. Dose reduction
c. Calcium and magnesium (Ca/Mg) infusion
34
1) Retrospective review that evaluated Ca/Mg infusions reported less frequent and severe
distal and lingual paresthesias and no reports of pseudolaryngospasm126, however
prospective trials found no benefit (see below)
8. Prevention of chronic oxaliplatin-induced neuropathy
a. Stop-and-Go Approach (OPTIMOX1)127
1) Patients undergoing treatment for metastatic disease were randomized to 1 of 2 arms
a) Arm A = FOLFOX4 every 14 days until disease progression or toxicity
b) Arm B = FOLFOX7 for 6 cycles, followed by 12 cycles of maintenance 5-FU and

leucovorin, and reintroduction of FOLFOX7 for an additional 6 cycles
2) Primary endpoint was duration of disease control (DDC), progression free survival (PFS)
3) Outcomes
a) Median DDC for Arm A was 9 months versus 10.6 months for Arm B (p=0.89)
b) Median PFS for Arm A was 9 months versus 8.7 months for Arm B (p=0.47)
c) Median OS for Arm A was 19.3 months versus 21.2 months for Arm B (p=0.49)
d) Oxaliplatin was reintroduced in 40% of patients per protocol guidelines. 11% had
residual neurotoxicity greater than grade 1
i. Reintroduction resulted in response or disease stabilization in 69% of patients
e) Grade 3 sensory neuropathy in 18% of patients in Arm A and 13% in Arm B (p=0.12)
4) Discontinuing oxaliplatin after 6 cycles followed by 5-FU maintenance achieved similar PFS,
OS, and response rates compared to continuing oxaliplatin until disease progression or
toxicity. Patients who received maintenance therapy experienced less grade 3 and 4
toxicities compared to those that received continuous therapy with FOLFOX, including less
neuropathy.
5) This approach may be considered for preventing and/or delaying the development of
sensory neuropathy in patients receiving oxaliplatin-based chemotherapy
b. Ca/Mg infusions120, 121, 123
1) Rationale: Increasing extracellular calcium facilitates sodium channel closing, decreasing

oxaliplatin-induced hyperexcitability of peripheral neurons, which is the mechanism
proposed for acute oxaliplatin neurotoxicity. Repeated episodes of hyperexcitability may
lead to structural damage of neurons, which may lead to the development of chronic
neurotoxicity.
2) Because there were mixed results and incomplete data from previous studies, the definitive
N08CB/Alliance128 trial was performed. This trial showed no significant evidence that Ca/Mg
infusions prevent oxaliplatin-induced neurotoxicity, therefore this strategy is not
recommended by NCCN Guidelines®2 nor ASCO.
a) The American Society of Clinical Oncology (ASCO) guideline for prevention and
management of chemotherapy-induced neuropathy does support a moderate
35
recommendation for the use of duloxetine for the treatment of chemotherapy-induced
peripheral neuropathy.129
RL is a 64-year-old female with metastatic, KRAS-wild-type colorectal cancer to her liver and lungs. She recently
started FOLFOX + panitumumab and presents today for Cycle 3. She reports a new rash that is pruritic,
occasionally weeps pus, and extends over her face and chest mainly, and partially covers her back.
What is the most appropriate intervention for RL’s grade 2 rash at this time?
A. Continue panitumumab at same dose and initiate topical hydrocortisone and topical clindamycin
B. Continue panitumumab at same dose and initiate oral doxycycline and topical hydrocortisone
C. Hold panitumumab this cycle and initiate oral doxycycline and oral prednisone
D. Dose reduce panitumumab and initiate oral doxycycline and topical hydrocortisone
D. Dermatologic toxicities
1. Hand-foot syndrome (HFS) vs hand foot skin reaction (HFSR)
a. Dose dependency, pain, and a palmoplantar distribution can be seen with both HFS and HFSR,
however they differ in both histopathological and clinical features130-133
b. HFSR is seen with multi-kinase inhibitors, including sorafenib, sunitinib, and regorafenib131-134
1) HFSR can be seen within the first 2 to 4 weeks after therapy is initiated
a) Presents with dysesthesias, erythema or paresthesias involving the palms and soles with
blisters which are followed by thick hyperkeratotic, tender lesions
b) Lesions arise in areas of friction and/or trauma including the flexural surface of
interphalangeal joints, distal phalanges or heels and may significantly impact weight-
bearing ability and mobility of patients
2) Loss of repair mechanisms by endothelial cells and fibroblasts, when combined with daily
trauma may result in the characteristic palmoplantar symptoms
3) May manifest as loss of fingerprints
4) Preemptive strategies are crucial in the management of HFSR135:
a) Perform full body exam to locate hyperkeratotic regions on palms / soles and removal of
all calluses
b) Wear thick cotton gloves and/or slippers or socks
c) Avoid:
i. Exposing skin to hot water
ii. Friction or trauma for the first 2-4 weeks of therapy
iii. Rigorous exercise (especially during first 4 weeks of therapy)
36
iv. Tight fitting shoes
v. Excessive pressure when applying lotions
d) Data emerging supporting topical urea prior to and during treatment
i. Randomized, open-label trial of 871 patients with hepatocellular cancer receiving

sorafenib received 10% urea-based cream versus placebo136
(a) 12-week incidence of any grade HFSR was 56% vs. 73.6% with significantly
longer time to first occurrence of HFSR (84 days vs 34 days)
c. HFS can be seen with conventional cytotoxic chemotherapies, including capecitabine and 5-FU130,
132, 137
1) Also known as palmar-plantar erythrodysesthesia
2) More diffuse regions of edema and erythema than seen with HFSR
3) Longer exposure to drug appears to increase incidence; e.g. continuous infusion 5-FU has
higher incidence versus bolus administration
4) Symptom onset is quite variable and may range from a few days to up to 10 months after
therapy initiation
5) Initial symptom is paresthesias followed by symmetrical painful erythema and edema of the
palms and soles after 3 to 4 days; if not managed the lesions may blister, desquamate, form
crusts, ulcerate or progress to epidermal necrosis
6) Conflicting data regarding use of pyridoxine (vitamin B6) for prevention and/or treatment of
HFS. A randomized controlled trial to prevent capecitabine-induced HFS was negative, so not
recommended.
7) Use of corticosteroids is also conflicting and cannot be recommended
8) Regional cooling strategies also lack adequate evidence to support its use
d. Management of HFS and HFSR134, 138
1) Grading based on CTCAE Version 5.0108
Grade 1 Grade 2 Grade 3

Minimal skin changes or dermatitis Skin changes (e.g., peeling, blisters, Severe skin changes (e.g., peeling,
(e.g., erythema, edema, or bleeding, fissures, edema, or blisters, bleeding, fissures, edema, or
hyperkeratosis) without pain hyperkeratosis) with pain; limiting hyperkeratosis) with pain; limiting self-
instrumental ADL care ADL
2) Prophylaxis recommended with ammonium lactate 12% cream BID or heavy moisturizer
(petroleum- or lanolin-based ointments) BID
3) Grade 1
a) Continue antineoplastic treatment at current dose and monitor for change in severity
b) Urea 20% cream BID AND clobetasol 0.05% cream daily
37
c) Reassess in 2 weeks; if reaction is worse or not improved proceed to treatment of next
grade
4) Grade 2
a) Continue antineoplastic treatment at current dose and monitor for change in severity
b) Urea 20% cream BID AND clobetasol 0.05% cream daily to BID AND pain control (with
NSAIDs or GABA agonists or opioids)
c) Reassess in 2 weeks; if reaction is worse or not improved proceed to treatment of next

grade
5) Grade 3
a) Hold antineoplastic therapy until severity decreases to grade 0 or 1
b) Clobetasol 0.05% cream BID AND pain control (with NSAIDs or GABA agonists or opioids)
c) Reassess in 2 weeks and if reaction is worse or not improved then dose interruption or
discontinuation per PI may be necessary
2. EGFR inhibitor papulopustular (acneiform) rash 131, 132, 139
a. Most common adverse effect seen with these agents
1) Incidence is 75 to 90% of patients receiving these medications
2) Most cases are mild to moderate in nature; however, up to 32% of providers will discontinue
therapy and up to 76% hold therapy
3) Rash onset is early, within the first two weeks of treatment
4) Rash more frequent with monoclonal antibodies than TKIs
b. EGFRs play an important role in the development, integrity and physiology of normal skin via the
regulation of keratinocyte proliferation, differentiation and survival
1) The direct inhibition of EGFRs is thought to be the underlying cause of the rash
2) It is thought that exposure of epithelial cells to medication leads to an increased synthesis of

a variety of chemokines that recruit inflammatory cells, including leukocytes and neutrophils
leading to an inflammatory response
3) Pathophysiology does not appear to involve underlying bacterial infection, however there
does appear to be some benefit from oral semisynthetic tetracycline antibiotics due to anti-
inflammatory effects140
c. Rash is characterized by papules and pustules coupled with pruritus and pain
1) Distributed in seborrheic areas, such as the face and scalp but is not acne as no comedones
are seen and histopathology differs
2) Changes in the appearance of the skin lesions, oozing of fluid, yellow and/or brown crusting
may be symptoms of superinfection and should be treated promptly
a) Superinfection has been reported in up to 38% of patients
38
d. Positive correlation between rash severity and occurrence with overall survival and tumor
response has been proven, therefore it is important to manage the rash so therapy can
continue139
e. Management of EGFR inhibitor-associated papulopustular rash
1) Grading based on CTCAE Version 5.0108
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

Papules and/or pustules Papules and/or pustules Papules and/or pustules Life-threatening Death
covering <10% BSA, which may covering 10-30% BSA, which covering >30% BSA with consequences
or may not be associated with may or may not be associated moderate or severe
symptoms of pruritus or with symptoms of pruritus or symptoms; limiting self-care
tenderness tenderness; associated with ADL; IV antibiotics indicated
psychosocial impact; limiting
instrumental ADL; papules
and/or pustules covering >30%
BSA with or without mild
symptoms
2) Multinational Association for Supportive Care in Cancer (MASCC) Skin Toxicity Study Group
clinical practice guidelines for prevention and treatment of EGFR inhibitor-associated
dermatologic toxicities132
a) Pre-emptive management should be used in all patients due to the high frequency of
rash and the fact that it consistently presents in the first 2 to 4 weeks of therapy
i. Hydrocortisone 1% combined with a moisturizer, sunscreen and doxycycline 100 mg

BID for the 1st 6 weeks is recommended based on trial data
ii. Another study showed that prophylactic minocycline 100 mg QD is also effective
iii. Note: doxycycline seems to be better tolerated than minocycline, especially in

patients with renal dysfunction. Minocycline is less photosensitizing; therefore,
preferred in areas with a high UV index.
b) Reactive management consists of the use of medium- to high-potency topical

corticosteroids (alclometasone 0.05% cream or fluocinonide 0.05% cream BID), topical
clindamycin 1%, and/or oral antibiotics (doxycycline or minocycline)
3) Other guidelines and recommendations exist, all espousing similar approach141, 142
4) Standard acne therapies should be avoided as they will worsen rash
f. STEPP: A phase II, open-label randomized trial evaluating a pre-emptive skin regimen in patients
receiving panitumumab143
1) Patients were assigned 1:1 to pre-emptive (n=48) or reactive (n=47) treatment
2) Pre-emptive treatment was started 1 day prior to 1st dose of panitumumab and continued
through weeks 1 to 6 and consisted of:
a) Skin moisturizer applied daily in the morning on rising
b) Sunscreen (PABA free, SPF > 15 UVA and UVB protection) before going outdoors
39
c) Topical hydrocortisone 1% cream at bedtime
d) Doxycycline 100 mg PO BID
3) Reactive skin care regimen consisted of:
a) Any treatments the investigator thought necessary to treat skin toxicity and could be
given at any time during weeks 1 to 6
4) Incidence of grade >2 skin toxicities was 29% and 62% for pre-emptive and reactive groups,
respectively
5) Patients in the pre-emptive group also reported less QOL impairment than patients in the
reactive arm
6) Authors emphasized the importance of a pre-emptive strategy to combat EGFR-induced

dermatologic toxicity
g. Summary of recommendations for treatment
1) Pre-emptive management
a) Hydrocortisone 1% with a moisturizer, sunscreen, and doxycycline 100 mg BID
i. For at least 1st 6 weeks
2) Reactive management
a) Grade 1: topical hydrocortisone and clindamycin
b) Grade 2: topical hydrocortisone, oral doxycycline or minocycline
c) Grade 3/4: Modify chemotherapy dose per PI; topical hydrocortisone, oral doxycycline
or minocycline, oral prednisone
Correct answer is B. Since RL’s rash is categorized as a Grade 2 rash, the most appropriate therapy would be to
continue panitumumab at the same dose and initiate therapy with topical steroids and an oral tetracycline.
Answer A would be appropriate for a Grade 1 rash
Answer C would be appropriate for a Grade 3 rash, either on first, second, or third occurrence
Answer D would be appropriate for a Grade 3 rash on second or third occurrence
V. Survivorship issues and long-term follow-up
A. Survivorship
1. Management of late sequelae of disease and/or treatment2, 125, 144, 145
a. Fatigue can last for years after completion of treatment and interventions
1) Physical activity should be encouraged
40
2) Patients may require other behavioral interventions including psychosocial interventions,
nutrition consultation, or behavioral therapy for sleep
3) Consider psychostimulants such as methylphenidate after ruling out other causes of fatigue
and failure of other interventions
b. Higher prevalence of chronic diarrhea in patients who have received radiation or an ostomy
1) Anti-diarrhea agents, bulk-forming agents, diet manipulation, pelvic floor rehabilitation, and
protective undergarments should be considered alone or in combination for management
c. Oxaliplatin-induced neuropathy
1) May worsen over the first 3 months after discontinuation of therapy
2) Some patients may have long-lasting or permanent neuropathy
3) Duloxetine can be considered for painful neuropathy, however it is not effective for
numbness, tingling, or cold sensitivity
2. Healthy lifestyle and wellness145
a. Patients should be encouraged to achieve and maintain healthy body weight through
appropriate diet and physical activity
1) Active lifestyle should be appropriately modified for any disease or treatment sequelae (IE,
ostomy, neuropathy)
2) Multiple large observational studies have shown that increased activity in non-metastatic
colorectal cancer survivors decreases mortality2
b. Aspirin
1) Numerous trials have shown the benefit of colorectal cancer survivors taking a low-dose
aspirin2
2) A large, population-based study with 23,162 patients with colorectal cancer showed that
low-dose aspirin therapy after diagnosis improved colorectal cancer-specific survival and
overall survival146
3) The NCCN® panel recommends that survivors consider taking aspirin 325mg daily to reduce
their risk of recurrence and death, if the potential risks of aspirin are discussed and
considered2
3. Disease-preventive measures
a. Follow immunization recommendations
b. Age and gender appropriate cancer screenings (e.g., breast, cervical, prostate)
B. Long-term follow-up recommendations

