Primary treatment is the first-line therapy, and in certain tumor types may be

referred to as induction therapy. Choice of primary treatment is governed by

observations made from clinical trials that demonstrate that a given regimen has the

highest known activity against the tumor. These regimens may include chemotherapy,

targeted agents, endocrine agents, or biologic response modifiers. Second-line

treatment is administered after the tumor has become refractory to primary therapy or

if the patient is unable to tolerate first-line therapy. Systemic therapy is frequently

used in different ways during the course of an individual’s malignancy. Primary

treatment can be either curative or palliative, depending on the specific type of tumor

(Table 93-6).

48 After primary therapy, patients may receive additional treatment in an

attempt to further eradicate residual disease and improve their chances for long-term

survival. This treatment may be termed consolidation, intensification, or maintenance

therapy. See subsequent chapters for specific discussion of the use of primary,

consolidation, or maintenance therapy in the treatment of hematologic and solid tumor

malignancies.

Adjuvant Therapy

CASE 93-8

QUESTION 1: F.R., a 58-year-old woman with no other medical problems, recently underwent surgical

resection for stage III ovarian cancer. She has been told that she currently has no evidence of cancer;

however, she also is told that she should now receive 6 months of chemotherapy. Why would chemotherapy be

recommended now when she has no detectable disease?

Micrometastases or residual disease may still be present in some patients after

primary treatment. These patients have a high probability of disease recurrence, even

though the primary treatment may have successfully removed all visual evidence of

the primary tumor. To eradicate any undetectable tumor in these patients, systemic

therapy after initial curative surgery (or radiation therapy) may be recommended.

Systemic treatment administered after primary therapy (in the case of F.R., primary

therapy was surgery) is referred to as adjuvant therapy. Because the tumor burden is

relatively low at this time, adjuvant therapy should immediately follow primary

therapy. For adjuvant therapy to provide benefit, the risk of tumor recurrence must be

high, and effective agents must be available to eradicate the tumor. Adjuvant therapy

is considered standard of care for some stages of breast, lung, and colorectal cancer,

but it also has benefited selected patients with ovarian cancer, Ewing sarcoma,

Wilms tumor, and other malignancies (Table 93-7).

48 The duration of administration

of adjuvant therapy varies depending on the type of cancer being treated and the

drugs being used, but is typically several weeks to months in duration. See

subsequent chapters for specific discussion of the use of adjuvant therapy in solid

tumor malignancies. F.R. will receive adjuvant chemotherapy with six to eight cycles

of carboplatin and paclitaxel.

Table 93-7

Neoplasms for Which Adjuvant Systemic Therapy is Indicated After Primary

Treatment

Anaplastic astrocytoma

Breast cancer

Colorectal cancer

Gastric cancer

Melanoma

Non-small-cell lung cancer

Osteogenic sarcoma

Ovarian cancer

Reprinted from DeVita VT Jr, Chu E. Principles of medical oncology: basic principles. In: DeVita VT Jr et al, eds.

DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 8th ed. Philadelphia, PA:

Lippincott Williams & Wilkins; 2008:339, with permission.

Because it is difficult to detect micrometastases or residual disease, it is a

challenge to determine which patients should receive adjuvant therapy. To help with

these decisions, clinicians frequently consider histologic and cytogenetic

characteristics of the primary tumor that are associated with high risk of relapse.

Neoadjuvant Therapy

Neoadjuvant therapy is given before the primary treatment (typically surgery or

radiation) in patients who present with locally advanced tumors (e.g., large tumors or

those that are impinging on surrounding vital structures) that are unlikely to be cured

with primary therapy alone. The objective of neoadjuvant therapy is to reduce the

tumor mass, thereby increasing the likelihood of eradication by subsequent surgery or

radiation. Neoadjuvant therapy also can lessen the amount of radical surgery the

patient needs, which can preserve cosmetic appearance and function of the

surrounding normal tissues. The tumor can be resistant to neoadjuvant therapy and

continue to grow, however, making surgery or radiation even more difficult. Patients

may also experience toxicities with neoadjuvant therapy that may delay surgery or

impair postsurgical healing. Locally advanced tumors in which neoadjuvant therapy

has been shown to improve survival rates include non-small-cell lung cancer, breast

cancer, sarcomas, esophageal cancers, laryngeal cancer, bladder cancer, and

osteogenic sarcoma (Table 93-8).

