Approach to the Patient with Cancer

Introduction to the Cancer Patient

Conveying or receiving an initial diagnosis of cancer, or the knowledge that cancer has recurred, is among the most difficult of human enterprises, and no amount of either specialized training or forewarning can adequately assuage the intensity of the emotions associated with these encounters. Patients often experience a storm of feelings that may limit useful discussion immediately following the receipt of a diagnosis of cancer. Even the most well-informed patient typically has difficulty processing the complexities of his or her individual situation, including the range of additional diagnostic tests that may be required and the potentially vast array of treatment options and outcomes that lie ahead. And yet, at some point prior to the initiation of treatment, the physician and the patient must discuss the diagnosis, its implications, and therapeutic alternatives. Because of the wide range of potential prognoses (from curable disseminated testicular cancer to the limited lifespan of patients with locally advanced gastric or pancreatic cancer), it is often useful for family members or close friends to be present in the consulting room when detailed discussions of the complexities of either disease or therapy are conducted, both to provide emotional support and to be another “set of ears” during the visit. It is helpful to ask patients directly: “What do you understand about your diagnosis and treatment?” Family members or close associates of the patient may also be especially helpful in developing a written or digital record of the questions posed to and answered by health care providers; many patients find such a record to be especially helpful for later reference.

If the physician is not familiar with the latest treatment options, prompt referral to a specialist, whether a surgical oncologist, radiation oncologist, or medical oncologist, is imperative. The generalist should not be a therapeutic nihilist unless she or he is intimately involved in the field and is well versed in the potential risks and benefits of currently available therapies and clinical trials.

Diagnosis

Diagnostic possibilities are protean for the wide range of human malignancies that may be discovered either in the presence of nonspecific but foreboding symptoms or signs (severe weight loss [see Fig. 118-4 ], hematuria [see Fig. 100-3 ], jaundice [see Fig. 133-1 ]) or in asymptomatic individuals (e.g., during a routine physical examination). The importance of the medical history and physical examination, however, must be emphasized whether or not a pathologic diagnosis of cancer has already been confirmed. One of the most important considerations that underlies the approach to both the diagnostic evaluation and choice of cancer treatment (surgical, radiation, and/or systemic therapy) is the patient’s basic physiologic condition or “performance status” ( Table 164-1 ). For example, a past medical history of prolonged tobacco smoking ( Chapter 363 ) is not only relevant to a possible diagnosis of lung cancer but also to the ability of a patient to tolerate potentially curable multimodality treatment. Underlying evidence of excessive alcohol consumption ( Chapter 364 ) may play a role in both the tolerance for and metabolism of systemic chemotherapeutic agents. Family histories of cancer can provide prognostic indicators as well as suggest molecularly guided treatment approaches in, for example, women with possible BRCA1 -related breast or ovarian cancer. It is also critical to assess the environment of care, including the patient’s support systems, which may be sorely tested by the experience of a cancer diagnosis and the interventions that ensue. Finally, the physical examination will define the extent of certain sites of measurable malignancy—for example, palpable lymph nodes or enlargement of the spleen or liver—as well as the patient’s muscle strength, the presence of possible malignant effusions, and potential central or peripheral neuropathies reflective of metastatic disease or paraneoplastic syndromes. Most importantly, however, the evaluation provides the treating physician with an initial sense of the patient’s well-being, or lack thereof, prior to the initiation of therapy.

TABLE 164-1

KARNOFSKY AND ZUBROD PERFORMANCE SCALES

KARNOFSKY PERFORMANCE STATUS SCALE
VALUE	LEVEL OF FUNCTIONAL CAPACITY
100	Normal, no complaints, no evidence of disease
90	Able to carry on normal activity, minor signs or symptoms of disease
80	Normal activity with effort, some signs or symptoms of disease
70	Cares for self, unable to carry on normal activity or to do active work
60	Requires occasional assistance but is able to care for most needs
50	Requires considerable assistance and frequent medical care
40	Disabled, requires special care and assistance
30	Severely disabled; hospitalization is indicated, although death is not imminent
20	Hospitalization is necessary; very sick, active supportive treatment necessary
10	Moribund; fatal processes progressing rapidly
0	Dead

EASTERN COOPERATIVE ONCOLOGY GROUP (ZUBROD) PERFORMANCE SCALE
PERFORMANCE STATUS	DEFINITION
0	Asymptomatic
1	Symptomatic; fully ambulatory
2	Symptomatic; in bed <50% of day
3	Symptomatic; in bed >50% of day
4	Bedridden

Diagnostic Procedures

After a lesion has been found, either on physical examination or following radiographic studies prompted by abnormal laboratory results, a percutaneous biopsy is often indicated for pathologic evaluation. The biopsy must be representative of the entire tumor and be robust enough in size that appropriate investigations (e.g., special immunohistologic stains, flow cytometry, cytogenetics, hormone assays, molecular testing) can be performed before treatment is initiated. If questions remain as to whether the lesion is benign or malignant or about its proper classification, consideration should be given to additional biopsies, and consultation with a reference pathologist may be indicated.

Molecular testing is increasingly useful for the early diagnosis of asymptomatic malignancy. For example, a small number of cases of occult cancer may be subsequently diagnosed among pregnant women whose noninvasive prenatal testing results show discordance with the fetal karyotype. Similarly, analysis of blood for circulating tumor cells (termed a liquid biopsy) or for methylation patterns of cell-free DNA shed into circulating blood by tumors can screen for some early cancers or a recurrence of tumor after treatment.

The wide range of molecularly targeted and immunotherapeutic agents active in solid tumors (see Table 164-2 for an abbreviated list of commonly used medications in cancer and https://www.cancer.gov/about-cancer/treatment/drugs/cancer-type for a full listing of all drugs approved by the U.S. Food and Drug Administration) has focused attention on obtaining sufficient tissue so that essential molecular studies (DNA sequencing, RNA expression analyses, FIH [fluorescence in situ hybridization], and immunologic profiling) are performed to guide choices among treatments. Although tumors removed by surgical resection are routinely of sufficient size to permit the full range of diagnostic examinations, active involvement of a skilled interventional radiologist or endoscopist is often required to produce both the size and number of tumor biopsies required for modern cancer therapeutic decision making. Emergent treatment is rarely required before appropriate pretreatment evaluations can be performed. For some tumor sites such as the colon ( Chapter 179 ), one predominant histology is seen, but critical molecular features of the tumor (presence or absence of a mutant Ras oncogene) can define therapy. For other tumors, such as in the lung ( Chapter 177 ), the distinction between small cell lung cancer and non–small cell lung cancer is critical for treatment. For breast cancer ( Chapter 183 ), the treating physician is interested in a variety of factors, such as histology, tumor grade, the presence (and its degree) or absence of estrogen and progesterone receptor proteins, the presence of HER2/neu overexpression, and other molecular characteristics. The rapidly increasing sophistication of molecular diagnostics has also greatly improved the potential to localize cancers of unknown primary origin (see the section Cancer of Unknown Origin later in this chapter).

TABLE 164-2

U.S. FDA-APPROVED DRUGS COMMONLY USED FOR THE SYSTEMIC TREATMENT OF CANCER ∗

From Collins JM. Cancer pharmacology. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology , 5th ed. Philadelphia: Churchill Livingston; 2014.