1. Carcinoembryonic antigen (CEA) level
a. May be useful in monitoring colorectal cancer response to treatment
b. Monitoring CEA is not recommended for colorectal cancer screening
c. Normal < 3 ng/mL; in smokers 0-6 ng/mL
41
d. CEA can be higher with elevated serum creatinine, hepatic dysfunction or chemo (5-FU) so may
see an increase in CEA and then a decrease after a few months of treatment
e. T ½ is ~ 7 days
2. NCCN Guidelines®2, 22
a. Stage I colon and rectal cancer
1) Colonoscopy at 1 year, if normal repeat in 3 years, then every 5 years
b. Stage II, III, and IV (with no evidence of disease) colon and rectal cancer
1) History and physical exam every 3-6 months for 2 years, then every 6 months for a total of 5
years
2) CEA every 3-6 months for 2 years, then every 6 months for a total of 5 years
3) CT of the chest, abdomen, and pelvis every 6-12 months for up to 5 years
4) Colonoscopy at 1 year, if normal repeat in 3 years, then every 5 years
3. ASCO guidelines147
a. Colonoscopy 1 year after initial surgery and then every 5 years, dictated by the findings of the
previous one. If not performed before diagnosis, a colonoscopy should be performed after
completion of adjuvant therapy before 1 year
b. History and physical examination every 3-6 months for 5 years
c. CEA every 3 to 6 months postoperatively for 5 years
d. Annual CT of the chest, abdomen, pelvis for 3 years after primary therapy
42
PANCREATIC CANCER
Patient Case #5 (ARS question #5):
JM is a 65-year-old male who underwent a Whipple procedure for resectable pancreatic cancer 10 weeks ago.
He now presents to the medical oncologist to begin adjuvant therapy. He did not receive neoadjuvant therapy.
He has recovered quite well from the surgery with an ECOG performance status of 0 and states that his goal is
to return to golfing 2-3 times a week.
What of the following is the most appropriate adjuvant treatment for JM?
A. Observation
B. Gemcitabine
C. Gemcitabine + nab-paclitaxel
D. mFOLFIRINOX
I. Genomics148
A. There are various genetic syndromes associated with increased risk of pancreatic cancer, thought to be
associated with about 10% of cases
1. These include Peutz-Jeghers syndrome, familial pancreatitis, melanoma-pancreatic cancer syndrome,

Lynch syndrome, hereditary breast-ovarian cancer syndrome, and familial pancreatic cancer
B. Lynch syndrome (more information also available in Colon and Rectal Cancer section)
1. Patients are at a 9- to 11-fold increase risk for pancreatic cancer
2. Because these patients have germline mutations in DNA mismatch repair genes, these tumors may be
susceptible to immunotherapy
3. The NCCN® panel supports testing patients with locally advanced or metastatic pancreatic
adenocarcinoma for MSI and/or dMMR (Category 2B)
C. Hereditary breast-ovarian cancer syndrome (more information also available in Breast Cancer and
Gynecologic Malignancies modules)
1. Patients are at a 2.4- to 6-fold increase risk for pancreatic cancer
2. The risk for pancreatic cancer is better established with mutations in BRCA2 vs BRCA1
3. The NCCN® Guidelines provide recommended systemic therapies specifically for patients with
mutations in BRCA1/2 (as well as PALB2 mutations), discussed further below
II. Treatment and symptom management148, 149
A. Treatment modalities
1. Principles of surgery
a. Only potential cure for pancreatic cancer
b. Only 15-20% patients eligible for complete surgical resection

c. The primary surgical procedure involves a radical pancreatic resection
43
1) Whipple procedure (pancreaticoduodenectomy) for tumors in the head of pancreas
2) Distal pancreatectomy for tumors in the head or tail of pancreas
3) Perioperative mortality rates of less than 4%
d. May be used in the palliative setting for duodenal bypass (gastrojejunostomy) or bypass of biliary
obstruction or biliary stent placement
2. Principles of radiation150, 151
a. Post-surgery, radiation alone does not improve survival
1) When combined with 5-FU, radiation offers significantly longer median survival (20.9 months
vs. 11 months) in patients who have had curative resection and no adjuvant therapy151
b. Neoadjuvant therapy with 5-FU and radiation has been shown to improve tumor resectability
rates with no change in OS
c. Intraoperative radiotherapy has been investigated but has not been shown to improve survival
d. Palliative radiotherapy can be used to control pain
e. Split-dose radiation used in most adjuvant trials – no longer recommended and may skew
adjuvant radiation results
3. Principles of chemotherapy
a. Systemic therapy is used in all stages of pancreatic cancer
b. Nearly all patients with pancreatic cancer should be evaluated for a clinical trial
c. 5-FU and gemcitabine are the most successful single agents available for the treatment of
pancreatic cancer
1) Response rates are low and non-curative in advanced disease
d. Combination chemotherapy improves response rates with minimal improvement in median

survival (Refer to the NCCN Guidelines® for Pancreatic Adenocarcinoma for most up-to-date
dosing recommendations)
1) FOLFIRINOX Q 14 days
a) Bolus 5-FU 400 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, and oxaliplatin 85
mg/m2 Day 1
c) mFOLFIRINOX is a modified version, often dropping the bolus 5-FU and with attenuated
doses of irinotecan and/or oxaliplatin
2) Gemcitabine + nab-paclitaxel Q 28 days
a) Gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 Days 1, 8 & 15
3) Gemcitabine + capecitabine Q 28 days
a) Gemcitabine 1000 mg/m2 IV Days 1, 8 & 15
b) Capecitabine 830 mg/m2 PO twice daily Days 1-21
44
4) Gemcitabine + cisplatin Q 28 days
a) Gemcitabine 1000 mg/m2 and cisplatin 50 mg/m2 Days 1 & 15 OR Gemcitabine 1000
mg/m2 and cisplatin 25 mg/m2 Days 1, 8, 15, 29, 36, & 43 of a 56-day cycle followed by
gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 Days 1, 8, & 15 of a 28-day cycle
e. Neoadjuvant chemotherapy
1) There is currently limited evidence to recommend specific neoadjuvant regimens for

resectable and borderline resectable tumors outside of a clinical trial
2) Typically given for 2-6 cycles:
a) FOLFIRINOX/mFOLFIRINOX (option for BRCA1/2 or PALB2 mutations)
b) Gemcitabine + nab-paclitaxel
c) Gemcitabine + cisplatin (only for BRCA1/2 or PALB2 mutations)
d) Chemotherapy can be followed by fluoropyrimidine- or gemcitabine-based

chemoradiation
B. Pancreatic cancer is treated based on clinical stage rather than TNM stage
C. Resectable disease152
1. Surgical resection remains the primary treatment modality and may occasionally lead to long-term
survival
2. In select patients with resectable disease, but poor prognostic features, neoadjuvant therapy may be
considered
a. Poor prognostic features include: highly elevated CA 19-9, large primary tumor, large regional
lymph nodes, excessive weight loss, or extreme pain
b. After neoadjuvant therapy, a staging laparoscopy may be performed.
c. Surgical resection should be attempted 4-8 weeks following neoadjuvant therapy
d. For patients who receive neoadjuvant chemotherapy with/without chemoradiation, additional

chemotherapy after surgery may be necessary based on pathologic findings
3. Adjuvant therapy
a. Radical pancreatic resection plus postoperative chemotherapy with or without radiation is

standard therapy
1) Historically, 5-FU with and without radiation was standard of care153, 154
2) Adjuvant chemotherapy can provide a 25% risk reduction for death (p = 0.001), whereas
adjuvant chemoradiotherapy provides no significant difference in survival compared to
chemotherapy alone (p = 0.43) 155, 156
a) ESPAC-1 trial revealed adjuvant radiation (with 5-fluorouracil) is deleterious to OS154
b. Gemcitabine (CONKO-001157)
1) Phase III trial that randomized resected patients to adjuvant chemotherapy with
gemcitabine versus observation
45
2) Patients who received gemcitabine had significantly better median disease-free survival
(13.4 months) versus those on observation (6.7 months)
3) OS was also statistically significantly improved in the gemcitabine arm versus observation
(22.8 months vs. 20.2 months, p=0.005)
c. 5-FU/leucovorin (ESPAC-3158)
1) Phase III study conducted by the EORTC compared observation vs. 5-FU / leucovorin vs.
gemcitabine following surgery
2) No significant difference in survival between adjuvant 5-FU / leucovorin and adjuvant

gemcitabine (23.0 vs. 23.6 months)
3) Supported the use of gemcitabine as standard of care for adjuvant therapy
d. Gemcitabine + capecitabine (ESPAC-4159)
1) Phase III study comparing gemcitabine vs. gemcitabine plus capecitabine following surgery
2) Median OS was significantly extended in the combination group compared to gemcitabine

alone (28.0 vs. 25.5 months; HR=0.82, 95% CI 0.68 – 0.98, p=0.032)
3) Rates of adverse events between the two groups were not significantly different
e. mFOLFIRINOX (PRODIGE 24/CCTG PA.6160)
1) Phase III trial comparing mFOLFIRINOX vs gemcitabine following surgery
2) Dosing of mFOLFIRINOX was as follows:
a) Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, 5-FU 2,400 mg/m2
continuous IV infusion over 46 hours
i. Irinotecan dose was further lowered to 150 mg/m2 per a safety analysis performed
after enrollment of 162 patients
3) Median disease-free survival (primary endpoint) was significantly extended in the

mFOLFIRINOX group at 21.6 months, vs 12.8 months in the gemcitabine group (HR 0.58, 95%
CI 0.46 - 0.73, p<0.001)
4) Median OS was significantly better in the mFOLFIRINOX group than the gemcitabine group:
54.4 vs 35.0 months (HR 0.64, 95% CI 0.48 – 0.86, p=0.003)
5) Grade 3/4 adverse events were reported in 75.9% patients in the mFOLFIRINOX group and
52.9% patients in the gemcitabine group
f. NCCN Guidelines® recommendations for post-operative adjuvant therapy148
1) Adjuvant therapy should be given to patients who did not receive neoadjuvant
chemotherapy and who have recovered from surgery. Treatment should be initiated within
12 weeks after surgery. If chemotherapy precedes chemoradiation, restaging should be
performed after each treatment modality.
2) Options include:
a) Clinical trial
46
b) Gemcitabine + capecitabine (category 1, preferred)
c) mFOLFIRINOX (category 1, preferred)
d) Gemcitabine (category 1)
i. Preferred over 5-FU/leucovorin as a single agent due to its more favorable toxicity
profile
e) Bolus 5-FU/leucovorin (category 1)
f) Continuous infusion 5-FU
g) Capecitabine (category 2B)
h) Induction chemotherapy (gemcitabine or 5-FU) followed by chemoradiation
i) Induction chemotherapy (gemcitabine or 5-FU) followed by chemoradiation followed by

subsequent chemotherapy
g. ASCO Guidelines for Potentially Curable Pancreatic Cancer161, 162
1) Adjuvant therapy should be offered to all patients with resected pancreatic cancer who did
not receive preoperative therapy
a) Adjuvant chemoradiation can be offered to patients with an R1 resection and/or

positive lymph nodes after completion of 4-6 months of adjuvant chemotherapy
2) Adjuvant treatment should start within 8 weeks of surgery and continued for 6 months
3) Preferred regimen is mFOLFIRINOX
4) Alternate regimens include:
a) Gemcitabine + capecitabine
b) Gemcitabine
c) Bolus 5-FU/leucovorin
Correct answer is D. Based on results from the PRODIGE 24 trial, both the NCCN Guidelines® and ASCO
guidelines recommend mFOLFIRINOX as a preferred regimen for adjuvant treatment of resected pancreatic
cancer for patients with good performance status
Answer A is incorrect because observation has shown inferior results to chemotherapy in the adjuvant setting
Answer B would be an option if JM was not able to tolerate mFOLFIRINOX or gemcitabine + capecitabine
Answer C is incorrect because at this time there are insufficient data to recommended gemcitabine + nab-
paclitaxel for adjuvant treatment
D. Borderline resectable disease
1. Typically treated with neoadjuvant therapy first to optimize resection
47
a. If deemed resectable, surgical resection to be attempted 4-8 weeks after completion of
neoadjuvant therapy
b. For patients who receive neoadjuvant therapy, additional adjuvant chemotherapy after surgery
may be necessary based on pathologic findings
2. Patients may undergo neoadjuvant therapy but never become resectable, in which case they are
treated as locally advanced unresectable or metastatic (if metastatic disease is discovered)
E. Locally advanced unresectable disease148, 150, 163, 164
1. At the time of diagnosis, over 85% of tumors have extended beyond the pancreas
2. Some patients are surgically unresectable, but may benefit from chemoradiation
a. Chemoradiation improved median survival (10.5 vs. 5.5 months, p<0.05) over radiotherapy alone
in unresectable disease 165
b. Chemoradiation improved 1-year survival (41% vs. 19%, p<0.05) vs. chemotherapy alone in
unresectable disease 166
c. There is no strong evidence to suggest that gemcitabine-based chemoradiation is better than 5-

