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InternalMed_Harrison. Camptothecin was isolated from extracts of a Chinese tree and had notable antileukemia activity in preclinical mouse models. Early human clinical studies with the sodium salt of the hydrolyzed camptothecin lactone showed evidence of toxicity with little antitumor activity. Identification of topoisomerase I as the target of camptothecins and the need to preserve lactone structure allowed additional efforts to identify active members of this series. Topoisomerase I is responsible for unwinding the DNA strand by introducing single-strand breaks and allowing rotation of one strand about the other. In S-phase, topoisomerase I–induced breaks that are not promptly resealed lead to progress of the replication fork off the end of a DNA strand. The DNA damage is a potent signal for induction of apoptosis. Camptothecins promote the stabilization of the DNA linked to the enzyme in a so-called cleavable complex, analogous to the action of etoposide with topoisomerase II. Topotecan is a


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InternalMed_Harrison. of apoptosis. Camptothecins promote the stabilization of the DNA linked to the enzyme in a so-called cleavable complex, analogous to the action of etoposide with topoisomerase II. Topotecan is a camptothecin derivative approved for use in gynecologic tumors and small-cell lung cancer. Toxicity is limited to myelosuppression and mucositis. CPT-11, or irinotecan, is a camptothecin with evidence of activity in colon carcinoma. In addition to myelosuppression, it causes a secretory diarrhea related to the toxicity of a metabolite called SN-38. Levels of SN-38 are particularly high in the setting of Gilbert’s disease, characterized by defective glucuronyl transferase and indirect hyperbilirubinemia, a condition that affects about 10% of the white population in the United States. The diarrhea can be treated effectively with loperamide or octreotide.


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InternalMed_Harrison. iNDirect moDulAtors of Nucleic AciD fuNctioN: ANtimetAbolites A broad definition of antimetabolites would include compounds with structural similarity to precursors of purines or pyrimidines, or compounds that interfere with purine or pyrimidine synthesis. Some antimetabolites can cause DNA damage indirectly, through misincorporation into DNA, abnormal timing or progression through DNA synthesis, or Chapter 103e Principles of Cancer Treatment altered function of pyrimidine and purine biosynthetic enzymes. They tend to convey greatest toxicity to cells in S-phase, and the degree of toxicity increases with duration of exposure. Common toxic manifestations include stomatitis, diarrhea, and myelosuppression. Second malignancies are not associated with their use.


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InternalMed_Harrison. Methotrexate inhibits dihydrofolate reductase, which regenerates reduced folates from the oxidized folates produced when thymidine monophosphate is formed from deoxyuridine mono-phosphate. Without reduced folates, cells die a “thymine-less” death. N5-Tetrahydrofolate or N5-formyltetrahydrofolate (leucovorin) can bypass this block and rescue cells from methotrexate, which is maintained in cells by polyglutamylation. The drug and other reduced folates are transported into cells by the folate carrier, and high concentrations of drug can bypass this carrier and allow diffusion of drug directly into cells. These properties have suggested the design of “high-dose” methotrexate regimens with leucovorin rescue of normal marrow and mucosa as part of curative approaches to osteosarcoma in the adjuvant setting and hematopoietic neoplasms of children and adults. Methotrexate is cleared by the kidney via both glomerular filtration and tubular secretion, and toxicity is augmented by renal


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InternalMed_Harrison. the adjuvant setting and hematopoietic neoplasms of children and adults. Methotrexate is cleared by the kidney via both glomerular filtration and tubular secretion, and toxicity is augmented by renal dysfunction and drugs such as salicylates, probenecid, and nonsteroidal anti-inflammatory agents that undergo tubular secretion. With normal renal function, 15 mg/m2 leucovorin will rescue 10−8 to 10−6 M methotrexate in three to four doses. However, with decreased creatinine clearance, doses of 50–100 mg/m2 are continued until methotrexate levels are <5 × 10−8 M. In addition to bone marrow suppression and mucosal irritation, methotrexate can cause renal failure itself at high doses owing to crystallization in renal tubules; therefore, high-dose regimens require alkalinization of urine with increased flow by hydration. Methotrexate can be sequestered in third-space collections and diffuse back into the general circulation, causing prolonged myelosuppression. Less frequent adverse effects


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InternalMed_Harrison. flow by hydration. Methotrexate can be sequestered in third-space collections and diffuse back into the general circulation, causing prolonged myelosuppression. Less frequent adverse effects include reversible increases in transaminases and hypersensitivity-like pulmonary syndrome. Chronic low-dose methotrexate can cause hepatic fibrosis. When administered to the intrathecal space, methotrexate can cause chemical arachnoiditis and CNS dysfunction.