DRUG NAME	DRUG CLASS AND/OR MECHANISM	PHARMACOKINETICS/METABOLISM	TOXICITY	INDICATIONS ^†
Abiraterone acetate (Zytiga)	Inhibits androgen biosynthesis	Do not take with food; inhibits CYP2D6	Joint swelling or discomfort; edema; monitor liver enzymes	Metastatic prostate cancer
Acalabrutinib (Calquence)	Bruton kinase inhibitor	Avoid with proton pump inhibitors, strong CYP3A inhibitors or inducers, and patients with severe hepatic impairment	Opportunistic infection, cytopenias, atrial tachyarrhythmias, headache, diarrhea, musculoskeletal pain	CLL, small lymphocytic lymphoma, mantle cell lymphoma
Afatinib (Gilotrif)	Selective covalent inhibitor of EGFR, HER2, and HER4; inhibits wild-type and selected EGFR mutants	Interacts with P-gp inhibitors which may require dose reduction; dose reduction for moderate renal dysfunction	Acneiform eruption; hypokalemia; diarrhea, stomatitis, and nausea; altered liver function studies; decreased creatinine clearance	NSCLC first line with EGFR exon 19 deletions or exon 21 (L858R) mutation as detected by appropriate diagnostic test
Alectinib (Alecensa)	Tyrosine kinase inhibitor inhibiting ALK gene abnormalities and RET mutations; can inhibit certain ALK mutations that follow treatment with crizotinib	Hepatic metabolism by CYP3A4; excreted in the feces	Bradycardia; CK elevations; interstitial pneumonitis	ALK-positive metastatic NSCLC progressive on crizotinib
Amivantamab-vmjw (Rybrevant)	Human EGFR and MET bispecific antibody targeting EGFR exon 20 insertion mutations	Disrupts EGFR and MET signaling by blocking ligand binding and degrading EGFR and MET ; terminal half-life of about 11 days	Rash; infusion reactions; paronychia; stomatitis; pruritus	NSCLC with EGFR exon 20 insertion mutations in patients who have progressed on platinum-based chemotherapy
Anastrozole (Arimidex)	Nonsteroidal aromatase inhibitor; blocks estrogen production selectively	Well absorbed from GI tract, maximum plasma levels within 2 hr; half-life is 50 hr; extensively metabolized in liver; despite hepatic and renal clearance being important, no adjustments needed for abnormal function of these organs because of the wide therapeutic index of this drug	Very well tolerated; asthenia, headache, and hot flashes occur in less than 15% of women; diarrhea, abdominal pain, anorexia, nausea, and vomiting occur in 10% or less; thrombophlebitis has been reported	As adjuvant therapy of breast cancer and for treatment of postmenopausal women with breast carcinoma who have progressed while being treated with tamoxifen
Apalutamide (Erleada)	Androgen receptor inhibitor	If no prior orchiectomy, prescribe a gonadotropin-releasing hormone analog concurrently	Ischemic cardiovascular events, fractures, fatigue, arthralgia, rash, decreased appetite, falls, weight decreased, hypertension, hot flush, diarrhea	Metastatic castration-sensitive prostate cancer or nonmetastatic castration-resistant prostate cancer
Arsenic trioxide (Trisenox)	Novel arsenical differentiating agent	Half-life of this compound is unknown; it is methylated in the liver and eliminated in the urine	The “differentiation syndrome” is dose limiting and includes leukocytosis, fever, dyspnea, chest pain, tachycardia, hypoxia, and sometimes death; corticosteroids seem to benefit this syndrome; QT prolongation is common; common adverse effects include rash, pruritus, headache, arthralgias, anxiety, bleeding, nausea, and vomiting; liver and renal toxicity are uncommon	Relapsed acute promyelocytic leukemia
l -Asparaginase (Elspar), colaspase	Naturally occurring enzyme derived from Escherichia coli or Erwinia carotovora that cleaves asparagine, an essential amino acid required by rapidly proliferating cells	After IV or IM injection, the drug is metabolized intravascularly by proteolysis; elimination half-life of 8-30 hr	Hypersensitivity can be life-threatening, requiring anaphylaxis precautions and a 2-unit test dose; coagulopathy is common and requires monitoring; nausea, vomiting, abdominal cramps, anorexia, elevated liver function tests, and transient renal insufficiency are common; lethargy, somnolence, fatigue, depression, and confusion are seen, as are pancreatitis and fever	ALL; also used in AML, late-stage CML, CLL, and non-Hodgkin lymphomas
Atezolizumab (Tecentriq)	Humanized monoclonal antibody that binds the programmed death ligand 1 (PD-L1) downregulating anti–T-cell function	No dosage adjustment for mild renal or hepatic insufficiency	Rash; endocrinopathies; immune hepatitis, pancreatitis, pneumonitis, colitis, adrenal insufficiency, diabetes; peripheral edema; fatigue; fever	NSCLC; small cell lung cancer; advanced urothelial cancer patients ineligible for or who have progressed after platinum-containing therapy; hepatocellular cancer; melanoma
Avelumab (Bavencio)	Programmed death ligand-1 (PD-L1) blocking antibody	Can cause fetal harm	Immune-mediated pneumonitis, hepatitis, colitis, endocrinopathies, nephritis; fatigue; musculoskeletal pain; rash; diarrhea	Adult and pediatric patients (12 yr of age and older) with metastatic Merkel cell carcinoma; renal cell carcinoma; urothelial carcinoma
Axitinib (Inlyta)	Avoid strong CYP3A inhibitors or reduce dose	Decrease dose 50% for CYP3A inhibitors, renal, hepatic impairment	Diarrhea, hypertension, fatigue, nausea	Advanced renal cell carcinoma after one treatment failure
Azacytidine (Vidaza)	Antimetabolite; induces hypomethylation of DNA, either inducing apoptosis or restoring normal function; at higher doses, acts as a cytidine analog	Not orally bioavailable; metabolized by the liver and excreted in urine; elimination half-life of 4 hr	Myelosuppression is dose limiting; leukopenia, thrombocytopenia, and transient elevation of liver function tests are common; nausea and vomiting and abdominal pain are common	Myelodysplastic syndromes
Bacillus Calmette-Guérin (TICE BCG, TheraCys), BCG	Immunostimulant/vaccine; induces a cellular immune response at the site of instillation	BCG is a live, attenuated bacteria culture; it does not enter the body in viable form; it has no detectable pharmacokinetic fate; in rare cases, a clinical infection can result from treatment, indicating invasion of the body at site of administration into systemic circulation	Urinary symptoms predominate, including dysuria, hematuria, hesitancy, urgency, frequency, and secondary infection; other toxicities include fever, chills, malaise, myalgias/arthralgias, anorexia, nausea, vomiting, and anemia; clinical mycobacterial infection is rare and generally seen only in immunocompromised patients	Intravesical instillation for noninvasive bladder cancer after removal of papillary tumors; also used for some experimental vaccine programs as an adjuvant to the vaccine
Belinostat (Beleodaq)	Histone deacetylase inhibitor; results in accumulation of acetyl groups on histone and nonhistone proteins causing cell cycle arrest and apoptosis	Hepatic metabolism via UGT1A1 and CYP2A6; excreted in urine	Myelosuppression; peripheral edema and prolonged QT interval; rash; nausea and vomiting; fatigue	Relapsed peripheral T-cell lymphoma
Bendamustine (Treanda)	Alkylating agent	Reduce dose for hematologic toxicity	Nausea, pyrexia, vomiting, hematologic abnormalities	CLL and B-cell non-Hodgkin lymphoma
Bevacizumab (Avastin)	Recombinant humanized monoclonal antibody that binds to all forms of VEGF, preventing binding to its receptors	Administered by IV infusion; half-life is 20 days; the fate of parent drug and metabolites is unknown	Asthenia, pain, nausea/vomiting, diarrhea, anorexia, stomatitis, dermatitis, hypertension, proteinuria; infusion-related reactions rare; hemoptysis, hemorrhage, delayed wound healing, GI perforations; increased risk of thromboembolic events can be severe or fatal	Metastatic colorectal cancer and NSCLC; renal cell carcinoma
Bicalutamide (Casodex)	Nonsteroidal antiandrogen	Well absorbed orally; highly protein bound; converted to inactive metabolites in liver via oxidation and glucuronidation; half-life of several days	Constitutional symptoms predominate, including hot flashes, decreased libido, depression, weight gain, edema, gynecomastia, early disease-site pain (flare reaction), and constipation; nausea, vomiting, anorexia, diarrhea, and dizziness are uncommon; dyspnea, anemia, fever, and rashes are rare	Stage D2 prostate cancer, in combination with an LHRH agonist agent
Binimetinib (Mektovi)	Mitogen-activated protein kinase 1 and 2 inhibitor	Reduce dose if moderate or severe hepatic impairment	Cardiomyopathy, retinopathy, interstitial lung disease, hepatotoxicity, rhabdomyolysis	Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation
Bortezomib (Velcade)	Proteasome inhibitor	Metabolized in the liver by CYP2C19 and 3A4; dose reduction for hepatic dysfunction	Cardiovascular; peripheral neuropathy; skin rash; nausea and diarrhea	Multiple myeloma; mantle cell lymphoma
Brentuximab vedotin (Adcetris)	CD30-directed antibody conjugate	Monitor patients taking CYP3A inducers or inhibitors	Progressive multifocal leukoencephalopathy; peripheral neuropathy; neutropenia	Hodgkin lymphoma and anaplastic large cell lymphoma
Brigatinib (Alunbrig)	Multikinase inhibitor	Interacts with strong CYP3A inhibitors; requires dose reduction; avoid grapefruit juice	Hypertension; skin rash; fatigue; increased liver function tests	ALK-positive NSCLC for patients who have progressed on crizotinib
Capecitabine (Xeloda)	Oral antimetabolite prodrug	Readily absorbed by the GI tract, metabolized in vivo to fluorouracil in the liver by carboxylesterase and cytidine deaminase, and then in turn in the peripheral tissues and tumor tissue by thymidine phosphorylase	Myelosuppression and palmar-plantar erythrodysesthesia are dose limiting; diarrhea, fatigue, stomatitis, and hyperbilirubinemia are uncommon; nausea, vomiting, and rash are rare	Metastatic breast cancer and metastatic colorectal cancer; used also in head and neck squamous cell cancer
Cabazitaxel (Jevtana)	Microtubule inhibitor	Caution for patients taking strong CYP3A inducers or inhibitors	Neutropenia and hypersensitivity	Metastatic hormone refractory prostate cancer when docetaxel fails
Cabozantinib	Inhibits many receptor tyrosine kinases; anti-angiogenic	55-hour half-life; take without food	Perforations, fistulas, and hemorrhage	Metastatic medullary thyroid cancer; advanced renal cell carcinoma; advanced hepatocellular cancer
Carboplatin (Paraplatin), Carbo, CBDCA	Atypical alkylator; produces intrastrand and interstrand cross-links in DNA via association bonds with the platinum molecule, leading to DNA strand breakage during replication	Rapidly cleared from the blood stream after IV infusion, with a terminal half-life of 2.5 hr; it is cleared largely as unchanged drug by the kidneys	Hemorrhage; thrombocytopenia	Ovarian cancer and used extensively in testicular cancer, squamous cell cancers of the head and neck and cervix, and lung cancer
Carfilzomib (Kyprolis)	Proteasome inhibitor	Drug-drug interactions unlikely; no adjustment for renal impairment; no experience with hepatic impairment	Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia; monitor for cardiac, pulmonary, tumor lysis, infusion reactions, thrombocytopenia	Multiple myeloma
Ceritinib (Zykadia)	Inhibitor of ALK tyrosine kinase as well as ROS1 ; also inhibits IGF-1R and the insulin receptor	Metabolized by CYP3A in the liver; dose reduction if concomitant strong CYP3A inhibitors are administered	Bradycardia; QTc prolongation; nausea, vomiting; hyperglycemia; interstitial pneumonitis	NSCLC that is ALK positive by an appropriate diagnostic test; demonstrated activity in crizotinib-resistant NSCLC xenograft models
Cetuximab (Erbitux)	Recombinant humanized monoclonal antibody, targeting EGFR ; competitively inhibits growth factor binding; inhibits autophosphorylation and cell signaling	Metabolism poorly understood; half-life 5-7 days with minimal clearance by kidneys or liver	Infusion reaction, characterized by rapid-onset dyspnea, fever, chills, urticaria, flushing, angioedema, and hypotension, is seen in 40-50% of patients; acneiform rash is common; constitutional symptoms; hypomagnesemia; interstitial lung disease is rare	Metastatic colorectal cancer, head and neck cancer in combination with radiation
Cisplatin (Platinol)—cDDP, DDP, cisplatinum, cis-diamminedichloro-platinum (II)	Atypical alkylator; produces intrastrand and interstrand cross-links in DNA via association bonds with the platinum molecule, leading to DNA strand breakage during replication	After IV infusion, rapid distribution to tissues takes place, and the drug is over 90% protein bound	Nephrotoxicity is dose limiting for an individual dose, and neurotoxicity, especially painful peripheral neuropathy, is dose limiting for cumulative doses; myelosuppression is mild; nausea and vomiting are common but manageable, and anorexia and diarrhea are common; cumulative ototoxicity is also common; chronic renal magnesium and potassium wasting is common and sometimes not reversible; elevated liver transaminases can be seen, whereas alopecia and cardiac conduction abnormalities are rare; adequate renal perfusion and urine output are critical for minimizing renal toxicity; therefore prehydration and adequate posttreatment hydration are used, usually with normal saline solution with or without mannitol, potassium, and magnesium	Used for almost every class of solid tumor and lymphoma; FDA approved for testicular and ovarian cancer and transitional cell carcinoma
Cobimetinib (Cotellic)	Inhibitor of MEK1 and MEK2 in the MAPK cascade	Detoxified in the liver by CYP3A4 and UGT2B7; use of strong CYP3A4 inhibitors should be avoided; excreted in feces	Cardiotoxicity; rhabdomyolysis; rash; retinopathy; bleeding	Metastatic or unresectable melanoma for patients with BRAF V600E or V600K mutations in combination with vemurafenib
Copanlisib (Aliqopa)	PI-3 kinase inhibitor	Avoid concomitant strong CYP3A inducers and reduce dose of strong CYP3A inhibitors	Hyperglycemia, hypertension, neutropenia, thrombocytopenia, diarrhea, severe cutaneous reactions, nausea, lower respiratory tract infections	Relapsed follicular lymphoma after at least two prior systemic therapies
Crizotinib (Xalkori)	ALK kinase inhibitor; also inhibits cMET	Avoid strong CYP3A inhibitors, inducers, or substrates	Hepatotoxicity; pneumonitis; QT interval prolonged	ALK -positive NSCLC
Cyclophosphamide	Alkylating agent	Metabolized to its active alkylating species by mixed function oxidases in hepatic microsomes including CYP2A6 and 3A4; decreased activation to therapeutic species in the face of severe hepatic dysfunction	Myelosuppression; immunosuppression; hemorrhagic cystitis; myocarditis; pneumonitis; secondary malignancies; infertility; hyponatremia; veno-occlusive disease; nausea and vomiting; mucositis	Hodgkin and non-Hodgkin lymphoma; leukemias; ovarian cancer; breast cancer; retinoblastoma; neuroblastoma
Cytarabine	Antimetabolite that inhibits DNA polymerase after activation to its nucleotide triphosphate, is incorporated into DNA and RNA and blocks cell cycle progression from G1 to S phase	Metabolized in the liver and excreted by the kidney	Myelosuppression; immunosuppression; CNS, cardiac, and pulmonary toxicity; infection; fever, bone and chest pain and rash within hours of administration (Ara-C syndrome); nausea, diarrhea; mucositis; hepatic dysfunction	AML in adults and children
Dabrafenib (Tafinlar)	BRAF kinase inhibitor; selectively inhibits BRAF V600E mutated kinase	Metabolized to active form by CYP isoforms in the liver; absorption delayed by a high-fat meal	Decreased LVEF; skin rash, alopecia, keratoacanthoma and squamous cell carcinoma, palmar-plantar erythrodysesthesia; hyperglycemia; diarrhea; lymphopenia and anemia; abnormal liver function tests	Metastatic or unresectable melanoma with BRAF V600 E mutation or in combination with trametinib if either BRAF V600E or V600K mutations present; NSCLC if BRAF V600E mutation detected by an approved test
Dasatinib (Sprycel)	Multikinase inhibitor including Bcr-Abl and Src	Use with caution in patients with hepatic impairment; CYP3A4 inhibitors: may increase dasatinib drug levels; avoid or monitor closely and consider reducing dose; CYP3A4 inducers: may decrease dasatinib drug levels; avoid or consider increasing dose; antacids: may decrease dasatinib drug levels; avoid simultaneous administration; if needed, administer the antacid at least 2 hr prior to or 2 hr after the dose; H2 antagonists/proton pump inhibitors: may decrease dasatinib drug levels; consider antacids in place of H2 antagonists or proton pump inhibitors	Myelosuppression, bleeding events, fluid retention, diarrhea, headache, musculoskeletal pain, and rash	(Ph+) chronic myeloid leukemia (CML) in chronic phase, or chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy
Daunorubicin	Anthracycline antitumor antibiotic; pleiotropic effects including free radical formation, topoisomerase II inhibition; altered mitochondrial function	After IV bolus, widely distributed and metabolized in liver to active and inactive metabolites; half-life of the parent drug is 18 hr, and 25 hr for active metabolite daunorubicinol	Daunorubicin is a vesicant; precautions are necessary; myelosuppression is dose limiting; alopecia, nausea, vomiting, and stomatitis are common; diarrhea, rash, elevated liver function tests, and transient arrhythmias are uncommon; dose-related cardiomyopathy is uncommon below cumulative doses of 400-500 mg/m ²	AML and ALL
Decitabine (Dacogen)	Antimetabolite; inhibits DNA methyltransferase, causing hypomethylation of DNA; this may induce apoptosis or restore normal function to genes that control cellular differentiation and proliferation	Deaminated by cytidine deaminase, found in liver, granulocytes, gut, and blood; elimination half-life is 30 min	Myelosuppression; nausea, vomiting, abdominal pain; constitutional symptoms; elevated liver functions, blood sugar, low serum magnesium, low serum potassium; respiratory toxicity	Myelodysplastic syndromes
Denosumab (Xgeva)	Monoclonal antibody; RANK ligand inhibitor	No drug interaction studies; more hypocalcemia for creatinine clearance <30 mL/min	Use calcium and vitamin D to treat or prevent hypocalcemia; fatigue/asthenia, hypophosphatemia, and nausea; osteonecrosis of jaw	Bone metastases from solid tumors; not in multiple myeloma; giant cell tumor of bone
Dexrazoxane (Zinecard)—ADR-529, ICRF-187	Iron-chelating agent that serves as a free-radical scavenger/cytoprotectant; widespread and rapid	Metabolism is mostly hepatic; half-life is 3-4 hr; parent drug and metabolites are excreted by the kidneys; hepatic impairment not studied; renal impairment suggests 50% dose reduction	Dexrazoxane appears to worsen slightly the leukopenia induced by doxorubicin; mild nausea and vomiting are common; fever, stomatitis, fatigue, anorexia, and hypotension are uncommon; seizure, respiratory arrest, deep venous thrombosis, and significant liver toxicity are rare	Prevent doxorubicin-induced cardiomyopathy
Docetaxel (Taxotere), RP-56976	Docetaxel is a semisynthetic taxane, a class of compounds that inhibit the mitotic spindle apparatus by stabilizing tubulin polymers, leading to death of mitotic cells	After a 1-hr infusion, docetaxel is widely distributed, with elimination half-life of 1 hr and a terminal half-life of 18 hr; extent and by-products of metabolism are not well known; the main excretion route is biliary	Myelosuppression is universal and dose limiting; alopecia is also universal; edema and fluid accumulation, including pleural effusions and ascites, are common and can be dose limiting; fluid accumulation is partially preventable with corticosteroid treatment before and after each cycle of docetaxel; mild sensory or sensorimotor neuropathy is common; mucositis and diarrhea are common and usually mild; hypersensitivity reactions are uncommon and can largely be prevented through premedication with corticosteroids and antihistamines; rash and elevated liver function tests are uncommon	Metastatic breast cancer and first- and second-line NSCLC
Doxorubicin (Adriamycin, Rubex), Adria, hydroxydaunorubicin	Anthracycline antitumor antibiotic; pleiotropic effects including free radical formation, topoisomerase II inhibition; altered mitochondrial function	After an IV dose, it is widely distributed in tissues and is 70% protein bound; it is metabolized in the liver to active and inactive forms; it has an elimination half-life of 18 hr or more; most of the drug and metabolites are excreted through the biliary route	Doxorubicin is a potent vesicant, and extravasation precautions are a must; myelosuppression is universal and usually dose limiting with each individual cycle; cardiotoxicity is common and can be dose limiting, although usually subclinical; chronic, cumulative cardiomyopathy is expected when the total dose exceeds 450 mg/m ² ; this toxicity can be lessened by the addition of dexrazoxane or by longer infusions; acute cardiac effects, including arrhythmias, are less often seen and are unpredictable; nausea and vomiting are common but manageable; diarrhea and stomatitis are common but usually mild; alopecia, rash, and hyperpigmentation are common	Approved for a variety of cancers and used for many more; most commonly used for breast carcinoma, adult sarcomas, pediatric solid tumors, Hodgkin disease, non-Hodgkin lymphomas, and ovarian cancer
