Adult Sarcomas: Learning Objectives

ADULT SARCOMAS
Janelle Mann, Pharm.D., BCOP

Manager of Clinical Pharmacy Services / Clinical Oncology Pharmacist
Alvin J. Siteman Cancer Center / Washington University School of Medicine
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, management, and monitoring plan taking into
consideration efficacy and safety outcomes from clinical trials and current treatment guidelines
for adult patients with sarcoma.
2. Adjust treatment and monitoring plans as needed based on the tumor genetics and
pharmacokinetics of anticancer and supportive-care agents (e.g., methotrexate).
3. Develop an appropriate plan for preventing, monitoring, and managing common problems
associated with the treatment of adult patients with cancer, including neurotoxicity from
ifosfamide and hemorrhagic cystitis.
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
SOFT TISSUE SARCOMAS (STS)
Patient Case #1:

W.H. is a 55-year-old man who presented with a gnawing pain in his right forearm. He can feel a
“knot,” that he claims has grown over the past several months. Core needle biopsy reveals a high
grade, 5 cm synovial sarcoma. Unfortunately, surgery was incomplete with positive margins. W.H.
undergoes adjuvant radiation therapy (RT), and the multidisciplinary team recommends
chemotherapy and has asked you to counsel WH.
Which of the following statements regarding the role of post-operative chemotherapy should be
included in your discussion?
A. Post-operative chemotherapy improves survival.
B. Post-operative chemotherapy decreases risk for relapse.
C. Post-operative chemotherapy increases risk of distant recurrence.
D. Post-operative chemotherapy improves survival and decreases risk for local recurrence.
Which chemotherapeutic agent(s) should be part of WH’s adjuvant regimen?

A. Gemcitabine
B. Pazopanib
C. Ifosfamide and doxorubicin
D. Ifosfamide and dacarbazine
I. Etiology and Pathogenesis
A. The etiology of STS is largely undetermined; however, factors such as genetic predisposition,
infectious diseases, occupational chemicals, and radiation therapy are associated with the
development of disease.1
1. Prior radiation therapy to the affected area is a risk factor for STS.2
2. Genetic Predisposition to STS
Selected Genetic Predisposition to STS3-5

Genetic Predisposition to STS Associated STS Subtype(s)
17q11.2 (NF-1 gene) – neurofibromatosis type I Malignant peripheral nerve sheath tumor, GIST and
rhabdomyosarcoma
13q14.2 (Rb-1 gene) – retinoblastoma Leiomyosarcoma, rhabdomyosarcoma

17p13.1 (TP53 gene) – Li Fraumeni syndrome Rhabdomyosarcoma (usually pediatric), fibrosarcoma,
Undifferentiated pleomorphic sarcoma
5q21 (APC gene) – Gardner’s syndrome Desmoid tumors
3. Cytogenetic aberrations associated with STS include those listed in the table below:
Selected Cytogenetic Aberrations Associated with STS3, 6, 7

Cytogenetic Aberrations Associated with STS
Cytogenetic aberration; gene – associated STS
t(12;16)(q13;p11);TLS-CHOP fusion gene – myxoid or round cell liposarcomas
t(X;18)(p11;q11); SS18-SSX1/SSX2 fusion – synovial sarcoma
t(12;22)(q13;q12); EWSR1-ATF1 – clear cell sarcoma
t(11;22)(p13;q12); EWSR1-WT1 – desmoplastic small round cell tumor
Multiple complex karyotypes – Malignant fibrous histiocytoma (MFH)/undifferentiated pleomorphic sarcoma 8
t(2,13)(q35;q14); PAX3-FKHR and PAX7-FKHR – alveolar rhabdomyosarcoma
B. Biopsy for STS
1. Specific subtype STS diagnosis and grade of disease is important to dictate treatment.
Determination of histologic grade evaluates tumor cell differentiation, mitotic activity, and
extent of necrosis using the French Federation of Cancer Centers Sarcoma Group (FNCLCC) or
AJCC/National Cancer Institute (NCI) system. If sarcoma is suspected, the biopsy should be
performed by an experienced surgeon (or interventional radiologist) in order to prevent tumor
rupture or tumor tracking through the biopsy track.4
C. Pathologic subtypes:
1. Heterogeneous group of tumors arising from mesenchymal cell origin
2. Sarcoma accounts for approximately 1% of adult malignant solid tumors and > 20% of pediatric
solid malignant tumors.2
3. The three most common subtypes are undifferentiated pleomorphic sarcoma, liposarcoma, and
leiomyosarcoma
Incidence of Soft Tissue Sarcoma Subtypes (1978-2001) 9, 10

Histologic Subtype %
Leiomyosarcoma (LMS) 23.9
Undifferentiated pleomorphic sarcoma 8 17.1
Sarcoma, not otherwise specified (NOS) 12.8
Liposarcoma 11.5
Dermatofibrosarcoma 10.5
Rhabdomyosarcoma 4.6
Angiosarcoma 4.1
II. Treatment
A. Surgery – surgical resection is the cornerstone of therapy for STS management. Treatment goals are
to achieve cure, avoid local recurrence, maximize function and minimize morbidity. Classic approach
is to achieve a 2 cm margin in all directions surrounding the tumor. With this approach alone, local
recurrence rates can be as high as 30-50%.11 Failure to achieve adequate margins may account for a
higher local recurrence rate. 12
1. Limb-sparing surgery (+ radiation) vs. amputation – higher local recurrence rate in the limb-
sparing surgery arm but no difference in overall survival. Most common type of surgery offered.
2. Amputation – reserved for tumors unable to be resected by any other surgical approach and
without metastatic disease; 95% of patients are able to have limb-sparing surgery.
3. Radical excision – not precisely defined term although the use of a 5 cm wide margin is
commonly used if feasible; decreases local recurrence to 25 - 30%. Radical excision is not
routinely necessary.
4. Anatomic compartment excision – local recurrence rate of 10 to 20%. Compartment excision is

not routinely necessary.
B. Radiation Therapy (RT) (See Table: Special Cases Where Radiation Should Be Considered) – can be
used as primary therapy, preoperative or post-operative treatment. Most commonly combined with
surgery to decrease the need for a radical excision to maintain functionality and decrease cosmetic
deformity or as an alternative to amputation. Typically, tumors have a slow rate of regression
following radiation therapy. Notable toxicities include: bone tissue damage/fracture, edema, fibrosis,
functional impairment, and impaired wound healing.13
1. Newer RT techniques such as brachytherapy, intraoperative RT and intensity-modulated RT

(IMRT) have improved outcomes over traditional external beam RT.
2. 2018 meta-analysis of 3958 patients evaluated the effects of external beam RT compared to no
radiation in both the preoperative and postoperative setting for STS.14
a. External beam RT reduced local recurrence and improved overall survival for
retroperitoneal STS
b. External beam RT reduced local recurrence for STS of extremity, head and neck or truck
wall (OR 0.49; p = 0.002)
c. Local recurrence rates were lower with preoperative RT than postoperative RT for
retroperitoneal STS (OR 0.03; p=0.02)
3. In a comparison of pre- and postoperative external beam radiation in STS of the limbs,
preoperative radiation had a small survival advantage (log rank p=0.0481), but significantly more
wound complications (35% preoperative vs. 17% postoperative, 95% CI 5-30, p=0.01)15
4. A retrospective review evaluated patients receiving preoperative RT compared to preoperative

