CANCER

CANCER
Large group of diseases characterized by DNA damage that
causes abnormal cell growth and development.

Develops from a complex interaction of exposure to

carcinogens and accumulated mutations in several genes.
 Carcinogenesis

Initiation
Exposure of normal cells to
carcinogen

Promotion
Exposure of mutated cells
to factors that enhance its
growth

Progression
Further genetic changes
leading to increased cell
proliferation
 Seven Warning Signs

C hange in bowel or bladder habits

A sore that doesn’t heal
U nusual bleeding or discharge
T hickening or lump in the breast or elsewhere
I ndigestion or difficulty swallowing
O bvious change in a wart or mole
N agging cough or hoarseness
 Tumor Classification by Tissue Type

Tissue of Origin Malignant

Epithelial tissue Carcinoma

Connective tissue Sarcoma

Bone marrow elements Leukemia

Lymphoid tissue Lymphoma

Breast Cancer
 Breast Cancer
Invasive breast cancer, the most common non-skin cancer
in women in the United States, will be diagnosed in about
180,000 women in 2010 and will result in approximately
40,000 deaths.

In the Philippines, breast cancer is the most common

form of cancer and has the lowest mortality to incidence
ratio at 0.58.

Incidence and mortality from breast cancer appear to be

dropping in the United States and parts of western Europe.

This decline is believed to reflect early detection by

screening mammography and widespread use of adjuvant
systemic therapy as well as decreased use of hormone
replacement therapy.
Risk Factors
 Signs & Symptoms
The most common symptom of breast cancer is a new
lump or mass. A painless, hard mass that has irregular
edges is more likely to be cancer, but breast cancers can be
tender, soft, or rounded.

Other possible symptoms of breast cancer include:

● Swelling of all or part of a breast (even if no distinct

lump is felt)
● Skin irritation or dimpling (sometimes looking like an
orange peel)
● Breast or nipple pain
● Nipple retraction (turning inward)
● Redness, scaliness, or thickening of the nipple or
breast skin
● Nipple discharge (other than breast milk)
 Common Histologic Classification

1. Carcinoma in situ
- Ductal carcinoma in situ (DCIS)
- Lobular carcinoma in situ (LCIS)

1. Invasive Cancer
 Molecular Subtypes
Luminal A
(ER+ &/or PR+, HER2-)
Luminal B
● Most common subtype
(ER+ &/or PR+, HER2+)
● Less aggressive
● Similar to Luminal A
● Lower histological grade
● More frequently ER+/PR-
● Good prognosis
● Worse outcome than Luminal A
● Hormone responsive
● Associated with increasing age

HER2+
Basal-like
(ER-)
(Triple negative, cytokeratin 5/6+ &/or
● Less common, highly aggressive
EGFR+)
subtype
● Aggressive subtype
● High grade histology
● High grade histology, and high
● Risk at younger age (<40)
mitotic rate
greater than luminal subtypes
● Risk at younger age (<40)
● Outcome improved with
● More likely premenopausal
therapies aimed at the HER2
African American women
protein
Pathophysiology
 Pathophysiology
Cancer Type Sites for Metastasis
Breast Axillary lymph nodes, lung, liver,
bone, brain
Early Detection
 Early Detection
Screening Recommendation
Mammogram Every year for ages 40 and older
Clinical breast exam Every year for ages 40 and older
Every 3 years for ages 20 to 39
Self breast exam Monthly for ages 20 and older
Diagnosing
Diagnosing
 TNM Staging

TNM Staging Description

T for Primary Tumor The anatomic extent of the primary

N for Nodal Involvement
M for Distant Metastasis
tumor depends on its size, depth of
invasion, and surface spread
Reflects the tumor’s spread to the
lymph nodes
Denotes the extent (or spread) of
disease
Stage TNM Catgory Recurrence Free at 10 Years (No systemic adjuvant
therapy)
0 TisN0M0 98%

I T1N0M0 80% (all stage 1 patients)

T<1cm 90%

Staging
T> 1-2cm 80-90%

IIA T0N1M0; T2N0M0 60-80%

IIA T1N1M0 50-60%

IIB T2N1M0 5-10% worse than IIA and based on node status

IIB T3N0M0 30-50%

IIIA T0 or T1 or T2N2M0; or 10-40%

T3N1 or N2M0
IIIB T4N0 or N1 or N2M0 5-30%

IIIC Any T, N3M0 15-20%

IV Any T, any NM1 <5%

EARLY BREAST CANCER

Stage 0 Stage 0 cancer means that the cancer is limited to the inside of the milk duct and is a non-invasive cancer. The
treatment approaches for these non-invasive breast tumors are often different from the treatment of invasive breast
cancer. Stage 0 breast tumors include ductal carcinoma in situ (DCIS)

Stage 1 These breast cancers are still relatively small and either have not spread to the lymph nodes or have only a tiny area of
cancer spread in the sentinel lymph node (the first lymph node to which cancer is likely to spread).

Stage 2 These breast cancers are larger than stage I cancers and/or have spread to a few nearby lymph nodes.

LOCALLY ADVANCED BREAST CANCER

Stage 3 These tumors are larger or are growing into nearby tissues (the skin over the breast or the muscle underneath), or they
have spread to many nearby lymph nodes.

ADVANCED OR METASTATIC BREAST CANCER

Stage 4 Stage IV cancers have spread beyond the breast and nearby lymph nodes to other parts of the body. Treatment for
stage IV breast cancer is usually a systemic (drug) therapy.
Treatment Guideline
Breast Cancer Treatments
 Breast Cancer Treatments

Lumpectomy Total Mastectomy Modified Radical

Mastectomy (MRM)
Breast Cancer Treatments

External Beam Radation Internal radiation

(brachytherapy)
 Breast Cancer Treatments

Chemotherapy Description

Neoadjuvant Used before surgery to shrink the

tumor so it can be removed with
less extensive surgery
Adjuvant Used to try to kill any cancer cells
that might have been left behind or
have spread but can’t be seen, even
on imaging tests
Palliative Used in patients with recurrent or
metastatic disease where there is
no realistic chance of cure but the
potential for prolongation of useful
life and/or relief of tumor-related
symptoms
Diagnosing
Diagnosing
 Breast CA
suspect (A)