Doxorubicin, liposomal (Doxil)	Novel liposomal preparation of the anthracycline doxorubicin	Doxorubicin metabolized in the liver; significant plasma levels of the principal metabolite, doxorubicinol, not observed with the liposomal preparation, likely because of slow distribution of free doxorubicin to liver; half-life of liposomes in plasma is 55 hr	Myelosuppression is mild but dose limiting; palmar-plantar erythrodysesthesia is common and can occasionally be severe and dose limiting; stomatitis and nausea are common but usually mild; alopecia is uncommon; acute infusion reactions including chest pain, back pain, dyspnea, and wheezing can occur uncommonly	Recurrent metastatic ovarian cancer and AIDS-related Kaposi sarcoma; also used commonly in metastatic breast cancer and multiple myeloma
Durvalumab (Imfinzi)	Human monoclonal antibody that inhibits binding of PD-L1 to PD-1 and CD80, enhancing antitumor effects of T cells	May need to reduce dose or discontinue in the presence of treatment-related nephritis or hepatitis	Hepatotoxicity; renal toxicity; rash; endocrinopathies; colitis and diarrhea; infusion reactions; pneumonitis	Locally advanced or metastatic urothelial carcinoma following progression on platinum-based therapy; extensive stage small cell lung cancer; NSCLC
Enasidenib (IDHIFA)	Inhibitor of the enzyme isocitrate dehydrogenase (IDH2) targeting the R140Q, R172S, and R172K mutant variants of IDH2 to reduce 2-hydroxyglutarate levels and reestablish myeloid differentiation	Hepatic metabolism by way of multiple CYP isoforms and UGTs; primarily excreted in the feces; reduce dose for bilirubin >3 times ULN	Differentiation syndrome (black box warning): fever, respiratory distress, pleural and pericardial effusions, edema, multiorgan dysfunction—must be treated with corticosteroids; electrolyte imbalance; hepatotoxicity; nausea, vomiting, diarrhea; tumor lysis syndrome	AML patients with IDH2 mutations defined by an appropriate diagnostic test
Entrectinib (Rozlytrek)	Tropomyosin receptor kinase inhibitor	Avoid moderate and strong CYP3A inducers, reduce dose with moderate and strong CYP3A inhibitors	Heart failure, CNS side effects, skeletal fractures, hepatotoxicity, hyperuricemia, QT interval prolongation, vision disorders	Metastatic ROS1- positive NSCLC
Enzalutamide (Xtandi)	Androgen receptor signaling inhibitor	Take with or without food; 2C8 substrate; no other pathways need adjustments	Fatigue, musculoskeletal pain, dizziness, weakness	Metastatic castrate-resistant prostate carcinoma
Epirubicin (Ellence)	Anthracycline; pleiotropic effects including free radical formation, topoisomerase II inhibition; altered mitochondrial function	Metabolized primarily by liver; parent drug and metabolites glucuronidated and excreted in bile much more than via renal clearance; reduce doses for mild to moderate hepatic dysfunction; severe hepatic dysfunction is contraindicated; half-life is 30-35 hr	Myelosuppression is universal and dose limiting; alopecia is expected; this drug is a vesicant, and precautions must be taken to avoid extravasation into soft tissue around veins; nausea and vomiting are common but usually manageable; stomatitis is common; fatigue is common; detectable cardiac dysfunction at somewhat higher cumulative doses than doxorubicin; secondary leukemia is rare	Adjuvant therapy after optimal surgical treatment of localized breast cancer with involved axillary lymph nodes
Erdafitinib (Balversa)	FGFR kinase inhibitor	Avoid moderate CYP2C9 or strong CYP3A4 inhibitors, moderate or strong CYP2C9 or CYP3A4 inducers, CYP3A4 substrates, OCT2 substrates	Central serous retinopathy retinal pigment epithelial detachment, hyperphosphatemia, stomatitis, fatigue, increased creatinine level, diarrhea, dry mouth, palmar-plantar erythrodysesthesia syndrome	Locally advanced or metastatic urothelial carcinoma with FGFR3 or FGFR2 genetic alterations progressing despite chemotherapy
Eribulin mesylate (Halaven)	Microtubule inhibitor	Reduce dose in patients with hepatic impairment and moderate renal impairment	Neutropenia, peripheral neuropathy, monitor for QT prolongations, nausea, fatigue	Persons with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease; prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting
Erlotinib (Tarceva)	Targeted agent	Inhibits the tyrosine kinase domain of the EGFR, leading to inhibition of EGFR autophosphorylation and signaling	Acneiform rash; diarrhea; interstitial lung disease	Second- or third-line therapy of NSCLC; pancreatic cancer, in combination with gemcitabine
Erythropoietin (Epogen, Procrit), EPO, epoetin alpha	Hematopoietic growth factor; stimulates erythrocytic precursors	Detectable in plasma for 24 hr after dosing; distributed to volume approximating total blood volume; degraded by proteolysis within blood compartment; half-life is 4-27 hr; onset of therapeutic effect takes at least 7 days; excretion of intact peptide is negligible	Hypertension is common but usually mild and not dose limiting; injection site pain is common but mild; flulike syndrome and diaphoresis are uncommon; nausea and vomiting are rare; seizures have been reported in patients undergoing dialysis who receive the drug; iron deficiency anemia can occur after prolonged therapy, and concomitant iron dosing may increase effectiveness of erythropoietin; hematocrit values should be monitored closely during therapy to prevent polycythemia and hyperviscosity	The oncology indication is chemotherapy-induced anemia that is symptomatic; also used for anemia of chronic renal failure and HIV-associated anemia
Etoposide (Vespid), VP-16, epipodophyllotoxin; also available as etoposide phosphate (Etopophos)	Plant alkaloid; topoisomerase II inhibitor; partially cell cycle dependent	Etoposide phosphate is rapidly converted to etoposide after IV infusion; etoposide itself is extensively protein bound, is metabolized in liver, and has a half-life of about 10 hr; 50% of oral etoposide is absorbed via GI tract, requiring oral doses to be twice as high as parenteral doses; excreted both unchanged in urine and as metabolites in bile	Myelosuppression, primarily leukopenia, is universal and dose limiting; nausea and vomiting are common with PO administration but rare when the drug is given by IV; stomatitis and diarrhea are rare with normal doses but common with high doses; alopecia is mild or absent; hepatic toxicity and neurologic effects (peripheral neuropathy and CNS changes) are rare; hypotension can occur with rapid administration of etoposide but does not occur commonly when etoposide phosphate is infused over 5 min; secondary AML has been reported after etoposide	Germ cell tumors and SCLC; also used for lymphomas, AML, brain tumors, non-SCLC, and as high-dose therapy in the transplant setting for breast cancer, ovarian cancer, and lymphomas
Everolimus (Afinitor)	m-TOR inhibitor	Hepatic impairment: for advanced HR+ BC, advanced PNET, advanced RCC, or renal angiomyolipoma with TSC patients with hepatic impairment, reduce the starting dose. Strong CYP 3A4 inhibitors: avoid concomitant use. Moderate CYP 3A4 and/or PgP inhibitors: if combination is required, use caution and reduce dose. Strong CYP 3A4 inducers: avoid concomitant use. If combination cannot be avoided, increase dose.	Noninfectious pneumonitis: monitor for clinical symptoms or radiologic changes; fatal cases have occurred. Infections: increased risk of infections, some fatal. Monitor for signs and symptoms, and treat promptly. Oral ulceration: mouth ulcers, stomatitis, and oral mucositis are common. Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed. Laboratory test alterations: elevations of serum creatinine, blood glucose, and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets may also occur. Monitor renal function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter. Avoid live vaccines and close contact with those who have received live vaccines. Advanced HR+ BC, advanced PNET, advanced RCC: most common adverse reactions include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. Renal angiomyolipoma with TSC: most common adverse reaction is stomatitis. SEGA with TSC: most common adverse reaction (incidence ≥30%) are stomatitis and respiratory tract infection.	Postmenopausal women with advanced hormone receptor-positive, HER2 negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Adults with progressive neuroendocrine tumors of creatic origin (PNET) that are unresectable, locally advanced, or metastatic. Adults with advanced RCC after failure of treatment with sunitinib or sorafenib. Adults with renal angiomyolipoma and TSC not requiring immediate surgery. Pediatric and adult patients with TSC who have SEGA that requires therapeutic intervention but cannot be curatively resected.
Exemestane (Aromasin)	Hormonal agent, steroidal aromatase inhibitor	40% of oral exemestane is absorbed from GI tract and increased by a fatty meal; it is highly protein bound in plasma; exemestane is metabolized in liver by cytochrome P450 3A4 and aldoketoreductases	Although generally well tolerated, exemestane is expected to cause or exacerbate hot flashes or intermittent flushing in some women; fatigue and mild nausea are common; vomiting, headache, and dyspnea are uncommon; it is teratogenic and should not be used in premenopausal women	Estrogen-responsive metastatic breast cancer in postmenopausal women whose disease has progressed while undergoing prior hormonal therapy
Filgrastim (Neupogen), G-CSF	Hematopoietic growth factor, relatively specific for the granulocyte lineage	After a bolus SQ injection, peak plasma levels of filgrastim occur in 2-6 hr, whereas the elimination half-life is generally 7 hr or less; metabolism is via proteolysis in the blood compartment; the intact molecule is largely absent from bile or urine	Mild bone pain is common; low-grade fever, myalgias, arthralgias, and transient hypotension are uncommon, as are hyperuricemia and elevations of lactate dehydrogenase and alkaline phosphatase; leukocytosis leading to hypoxia or capillary leak syndrome has been reported; anaphylaxis or allergic reaction is rare	Approved for minimization of granulocytopenia after myelosuppressive chemotherapy; also used to speed recovery of granulocytes in the setting of neutropenic fever after chemotherapy, for myelodysplastic syndromes, for congenital agranulocytosis, for cyclic neutropenia, and for mobilization of peripheral blood stem cells from patients or donors for transplant
Fludarabine (Fludara), FAMP	Purine nucleotide analog antimetabolite; only partially cell cycle–dependent	Fludarabine is available only by the parenteral route; after IV administration, the drug is metabolized to 2-fluoroara-A and widely distributed in tissues; it has an elimination half-life of 9-10 hr; the drug and metabolite are excreted primarily by the kidneys	Neurotoxicity, including cortical blindness, confusion, somnolence, coma, and demyelinating lesions, is dose limiting, but the lower doses that are conventionally used rarely produce these adverse effects; at these doses, mild myelosuppression is the most common toxicity, with cumulative lymphopenia being the most clinically important; nausea, vomiting, and other GI toxicities are rare; alopecia and rash are also rare	Approved for the treatment of CLL; also used for low-grade lymphomas and for AML
5-Fluorouracil (Adrucil, Efudex), 5-FU	Pyrimidine antimetabolite; inhibitor of thymidylate synthase; partially cell cycle dependent	80% of IV drug is metabolized to inactive dihydro-5-FU by dihydropyrimidine dehydrogenase in the liver; the rest of the drug is activated to fluorodeoxyuridine monophosphate in target cells; elimination half-life is 20 min; excretion is via the kidneys	GI toxicities, primarily mucositis for bolus injections and diarrhea for prolonged infusions, are dose limiting; rare patients with dihydropyrimidine dehydrogenase deficiency have excessive GI toxicity; myelosuppression is generally less with continuous infusion schedules; nausea and vomiting are uncommon and mild; dermatitis and other cutaneous toxicities, including hand-foot syndrome, are common; cerebellar ataxia and myocardial ischemia are rare	Approved for colon, rectum, gastric, pancreas, and breast carcinomas and used for a wide range of other neoplasms in combination regimens; used for intrahepatic arterial infusion for liver metastases from GI tumors; also used topically for various cutaneous neoplasms and disorders
Flutamide (Eulexin)	Nonsteroidal antiandrogen	Good oral bioavailability, with peak plasma levels after an oral dose at 1-2 hr; metabolized to active and inactive forms in the liver; half-life is 8-10 hr	Generally well tolerated; gynecomastia, galactorrhea, and impotence are common; nausea, vomiting, diarrhea, mild myelosuppression, myalgias, and elevated liver function tests are rare	Prostate carcinoma
Fulvestrant (Faslodex) estrogen receptor antagonist	Binds to the ER, leading to degradation and loss of ER from the cell	Peak plasma levels reached in 7 days, half-life is 40 days; metabolized by the liver microsomal P4503A4 systems	Constitutional symptoms, including hot flashes; peripheral edema; nausea, vomiting	ER+ metastatic breast cancer in postmenopausal women
Gemcitabine (Gemzar)	Antimetabolite; gemcitabine is a nucleoside analog that exhibits cell cycle–dependent and S-phase–specific cytotoxicity, likely because of inhibition of DNA synthesis	After IV infusion, the drug is rapidly distributed and has a half-life of less than 2 hr; it is metabolized throughout the body to inactive forms; parent drug and metabolite are excreted principally by the kidneys	Myelosuppression, including anemia, is mild but dose limiting; nausea and vomiting are mild but common; diarrhea and edema are sometimes seen; elevated transaminases are common, as is fever during drug administration; hematuria and proteinuria are uncommon; acute dyspnea and rash are uncommon; paresthesias and CNS depression are rare	Advanced pancreatic adenocarcinoma, NSCLC, and metastatic breast cancer; also extensively used in bladder cancer
Hydroxyurea (Hydrea)—hydroxycarbamide	Antimetabolite; inhibitor of ribonucleotide reductase, which converts nucleotides to the deoxyribose forms for DNA synthesis; cell cycle dependent	The drug is well absorbed; drug levels peak in the blood 2 hr after the dose is administered; half-life is 2-5 hr; metabolism to inactive forms in the liver; renal excretion is the route of elimination	Myelosuppression is common and dose limiting; other toxicities include rash, headache, fever, and hyperuricemia; nausea and vomiting are uncommon; liver toxicity and serious neurologic toxicity are rare	FDA approved for CML; commonly used for other myeloproliferative disorders; also used occasionally for metastatic melanoma, refractory ovarian carcinoma, and squamous cell carcinoma of the cervix and the head and neck
Ibrutinib (Imbruvica)	Irreversible inhibitor of Bruton tyrosine kinase altering B-cell receptor signaling	Hepatic metabolism by CYP3A and CYP2D6; dose reduction for hepatic dysfunction	Myelosuppression; cardiovascular; fatigue; skin rash; hyperuricemia; diarrhea, nausea; dry eyes; musculoskeletal pain	CLL and small lymphocytic lymphoma; mantle cell lymphoma; marginal zone lymphoma; Waldenström macroglobulinemia; chronic GVHD
Idelalisib (Zydelig)	Phosphatidylinositol 3-kinase delta inhibitor; results in apoptosis of malignant B cells	Metabolized in the liver by aldehyde oxidase and CYP3A	Hepatotoxicity; allergic reactions; myelosuppression; diarrhea; cutaneous reactions; infection; pneumonitis	Second-line therapy of CLL in combination with rituximab; follicular B-cell NHL; small lymphocytic lymphoma
Ifosfamide (Ifex)	Classic alkylating agent; not cell cycle dependent	After an intravenous dose, ifosfamide is activated by hepatic microsomal enzymes; it is then converted to inactive metabolites in the liver; the active form of the drug is the same as that for cyclophosphamide; the elimination half-life of the drug is 7-15 hr; the metabolites and some unchanged drug are excreted in the urine	Myelosuppression, hemorrhagic cystitis, and CNS toxicity are all fairly common and can be dose limiting; hemorrhagic cystitis can largely be prevented by co-administration of the uroprotective agent mesna, and nausea and vomiting are minimized with modern antiemetic regimens; the CNS toxicity, including lethargy, stupor, coma, myoclonus, and seizures, is usually mild and completely reversible; it is worse with impaired renal function; renal dysfunction, usually reversible, is also seen with ifosfamide; hepatic toxicity, diarrhea, and rash are rare	Approved for the treatment of recurrent germ cell tumors; used for many other tumor types, including adult sarcomas, lymphoma, Hodgkin disease, breast cancer, and ovarian cancer
Imatinib (Gleevec)	Bcr-Abl tyrosine kinase inhibitor; also inhibits platelet-derived growth factor (PDGF), c-Kit, and stem cell factor (SCF)	Rapid oral absorption; metabolized in the liver by CYP3A4; AUC increased by severe hepatic dysfunction; dose reduction for renal dysfunction	Edema, ascites, chest pain; fatigue; skin rash; increased LDH; nausea, diarrhea; muscle cramps; increased serum creatinine and liver function tests	CML; ALL that is Philadelphia chromosome positive; gastrointestinal stromal tumors; myelodysplastic syndrome associated with PDGF receptor gene rearrangements
Infigratinib (Truseltiq)	Receptor tyrosine kinase inhibitor that blocks fibroblast growth factor receptors FGFR1, FGFR2, FGFR3; blocks FGFR signaling from activating receptor mutations and gene fusions	Metabolized by CYP3A4; excreted in feces. Steady-state concentrations increased by 50-100% in patients who have mild to moderate liver dysfunction, so the dose must be reduced. Avoid coadministration of proton pump inhibitor.	Hyperphosphatemia requiring monitoring and dose adjustment	Unresectable or locally advanced/metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement
Ipilimumab (Yervoy)	Human CTLA-4–blocking antibody	No formal pharmacokinetic drug interaction studies have been conducted; no clinically important differences in clearance of ipilimumab were found between patients with renal impairment and patients with normal renal function; no clinically important differences in clearance of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function	Immune-mediated adverse reactions; fatigue, diarrhea, pruritus, rash, and colitis	Unresectable or metastatic melanoma; NSCLC; mesothelioma; renal cell cancer; hepatocellular cancer; colorectal cancer (MSI-high)
Irinotecan (Camptosar)—CP T-11	Semisynthetic camptothecin, which functions as a topoisomerase I inhibitor; partly cell cycle dependent	Converted partially from active lactone form to inactive carboxylate form; active metabolite of irinotecan, SN-38, also exists in lactone and inactive carboxylate form in equilibrium in plasma; SN-38 is inactivated by glucuronidation in the liver; SN-38 is responsible for the majority of antitumor activity attributed to parent drug; half-life of irinotecan is 8 hr, whereas half-life of SN-38 is 12 hr	Myelosuppression, primarily neutropenia, is common and dose limiting; diarrhea is also common and can be dose limiting; diarrhea can occur as part of a cholinergic syndrome, along with cramping, nausea, and vomiting, during or immediately after drug administration or for several days after drug administration; anticholinergic and antidiarrheal agents will curtail the immediate diarrhea and other GI symptoms partially but are less effective in treating the delayed diarrhea; flushing, rash, and alopecia are common; significant hepatic, renal, neurologic, or pulmonary toxicities are rare	Irinotecan is FDA approved for refractory or recurrent metastatic colon cancer, and it has now been used in other malignancies, including lung cancer, ovarian cancer, and lymphoma
Ixabepilone (Ixempra)	Microtubule inhibitor	In combination with capecitabine, must not be given to patients with AST or ALT >2.5 × ULN or bilirubin >1 × ULN; dose reduction is recommended when administering ixabepilone as monotherapy to patients with hepatic impairment; no formal renal impairment study; inhibitors of CYP3A4 may increase plasma concentrations of ixabepilone; dose of ixabepilone must be reduced with strong CYP3A4 inhibitors; inducers of CYP3A4 may decrease plasma concentrations of ixabepilone; alternative therapeutic agents with low enzyme induction potential should be considered	Peripheral neuropathy: monitor for symptoms of neuropathy, primarily sensory; neuropathy is cumulative, generally reversible, and should be managed by dose adjustment and delays; myelosuppression: primarily neutropenia; monitor with peripheral blood cell counts and adjust dose as appropriate; hypersensitivity reaction: must premedicate all patients with an H1 antagonist and an H2 antagonist before treatment; fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain	Combination with capecitabine is indicated for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane; as monotherapy is indicated for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine
Ixazomib (Ninlaro)	Inhibits 20 S proteasome	Absorption decreased by high-fat meals; hepatic metabolism; reduce dose for CrCl <30 mL/min and for total bilirubin >1.5 ULN	Myelosuppression; skin rash; peripheral neuropathy	Multiple myeloma in combination with lenalidomide and dexamethasone as second-line therapy
Lapatinib (Tykerb)	EGRF and HER2 tyrosine kinase inhibitor	Extensive metabolism spread over several enzymes	Hepatotoxicity; decreased left ventricular ejection fraction; diarrhea; some QT interval prolongation	HER2+ breast cancer, with capecitabine; treatment with anthracycline, taxane, trastuzumab failed
Larotrectinib (Vitrakvi)	Neurotrophic receptor tyrosine kinase inhibitor	Avoid strong CYP3A4 inhibitors, strong CYP3A4 inducers, and sensitive CYP3A4 substrates	Neurotoxicity, hepatotoxicity, nausea, vomiting, dizziness, cough, constipation, diarrhea	Metastatic or unresectable solid tumors with a neurotrophic receptor tyrosine kinase gene fusion
Lenalidomide (Revlimid)	Antiangiogenesis agent, immunomodulator	Mechanism of action not fully characterized; an immunomodulatory agent that inhibits angiogenesis in some cells; inhibits bone marrow secretion of IL-6, VEGF, and TNF-α	Myelosuppression; diarrhea, rash, fatigue; increased risk of DVT and PE	Transfusion-dependent anemia due to low- or intermediate-risk myelodysplasia with 5q deletion; multiple myeloma
Lenvatinib (Lenvima)	Multitargeted tyrosine kinase inhibitor (VEGFR, FGFR, PDGFR, KIT, RET)	Metabolized in the liver by CYP3A and aldehyde oxidase; dose reduction for hepatic insufficiency	Hypertension; alters thyroid suppression with TSH elevation and hypothyroidism; gastrointestinal toxicity and bowel fistula formation; hepatotoxicity; skin toxicity; hypocalcemia; renal toxicity	Renal cell carcinoma in combination with everolimus; differentiated thyroid cancer that is radioactive iodine refractory
Letrozole (Femara)	Nonsteroidal aromatase inhibitor	Letrozole has nearly 100% bioavailability, is metabolized in the liver, glucuronidated, and excreted by the kidneys; half-life is 2 days; with daily administration, steady-state plasma levels are reached in 2-6 wk	This drug is generally well tolerated; muscle aches and nausea are uncommon; hot flashes and fatigue are uncommon; weight change, urticaria, and dyspepsia are rare	Metastatic estrogen-responsive breast cancer in postmenopausal patients
Leucovorin calcium (Wellcovorin) citrovorum factor, folinic acid, FA, LV	Tetrahydrofolate derivative and enzyme cofactor for thymidylate synthase and other purine and pyrimidine synthesis steps; bypasses the dihydrofolate reductase step, which is inhibited by methotrexate and therefore can be used to “rescue” normal cells from the toxicity of methotrexate after high doses are administered; in addition, leucovorin potentiates the toxicity of fluoropyrimidines such as fluorouracil by strengthening the association of the drug	Leucovorin has excellent bioavailability by the oral or parenteral route; it is oxidized in cofactor reactions throughout the body and is also partly metabolized; it has an elimination half-life of 2-4 hr; excreted in the urine	Leucovorin is generally very well tolerated; it occasionally causes stomach upset or nausea, rash, diarrhea, and headache; allergic reactions have been reported	Used for rescue of high-dose methotrexate therapy for a variety of neoplasms and as a potentiator of fluoropyrimidines therapy in GI malignancies, particularly colorectal cancer
Leuprolide acetate (Lupron)—leuprorelin acetate	Gonadotropin-releasing hormone agonist, which serves to paradoxically shut down the pituitary release of gonadotropins with chronic exposure; this results in a dramatic decrease in gonadal estrogens and androgens and growth inhibition of hormone-dependent neoplasms	After an SQ injection, about 90% of the drug is eventually absorbed; the depot form of the drug is absorbed slowly over days, whereas the injectable solution is absorbed over several hours; the elimination half-life of the drug once in the serum is 3 hr; metabolism and excretion are not well delineated but are clinically unimportant	Usually well tolerated, but adverse effects can affect many systems, including endocrine (hot flashes, impotence, gynecomastia, breast tenderness, diminished libido, amenorrhea, atrophic vaginitis, increased cholesterol); GI (nausea, constipation, anorexia, diarrhea); hepatic (elevation of transaminases); dermatologic (rash, changes in body hair composition, pruritus); and neuropsychiatric (insomnia, depression, emotional lability, lethargy, memory loss); significant cardiac toxicity is rare	Approved for the treatment of hormone-dependent advanced prostate cancer; also used for breast cancer and endometriosis
Lurbinectedin (Zepzelca)	Alkylating agent	Avoid strong or moderate CYP3A inhibitors and strong or moderate CYP3A inducers	Myelosuppression, hepatotoxicity, increased creatinine level, hyperglycemia, nausea, musculoskeletal pain, constipation, dyspnea, decreased sodium level	Metastatic SCLC progressing despite platinum-based chemotherapy
Methotrexate (Mexate, Folex, others)—MTX, amethopterin	Antifolate antimetabolite; interferes with nucleotide synthesis by inhibiting dihydrofolate reductase; cell cycle dependent	Good oral bioavailability at low doses; after oral or IV dosing, it is distributed throughout the body water compartment; it will accumulate in “third-space” fluid compartments and exhibit prolonged toxicity and therefore should be used with caution, if at all, in patients with significant pleural or peritoneal fluid; minimally metabolized in the liver; half-life is 3 hr; even low concentrations of drug after most of the drug is eliminated can contribute to significant toxicity; therefore dosing based on renal function is critical; excretion of this drug is mostly renal	Myelosuppression is expected and is usually dose limiting; stomatitis and diarrhea are common; nausea and vomiting are uncommon; renal toxicity is uncommon and usually reversible but can be severe; many types of skin reactions can occur but are uncommon; pulmonary fibrosis and hepatic fibrosis are rare; encephalopathy is rare with moderate- to low-dose therapy but is more common with high doses, intrathecal administration, or concomitant CNS radiation; it can be severe and permanent	Approved for a wide spectrum of malignant and nonmalignant diseases; most often used for acute leukemias, lymphomas, breast cancer, bladder cancer, squamous cell cancers, and sarcomas
Midostaurin (Rydapt)	Tyrosine kinase inhibitor targeting FLT3, FLT3 ITD, KIT, PDGFR, VEGFR2 , and PKC family	Metabolized by CYP3A4 in the liver	Cardiovascular (edema and QTc prolongation); headache and fatigue; electrolyte abnormalities and hyperglycemia; nausea and vomiting; myelosuppression; abnormal liver function tests; infection	FLT3 mutation-positive AML in combination with cytarabine and daunorubicin; mast cell leukemia; systemic mastocytosis
Neratinib (Nerlynx)	Irreversible inhibitor of EGFR and HER2 kinases	Hepatic metabolism by CYP3A4; dose reduction for severe hepatic dysfunction	Severe diarrhea with dehydration; hepatic toxicity requiring careful monitoring of liver function	Adjuvant therapy of HER2-positive breast cancer following adjuvant trastuzumab-associated therapy
Nilotinib (Tasigna)	Kinase inhibitor including Bcr-Abl	Dose adjustment may be required for hematologic and nonhematologic toxicities and drug interactions; lower starting dose is recommended in patients with impairment (at baseline); do not consume food for at least 2 hr before the dose is taken and for at least 1 hr after	Prolongs QT interval; rash, pruritus, headache, nausea, fatigue, myalgia, nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, pyrexia, upper respiratory tract infection, back pain, cough, and asthenia; hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia, and anemia	Newly diagnosed adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase; also, the treatment of chronic and accelerated phase Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib
Niraparib (Zejula)	Poly (ADP-ribose) polymerase enzyme inhibitor	Metabolized by carboxylesterases and then glucuronidated	Hypertension; skin rash; fatigue; nausea and constipation; myelosuppression; weakness and back pain; hepatic dysfunction	Ovarian and primary peritoneal cancers in complete or partial response following platinum-containing chemotherapy
Nivolumab (Opdivo)	Human anti-PD-1 monoclonal antibody; releases PD-1 pathway inhibition to improve immune response	Prolonged (>20 day) half-life	Endocrinopathies; colitis; encephalitis; pneumonitis; hypophysitis; rash; if severe may require systemic corticosteroids; infusion reactions	Colorectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) that is metastatic and has progressed following fluoropyrimidine, oxaliplatin, and irinotecan; head and neck squamous cell cancer that is recurrent or progressed on platinum-containing chemotherapy; Hodgkin lymphoma; metastatic melanoma; NSCLC; advanced renal cancer; advanced urothelial cancer; esophageal cancer or gastroesophageal junction adenocarcinoma; hepatocellular cancer; mesothelioma; squamous cancer of the head and neck
Obinutuzumab (Gazyva)	Anti-CD20 monoclonal antibody; upon binding to CD20 on B cells, initiates ADCC	No dosage adjustments for renal or hepatic dysfunction	Hypophosphatemia; hypocalcemia; hyperkalemia; blood count suppression; altered liver and kidney function; infection; cough	CLL previously untreated in combination with chlorambucil; follicular lymphoma in combination with bendamustine in patients refractory to rituximab-containing regimens
Octreotide, octreotide long-acting (Sandostatin, Sandostatin LA), l-cysteinamide	Synthetic peptide analog of somatostatin; inhibits other GI peptide actions, such as serotonin, insulin, glucagon, and gastrin	Not orally bioavailable but rapidly absorbed after SQ administration; metabolized by hydrolysis throughout the body; no active metabolites; half-life of elimination is about 1.5 hr; intact drug is cleared via the kidneys	GI adverse effects are dose limiting and include abdominal pain, vomiting, loose stool, occasional fat malabsorption, bloating, and cholelithiasis; elevations of liver function tests can also occur, but frank hepatitis is rare; skin reactions, such as pain at the injection site or flushing, rash, or skin thinning, are sometimes seen; constitutional symptoms, including rhinorrhea, xerostomia, sweating, throat discomfort, and vertigo, can be bothersome; hyperglycemia or hypoglycemia can occur; cardiac side effects, including angina, congestive heart failure, and hypotension or hypertension, are uncommon; anxiety, depression, fatigue, and anorexia are uncommon, and seizures are rare	Approved for carcinoid tumors causing carcinoid syndrome and for vasoactive peptide–secreting tumors; also used for refractory diarrhea, either cancer related or treatment related, in patients with cancer
Olaparib (Lynparza)	Inhibitor of poly (ADP-ribose) polymerase enzyme; produces synthetic lethality in BRCA1/2-deficient tumor cells	Hepatic metabolism by CYP3A4; Cmax increased in patients with mild hepatic dysfunction; avoid concomitant use of CYP3A inhibitors	Peripheral edema; fatigue and headache; skin rash; nausea and abdominal pain; anemia and lymphopenia; myalgias; increased serum creatinine	BRCA -mutant ovarian cancer previously treated with three or more lines of therapy; maintenance therapy for ovarian cancer in complete or partial remission following platinum-based therapy
Osimertinib (Tagrisso)	Irreversible inhibitor of EGFR tyrosine kinase; binds to mutant forms of EGFR ( T970M, L858R , exon 19 deletions); less active against wild-type EGFR	Metabolized by CYP3A and excreted in the feces; avoid concomitant use of strong CYP3A4 inducers	Bone marrow suppression; cardiotoxicity, decline in LVEF and prolongation of QTc; skin rash; impaired fertility; diarrhea; keratitis; pneumonitis	Metastatic NSCLC that is T790M mutation positive
Oxaliplatin (Eloxatin)	Platinating agent; DNA disrupted via intrastrand and interstrand cross-links with two strong platinum association bonds in the molecule, which induces apoptosis beyond a certain level of DNA damage in malignant cells	After IV administration, rapid distribution into tissues occurs, as well as rapid spontaneous conversion via hydrolysis into active drug and metabolites; the terminal half-life is long (>300 hr) but represents minimal plasma levels of the hydrolyzed drug; elimination of platinum metabolites is via the kidneys	Neurotoxicity, in the form of a transient neuropathy with each dose and a persistent, cumulative typical sensory polyneuropathy, is very common and dose limiting; myelosuppression is expected but mild and only sometimes dose limiting; fatigue and nausea are common but mild; diarrhea, stomatitis, edema, cough, hypersensitivity reactions, and extravasation injury are rare	Approved for metastatic colorectal cancer in combination with 5-FU/leucovorin
Paclitaxel (Taxol, Onxol)	Naturally occurring taxane molecule; inhibits depolymerization of tubulin in the spindle apparatus, thereby inducing apoptosis in dividing cells	After IV administration, the drug exhibits a large volume of distribution and undergoes metabolism in the liver; the elimination half-life is 15-50 hr; excretion of drug and metabolites is predominantly via the bile	Paclitaxel is an irritant or mild vesicant when extravasated into subcutaneous tissue; myelosuppression, predominantly neutropenia, is expected and is dose limiting; shorter infusions of the same dose produce less neutropenia; mucositis is also very common, particularly with longer infusions; peripheral neuropathy is common, usually mild, and increases with cumulative dose; acute neuromyopathy is also common and occurs for several days after each dose; this syndrome may require opiate analgesics to control pain; cardiovascular adverse effects, including hypertension, hypotension, premature contractions, and bradyarrhythmias, are common but rarely require intervention; hypersensitivity reactions to paclitaxel, including urticaria, wheezing, chest pain, dyspnea, and hypotension, are common but are reduced in frequency and severity by premedication with corticosteroids and histamine-1 and histamine-2 antihistamines (the recommended regimen is dexamethasone, 20 mg PO 12 and 6 hr prior to paclitaxel and diphenhydramine, 50 mg, and cimetidine)	Approved for salvage therapy in ovarian cancer and for breast cancer in both the metastatic and adjuvant settings; used also in persons with lung cancer, head and neck cancer, and bladder cancer
Paclitaxel, protein bound (Abraxane)	Taxane; an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers	No change in patients with mild to moderate hepatic dysfunction	Neutropenia, thrombocytopenia, anemia, hypersensitivity reactions, hypotension, cardiovascular events, dyspnea, cough, sensory neuropathy, arthralgias/myalgias, nausea/vomiting, asthenia	Metastatic breast cancer after failure of combination chemotherapy or relapse with 6 mo of adjuvant chemotherapy; also approved for NSCLC
Palbociclib (Ibrance)	Reversible small molecule inhibitor of cyclin-dependent kinases 4 and 6 affecting cell cycle progression through the G1/S phase	Metabolized by the liver by CY3A and sulfotransferase; avoid simultaneous use of strong CYP3A inhibitors	Fatigue; alopecia and skin rash; nausea, stomatitis, diarrhea, infection; blood count suppression, infection	Advanced breast cancer that is ER positive, HER2 negative in combination with an aromatase inhibitor as initial therapy for postmenopausal women
Pamidronate (Aredia), APD, aminohydroxypropylidene diphosphonate	Organic bisphosphonate; inhibitor of bone resorption by osteoclasts	After IV administration, the drug concentrates in the bone, spleen, and liver; its metabolism is not well characterized; it has a terminal half-life of about 27 hr; 50% of the parent drug is eliminated in the urine	Pamidronate is usually quite well tolerated; hypotension, syncope, tachycardia, and even atrial fibrillation have been reported uncommonly during the infusion; hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia occur commonly but only rarely require intervention; nausea, vomiting, and somnolence are rare	Approved for malignancy-induced hypercalcemia; may lead to pain relief and even tumor shrinkage of bone metastases in multiple myeloma, breast cancer, and prostate cancer
Panitumumab (Vectibix)	Recombinant, fully humanized IgG2 kappa monoclonal antibody that binds specifically to EGFR, competitively inhibiting ligand binding to the receptor	Steady-state levels are reached by the third infusion; elimination half-life is about 7.5 days	Rash, which may be severe; diarrhea; infusion reactions; hypomagnesemia; pulmonary fibrosis	Previously treated EGFR-expressing metastatic colorectal cancer
Panobinostat (Farydak)	Histone deacetylase inhibitor, affects chromatin remodeling	Hepatic metabolism in part through CYP3A; reduce dose for hepatic dysfunction	ECG abnormalities; fatigue; electrolyte abnormalities; diarrhea; blood count suppression; infection; hyperbilirubinemia	Multiple myeloma in combination with bortezomib and dexamethasone in patients who have received 2 prior regimens
Pazopanib (Votrient)	Inhibits large number of tyrosine kinases	Take without food; reduce dose for mild to moderate hepatic impairment; avoid severe hepatic impairment; interacts with many metabolizing enzymes	Diarrhea, hypertension, nausea, anorexia, vomiting, hair color depigmentation	Renal cell carcinoma; also approved for soft tissue sarcoma
Pembrolizumab (Keytruda)	Human monoclonal antibody against programmed cell death-1 (PD-1) activity that inhibits negative immune regulation to enhance antitumor effects	Long half-life (22 days)	Peripheral edema; rash; fatigue; endocrinopathies; electrolyte abnormalities; hyperglycemia; nausea, diarrhea, colitis; abnormal liver function tests	Squamous cell cancers of the head and neck; Hodgkin lymphoma, melanoma, microsatellite instable (MSI-H) or mismatch repair deficient solid tumors and colorectal cancers that have no alternative treatment options; NSCLC first-line metastatic in patients with high (50%) PD-L1 expression that are EGFR or ALK negative and first-line therapy for metastatic nonsquamous NSCLC in combination with pemetrexed and carboplatin; urothelial carcinoma that has progressed on platinum-containing therapy; triple-negative breast cancer; cervical cancer; cutaneous squamous cell cancer; endometrial cancer that is MSI-high; esophageal, gastric, and gastroesophageal junction adenocarcinoma; hepatocellular cancer; Merkel cell carcinoma; renal cell cancer; primary large B-cell lymphoma
Pemetrexed (Alimta)	Antimetabolite; inhibits folate-dependent enzymes thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, which are involved in the de novo synthesis of thymidine and purine nucleotides, leading to inhibition of DNA and RNA synthesis and function; metabolized intracellularly to its highly active polyglutamated form	Excreted in urine with 90% of drug unchanged	Myelosuppression; nausea, vomiting, diarrhea; rash; dyspnea and fatigue	Mesothelioma and NSCLC
Pertuzumab (Perjeta)	HER2/neu receptor antagonist antibody; HER2 testing: perform using FDA-approved tests by laboratories with demonstrated proficiency	Of 402 patients who received Perjeta in the randomized trial, 60 patients (15%) were 65 yr of age and 5 patients (1%) were 75 yr of age; no overall differences in efficacy and safety of Perjeta were observed between these patients and younger patients; based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients <65 yr (n = 306) and patients ≥65 yr (n = 175)	Left ventricular dysfunction: monitor LVEF and withhold dosing as appropriate; reactions, hypersensitivity reactions/anaphylaxis: monitor for signs and symptoms; if a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies; in combination with trastuzumab and docetaxel: diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy	First-line HER2+ metastatic breast cancer