FU- based chemoradiation 167
d. CALGB 80003 analyzed both 5-FU and gemcitabine with radiation168
1) Demonstrated acceptable toxicity and a median survival of 12.2 months with a median time
to progression of 10 months
3. Chemotherapy alone may be used for management of locally advanced, unresectable pancreatic
cancer
a. Recent trials have examined gemcitabine alone or different chemotherapy combinations in

mixed populations of patients with locally advanced, unresectable and metastatic disease
b. Median survival values have been similar to those demonstrated in trials utilizing
chemoradiotherapy for unresectable patients
c. As a result, many institutions consider gemcitabine alone to be the standard approach to this
patient population
4. NCCN Guidelines® recommendations for locally advanced unresectable disease
a. Good performance status (ECOG performance status 0-1, good pain management, patent biliary
stent, and adequate nutritional intake)
1) Recommended chemotherapy regimens (refer to Metastatic disease section for expanded

information on regimens):
a) FOLFIRINOX or mFOLFIRINOX (preferred; option for BRCA1/2 or PALB2 mutations)
b) Gemcitabine + nab-paclitaxel (preferred)
c) Gemcitabine
d) Gemcitabine + erlotinib
e) Gemcitabine + capecitabine
48
f) Capecitabine or continuous infusion 5-FU (category 2B)
g) Fixed dose rate (FDR) gemcitabine, docetaxel, capecitabine (GTX; category 2B)
h) Fluoropyrimidine + oxaliplatin (category 2B)
i) Gemcitabine + cisplatin (only for BRCA1/2 or PALB2 mutations)
2) Chemoradiation with a fluoropyrimidine or gemcitabine may be considered following an

adequate course of chemotherapy (4-6 cycles) for patients who remain without metastatic
disease for consolidation
3) For patients with poor pain control or obstructive symptoms, chemoradiation may be
preferred prior to initiation chemotherapy
b. Poor performance status
1) Gemcitabine (standard or FDR; FDR is category 2B)
2) Capecitabine or continuous infusion 5-FU (category 2B)
3) Palliative and best supportive care
5. ASCO Guidelines for locally advanced, unresectable pancreatic cancer169
a. Goals of care, patient preferences, psychological status, patient support systems, and symptoms
should guide treatment decisions
b. ECOG PS 0-1 and favorable comorbidity profile: combination regimen for 6 months
1) Clinical trial
2) FOLFIRINOX
3) Gemcitabine + nab-paclitaxel
c. Borderline ECOG PS or patient preference for less toxic regimen
1) Gemcitabine
2) Gemcitabine + capecitabine
d. Patients who have local progression on first-line therapy may be offered radiation therapy
e. Patients who have systemic progression on first-line therapy should be treated per the
metastatic disease recommendations
49
TS is a 74-year-old male who presented to his primary care physician with painless jaundice. Further workup
reveals a mass in the pancreatic head compressing the bile ducts, resulting in a total bilirubin of 7.4 mg/dL. A CT
of his chest, abdomen, and pelvis reveals suspicious lesions in his liver, which are found to be adenocarcinoma,
consistent with a pancreatic primary. After placement of a biliary stent, he is referred to a medical oncologist.
Today his bilirubin is 1.6 mg/dL and he states he currently walks 2 miles a day to and from the local park where
he plays with his dog. TS states he “wants to fight this cancer” for his family. His ECOG performance status is 0.
Which of the following is the most appropriate initial treatment for TS’s metastatic pancreatic cancer?
A. Gemcitabine
B. Gemcitabine + erlotinib
C. Gemcitabine + nab-paclitaxel
D. Fluoropyrimidine + oxaliplatin
F. Metastatic disease148, 170
1. Chemotherapy utilizing gemcitabine, 5-FU or other new anticancer agents may be used
a. Median survival with chemotherapy is 4-6 months
2. Gemcitabine as a single agent
a. Burris et al.171
1) Gemcitabine weekly x 7 followed by 1 week of rest, then weekly x 3 every 4-week vs 5-FU
weekly
2) Gemcitabine improved median OS (5.65 vs 4.41 months; P=0.0025), 1-year survival (18% vs
2%), and clinical benefit response (23.8% vs 4.8%; P=0.0022)
a) Clinical benefit is defined as an improvement in pain, lean body mass and Karnofsky
performance status
3) Gemcitabine received FDA approval for metastatic pancreatic cancer based on the significant
improvement in clinical benefit
b. Fixed-dose rate (FDR) infusions of gemcitabine172
1) Longer infusion increases pharmacokinetic benefit
a) Intracellular activation of gemcitabine to the active triphosphate form by deoxycytidine

kinase is saturated at infusion rates of approximately 10 mg/m2/min (fixed-dose rate
infusion)
b) Theoretically, this allows for higher concentrations of the active form of gemcitabine
which may correlate with improved cytotoxicity and enhanced clinical effectiveness
2) Tempero et al.173
a) Gemcitabine over 30 minutes on days 1, 8, and 15 every 28 days (standard arm) vs

gemcitabine over 150 minutes on days 1, 8, 15 every 28 days (FDR arm)
50
b) FDR improved median OS (8.0 vs 5.0 months; p=0.013), 1-year survival (29% vs 9%;
P=0.014), and 2-year survival (18.3% vs 2.2%; P=0.007)
c) Patients in the FDR arm experienced more grade 3 and 4 anemia, thrombocytopenia,
and neutropenia
d) Despite these promising results, preliminary data from a phase III combination therapy
trial was not able to confirm a benefit with FDR gemcitabine174
e) According to the NCCN Guidelines®, FDR infusion of gemcitabine may be used in place of
the standard 30-minute infusion
3. Combination chemotherapy
a. Several randomized trials have been conducted comparing gemcitabine monotherapy to

gemcitabine-containing combination regimens including gemcitabine with 5-FU175, cisplatin176,
irinotecan177, oxaliplatin178, and capecitabine179
1) Although the results of these combination therapy trials indicate favorable response rates
and even time to tumor progression, median OS is still not statistically significant when
compared to gemcitabine alone
b. Gemcitabine + erlotinib180
1) Gemcitabine weekly x 7 for 8 weeks then weekly x 3 every 4 weeks PLUS placebo OR
erlotinib 100 mg PO daily
2) The erlotinib combination improved median OS (6.24 vs 5.9 months; P=0.038), 1-year
survival (23% vs 17%; P>0.023), and overall response rate (57% vs 49%; P>0.07)
3) QOL was similar in both arms except diarrhea was worse in combination arm
4) Severity of rash directly correlated with improved OS in combination arm (10.5 months with
grade 2 rash vs. 5.2 months with no rash, p=0.0001) and 1 year survival (43% vs. 16%), but
no correlation with EGFR expression
5) Although erlotinib in combination with gemcitabine has a NCCN Guidelines® category 1

recommendation for first-line treatment, it is not considered a preferred regimen due to
minimal improvement in survival and increased toxicities
c. FOLFIRINOX181
1) Phase II/III study that included patients less than or equal to 75 years old with newly
diagnosed metastatic pancreatic adenocarcinoma (no prior systemic therapy) and ECOG
performance status 0 or 1
2) FOLFIRINOX was compared against gemcitabine single agent
3) FOLFIRINOX improved median OS (11 vs 6.8 months; P<0.001), PFS (6.4 vs 3.3 months;
P<0.001), and ORR (31.6% vs 9.4%; P<0.001)
4) QOL was similar in both arms for the first 8 cycles except for diarrhea, which was worse with
FOLFIRINOX
51
5) Patients in FOLFIRINOX group experienced significantly more neutropenia (45.7%), febrile
neutropenia (5.4%), thrombocytopenia (9.1%), diarrhea (12.7%), and neuropathy (9%).
Patients in FOLFIRINOX group also had more grade 2 alopecia.
d. Gemcitabine + nab-paclitaxel182
1) Phase III trial including patients over the age of 18 (no maximum age) with newly diagnosed
metastatic pancreatic adenocarcinoma (no prior systemic therapy) and Karnofsky
performance status > 70
2) Nab-paclitaxel plus gemcitabine vs gemcitabine single agent
3) The addition of nab-paclitaxel to gemcitabine improved median OS (8.5 vs 6.7 months;

P<0.001), PFS (5.5 vs 3.7 months; P<0.001), and ORR (23% vs 7%; P<0.001)
4) 44% in the nab-paclitaxel arm had at least a 20% decrease in CA 19-9 (p < 0.001). 31% vs.
14% had a decrease of at least 90% (p < 0.001).
5) Most frequent adverse events in nab-paclitaxel group were fatigue, alopecia, and nausea
a) Nab-paclitaxel group had more grade 3, 4 adverse events of neutropenia, fatigue, and
peripheral neuropathy
4. Maintenance treatment
a. Olaparib has emerged as the first option for maintenance therapy in metastatic pancreatic
cancer in patients with BRCA1/2 mutations
b. The POLO trial183 evaluated olaparib 300 mg PO twice daily vs placebo in patients who had not
progressed during first-line platinum-based chemotherapy
1) Patient had to have received at least 16 weeks of first-line platinum-based chemotherapy
2) Patients were randomized 3:2 to receive olaparib (300 mg PO twice daily) or placebo and
started 4-8 weeks after last dose of chemotherapy
3) The primary endpoint of PFS was significantly longer in the olaparib group (7.4 vs 3.8
months; HR 0.53, 95% CI 0.35-0.82, P=0.004)
4) The adverse effects experiences by the olaparib group were similar to those previously
documented, including fatigue, nausea, anemia, abdominal pain, and diarrhea
5) Of note, the authors state the POLO trial was initiated when FOLFIRINOX chemotherapy was
recommended for only 6 months for metastatic patients; it does not take into account
patients who may continue chemotherapy past 6 months
6) The NCCN Guidelines® support the use of olaparib as maintenance for patients with
BRCA1/2 mutations, good performance status, metastatic disease, and no disease
progression during the first 16 weeks of first-line, platinum-based chemotherapy
52
The correct answer is C. TS has a PS ECOG score of 0, no pertinent comorbidities, minimal symptoms, good
family support, and his goal is to treat; therefore, he is a good candidate for aggressive chemotherapy with
gemcitabine + nab-paclitaxel or FOLFIRINOX, which are preferred category 1 recommendations from NCCN
Guidelines®.
Answer A is not appropriate because TS is eligible and willing to receive more aggressive chemotherapy.
Gemcitabine alone would be appropriate if his ECOG PS was 2-3.
Answer B is not the most appropriate option because gemcitabine + erlotinib is not considered a preferred
regimen by NCCN Guidelines® despite a category 1 recommendation.
Answer D is not the most appropriate option because although fluoropyrimidine + oxaliplatin is acceptable as
first-line therapy for metastatic disease, it is only a category 2B recommendation and TS can tolerate preferred
regimens at this time
53
First-line recommendations for metastatic pancreatic cancer148, 170
Poor Performance Status Good Performance Status*
NCCN Guidelines®
• Gemcitabine (category 1) Preferred Regimens
• Gemcitabine fixed-dose rate (category 2B) • FOLFIRINOX (category 1) or mFOLFIRINOX (options for BRCA
• Capecitabine or continuous infusion 5-FU (category 2B) 1/2 or PALB2 mutations)
• Gemcitabine + nab-paclitaxel (category 1)
• Gemcitabine + cisplatin (only for BRCA 1/2 or PALB2
mutations)
Other Regimens
• Gemcitabine (category 1)
• Gemcitabine + erlotinib (category 1)
• Gemcitabine + capecitabine
• Fixed-dose rate gemcitabine, docetaxel, capecitabine (GTX;
category 2B)
• Fluoropyrimidine + oxaliplatin (category 2B)
ASCO Guidelines®
• Gemcitabine • FOLFIRINOX
• Gemcitabine + erlotinib can be considered • Favorable comorbidity profile, patient preference,
• Gemcitabine + capecitabine can be considered support for aggressive therapy, access to port and
• Best supportive care infusion pump management services
• Gemcitabine + nab-paclitaxel
• Relatively favorable comorbidity profile, patient
preference, support for relatively aggressive therapy
* Good performance status defined as ECOG PS of 0-1, good pain management, patent biliary stent and adequate
nutritional intake
Patient Case #6, continued (ARS question #7):
TS received 6 cycles of gemcitabine + nab-paclitaxel, complicated by grade 2 neuropathy. He returns today to

review a recent CT scan. Unfortunately, his CT of the chest shows new lung lesions and CT of the abdomen
shows enlarged liver lesions. All labs are within normal limits, and his ECOG is now 1.
What would be most appropriate subsequent therapy for TS?
A. Capecitabine monotherapy
B. FOLFOX
C. 5-FU/leucovorin + liposomal irinotecan
D. Best supportive care
5. Subsequent chemotherapy
a. Therapy for patients who have progressed in the front-line setting has been poorly studied and,
at this time, there is no preferred regimen
1) Good performance status
54
a) Received prior fluoropyrimidine-based therapy
i. Gemcitabine
ii. Gemcitabine + nab-paclitaxel
iii. Gemcitabine + cisplatin (only for BRCA 1/2 or PALB2 mutations)
iv. Gemcitabine + erlotinib
v. 5-FU + liposomal irinotecan (if no previous irinotecan)
b) Received prior gemcitabine-based therapy
i. 5-FU + liposomal irinotecan (category 1)
ii. FOLFIRI
iii. FOLFIRINOX/mFOLFIRINOX
iv. Fluoropyrimidine + oxaliplatin
v. Capecitabine or continuous infusion 5-FU
c) Pembrolizumab for tumors with MSI-H/dMMR
d) Larotrectinib for NTRK gene fusions
e) Chemoradiation if not given previously
2) Poor performance status
a) Gemcitabine (standard is category 1, FDR is category 2B)
b) Capecitabine or continuous infusion 5-FU
b. 5-FU + liposomal irinotecan (NAPOLI-1)184
1) Phase III trial including patients with metastatic pancreatic adenocarcinoma who progressed
on previous gemcitabine-based therapy given in the neoadjuvant, adjuvant (if distant
metastases developed within 6 months of completing adjuvant therapy), locally advanced,
or metastatic settings
1) Liposomal irinotecan, folinic acid, 5-FU infusion every 2 weeks vs folinic acid + 5-FU infusion
weekly x 4 weeks repeated every 6 weeks
a) UGT1A1 genotype testing was performed for all patients
b) Dose modification of liposomal irinotecan from 70 mg/m2 to 50 mg/m2 is recommended