48 See subsequent chapters for specific discussion

of the use of neoadjuvant therapy in solid tumors.

CASE 93-9

QUESTION 1: H.P. is a 57-year-old man who is currently undergoing a staging workup for a presumed

diagnosis of metastatic adenocarcinoma of the lung. He has heard that cytotoxic “chemotherapy is the only

thing available to treat metastatic cancer.” What other agents are being used to treat cancer besides those that

are considered cytotoxic?

TARGETED THERAPY

By understanding the mechanisms by which cancer cells exhibit unregulated growth

and immortality and possess the ability to invade tissues and metastasize, it has been

possible to design drugs that inhibit these processes.

Monoclonal Antibodies

Directed at specific receptors associated with cancer, monoclonal antibodies block

ligands from binding to their targets. Unlike traditional chemotherapy, monoclonal

antibodies selectively target receptors or their ligands known to potentiate cancer

pathways, and as a result, minimize toxicity to noncancer cells. Table 93-9 provides

a list of monoclonal antibodies currently approved by the US Food and Drug

Administration to treat malignancy.

35

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) are small molecules that directly inhibit tyrosine

kinase activation by competing with ATP for binding to the intracellular tyrosine

kinase domain. Advantages of these inhibitors include inhibiting cells that may not

overexpress the receptor on their surface or have mutated forms of the receptor that

result in its activation and direct inhibition of cell signaling. Even though most TKIs

are designed to inhibit a single target, they often have inhibitory properties for

additional molecules, which could affect an internal cascade of biologic activity

resulting in antitumor activity and toxicity.

p. 1958

p. 1959

Table 93-8

Neoplasms for Which Neoadjuvant Systemic Therapy is Indicated for Locally

Advanced Disease

Anal cancer

Bladder cancer

Breast cancer

Cervical cancer

Gastroesophageal cancer

Lung cancer

Head and neck cancer

Ovarian cancer

Osteogenic sarcoma

Pancreatic cancer

Reprinted with permission from DeVita VT, Jr, Chu E. Principles of medical oncology: basic principles. In: DeVita

VT, Jr et al, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 8th ed.

Philadelphia, PA: Lippincott Williams & Wilkins; 2008:338.

This class of drug is taken orally. Due to varying pharmacokinetics, specific

instructions on self-administration should be provided to patients (i.e., take on an

empty stomach, take with a full meal). Additionally, many TKIs are substrates,

inhibitors, and inducers of CYP P450 enzymes. Attention to potential drug interaction

is crucial to safe medication use.

Table 93-10 provides the TKIs currently approved by the US Food and Drug

Administration to treat malignancies.

35

Other Targeted Therapy

Because more information is learned regarding signal transduction pathways and

cellular growth and proliferation, more drugs are being developed that target these

key molecules. Histone deacetylase (HDAC) inhibitors, mammalian target of

rapamycin (mTOR) inhibitors, and proteasome inhibitors are examples of drugs that

have novel mechanism(s) of action. Table 93-11 lists these and other targeted agents

currently approved by the US Food and Drug Administration to treat malignancies.

35

Combination Therapy with Targeted Agents

The optimal activity of adding targeted agents to cytotoxic chemotherapy is difficult

to predict. Knowledge about how to combine targeted agents with chemotherapy is

limited, although clinical investigations are ongoing. See subsequent chapters for

specific discussion of the use of targeted therapy with chemotherapy in solid tumor

and hematologic malignancies.

ENDOCRINE THERAPY

Endocrine therapy can be used to treat several common cancers, including breast,

prostate, and endometrial cancers, which arise from hormone-sensitive tissues

(Table 93-12). These tumors grow in response to endogenous hormones that trigger

growth signals. Current endocrine therapies inhibit tumor growth by blocking

hormone receptors or by eliminating endogenous hormone feeding the tumor. Not all

tumors arising from hormone-sensitive tissues respond to endocrine manipulation.