Stage (D)
Open biopsy (B) Y Excision -
LCIS
? (E) Observation
Y
0? N
Y Adjuvant
Lumpectomy with ER/PR
Positive Y Hormonal TX
DCIS nodal sampling or +?(F)
cancer? (C)
MRM
N
N
Observe
Refer
Stage (D)
Ax Y Y
ER/PR/HER2 Adjuvant
LN+? Chemotherapy
Y Breast (-)? (F)
I or (H)
Conservation
II? or MRM (G)
N N

Y
Adjuvant Chemotx ±
Premenopausal? Hormonal Tx ± Trastuzumab N
Positive Observe
Tumor size >= 1.0 Y margin?
cm or with N
unfavorable
prognostic factors Y
Menopausal Hormonal ± Adjuvant
Chemotx ± Trastuzumab
N Adjuvant
Radiotherapy (I)

Observe
 Treatment: Early Breast Cancer
I. Local-Regional Therapy

● Surgery alone can cure most patients with in situ cancers and approximately one-half of those with stage II
cancers.
● Breast-conserving therapy (BCT) is appropriate primary therapy for most women with stage I and II disease;
it is preferable to modified radical mastectomy because it produces equivalent survival rates with cosmetically
superior results. BCT consists of lumpectomy (i.e., excision of the primary tumor and adjacent breast tissue)
followed by radiation therapy (RT) to prevent local recurrence.
● RT is administered to the entire breast over 4 to 6 weeks to eradicate residual disease after BCT.
Reddening and erythema of the breast tissue with subsequent shrinkage of total breast mass are minor
complications associated with RT.
● Simple or total mastectomy involves removal of the entire breast without dissection of underlying muscle or
axillary nodes. This procedure is used for carcinoma in situ where the incidence of axillary node involvement is
only 1% or with local recurrence following breast conservation therapy.
● Axillary lymph nodes should be sampled for staging and prognostic information. Lymphatic mapping with
sentinel lymph node biopsy is a new, less invasive alternative to axillary dissection; however, the procedure is
controversial because of the lack of long-term data.
 Treatment: Early Breast Cancer
II. Systemic Adjuvant Therapy

● Systemic adjuvant therapy is the administration of systemic therapy following definitive local therapy (surgery,
radiation, or both) when there is no evidence of metastatic disease but a high likelihood of disease recurrence.

● Chemotherapy, hormonal therapy, or both result in improved disease-free survival and/or overall survival (OS)
for all treated patients.

● The National Comprehensive Cancer Network practice guidelines reflect the trend toward the use of
chemotherapy in all women regardless of menopausal status, and the addition of hormonal therapy in all
women with receptor-positive disease regardless of age or menopausal status.

● Genetic tests are being prospectively validated as decision-support tools for adjuvant chemotherapy in node-
negative patients to identify characteristics of the primary tumor that may predict for the likelihood of
metastases and death.
 Agents Used in Adjuvant Systemic Therapy
● Taxanes: Among the most active and commonly used chemotherapeutic agents for the treatment of early stage
breast cancer
● Anthracyclines: Used in the treatment of early stage breast cancer for decades, although concerns regarding
anthracycline-associated cardiotoxicity or leukemogenic potential remain
● Pertuzumab: Use in combination with trastuzumab and chemotherapy as adjuvant treatment of patients with HER2-
positive early breast cancer at high risk of recurrence
● Trastuzumab: Used in the (neo)adjuvant treatment in patients with HER2-positive breast cancer
● Tamoxifen: Used in the treatment of estrogen receptor (ER) ̶ positive breast cancer; decreases estrogen's ability to
stimulate existing micrometastases or dormant cancer cells
● Aromatase inhibitors (AIs): Inhibit aromatase, the enzyme responsible for converting other steroid hormones into
estrogen

Neoadjuvant chemotherapy
The best candidates for neoadjuvant chemotherapy are patients with ER-negative and/or HER2-positive expressing
tumors whose pathologically complete response (pCR) rates can approach 65% and predict long-term survival. Patients
with ER-positive, HER2-negative locally advanced breast cancer (LABC) are unlikely to achieve a pCR from currently
available chemotherapy.
Adjuvant Treatment Guidelines
Stage (D)

Y Y Adjuvant Chemotx ± Adjuvant RT to breast

Y
III? Operable? MRM ER/PR/HER2 Hormonal Tx ± and regional nodes
(+)? (F) Trastuzumab
N
N
Neoadjuvant
Chemotherapy (J) MRM Adjuvant RT to breast
Adjuvant
and regional nodes
Chemotherapy

Chemotherapy
with RT
 Treatment: Locally Advanced Breast Cancer (III)
● Neoadjuvant or primary chemotherapy is the initial treatment of choice.
● Benefits include rendering inoperable tumors resectable and increasing the rate of BCT.
● Primary chemotherapy with either an anthracycline- or taxane-containing regimen is recommended. The use of
trastuzumab with chemotherapy is appropriate for patients with HER2-positive tumors.
● Surgery followed by chemotherapy and adjuvant RT should be administered to minimize local recurrence.
● Cure is the primary goal of therapy for most patients with Stage III disease.
Stage (D)

Y Palliative Palliative Radiotherapy

IV?
Palliative surgery (F) chemotherapy/ or Best Supportive
(K)
Hormonal therapy/ Care (BSC)
Trastuzumab or BSC
Treatment Guideline for Breast Cancer (IV)
 Treatment: Metastatic Breast Cancer (IV)
I. Endocrine Therapy

● Endocrine therapy is the treatment of choice for patients who have hormone receptor-positive
metastases in soft tissue, bone, pleura, or, if asymptomatic, viscera. Compared with chemotherapy,
endocrine therapy has an equal probability of response and a better safety profile.

● Patients are sequentially treated with endocrine therapy until their tumors cease to respond, at which
time chemotherapy can be given.

● Historically, the choice of an endocrine therapy was based primarily on toxicity and patient preference
but study results have led to changes in MBC treatment.

● Aromatase inhibitors reduce circulating and target organ estrogens by blocking peripheral conversion
from an androgenic precursor, the primary source of estrogens in postmenopausal women. Newer
agents are more selective and better tolerated than the prototype, aminoglutethimide.Anastrozole,
letrozole, and exemestane are approved as second-line therapy; anastrozole and exemestane have
been shown to improve OS and time to progression compared with progestins. As first-line therapy,
anastrozole and letrozole increase time to progression and are better tolerated compared with
tamoxifen.
 Treatment: Metastatic Breast Cancer (IV)

I. Endocrine Therapy (cont…)

● Tamoxifen is the antiestrogen of choice in premenopausal women whose tumors are hormone-
receptor positive, unless metastases occur within 1 year of adjuvant tamoxifen. Maximal beneficial
effects do not occur for at least 2 months. In addition to the side effects described for adjuvant
therapy, tumor flare or hypercalcemia occurs in approximately 5% of patients with MBC.