RT with a postoperative boost and showed no difference in rates of local recurrence, distant
metastasis or death indicating that a post-operative RT boost is not necessary.16
Special Cases Where Radiation Should Be Considered3
Clinical Scenario Therapy
Positive margins of resection or close Brachytherapy and external beam radiotherapy have
resection margins (less than 1 cm) been utilized and case series data suggest benefit with
radiotherapy following surgery compared to surgery
alone.17
Small soft tissue sarcomas Excisions with negative margins do not appear to
benefit from adjuvant radiation therapy; positive
margins may benefit from adjuvant radiation; studies
are inadequate to answer the question definitively.
Soft tissue sarcomas of the hands and The complexity of the surgery in the distal extremities
feet makes wide excision difficult. More conservative
surgery with adjuvant radiation is standard of practice.
Definitive radiation Reserved for patients where surgical resection is not an
option. Local control and survival decreases with
increasing tumor size.
C. Chemotherapy
1. Soft tissue sarcoma comprises greater than 70 histologies. Given the greater number of
histologies for this tumor type one should consider the heterogeneity of the data shared to
support the below chemotherapy options and the impact on results for all patients, especially
those with less common histologies.
2. Preoperative therapy – Rationale for administering is to decrease tumor size prior to surgery
allowing for less extensive surgery, treating micrometastatic disease earlier in disease course
prior to development of drug resistance, administering chemotherapy prior to surgery-induced
damage to the local vasculature surrounding the tumor site and discerning pathologic tumor
response to chemotherapy following resection.
a. Data published consists mainly of single institution retrospective case series with
inconsistent results.18
b. Only one randomized prospective trial in which 150 patients with potentially resectable STS
were randomized to definitive local treatment alone versus preoperative chemotherapy with
doxorubicin and ifosfamide followed by definitive local treatment.
1) Median follow-up was 7.3 years.
2) Estimated 5-year disease-free survival (DFS) was 52% for the no chemotherapy arm and
56% for the chemotherapy arm (p = 0.3548) with a corresponding 5-year overall survival
was 64% and 65% (p=0.2204).18
c. International, open-label, randomized, phase 3 trial with STS of extremities or trunk wall
comparing standard chemotherapy vs. histotype-tailored chemotherapy in the preoperative,
neoadjuvant setting19
1) 287 patients randomized to standard chemotherapy of 3 cycles of epirubicin +

ifosfamide OR histotype-tailored chemotherapy as below prior to definitive therapy
a) Myxoid liposarcoma: trabectedin
b) Leiomyosarcoma: gemcitabine + dacarbazine
c) Synovial sarcoma: ifosfamide
d) Malignant peripheral nerve sheath tumors: etoposide + ifosfamide
e) Undifferentiated pleomorphic sarcoma: gemcitabine + docetaxel
2) Median follow-up of 12.3 months, projected disease-free survival at 46 months was 62%
in standard chemotherapy arm and 38% in histotype-tailored chemotherapy group (HR
2; p=0.004)
3) Study was closed to recruitment in advance for futility, but potential signal that
traditional chemotherapy could have a role in the pre-operative setting.
d. It is unclear which patients will benefit most from preoperative chemotherapy alone.
Outside of a clinical trial, preoperative therapy is reserved for highly selected patients with
the goal of avoiding more aggressive surgery or amputation.
3. Postoperative therapy – The role of adjuvant chemotherapy in STS has been explored by a
number of randomized trials since the late 1970’s. These studies varied in size from less than 50
patients to the largest single trial with 468 patients, with most enrolling less than 100 patients.
Most of these trials found equivocal results.
a. Meta-analyses were conducted and published to examine the pooled data.
1) In 1997, the Sarcoma Meta-Analysis Collaboration (SMAC) of Britain conducted a meta-

analysis of trials conducted assessing adjuvant therapy for localized, resectable STS by
collecting individual patient data and performing an intention-to-treat analysis.
a) Findings from 14 randomized trials (N=1568 patients) of doxorubicin-containing

chemotherapy regimens with a median follow-up of 9.4 years concluded that
adjuvant therapy significantly improved local and distant recurrence-free survival,
and overall recurrence-free survival.
b) There was a trend towards adjuvant chemotherapy improving overall survival,

although it was not statistically significant (HR of 0.89 (0.76-1.03), p = 0.12).20
2) In 2008, an updated meta-analysis included four additional trials (N=1953).
a) The odds ratios (OR) for local recurrence was 0.73 (95% CI 0.56-0.94; P = 0.02) in
favor of chemotherapy.
b) For distant and overall recurrence, the OR was 0.67 (95% CI 0.56-0.82; P = 0.0001)
in favor of chemotherapy.
c) In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68-1.03; P =

0.09), which was not statistically significant. However, the OR for survival with
doxorubicin combined with ifosfamide was 0.56 (95% CI, 0.36-0.85; P = 0.01) in
favor of chemotherapy. This resulted in an absolute risk reduction in death of 11%
with adjuvant doxorubicin and ifosfamide (95% CI, 3%-19%; p=0.01).21
b. Summary: There is no “proven” role for postoperative chemotherapy for adult soft tissue
sarcoma due to conflicting data regarding an overall survival benefit. However, it appears
that doxorubicin and ifosfamide combination may have the most activity. Toxicity and
individual patient factors such as tumor subtype, location and grade, as well as patient age
and performance status should be considered.
Patient Case #1, continued:

Question 1:
Answer: B. WH can expect an improvement in relapse free survival but not overall survival by initiating
chemotherapy after surgery and radiation therapy for his synovial sarcoma.
Question 2:
Answer: C. WH should receive an adjuvant chemotherapy regimen that contains doxorubicin. Additional
active chemotherapeutic agents include ifosfamide and dacarbazine, but the most common combination
utilized in synovial sarcoma is doxorubicin and ifosfamide. Targeted agents do not have a role yet in the
adjuvant setting.
4. Metastatic Disease – at initial diagnosis < 10% of patients with STS will have metastatic disease.22
However, approximately half of patients will relapse with their disease at a distant site, and many
patients will require systemic therapy for palliation.
a. Surgical excision and radiotherapy may benefit select patients to extend DFS.
b. STS is poorly responsive to cytotoxic chemotherapy, in general. However, certain histological

subtypes have higher response rates to chemotherapy (See Table: Histology Driven
Chemotherapy).
1) Doxorubicin has long been considered a drug of choice because of its slightly superior
single agent activity relative to other agents (RR – 20%).
2) Other commonly used drugs include:
a) Ifosfamide (RR - 15 to 20%)
b) Dacarbazine (RR - 15 to 20%)
c) Epirubicin (RR – 15%)
d) Gemcitabine (RR – 7%)
e) Temozolomide (RR – 8%)
f) Cyclophosphamide (RR – 10%)
g) Vinorelbine (RR – 6%)
h) Dactinomycin (RR – 15%)
Histology Driven Chemotherapy*23-25
Histological Subtype Chemotherapeutic Agent(s) Response Rate (%)