Lack of response may be associated with hormone-resistant tumor cells or inadequate

suppression of the endogenous feeding hormones.

49

IMMUNOTHERAPY

Immune therapy is comprised of substances that stimulate the body’s immune system

to identify circulating tumor cells. Some agents target certain cells of the immune

system; other agents are more nonspecific.

34 An individual’s immune system plays a

crucial role in developing or eradicating cancer. Normally, an intact immune system

can protect the host against malignant cells and infectious pathogens, but current

evidence shows that individuals with “weakened” immune systems are at an

increased risk of developing cancer. Immunotherapy can include vaccines, cytokines,

and checkpoint inhibitors.

Table 93-9

Monoclonal Antibodies

Class

a Agent (Trade Name) Mechanism of Action Notable Toxicities

Anti-CD19,

Anti-CD3

Blinatumomab (Blincyto) Binds to CD19 on B cells and

CD3 on T cells; causes

formation of cytolytic synapses

between B and T cells

Neurotoxicity; infection; tremor;

fever; edema, rash; nausea,

diarrhea, constipation; cytokine

release syndrome

Anti-CD20 Obinutuzumab (Gazyva) Binds to CD20 on B cells;

induces cell death via ADCC,

CDC, and antibody-dependent

cellular phagocytosis

Myelosuppression; hepatic and

renal dysfunction; electrolyte

abnormalities; infection; infusion

reaction

Ofatumumab (Arzerra) Binds to CD20 on B cells at

different binding sites than

rituximab; induces cell death via

ADCC and CDC

Cough; diarrhea, nausea;

fatigue; myelosuppression;

hypersensitivity reaction,

pyrexia; rash; infection

Rituximab (Rituxan) Binds to CD20 on B cells;

induces cell death via ADCC

and CDC

Hypersensitivity reaction;

myelosuppression; infection;

tumor lysis syndrome

Anti-CD20

Radiation

Ibritumomab tiuxetan

(Zevalin)

Yttrium-90 (Y-90) linked to

rituximab; binds to CD20 on B

cells and releases radiation (β

particles); induces cell damage

via free radicals

Infusion-related reaction; chills,

nausea; fatigue;

myelosuppression; see notable

toxicities for rituximab

Tositumomab (Bexxar) Iodine-131 linked to rituximab;

binds to CD20 on B cells and

Infusion-related reaction;

nausea; myelosuppression,

binds to CD20 on B cells and

releases radiation; induces cell

death via ADCC and CDC

nausea; myelosuppression,

infection; hypothyroidism; see

notable toxicities for rituximab

p. 1959

p. 1960

Anti-CD30 Brentuximab vedotin

(Adcetris)

Three-component antibody drug

conjugate; binds to cells

expressing CD30 and is

internalized; monomethyl

auristatin E is then released

which disrupts the microtubule

network

Myelosuppression; peripheral

neuropathy; fatigue; nausea,

vomiting, diarrhea; fever; rash;

upper respiratory infection

Anti-CD52 Alemtuzumab (Campath) Binds to CD52, leading to lysis

of CD52-positive leukemic cells

Hypersensitivity reaction;

myelosuppression, opportunistic

infection, fever; nausea, rash

Anti-EGFR Cetuximab (Erbitux) Binds to EGFR, preventing

activation and inhibiting cell

proliferation

Papulopustular rash;

hypersensitivity reaction;

fatigue; nausea, vomiting,

stomatitis; hypomagnesemia

Panitumumab (Vectibix) Binds to EGFR with higher

affinity than cetuximab,

preventing activation and

inhibiting cell proliferation

Papulopustular rash, pruritus;

fatigue; hypersensitivity

reactions; abdominal pain,

nausea, diarrhea;

hypomagnesemia; paronychia

Anti-HER2 Ado-Trastuzumab

emtansine (Kadcyla)