● Toremifene has similar efficacy and tolerability as tamoxifen and is an alternative to tamoxifen in
postmenopausal patients. Fulvestrant is a second-line intramuscular agent with similar efficacy and
safety when compared to anastrozole in patients who progressed on tamoxifen. Ovarian ablation
(oophorectomy) is considered by some to be the endocrine therapy of choice in premenopausal
women and produces similar overall response rates as tamoxifen. Medical castration with an LHRH
analog, goserelin, leuprolide, or triptorelin, is a reversible alternative to surgery.

● Progestins are generally reserved for third-line therapy. They cause weight gain, fluid retention, and
thromboembolic events.
 Treatment: Metastatic Breast Cancer (IV)
II. Chemotherapy

● Chemotherapy is preferred to endocrine therapy for women with hormone receptor-negative tumors; rapidly
progressive lung, liver, or bone marrow involvement; or failure of endocrine therapy.

● The choice of treatment depends on the individual. Agents used previously as adjuvant therapy can be
repeated unless the cancer recurred within 1 year.

● Single agents are associated with lower response rates than combination therapy, but time to progression and
OS are similar. Single agents are better tolerated, an important consideration in the palliative metastatic
setting.

● Combination regimens produce objective responses in approximately 60% of patients previously unexposed to
chemotherapy, but complete responses occur in less than 10% of patients. The median duration of response
is 5 to 12 months; the median survival is 14 to 33 months.
 Treatment: Metastatic Breast Cancer (IV)
II. Chemotherapy

● Anthracyclines and taxanes produce response rates of 50% to 60% when used as first-line therapy for MBC.
Single agent capecitabine, vinorelbine, or gemcitabine have response rates of 20% to 25% when used after an
anthracycline and a taxane.

● Ixabepilone, a microtubule stabilizing agent, is indicated as monotherapy or in combination with capecitabine

in MBC patients who have previously received an anthracycline and a taxane. Response rates and time to
progression were increased with combination therapy as compared with capecitabine alone. Adverse effects
include myelosuppression, peripheral neuropathy, and myalgias/arthralgias.
 Treatment: Metastatic Breast Cancer (IV)
II. Biologic Therapy

● Trastuzumab, a monoclonal antibody that binds to HER2, produces response rates of 15% to 20% when used
as a single agent and increases response rates, time to progression, and OS when combined with
chemotherapy. It has been studied in doublet (taxane-trastuzumab; vinorelbinetrastuzumab) and triplet
(trastuzumab-taxane-platinum) combinations but the optimum regimen is unknown.

● Trastuzumab is well tolerated, but the risk of cardiotoxicity is 5% with single-agent trastuzumab and
unacceptably high in combination with an anthracycline.

● Lapatinib, a tyrosine kinase inhibitor that targets both HER2 and the epidermal growth factor receptor,
improved response rates and time to progression in combination with capecitabine, as compared to
capecitabine alone, in patients previously treated with an anthracycline, taxane, and trastuzumab. The most
common adverse events were rash and diarrhea.

● The role of bevacizumab, a monoclonal antibody targeted against vascular endothelial growth factor, in MBC
is currently not clearly defined.
 NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is
appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the
intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is
appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is
appropriate.

All recommendations are category 2A unless otherwise noted.

 Chemotherapy
Class Agent Action

Anthracycline Doxorubicin It blocks DNA and RNA synthesis by inserting between

adjacent base pairs and binding to the sugar-phosphate
backbone of DNA, which causes DNA polymerase inhibition.

Anthracycline Epirubicin Epirubicin is a cell cycle phase inhibitor–nonspecific

anthracycline derivative of doxorubicin with maximum cytotoxic
effects on the S and G2 phases of the cell cycle.

Alkylating Agent Cyclophosphamide The mechanism of action of the active metabolites may involve
cross-linking of DNA, which may interfere with the growth of
normal and neoplastic cells.

Alkylating Agent Carboplatin Carboplatin is an analogue of cisplatin. It is a heavy metal

coordination complex that exerts its cytotoxic effect by
platination of DNA, a mechanism analogous to alkylation,
leading to interstrand and intrastrand DNA cross-links and
inhibition of DNA replication.
 Class Agent Action

Anti-Microtubular Docetaxel Inhibits cancer cell growth by promoting assembly and blocking
the disassembly of microtubules, thereby preventing cancer cell
division and leading to cell death.

Anti-microtubular Paclitaxel Acts via tubulin polymerization and microtubule stabilization,

which, in turn, inhibit mitosis and may result in the breakage of
chromosomes.

Vinca Alkaloid Vinorelbine Vinorelbine is a semisynthetic vinca alkaloid that inhibits tubulin
polymerization during the G2 phase of cell division, thereby
inhibiting mitosis.

Tyrosine Kinase Inhibitor Lapatinib Lapatinib is a 4-anilinoquinazoline kinase that inhibits the
intracellular tyrosine kinase domains of epidermal growth factor
receptor (EGFR [ErbB1]) and HER2 (ErbB2).
 Class Agent Action

Antimetabolite Capecitabine Rapidly converted to 5-FU in tumor tissue, which leads to

thymidylate synthase inhibition and incorporation into RNA and
DNA.

Antimetabolite Gemcitabine Gemcitabine is a pyrimidine analogue that is metabolized

intracellularly to an active nucleotide. It inhibits ribonucleotide
reductase and competes with deoxycytidine triphosphate for
incorporation into DNA. It is cell-cycle specific for the S phase.

Anti-Metabolite Methotrexate Methotrexate is an antimetabolite that inhibits dihydrofolate

reductase, thereby hindering DNA synthesis and cell
reproduction in malignant cells.
 Class Agent Action

Antimetabolite Capecitabine Rapidly converted to 5-FU in tumor tissue, which leads to

thymidylate synthase inhibition and incorporation into RNA and
DNA.

Antimetabolite Gemcitabine Gemcitabine is a pyrimidine analogue that is metabolized

intracellularly to an active nucleotide. It inhibits ribonucleotide
reductase and competes with deoxycytidine triphosphate for
incorporation into DNA. It is cell-cycle specific for the S phase.