Uterine leiomyosarcoma26 Gemcitabine and docetaxel 35.8
Myxoid liposarcomas26 Doxorubicin 48
Doxorubicin and dacarbazine 44
Pleomorphic liposarcomas26 Doxorubicin 33
Dedifferentiated Doxorubicin 25
liposarcomas26
Angiosarcoma27 Doxorubicin 33
Paclitaxel 31
Doxorubicin liposomal 33
Synovial sarcoma26 Doxorubicin and ifosfamide 58
*small studies, most retrospective analyses
c. Single agent therapy compared to combination chemotherapy
1) Comparative trials have demonstrated an increase in response rate with multiagent

regimens. Most combination regimens have not shown an improvement in overall
survival; however, the combination of gemcitabine and docetaxel versus gemcitabine
alone improved both PFS (6.2 vs 3 months) and OS (17.9 vs 11.5 months) in a Phase II
study.28
2) Outcomes with chemotherapy have been evaluated in over 2,000 patients in a meta-
analysis. The overall median survival was approximately one year. Factors predicting a
favorable response include performance status, lack of hepatic involvement, low-grade
histology, long DFS from diagnosis, and age.29
3) A phase III trial of 228 patients compared doxorubicin (75 mg/m2 bolus or 72-hour
continuous infusion) to doxorubicin (75 mg/m2 or 25 mg/m2 Days 1-3) intensified with
ifosfamide (10 gm/m2 over 4 days with mesna and pegfilgrastim).30
a) There was no difference in OS. Median overall survival was 12.8 months [95.5% CI
10.5–14.3] in the doxorubicin group vs 14.3 months [12.5–16.5] in the doxorubicin
and ifosfamide group; hazard ratio [HR] 0.83 [95.5% CI 0.67–1.03]; stratified log
rank test (p=0.076).
b) Median PFS was significantly higher for the doxorubicin and ifosfamide group (7.4
months [95% CI 6.6–8.3]) than for the doxorubicin group (4.6 months [2.9–5.6]; HR
0.74 [95% CI 0.60–0.90], stratified log-rank test p=0.003).
c) More patients in the doxorubicin and ifosfamide group than in the doxorubicin
group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228;
p<0.0006).
d) There was more toxicity in the ifosfamide/doxorubicin arm.
e) Authors concluded intensified doxorubicin and ifosfamide for palliation in the

advanced STS is not supported unless the specific goal is tumor shrinkage.
4) The GeDDIS phase III trial randomized 257 patients with advanced or metastatic soft
tissue sarcoma to either doxorubicin (75 mg/m2) day 1 every 3 weeks as monotherapy
or gemcitabine (675 mg/m2) day 1 and 8 + docetaxel (75 mg/m2) day 8 every 3 weeks.31
a) Primary endpoint was the proportion of patients alive and progression-free at 24
weeks after the date of randomization.
i. Doxorubicin 46.3% vs. gemcitabine/docetaxel 46.4%
b) Median progression-free survival was not statistically different between the groups
(23.3 weeks vs. 23.7 weeks; HR 1.28; p = 0.06)
c) Overall survival did not differ between groups.
d) Side effect profiles were similar between the regimens.
e) Doxorubicin remains a viable option as a single agent for the treatment of advanced
or metastatic soft tissue sarcoma.
5. Selected Regimens
Selected Chemotherapy Regimens for STS4
Place in Cycle Response Rate

Regimen
treatment Duration (%)
Doxorubicin 75 mg/m2 IV day 132 Non-surgical 21 days 10 – 25 (most
or Metastatic PR)
Pegylated liposomal doxorubicin (PLD) 50 mg/m2 IV day 133 Non-surgical 28 days 10
or Metastatic
Epirubicin 75 mg/m2 IV day 134 Post- 21 days 18
operative
Ifosfamide 1800 mg/m2/IV days 1-535, 36 Post- 21 days 19
operative,
non-surgical
or metastatic
Doxorubicin 25 mg/m2 IV continuous infusion day 1-3 (total Pre- 21 days 26
75 mg/m ) 2
operative,
Ifosfamide 2500 mg/m2 IV over 3 hours daily, days 1-4 non-surgical
Mesna 500 mg/m2 over 15 minutes before the ifosfamide, or metastatic
then at 4 and 8 hours from the start of each ifosfamide
dose on days 1-4 (also known as AI or AIM)30
Mesna 2500 mg/m2 IV continuous infusion days 1 – 4 Non-surgical 21 days 37
Doxorubicin 20 mg/m IV continuous infusion days 1 – 3
2
or metastatic
Ifosfamide 2500 mg/m2 IV continuous infusion days 1 – 3
Dacarbazine 300 mg/m2 IV continuous infusion days 1 – 3
(also known as MAID)37
Gemcitabine 675 - 900 mg/m2 IV over 90 min on days 1, 8 Non-surgical
21 days 53 (LMS)
Docetaxel 100 mg/m IV over 60 minutes on day 8
2 28, 38
or metastatic
Gemcitabine 800 mg/m2 IV over 90 min on days 1,8 Non-surgical 21 days
25 (clinical
Vinorelbine 25 mg/m IV on days 1,8
2 39
or metastatic
benefit)*
(Schedule could be modified to Days 1 and 15 for toxicity) 28 days
Gemcitabine 1800 mg/m2 at infusion rate of 10 mg/m2/min 2nd line
14 days 49
followed by Dacarbazine 500 mg/m2 Day 1 40
Eribulin 1.4 mg/m2 IV push on day 1 and 8 (Liposarcoma)41 2nd line 21 days 46
Trabectedin 1.5 mg/m as a 24-hour infusion (Liposarcoma,
2
2 line
nd
21 days 9.9
Leiomyosarcoma)42
* Clinical Benefit was defined either as objective response or RECIST-defined stable disease for a
minimum of 4 months
6. Pegylated liposomal doxorubicin versus conventional doxorubicin33

a. Randomized phase II compared pegylated liposomal doxorubicin (PLD) 50 mg/m2 IV every 28
days to doxorubicin 75 mg/m2 IV Q21 days showed no difference in response rate (10% PLD
vs 9% doxorubicin), but differences in tolerability.
a) Myelosuppression – grade 3/4 neutropenia: PLD 6%, doxorubicin 77%
b) Palmar-plantar erythrodysesthesia – PLD 50% vs doxorubicin 0%; PLD grade 3/4
20%
c) Additional considerations: PLD showed less cardiotoxicity, alopecia, and

requirements for aggressive antiemetics compared to doxorubicin
7. Fixed Dose Rate Gemcitabine43
a) Gemcitabine infused over 10 mg/m2/min
b) Theory: Prolonging the infusion rate increased the amount of active triphosphate
metabolite which would then increase efficacy
c) Increased efficacy has not been proven, but this is the way gemcitabine was
administered in the regimens above and, therefore, how it is still commonly
administered in clinical practice.
8. Eribulin41
a. Approved for unresectable, metastatic liposarcoma
1) Randomized, phase III, open-label in advanced or metastatic liposarcoma or

leiomyosarcoma refractory to a least 2 other regimens (including an anthracycline)
a) Eribulin 1.4 mg/m2 IV on day 1 and 8 q3 weeks (n = 228) vs. Dacarbazine 850-1200
mg/m2 IV on Day 1 q3 weeks (n = 224)
2) Primary end-point: overall survival
a) 13.5 months vs. 11.5 months (HR 0.77; CI 0.62 – 0.95; p=0.0169)
i. Results driven by liposarcoma results: FDA only approved in liposarcoma
ii. Liposarcoma: 15.6 months vs 8.4 months (HR 0.51; 95 % CI 0.346 – 0.753)
iii. Leiomyosarcoma: 12.7 months vs 13 months (HR 0.927; 95 % CI 0.714 – 1.203)
9. Trabectedin42
a. Phase III, randomized, open-label in advanced or metastatic liposarcoma or

leiomyosarcoma after at least 2 systemic therapy (including an anthracycline)
1) Trabectedin 1.5 mg/m2 IV over 24 hours q3 weeks (n = 345) vs. dacarbazine 1000 mg/m2
IV over 20-120 min q3 weeks (n =173)
b. Primary end-point: Overall survival
1) The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of

death in the trabectedin arm compared with dacarbazine (median OS for trabectedin vs
dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; p = 0.37)
c. Median Progression Free Survival

1) 4.2 months trabectedin vs. 1.5 months dacarbazine; HR, 0.55; P<0.001
d. Conclusions: Although the interim analysis of OS did not show a statistically significant
improvement in overall survival, trabectedin did demonstrate a significant improvement in
progression-free survival. The authors proposed that a difference in overall survival was not
shown due to the use of effective subsequent therapies.
D. Targeted Therapy
1. Olaratumab + Doxorubicin44
a. Based on the phase II results, the FDA granted accelerated approval of olaratumab in
combination with doxorubicin with the requirement to complete a phase III larger study to
confirm the clinical benefit. January 24th, 2019, the FDA received results from the
ANNOUNCE phase III clinical trial. This trial did not confirm the clinical benefit of
olaratumab and did not meet the primary endpoint of improvement in overall survival.
The FDA recommends that patients who are currently receiving olaratumab should consult
with their physician about whether to remain on treatment and olaratumab should not be
initiated in new patients outside of a clinical study. NCCN Guidelines® have been updated to
reflect the removal of olaratumab.4, 45
2. Pazopanib – Approved by FDA for the treatment of patients with advanced STS (not liposarcoma)
who have received prior chemotherapy. Pazopanib, a multitargeted tyrosine kinase inhibitor,
seems particularly beneficial in leiomyosarcoma.
a. Phase III, randomized, multi-center, double-blind placebo-controlled (PALETTE study) trial.