Pomalidomide (Pomalyst)	Immunomodulator, analog of thalidomide, decreases proliferation of myeloma cells, enhances T-cell–mediated immunity, and has antiangiogenic properties	Metabolized by CYP3A4 and CYP1A2; systemic exposure increased by hepatic dysfunction; avoid use with concomitant CYP1A2 inhibitors; reduce dose for renal or hepatic dysfunction	Thromboembolism; hematologic toxicity; hepatotoxicity; hypersensitivity; neurotoxicity; confusion; tumor lysis syndrome; fatigue; nausea; diarrhea; infection	Multiple myeloma in combination with dexamethasone as third-line therapy
Ponatinib (Iclusig)	Kinase inhibitor	For strong CYP3A inhibitors: reduce dose if co-administration cannot be avoided; renal or hepatic impairment not studied	Arterial thrombosis and hepatotoxicity have boxed warnings; nonhematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia; hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia	CML and Philadelphia chromosome–positive acute ALL
Ramucirumab (Cyramza)	Monoclonal antibody targeting the vascular growth factor receptor 2, inhibiting endothelial cell proliferation and angiogenesis	Half-life 14 days	Infusion reaction; hypertension; proteinuria; arterial thrombosis; GI perforation; bleeding	Metastatic colorectal cancer in combination with FOLFIRI following progression on FOLFOX and bevacizumab; gastric cancer as a single agent or in combination with paclitaxel following progression on a fluoropyrimidine- or platinum-containing regimen; NSCLC in combination with paclitaxel for advanced disease after platinum-based treatment
Regorafenib (Stivarga)	Inhibits many membrane and intracellular kinases including RET, VEGFR, KIT, PDGFR, FGF, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF , and CSF1R	Take with food; decreased exposure with strong inducers of CYP3A	Hepatotoxicity, fatigue, decreased appetite, hand-foot skin reaction	Previously treated metastatic colorectal cancer; gastrointestinal stromal tumor; hepatocellular carcinoma
Ribociclib (Kisqali)	Small molecule inhibitor of cyclin-dependent kinases 4 and 6; produces G1 cell cycle arrest; combined with aromatase inhibitors leads to enhanced tumor cell growth control	Metabolized in the liver by CYP3A4	Bone marrow suppression; hepatotoxicity with abnormal liver function; QT prolongation; peripheral edema; fatigue; alopecia; skin rash; hypokalemia; nausea and diarrhea; increased serum creatinine	Advanced breast cancer for patients with HR-positive, HER2-negative disease in combination with an aromatase inhibitor as initial endocrine therapy
Rituximab (Rituxan)	Monoclonal antibody directed against the B-cell surface antigen CD20	When given IV, it is taken up by B lymphocytes and then degraded throughout the body by proteolysis, with a wide-ranging serum half-life of 11-105 hr (mean 60 hr) with the first dose; there is no appreciable excretion of this polypeptide	Fever, chills, and malaise are common during administration, even with premedication with acetaminophen and diphenhydramine; other infusion-related symptoms include nausea, vomiting, flushing, urticaria, angioedema, hypotension, dyspnea, bronchospasm, fatigue, headache, rhinitis, and pain at disease sites; these symptoms are generally self-limited, improve with slowing of the infusion, and resolve after infusion; short-lived myelosuppression, abdominal pain, and myalgia are uncommon; arrhythmias and angina pectoris are rare	Relapsed or refractory low-grade or follicular, CD20-positive, B-cell lymphomas
Rucaparib (Rubraca)	Inhibits poly (ADP-ribose) polymerase enzyme isoforms essential for DNA repair; increased cell killing in tumors deficient in BRCA1/2 repair pathway	Metabolized by CYP2D6 in the liver	Fatigue and dizziness; skin rash; increased cholesterol; nausea, constipation; diarrhea; blood count suppression; increased liver function tests; increased serum creatinine; weakness; dyspnea; fever	Advanced ovarian cancer in the presence of BRCA mutations (germline or somatic) detected by an approved diagnostic test as third-line therapy
Ruxolitinib (Jakafi)	Janus kinase signaling inhibitor	With or without food; reduce dose 50% with strong CYP3A inhibitors, moderate renal or hepatic impairment	Thrombocytopenia, anemia, bruising, dizziness, headache	Intermediate- or high-risk myelofibrosis
Sacituzumab govitecan-hziy (Trodelvy)	Trop-2–directed antibody and topoisomerase inhibitor conjugate	Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) ∗ 28 allele are at increased risk for neutropenia	Neutropenia, severe diarrhea, hypersensitivity reactions, nausea, vomiting, anemia, alopecia, constipation, rash, abdominal pain	Metastatic triple-negative breast cancer despite at least two prior therapies
Selinexor (Xpovio)	Nuclear export inhibitor	95% protein bound; metabolized by liver	Thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, serious infection, neurologic toxicity	With dexamethasone for relapsed or refractory multiple myeloma despite at least four prior therapies; or refractory diffuse large B-cell lymphoma, including disease arising from follicular lymphoma, after at least two lines of systemic therapy
Sonidegib (Odomzo)	Hedgehog pathway inhibitor that binds and inhibits Smoothened, a transmembrane protein essential for hedgehog signaling	Metabolized in the liver by CYP3A	Fatigue; alopecia; hyperglycemia; abnormal liver function tests; anemia; increased CK, muscle pain; increased serum creatinine	Locally advanced basal cell carcinoma recurrent after surgery or radiation therapy
Sorafenib (Nexavar)	Oral multikinase inhibitor that interacts with multiple intracellular (CRAD, BRAF) and cell surface kinases (KIT, FLT-3, VEGFR-2, and PDGFR); may inhibit angiogenesis	Metabolized in the liver; drug and metabolites are excreted primarily in the feces	Skin toxicity with rash and hand-foot syndrome; nausea, vomiting, anorexia, diarrhea; asthenia, pain, arthralgias; hypertension; bleeding events, especially in anticoagulated patients; cardiac ischemia; myelosuppression	Advanced renal cell carcinoma
Sotorasib (Lumakras)	Selective, orally active inhibitor that covalently binds to Cys12 of KRAS; inhibits signaling only in tumors that exhibit the KRAS-G12C mutation	Avoid proton pump inhibitors and histamine-2 receptor antagonists	Drug-induced hepatitis with increased ALT/AST requires monitoring of liver function tests; interstitial lung disease; diarrhea; musculoskeletal pain; nausea; fatigue	Adults with KRAS-G12C -mutated locally advanced or metastatic NSCLC
Sunitinib maleate (Sutent)	Inhibits PDGFR-A, PDGFR-B, and VEGFR1-3, stem cell factor receptor, FLT-3, CSF-1R, and the neurotrophic factor receptor; this inhibition inhibits tumor growth and metastases	Metabolized in the liver with elimination primarily in the feces; half-life is 40-60 hr for the drug and 80-110 hr for its primary metabolite	Cardiotoxicity—usually reversible; bleeding event, epistaxis most common; hypertension; myelosuppression; nausea, vomiting; rash; liver function test alterations	Advanced renal cell carcinoma; second-line therapy for GIST cell tumors; also approved for pancreatic neuroendocrine tumors
Talazoparib (Talzenna)	PARP inhibitor	Reduce dose if moderate renal impairment (creatinine clearance 30-59 mL/min)	Myelodysplastic syndrome, AML, myelosuppression, nausea, headache, vomiting, alopecia, diarrhea	Germline BRCA -mutated HER2-negative locally advanced or metastatic breast cancer
Tamoxifen (Nolvadex)	Nonsteroidal antiestrogen; cytostatic effects on estrogen-dependent and nondependent malignant cells	Tamoxifen has good oral bioavailability, is metabolized in the liver, and has an elimination half-life of about 7 days; neither tamoxifen nor its major metabolite is found in the bile or urine	Tamoxifen is usually very well tolerated; constitutional symptoms are most prevalent and usually dose limiting; hot flashes, sweating, mood changes, weight gain or loss, and stomach upset are most common; nausea, vomiting, diarrhea, and constipation are less common; menstrual changes, including significant vaginal bleeding, are uncommon; venous thromboembolism, myelosuppression, and retinopathy are rare	Approved for the treatment of breast cancer, generally in postmenopausal patients or those with ER+ tumors; the same dose has been approved for chemoprevention of breast cancer in high-risk individuals; higher doses are used for melanoma and pancreatic cancer
Tazemetostat (Tazverik)	Methyltransferase inhibitor	Avoid strong and moderate CYP3A inhibitors and strong and moderate CYP3A inducers	Fatigue, nausea, vomiting, constipation, upper respiratory tract infection, musculoskeletal pain, abdominal pain	Metastatic or unresectable locally advanced epithelioid sarcoma, relapsed or refractory follicular lymphoma with an EZH2 mutation or no alternative treatment options
Temozolomide (Temodar)	Atypical alkylator (semiselective DNA methylator) drug sharing the same active metabolite as dacarbazine, MTIC but, unlike dacarbazine, is spontaneously converted to MTIC and also penetrates the blood-brain barrier effectively	Temozolomide had good bioavailability, enhanced by an empty stomach; after absorption into the blood stream, it is spontaneously converted to the active moiety MTIC; peak plasma concentrations occur in about 1 hr; the elimination half-life is about 1.8 hr; parent drug, MTIC, and other metabolites are eliminated in the urine	Myelosuppression is expected and dose-limiting; it may be cumulative; nausea is common but generally mild and treatable; headache and fatigue are common; rash or other cutaneous reactions are uncommon; infections are common in this population, and some are probably caused by immunosuppression that is known to occur with temozolomide	Approved for treatment of recurrent high-grade astrocytomas; used commonly for other gliomas and also for metastatic melanoma
Temsirolimus (Torisel)	Inhibitor of mTOR	Antihistamine pretreatment is recommended; dose reduction is required in patients with mild hepatic impairment; strong inducers of CYP3A4/5 and inhibitors of CYP3A4 may affect concentrations of the primary metabolite, sirolimus; if alternatives cannot be used, dose modifications are recommended	Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions) can occur early in the first infusion; patients should be monitored throughout the infusion; monitor for symptoms or radiographic changes of ILD; if ILD is suspected, discontinue drug, and consider use of corticosteroids and/or antibiotics; bowel perforation may occur; evaluate fever, abdominal pain, bloody stools, and/or acute abdomen promptly; elderly patients may be more likely to experience certain adverse reactions, including diarrhea, edema, and pneumonia	Advanced renal cell carcinoma
Tepotinib (Tepmetko)	Tyrosine kinase inhibitor that blocks signaling through a MET exon 14 skipping mutation	Avoid use with strong CYP3A and P-gp inhibitors; metabolized in the liver and excreted in feces	Edema; fatigue; nausea; diarrhea; interstitial lung disease; hepatotoxicity	NSCLC with MET exon 14 skipping mutation
Tisagenlecleucel (Kymriah)	Anti-CD19 CAR–T-cell immunotherapy	No contraindications	Cytokine release syndrome; neurologic toxicity	ALL B-cell precursor type refractory to primary therapy
Topotecan (Hycamtin), hycamptamine	Semisynthetic camptothecin molecule; an inhibitor of topoisomerase I, which is required by cells for both transcription and replication	After IV administration, the drug is not extensively metabolized, and it has an elimination half-life of about 3 hr; a significant portion of the drug is excreted unchanged in the urine	Myelosuppression, especially leukopenia, is expected and dose limiting; thrombocytopenia and anemia are common but mild; nausea, vomiting, and diarrhea are common but usually not severe; headache, fever, fatigue, anorexia, malaise, and elevated liver function tests are also common; hypertension, tachycardia, urticaria, renal insufficiency, hematuria, neuropathy, and mucositis are uncommon	Approved for the treatment of refractory, relapsed ovarian carcinoma and for relapsed small cell lung cancer; also used in myeloid leukemias
Trabectedin (Yondelis)	Alkylating agent that binds the minor groove of DNA-producing adducts	Avoid strong CYP3A inhibitors or inducers	Neutropenic sepsis; rhabdomyolysis; hepatotoxicity; cardiotoxicity; fetal harm	Unresectable or metastatic liposarcoma or leiomyosarcoma after prior anthracycline therapy
Trametinib (Mekinist)	Selective inhibitor of mitogen-activated extracellular kinase (MEK) 1 and 2; decreases cellular proliferation; combination with BRAF inhibitors increases inhibition of MAPK pathway	Deacetylated and glucuronidated in liver; no dose adjustments for mild renal or hepatic dysfunction	Cardiovascular (hypertension, decreased LVEF); acneiform rash and palmar-plantar erythrodysesthesia; diarrhea; anemia; peripheral edema	Advanced melanoma in patients with BRAF V600E or V600K mutations alone or in combination with dabrafenib; metastatic NSCLC with BRAF V600E mutation in combination with dabrafenib
Aldo-trastuzumab emtansine (Kadcyla)	Antibody-drug conjugate targeting HER2; composed of trastuzumab covalently linked to a maytansine derivative (DM1) with microtubule inhibitory properties; after binding to HER2, it is internalized with release of DM1 and tubulin disruption	Metabolized in the liver by CYP3A4	Hepatotoxicity; left ventricular dysfunction; infusion reaction; pneumonitis; blood count suppression	HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane
Fam-trastuzumab deruxtecan-nxki (Enhertu)	HER2-directed antibody and topoisomerase inhibitor conjugate	Intravenous infusion only, but not with sodium chloride	Interstitial lung disease, neutropenia, left ventricular dysfunction, nausea, vomiting, fatigue, alopecia, constipation, anemia, diarrhea, thrombocytopenia	Unresectable or metastatic HER2-positive breast cancer despite two or more prior anti-HER2-based regimens
Trastuzumab (Herceptin)	Genetically engineered humanized mouse monoclonal antibody directed against HER2/neu growth factor receptor that is overexpressed in many invasive breast carcinomas; mechanism of action for clinical activity in breast cancer is unknown but may be complement-mediated cell lysis, antibody-dependent cellular cytotoxicity, or induction of apoptosis	Binding studies show strong binding to cells overexpressing HER2/neu molecules; very little else is known regarding the distribution and metabolic fates of this molecule; half-life should be very short with minimal distribution outside the vascular compartment and minimal clearance by kidneys or liver (similar to other monoclonal agents)	Common toxicities include acute fever, chills, nausea, vomiting, and headache; trastuzumab seems to worsen leukopenia, anemia, and diarrhea when given with chemotherapy compared with chemotherapy alone; also, trastuzumab may have uncommon acute cardiotoxicity, which may add to the more common anthracycline-induced cardiotoxicity; therefore, the use of trastuzumab with doxorubicin is not indicated by the FDA	Approved for HER2/neu overexpressing metastatic or locally advanced breast cancer; has shown clinical benefit as a single agent and in conjunction with paclitaxel-based chemotherapy; also approved for gastric cancer
Tucatinib (Tukysa)	HER2 tyrosine kinase inhibitor	Avoid strong CYP3A inducers, moderate CYP2C8 inducers, strong CYP2C8 inhibitors, CYP3A substrates, and P-gp substrates	Diarrhea, hepatotoxicity	In combination with trastuzumab and capecitabine for advanced unresectable or metastatic HER2-positive breast cancer despite other anti-HER2 regimens
Umbralisib (Ukoniq)	Oral kinase inhibitor active against PI3K-delta and casein kinase CK1-epsilon	No dosage reduction required for mild renal or hepatic dysfunction; rapidly absorbed and excreted predominantly in feces	Neutropenia; diarrhea; noninfectious colitis; hepatotoxicity; cutaneous reactions	Marginal zone lymphoma relapsed or refractory following at least one prior anti–CD20-based regimen; follicular lymphoma relapsed or refractory after at least three lines of systemic therapy
Vandetanib (Caprelsa)	Kinase inhibitor	The concomitant use of known strong CYP 3A4 inducers may reduce drug levels of vandetanib and should be avoided. No clinically significant drug interaction was shown with vandetanib and the potent CYP 3A4 inhibitor, itraconazole. The administration of vandetanib with agents that may prolong the QT interval should be avoided. In total, 18% of medullary thyroid cancer patients treated with vandetanib were age 65 yr or older, and 3% were 75 yr and older. No overall differences in safety and efficacy were observed between elderly and younger patients. No adjustment in starting dose is required for patients over 65 yr of age. There are limited data for patients over the age of 75 yr. Limited data for renal or hepatic impairment point toward dose reductions	QT prolongation: sudden death has been reported. Monitor electrocardiograms and levels of serum potassium, calcium, magnesium, and TSH at baseline, 2-4 wk and 8-12 wk after starting treatment, and every 3 mo thereafter and following dose adjustments. Dose reduction as appropriate. Stevens-Johnson syndrome resulting in death has been observed. Severe skin reactions may prompt permanent discontinuation of the drug. Interstitial lung disease resulting in death has been reported. Interrupt dosing and investigate unexplained dyspnea, cough, and fever. Appropriate measures should be taken for ILD. Ischemic cerebrovascular events, hemorrhage, heart failure, diarrhea, hypothyroidism, hypertension, and reversible posterior leukoencephalopathy syndrome have been observed. Other common adverse events: diarrhea, rash, acne, nausea, hypertension, headache, fatigue, upper respiratory tract infections, decreased appetite, and abdominal pain. The most common laboratory abnormalities were decreased calcium, increased ALT, and decreased glucose	Thyroid cancer unresectable locally advanced or metastatic
Vemurafenib (Zelboraf)	Inhibits V600E serine-threonine and other kinases	Take with or without food; inhibits CYP1A2, 2D6; enhances CYP3A	Produces cutaneous squamous cell carcinoma, hypersensitive and dermatologic reagins, QT prolonged, liver lab abnormalities	Metastatic BRAF+ melanoma
Venetoclax (Venclexta)	BCL-2 inhibitor	Take with meal and water; prophylaxis for tumor lysis syndrome with anti-hyperuricemic agents and adequate hydration; do not use strong inhibitors of CYP3A at initiation and during ramp-up phase	Tumor lysis syndrome; neutropenia; fetal harm; diarrhea, nausea; anemia; upper respiratory tract infection	CLL with 17p deletion, per FDA-approved test, after at least one prior therapy
Vinorelbine (Navelbine), 5ʹ-noranhydrovinblastine, NVB	Semisynthetic vinca alkaloid; inhibitor of tubulin polymerization and thereby mitosis; G2-phase specific	Metabolized by the liver and has an elimination half-life of about 24 hr; excretion is predominantly in the bile	Vinorelbine is a mild vesicant, requiring extravasation precautions; myelosuppression, mostly leukopenia, is expected and dose limiting; significant nausea and vomiting are uncommon; neurotoxicity in the form of neuropathy is less common and milder than that seen with vincristine; tumor pain during administration has been reported; acute reaction such as dyspnea, chest pain, and wheezing have occurred during administration and may be prevented by premedication with corticosteroids	Approved for the treatment of relapsed metastatic breast cancer and for NSCLC as a single agent or combined with a platinating agent
Vismodegib (Erivedge)	Hedgehog pathway inhibitor	Safety and effectiveness have not been established for hepatic or renal impairment; absorption is saturable as evidenced by the lack of dose-proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib; may be taken without regard to meals because the systemic exposure of vismodegib at steady state is not affected by food	The most common adverse reactions (incidence of ≥10%) are muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia. Advise patients not to donate blood or blood products while receiving vismodegib and for at least 7 mo after the last dose.	Metastatic basal cell carcinoma or locally advanced basal cell carcinoma that has recurred following surgery or patients who are not candidates for surgery and who are not candidates for radiation
Zoledronic acid (Zometa)	Bisphosphonate inhibitor of bone metastases	Zoledronic acid is poorly absorbed by the GI tract and is therefore given as an IV infusion; it is not metabolized and is excreted by the kidneys; it has a plasma terminal elimination half-life of about 150 hr	Zoledronic acid is generally well tolerated; the most common infusional adverse effect is fever, which is usually mild and treatable; nausea and constipation are also common; dyspnea, fatigue, diffuse pain, rash, and headache are uncommon; renal insufficiency is uncommon and generally reversible after discontinuation of the drug, but it is more likely with higher doses than with the approved and recommended 4-mg dose	Approved for treatment of hypercalcemia of malignancy and for prevention of pathologic fractures in multiple myeloma and solid tumors with known bone metastases