Antimetabolite 5-Fluorouracil Its active metabolite inhibits thymidylate synthase, resulting in

the depletion of thymidine triphosphate (TTP), one of the four
nucleotide triphosphates used in the in vivo synthesis of DNA.
 Hormonal Therapy
Class Agent Action

Aromatase Inhibitor Anastrazole Significantly lowers serum estradiol concentrations by inhibiting the
conversion of adrenally generated androstenedione to estrone.

Aromatase Inhibitor Letrozole Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme
system. It inhibits the conversion of androgens to estrogens.

Aromatase Inhibitor Exemestane Exemestane elicits irreversible steroidal aromatase inactivation by acting
as a false substrate for the aromatase enzyme. It binds irreversibly to the
aromatase enzyme active site, causing inactivation
 Hormonal Therapy
Class Agent Action

Estrogen Receptor Tamoxifen* Tamoxifen is a nonsteroid with potent antiestrogenic effects in the breast;
Antagonist however, it may be an estrogen agonist in the uterus.

Estrogen Receptor Raloxifene Raloxifene is a selective nonsteroidal benzothiophene ER modulator.

Antagonist

Estrogen Receptor Toremifene Toremifene is a nonsteroidal triphenylethylene derivative that binds to

Antagonist estrogen receptors. It may exert estrogenic activities, antiestrogenic
activities, or both.
 Targeted Therapy
Class Agent Action

Tyrosine Kinase Inhibitor Lapatinib Lapatinib is a 4-anilinoquinazoline kinase that

inhibits the intracellular tyrosine kinase domains of
epidermal growth factor receptor (EGFR [ErbB1])
and HER2 (ErbB2).

Monoclonal Antibody Bevacizumab (no longer approved by blocks the growth of new blood vessels that
the FDA Nov 2011) cancer cells depend on to grow and function.

Monoclonal Antibody Trastuzumab It mediates antibody-dependent cellular

cytotoxicity against cells that overproduce HER2.

Monoclonal Antibody Ado-Trastuzumab Emtansine HER2-targeted antibody (trastuzumab) covalently

linked to a microtubule inhibitor (DM1, a
maytansine derivative).
 Supportive Care
Disease Treatment
Pain Analgesics, non-narcotic and
narcotic

Nausea and vomiting 5-HT3 receptor antagonists

Anemia Erythropoietin

Tumor-induced Bisphosphonates and

hypercalcemia zoledronate

Anxiety & Depression Paroxetine, venlafaxine,

antidepressants
Summary
Case
Case I
● A 46-year-old female patient had her first mammogram screening and a spiculated density was discovered in her
medial left breast. The patient then acknowledged she was able to appreciate a palpable prominence in her medial
breast and a “lump” in her left axilla.
○ Further Screening: An ultrasound disclosed a highly suspicious mass that measured 15x14x15 mm in the
breast, and a left axillary mass that measured 35x29x14 mm. Ultrasound-guided core biopsies of the tumor
and the axillary mass. Pathologic examination of both lesions revealed a Grade III infiltrating ductal carcinoma,
which was estrogen and progesterone receptor negative, and HER-2/neu positive.
○ Staging: Based on the patient’s aggressive and advanced breast cancer, the surgeon felt she should be
considered for neoadjuvant chemotherapy.
○ Treatment: A course to include neoadjuvant chemotherapy followed by surgery and postoperative radiation
therapy was chosen. The patient was treated with Adriamycin and Cytoxan followed by Taxol and Herceptin.
Six months after her original presentation, underwent a mastectomy with sentinel lymph node biopsy
○ Response to Treatment: She had a dramatic clinical response with resolution of all palpable disease. . The
pathology examination found no residual carcinoma in either the breast or lymph nodes. The patient plans to
undergo breast reconstruction after completing her radiation therapy. She has tolerated her treatments with
minimal side effects and no complications.
Lung Cancer
 Lung Cancer
● Starts in the cell of the lungs become abnormal and begin to grow out of control
● Can form into a tumor and spread to other parts of the body
● Higher in men than women
 Two Types of Lung Cancer
1. Small cell lung cancer (SCLC)
○ Also called “Oat Cell Cancer”
○ About 10-15% of lung cancers
○ A neuroendocrine carcinoma that exhibits aggressive behavior, rapid growth, early spread to
distant sites
○ Cigarette smoking is a common predisposing factor
○ Surgery is not generally an option, due to early spread of the disease
○ Chemotherapy combined with radiotherapy is most commonly used as treatment
Two Types of Lung Cancer
2. Non-small cell lung cancer
○ More common (80-85%)
○ Cigarette smoking and/or asbestos
exposure are common risk factors
○ Treatment is dependent on the stage
of disease; options may be surgery,
chemotherapy and/or radiotherapy
and targeted therapy
○ Types:
■ Adenocarcinoma
■ Large-cell carcinomas
■ Squamous cell carcinoma -
also called “Epidermoid
carcinoma”
Pathophysiology
 Pathophysiology
SCLC
● TSG Inactivation (Tumor Suppressor Gene)
● Oncogene Activation

NSCLC
● TSG Inactivation (Tumor Suppressor Gene)
● Oncogene Activation → EGFR activation
● Telomerase Activation
● Evasion of Apoptosis
○ Tumor Growth and Maintenance
● Angiogenesis
 Pathophysiology

https://www.youtube.com/watch?v=J5UfBV18Bis
 Signs
Computed Tomography (CT) Scan
• Features of Nodule → no calcium build up; rough edges and odd shapes
o Size → larger than normal since grows faster
o Density
▪ Solid
▪ Part-solid
• Abnormal Lung Tissue → inflammation, scarring or both

Positron Emission Tomography

• Uses sugar as radiotracer
• PET Hot Spots
• Appears brighter (hotter)
 Symptoms
Elsewhere in the body:
In the chest
● Loss of appetite of unexplained weight
○ Coughing
loss
○ Pain in the chest, shoulder, or back,
● Muscle wasting (cachexia)
unrelated to pain from coughing
● Fatigue
○ Change in color or volume of sputum
● Headaches, bone or joint pain
○ Shortness of breath
● Bone fractures not related to accidental
○ Changes in the voice (hoarse)
history
○ Harsh sounds with each breath (stridor)
● Neurological symptoms, such as
○ Recurrent lung problems, such as
unsteady gait or memory loss
bronchitis or pneumonia
● Neck or facial swelling
○ Coughing up phlegm or mucus, especially
● General weakness
if tinged with blood
● Bleeding
○ Coughing up blood
● Blood clots
 Risk Factors
❖ Smoke or have smoked
❖ Have a major exposure to secondhand smoke
❖ Older in age
❖ Have certain other cancers
❖ Have a parent, sibling, or child who has had lung cancer
❖ Have exposure to cancer-causing agents
❖ Have certain other lung diseases
 Epidemiology
Lung cancer has been the most common cancer in the world for several decades. There
are estimated to be 1.8 million new cases in 2012 (12.9% of the total), 58% of which
occurred in the less developed regions.Lung cancer is the most common cause of death
from cancer worldwide, estimated to be responsible for nearly one in five (1.59 million
deaths, 19.4% of the total).