Evaluated activity of pazopanib in patients with non-adipocytic soft-tissue sarcoma after
failure of standard chemotherapy (containing anthracycline).
1) Patients received pazopanib 800 mg daily or placebo with no subsequent cross-over.

Total 369 (246 vs. 123) patients were randomized and majority had high grade STS.46
2) Primary end-point of median progression free survival was significantly longer with
pazopanib at 4.6 months compared with 1.6 months with placebo.
3) Best overall response was 6% with pazopanib and 0% with placebo (HR 0.31, p <
0.0001).
4) Significant improvement in progression free survival did not result in significant

improvement in median overall survival (12.5 vs. 10.7 months, HR 0.86, p=0.25).
E. Unique subtypes of STS
Patient Case 2:
MR is a 48-year-old man who undergoes successful resection of his 6 cm gastric gastrointestinal stromal
tumor. Pathology indicates that the tumor is cKIT positive and 7 mitoses per 50 high power field. What is the
best treatment for MR?
A. Imatinib for 1 year
B. Imatinib for 3 years
C. Sunitinib for 1 year
D. Sunitinib for 3 years
1. Gastrointestinal stromal tumors (GIST)47
a. Most common STS of the gastrointestinal tract resulting from KIT or PDGFRA activating
mutations.48
1) 60% stomach
2) 30% small intestine
3) 4-5% duodenum
4) 4% rectum
b. Expression of the KIT (or CD117) tyrosine kinase encoded by the c-kit gene is activated in
about 85% to 90% GIST. KIT is inhibited by tyrosine kinases such as imatinib, sunitinib and
regorafenib.
1) Approximately 80% of GIST will have a mutation within KIT
a) KIT exon 11 mutations: most common presentation of GIST
b) KIT exon 9 mutations: more common presentation for intestinal GIST
c. PDGFRA mutations have been identified in about 5-10% of patients with GIST with the
majority having a genetic mutation in exon 18.
1) Most common presentation of PGDFRA exon 18 mutations occur in gastric GISTs.
d. Only 10-15% of GIST tumors do not have any detectable mutations either within KIT or
PDGFRA, but still mostly express KIT (wild-type GIST)
e. GIST tumors are poorly responsive to cytotoxic chemotherapy and radiation therapy. If
resectable, surgery is the primary treatment.
f. Prognostic factors4, 48
1) Tumor size
2) Location
3) Mitotic rate (defined as number of mitoses per 50 High Power Field (HPF))
4) KIT mutational status is not used to determine the malignant potential of a primary
GIST, but can be used as a predictive response to TKI therapy. For example, patients
with wild type GIST do not respond well to TKI therapy.
Risk of metastasis for GIST48

Risk of Metastasis Location of GIST, Size, and Mitotic Rate
Low risk for metastasis • Gastric GIST ≤ 10 cm and ≤ 5 mitoses per 50 HPFs
• Intestinal GIST ≤ 5 cm and ≤ 5 mitosis per 50

HPFs
Moderate risk for metastasis • Intestinal GIST > 5 cm independent of mitotic

rate (can fall into high if > 5 mitoses per 50 HPFs)
High risk for metastasis • Gastric GIST > 5 cm and > 5 mitosis per 50 HPFs
• Intestinal GIST independent of size with > 5

mitoses per 50 HPFs
g. Prior to initiation of therapy, all patients should be evaluated and managed by a multi-
disciplinary team with experience and expertise in sarcoma.
h. Pre-operative imatinib
1) Several small studies have incorporated pre-operative imatinib prior to surgery and then
continuing post operatively. These studies have demonstrated the safety and efficacy in
the pre-operative setting, but because all patients received post-operative imatinib, a
survival benefit could not be shown.49-51
2) There is not a definitive role for the use of pre-operative imatinib at this time.
i. Post-operative imatinib
1) Complete resection is only possible in about 85% of patients with at least 50% of those
patients developing recurrence or metastatic disease. This is associated with a 5-year
survival of 50%.
2) A Phase III, randomized, double-blind, placebo-controlled trial evaluated efficacy of

imatinib 400 mg daily in 713 patients with complete resection of a primary GIST at least
3 cm in size and positive for KIT.
a) Imatinib or placebo was given for 1 year after surgery.
b) Recurrence free survival of 98% for patients on imatinib compared with 83% for
patients on placebo (p <0.0001).52
3) A phase III trial conducted by Scandinavian Sarcoma Group and Sarcoma Group of the
AIO suggested that outcome could be further improved with longer adjuvant imatinib
therapy.
a) 400 patients with high risk for recurrence were randomized to receive either
imatinib for 1 year or 3 years following resection of the tumor.
b) Median follow-up of 90 months, better 5-year recurrence free survival for patients
on 3-year adjuvant imatinib (71.1% vs. 52.3%; HR = 0.6; P < 0.001).
c) Five year overall survival was significantly longer at 93.4% with 3-year vs. 86.8% 1-
year adjuvant therapy (HR, 0.53; p = .024)
d) Higher rate of discontinuation in 3-year arm (13.6% vs. 7.7%).53, 54
e) This study established adjuvant imatinib for 36 months as the standard of care for
patients who are high risk of relapse.
j. Metastatic
1) First-line therapy: The results of the two major trials completed to date are summarized
below
Summary of Demetri and Verweij Articles52, 55
Number of Median Follow-

Author Imatinib Dose Response
patients up
Demetri 400 mg 73 9 months PR 49%; SD 32%
600 mg 74 PR 58%; SD 24%
Verweij 400 mg 473 24 months CR 5%; PR 45%; SD 32%
800 mg 473 CR 6%; PR 48%; SD 32%
2) Imatinib response based on KIT mutation
a) A study investigated relationship between kinase genotype and treatment outcome
in 428 patients with advanced GIST in phase III trial of 400 mg or 800 mg daily of
imatinib.56
i. This study suggested favorable outcome in patients with KIT exon 11 mutations
compared with patients with KIT exon 9 mutation or wild-type for KIT
mutations.
ii. In addition to better response rate and time to tumor progression, patients
with exon 11 mutation had 60 months overall survival compared with 38 and
49 months survival for exon 9 mutation and wild-type respectively.
iii. Patients with exon 9 mutation had better response rate with 800 mg compared
with 400 mg dose (67% vs. 17%, P = 0.02).56
b) Patients should be initiated on imatinib 400 mg daily, and monitored for toxicity.
c) Patients that have progressed on imatinib 400 mg daily or those with a KIT exon 9
mutation and ability to tolerate the agent may be increased to a maximum of
imatinib 400 mg twice daily.4
3) Imatinib response based on PDGFRA mutation
a) International survey of 58 patients with PDGFRA-mutated GIST treated with