in the label for patients who are homozygous for UGT1A1*28185
2) Addition of liposomal irinotecan to 5-FU improved median OS (6.1 vs 4.22 months; P=0.012),
median PFS (3.1 vs 1.5 months; P=0.0001), median time to treatment failure (2.3 vs 1.4
months; P=0.0002), and ORR (16% vs 1%)
3) Liposomal irinotecan was associated with more diarrhea, nausea/vomiting, fatigue,

neutropenia, and anemia
55
4) Liposomal irinotecan + 5-FU / leucovorin has a NCCN Guidelines® category 1
recommendation and FDA approval for treatment of patients with metastatic disease who
have been previously treated with gemcitabine-based therapy
c. Oxaliplatin + 5-FU186
1) Phase III study including patients with metastatic pancreatic adenocarcinoma who
progressed while receiving first-line gemcitabine therapy
2) 5-FU and oxaliplatin plus BSC VS BSC alone
a) BSC consisted of pain management, treatment of infection, biliary-stent intervention,

nutrition consultation, and psychosocial support
3) Study was stopped early due to low recruitment due to decreased acceptance of BSC alone,
however the addition of chemotherapy to BSC improved median survival (4.82 vs 2.3
months; P=0.008) and OS (9.9 vs 7.9 months)
a) Best response was stable disease

4) Most frequent adverse events in the treatment group were neuropathy, diarrhea,
nausea/vomiting. No grade 3/4 hematologic toxicities were reported.
Patient Case #6, continued (ARS question #7):
The correct answer is C. 5-FU/leucovorin + liposomal irinotecan is an NCCN Guidelines® Category 1

recommendation for second-line chemotherapy for metastatic pancreatic cancer previously treated with
gemcitabine-based chemotherapy. This recommendation is based on the results of the NAPOLI-1 trial and
applies to patients with good performance status.
Answer A would be considered if TS had a poor performance status, but he can tolerate a combination regimen
at this time
Answer B is not most appropriate as this is an NCCN Guidelines® Category 2A recommendation for second-line
therapy and TS is eligible for a Category 1 regimen
Answer D would not be considered at this time due to TS’s good performance status and otherwise healthy
demeanor
III. Supportive care 148, 170
A. Palliative care focusing on symptom relief and quality of life is an important adjunct in the management of
pancreatic cancer
B. Obstructive jaundice
1. Approximately 65-75% of patients will develop symptomatic biliary obstruction
2. Biliary decompression (should be resolved prior to initiation of chemotherapy or chemoradiation)
a. Endoscopic biliary stent (preferred)
b. Percutaneous biliary drainage catheter
56
c. Surgical biliary bypass
C. Gastric outlet obstruction
1. Symptomatic gastric outlet obstruction occurs in 10-25% of patients
2. Good performance status
a. Surgical intervention (gastrojejunostomy)
b. Consider enteral stent
3. Poor performance status or short life expectancy
a. Enteral sent
b. Venting percutaneous endoscopic gastrostomy (PEG) tube for gastric decompression
D. Pain
1. Most patients with pancreatic cancer develop cancer-related pain
a. Advanced pancreatic cancer often infiltrates the retroperitoneal nerves of the upper abdomen
2. Pharmacologic approaches
a. Systemic narcotics
1) Long- and short-acting formulations often used together
2) Oral, sublingual, buccal, rectal, subcutaneous, IV, topical
b. Adjunctive therapies (non-steroidal agents, neuropathic agents, steroids)
c. Topical analgesics
3. Invasive techniques should be considered for patients who may be unresponsive to narcotics or those
who develop undesirable side effects
a. Intrathecal pumps
b. Nerve blocks (celiac plexus neurolysis)
c. Epidural pumps
d. Palliative radiation with or without chemotherapy
E. Depression and anxiety
1. Screen and evaluate all patients and refer to specialists if needed
2. Encourage discussion about the natural history of the disease and provide support through the
primary oncology team and specialists
3. Pharmacologic interventions may be necessary and can be helpful
F. Pancreatic enzyme insufficiency 187, 188
1. 65% of patients with pancreatic cancer will have some degree of fat malabsorption due to pancreatic
exocrine insufficiency
57
2. Develops due to loss of pancreatic parenchyma, obstruction of main pancreatic duct, decreased
pancreatic stimulation, or acid mediated inactivation of pancreatic enzymes.
3. Signs and symptoms
a. Weight loss (malnutrition)
b. Epigastric discomfort, abdominal distension
c. Flatulence, steatorrhea, malodorous stools
4. Management
a. Diet187
1) Fat restriction should not be considered, as it may lead to insufficient intake of fat-soluble
vitamins
2) Frequent, low volume meals
3) Avoidance of foods difficult to digest
4) Consider addition of fat-soluble vitamin supplementation
b. Pancreatic enzymes148, 187
1) Goal is to relieve symptoms and achieve normal nutritional status
2) Dose is based on lipase units and titrated based on clinical symptoms, degree of steatorrhea
and the fat content of the diet
3) Starting dose is generally 500 lipase units/kg/meal rounded to the closest dosage form
available. Half of the prescribed dose should be given with each snack. The maximum dose
is 10,000 lipase units/kg/day.
a) Efficacy appears to be higher when enzymes are administered either portioned along
with meals or after completion of meals compared to before meals
b) NCCN Guidelines® recommends administering half the dose at the beginning of the
meal, and half the dose in the middle of the meal
4) Several products are commercially available; however, products are not interchangeable
5) Insufficient response
a) Confirm compliance and proper use
b) Increase enzyme dose
c) H2-antagonist or proton pump inhibitor (PPI) may improve efficacy of enzymes by

increasing gastric pH and decreasing acid in duodenum where enzymes are absorbed
d) Assess for bacterial overgrowth
G. Thromboembolic disease
1. Pancreatic cancer patients are at a substantial risk for venous thromboembolic disease
2. There is a lack of evidence supporting the use of prophylactic anticoagulation, therefore the NCCN®
panel only recommends treatment of venous thromboembolisms148
58
3. Treatment
a. Based on results of the CLOT and CONKO-004 trials, low-molecular weight heparins are the
preferred therapy over warfarin189, 190
b. The NCCN® panel does not address the use of direct-acting oral anticoagulants at this time
IV. Survivorship issues and long-term follow-up 148
A. Surveillance following curative intent therapy
1. Local recurrence after surgery alone for non-metastatic disease occurs in 85% of the patients
a. Liver metastases are most common, occurring in 50-70% of the patients after potentially curative
resection followed by adjuvant chemo-radiotherapy
2. History and physical exam, CA 19-9, and CT scan of chest, abdomen, and pelvis should be performed
every 3-6 months for 2 years, then every 6-12 months
B. CA 19-9148
1. Tumor associated antigen
2. Not specific for pancreatic cancer; levels can be elevated in other GI cancers
a. Can help differentiate between benign disease and pancreatic cancer
b. Levels may also be elevated in the presence of biliary inflammation, obstruction, or infection,
thus accurate levels may only be obtained after total bilirubin has returned to normal limits
3. Frequently normal in the early stages of pancreatic cancer so it is not suitable for screening
4. Useful in patients with suspected pancreatic cancer when accompanied by other tests and in follow-
up during and after treatment
C. Extremely poor prognosis overall170, 191
1. Only 8.2% of patients are alive at five years after diagnosis
2. Supportive care (see above) should be incorporated into survivorship care
59
ANAL CANCER
I. Prevention and screening192-195
A. Risk Factors
1. Human papilloma virus (HPV) infection
a. Approximately 6,000 cases of anal cancer are caused by HPV196, out of the total 8580 new cases
each year
b. Persistent infection with high-risk subtypes or infection with multiple HPV genotypes
1) Over 80 different HPV subtypes, at least 23 of which infect the anogenital mucosa
2) HPV-16 associated with approximately 73% of HPV-positive cases; HPV-18 also a high-risk
form
2. HIV infection
a. Difficult to fully separate from confounders (anoreceptive intercourse, men who have sex with
men)
b. Population-based study demonstrated that incidence relatively similar before the introduction of
HAART therapy (0.8 per 100,000) versus after the introduction of HAART therapy (1.0 per
100,000)
1) Reflects the lack of impact of HAART on anal cancer precursors
3. Immunosuppression
a. After solid organ transplantation, patients at higher risk for any squamous cell carcinoma
b. Corticosteroid use shown to increase risk in both men (OR, 3.2) and women (OR, 2.3)
4. Cigarette smoking
a. Risk increases for current smokers vs former smokers for both men (OR, 3.9; 95% CI 1.9-8.0 vs
OR, 0.9; 95% CI 0.4-1.9) and women (OR, 3.8; 95% CI 2.3-6.2 vs OR, 1.5; 95% CI 0.9-2.6)
regardless of age and other risk factors
b. Current smoking appears to have a promotional effect at late stages of disease progression
5. History of receptive anal intercourse
a. Men who are not exclusively heterosexual have increased risk vs men who are (OR, 17.3; 95% CI,
8.2 – 36.1)
b. Women who reported anoreceptive intercourse at higher risk (overall adjusted OR, 2.2; 95% CI
1.4 – 3.3)
B. Routine screening for anal cancer not recommended, even in high-risk individuals
C. Prevention: HPV immunization
1. The quadrivalent vaccine (active against HPV-6, -11, -16, -18 valents) has been shown to reduce the
occurrence of anal intraepithelial neoplasia (AIN) vs placebo in men who have sex with men (16 to 26
years of age) with an observed efficacy of 77.5% (95% CI, 39.6 – 93.3)197
60
a. The vaccine also reduced persistent infection with HPV-6,- 11, -16, or -18 with an observed
efficacy of 59.4%
b. High-grade AIN believed to be precursor to anal cancer
1) Although no anal cancers developed in either group during the 3-year observation period, it
is believed that the reduction in the rates of AIN could lead to a reduction in the rates of anal
cancer in this population
c. The quadrivalent vaccine is no longer available in the United States
2. The 9-valent vaccine (active against HPV-6, -11, -16, -18, -31, -33, -45, -52, -58 valents) is the only HPV
vaccine available in the United States
a. Although the 9-valent vaccine has no published data regarding prevention of AIN and/or anal
cancer, it is predicted to prevent 464 cases of anal cancer annually192
3. The Advisory Committee on Immunization Practices (ACIP)196 and the American Cancer Society
(ACS)198 both support HPV vaccination for males and females aged 9 through 26 years
a. Although the 9-valent vaccine is FDA-approved for adults aged up to 45 years, the ACIP does not
recommend “catch-up” vaccination for adults aged 27 to 45, but rather recommends shared
clinical decision making with those who are not adequately vaccinated
Patient Case #7:
VP is a 64-year-old female with HIV since 1996 on HAART therapy who presents with increasing discomfort with
defecation over the past two months. A sigmoidoscopy demonstrated a firm, fixed obstructing rectal mass 3 cm
from the anal verge. This was biopsied and found to be consistent with a squamous cell carcinoma. She has no
evidence of metastatic disease.
Which of the following treatment options is most appropriate for VP’s localized anal cancer?
A. Abdominoperineal resection with permanent colostomy
B. Radiation alone
C. Chemoradiation with 5-FU and mitomycin
D. Chemoradiation with 5-FU and cisplatin
II. Treatment and symptom management
A. Treatment modalities focus on radiation and chemotherapy192
1. Historically, primary treatment was abdominoperineal resection (APR)
a. High local recurrence rates (40-70%)
b. High morbidity (requires removal of anorectum, necessitating a permanent colostomy)
2. Refer to the NCCN Guidelines® for Anal Carcinoma for dosing and schedules of chemoradiation and
chemotherapy regimens
B. Treatment of localized anal carcinoma192
1. Chemoradiation with 5-FU + mitomycin
61
a. Nigro protocol199
1) Nigro and colleagues were the first to show complete tumor regression in some patients
treated with neoadjuvant chemoradiation
2) Of the 28 patients included in trial, 24 patients had no gross tumor in the anal canal
following treatment
3) Authors concluded that definitive chemoradiation can avoid APR
b. Further trials have compared 5-FU plus mitomycin with concurrent radiotherapy vs radiotherapy
alone200-202
1) The addition of chemotherapy to radiation improved complete remission rates, reduced

locoregional recurrence, and decreased risk of having a colostomy, however have not shown
statistically significant increase in OS
c. These trials affirmed that the standard of care for non-metastatic anal cancer should be
chemotherapy regimen of 5-FU and mitomycin concurrent with radiotherapy
1) 5-FU 1000 mg/m2/day CIVI Days 1-4 & 29-32
2) Mitomycin 10 mg/m2 IV Days 1 & 29 OR 12 mg/m2 Day 1
a) Capped at 20 mg
2. Chemoradiation with capecitabine + mitomycin
a. Capecitabine known to be an acceptable alternative to 5-FU in colon and rectal cancer data
b. EXTRA (prospective, phase II)203
1) Capecitabine 825 mg/m2 BID on days of radiation only (Monday through Friday), with
mitomycin on day 1, had expected toxicities of severe moist skin desquamation, diarrhea,
and myelosuppression
2) Local control at the timing endpoint of 6 months was seen in 28 patients (90%)
c. Retrospective data have found lower toxicities with capecitabine-based chemoradiation204 and
no significant differences in clinical complete response or longer term outcomes when compared
with 5-FU-based chemoradiation205
d. The NCCN Guidelines® consider capecitabine an acceptable substitute for 5-FU
3. Chemoradiation with 5-FU + cisplatin
a. Intergroup RTOG 98-11206 compared 5-FU + mitomycin against 5-FU + cisplatin both with
concurrent radiotherapy
1) 5-FU + cisplatin regimen involved an induction period with chemotherapy alone followed by
the same chemotherapy with radiation
a) 5-FU 1000 mg/m2/day CIVI Days 1-4, cisplatin 75 mg/m2 Day 1; repeat every 4 weeks
b. Although not statistically significant, trends favored the mitomycin group in local-regional
relapse, disease-free survival, and OS
c. Colostomy rates were significantly increased in the cisplatin group at 3 and 5 years (p=0.02)
62
d. Grade 3/4 nonhematologic toxicities were the same in each group (74%), but grade 3/4
hematologic toxicities were significantly worse with the mitomycin group (61% vs 42%, p<0.001)
e. Authors concluded cisplatin-based chemoradiation should generally be avoided for patients with
localized anal cancer unless they are unable to tolerate mitomycin
4. Summary
a. Surgery plays a minimal role in localized disease; the preferred primary treatment is
chemotherapy with radiation
b. Preferred regimens
1) 5-FU + mitomycin + radiation
2) Capecitabine + mitomycin + radiation
c. Other regimen
1) 5-FU + cisplatin + radiation (Category 2B)
Patient Case #7:

The correct answer is C. Chemoradiation with 5-FU and mitomycin (or capecitabine in place of 5-FU) is the
preferred first-line treatment for localized anal cancer
Answer A is not appropriate because APR is not recommended for first-line therapy of anal cancer due to long-
term morbidity complications and high local recurrence rates
Answer B is not appropriate because the addition of chemotherapy to radiation has been shown to improve
complete remission rates, reduce locoregional recurrence, and decrease risk of having a colostomy compared to
radiation alone
Answer D is not appropriate because chemoradiation with 5-FU and cisplatin has been shown to have non-
superior outcomes and increased colostomies compared to 5-FU and mitomycin. In addition, it is only a
Category 2B recommendation from NCCN®.
C. Treatment of locally progressive or recurrent anal cancer192
1. Locoregional failure rates are 10-30%
2. Higher recurrence rates associated with tumor size >5cm, male sex, and positive local lymph nodes
3. Patients who develop locally progressive disease should undergo APR and colostomy
D. Treatment of metastatic anal cancer192, 207
1. Because of the rarity of metastatic anal cancer, there are limited data on treatment
a. Extrapelvic, metastatic disease only seen in 10-20% of patients
b. No prospective data available
2. Enrollment on a clinical trial is encouraged
3. First-line treatment
63
a. 5-FU + cisplatin208
1) Out of 19 patients, response rate was 66% with 1 complete response and 11 partial
responses
2) Median survival was 34.5 months
3) Authors concluded that 5-FU plus cisplatin had acceptable toxicity
b. Eng and colleagues conducted a retrospective review of metastatic anal cancer patients, which to
date is the largest of its kind207
1) Of the 77 patients included in the review, 42 (55%) received 5-FU plus cisplatin, 24 (31%)
received carboplatin plus paclitaxel, and 11 (14%) received another regimen
2) The median survival favored 5-FU plus cisplatin (8 months, 95% CI 4.5 – 11.5 months) vs
carboplatin plus paclitaxel (4 months, 95% CI 1.7 – 6.3), however not to a significant degree
3) Authors concluded that either cisplatin + 5-FU or carboplatin + paclitaxel are reasonable
options for treatment of metastatic anal cancer
c. FOLFOX can be considered for patients, especially those with adenocarcinoma histology
d. 5-FU + cisplatin, carboplatin + paclitaxel, or FOLFOX can be given alone or in combination with
radiation
e. Preferred regimen
1) Carboplatin + paclitaxel (various dosing strategies)
f. Other regimens
1) 5-FU + cisplatin ± leucovorin (various dosing strategies)
2) FOLFOX
4. Subsequent treatment192
a. Nivolumab or pembrolizumab are preferred options
1) MSI and/or PD-L1 testing is not required
2) Nivolumab was studied in patients regardless of PD -L1 status, however pembrolizumab was
studied only in patients who were PD-L1 positive (PD-L1 > 1%)
b. If patients progress on a platinum-based regimen in the first-line, they should not be given a
platinum-based regimen in the second-line setting
III. Supportive care
A. Toxicity from chemoradiation192, 209
1. Acute toxicities include anoproctitis, perineal dermatitis, moist desquamation, pain, fatigue,
genitourinary complications, and diarrhea
a. Grade 3/4 skin toxicity reported in >80% patients
2. Long-term toxicities include increased frequency and urgency of defecation, chronic perineal
dermatitis, dyspareunia, impotence, infertility, and bone injury
64
3. Both men and women should discuss fertility issues, if relevant, with their oncologist
B. Skin toxicity from radiation210
1. Radiation dermatitis can appear as red, irritated, swollen, blistered, or sunburned
2. Patients should be advised to care for the area by avoiding tight clothes that may rub or irritate the
area
3. Cleaning the area may be difficult; patients should use lukewarm water and mild soap without
perfumes or dyes
C. Diarrhea management (see diarrhea management in Colon and Rectal Cancer Supportive Care)
IV. Survivorship issues and long-term follow-up
A. Development of metastatic disease seems to be highest within first 2 years after treatment for locally
advanced disease207
B. Follow-up after treatment for non-metastatic disease192
1. Patients should be re-evaluated by digital rectal exam (DRE) between 8 to 12 weeks after completion
of chemoradiation
2. About 1/3 of patients who do not show a complete response by this time may take up to 26 weeks or
longer to achieve a complete clinical response
3. The NCCN® panel recommends to follow these patients for up to 6 months after completion of
treatment
4. If clinical evidence of disease is absent, patients are recommended to undergo evaluation with DRE,
anoscopic evaluation, and inguinal node palpation every 3 to 6 months for 5 years
5. For patients with slow disease regression, annual chest, abdominal, and pelvic imaging is
recommended for 3 years
C. Long-term side effects from treatment affects quality of life209, 211, 212
1. Avoidance of APR and permanent colostomy is the main reason for transition to definitive
chemoradiation
2. Bowel dysfunction (diarrhea, fecal incontinence, flatulence) and sexual dysfunction (impotence,
dyspareunia) are the most commonly reported issues after chemoradiation in quality of life literature
3. Long-term effects can persist for years after treatment
D. Sexual dysfunction145
1. Patients should be referred to a sexual health specialist if interested and re-evaluated at regular
intervals
2. Patients with global symptoms of distress may benefit from anxiolytics or antidepressants
3. Females with vaginal dryness or other issues may benefit from topical therapies (vaginal
moisturizers/lubricants, topical hormones, topical anesthetics)
4. Males with impotence may benefit from oral phosphodiesterase type 5 inhibitors
65
RECOMMENDED READINGS
Colon and Rectal Cancer
1. Cersosimo RJ. Management of advanced colorectal cancer, part 1. Am J Health Syst Pharm. 2013; 70:395-
406. (http://www.ncbi.nlm.nih.gov/pubmed/23413162)
2. Cersosimo RJ. Management of advanced colorectal cancer, part 2. Am J Health Syst Pharm. 2013; 70:491-
506. (http://www.ncbi.nlm.nih.gov/pubmed/23456402)
3. Jimeno A, Messersmith WA, Hirsch FR, et al. KRAS mutations and sensitivity to epidermal growth factor
receptor inhibitors in colorectal cancer: practical application of patient selection. J Clin Oncol. 2009;
27(7):1130-6. (http://www.ncbi.nlm.nih.gov/pubmed/19124802)
Anal Cancer
1. Uronis HE, Bendell JC. Anal cancer: an overview. Oncologist. 2007;12(5):524-34.