According to the latest WHO data published in 2017 Lung Cancers Deaths in Philippines
reached 11,365 or 1.84% of total deaths. The age adjusted Death Rate is 16.99 per
100,000 of population ranks Philippines #72 in the world.
 Staging (SCLC)
1. Limited Stage
○ Stage I to III of NSCLC excluding T3-T4
○ found on one side of the chest, involving only one part of the lung and the nearby
lymph nodes
2. Extensive Stage
○ Stage IV or T3-T4
○ cancer has spread to other regions of the lungs, or other parts of the body
TNM Classification
❏ American Joint Committee on
Cancer staging system → used to
stage lung cancer
❏ T, N, and M → used to describe
areas of cancer growth
❏ T - tumor
❏ How large or where the
primary tumor is grown
❏ N - nodes
❏ How far the cancer has
spread through the lymph
❏ M - metastasis
TNM Classification
Staging (NSCLC)
○ Stage I - located only in the lungs
○ Stage II - in the lung and nearby lymph
nodes
○ Stage III - found in the lungs and in the
lymph nodes in the middle of the chest;
locally advanced
■ IIIA - if the cancer spread to the lymph
nodes on the same side of the chest
where the cancer started
■ IIIB - if the cancer has spread to the
lymph nodes on the opposite side of
the chest or above the collar bone
○ Stage IV - most advanced stage; when the
cancer has spread to both lungs, to fluid in
the area around the lungs, or to another
part of the body, such as the liver or other
organs.
Diagnostic Tests (NSCLC)
❖ Blood Tests
➢ Complete Blood Count (CBC)
➢ Chemistry Profile
❖ Imaging Test
➢ Diagnostic CT
➢ FDG PET/CT
➢ Brain MRI
➢ MRI of spine and thoracic inlet
❖ Bronchoscopy
❖ Lung Function Test
FDG PET/CT
❖ Biopsy
➢ TTNA
➢ Mediastinoscopy
➢ EBUS-TBNA
➢ EUS-FNA
➢ Thoracentesis
➢ Pericardiocentesis
➢ Thoracoscopy
Cancer lab test
● Histologic typing
● Biomarker testing
○ Overactive EGFR mutation
○ ALK gene rearrangement
○ ROS1 gene rearrangement
○ BRAF V600E mutation
 Lung CA
suspect (A)
No other Y No Y Close follow
CA site? CT Scan (C)
Chest X-ray Mass? up; Refer
PAL (B) N N
Manage by
No Y
case; Refer
Mass?
N
Centrally Y Bronchoscopy w/
located? biopsy or cytology
(D)
N
Peripheral Y Percutaneous
location? FNAB (E)
Cancer? Y
N A
(G)
Enlarged Y
neck Biopsy N
nodes?
Highly Y
N suspect Radio tx
Pleural Y Thoracentesis w/ cancer?
effusion? cytology (F)
 No case; Refer
Mass?
N
Centrally Y Bronchoscopy w/
located? biopsy or cytology
(D)
N
Peripheral Y Percutaneous
location? FNAB (E)
Cancer? Y
N A
(G)
Enlarged Y
neck Biopsy N
nodes?
Highly Y
N suspect Radio tx
Pleural Y Thoracentesis w/ cancer?
effusion? cytology (F)
N
Close follow-
N Refer up
Highly suspect Y
Radio tx
cancer?

N
Close
Refer
surveillance
 A

Positive lung
cancer? (G)

Y Stage Y Y
Not Rt +/- chemo
SCLC? T1T2N0M
operable?
0? (H)

N N
Adjuvant Rt (K)
Lobectomy (J) and/or Chemo (L)

Stage Y
T3T4N1- Chemo +/- Rt
3M0? (H)

N
Palliative
Metastatic? Chemo +/- Rt
 Management of Small Cell Lung Cancer
1. Chemotherapy
○ Typical treatment for SCLC
○ SCLC has usually already spread by the time it is found, so other treatments such as surgery
or radiation therapy would not reach all areas of cancer
● For people with limited stage SCLC, chemo is often given along with radiation therapy.
This is known as chemoradiation.
● For people with extensive stage SCLC, chemo alone is usually the main treatment
2. Immunotherapy
○ Nivolumab (Opdivo)
● targets PD-1, a protein on T cells that normally helps keep these cells from attacking
other cells in the body. By blocking PD-1, this drug boosts the immune response against
SCLC shrinking tumor cells.
● It is used in people with advanced small cell lung cancer whose cancer continues to
grow after at least two previous systemic treatments including cisplatin or carboplatin.
 Management of Small Cell Lung Cancer
3. Radiation Therapy
○ uses high-energy rays (such as x-rays) or particles to kill cancer cells
○ Can be given with chemotherapy in limited stage of SCLC
○ can also be given after the chemo is finished
● done for patients with extensive stage disease
● or it can be used for people with limited stage as an alternative to chemoradiation
○ can be given to the brain to help lower the chances of problems from cancer spread there.
● prophylactic cranial irradiation
■ most often used to treat people with limited stage SCLC, but it can also help some
people with extensive stage SCLC
○ used to shrink tumors to relieve (palliate) symptoms of lung cancer such as pain, bleeding,
trouble swallowing, cough, shortness of breath, and problems caused by spread to other
organs such as the brain.
 Management of Small Cell Lung Cancer
4. Surgery
○ rarely used as part of the main treatment
○ Early-stage cancer
● If cancer is found as only a single lung tumor, with no spread to lymph nodes or other
organs
○ followed by additional treatment
○ Types of Surgery
● Pneumonectomy
● Lobectomy
● Segmentectomy or wedge resection
● Sleeve resection
 Management of Small Cell Lung Cancer
5. Palliative Procedure
○ aimed at relieving symptoms and improving a person’s quality of life
○ Treating an airway blocked by a tumor
■ Photodynamic therapy (PDT)
■ Laser therapy
■ Stent placement
○ Treating fluid buildup in the area around the lung
■ Thoracentesis
■ Pleurodesis
■ Catheter placement
○ Treating fluid buildup around the heart
■ Pericardiocentesis
■ Creating a pericardial window
TREATMENT GUIDELINE FOR SMALL CELL LUNG CANCER
Chemotherapy for SCLC
➔ As primary or adjuvant therapy