imatinib57
i. 69% gastric site of tumor
ii. 55% PDGFRA-D842V substitutions (within exon 18)
iii. 29% mutations affecting other areas of exon 18
iv. 16% mutations outside of exon 18
v. Median PFS 2.8 months with D824V substitution vs. 28.5 months with other
PDGFRA mutations (95% CI 5.4-51.6; p = 0.0001)
vi. Median OS 14.7 months with D824V mutation vs. not reached for other
mutations
vii. Most PDGFRA exon 18 mutated GISTs will respond to imatinib with the
exception of the D842V substitution that does not respond.
4) Metastatic Second-line therapy:
a) Primary resistance to imatinib can develop in 20% of patients.
b) Sunitinib is a receptor tyrosine kinase inhibitor exhibiting antitumor and

antiangiogenic activity.
i. Sunitinib inhibits the signaling pathways of vascular endothelial growth factor
isoforms VEGF-1, VEGF-2, and VEGF-3, platelet derived growth factor receptors
α and β, c-Kit and Flt-3.
ii. A Phase III trial randomized patients with GIST that had failed initial treatment
with imatinib to sunitinib 50 mg PO daily x 4 weeks with 2 weeks off or placebo.
The primary endpoint was time to tumor progression (See Table: Second-Line
Therapy). FDA approval was granted in 2006.58
Second-Line Therapy58
Sunitinib Placebo
N 207 105
Time to progression (TTP) 6.3 months 1.5 months
Partial Response (PR) 8% 0%

Stable Disease (SD) 58% 50%
Progressive Disease (PD) 20% 39%
5) Metastatic Third-line therapy:
a) Regorafenib: a multi-tyrosine kinase inhibitor (RET, VEFGR, KIT, PDGF, FGFR, TIE,
DDR, RAF, BRAF, and others) was evaluated in GRID Trial, phase III, randomized trial
for patients with treatment-refractory metastatic GIST. All patients had received
prior imatinib and sunitinib.59
i. Patients were randomized to receive regorafenib 160 mg daily for 3 weeks,

then 1 week off every 4 weeks or placebo.
ii. In 199 evaluable patients regorafenib improved the median progression free
survival to 4.8 months from 0.9 month in placebo (HR 0.27, p < 0.0001).
iii. 85% of patients on placebo crossed over to regorafenib upon progression.

Answer: B. MR should be treated with adjuvant imatinib for a total of 3 years as he is at high-risk for
recurrence due to the size of his gastric tumor and the mitosis rate being ≥ 5 mitoses per 50 HPF. He is
also cKIT positive. 3 years of therapy with imatinib improved overall survival when compared to 1 year
of therapy.
Patient Case #3:

PL is a 63-year-old male with synovial sarcoma who is scheduled to start therapy with ifosfamide 1500
mg/m2/day on days 1-4 and doxorubicin 20 mg/m2/day on days 1-3. What supportive care is required
for PL’s chemotherapy?
1. Mesna only
2. Mesna and hydration with sodium bicarbonate
3. Mesna and hydration with normal saline
4. Hydration with sodium bicarbonate
III. Caveats of Ifosfamide Therapy60, 61
A. Toxicities of Ifosfamide
1. Dose-limiting hemorrhagic cystitis due to the formation of metabolite acrolein
a. Mesna and hydration are required therapies for prevention
1) Must use with mesna (sodium 2-mercaptoethanesulfonate) to prevent hemorrhagic
cystitis.
2) Intravenous mesna can be dosed by the following schema:
a) 20% of ifosfamide dose immediately before and then 20% at 4 hours and 20% at 8
hours after IV boluses of ifosfamide.
b) When ifosfamide is given as a continuous infusion the mesna is usually given

concurrently (in the same bag in some institutions).
c) The dose varies and ranges from the 60% of the ifosfamide dose (as with the bolus
infusions) up to 100%. Different schedules (including oral mesna administration)
exist.
d) Patients that vomit within 2 hours of taking oral mesna should repeat the dose or
receive intravenous mesna60
e) Oral mesna is 50% bioavailable, so the oral dose is twice the intravenous dose.
f) Can utilize the IV solution orally and dilute in cola to mask smell.
3) The efficacy of mesna for urothelial protecting with doses of ifosfamide > 2.5g/m2/day
has not been established.60
4) Vigorous hydration with 1.5 - 2 liters of NS pre- and post-hydration. Encourage patient
to increase oral fluid intake to 2-3 liters of fluid per day. Encourage frequent bladder
emptying while awake, and first thing in the morning.
5) IV fluids such as D5W are not appropriate as the fluid does not stay in the intravascular
space and does not promote urinary excretion of acrolein.
6) Historically fluids with sodium bicarbonate were utilized in conjunction with ifosfamide,
but it hasn’t been shown to be more effective than normal saline alone for prevention.
7) Patients who develop ifosfamide-induced renal tubular acidosis may be managed with
either sodium bicarbonate or sodium acetate-based fluids.
2. Encephalopathy/Neurotoxicity
a. Presents as confusion, somnolence, hallucinations, myoclonus, coma
b. Attributed to chloroacetaldehyde metabolite
c. Risk factors: organ dysfunction, hypoalbuminemia, rapid infusion, previous cisplatin use
d. Discontinue ifosfamide
1) Consider methylene blue for prophylaxis, treatment62-64
a) Based on multiple published case reports only
b) 50 mg IV every 6 hours (prophylaxis)
c) 50 mg IV every 3 – 6 hours (treatment)
2) Consider changing bolus ifosfamide to continuous infusion
3) Consider re-challenging with ifosfamide if only mild symptoms with prophylactic

methylene blue or a different rate of ifosfamide infusion.
Patient Case #3:
Answer: C.
Ifosfamide based therapy should always include mesna as well as aggressive hydration with normal
saline. The addition of sodium bicarbonate to the fluids has not been shown to provide any additional
urothelial protection.
SARCOMAS OF BONE
Patient Case #4:

TB is a 34 year old male who presented with left knee pain that remained persistent and intermittent after he
had fallen during a soccer game. NSAIDs and a lidocaine patch were not beneficial and the pain continued to
worsen, leaving TB unable to play soccer. TB’s primary care physician orders radiographic imaging after physical
therapy. Knee radiograph demonstrates a lytic lesion in the left tibia, approximately 4 cm. MRI showed a
defined area of marrow replacement by the lesion. An open biopsy is performed revealing the diagnosis of high
grade osteosarcoma.
The treatment plan for TB is neoadjuvant chemotherapy followed by surgery.
Which of the following would be the most appropriate regimen for neoadjuvant therapy for TB?
A. High dose methotrexate, cisplatin and doxorubicin
B. High dose methotrexate, cisplatin and ifosfamide
C. Cyclosphosphamide and topotecan
D. Regorafenib
I. Osteosarcoma65
A. Most common primary malignant bone tumor in children and young adults. In adults > 65 years,
osteosarcoma can develop as a secondary malignancy related to Paget’s disease of the bone.
B. When osteosarcoma is suspected, the biopsy should always be performed by an experienced surgeon
or radiologist to minimize the risk of pathologic fracture.
II. Treatment
A. Osteosarcoma3, 66
1. Surgery – Limb-sparing procedures for extremity lesions are performed when surgically feasible.
Amputation is reserved for patients who would gain functional independence from a prosthesis
or in whom limb-sparing procedures are not surgically feasible. 15% of patients are cured with
surgery as only therapy.
2. Radiation – Osteosarcoma is relatively resistant to radiation, therefore minimizing the role for
radiation as an alternate primary therapy to surgery. Role is relegated to combination therapy
with chemotherapy in limited circumstances and palliation.
3. Chemotherapy
a. Improves cure rate when given with surgery upwards of 75%.
1) Active agents – cisplatin, cyclophosphamide, doxorubicin, ifosfamide, and high-dose