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InternalMed_Harrison. Pemetrexed is a novel folate-directed antimetabolite. It is “multitargeted” in that it inhibits the activity of several enzymes, including thymidylate synthetase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, thereby affecting the synthesis of both purine and pyrimidine nucleic acid precursors. To avoid significant toxicity to the normal tissues, patients receiving pemetrexed should also receive low-dose folate and vitamin B12 supplementation. Pemetrexed has notable activity against certain lung cancers and, in combination with cisplatin, also against mesotheliomas. Pralatrexate is an antifolate approved for use in T cell lymphoma that is very efficiently transported into cancer cells.


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InternalMed_Harrison. 5-Fluorouracil (5FU) represents an early example of “rational” drug design in that it originated from the observation that tumor cells incorporate radiolabeled uracil more efficiently into DNA than normal cells, especially gut. 5FU is metabolized in cells to 5´FdUMP, which inhibits thymidylate synthetase (TS). In addition, misincorporation can lead to single-strand breaks, and RNA can aberrantly incorporate FUMP. 5FU is metabolized by dihydropyrimidine dehydrogenase, and deficiency of this enzyme can lead to excessive toxicity from 5FU. Oral bioavailability varies unreliably, but orally administered analogues of 5FU such as capecitabine have been developed that allow at least equivalent activity to many parenteral 5FU-based approaches. Intravenous administration of 5FU leads to bone marrow suppression after short infusions but to stomatitis after prolonged infusions. Leucovorin augments the activity of 5FU by promoting formation of the ternary covalent complex of 5FU, the reduced


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InternalMed_Harrison. suppression after short infusions but to stomatitis after prolonged infusions. Leucovorin augments the activity of 5FU by promoting formation of the ternary covalent complex of 5FU, the reduced folate, and TS. Less frequent toxicities include CNS dysfunction, with prominent cerebellar signs, and endothelial toxicity manifested by thrombosis, including pulmonary embolus and myocardial infarction.


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InternalMed_Harrison. Cytosine arabinoside (ara-C) is incorporated into DNA after formation of ara-CTP, resulting in S-phase–related toxicity. Continuous infusion schedules allow maximal efficiency, with uptake maximal at 5–7 μM. Ara-C can be administered intrathecally. Adverse effects include nausea, diarrhea, stomatitis, chemical conjunctivitis, and cerebellar ataxia. Gemcitabine is a cytosine derivative that is similar to ara-C in that it is incorporated into DNA after anabolism to the triphosphate, rendering DNA susceptible to breakage and repair synthesis, which differs from that in ara-C in that gemcitabine-induced lesions are very inefficiently removed. In contrast to ara-C, gemcitabine appears to have useful activity in a variety of solid tumors, with limited nonmyelosuppressive toxicities.


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InternalMed_Harrison. 6-Thioguanine and 6-mercaptopurine (6MP) are used in the treatment of acute lymphoid leukemia. Although administered orally, they display variable bioavailability. 6MP is metabolized by xanthine oxidase and therefore requires dose reduction when used with allopurinol. 6MP is also metabolized by thiopurine methyltransferase; genetic deficiency of thiopurine methyltransferase results in excessive toxicity.


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InternalMed_Harrison. Fludarabine phosphate is a prodrug of F-adenine arabinoside (F-ara-A), which in turn was designed to diminish the susceptibility of ara-A to adenosine deaminase. F-ara-A is incorporated into DNA and can cause delayed cytotoxicity even in cells with low growth fraction, including chronic lymphocytic leukemia and follicular B cell lymphoma. CNS and peripheral nerve dysfunction and T cell depletion leading to opportunistic infections can occur in addition to myelosuppression. 2-Chlorodeoxyadenosine is a similar compound with activity in hairy cell leukemia. 2-Deoxycoformycin inhibits adenosine deaminase, with resulting increase in dATP levels. This causes inhibition of ribonucleotide reductase as well as augmented susceptibility to apoptosis, particularly in T cells. Renal failure and CNS dysfunction are notable toxicities in addition to immunosuppression. Hydroxyurea inhibits ribonucleotide reductase, resulting in S-phase block. It is orally bioavailable and useful for the acute


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InternalMed_Harrison. CNS dysfunction are notable toxicities in addition to immunosuppression. Hydroxyurea inhibits ribonucleotide reductase, resulting in S-phase block. It is orally bioavailable and useful for the acute management of myeloproliferative states.


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InternalMed_Harrison. Asparaginase is a bacterial enzyme that causes breakdown of extracellular asparagine required for protein synthesis in certain leukemic cells. This effectively stops tumor cell DNA synthesis, as DNA synthesis requires concurrent protein synthesis. The outcome of asparaginase action is therefore very similar to the result of the small-molecule antimetabolites. Because asparaginase is a foreign protein, hypersensitivity reactions are common, as are effects on organs such as pancreas and liver that normally require continuing protein synthesis. This may result in decreased insulin secretion with hyperglycemia, with or without hyperamylasemia and clotting function abnormalities. Close monitoring of clotting functions should accompany use of asparaginase. Paradoxically, owing to depletion of rapidly turning over anticoagulant factors, thromboses particularly affecting the CNS may also be seen with asparaginase.