Limited stage (maximum of 4–6 cycles):

❏ Cisplatin 60 mg/m2 day 1 and etoposide 120 mg/m2 days 1,2,3
❏ Cisplatin 80 mg/m2 day 1 and etoposide 100 mg/m2 days 1,2,3
❏ Carboplatin AUC 5–6 day 1 and etoposide 100 mg/m2 days 1,2,3
❏ During systemic therapy + RT, cisplatin/etoposide is recommended (category 1).

❏ The use of myeloid growth factors is not recommended during concurrent

systemic therapy plus radiotherapy (category 1 for not using GM-CSF).
Chemotherapy for SCLC
Extensive stage (maximum of 4–6 cycles):
❏ Carboplatin AUC 5–6 day 1 and etoposide 100 mg/m2 days 1,2,3
❏ Cisplatin 75 mg/m2 day 1 and etoposide 100 mg/m2 days 1,2,3
❏ Cisplatin 80 mg/m2 day 1 and etoposide 80 mg/m2 days 1,2,3
❏ Cisplatin 25 mg/m2 days 1, 2, 3 and etoposide 100 mg/m2 days 1,2,3
❏ Carboplatin AUC 5 day 1 and irinotecan 50 mg/m2 days 1,2,3
❏ Cisplatin 60 mg/m2 day 1 and irinotecan 60 mg/m2 days 1,8
❏ Cisplatin 30 mg/m2 and irinotecan 65 mg/m2 days 1,8,15
❏ Carboplatin AUC 5 day 1 and irinotecan 50 mg/m2 days 1,8,15

Subsequent chemotherapy
➔ Clinical Trial preferred
Chemotherapy for SCLC
Relapse ≤6 mo, PS 0-2:
➢ topotecan PO or IV
➢ irinotecan
➢ paclitaxel
➢ docetaxel
➢ temozolomide
➢ nivolumab ± ipilimumab
➢ vinorelbine
➢ oral etoposide
➢ gemcitabine
➢ cyclophosphamide/doxorubicin/vincristine (CAV)
➢ bendamustine (category 2B)

Relapse >6 mos: original regimen

➔ Consider dose reduction or growth factor support for patients with PS 2
Radiotherapy for SCLC
Limited Stage:
➢ Radiotherapy + chemotherapy is preferred. RT should start early with cycle 1
or 2 of chemotherapy.
➢ PET/CT should be obtained w/in 4 weeks and no more than 8 weeks before
treatment.
➢ Dose & schedule: optimal not established
○ 45 Gy in 3 weeks (1.5 Gy BID) is superior to 45 Gy in 5 weeks (1.8 Gy daily)
○ Must have an interval of 6 hrs if BID

Extensive Stage:
➢ Consolidative thoracic RT is beneficial for selected patients that responds to
systemic therapy
○ well-tolerated
Radiotherapy for SCLC
Prophylactic Cranial Irradiation (PCI)
➢ Preferred dose: 25 Gy in 10 daily fractions
○ Shorter course (20 Gy in 5 fractions) for selective extensive-stage
disease
➢ Not recommended in patients with poor performance status or impaired
neurocognitive functioning

Brain Metastases
➢ Should be treated with whole brain radiation therapy (WBRT) rather than
stereotactic radiotherapy/radiosurgery (SRT/SRS) alone
➢ Recommended dose: 30 Gy in 10 daily fractions
SCLC?

NSCLC Y Y Y
Surgery (J) Positive
Stage I? Operable? Rt
margins?
(I)

N N N
Chemo +/- Close follow-
RT (L) up

Y Y Y
Stage Surgery Positive
Operable? Rt
II/III? margins?

N N
Chemo +/- Close follow-
Stage IV RT (L) up

Y Y
Single site Palliative
Operable?
metastasis? Surgery Chemo +/- Rt

N N

Palliative treatment Chemo +/- RT (L)

TREATMENT GUIDELINE FOR NON-SMALL CELL LUNG
CANCER
Overview of treatment
1. Surgery
○ Commonly used to treat Stage I, II, and some III cancer
○ Lung tumor surgery
■ Wedge resection
■ Segmentectomy
■ Lobectomy
■ Sleeve lobectomy
■ Pneumonectomy
○ Lymph node surgery
2. Ablation
○ Uses heat from electrodes that are passed through a bronchoscope
3. Radiation therapy
○ May be used for all stages of lung cancer
○ May be used to treat cancer or reduce the symptoms
○ May be used alone or with other types of cancer treatment
○ External beam radiation therapy
4. Chemotherapy
○ Includes drugs that disrupts the life cycle of cancer cells
5. Targeted therapy
○ Works by stopping key molecules that help cancer cells grow
 Targeted Therapy Drugs
Chemotherapy Drugs
● EGFR
● Alkylating Agents ○ Erlotinib
○ Carboplatin ○ Gefitinib
○ Cisplatin ○ Afatinib
● Chromatin function inhibitors ○ Osimertinib
○ Docetaxel ● Ado-trastuzumab
○ Paclitaxel ● Alectinib
○ Paclitaxel, albumin bound ● Bevacizumab
○ Etoposide, etoposide, ● Brigatinib
phosphate ● Ceritinib
○ Vinblastine sulfate ● Cetuximab
○ Vinorelbine tartrate ● Crizotinib
● Gemcitabine hydrochloride ● Dabrafenib
● Antimetabolite ● Ramucirumab
○ Pemetrexed
● Trametinib
● Vandetanib
● Vemurafenib
6. Immunotherapy
○ PD-1 and PD-L1 inhibitors
■ Atezolizumab
■ Durvalumab
■ Nivolumab
■ Pembrolizumab
Treatment for Stage I NSCLC
Initial Pathologic Margin Status Adjuvant
Treatment Stage

Lung tumor Stage IA No cancer in the margin start survivorship plan

and lymph
node surgery
Cancer in the margin another surgery (preferred)
radiation therapy