methotrexate (leucovorin rescue is required).
2) Typically, the combination of doxorubicin and cisplatin is used with or without high-dose
methotrexate, or alternatively, two drugs from the preceding list of active agents based
on a published regimen may be substituted.
3) The addition of ifosfamide and etoposide increases response but does not improve
overall survival67
4) Two to six cycles of neoadjuvant therapy are recommended prior to surgery for all
patients with resectable osteosarcoma. Response to neoadjuvant therapy should be
evaluated from the surgical pathologic specimen.
a) With good histologic response (>90% tumor necrosis), adjuvant chemotherapy may
be used in sequence following surgery for 2 to 12 cycles.
b) The same chemotherapy regimen is used for a good pathologic response
c) Patients with poor histological response may require more intensive therapy.
Colony stimulating factors are often used to maintain dose and schedule.
B. Selected Initial Regimens66, 68-70
1. Below are first-line regimens that are utilized in the neoadjuvant and adjuvant setting for
patients that are able to have their sarcoma surgically resected.
2. NCCN® recommends as Category 1 recommendations either cisplatin with doxorubicin or (MAP)

cisplatin, doxorubicin and high-dose methotrexate66.
3. If the tumor is not able to be resected or the patient has metastatic disease at diagnosis, the
same regimens are recommended without the surgery component. This is due to cisplatin,
doxorubicin, methotrexate, epirubicin and ifosfamide having the most activity for osteosarcoma.
Selected Regimens for Osteosarcomas66

Event Free
Regimen Cycle Duration
Survival
Methotrexate 8000 mg/m2 IV followed by leucovorin 20 Weeks 0, 6 prior to
hours after completion of dose until methotrexate serum surgery; weeks 15,
concentration <100 nmol / L; additional leucovorin 18, 22, 25, 28, 32
administered for renal toxicity or elevated methotrexate following surgery 78% at 5
serum concentration69 years
Doxorubicin 25 mg/m2 IV continuous infusion daily x 3 days Weeks 1, 7 prior to
Cisplatin 120 mg/m2 IV x 1 surgery; weeks 12,
19, 26 following
surgery
Cisplatin 100 mg/m2 IV continuous infusion over 24 hours 21 days X 6 cycles 5-year
Day 168 surgery between estimated
Doxorubicin 25 mg/m2 IV continuous infusion over 4 hours cycles 2 and 3 PFS: 39% for
Days 1-3 (Conventional = Regimen C vs.
Regimen C) 41% for D1
(HR 0.98,
Compared to dose- p=0.83.
intensified (D1) with
G-CSF support as 14
days x 6 cycles with
surgery at week 6
Cisplatin 120 mg/m2 IV Day 170 Weeks 1 and 6 (pre 71% at 3
local control) years
Doxorubicin 25 mg/m2 IV continuous infusion over 24 hours Weeks 13 and 18
Days 1-3 (post local control)
Weeks 23 and 28
Doxorubicin 25 mg/m IV continuous infusion over 24 hours
2
(post local control)
Days 1-3
Weeks 4, 5, 9 and
Methotrexate 12 g/m2 IV (max 20 grams) IV over 4 hours 10 (pre local
Day 1 control)
Leucovorin 10 mg IV q6 hours starting Day 2, 24 hours after Weeks 16, 17, 21,
initiation of methotrexate until methotrexate level < 0.05 22, 26, 27, 31, and
micromol/L and at least 8 doses 32 (post local
control)
Cisplatin 60 mg/m2 IV Day 1-271 Weeks 1 and 6 (pre 59% at 3
Doxorubicin 37.5 mg/m2 IV continuous infusion over 24 local control) years
hours Days 1-2 Weeks 12 and 17
(post local control)
Doxorubicin 37.5 mg/m2 IV continuous infusion over 24 Weeks 22 and 26

hours Days 1-2 (post local control)
Methotrexate 12 g/m2 IV (max 20 grams) IV over 4 hours Weeks 4, 5, 9 and

Day 1 10 (pre local
Leucovorin 10 mg IV q6 hours starting Day 2, 24 hours after control)
initiation of methotrexate until methotrexate level < 0.05 Weeks 15, 16, 20,
micromol/L and at least 8 doses 21, 24, 25, 28, and
29 (post local
control)
C. Selected second line regimens
1. Osteosarcoma
a. Preferred Regimens:
1) Ifosfamide 3 g/m2 IV daily x 4 days, given with mesna, etoposide 75 mg/m2 IV daily x 4
days Q 21-28 days. ORR = 48%.72 (Category 2A)
a) Other Ifosfamide/Etoposide regimens:
• Ifosfamide 1800 mg/m2 IV daily x 5 days, given with mesna, etoposide 100
mg/m2 IV daily x 5 days Q 21 days73
• Ifosfamide 3.5 g/m2 IV daily x 5 days, given with mesna, etoposide 100 mg/m2
IV daily x 5 days Q 21 days74
2) Regorafenib 160 mg PO daily x 21 days in a 28 day cycle. (Category 1)
a) A phase 2 trial of regorafenib in specific sarcoma subtypes, including advanced

osteosarcoma in a randomized manner versus placebo. (SARC024)66, 75
• 42 patients enrolled with a median age of 37 yo (range, 18-76 yo)
• Patients received on average 2.3 prior lines of therapy
• Primary endpoint of PFS was 3.6 months for regorafenib and 1.7 months for
placebo (P=0.17)
• 20 patients required dose interruption (13 assigned to regorafenib, 7 assigned

to placebo). Dose was reduced for 12 patients assigned to regorafenib and 1
assigned to placebo. Median dose at end of blinded treatment was 120 mg
(range, 80-160 mg) for regorafenib and 160 mg (range, 40 -160 mg) for
placebo.
b) SARC024 demonstrated a benefit of regorafenib in patients with relapsed

metastatic osteosarcoma, with a doubling of median PFS compared to placebo.
Additionally NCCN added regorafenib as a category 1 preferred regimen for
second-line relapsed/refractory or metastatic disease.
3) Sorafenib 400 mg PO daily until disease progression
4) Sorefenib 800 mg PO daily + everolimus 5 mg PO daily until disease progression

(Category 2B)
b. Other Recommended Regimens:
1) Gemcitabine 675 mg/m2 IV days 1 and 8, docetaxel 75 – 100 mg/m2 IV day 8, both Q21
days. ORR = 29%, median response duration was 4.8 months.76
2) Cyclophosphamide 250 mg/m2/day plus topotecan 0.75 mg/m2/day, each daily for 5
days Q21 days. Partial response in 2/18.77
c. Useful in Certain Circumstances:
1) Cyclophosphamide 4 g/m2 once on day 1 plus etoposide 200 mg/m2/day on days 2,3,4
Q21-28 x 2 cycles. ORR = 19%, 1 year OS = 50%.78
2) Ifosfamide 1,800 mg/m2 IV daily x 5 days, given with mesna, carboplatin 400 mg/m2/day
days 1-2, etoposide 100 mg/m2 IV daily x 5 days. ORR = 51%, OS at 1 and 2 years was
49% and 28%. Trial included other sarcoma subtypes when reporting OS results. 29
III. Prognosis
A. Osteosarcoma
1. Tumor site and size – larger tumor and axial site of disease worse outcome
2. Tumor necrosis (>90%) following pre-operative chemotherapy: good histologic response
3. Primary metastasis at diagnosis
4. Completeness of surgical resection
5. Age > 40 is worse outcome
IV. Other bone sarcomas3, 66
1. Chondrosarcoma
a. Surgical excision is primary therapy
b. High-grade histology can be treated with chemotherapy but poor response; recurrence can
be treated with radiation therapy.
c. For unresectable or metastatic chondrosarcoma, de-differentiated lesions – treat like