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InternalMed_Harrison. mitotic spiNDle iNhibitors Microtubules are cellular structures that form the mitotic spindle, and in interphase cells, they are responsible for the cellular “scaffolding” along which various motile and secretory processes occur. Microtubules are composed of repeating noncovalent multimers of a heterodimer of α and β isoform of the protein tubulin. Vincristine binds to the tubulin dimer with the result that microtubules are disaggregated. This results in the block of growing cells in M-phase; however, toxic effects in G1 and S-phase are also evident, reflecting effects on normal cellular activities of microtubules. Vincristine is metabolized by the liver, and dose adjustment in the presence of hepatic dysfunction is required. It is a powerful vesicant, and infiltration can be treated by local heat and infiltration of hyaluronidase. At clinically used intravenous doses, neurotoxicity in the form of glove-and-stocking neuropathy is frequent. Acute neuropathic effects include jaw pain,


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InternalMed_Harrison. local heat and infiltration of hyaluronidase. At clinically used intravenous doses, neurotoxicity in the form of glove-and-stocking neuropathy is frequent. Acute neuropathic effects include jaw pain, paralytic ileus, urinary retention, and the syndrome of inappropriate antidiuretic hormone secretion. Myelosuppression is not seen. Vinblastine is similar to vincristine, except that it tends to be more myelotoxic, with more frequent thrombocytopenia and also mucositis and stomatitis. Vinorelbine is a vinca alkaloid that appears to have differences in resistance patterns in comparison to vincristine and vinblastine; it may be administered orally.


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InternalMed_Harrison. The taxanes include paclitaxel and docetaxel. These agents differ from the vinca alkaloids in that the taxanes stabilize micro-tubules against depolymerization. The “stabilized” microtubules function abnormally and are not able to undergo the normal dynamic changes of microtubule structure and function necessary for cell cycle completion. Taxanes are among the most broadly active anti-neoplastic agents for use in solid tumors, with evidence of activity in ovarian cancer, breast cancer, Kaposi’s sarcoma, and lung tumors. They are administered intravenously, and paclitaxel requires use of a Cremophor-containing vehicle that can cause hypersensitivity reactions. Premedication with dexamethasone (8–16 mg orally or intravenously 12 and 6 h before treatment) and diphenhydramine (50 mg) and cimetidine (300 mg), both 30 min before treatment, decreases but does not eliminate the risk of hypersensitivity reactions to the paclitaxel vehicle. Docetaxel uses a polysorbate 80 formulation, which can


InternalMed_Harrison

InternalMed_Harrison. (300 mg), both 30 min before treatment, decreases but does not eliminate the risk of hypersensitivity reactions to the paclitaxel vehicle. Docetaxel uses a polysorbate 80 formulation, which can cause fluid retention in addition to hypersensitivity reactions, and dexamethasone premedication with or without antihistamines is frequently used. A protein-bound formulation of paclitaxel (called nab-paclitaxel) has at least equivalent antineoplastic activity and decreased risk of hypersensitivity reactions. Paclitaxel may also cause hypersensitivity reactions, myelosuppression, neurotoxicity in the form of glove-and-stocking numbness, and paresthesia. Cardiac rhythm disturbances were observed in phase 1 and 2 trials, most commonly asymptomatic bradycardia but also, much more rarely, varying degrees of heart block. These have not emerged as clinically significant in the majority of patients. Docetaxel causes comparable degrees of myelosuppression and neuropathy. Hypersensitivity reactions,


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InternalMed_Harrison. of heart block. These have not emerged as clinically significant in the majority of patients. Docetaxel causes comparable degrees of myelosuppression and neuropathy. Hypersensitivity reactions, including bronchospasm, dyspnea, and hypotension, are less frequent but occur to some degree in up to 25% of patients. Fluid retention appears to result from a vascular leak syndrome that can aggravate preexisting effusions. Rash can complicate docetaxel administration, appearing prominently as a pruritic maculopapular rash affecting the forearms, but it has also been associated with fingernail ridging, breakdown, and skin discoloration. Stomatitis appears to be somewhat more frequent than with paclitaxel. Cabazitaxel is a taxane with somewhat better activity in prostate cancers than earlier generations of taxanes, perhaps due to superior delivery to sites of disease.