ABMT = autologous bone marrow transplantation; AC = accelerated phase; ADCC = antibody-dependent cell-mediated cytotoxicity; ADP = adenosine diphosphate; AIDS = acquired immunodeficiency syndrome; ALK = anaplastic lymphoma kinase; ALL = acute lymphoblastic lymphoma; ALT = alanine aminotransferase; AML = acute myelogenous leukemia; AST = aspartate aminotransferase; AUC = area under the curve; BC = breast cancer; BID = twice a day; CK = creatine kinase; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; CNS = central nervous system; CP = chronic phase; CTCL = cutaneous T-cell lymphoma; CTLA-4 = cytotoxic T-lymphocyte antigen 4; CYP = cytochrome; D5W = 5% dextrose in water; dATP = deoxyadenosine triphosphate; DMHHT = demethyl-homoharringtonine; DVT = deep vein thrombosis; ECG = electrocardiogram; EGFR = epidermal growth factor receptor; ER = estrogen receptor; FAMP = fludarabine monophosphate; FDA = Food and Drug Administration; 5-FU = 5-fluorouracil; FSH = follicle-stimulating hormone; G6PD = glucose-6-phosphate dehydrogenase; G-CSF = granulocyte-colony stimulating factor; GGT = gamma-glutamyltransferase; GI = gastrointestinal; GIST = gastrointestinal stromal tumor; GM-CSF = granulocyte-macrophage colony-stimulating factor; GnRH = gonadotropin-releasing hormone; GVHD = graft-versus-host disease; HDAC = histone deacetylase; HIV = human immunodeficiency virus; HMM = hexamethyl melamine; HR-positive = hormone receptor positive; HRT = hormone replacement therapy; HSC = hematopoietic stem cell; IFN = interferon; IGF = insulin-like growth factor; IgG2 = immunoglobulin G2; IL = interleukin; ILD = interstitial lung disease; IM = intramuscular; INR = International Normalized Ratio; IV = intravenous; LDH = lactate dehydrogenase; LH = luteinizing hormone; LHRH = luteinizing hormone–releasing hormone; LVEF = left ventricular ejection fraction; MAPK = mitogen-activated protein kinase; MDS = myelodysplastic syndrome; MET = mesenchymal epithelial transition factor receptor; MOPP = mechlorethamine, vincristine, procarbazine, and prednisone; MSI = microsatellite instability; MTIC = 5-(3-,ethyltriazen-1-yl)imidazole-4-carboxamide; mTOR = mammalian target of rapamycin; NHL = non-Hodgkin lymphoma; NSAIDs = nonsteroidal anti-inflammatory drugs; NSCLC = non–small cell lung cancer; PARP = poly (ADP-ribose) polymerase; PDGF = platelet-derived growth factor; PD-L1 = programmed death ligand 1; PE = pulmonary embolism; P-gp = P-glycoprotein; PI = phosphoinositide; PNET = progressive neuroendocrine tumor; PO = by mouth; PT = prothrombin time; RANK = receptor activator of nuclear factor– k B; RCC = renal cell carcinoma; SCLC = small cell lung cancer; SEGA = subependymal giant cell astrocytoma; SQ = subcutaneous; TID = three times a day; TNF = tumor necrosis factor; TSC = tuberous sclerosis; TSH = thyroid-stimulating hormone; UGTs = UDP-glucuronosyltransferases; ULN = upper limit of normal; VEGF = vascular endothelial growth factor.