Stage IB No cancer in the margin start survivorship plan

chemotherapy

Cancer in the margin another surgery ± chemotherapy

radiation therapy ± chemotherapy

Radiation Stage IA start survivorship plan

therapy

Stage IB consider chemotherapy

Treatment for Stage II NSCLC (T2 or T3 w/o invasion)
Initial Pathologic Margin Status Adjuvant
Treatment Stage

Lung tumor Stage IIA No cancer in the margin start survivorship plan
and lymph chemotherapy
node surgery
Cancer in the margin another surgery (preferred)
chemoradiation

Stage IIB No cancer in the margin chemotherapy

Cancer in the margin another surgery +chemotherapy

(seen with microscope) chemoradiation

Cancer in the margin another surgery +chemotherapy

(seen with naked eye) chemoradiation

Radiation chemotherapy
therapy
Treatment for Stage II NSCLC (T3 superior sulcus tumor)
Treatment

Surgery + chemotherapy

Chemoradiation (at the same time)

Treatment for Stage II NSCLC (T3 other invasive tumor)
Initial Treatment Margin Status Adjuvant

Surgery No cancer in the margin Chemotherapy

Cancer in the margin Another surgery + chemotherapy

(seen w/ microscope) chemoradiation

Cancer in the margin Another surgery + chemotherapy

(seen w/ naked eye) chemoradiation

Preoperative No cancer in the margins start survivorship plan

chemoradiation (at the
same time) followed by Cancer in the margins another surgery
surgery

Chemoradiation (at the

same time)
Survivorship Plan (Stage I and II)
Treatment for Stage III NSCLC (N0 or N1 disease)
Tumors without invasion

Initial Treatment Margin Status Adjuvant

Lung tumor and No cancer in the margin Chemotherapy

lymph node surgery
Cancer in the margin (seen w/ microscope) Chemoradiation

Cancer in the margin (seen w/ naked eye) Chemoradiation

Chemoradiation (at Durvalumab

the same time)
Treatment for Stage III NSCLC (N0 or N1 disease)
Superior sulcus tumors

Initial Treatment Surgery Status Adjuvant

Chemoradiation (at Surgery is an option Chemotherapy

the same time)
Surgery is not an option complete radiation therapy +
chemotherapy + durvalumab

Chemoradiation (at Durvalumab

the same time)
Treatment for Stage III NSCLC (N0 or N1 disease)
Other invasive tumors

Initial Treatment Margin Status Adjuvant

Surgery No cancer in the margin Chemotherapy

Cancer in the margin Another surgery + chemotherapy

(seen w/ microscope) Chemoradiation

Cancer in the margin Another surgery + chemotherapy

(seen w/ naked eye) Chemoradiation

Chemoradiation (at No cancer in the margins Start survivorship plan

the same time) +
surgery Cancer in the margins Another surgery

Chemotherapy + No cancer in the margins Start survivorship plan

surgery
Cancer in the margins Another surgery

Chemoradiation (at Durvalumab

the same time)
Treatment for Stage III NSCLC (N2 disease)
Initial Treatment Post-initial treatment

Chemoradiation Durvalumab

Induction chemotherapy ± radiation therapy Adjuvant radiation (if not received before) ± chemotherapy

For N2 found after surgery

Margin status Adjuvant

Surgery No cancer in the margins Chemotherapy

Chemoradiation

Cancer in the margins Chemoradiation

(seen w/ microscope)

Cancer in the margins Chemoradiation

(seen w/ naked eye)
Treatment for Stage III NSCLC (N3 disease)
Initial Treatment Post-initial treatment

Chemoradiation Durvalumab
Survivorship plan (Stage III)
Treatment for Stage IV NSCLC
Overactive EGFR mutation

First-line Treatment Next-in-line Treatment

Erlotinib Stay on first-line treatment ± local treatment

Switch to osimertinib if T790M is present
Afatinib Start treatment for histologic type it T790M is not present
● Adrenocarcinomas, large cell, unknown types
Gefitinib ● Squamous cell carcinoma

Osimertinib Stay on osimertinib ± local treatment

Start treatment for histologic type

ALK gene rearrangement

First-line Treatment Next-in-line Treatment

Alectinib Stay on first-line treatment ± local treatment

Switch from crizotinib to ceritinib, alectinib, or brigatinib ± local treatment
Crizotinib Start treatment for histologic type it T790M is not present
● Adrenocarcinomas, large cell, unknown types
Ceritinib ● Squamous cell carcinoma
Treatment for Stage IV NSCLC
ROS1 gene rearrangement

First-line Treatment Next-in-line Treatment

Crizotinib Start treatment for histologic type it T790M is not present

● Adrenocarcinomas, large cell, unknown types
Ceritinib ● Squamous cell carcinoma

BRAF V600E mutation

Dabrafenib + trametinib

Start treatment for histologic type it T790M is not present

● Adrenocarcinomas, large cell, unknown types
● Squamous cell carcinoma

PD-L1 positive >= 50%

Pembrolizumab

Start treatment for histologic type it T790M is not present

● Adrenocarcinomas, large cell, unknown types
● Squamous cell carcinoma
Treatment for Stage IV NSCLC
Adrenocarcinomas, large cell carcinomas, and unknown types

Performance First-line treatment Maintenance Treatment Next-in-line Treatment

score

0 or 1 Platinum-based chemotherapy Continuation: Nivolumab

Bevacizumab + platinum-based ● Bevacizumab Pembrolizumab
chemotherapy ● Pemetrexed Atezolizumab
Pembrolizumab + ● Bevacizumab + Docetaxel
chemotherapy pemetrexed Pemetrexed
● Gemcitabine Gemcitabine
2 Chemotherapy Switch: Ramucirumab + docetaxel
● Pemetrexed
3 or 4 Supportive care Start close observation Supportive care
Treatment for Stage IV NSCLC
Squamous cell carcinoma

Performance First-line treatment Maintenance Treatment Next-in-line Treatment

score

0 or 1 Platinum-based chemotherapy Continuation: Nivolumab

● Gemcitabine Pembrolizumab
2 Chemotherapy Switch: Atezolizumab
● Docetaxel Docetaxel
Start close observation Gemcitabine
Ramucirumab + docetaxel