HER2-antibody drug conjugate

of trastuzumab and microtubule

inhibitor DM1; binds to HER2

inducing cell cycle arrest and

cell death

Myelosuppression, nausea,

constipation, diarrhea; fatigue,

peripheral neuropathy;

hypokalemia, fever

Pertuzumab (Perjeta) Binds to HER2, inhibiting HER2

dimerization and downstream

signaling, halting cell growth

Myelosuppression;

cardiomyopathy; fatigue,

alopecia; nausea, vomiting,

diarrhea

Trastuzumab (Herceptin) Binds to HER2; induces cell

death via ADCC

Cardiomyopathy; nausea,

vomiting, diarrhea; infusionrelated reaction

Anti-VEGF Bevacizumab (Avastin) Binds to and inhibits VEGF

ligand interaction with receptors,

blocking angiogenesis

Hypertension; bleeding,

thrombosis; gastrointestinal

perforation; impaired wound

healing; proteinuria

Ramucirumab (Cyramza) Binds to and inhibits VEGF2

ligand interaction with receptors

(VEGF-A, VEGF-C, VEGF-D),

blocking angiogenesis

Hypertension; proteinuria;

infusion-related reaction;

bleeding; thrombosis;

gastrointestinal perforation

Immune

Checkpoint

Inhibitors

Ipilimumab (Yervoy) Enhances T-cell activation and

proliferation by inhibiting CTLA4; restoring antitumor immune

response

Fatigue; nausea, anorexia,

diarrhea, colitis; pruritus, rash;

hepatic dysfunction;

hypophysitis

Nivolumab (Opdivo) Enhances T-cell activation and

proliferation by inhibiting PD-1

Rash, pruritus; nausea,

constipation, diarrhea; fatigue;

activity, which is a negative

regulator of T-cell pathways;

restores antitumor immune

response

electrolyte abnormalities;

hepatic dysfunction;

musculoskeletal pain; cough,

pneumonitis

Pembrolizumab

(Keytruda)

Fatigue; pruritus, rash;

electrolyte abnormalities;

hepatic dysfunction; nausea,

constipation, diarrhea;

arthralgia; cough, pneumonitis

Other Dinutuximab (Unituxin) Cell lysis of GD-2-expressing

neuroblastoma cells via ADCC

and CDC

Myelosuppression; urticaria;

diarrhea, nausea, vomiting;

hepatotoxicity; fever; capillary

leak syndrome; infusion-related

reaction; peripheral neuropathy

aAll monoclonal antibodies are administered intravenously, IV.

ADCC, antibody-dependent cellular toxicity; CDC, complement-dependent cytotoxicity; CTLA-4, cytotoxic Tlymphocyte-associated antigen-4; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor

receptor; PD-1, programmed cell death-1; VEGF, vascular endothelial growth factor.

Sipuleucel-T (Provenge) is a cancer vaccine approved for patients with metastatic

prostate cancer that is resistant to prior endocrine therapy.

50 The immune system is

stimulated to recognize the patient’s own cancer cells. The cytokines, interferon-α

and interleukin 2, were the first immune-modulating therapies available. They

nonspecifically stimulate B- and T-cell proliferation and differentiation along with

activity on other immune functions.

51–56

Immune checkpoint inhibitors release the

brakes on the immune system, allowing it to identify and kill cancer cells better.

34

If H.P. is in fact diagnosed with stage IV adenocarcinoma of the lung, he may

receive other agents besides chemotherapy during the course of treatment for his

disease. For specific discussion of which noncytotoxic agents H.P may receive, refer

to Chapter 98, Lung Cancer.