osteosarcoma; mesenchymal – treat like Ewing’s Sarcoma (discussed in the Pediatric
Oncology Module).
d. Dasatinib was studied in a phase 2 trial enrolling patients with multiple rare types of
sarcoma including chondrosarcoma and chordoma79
1) Primary outcome was obtaining at least a 50% 6-month progression free survival rate
a) 6-month PFS: 48% with median PFS of 5.8 months (failed to meet primary end-
point)
b) Subgroup of chondrosarcoma and chordoma patients has 18% objective response

rate with more than 10% having stable disease for 1 year.
2) Dasatinib added to NCCN as an option based on subgroup analysis as a potential option

for metastatic or systemic recurrence
2. Chordoma66
a. Surgical excision is primary therapy
b. Radiation can be used with surgery for resectable sacral and base of skull tumors
c. Radiation is the primary treatment for unresectable tumors; unresponsive to chemotherapy
d. Recurrent tumors can be treated with surgery, radiation or selected targeted therapies such
as: imatinib, sirolimus, erlotinib, sunitinib, lapatinib (EGFR-positive), sorafenib or dasatinib
based on pathways thought to be responsible for chordoma development.
e. Dedifferentiated should be treated as STS.
3. Undifferentiated Pleomorphic Sarcoma of Bone
a. Surgery for first-line therapy
b. Osteosarcoma-like regimens may be used for both neoadjuvant and adjuvant chemotherapy
(NCCN Category 2B recommendation)
4. Giant Cell Tumor
a. Surgery for first-line therapy or serial arterial embolizations
b. Radiation for local recurrence or inoperable lesion
c. Denosumab (120 mg subcutaneous every 4 weeks with an additional 120 mg on days 8 and
15 of the first month)
d. Interferon/peginterferon can be treatment options

Answer: A. TB should receive chemotherapy with high dose methotrexate, cisplatin and doxorubicin
(MAP). Doxorubicin and cisplatin are typical agents, with or without high dose methotrexate.
Regorafenib and cyclophosphamide + topotecan would be considered options for recurrence based on
additional patient characteristics.
After TB received his first dose of high dose methotrexate 12,000 mg/m2 IV over 4 hours, the 48 hour
methotrexate level was 6.8µM. His baseline serum creatinine was 0.9 mg/dL and currently is 2.7 mg/dL.
What is the most appropriate treatment recommendation at this time?
A. Increase leucovorin
B. Start glucarpidase
C. Increase sodium bicarbonate infusion to obtain a urine pH >8
D. Start dexrazoxane
V. Caveats of High Dose Methotrexate (MTX) Therapy80
A. High dose therapy (500-12,000 mg/m2) requires leucovorin rescue until MTX levels are less than
0.1µM (or 1 x 10-7M) or 0.05µM (or 5 x 10-8 M). Depending on the algorithms followed targets of
nmol/L may be listed. (0.1 µM = 100 nmol/L)
1. High dose MTX is lethal unless reversed by leucovorin rescue initiated within 42 hours.
2. Calcium leucovorin is a reduced folate. It can replenish the supply of folate metabolites depleted
by MTX. Leucovorin enters cells by passive diffusion, requiring serum concentrations to be much
higher than MTX for rescue effect. It allows DNA synthesis to begin again even in the presence of
MTX. This process of recovery of DNA synthesis is called “rescue.”
3. Leucovorin is available PO, IM, and IV. Oral bioavailability varies, good at doses less than 35 mg,
but above that, ranges from 5-50%. Half-life is about 3 hours, widely distributed, metabolized in
tissues.
4. Levo-leucovorin is an IV isomer of leucovorin and is dosed at 50% of the usual dose of leucovorin.
5. Leucovorin dose is generally started at 15 mg/m2 and titrated according to the MTX serum
concentration. Generally started 20-24 hours after the end of the infusion of MTX. The rescue
(i.e. leucovorin + hydration/alkalinization) can be stopped when the concentration of MTX is less
than 1 x 10-7M (0.1 µM), although some algorithms recommend concentrations of less than 5 x
10-8 M (0.05 µM).
6. Dose of leucovorin may need to be increased in the case that methotrexate clearance is delayed.
B. Precautions:
1. Third space fluids such as ascites, edema, or pleural effusions can significantly influence the
volume of distribution and terminal t1/2. High dose methotrexate should not be given in these
scenarios. However, if it must be given or third spacing is discovered after drug administration,
these patients will usually require prolonged leucovorin rescue until all methotrexate has been
cleared.
2. Renal tubular necrosis is not prevented by leucovorin. Urine alkalinization and vigorous
hydration are required to increase solubility of methotrexate and its metabolites.
a. 2-3 liters/m2/day is recommended
b. Add sodium bicarbonate to fluids or utilize oral sodium bicarbonate tablets to maintain urine
pH
c. Achieve urine pH > 7 prior to the initiation of high dose methotrexate, and should be
maintained until the agent is cleared
d. Urine pH checks should occur with each void
C. Drug Interactions
1. Drugs that are highly protein bound may displace MTX from albumin and increase toxicity
(sulfonamides, salicylates, phenytoin, and tetracycline).
2. Weak organic acids (penicillins) increase toxicity81
3. NSAIDS compete for renal excretion of MTX and increase levels.
4. Vitamin C will acidify the urine and may increase MTX levels
5. Proton pump inhibitors may inhibit methotrexate clearance82
D. Consider glucarpidase (also known as carboxypeptidase G2) for toxic methotrexate levels with renal
impairment 83, 84
1. Carboxypeptidase enzyme approved by FDA in 2012 for toxic plasma methotrexate levels in
patients with delayed clearance due to renal impairment
2. MOA: recombinant bacterial enzyme that cleaves methotrexate into inactive metabolites
3. Not to be used in patients who exhibit the expected clearance of methotrexate (plasma
methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion
curve specific for the dose of methotrexate administered); patients with normal or mildly
impaired renal function because of the potential risk of subtherapeutic exposure to
methotrexate
4. Dose is 50 units/kg IV over 5 minutes
5. Main efficacy trial included sarcoma patients
6. Leucovorin should not be administered within 2 hours before or after a glucarpidase dose
because leucovorin is a substrate for glucarpidase.
7. Alkalinization/hydration and leucovorin should be continued until methotrexate concentration is

maintained below the leucovorin treatment threshold for a minimum of 3 days. For the first 48
hours after glucarpidase administration, administer the same dose of leucovorin dose as given
prior to glucarpidase, beyond 48 hours, administer leucovorin based on methotrexate
concentration.
a. Immunoassay for methotrexate levels is unreliable for 48 hours after glucarpidase

administration
8. A pooled analysis demonstrated in patients with renal toxicity and delayed methotrexate
clearance that levels were lowered to < 1 µM in 59% of patients and that 64% of patients with
grade 2 renal impairment recovered to grade 0-1 at 12.5 days (median).85
9. No direct comparison with dialysis to date
10. Recent consensus guideline was published with recommendations for clinical use of glucarpidase
based on expert opinions in the field and review of the literature.86
a. Glucarpidase administration should optimally occur within 48-60 hours from the start of the
methotrexate infusion.
b. Methotrexate infusions over 24-42 hours (1-8 g/m2)
1) After a 24 hour infusion, if the plasma methotrexate concentration is > 120 microM/L at
the end of the infusion or a ≥ 50% increase in serum creatinine over baseline a level
should be drawn at 36 hours.
a) If the 36-hour level is > 30 microM/L, the 42-hour level > 10 microM/L or 48-hour
level > 5 microM/L and the serum creatinine is elevated, glucarpidase may be
indicated.
2) After a 36-42 hour infusion of methotrexate, if the methotrexate level is > 5 microM/L at
48 hours, glucarpidase may be indicated.
c. Methotrexate infusions over ≤ 6 hours (8-12 g/m2)
1) If the 24-hour concentration is > 50 microM/L, 36-hour level >30 microM/L, 42-hour
level > 10 microM/L or 48-hour level > 5 microM/L and serum creatinine is elevated
relative to baseline, glucarpidase may be indicated.
d. Leucovorin should be dosed according to standard guidelines until glucarpidase can be given.
Leucovorin should be held 2 hours prior to and 2 hours after glucarpidase administration.
e. Repeat administration of glucarpidase within 48 hours of the first dose is not recommended
due to decreased efficacy.