(https://www.ncbi.nlm.nih.gov/pubmed/17522240)
2. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil,
cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA.
2008;299(16):1914-21. (https://www.ncbi.nlm.nih.gov/pubmed/18430910)
Pancreatic Cancer
1. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with
gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-
label, randomised, phase 3 trial. Lancet. 2017;389:1011-1024.
(https://www.ncbi.nlm.nih.gov/pubmed/28129987)
2. Wang-Gillam A, Li C-P, Bodoky Gr, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in
metastatic pancreatic cancer after previous gemcitabine-based therapy (napoli-1): A global, randomised,
open-label, phase 3 trial. Lancet. 2016; 387: 545-57. (http://www.ncbi.nlm.nih.gov/pubmed/26615328)
3. Conroy T, Hammel P, Hebbar M et al. Folfirinox or gemcitabine as adjuvant therapy for pancreatic cancer.
N Engl J Med. 2018; 379: 2395-406. (https://www.ncbi.nlm.nih.gov/pubmed/30575490)
REFERENCES
1 Libutti SK, Saltz L, Willett C et al. In: V. T. DeVita, T. S. Lawrence and S. A. Rosenberg eds. Cancer: Principles &
practice of oncology. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015.
2 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer
v.4.2019 © National Comprehensive Cancer Network. Inc 2019. All rights reserved. Accessed December 15,
2019.
3 Calvert PM and Frucht H. The genetics of colorectal cancer. Ann Intern Med. 2002; 137: 603-12.
4 Ribic CM, Sargent DJ, Moore MJ et al. Tumor microsatellite-instability status as a predictor of benefit from
fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003; 349(3): 247-57.
5 Sargent DJ, Marsoni S, Monges G et al. Defective mismatch repair as a predictive marker for lack of efficacy of
fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010; 28(20): 3219-26.
6 Sinicrope FA, Foster NR, Thibodeau SN et al. DNA mismatch repair status and colon cancer recurrence and
survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 2011; 103(11): 863-75.
7 Le DT, Uram JN, Wang H et al. Pd-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;
372: 2509-20.
8 Overman MJ, Lonardi S, Wong KYM et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA
mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer. J Clin Oncol. 2018;
36(8): 773-79.
66
9 Overman MJ, McDermott R, Leach JL et al. Nivolumab in patients with metastatic DNA mismatch repair-de
cient or microsatellite instability-high colorectal cancer (checkmate 142): An open-label, multicentre, phase 2
study. Lancet Oncol. 2017; 18: 1182-91.
10 Morel A, Boisdron-Celle M, Fey L et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene
single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther. 2006; 5(11): 2895-904.
11 van Kuilenburg ABP. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J
Cancer. 2004; 40: 939-50.
12 Amstutz U, Henricks LM, Offer SM et al. Clinical pharmacogenetics implementation consortium (cpic)
guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clinical
Pharmacology & Therapeutics. 2017; doi:10.1002/cpt.911.
13 Pizzolato JF and Saltz LB. The camptothecins. Lancet. 2003; 361: 2235-42.
14 Wallace BD, Wang H, Lane KT et al. Alleviating cancer drug toxicity by inhibiting a bacterial enzyme. Science.
2010; 330(6005): 831-35.
15 Hoskins J, Goldberg R, Qu P et al. Ugt1a1*28 genotype and irinotecan-induced neutropenia: Dose matters. J
Natl Cancer Inst. 2017; 99(17): 1290-5.
16 Irinotecan hydrochloride. Prescribing information. Cipla Ltd., Verna Goa, India. Revised: 11/2015.
17 Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced
colorectal cancer. N Engl J Med. 2008; 359(17): 1757-65.
18 Amado RG, Wolf M, Peeters M et al. Wild-type kras is required for panitumumab efficacy in patients with
metastatic colorectal cancer. J Clin Oncol. 2008; 26(10): 1626-34.
19 Jimeno A, Messersmith WA, Hirsch FR et al. Kras mutations and sensitivity to epidermal growth factor
receptor inhibitors in colorectal cancer: Practical application of patient selection. J Clin Oncol. 2009; 27(7):
1130-36.
20 Di Nicolantonio F, Martini M, Molinari F et al. Wild-type braf is required for response to panitumumab or
cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008; 26(35): 5705-12.
21 Sepulveda AR, Hamilton SR, Allegra CJ et al. Molecular biomarkers for the evaluation of colorectal cancer:
Guideline from the american society for clinical pathology, college of american pathologists, association for
molecular pathology, and the american society of clinical oncology. J Clin Oncol. 2017; 35(13): 1453-86.
22 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer
2019.
23 Ursem C, Atreya CE and Loon KV. Emerging treatment options for braf-mutant colorectal cancer. Gastrointest
Cancer Res. 2018; 8: 13-23.
24 Wactawski-Wende J, Kotchen JM, Anderson GL et al. Calcium plus vitamin d supplementation and the risk of
25 Baron JA, Barry EL, Mott LA et al. A trial of calcium and vitamin d for the prevention of colorectal adenomas.
N Engl J Med. 2015; 373(16): 1519-30.
26 Park Y, Hunter DJ, Spiegelman D et al. Dietary fiber intake and risk of colorectal cancer. JAMA. 2005; 294(22):
2849-57.
27 Chan AT, Giovannucci EL, Meyerhardt JA et al. Long-term use of aspirin and nonsteroidal anti-inflammatory
drugs and risk of colorectal cancer. JAMA. 2005; 294: 914-23.
28 Arber N, Eagle CJ, Spicak J et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med.
2006; 355: 885-95.
29 Bertagnolli MM, Eagle CJ, Zauber AG et al. Celecoxib for the prevention of sporadic colorectal adenomas. N
Engl J Med. 2006; 355: 873-84.
30 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Genetic/Familial
High-Risk Assessment: Colorectal v.3.2019 © National Comprehensive Cancer Network. Inc 2019. All rights
reserved. Accessed December 15, 2019.
31 U.S. Preventive Services Task Force. Final update summary: Aspirin use to prevent cardiovascular disease and
colorectal cancer: Preventive medication. Available from:
https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/aspirin-to-prevent-
cardiovascular-disease-and-cancer (accessed 2018 September 12).
67
32 Steinbach G, Lynch PM, Phillips RKS et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial
adenomatous polyposis. N Engl J Med. 2000; 342(26): 1946-52.
33 Samadder NJ, Neklason DW, Boucher KM et al. Effect of sulindac and erlotinib vs placebo on duodenal
neoplasia in familial adenomatous polyposis a randomized clinical trial. JAMA. 2016; 315(12): 1266-75.
34 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colorectal Cancer
Screening v.2.2019 © National Comprehensive Cancer Network. Inc 2019. All rights reserved. Accessed
December 15, 2019.
35 American Cancer Society. American cancer society recommendations for colorectal cancer early detection.
Available from:
http://www.cancer.org/cancer/colonandrectumcancer/moreinformation/colonandrectumcancerearlydetecti
on/colorectal-cancer-early-detection-acs-recommendations (accessed 2018 September 12).
36 Giardiello FM, Allen JI, Axilbund JE et al. Guidelines on genetic evaluation and management of lynch
syndrome: A consensus statement by the us multi-society task force on colorectal cancer. Gastroenterology.
2014; 147: 502-26.
37 Rex DK, Boland CR, Dominitz JA et al. Colorectal cancer screening: Recommendations for physicians and
patients from the u.S. Multi-society task force on colorectal cancer. Am J Gastroenterol. 2017; 112: 1016-30.
38 Wolf AMD, Fontham ETH, Church TR et al. Colorectal cancer screening for average-risk adults: 2018 guideline
update from the american cancer society. CA Cancer J Clin. 2018; 000: 000-00.
39 U.S. Preventive Services Task Force. Final recommendation statement: Colorectal cancer: Screening.
https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/colorecta
l-cancer-screening2 (accessed 2019 July 2).
40 Rockey DC, Paulson E, Niedzwiecki D et al. Analysis of air contrast barium enema, computed tomographic
colonography, and colonoscopy: Prospective comparison. Lancet. 2005; 365: 305-11.
41 Delaunoit T, Alberts SR, Sargent DJ et al. Chemotherapy permits resection of metastatic colorectal cancer:
Experience from intergroup n9741. Ann Oncol. 2005; 16(3): 425-29.
42 Gruenberger B, Tamandl D, Schueller J et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant
therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008; 26(11): 1830-35.
43 Wong R, Cunningham D, Barbachano Y et al. A multicentre study of capecitabine, oxaliplatin plus
bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not
selected for upfront resection. Ann Oncol. 2011; 22(9): 2042-48.
44 Nasti G, Piccirillo MC, Izzo F et al. Neoadjuvant folfiri+bevacizumab in patients with resectable liver
metastases from colorectal cancer: A phase 2 trial. Br J Cancer. 2013; 108(8): 1566-70.
45 Ye L-C, Liu T-S, Ren L et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with kras
wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013; 31(16): 1931-38.
46 Primrose J, Falk S, Finch-Jones M et al. Systemic chemotherapy with or without cetuximab in patients with
resectable colorectal liver metastasis: The new epoc randomised controlled trial. Lancet Oncol. 2014; 15(6):
601-11.
47 Folprecht G, Gruenberger T, Bechstein W et al. Survival of patients with initially unresectable colorectal liver
metastases treated with folfox/cetuximab or folfiri/cetuximab in a multidisciplinary concept (celim study).
Ann Oncol. 2014; 25(5): 1018-25.
48 Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage iii colon cancer. N Engl J
Med. 2005; 352(26): 2696-704.
49 André T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for
colon cancer. N Engl J Med. 2004; 350: 2343-51.
50 André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as
adjuvant treatment in stage ii or iii colon cancer in the mosaic trial. J Clin Oncol. 2009; 27(19): 3109-16.
51 Haller DG, Tabernero J, Maroun J et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic
acid as adjuvant therapy for stage iii colon cancer. J Clin Oncol. 2011; 29(11): 1465-71.
52 Schmoll H-J, Tabernero J, Maroun J et al. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid
as adjuvant therapy for stage iii colon cancer: Final results of the no16968 randomized controlled phase iii
trial. J Clin Oncol. 2015; 33(32): 3733-40.
53 Benson AB, 3rd, Schrag D, Somerfield MR et al. American society of clinical oncology recommendations on
adjuvant chemotherapy for stage ii colon cancer. J Clin Oncol. 2004; 22(16): 3408-19.
68
54 Grothey A, Sobrero AF, Shields AF et al. Duration of adjuvant chemotherapy for stage iii colon cancer. N Engl J
Med. 2018; 378(13): 1177-88.
55 Bosset J-F, Calais G, Mineur L et al. Enhanced tumorocidal effect of chemotherapy with preoperative
radiotherapy for rectal cancer: Preliminary results—eortc 22921. J Clin Oncol. 2005; 23: 5620-7.
56 Bosset J-Fo, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J
Med. 2006; 355: 1114-23.
57 Hofheinz R-D, Wenz F, Post S et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally
advanced rectal cancer: A randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol. 2012; 13:
579-88.
58 O'Connell MJ, Colangelo LH, Beart RW et al. Capecitabine and oxaliplatin in the preoperative multimodality
treatment of rectal cancer: Surgical end points from national surgical adjuvant breast and bowel project trial
r-04. J Clin Oncol. 2014; 32(18): 1927-34.
59 Allegra CJ, Yothers G, O’Connell MJ et al. Neoadjuvant 5-fu or capecitabine plus radiation with or without
oxaliplatin in rectal cancer patients: A phase iii randomized clinical trial. J Natl Cancer Inst. 2015; 107(11):
djv248.
60 Van Cutsem E, Twelves C, Cassidy J et al. Oral capecitabine compared with intravenous fluorouracil plus
leucovorin in patients with metastatic colorectal cancer: Results of a large phase iii study. J Clin Oncol. 2001;
19(21): 4097-106.
61 de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line
treatment in advanced colorectal cancer. J Clin Oncol. 2000; 18(16): 2938-47.
62 Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil
alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet. 2000;
355: 1041-47.
63 Cassidy J, Clarke S, Díaz-Rubio E et al. Randomized phase iii study of capecitabine plus oxaliplatin compared
with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol.
2008; 26(12): 2006-12.
64 Cassidy J, Clarke S, Diaz-Rubio E et al. Xelox vs folfox-4 as first-line therapy for metastatic colorectal cancer:
No16966 updated results. Br J Cancer. 2011; 105(1): 58-64.
65 Falcone A, Ricci S, Brunetti I et al. Phase iii trial of infusional fluorouracil, leucovorin, oxaliplatin, and
irinotecan (folfoxiri) compared with infusional fluorouracil, leucovorin, and irinotecan (folfiri) as first-line
treatment for metastatic colorectal cancer: The gruppo oncologico nord ovest. J Clin Oncol. 2007; 25(13):
1670-6.
66 Tournigand C, Andre T, Achille E et al. Folfiri followed by folfox6 or the reverse sequence in advanced
colorectal cancer: A randomized gercor study. J Clin Oncol. 2004; 22(2): 229-37.
67 Saltz LB, Clarke S, Díaz-Rubio E et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as
first-line therapy in metastatic colorectal cancer: A randomized phase iii study. J Clin Oncol. 2008; 26(12):
2013-19.
68 Hochster HS, Hart LL, Ramanathan RK et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens
with or without bevacizumab as first-line treatment of metastatic colorectal cancer: Results of the tree study.
J Clin Oncol. 2008; 26(21): 3523-9.
69 Fuchs CS, Marshall J and Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral
fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Updated results from the bicc-c
study. J Clin Oncol. 2008; 26(4): 689-90.
70 Fuchs CS, Marshall J, Mitchell E et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral
fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the bicc-c study. J Clin
Oncol. 2007; 25(30): 4779-86.
71 Loupakis F, Cremolini C, Masi G et al. Initial therapy with folfoxiri and bevacizumab for metastatic colorectal
cancer. N Engl J Med. 2014; 371(17): 1609-18.
72 Cremolini C, Loupakis F, Antoniotti C et al. Folfoxiri plus bevacizumab versus folfiri plus bevacizumab as first-
line treatment of patients with metastatic colorectal cancer: Updated overall survival and molecular
subgroup analyses of the open-label, phase 3 tribe study. Lancet Oncol. 2015; 16: 1306-15.
69
73 Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first-line combination
chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 mrc coin trial.
Lancet. 2011; 377: 2103-14.
74 Douillard JY, Siena S, Cassidy J et al. Final results from prime: Randomized phase iii study of panitumumab
with folfox4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014; 25(7): 1346-55.
75 Douillard JY, Siena S, Cassidy J et al. Randomized, phase iii trial of panitumumab with infusional fluorouracil,
leucovorin, and oxaliplatin (folfox4) versus folfox4 alone as first-line treatment in patients with previously
untreated metastatic colorectal cancer: The prime study. J Clin Oncol. 2010; 28(31): 4697-705.
76 Van Cutsem E, Köhne C-H, Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic
77 Moretto R, Cremolini C, Rossini D et al. Location of primary tumor and benefit from anti-epidermal growth
factor receptor monoclonal antibodies in patients with ras and braf wild-type metastatic colorectal cancer.
The Oncologist. 2016; 21: 988-94.
78 Brulé SY, Jonker DJ, Karapetis CS et al. Location of colon cancer (right-sided versus left-sided) as a prognostic
factor and a predictor of benefit from cetuximab in ncic co.17. Eur J Cancer. 2015; 51: 1405-14.
79 Lee MS, Advani SM, Morris Jr et al. Association of primary (1°) site and molecular features with progression-
free survival (pfs) and overall survival (os) of metastatic colorectal cancer (mcrc) after anti- epidermal growth
factor receptor (αegfr) therapy. J Clin Oncol. 2016; 34(no. 15_suppl (May 2016)): 3506.
80 Venook AP, Niedzwiecki D, Innocenti F et al. Impact of primary (1o) tumor location on overall survival (os)
and progression-free survival (pfs) in patients (pts) with metastatic colorectal cancer (mcrc): Analysis of
calgb/swog 80405 (alliance). J Clin Oncol. 2016; 34(no. 15_suppl (May 2016)): 3504.
81 Venook AP, Niedzwiecki D, Lenz H-J et al. Calgb/swog 80405: Phase iii trial of irinotecan/5fu/leucovorin
(folfiri) or oxaliplatin/5fu/leucovorin (mfolfox6) with bevacizumab (bv) or cetuximab (cet) for patients (pts)
with kras wildtype (wt) untreated metastatic adenocarcinoma of the colon or rectum (mcrc). J Clin Oncol.
2014; 32(15): LBA3.
82 Bennouna J, Sastre J, Arnold D et al. Continuation of bevacizumab after first progression in metastatic
colorectal cancer (ml18147): A randomised phase 3 trial. Lancet Oncol. 2013; 14: 29-37.
83 Van Cutsem E, Tabernero J, Lakomy R et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan
improves survival in a phase iii randomized trial in patients with metastatic colorectal cancer previously
treated with an oxaliplatin-based regimen. J Clin Oncol. 2012; 30(28): 3499-506.
84 Tabernero J, Yoshino T, Cohn AL et al. Ramucirumab versus placebo in combination with second-line folfiri in
patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with
bevacizumab, oxaliplatin, and a fluoropyrimidine (raise): A randomised, double-blind, multicentre, phase 3
study. Lancet Oncol. 2015; 16(5): 499-508.
85 Sobrero AF, Maurel J, Fehrenbacher L et al. Epic: Phase iii trial of cetuximab plus irinotecan after
fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;
26(14): 2311-19.
86 Peeters M, Price TJ, Cervantes A et al. Randomized phase iii study of panitumumab with fluorouracil,
leucovorin, and irinotecan (folfiri) compared with folfiri alone as second-line treatment in patients with
metastatic colorectal cancer. J Clin Oncol. 2010; 28(31): 4706-13.
87 Jonker DJ, O'Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J
Med. 2007; 357(20): 2040-48.
88 Van Cutsem E, Peeters M, Siena S et al. Open-label phase iii trial of panitumumab plus best supportive care
compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal
cancer. J Clin Oncol. 2007; 25(13): 1658-64.
89 Kopetz S, McDonough SL, Lenz H-J et al. Randomized trial of irinotecan and cetuximab with or without
vemurafenib in braf-mutant metastatic colorectal cancer (swog s1406). J Clin Oncol. 2017; 35: DOI:
10.1200/JCO.2017.35.15_suppl.3505.
90 Atreya CE, Cutsem EV, Bendell JC et al. Updated efficacy of the mek inhibitor trametinib (t), braf inhibitor
dabrafenib (d), and anti-egfr antibody panitumumab (p) in patients (pts) with braf v600e mutated (brafm)
metastatic colorectal cancer (mcrc). J Clin Oncol. 2015; 33: DOI: 10.1200/jco.2015.33.15_suppl.103.
70
91 Cutsem EV, Huijberts S, Grothey A et al. Binimetinib, encorafenib, and cetuximab triplet therapy for patients
with braf v600e–mutant metastatic colorectal cancer: Safety lead-in results from the phase iii beacon
colorectal cancer study. J Clin Oncol. 2019; 37: 1460-9.
92 The ASCO Post. Fda grants breakthrough therapy designation for encorafenib plus binimetinib and cetuximab
in braf v600e–mutant metastatic colorectal cancer.
https://www.ascopost.com/News/59160?utm_source=TrendMD&utm_medium=cpc&utm_campaign=The_A
SCO_Post_TrendMD_0 (accessed 2019 June 28).
93 Sartore-BIanchi A, Trusolino L, Martino C et al. Dual-targeted therapy with trastuzumab and lapatinib in
treatment-refractory, kras codon 12/13 wild-type, her2-positive metastatic colorectal cancer (heracles): A
proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016; 17: 738-46.
94 Meric-Bernstam F, Hurwitz H, Raghav KPS et al. Pertuzumab plus trastuzumab for her2-amplified metastatic
colorectal cancer (mypathway): An updated report from a multicentre, open-label, phase 2a, multiple basket
study. Lancet Oncol. 2019; 20: 518-30.
95 Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic
colorectal cancer (correct): An international, multicentre, randomised, placebo-controlled, phase 3 trial.
Lancet. 2013; 381: 303-12.
96 Bekaii-Saab TS, Ou F-S, Anderson DM et al. Regorafenib dose optimization study (redos): Randomized phase ii
trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mcrc) an accru
network study. J Clin Oncol. 2018; 36: DOI: 10.1200/JCO.2018.36.4_suppl.611
97 Mayer RJ, Van Cutsem E, Falcone A et al. Randomized trial of tas-102 for refractory metastatic colorectal
98 Drilon A, Laetsch TW, Kummar S et al. Efficacy of larotrectinib in trk fusion– positive cancers in adults and
children. N Engl J Med. 2018; 378: 731-9.
99 Pozzo C, Basso M, Cassano A et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and
5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol. 2004; 15: 933-39.
100 Alberts SR, Horvath WL, Sternfeld WC et al. Oxaliplatin, fluorouracil, and leucovorin for patients with
unresectable liver-only metastases from colorectal cancer: A north central cancer treatment group phase ii
study. J Clin Oncol. 2005; 23: 9243-9.
101 Souglakos J, Androulakis N, Syrigos K et al. Folfoxiri (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs
folfiri (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (mcc):
A multicentre randomised phase iii trial from the hellenic oncology research group (horg). Br J Cancer. 2006;
94(6): 798-805.
102 Masi G, Vasile E, Loupakis F et al. Randomized trial of two induction chemotherapy regimens in metastatic
colorectal cancer: An updated analysis. J Natl Cancer Inst. 2011; 103: 21-30.
103 Vauthey J-N, Pawlik TM, Ribero D et al. Chemotherapy regimen predicts steatohepatitis and an increase in
90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006; 24(13): 2065-72.
104 Folprecht G, Gruenberger T, Bechstein WO et al. Tumour response and secondary resectability of colorectal
liver metastases following neoadjuvant chemotherapy with cetuximab: The celim randomised phase 2 trial.
Lancet Oncol. 2010; 11: 38-47.
105 Petrelli F and Barni S. Resectability and outcome with anti-egfr agents in patients with kras wild-type
colorectal liver-limited metastases: A meta-analysis. Int J Colorectal Dis. 2012; 27: 997-1004.
106 Stein A, Voigt W and Jordan K. Chemotherapy-induced diarrhea: Pathophysiology, frequency and guideline-
based management. Ther Adv Med Oncol. 2010; 2(1): 51-63.
107 Richardson G and Dobish R. Chemotherapy induced diarrhea. J Oncol Pharm Pract. 2007; 13: 181-98.
108 National Cancer Institute. Common terminology criteria for adverse events (ctcae) version 5.0. Available
from:
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.
5x11.pdf (accessed 2018 September 20).
109 Saliba F, Hagipantelli R, Misset J-L et al. Pathophysiology and therapy of irinotecan-induced delayed-onset
diarrhea in patients with advanced colorectal cancer: A prospective assessment. J Clin Oncol. 1998; 16: 2745-
51.
110 Abigerges D, Armand J-P, Chabot GG et al. Irinotecan (cpt-11) high-dose escalation using intensive high-dose
loperamide to control diarrhea. J Natl Cancer Inst. 1994; 86(6): 446-9.
71
111 Rothenberg ML, Eckardt JR, Kuhn JG et al. Phase ii trial of irinotecan in patients with progressive or rapidly
recurrent colorectal cancer. J Clin Oncol. 1996; 14: 1128-35.
112 Benson AB, 3rd, Ajani JA, Catalano RB et al. Recommended guidelines for the treatment of cancer treatment-
induced diarrhea. J Clin Oncol. 2004; 22(14): 2918-26.
113 Gobel BH. Hypersensitivity reactions to biological drugs. Semin Oncol Nurs. 2007; 23(3): 191-200.
114 Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007; 12(5):
601-9.
115 Syrigou EA, Makrilla NA, Koti LA et al. Hypersensitivity reactions to antineoplastic agents: An overview.
Anticancer Drugs. 2009; 20(1): 1-6.
116 Kang S and Saif MW. Infusion-related and hypersensitivity reactions of monoclonal antibodies used to treat
colorectal cancer--identification, prevention, and management. J Support Oncol. 2007; 5(9): 451-7.
117 Kingsley CD. In: M. C. Perry, D. C. Doll and C. E. Freter eds. Perry's the chemotherapy source book. 5th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
118 O’Neil BH, Allen R, Spigel DR et al. High incidence of cetuximab-related infusion reactions in tennessee and
north carolina and the association with atopic history. J Clin Oncol. 2007; 25(24): 3644-48.
119 George TJ, LaPlant KD, Walden EO et al. Managing cetuximab hypersensitivity-infusion reactions: Incidence,
risk factors, prevention, and retreatment. J Support Oncol. 2010; 8: 72-77.
120 Pachman DR, Barton DL, Watson JC et al. Chemotherapy-induced peripheral neuropathy: Prevention and
treatment. Clin Pharmacol Ther. 2011; 90(3): 377-87.
121 Cersosimo RJ. Oxaliplatin-associated neuropathy: A review. Ann Pharmacother. 2005; 39(Jan): 128-35.
122 Cavaletti G and Zanna C. Current status and future prospects for the treatment of chemotherapy-induced
peripheral neurotoxicity. Eur J Cancer. 2002; 38(14): 1832-37.
123 Argyriou AA, Bruna J, Marmiroli P et al. Chemotherapy-induced peripheral neurotoxicity (cipn): An update.
Crit Rev Oncol Hematol. 2012; 82(1): 51-77.
124 Hoff P, Saad E, Costa F et al. Literature review and practical aspects on the management of oxaliplatin-
associated toxicity. Clin Colorectal Cancer. 2012; 11(2): 93-100.
125 Pachman DR, Qin R, Seisler DK et al. Clinical course of oxaliplatin-induced neuropathy: Results from the
randomized phase iii trial n08cb (alliance). J Clin Oncol. 2015; 33(30): 3416-22.
126 Gamelin L, Boisdron-Celle M, Delva R et al. Prevention of oxaliplatin-related neurotoxicity by calcium and
magnesium infusions: A retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil
and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004; 10(12): 4055-61.
127 Tournigand C, Cervantes A, Figer A et al. Optimox1: A randomized study of folfox4 or folfox7 with oxaliplatin
in a stop-and-go fashion in advanced colorectal cancer—a gercor study. J Clin Oncol. 2006; 24(3): 394-400.
128 Loprinzi CL, Qin R, Dakhil SR et al. Phase iii randomized, placebo-controlled, double-blind study of intravenous
calcium and magnesium to prevent oxaliplatin-induced sensory neurotoxicity (n08cb/alliance). J Clin Oncol.
2014; 32(10): 997-1005.
129 Hershman DL, Lacchetti C, Dworkin RH et al. Prevention and management of chemotherapy-induced
peripheral neuropathy in survivors of adult cancers: American society of clinical oncology clinical practice
guideline. J Clin Oncol. 2014; 32(18): 1941-67.
130 Payne AS, James WD and Weiss RB. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol. 2006;
33(1): 86-97.
131 Balagula Y, Lacouture ME and Cotlair JA. Dermatologic toxicities of targeted anticancer therapies.
Www.SupportiveOncology.net. 2010; 8(4): 149-61.
132 Balagula E and Lacouture ME. In: I. N. Olver ed. The mascc textbook of cancer supportive care and
survivorship. New York: Springer; 2011:361-80.
133 Wood LS, Lemont H, Jatoi A et al. Practical considerations in the management of hand-foot skin reaction
caused by multikinase inhibitors. Community Oncol. 2010; 7(1): 23-9.
134 Urban C and Anadkat MJ. A review of cutaneous toxicities from targeted therapies in the treatment of
colorectal cancers. J Gastrointest Oncol. 2013; 4(3): 319-27.
135 Macedo LT, Lima JP, dos Santos LV et al. Prevention strategies for chemotherapy-induced hand-foot
syndrome: A systematic review and meta-analysis of prospective randomised trials. Support Care Cancer.
2014; 22(6): 1585-93.
72
136 Ren Z, Zhu K, Kang H et al. Randomized controlled trial of the prophylactic effect of urea-based cream on
sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin
Oncol. 2015; 33(8): 894-900.
137 Ailor SK and Miles SC. In: M. C. Perry ed. The chemotherapy source book. 4th ed. Philadelphia: Lippincott
Williams & Wilkins; 2008:1136-147.
138 Lacouture ME, Reilly LM, Gerami P et al. Hand foot skin reaction in cancer patients treated with the
multikinase inhibitors sorafenib and sunitinib. Ann Oncol. 2008; 19(11): 1955-61.
139 Lacouture ME. Management of dermatologic toxicities. J Natl Compr Canc Netw. 2015; 13: 686-9.
140 Bachet J, Peuvrel L, Bachmeyer C et al. Folliculitis induced by egfr inhibitors, preventive and curative efficacy
of tetracyclines in the management and incidence rates according to the type of egfr inhibitor administered:
A systematic literature review. Oncologist. 2012; 17(4): 555-68.
141 Reguiai Z, Bachet J, Bachmeyer C et al. Management of cutaneous adverse events induced by anti-egfr
(epidermal growth factor receptor): A french interdisciplinary therapeutic algorithm. Support Care Cancer.
2012; 20(7): 1395-404.
142 Baas J, Krens L, Guchelaar H et al. Recommendations on management of egfr inhibitor-induced skin toxicity:
A systematic review. Cancer Treat Rev. 2012; 38(5): 505-14.
143 Lacouture M, Mitchell E, Piperdi B et al. Skin toxicity evaluation protocol with panitumumab (stepp), a phase
ii, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin
toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010; 28(8): 1351-7.
144 Schneider EC, Malin JL, Kahn KL et al. Surviving colorectal cancer. Cancer. 2007; 110: 2075-82.
145 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Survivorship
2019.
146 Bains SJ, Mahic M, Myklebust TA et al. Aspirin as secondary prevention in patients with colorectal cancer: An
unselected population-based study. J Clin Oncol. 2016; 34: 2501-8.
147 Meyerhardt JA, Mangu PB, Flynn PJ et al. Follow-up care, surveillance protocol, and secondary prevention
measures for survivors of colorectal cancer: American society of clinical oncology clinical practice guideline
endorsement. J Clin Oncol. 2013; 31(35): 4465-70.
148 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Pancreatic
Adenocarcinoma v.1.2020 © National Comprehensive Cancer Network. Inc 2019. All rights reserved.
Accessed December 15, 2019.
149 Winter JM, Brody JR, Abrams RA et al. In: V. T. DeVita, T. S. Lawrence and S. A. Rosenberg eds. Cancer:
Principles & practices of oncology. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015.
150 Yang G, Wagner T, Fuss M et al. Multimodality approaches for pancreatic cancer. CA Cancer J Clin. 2005;
55(6): 352-67.
151 Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and
chemotherapy following curative resection of pancreatic cancer. Gastrointestinal tumor study group. Cancer.
1987; 59(12): 2006-10.
152 Chua YJ and Cunningham D. Adjuvant treatment for resectable pancreatic cancer. J Clin Oncol. 2005; 23(20):
4532-7.
153 Klinkenbijl JH, Jeekel J, Sahmoud T et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of
cancer of the pancreas and periampullary region: Phase iii trial of the eortc gastrointestinal tract cancer
cooperative group. Ann Surg. 1999; 230(6): 776-82; discussion 82-4.
154 Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy
after resection of pancreatic cancer. N Engl J Med. 2004; 350(12): 1200-10.
155 Khorana AA, McKernin SE, Berlin J et al. Potentially curable pancreatic adenocarcinoma: Asco clinical practice
guideline update. J Clin Oncol. 2019; 37: DOI https://doi.org/10.1200/JCO.19.00946.
156 Stocken DD, Buchler MW, Dervenis C et al. Meta-analysis of randomised adjuvant therapy trials for
pancreatic cancer. Br J Cancer. 2005; 92(8): 1372-81.
157 Oettle H, Post S, Neuhaus P et al. Adjuvant chemotherapy with gemcitabine vs observation in patients
undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA. 2007; 297(3):
267-77.
73
158 Neoptolemos JP, Stocken DD, Bassi C et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs
gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA. 2010; 304(10):
1073-81.
159 Neoptolemos JP, Palmer DH, Ghaneh P et al. Comparison of adjuvant gemcitabine and capecitabine with
gemcitabine monotherapy in patients with resected pancreatic cancer (espac-4): A multicentre, open-label,
randomised, phase 3 trial. Lancet. 2017; 389: 1011-24.
160 Conroy T, Hammel P, Hebbar M et al. Folfirinox or gemcitabine as adjuvant therapy for pancreatic cancer. N
Engl J Med. 2018; 379: 2395-406.
161 Khorana AA, Mangu PB, Berlin J et al. Potentially curable pancreatic cancer: American society of clinical
oncology clinical practice guideline. J Clin Oncol. 2016; 34(21): 2541-56.
162 Khorana AA, Mangu PB, Berlin J et al. Potentially curable pancreatic cancer: American society of clinical
oncology clinical practice guideline update. J Clin Oncol. 2017; 35(20): 2324-28.
163 Willett CG, Czito BG, Bendell JC et al. Locally advanced pancreatic cancer. J Clin Oncol. 2005; 23(20): 4538-44.
164 Czito BG, Willett CG, Clark JW et al. Current perspectives on locally advanced pancreatic cancer. Oncology
(Williston Park). 2000; 14(11): 1535-45; discussion 46, 49-52.
165 Moertel CG, Frytak S, Hahn RG et al. Therapy of locally unresectable pancreatic carcinoma: A randomized
comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil),
and high dose radiation + 5-fluorouracil: The gastrointestinal tumor study group. Cancer. 1981; 48(8): 1705-
10.
166 Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas:
Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone.
Gastrointestinal tumor study group. J Natl Cancer Inst. 1988; 80(10): 751-5.
167 Crane CH, Abbruzzese JL, Evans DB et al. Is the therapeutic index better with gemcitabine-based
chemoradiation than with 5-fluorouracil-based chemoradiation in locally advanced pancreatic cancer? Int J
Radiat Oncol Biol Phys. 2002; 52(5): 1293-302.
168 Mamon HJ, Niedzwiecki D, Hollis D et al. A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy
in locally advanced nonmetastatic pancreatic adenocarcinoma. Cancer. 2011; 117: 2620-8.
169 Balaban EP, Mangu PB, Khorana AA et al. Locally advanced, unresectable pancreatic cancer: American society
of clinical oncology clinical practice guideline. J Clin Oncol. 2016; 34(22): 2654-68.
170 Sohal DP, Mangu PB, Khorana AA et al. Metastatic pancreatic cancer: American society of clinical oncology
clinical practice guideline. J Clin Oncol. 2016; 34(23): 2784-96.
171 Burris HA, 3rd, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as
first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol. 1997; 15(6):
2403-13.
172 Grunewald R, Kantarjian H, Keating MJ et al. Pharmacologically directed design of the dose rate and schedule
of 2',2'-difluorodeoxycytidine (gemcitabine) administration in leukemia. Cancer Res. 1990; 50(21): 6823-6.
173 Tempero M, Plunkett W, Ruiz Van Haperen V et al. Randomized phase ii comparison of dose-intense
gemcitabine: Thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma.
J Clin Oncol. 2003; 21(18): 3402-8.
174 Poplin E, Feng Y, Berlin J et al. Phase iii, randomized study of gemcitabine and oxaliplatin versus gemcitabine
(fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic
carcinoma e6201: A trial of the eastern cooperative oncology group. J Clin Oncol. 2009; 27(23): 3778-85.
175 Berlin JD, Catalano P, Thomas JP et al. Phase iii study of gemcitabine in combination with fluorouracil versus
gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern cooperative oncology group trial
e2297. J Clin Oncol. 2002; 20(15): 3270-5.
176 Heinemann V, Quietzsch D, Gieseler F et al. Randomized phase iii trial of gemcitabine plus cisplatin compared
with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006; 24(24): 3946-52.
177 Rocha Lima CM, Green MR, Rotche R et al. Irinotecan plus gemcitabine results in no survival advantage
compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer
despite increased tumor response rate. J Clin Oncol. 2004; 22(18): 3776-83.
178 Louvet C, Labianca R, Hammel P et al. Gemcitabine in combination with oxaliplatin compared with
gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a gercor and giscad phase iii
trial. J Clin Oncol. 2005; 23(15): 3509-16.
74
179 Cunningham D, Chau I, Stocken DD et al. Phase iii randomized comparison of gemcitabine versus gemcitabine
plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009; 27(33): 5513-8.
180 Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in
patients with advanced pancreatic cancer: A phase iii trial of the national cancer institute of canada clinical
trials group. J Clin Oncol. 2007; 25(15): 1960-6.
181 Conroy T, Desseigne F, Ychou M et al. Folfirinox versus gemcitabine for metastatic pancreatic cancer. N Engl J
Med. 2011; 364(19): 1817-25.
182 Von Hoff DD, Ervin T, Arena FP et al. Increased survival in pancreatic cancer with nab-paclitaxel plus
gemcitabine. N Engl J Med. 2013; 369(18): 1691-703.
183 Golan T, Hammel P, Reni M et al. Maintenance olaparib for germline brca-mutated metastatic pancreatic
184 Wang-Gillam A, Li C-P, Bodoky Gr et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in
metastatic pancreatic cancer after previous gemcitabine-based therapy (napoli-1): A global, randomised,
open-label, phase 3 trial. Lancet. 2016; 387: 545-57.
185 Onivyde (irinotecan liposome injection). Prescribing information. Merrimack Pharmaceuticals, Inc.,
Cambridge, MA. Revised: 10/2015.
186 Pelzer U, Schwaner I, Stieler J et al. Best supportive care (bsc) versus oxaliplatin, folinic acid and 5-fluorouracil
(off) plus bsc in patients for second-line advanced pancreatic cancer: A phase iii-study from the german
conko-study group. Eur J Cancer. 2011; 47(11): 1676-81.
187 Domínguez-Muñoz JE. Pancreatic exocrine insufficiency: Diagnosis and treatment. J Gastroenterol Hepatol.
2011; 26(Suppl 2): 12-16.
188 Berry AJ. Pancreatic enzyme replacement therapy during pancreatic insufficiency. Nutr Clin Pract. 2014;
29(3): 312-21.
189 Lee AYY, Levine MN, Baker RI et al. Low-molecular-weight heparin versus a coumarin for the prevention of
recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003; 349: 146-53.
190 Pelzer U, Opitz B, Deutschinoff G et al. Efficacy of prophylactic low–molecular weight heparin for ambulatory
patients with advanced pancreatic cancer: Outcomes from the conko-004 trial. J Clin Oncol. 2015; 33: 2028-
34.
191 SEER Stat Fact Sheets. Pancreas cancer, national cancer institute, bethesda, md. Available from:
http://seer.cancer.gov/statfacts/html/pancreas.html (accessed 2017 September 16).
192 Referenced from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Anal Carcinoma
2019.
193 Watson AJ, Smith BB, Whitehead MR et al. Malignant progression of anal intra-epithelial neoplasia. ANZ J
Surg. 2006; 76(8): 715-7.
194 Uronis HE and Bendell JC. Anal cancer: An overview. Oncologist. 2007; 12(5): 524-34.
195 Daling JR, Madeleine MM, Johnson LG et al. Human papillomavirus, smoking, and sexual practices in the
etiology of anal cancer. Cancer. 2004; 101(2): 270-80.
196 Meites E, Szilagyi PG, Chesson HW et al. Human papillomavirus vaccination for adults: Updated
recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep.
2019; 68(32): 698-702.
197 Palefsky JM, Giuliano AR, Goldstone S et al. Hpv vaccine against anal hpv infection and anal intraepithelial
neoplasia. N Engl J Med. 2011; 365: 1576-85.
198 American Cancer Society. American cancer society recommendations for human papillomavirus (hpv) vaccine
use. https://www.cancer.org/cancer/cancer-causes/infectious-agents/hpv/acs-recommendations-for-hpv-
vaccine-use.html (accessed 2019 August 27).
199 Nigro ND, Seydel G, Considine B et al. Combined preoperative radiation and chemotherapy for squamous cell
carcinoma of the anal canal. Cancer. 1983; 51: 1826-29.
200 Bartelink H, Roelofsen F, Eschwege F et al. Concomitant radiotherapy and chemotherapy is superior to
radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase iii randomized trial of
the european organization for research and treatment of cancer radiotherapy and gastrointestinal
cooperative groups. J Clin Oncol. 1997; 15: 2040-49.
75
201 Northover J, Glynne-Jones R, Sebag-Montefiore D et al. Chemoradiation for the treatment of epidermoid anal
cancer: 13-year follow-up of the first randomised ukcccr anal cancer trial (act i). Br J Cancer. 2010; 102: 1123-
28.
202 UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: Results from the ukcccr randomised trial of
radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996; 348: 1049-54.
203 Glynne-Jones R, Meadows H, Wan S et al. Extra—a multicenter phase ii study of chemoradiation using a 5 day
per week oral regimen of capecitabine and intravenous mitomycin c in anal cancer. Int J Radiat Oncol Biol
Phys. 2008; 72(1): 119-26.
204 Goodman KA, Rothenstein D, Lajhem C et al. Capecitabine plus mitomycin in patients undergoing definitive
chemoradiation for anal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2014; 90: S32-S33.
205 Meulendijks D, Dewit L, Tomasoa NB et al. Chemoradiotherapy with capecitabine for locally advanced anal
carcinoma: An alternative treatment option. Br J Cancer. 2014; 111: 1726-33.
206 Ajani JA, Winter KA, Gunderson LL et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin,
and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. J Am Med Assoc. 2008;
299(16): 1914-21.
207 Eng C, Chang GJ, You YN et al. The role of systemic chemotherapy and multidisciplinary management in
improving the overall survival of patients with metastatic squamous cell carcinoma of the anal canal.
Oncotarget. 2014; 5(22): 11133-42.
208 Faivre C, Rougier P, Ducreux M et al. 5-fluorouracile and cisplatinum combination chemotherapy for
metastatic squamous-cell anal cancer. Bull Cancer. 1999; 86(10): 861-5.
209 Sodergren SC, Vassiliou V, Dennis K et al. Systematic review of the quality of life issues associated with anal
cancer and its treatment with radiochemotherapy. Support Care Cancer. 2015; 23: 3613-23.
210 American Cancer Society. A guide to radiation therapy.
http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/radiation/understandingradiat
iontherapyaguideforpatientsandfamilies/understanding-radiation-therapy-common-side-effects (accessed
2016 September 21).
211 Bentzen AG, Balteskard L, Wanderas EH et al. Impaired health-related quality of life after chemoradiotherapy
for anal cancer: Late effects in a national cohort of 128 survivors. Acta Oncol. 2013; 52(4): 736-44.
212 Knowles G, Haigh R, McLean C et al. Late effects and quality of life after chemo-radiation for the treatment of
anal cancer. Eur J Oncol Nurs. 2015; 19: 479-85.
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LOWER GASTROINTESTINAL AND PANCREATIC CANCERS