p. 1960

p. 1961

Table 93-10

Tyrosine Kinase Inhibitors

Class

a

Agent (Trade

Name) Mechanism of Action Notable Toxicities

ALK inhibitor Inhibits ALK thereby reducing

tumor cell proliferation in cells

expressing ALK fusion protein;

also inhibits ROS1 kinase

Myelosuppression, visual

disturbances; liver enzyme

elevations; diarrhea, nausea,

vomiting; fatigue

Ceritinib (Zykadia) Also inhibits IGF-1R, insulin

receptor kinases

Also: increased creatinine;

hyperglycemia

Crizotinib (Xalkori) Also: dysgeusia; edema;

bradycardia

BCR-ABL inhibitor Inhibits BCR-ABL kinase, cKIT, and PDGFR kinases

Myelosuppression; nausea,

vomiting, diarrhea; fatigue;

dermatologic toxicity

Bosutinib (Bosulif) Includes activity against most

imatinib-resistant BCR-ABL

mutations and SRC kinases

Also: electrolyte disturbances;

liver enzyme elevations; fever;

cough, dyspnea

Dasatinib (Sprycel) Inhibits most imatinib-resistant

BCR-ABL mutation kinases and

SRC kinases

Also: headache; fluid retention,

pleural effusion

Imatinib mesylate

(Gleevec)

Also: fluid retention; headache;

hepatic toxicity; musculoskeletal

pain

Nilotinib (Tasigna) Inhibits most imatinib-resistant

BCR-ABL mutation kinases

Also: musculoskeletal pain;

hepatic toxicity; hyperglycemia;

QT prolongation

Ponatinib (Iclusig) Inhibits most imatinib-resistant

BCR-ABL mutation kinases and

VEGFR, SRC RET, and FLT3

kinases

Also: hypertension; edema,

arterial ischemia; headache;

arthralgias; constipation; hepatic

dysfunction; dyspnea, pleural

effusion

BTK inhibitor Irreversibly inhibits the BTK of

the B-cell receptor signaling

pathway

Myelosuppression; nausea,

diarrhea; fatigue, edema, fever;

dermatologic toxicity;

musculoskeletal pain; tumor

lysis syndrome

Ibrutinib (Imbruvica)

EGFR inhibitor Inhibits EGFR TK; resulting

tumor growth inhibition

Rash, dry skin, pruritis;

paronychia; diarrhea

Afatinib (Gilotrif) Irreversible inhibitor of EGFR as

well as HER2 and HER4

Also:stomatitis, decreased

appetite

Erlotinib (Tarceva) Reversible inhibitor of EGFR

HER2 inhibitor Reversibly inhibits HER2 and

EGFR TK

Nausea, diarrhea; dermatologic

toxicity; myelosuppression;

hepatic toxicity;

cardiomyopathy, QT

prolongation; pulmonary toxicity

Lapatinib (Tykerb)

MEK inhibitor Decreased cell proliferation and

increased apoptosis by inhibiting

MEK activation, which is a

downstream effector of BRAF

(mutant)

Cardiomyopathy; acneiform

rash; diarrhea; hepatic

dysfunction; edema; QT

prolongation; hypoalbuminemia

Trametinib

(Mekinist)

PI3K inhibitor Inhibits PI3K expressed on B

cells

Myelosuppression; nausea,

diarrhea, colitis, gastrointestinal

perforation; fatigue; hepatic

toxicity; pulmonary toxicity

Idelalisib (Zydelig)

VEGF inhibitor Inhibits VEGF receptor tyrosine Hypertension; diarrhea, nausea,

kinases thereby blocking

angiogenesis and tumor growth

vomiting

Axitinib (Inlyta) Also: electrolyte disturbances;

creatinine increased; fatigue;

myelosuppression; proteinuria

Cabozantinib

(Cometriq)

Also inhibits FLT-3, KIT, MET,

RET kinases

Also: liver enzyme elevation;

stomatitis, weight loss, anorexia;

fatigue; electrolyte disturbances;

hand-foot syndrome, hair color

changes

Lenvatinib

(Lenvima)

Also inhibits PDGFR, KIT, and

RET kinases

Also: palmar-plantar

erythrodysesthesia; proteinuria;

thrombosis, bleeding; hepatic

toxicity; gastrointestinal

perforation

p. 1961

p. 1962

Pazopanib (Votrient) Also inhibits c-KIT, PDGFR,

FGFR kinases

Also: depigmentation of hair and

skin; dysgeusia, visual

disturbances; muscle spasms;

alopecia, rash

Regorafenib

(Stivarga)