As indicated throughout this chapter, the pace has accelerated for approvals of new drugs and new indications. Updated information should be checked on the FDA website ( www.fda.gov/drugs ) or other authoritative sources.

∗ Full listing of all FDA-approved agents appears online at https://www.cancer.gov/about-cancer/treatment/drugs/cancer-type .

† Note that indications may change based on the results of clinical trials and other data.

Staging and Multidisciplinary Evaluation

After a tissue diagnosis has been established, careful staging is required to determine the extent of disease. The American Joint Committee on Cancer staging system, which is the standard in the United States, is based on the TNM (tumor, node, metastasis) system that is anatomically and pathologically based. The approach to staging from a clinical perspective depends on the type of cancer, but it commonly includes computed tomography (CT), magnetic resonance imaging (MRI), and, increasingly, positron emission tomography (PET) and PET-CT. These studies are supplemented by routine hematologic and chemistry profiles, tumor markers, and molecular characterization (when appropriate), as well as by bone marrow aspiration and biopsy in some cases.

The goal of tumor staging is to define the extent of a patient’s disease. Tumor stage provides critical prognostic information that will inform the therapeutic approach that is most appropriate. Accurate staging involves delineating the magnitude of the tumor determined by imaging procedures, as well as confirming the pathologic limits of disease spread from tissues removed at surgery. In essence, for most solid tumor patients, the tumor stage will establish whether the treatment will focus on a local (usually confined to an organ), regional, or disseminated pattern of malignancy and can determine whether the expected outcome of therapy is curative or palliative. Conversely, hematopoietic malignancies are often disseminated at diagnosis and demand their own prognostic classifiers.

The focus of the staging evaluation is to identify potential sites of metastases and to establish indicator lesions with which to monitor therapy. For most solid tumors, CT scans can accomplish both goals; however, in some circumstances, other imaging modalities are more appropriate for therapeutic monitoring (e.g., MRI when central nervous system [CNS] metastases are likely [e.g., small cell lung cancer], or combined PET/CT imaging to establish that a given lesion is likely to be metabolically active and malignant, or in diseases in which early metabolic responses to treatment can be confirmed [such as for gastrointestinal stromal tumors]). In patients with established advanced disease, indicator lesions for therapeutic monitoring should be carefully chosen prior to the initiation of treatment, be well documented in the medical record, and be evaluated with the minimum frequency of imaging procedures required for accurate follow-up, consistent with evidence-based medical practice or the clinical protocol on which the patient is entered.

The consulting medical oncologist may often be advised by a local tumor board composed of other medical, surgical, and radiation oncologists, pathologists, radiologists, and members of the cancer care team (oncology nurses, social workers, and palliative care specialists). In such a multidisciplinary environment, the patient’s overall prognosis can be reviewed and alternatives for care, including standard therapy, possible clinical trials, a second opinion, or no treatment, can be considered. The outcome of such an evaluation is usually viewed by patients and families as an important component in the coordinated development of an overall plan for either further diagnostic procedures or therapy. Finally, many oncologists actively participate in clinical trials that may make investigational drugs or other investigational procedures available for patients, or they may suggest referral to a tertiary cancer center where disease-specific or molecularly defined clinical trials are available.

Treatment

Therapeutic Plan

Intention of Treatment

Based on the multidisciplinary evaluation of an accurately staged patient, the chosen intent of treatment may be curative or palliative. Whether or not this choice is made during a formal tumor board or multidisciplinary case conference, clarity must be reached regarding the specific choice of therapeutic options (and their potential risks and benefits, overall goals, and alternatives) when considered in the context of the wishes of the patient and family. This issue is particularly relevant when the side effects of treatment are substantial (such as for the multidisciplinary management of non–small cell lung cancer or esophageal cancer). For cancers that are amenable to surgery, resection is often an initial alternative if the patient is a suitable candidate for anesthesia and is otherwise in acceptable condition in terms of comorbid illnesses ( Chapter 399 ). Determination of the patient’s performance score (see Table 164-1 ) is a simple means of assessing functional status. If life expectancy is limited or if the patient is not a good candidate for surgery, more limited approaches to palliative radiation or systemic therapy may be appropriate. Substantial data indicate that the extent of surgery required for an optimal long-term outcome may be reduced for certain solid tumors through the use of presurgical, so-called “neoadjuvant” chemotherapy, often as part of an “organ-sparing” approach. Concomitant or sequential multimodality treatments also have the potential to produce long-term disease-free remissions. When the best therapeutic outcomes require the combined skills of surgical, radiation, and medical oncologists, the need for coordination of care among a variety of specialists becomes paramount and the use of predefined treatment regimens critical.

Therapeutic Paradigm and Therapeutic Index

The therapeutic paradigm in oncology, although still directed at improving the multidisciplinary care model, has begun to change from one focused on delivering treatments at the “maximally tolerated dose” for normal tissues to therapy that is personalized based on both the molecular characteristics of the patient’s tumor as well as any individual germline features that could modify treatment tolerance ( Chapter 166 ). Based on the rapid expansion of information regarding somatic mutations in human malignancies and the ability to produce therapeutic molecules that can target specific defects in tumoral DNA repair, growth factor signaling, energy balance, or immunocompetence, for example, the current approach to cancer therapeutics involves the use of predictive molecular markers (“biomarkers”) whenever possible to guide all modalities of cancer care for the benefit of unique cancer patients. Hence, the focus of oncologists is on the elaboration of treatments that can be administered with a high therapeutic index, defined as the comparison of the amount of treatment that is effective as compared with the amount that causes toxicity. The goal of precision cancer medicine therapy is to minimize toxicity to normal tissues and to preserve quality of life by advancing therapies or procedures that are targeted only to the specific molecular dependencies of the patient’s tumor.

Surgical Therapy

Surgery is used to biopsy a suspected lesion, remove the primary tumor, bypass obstructions, provide palliation, and prevent cancers in patients at very high risk because of genetic predispositions or chronic inflammatory states. Surgical staging also establishes the extent of disease. For example, patients with ovarian cancer ( Chapter 184 ) benefit from surgical “debulking” to remove all visible disease, leave minimal residual tumor, and thereby enhance the effectiveness of systemic treatment. Placement of a venous access device at the time of surgery, if considered proactively, may eliminate the need for a second procedure.

Risk-reducing bilateral mastectomy and risk-reducing salpingo-oophorectomy are options for the primary prevention of breast ( Chapter 183 ) and ovarian cancers in individuals who are genetically predisposed to these malignancies. Although these operations provide considerable efficacy in terms of cancer prevention, they can be associated with profound adverse physical and psychosexual effects. Decisions to proceed with such risk-reducing surgery are complex and emotionally charged. Patients require clearly understandable information and counseling, as well as adequate time and support to think through their options.

Surgery remains the most common method to cure localized cancers such as breast cancer ( Chapter 183 ), colorectal cancer ( Chapter 179 ), and lung cancer ( Chapter 177 ), but it is limited by the location of the tumor, its extension, and distant metastases. Even if a tumor cannot be removed, surgical biopsy provides confirmation of the diagnosis and additional tissue for molecular analysis. Occasionally, an obstructing lesion can be bypassed to provide palliation.

In specific circumstances when the primary tumor has been controlled, removal of a single metastasis (metastasectomy) can result in long-term survival; an example is resection of a solitary liver metastasis found at the time of colectomy for colorectal cancer ( Chapter 179 ). A variety of surgical techniques, such as radiofrequency ablation or cryoablation, can also be used to treat hepatic metastases in carefully selected patients. Adjuvant chemotherapy is often given after surgery in this situation to treat microscopic metastases.

The careful application of reconstructive surgery after a disfiguring procedure is critical to long-term physical and emotional well-being. Examples include postmastectomy breast reconstruction ( Chapter 183 ) and plastic surgical procedures to correct deformities following head and neck surgery ( Chapter 176 ).

Radiation Therapy

Ionizing radiation ( Chapter 18 ) can be delivered using beams of high-energy rays, known as teletherapy , via a linear accelerator; by brachytherapy, through the application of sealed radioactive implants, seeds, wires, or plaques; and intravenously by using radioisotopes, either directly or attached to antibodies or other targeting molecules. Radiation interacts with water molecules to induce free radical species, including hydroxyl radicals, which damage DNA, proteins, and lipid membranes, thereby leading to cell death. As with chemotherapy, radiation therapy is most effective against rapidly dividing cells that are well oxygenated. Radiation-induced DNA damage may also increase sensitivity to chemo- or immunotherapy.

The utility of radiation therapy is limited by the inapparent extension of disease outside a local treatment field, by the location of tumors next to normal structures that must be preserved, and by the presence of distant metastases. Normal tissue tolerance, which varies across different organs and tissues, often prevents the use of radiation doses that could uniformly eradicate cancers. Radiation therapy is also limited by tumor hypoxia: large, bulky tumors are frequently relatively radioresistant, whereas well-oxygenated tumors can be more effectively treated at lower doses. In addition to acute radiation-related toxicities ( Chapter 18 ), late effects of radiation therapy include second malignancies, such as breast cancers that may occur decades after administering thoracic radiation fields during curative treatment for Hodgkin disease.

Radiation therapy can be used as primary treatment, as part of multimodality therapy, in the adjuvant setting, and for palliation. As a single modality, radiation therapy can be curative for early-stage malignancies such as laryngeal cancer ( Chapter 176 ), cervical cancer ( Chapter 184 ), and prostate cancer ( Chapter 186 ). Breast-conserving surgery ( Chapter 183 ) requires the use of radiation to treat the remaining breast. Partial irradiation techniques using three-dimensional planning with external beam radiation can be used in selected patients with appropriately placed and sized breast cancers. For certain patients who have localized prostate cancer ( Chapter 186 ), implanted radioactive seeds of gold or palladium offer an alternative to surgery or external beam radiation therapy.

Intensity-modulated radiation therapy (IMRT) permits more exact tailoring of the dose to the target, thereby reducing damage to the surrounding normal tissues. Stereotactic radiation therapy or gamma knife techniques allow the treatment of primary or metastatic brain tumors ( Chapter 175 ) measuring up to 3 cm with enhanced accuracy, thereby minimizing damage to normal brain. An analogous approach may help patients whose primary tumor has been controlled and who have a limited number of metastatic lesions. Particle-based treatment with protons can deliver higher radiation doses locally. However, no randomized studies demonstrate its superiority over other approaches that use computational techniques (e.g., IMRT) to improve the specificity of the delivery of radiation. However, proton therapy is generally recommended for some uveal melanomas, base-of-skull tumors, and a few pediatric malignancies.

Low- to moderate-dose palliative radiation is used to ameliorate symptomatic cancer when cure is no longer the goal. For instance, radiation therapy can improve symptoms from brain metastases ( Chapter 175 ), relieve pain from bone lesions ( Chapter 187 ), relieve some obstructing lesions, and sometimes improve hemoptysis caused by lung cancer ( Chapter 177 ) or bleeding from a gynecologic malignancy ( Chapter 184 ). Bone-seeking radioisotopes of samarium, strontium, or radium may relieve pain from bone metastases in prostate cancer ( Chapter 186 ) or breast cancer ( Chapter 183 ).

Systemic Therapy

Cancer Pharmacology

Principles

The fundamental goal of cancer pharmacology is the development of treatments that can be matched to the intrinsic sensitivity of specific tumors and that can be delivered in concentrations that affect the molecular target of interest with an acceptable therapeutic index. Three properties of all cancer therapeutic agents underlie their clinical utility: pharmacogenetics of the drug (how the germline or somatic expression of genes alters normal tissue toxicity or antitumor efficacy); action of the drug (pharmacodynamics, or what the drug does to the tumor/body); and delivery of the drug (pharmacokinetics, or what the body does to the drug).

Pharmacogenetics

Pharmacogenetics, which is the study of inherited interindividual differences in drug disposition and effects, is important in cancer therapy because genetic polymorphisms in drug-metabolizing enzymes may be responsible for the variations in efficacy and toxicity that are observed with many chemotherapeutic agents. Drugs potentially affected by polymorphisms include the thiopurines, 5-fluorouracil, irinotecan, taxanes, and platinum agents. In patients who are heterozygous or homozygous for deficiencies in metabolizing enzymes, toxicity can be dramatically enhanced. Testing for pharmacogenetic variations that predict for altered normal tissue tolerance is currently available for thiopurines and irinotecan.

Molecular Targeting and Pharmacodynamics

Molecular diagnostic testing, which began with testing to predict the antitumor activity of hormonal and anti-HER2 therapeutics, is now relevant to a wider range of tumors for which molecularly targeted and immunotherapeutic anticancer agents are useful only after demonstration of specific molecular abnormalities. Examples of such diagnostic/drug pairs include the prototypical BCR-ABL mutation in chronic myelogenous leukemia and imatinib; EGFR mutations in lung adenocarcinomas and erlotinib; ALK tyrosine kinase translocations in lung adenocarcinomas and crizotinib; BRAF ^V600E mutations in melanoma and vemurafenib, NTRK fusions and larotrectinib; and KRAS mutations in various solid tumors. Molecular targeting can also involve the expression of mismatch repair genes and immunologic checkpoint inhibitors.

Pharmacokinetics and Drug Delivery

Dose selection in oncology is a critical issue, primarily because anticancer agents have among the smallest therapeutic ratios in all of medicine. When tumors are responsive to treatment, higher doses may or may not be more effective but are likely to be more toxic to normal tissues. The clearance of a drug from both the systemic circulation and, potentially, from specific physiologic compartments (CNS, pleural, or peritoneal effusions), as evidenced by its systemic exposure, is the most important determinant of the recommended dose for a particular patient. Clearance, which is a composite of all the routes and mechanisms by which the drug can be eliminated from the body, determines dosing and dose adjustments in the face of changes in drug metabolism, transport, or altered organ function. Although a clear understanding of drug half-lives is important to establish initial dosing schedules, systemic exposure will be the actual determinant of the dose of drug that can be safely administered. Another aspect of drug delivery is the use of body surface area dosing versus flat dosing (using fixed amounts of a drug) in oncologic practice. Although dosing based on body surface area has a long history in oncology, very little data support this approach; for most agents in common use, empirically determined pharmacokinetic variability from patient to patient is far greater than what could reasonably be determined by dosing based on weight or surface area.

Routes of Drug Dosing

Although some agents require intravenous administration, oral agents that permit outpatient therapy are increasingly being used. The oral route of administration highlights drug delivery issues, such as adherence (does the patient take his/her medication), variability in absorption (due to food effects), emesis prior to drug absorption, first-pass metabolism in the liver or intestine, and difficulties in swallowing. For example, whether the orally administered anti-HER1/2 drug lapatinib is taken with food or on an empty stomach can alter its absorption by as much as 10-fold.

In addition to intravenous or oral dosing, anticancer drugs may be used for intrathecal delivery (to overcome the blood-brain barrier) in the treatment or prevention of meningeal spread of leukemia; for intravesicle therapy of early-stage bladder cancer; for intra-arterial delivery of fluoropyrimidines or other agents to treat hepatic metastases from colon cancer or hepatocellular carcinoma; and for intraperitoneal administration of drugs such as platinum agents for ovarian cancer therapy. In almost all cases, administration of anticancer agents by other than the oral or intravenous routes requires intimate involvement of an oncologic specialist.

Clinical Trials

Clinical trials in oncology are defined by the steps in which new diagnostic approaches, therapeutic agents, or procedures are tested to determine whether they will become part of the standard care for cancer patients. During interventional (rather than observational) clinical trials, specific treatments or procedures are assigned to participants, and the effects of the interventions are measured. For trials of new oncologic drugs, the U.S. Food and Drug Administration (FDA) recognizes several states in the drug development process. Exploratory studies of new drugs examined for the first time in humans (phase 0 trials) may be conducted in a limited number of patients to define a drug’s mechanism of action or biodistribution and to guide subsequent dosing in larger studies. Phase I trials use a variety of dose-escalation strategies to define the maximum dose that can be safely administered to humans and the most appropriate schedule for drug administration, as well as the pharmacokinetic and pharmacodynamic profile of the drug. Phase II trials often enroll 50 to 150 subjects and focus on testing the drug to determine its effectiveness and side effect profile in a specific malignancy (or for a specific cancer-related molecular abnormality). If a drug demonstrates anticancer activity in a phase II study, phase III trials are performed to compare the usefulness of an investigational treatment to a control group of patients who receive the standard of care; patients in most phase III studies are randomly assigned to the new or standard treatment to avoid a biased assessment of the results of the study. Finally, after approval of a new drug by the FDA, usually based on the results of phase III studies, phase IV trials may be performed to collect safety information on larger patient populations to define the prevalence of side effects that may be rare but serious.