3 or 4 Supportive care Supportive care

Case
History of Present Illness
A 61-year-old patient developed pain in his neck (stiff neck). He sees his local
physician who orders an X-ray of his neck, which is negative. Patient’s neck pain
persists over the next two months, and he develops decreased appetite, decreased
energy, and a dry cough. His physician orders an MRI of the neck that reveals a
spine lesion and a right lung mass. Chest CT scan shows a 4-cm right upper lung
mass with enlarged right hilar and right paratracheal lymph nodes. A PET scan
shows uptake in the right upper lobe mass, the hilar and paratracheal nodes as well
as in several cervical and thoracic vertebrae. An MRI of the brain shows no
metastases. A CT-guided biopsy of the right upper lobe mass shows a TTF-1
positive adenocarcinoma; T2N2M1b, stage IV lung cancer. Molecular testing shows
no EGFR, ALK, ROS, RET, BRAF, HER2, or NTRK alterations. PD-L1 testing was
also negative with no positive cells. Labs show elevated CEA (26), low albumin
(3.4), normal creatinine, CBC, and liver function.
Case
Past Medical History
● Former smoker
● Hypercholesterolemia treated with pravastatin
● No allergies
● No family history of lung cancer

Social History
● Employed full-time as an accountant
● Married with 2 children
● Youngest son is about to graduate from US Air Force Academy

Initial Treatment
● Patient was started on chemotherapy with pemetrexed and a platinum every
three weeks (with vitamin B12 and folic acid supplementation)
Case
Physical Exam/Review of Symptoms at Progression
● ECOG PS 1
● No palpable lymph nodes
● Decreased breath sounds in right upper lobe

Response Assessment/Follow-Up Imaging

● After the first cycle, there was no change in his neck pain, appetite, and dry
cough, and his fatigue had increased. His CEA increased to 28 and CBC
revealed mild anemia (Hgb 11.0). After his second cycle, a chest CT scan
showed an increase in the right lung mass to 5.2 cm, a progression of the bone
lesions, an increase in CEA (34), a decrease in albumin (3.2), and decrease in
hemoglobin (10.2).
Case
Patient Attitude/Characteristics
● Patient wants to continue working
● He wants to see his son graduate from the Air Force Academy
● He strongly desires further treatment
● Determined to do all he can for a chance to slow progression and extend his life

Treatment Plan
● Because the patient has progressive disease with symptoms, a discussion was
had with the patient regarding his options, which included immunotherapy as
well as docetaxel with ramucirumab. After an explanation of both options,
including the available data, the patient elects to receive docetaxel and
CYRAMZA.
Case
Why adding CYRAMZA may be appropriate
● Patient presents with rapidly progressing disease†
● Patient has a good performance status (ECOG PS 1)
● Patient has aggressive disease, with progressive disease as best response to
initial therapy
● Patient wants a chance to see a response to treatment and slow progression
● He is determined to do all he can to try and continue working to support his
family and to be able to see his son graduate from the Air Force Academy
References
American Cancer Society. (2018). Treating Small Cell Lung Cancer. Retrieved from https://www.cancer.org/cancer/small-cell-lung-
cancer/treating.html
American Cancer Society. (2018). What Causes Small Cell Lung Cancer? Retrieved from https://www.cancer.org/cancer/small-cell-lung-
cancer/causes-risks-prevention/what-causes.html
American Joint Committee on Cancer. (2009). Lung Cancer Staging. Retrieved from http://cancerstaging.org/references-
tools/quickreferences/documents/lungmedium.pdf
Dholaria, B., Hammond, W., Shreders, A., & Lou, Y. (2016). Emerging therapeutic agents for lung cancer. Journal of hematology & oncology, 9(1),
138. https://doi.org/10.1186/s13045-016-0365-z
Haymarket Media, Inc. (2014). Lung Cancer Treatment Regimens. Retrieved from
http://media.chemotherapyadvisor.com/documents/32/lungcancer_7894.pdf
Lung Foundation Australia. (2014). Types of Lung Cancer. Retrieved from https://lungcancernetwork.com.au/about-lung-cancer/types-of-lung-cancer/
Mechanisms in Medicine. (2012, March 14). The Pathophysiology of Non-small Cell Lung Cancer. Retrieved from
https://www.youtube.com/watch?v=J5UfBV18Bis
Nasser, N. J. (2010). The Best Oncologist TM. Retrieved from
http://www.thebestoncologist.com/Cancer_Diseases/Lung_Cancer/Staging_of_Lung_Cancer.html
National Comprehensive Cancer Network. (2016, September 15). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Small Cell
Lung Cancer. Retrieved from https://www2.tri-kobe.org/nccn/guideline/lung/english/small.pdf
National Comprehensive Cancer Network. (2018). Non-small cell lung cancer. Retrieved from https://www.nccn.org/patients/guidelines/lung-
nsclc/files/assets/common/downloads/files/nsclc.pdf
Philippine Cancer Society. (2014). Tertiary prevention of cancer: Clinical treatment guidelines. Retrieved from http://www.philcancer.org.ph/wp-
content/uploads/2014/04/PCSI-Tertiary-Cancer-Treatment-Guidelines.pdf
Philippine Society of Medical Oncology. (2005). CPM 8th Breast Cancer and Lung Cancer. Retrieved from
https://www.thefilipinodoctor.com/cpm_pdf/CPM8th Breast Cancer and Lung Cancer.pdf
World Health Organization. (2018). Cancer. Retrieved from http://www.who.int/cancer/en/
World Health Organization. (2015). Globocan. Retrieved from http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung
World Health Rankings. (2017). Lung Cancers in Philippines. Retrieved from http://www.worldlifeexpectancy.com/philippines-lung-cancers
References
Fauci, A.. et al. (2008). Harrison’s Principle of Internal Medicine (17th edition). United States of America: The McGraw-Hill Companies Inc.
Goldman, L., Schaffer, A. (2012). Goldman’s Cecil Medicine (24th edition). Philadelphia, PA: Elsevier Saunders.
Gradishar, W. MD et al., (2017). NCCN Guidelines Insight. Journal of the National Comprehensive Cancer Network. (15)4. p. 433
Philippine Cancer Society (2015). Tertiary Prevention of Cancer: Clinical Treatment Guidelines. Retrieved from http://www.philcancer.org.ph/wp-
content/uploads/2014/04/PCSI-Tertiary-Cancer-Treatment-Guidelines.pdf
Wells, B. et al. (2009). Pharmacotherapy Handbook (7th edition). United States of America: The McGraw-Hill Companies Inc.