Also inhibits PDGFR-α and -β,

RET, RAF-1 kinases

Also: mucositis; fatigue;

proteinuria; palmar-plantar

erythrodysesthesia: rash;

dysphonia; fever;

myelosuppression; infection

Sorafenib (Nexavar) Also inhibits RAF kinases,

PDGFR-β, FLT-3, c-KIT, RET

kinases

Also: rash, palmar-plantar

erythrodysesthesia;

myelosuppression

Sunitinib (Sutent) Also inhibits PDGFR-α and -

FLT-3 kinases

Also: Myelosuppression;

prolonged QT interval; palmarplantar erythrodysesthesia, skin

discoloration

Vandetanib

(Caprelsa)

Also inhibits EGFR, RET, SRC

kinases

Also: QT prolongation;

headache; colitis; hepatic

dysfunction; leukopenia; rash,

photosensitivity

a All tyrosine kinase inhibitors are administered orally, PO.

ALK, anaplastic lymphoma kinase; ROS1, c-ros oncogene 1; IGF-1R, insulin-like growth factor 1 receptor; BCRABL, breakpoint cluster region-ABL1 gene fusion gene; KIT, tyrosine-protein kinase kit; PDGFR, platelet-derived

growth factor; SRC, steroid receptor coactivator; VEGFR, vascular endothelial growth factor receptor; RET, cRET oncogene; FLT-3, Fms-like tyrosine kinase 3; BTK, Bruton tyrosine kinase; EGFR, epidermal growth factor

receptor; TK, tyrosine kinase; HER2, human epidermal growth factor receptor 2; HER4, human epidermal growth

factor receptor 4; MEK, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)

kinase; BRAF, proto-oncogene b-Raf; PI3K, phosphatidylinositol 3-kinase; MET, proto-oncogene c-Met; FGFR,

fibroblast growth factor receptor; RAF, MAPK 3 kinase

Administration

Systemic

Systemic chemotherapy is most commonly administered by the intravenous route,

either as a bolus injection (generally <15 minutes), short infusion (15 minutes to

several hours), or as a continuous infusion (lasting 24 hours to several weeks). Some

chemotherapy can also be administered orally, intramuscularly, or subcutaneously.

Targeted agents are most commonly administered intravenously or orally.

Monoclonal antibodies are primarily administered intravenously, whereas smallmolecule TKIs are primarily administered by mouth. Endocrine agents are primarily

administered orally or subcutaneously.

Although chemotherapy was initially developed for systemic use, techniques have

been developed to administer agents directly to specific sites of the body affected by

the tumor (Table 93-13). Regionally or locally administered chemotherapy allows

for high concentrations of drug at the tumor site while reducing systemic exposure

and subsequent toxicity. However, a potential disadvantage is that distant

micrometastases may not be exposed to chemotherapy, allowing continued growth of

tumor cells.

Assessing Response to Therapy

CASE 93-10

QUESTION 1: G.K. is a 67-year-old woman who was recently diagnosed with metastatic breast cancer. Her

symptoms include widespread pain, anorexia, and fatigue. She has received two cycles of treatment with a

combination chemotherapy regimen. A recent CT scan of her abdomen showed marked shrinkage at several

tumor sites and her pain has decreased. How long should she continue to receive this chemotherapy?

An important step in the treatment process is assessing response to treatment. This

assessment should include evaluation of efficacy as well as toxicity, including impact

on the patient’s overall quality of life. Re-evaluation should occur at regularly

scheduled intervals and include physical examination, laboratory tests, and repeat

diagnostic imaging.

Response Evaluation Criteria in Solid Tumors (RECIST) was introduced in 2000

to unify response assessment criteria, define how to choose evaluable tumors, and

enable the use of new imaging technologies (spiral CT and MRI). The World Health

Organization, National Cancer Institute, and European Organization for Research and

Treatment of Cancer have adopted RECIST criteria as the standard for evaluating

tumor response (Table 93-14).

57