Courtney C. Cavalieri, Pharm.D., BCOP

A. Genetic alterations 1-3

1. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch Syndrome

a. Accounts for 2-4% of all colorectal cancers

b. Not characterized by excessive polyps

1) Patients’ lifetime risk of colon cancer up to 80%

2) Women have up to 60% risk of endometrial cancer

d. Onset of colon cancer occurs around 43 years of age

2. Familial adenomatous polyposis (FAP)

a. Accounts for about 1% of all colorectal cancers

d. If left untreated, 100% will progress to colorectal cancer by early 40’s

3. Other genetic entities include Muir-Torre, Turcot, Gardner, Cowden, Bannayan-Riley-Ruvalcaba,

B. Defective DNA mismatch repair (dMMR)2

a. Approximately 3.5-6.5% of stage IV colorectal tumors are dMMR/MSI-H2

d. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend

1. Dihydropyridine dehydrogenase (DPD) deficiency and 5-FU10-12

a. 5-FU is metabolized by 2 routes

2) 80% catabolic (mainly occurs in liver)

2) High concentration of DPD = decreased 5-FU activity

5) Currently, there is no universally used test for DPD deficiency

6) The Clinical Pharmacogenetics Implementation Consortium (CPIC®) provides dose

i. DPYD normal metabolizer: an individual carrying 2 normal function alleles

ii. No dose modifications recommended

b) Activity Score 1 or 1.5

i. DPYD intermediate metabolizer: an individual carrying 1 normal function allele and

ii. Reduce starting dose by 25-50%

c) Activity Score 0 or 0.5

i. DPYD poor metabolizer: an individual carrying 2 no function alleles, or 1 no function

2. Uridine diphosphate glycosyltransferase 1 family polypeptide A1 (UGT1A1) and irinotecan13, 14

a. Metabolism and pharmacokinetics of irinotecan

1) Irinotecan has a dipiperidino side-chain linked to the captothecin base molecule

a) SN-38 is about 1000-fold more potent inhibitor of topoisomerase I than irinotecan

b. Reduced activity of UGT1A1 can lead to significant toxicities15

1) Patients with a UGT1A1*28 polymorphism, especially a homozygous mutation, are at much

2) Approximately 10% of US population is homozygous for UGT1A1*28 allele

2. RAS (KRAS, NRAS, and HRAS)

a. RAS mutations predict lack of response to anti-EGFR MABs

d. ASCO Guideline on Molecular Biomarkers for the Evaluation of Colorectal Cancer21

a) KRAS and NRAS

i. Exon 2, codons 12 and 13

ii. Exon 3, codons 59 and 61

iii. Exon 4, codons 117, and 146

b. RAS and BRAF mutations are typically mutually exclusive at diagnosis

2) ASCO recommends BRAF mutational analysis be performed for prognostic stratification21

II. Prevention and screening

2) Women’s Health Initiative

a) 18,176 participants randomly assigned to receive supplemental calcium and vitamin D,

4) Selenium supplementation has shown mixed results in observational studies

a. Cyclooxygenase COX-2 expression is enhanced in up to 90% of colorectal carcinomas

2) U.S. Preventive Services Task Force (USPSTF) recommendations on initiating aspirin31

c) There is currently insufficient evidence to make a recommendation for adults younger

3) Chemoprevention in familial adenomatous polyposis (FAP)30

a) Cyclooxygenase-2 (COX-2) inhibition32

i. Primary objective: to determine whether inhibition of COX-2 reduces the extent of

c) Currently, there are no FDA-approved medications for chemoprevention of colorectal

FIT-DNA test every 1 or 3 years#

≥1 second-degree relative age <50: initiate at