Traditionally designed phase II trials test one treatment at a time in heterogenous groups of patients and are therefore not an efficient use of clinical resources. Adaptive multigroup clinical trials have the potential to answer several questions simultaneously and more efficiently by matching targeted therapies to the cancer patients who are most likely to benefit from them. Some trials for breast cancer, for example, use a platform to compare up to 12 experimental therapies with a single, common control group in subgroups of breast cancer patients with 10 distinct biomarker signatures. New drugs enter the platform as they emerge from phase I testing and exit the platform with an estimate of the chances of future success in a phase III trial of prespecified size. Despite some significant unresolved issues, the adaptive strategy is likely to become an important addition to the inventory of clinical trial designs. Another approach is so-called master protocols, which evaluate one or more agents against a specific molecular characteristic possessed by the tumor rather than its histology.

Drug Interactions

Many drug interactions affect the toxicity profile of anticancer agents, usually because concomitant administration of a second drug changes the clearance of the cancer therapeutic, thereby potentially enhancing side effects if the clearance is decreased or diminishing efficacy because of reduced drug exposure. Most often these interactions occur because one drug affects the metabolism of the other by inhibiting or enhancing the activity of cytochrome P-450 isoforms (such as CYP3A) in the liver. This interaction is particularly true for agents administered orally, such as imatinib, crizotinib, enzalutamide, pazopanib, and lapatinib. Concomitant drug-related as well as pharmacogenetic variations in proteins that affect the transport of anticancer agents across tumor and normal cell membranes, such as efflux pumps, also affect the sensitivity or resistance of many classes of cancer drugs. For example, certain drugs that are well-known inducers of hepatic metabolism (e.g., phenytoin and rifampin) also induce the expression of drug transport proteins.

Combination Therapy

Virtually all curative chemotherapy regimens developed for hematologic malignancies or solid tumors use combinations of active agents. Combination chemotherapy is usually superior to the use of single agents in adjuvant and neoadjuvant therapy as well. The improved results achieved by combination chemotherapy can be explained in several ways. Mechanisms of resistance to any particular single agent are almost always present in the tumor genome at diagnosis, even in clinically responsive tumors. Tumors that are initially “sensitive” to systemic therapy rapidly acquire resistance to single agents, either as a result of selection of a preexisting clone of resistant tumor cells or because of a variety of potential acquired molecular changes (e.g., increased drug efflux, enhanced DNA repair, insensitivity to apoptosis) that lead to clinical drug resistance. Combination therapy may address these phenomena by providing a broader range of mechanisms of drug action against initially resistant tumor cells, thereby preventing or slowing the selection of resistant clones.

The development of combination systemic therapy regimens follows a set of principles ( Table 164-3 ). For standard cytotoxic agents, each drug in the combination must be active against the tumor, and all drugs must be given at an optimal dose and on an appropriate schedule. The drugs should have different mechanisms of antitumor activity as well as different toxicity profiles, and the drugs should be given at consistent intervals for the shortest possible treatment time. The use of molecularly targeted agents in combination requires that each agent engages its specific target and that the combination enhances the inhibition of the tumor’s growth. Toxicities of targeted agents should be moderate to allow prolonged administration and maximum target inhibition.

TABLE 164-3

PRINCIPLES OF COMBINATION THERAPY

CYTOTOXIC AGENTS	MOLECULARLY TARGETED DRUGS
Drugs are each active against the tumor	Agent has therapeutic effect on molecular pathway in vivo
Drugs have different mechanisms of action	Agents have complementary effects on the same target or other targets in the same pathway or pathways that cross-talk to control tumor growth
Drugs have different clinical toxicities to allow full doses of each to be administered	Toxicities do not overlap with cytotoxics and are moderate to low to allow prolonged administration. Consider physiologic consequences of target engagement in relation to toxicity profile
Intermittent intensive therapy is preferred to continuous treatment for cytoreduction and reducing immunosuppression	Schedule is chosen to maximize target inhibition

Therapeutic Settings

Systemic therapy is used in a variety of settings with or without and before, during, or after surgery and radiation therapy ( Table 164-4 ). Considerable experimental evidence suggests that cancers are most sensitive to chemotherapy during early stages of growth because of higher growth fractions and shorter cell cycle times. As a result, a given dose of a cytotoxic drug may exert a greater therapeutic effect against a rapidly growing tumor than against a larger quiescent tumor.

TABLE 164-4

COMMON EXAMPLES OF THERAPEUTIC SETTINGS

ADJUVANT THERAPY	NEOADJUVANT THERAPY	ORGAN-SPARING THERAPY	COMBINATION CHEMOTHERAPY
Stage I and II breast cancer Stage III colorectal cancer Stage II lung cancer	Stage III breast cancer	Anal cancer Laryngeal cancer Esophageal cancer	Metastatic solid tumors ∗ Hematologic malignancies

∗ Usually palliative.

Neoadjuvant therapy , also called primary or induction systemic therapy, is used before surgery or radiation therapy to decrease the size of locally advanced cancers, thereby permitting a more complete surgical resection or eradication of undetectable metastases. Neoadjuvant therapy also affords an opportunity to evaluate the effectiveness of treatment by histologic and molecular analysis of resected tissue. This approach is most often used for locally advanced breast cancer ( Chapter 183 ).

Organ-sparing therapy is another use of chemotherapy, radiation therapy, or both to salvage organs that would have been surgically removed if cure were the intended result. This technique is often effective in patients with cancers of the larynx ( Chapter 176 ), esophagus ( Chapter 178 ), and anus ( Chapter 179 ).

Adjuvant chemotherapy is used in patients whose primary tumor and all visible evidence of cancer (e.g., regional lymph nodes) have been surgically removed or treated definitively with radiation, but in whom the risk of recurrence is high because of involved lymph nodes or certain morphologic or biologic characteristics of the cancer. Common examples include cancers of the breast ( Chapter 183 ) and colon ( Chapter 179 ). The typical end points of chemotherapy, such as shrinkage of measurable tumor on serial radiographic studies, are not available in this situation; instead, relapse-free survival and overall survival are the principal measures of a treatment’s effect. The benefit of adjuvant therapy cannot be assessed in individual patients who receive it, so decisions about its use must be based on evidence from clinical trials.

Assessment of Response

Assessment of the response to therapy (usually performed using RECIST [Response Evaluation Criteria in Solid Tumors]) depends largely on the tumor’s size, as determined by either direct measurement or diagnostic imaging studies, using predefined categories. The categories of response are “complete response,” with total absence of tumor and correction of tumor-associated changes measured twice at least 4 weeks apart; “partial response,” defined as 30% or greater reduction in the sum of the longest diameters of up to five target lesions per organ, confirmed by repeat measurement 4 weeks later; “progressive disease,” characterized by either 20% or greater increase over the smallest sum of the longest diameters of target lesions or the development of new tumors; and “stable disease,” defined as meeting criteria for neither partial response nor progressive disease. Leukemias are assessed by bone marrow biopsies and molecular diagnostic tests for residual disease, and multiple myeloma is typically assessed by the measurement of monoclonal proteins, peripheral blood counts, and percentages of malignant plasma cells in bone marrow samples, as well as imaging of bone lesions. Accurate assessment of response following systemic therapy is essential because of the tight relationship between the degree of response and the duration of disease control.

Classes of Therapeutic Agents

Cytotoxic Agents, Targeted Small Molecules, and Antibodies

An understanding of the pharmacologic properties and therapeutic indications of the most commonly used cytotoxic and molecularly targeted chemotherapeutic agents and antibodies approved by the FDA (see Table 164-2 ) is critical for prescribing physicians and is also important for physicians who participate in the patient’s care. Current information should be sought from the manufacturer before therapy is initiated.

The administration of chemotherapy should be overseen by specifically trained individuals because of the dual acute risks of hypersensitivity reactions and extravasation. No doses or schedules are universally recommended because these agents are often used in combination, and the doses of each drug may need to be reduced when the compounds are combined, as well as when they are prescribed to patients who may have impaired liver or kidney function or a higher risk of adverse effects.

Unless otherwise specified, most cytotoxic chemotherapeutic agents may produce some degree of nausea and vomiting, myelosuppression, alopecia, mucositis, and/or diarrhea after treatment; many agents are also teratogenic, mutagenic, and carcinogenic. Specific drugs (see Table 164-2 ) often can be used to prevent agent-specific toxicities.

Small molecule anticancer agents with more precisely targeted mechanisms of action have become a standard part of oncologic practice (see Table 164-2 ). Although the molecular dependencies within the tumor cells against which these drugs are targeted are broad in scope, including tyrosine kinase growth factors or their receptors, they are functionally much more specific than prior generations of systemic cancer therapies. This specificity allows for a better appreciation of the clinical situations in which certain drugs might be beneficial, as well as the possibility of developing agents for use in specific tumors based on their genetic susceptibilities. The toxicity profiles of molecular targeted agents most often reflect alterations that are produced in biochemical pathways that control normal organ function, rather than a general pattern of toxicity consistent with injury to rapidly growing tissues, such as the bone marrow or gastrointestinal tract.

The development of monoclonal antibodies directed against proteins or other molecular determinants of cancer cells represents an additional approach to molecular targeting of systemic therapy. Examples include cetuximab (targeting the epidermal growth factor receptor), rituximab (targeting the B-cell CD20 surface antigen), and trastuzumab (which blocks HER2). These monoclonal antibodies can be used alone or in the form of recombinant bispecific or multispecific antibodies that provide multifunctional receptor targeting, they can be labeled with a radioactive molecule, or they can be conjugated to another cytotoxin to enhance cell killing. Radioimmunoconjugate approaches have been most effective in the treatment of non-Hodgkin lymphoma ( Chapter 171 ) and chronic lymphocytic leukemia ( Chapter 169 ). The effectiveness of monoclonal antibodies in specific tumor types is not identical to small molecules developed against the same target, in part because of the induction of immunologically mediated mechanisms of tumor cell killing that are unique to antibodies.

A major challenge with targeted therapy for malignancies is that drug resistance often develops. Cancers are characterized by extensive intratumor genetic heterogeneity, and resistance to molecularly targeted therapies can arise from the selected growth of preexisting subclones that are present within the bulk of the tumor and that carry drug-resistant mutations, which have a survival advantage for the tumor.

Hormonal Therapies

Endocrine or hormonal therapy is almost entirely limited to breast cancer ( Chapter 183 ) and prostate cancer ( Chapter 186 ). Many premenopausal breast cancers are thought to be under the influence of ovarian estrogens, and hormonal deprivation (ablation) may produce long-term responses in properly selected patients (patients whose tumors express estrogen and/or progesterone receptors and who have predominantly soft tissue or bone disease). The antiestrogen tamoxifen is effective against breast cancer, and it may decrease the incidence of contralateral breast cancers in both premenopausal and postmenopausal women with breast cancer ( Chapter 183 ). Tamoxifen also has an estrogen-like activity that is responsible for an increased rate of endometrial cancers. Postmenopausal women who are candidates for hormonal therapy may also respond to tamoxifen; however, aromatase inhibitors (e.g., anastrozole, letrozole, exemestane), which decrease the conversion of metabolites in fat and muscle into estrogen, are more effective than tamoxifen as first-line therapy in both the adjuvant and metastatic settings.

Prostate cancer ( Chapter 186 ) is usually androgen-dependent, and androgen deprivation can produce meaningful responses. The recent introduction of more potent inhibitors of androgen biosynthesis (abiraterone) and androgen receptor-mediated signal transduction (enzalutamide) has further enhanced the range and effectiveness of androgen deprivation therapy for this disease.

The corticosteroids ( Chapter 28 ), typically prednisone or dexamethasone, are widely used in the treatment of hematologic and oncologic cancers. In Hodgkin disease ( Chapter 172 ), the non-Hodgkin lymphomas ( Chapter 171 ), and multiple myeloma ( Chapter 173 ), corticosteroids have antitumor activity. In solid tumor patients, they are used as antiemetics, for the symptomatic relief of cerebral edema in cases of CNS metastases ( Chapter 175 ), or as an adjunct to radiation therapy for spinal cord metastases.

Epigenetic Therapies

Just as DNA mutations contribute to the progression of tumors, epigenetic alterations in the transcription of DNA also participate in the growth of tumors and their resistance to chemotherapy ( Chapter 166 ). The two best characterized epigenetic mechanisms are DNA methylation and histone modification. DNA methylation is controlled by DNA methyltransferases, whereas histone modification (acetylation) is controlled by histone acetyltransferases. The DNA methyltransferase inhibitors (azacitidine and decitabine) produce durable responses and survival benefit in patients with myelodysplastic syndrome ( Chapter 167 ) and acute myelogenous leukemia ( Chapter 168 ). The histone deacetylase inhibitors (vorinostat and romidepsin) have clinical benefit for the treatment of cutaneous T-cell lymphoma ( Chapter 171 ).

The DNA methyltransferase inhibitors also have an immune-based mechanism of action. Current clinical trials are testing the combination of epigenetic therapy plus immunotherapy in cancer treatment.

Immunotherapy

Cancer immunotherapy blocks the processes by which tumors suppress the immune system. These agents have yielded dramatic clinical benefits for patients with a remarkably wide variety of advanced cancers, including melanoma, kidney, bladder, head and neck, esophageal, gastric, triple-negative breast, hepatocellular, and lung cancers, as well as Hodgkin and non-Hodgkin lymphoma. Immune checkpoint therapy targets regulatory pathways in T cells to enhance their antitumor immune responses. The goal of immune checkpoint blockade is not to activate the immune system to attack particular targets on tumor cells, but rather to remove inhibitory pathways that block effective antitumor T-cell responses. The survival of men and women with metastatic melanoma ( Chapter 188 ) is significantly increased following treatment with antibodies (anti-CTLA-4 ipilimumab and anti-PD-1 nivolumab) that neutralize proteins that protect tumor cells against destruction by the immune system. PD-1 antibodies also provide a survival benefit compared with platinum-based chemotherapy for patients with non–small cell lung cancer. Additional antibodies that target other immunologic checkpoint molecules (anti-PD-L1) provide substantive clinical benefits for patients with melanoma, renal cancer, non–small cell lung cancer, and a variety of other solid tumors and lymphomas. However, a broad range of toxicities can be associated with the use of checkpoint inhibitor therapy.

Another approach to cancer immunotherapy is through adoptive cell transfer, which involves the engineering of the patient’s own immune cells to recognize and attack their own tumors. In this form of treatment (CAR T-cell therapy), T cells collected from a patient are genetically engineered to produce special receptors on their surface called “chimeric antigen receptors” (or “CARs”). Targeted CAR T cells have provided impressive responses in patients with B-cell malignancies and led to their FDA approval for an increasing number of indications despite a high risk of side effects, including cytokine release syndrome and acute neurologic complications.

Drugs for Prevention or Treatment of Toxicity

In addition to the hematopoietic growth factors used to reduce the adverse effects of systemic cancer therapies on the bone marrow (discussed later under Management of Complications), drugs have been developed to ameliorate important side effects of cytotoxic chemotherapy (see Table 164-2 ). These agents include dexrazoxane, which is an iron chelating agent that can prevent the cardiac toxicity of the anthracyclines (doxorubicin and daunorubicin); leucovorin, which can diminish the hematologic side effects of folic acid antagonists; and mesna, a thiol-containing compound that blocks damage to the bladder mucosa from metabolites of cyclophosphamide. Uridine triacetate is FDA-approved for the treatment of patients who receive an overdose of fluorouracil or capecitabine or who develop severe or life-threatening toxicities within 4 days of receiving them.

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