Answer: B. Glucarpidase should be considered in this patient. Although leucovorin is necessary to
prevent toxicity and should be continued, the patient has delayed clearance and evidence of new
organ damage.
Answer: B. Glucarpidase should be considered in this patient. Although leucovorin is necessary to
prevent toxicity and should be continued, the patient has delayed clearance and evidence of new
organ damage. Increasing sodium bicarbonate is an option but this change alone without
implementation of glucarpidase will not effectively reduce serum methotrexate levels in a timely
manner given the patient’s current renal function and methotrexate level. Dexrazoxane does not have
role in improving methotrexate clearance, instead is an agent recommended for extravasation of
doxorubicin or to prevent cardiomyopathy as a result of doxorubicin therapy.
RECOMMENDED READINGS AND REFERENCES
General
1. Skubitz KM, D’Adamo DR. Sarcoma. Mayo Clin Proc. 2007; 82:1409-32.
(https://www.ncbi.nlm.nih.gov/pubmed/17976362 )
2. Schaefer I-M, Cote GM, Hornick JL. Contemporary sarcoma diagnosis, genetics and genomics. J Clin Oncol
2018; 36: 101-110. (https://www.ncbi.nlm.nih.gov/pubmed/29220288)
Soft-Tissue Sarcoma
1. Clark MA, Fisher C, Judson I et al. Soft-tissue sarcomas in adults. N Engl J Med. 2005; 353:701-11.
2. Haas RL, Gronchi A, van de Sande MA et al. Perioperative management of extremity soft tissue sarcomas. J Clin
Oncol 2018; 36: 118-124. (https://www.ncbi.nlm.nih.gov/pubmed/29220299 )
3. Von Mehren M, Joensuu H. Gastrointestinal stromal tumors. J Clin Oncol 2018; 36: 136-143.
Sarcomas of Bone
1. Whelan JS, Davis LE. Osteosarcoma, chondrosarcoma, and chordoma. J Clin Oncol 2018; 36: 188-193.
2. Luetke A, Meyers PA, Lewis I et al. Osteosarcoma treatment – where do we stand? Cancer Treat Rev. 2014;
40:523-32. (https://www.ncbi.nlm.nih.gov/pubmed/24345772 )
3. Meyers PA, Heller G, Healy J et al. Chemotherapy for nonmetastatic osteogenic sarcoma: The Memorial Sloan-
Kettering experience. J Clin Oncol. 1992; 10:5-15. (https://www.ncbi.nlm.nih.gov/pubmed/1370176 )
4. Pollack S, Ingham M, Spraker, M et al. Emerging targeted and immune-based therapies in sarcoma. J Clin Oncol
2018; 36: 125-135. (https://www.ncbi.nlm.nih.gov/pubmed/29220291 )
Methotrexate Toxicities
1. Ramsey LB, Balis FM, O'Brien MM et al. Consensus guideline for use of glucarpidase in patients with high-dose
methotrexate induced acute kidney injury and delayed methotrexate clearance. Oncologist. 2018; 23(1): 52-
61. (https://www.ncbi.nlm.nih.gov/pubmed/29079637)
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Adult Sarcomas: Learning Objectives

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Adult Sarcomas: Learning Objectives

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ADULT SARCOMAS

Janelle Mann, Pharm.D., BCOP

Patient Case #1:

Which chemotherapeutic agent(s) should be part of WH’s adjuvant regimen?

I. Etiology and Pathogenesis

2. Genetic Predisposition to STS

Selected Genetic Predisposition to STS3-5

13q14.2 (Rb-1 gene) – retinoblastoma Leiomyosarcoma, rhabdomyosarcoma

Selected Cytogenetic Aberrations Associated with STS3, 6, 7

B. Biopsy for STS

1. Heterogeneous group of tumors arising from mesenchymal cell origin

Incidence of Soft Tissue Sarcoma Subtypes (1978-2001) 9, 10

4. Anatomic compartment excision – local recurrence rate of 10 to 20%. Compartment excision is

1. Newer RT techniques such as brachytherapy, intraoperative RT and intensity-modulated RT

4. A retrospective review evaluated patients receiving preoperative RT compared to preoperative

1) Median follow-up was 7.3 years.

1) 287 patients randomized to standard chemotherapy of 3 cycles of epirubicin +

a) Myxoid liposarcoma: trabectedin

c) Synovial sarcoma: ifosfamide

d) Malignant peripheral nerve sheath tumors: etoposide + ifosfamide

e) Undifferentiated pleomorphic sarcoma: gemcitabine + docetaxel

a. Meta-analyses were conducted and published to examine the pooled data.

1) In 1997, the Sarcoma Meta-Analysis Collaboration (SMAC) of Britain conducted a meta-

a) Findings from 14 randomized trials (N=1568 patients) of doxorubicin-containing

b) There was a trend towards adjuvant chemotherapy improving overall survival,

2) In 2008, an updated meta-analysis included four additional trials (N=1953).

c) In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68-1.03; P =

Patient Case #1, continued:

b. STS is poorly responsive to cytotoxic chemotherapy, in general. However, certain histological

2) Other commonly used drugs include:

a) Ifosfamide (RR - 15 to 20%)

b) Dacarbazine (RR - 15 to 20%)

c) Epirubicin (RR – 15%)

d) Gemcitabine (RR – 7%)

e) Temozolomide (RR – 8%)

f) Cyclophosphamide (RR – 10%)

g) Vinorelbine (RR – 6%)

h) Dactinomycin (RR – 15%)

Histological Subtype Chemotherapeutic Agent(s) Response Rate (%)

c. Single agent therapy compared to combination chemotherapy

1) Comparative trials have demonstrated an increase in response rate with multiagent

d) There was more toxicity in the ifosfamide/doxorubicin arm.

e) Authors concluded intensified doxorubicin and ifosfamide for palliation in the

i. Doxorubicin 46.3% vs. gemcitabine/docetaxel 46.4%

c) Overall survival did not differ between groups.

d) Side effect profiles were similar between the regimens.

Selected Chemotherapy Regimens for STS4

Place in Cycle Response Rate

6. Pegylated liposomal doxorubicin versus conventional doxorubicin33

a) Myelosuppression – grade 3/4 neutropenia: PLD 6%, doxorubicin 77%

c) Additional considerations: PLD showed less cardiotoxicity, alopecia, and

7. Fixed Dose Rate Gemcitabine43

a) Gemcitabine infused over 10 mg/m2/min

a. Approved for unresectable, metastatic liposarcoma

1) Randomized, phase III, open-label in advanced or metastatic liposarcoma or

2) Primary end-point: overall survival

i. Results driven by liposarcoma results: FDA only approved in liposarcoma

iii. Leiomyosarcoma: 12.7 months vs 13 months (HR 0.927; 95 % CI 0.714 – 1.203)

a. Phase III, randomized, open-label in advanced or metastatic liposarcoma or

b. Primary end-point: Overall survival

1) The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of

c. Median Progression Free Survival

a. Phase III, randomized, multi-center, double-blind placebo-controlled (PALETTE study) trial.