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InternalMed_Harrison. Resistance to taxanes has been related to the emergence of efficient efflux of taxanes from tumor cells through the p170 P-glycoprotein (mdr gene product) or the presence of variant or mutant forms of tubulin. Epothilones represent a class of novel microtubule-stabilizing agents that have been conscientiously optimized for activity in taxane-resistant tumors. Ixabepilone has clear evidence of activity in breast cancers resistant to taxanes and anthracyclines such as doxorubicin. It retains acceptable expected side effects, including myelosuppression, and can also cause peripheral sensory neuropathy. Eribulin is a microtubule-directed agent with activity in patients who have had progression of disease on taxanes and is more similar to vinca alkaloids in its action but has similar side effects as vinca alkaloids and taxanes.


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InternalMed_Harrison. Estramustine was originally synthesized as a mustard derivative that might be useful in neoplasms that possessed estrogen receptors. However, no evidence of interaction with DNA was observed. Surprisingly, the drug caused metaphase arrest, and subsequent study revealed that it binds to microtubule-associated proteins, resulting in abnormal microtubule function. Estramustine binds to estramustinebinding proteins (EMBPs), which are notably present in prostate tumor tissue, where the drug is used. Gastrointestinal and cardiovascular adverse effects related to the estrogen moiety occur in up to 10% of patients, including worsened heart failure and thromboembolic phenomena. Gynecomastia and nipple tenderness can also occur.


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InternalMed_Harrison. Targeted Chemotherapy • hormoNe receptor–DirecteD therApy Steroid hormone receptor–related molecules have emerged as prominent targets for small molecules useful in cancer treatment. When bound to their cognate ligands, these receptors can alter gene transcription and, in certain tissues, induce apoptosis. The pharmacologic effect is a mirror or parody of the normal effects of the agents acting on nontransformed normal tissues, although the effects on tumors are mediated by indirect effects in some cases. While in some cases, such as breast cancer, demonstration of the target hormone receptor is necessary, in other cases such prostate cancer (androgen receptor) and lymphoid neoplasms (glucocorticoid receptor), the relevant receptor is 103e-15 always present in the tumor.


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InternalMed_Harrison. Glucocorticoids are generally given in “pulsed” high doses in leukemias and lymphomas, where they induce apoptosis in tumor cells. Cushing’s syndrome and inadvertent adrenal suppression on withdrawal from high-dose glucocorticoids can be significant complications, along with infections common in immunosuppressed patients, in particular Pneumocystis pneumonia, which classically appears a few days after completing a course of high-dose glucocorticoids.


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InternalMed_Harrison. Tamoxifen is a partial estrogen receptor antagonist; it has a 10-fold greater antitumor activity in breast cancer patients whose tumors express estrogen receptors than in those who have low or no levels of expression. It might be considered the prototypic “molecularly targeted” agent. Owing to its agonistic activities in vascular and uterine tissue, side effects include a somewhat increased risk of cardiovascular complications, such as thromboembolic phenomena, and a small increased incidence of endometrial carcinoma, which appears after chronic use (usually >5 years). Progestational agents—including medroxyprogesterone acetate, androgens including fluoxymesterone (Halotestin), and, paradoxically, estrogens—have approximately the same degree of activity in primary hormonal treatment of breast cancers that have elevated expression of estrogen receptor protein. Estrogen itself is not used often owing to prominent cardiovascular and uterotropic activity.


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InternalMed_Harrison. Aromatase refers to a family of enzymes that catalyze the formation of estrogen in various tissues, including the ovary and peripheral adipose tissue and some tumor cells. Aromatase inhibitors are of two types, the irreversible steroid analogues such as exemestane and the reversible inhibitors such as anastrozole or letrozole. Anastrozole is superior to tamoxifen in the adjuvant treatment of breast cancer in postmenopausal patients with estrogen receptor–positive tumors. Letrozole treatment affords benefit following tamoxifen treatment. Adverse effects of aromatase inhibitors may include an increased risk of osteoporosis.


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InternalMed_Harrison. Prostate cancer is classically treated by androgen deprivation. Diethylstilbestrol (DES) acting as an estrogen at the level of the hypothalamus to downregulate hypothalamic luteinizing hormone (LH) production results in decreased elaboration of testosterone by the testicle. For this reason, orchiectomy is equally as effective as moderate-dose DES, inducing responses in 80% of previously untreated patients with prostate cancer but without the prominent cardiovascular side effects of DES, including thrombosis and exacerbation of coronary artery disease. In the event that orchiectomy is not accepted by the patient, testicular androgen suppression can also be effected by luteinizing hormone–releasing hormone (LHRH) agonists such as leuprolide and goserelin. These agents cause tonic stimulation of the LHRH receptor, with the loss of its normal pulsatile activation resulting in decreased output of LH by the anterior pituitary. Therefore, as primary hormonal manipulation in prostate cancer,


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InternalMed_Harrison. of the LHRH receptor, with the loss of its normal pulsatile activation resulting in decreased output of LH by the anterior pituitary. Therefore, as primary hormonal manipulation in prostate cancer, one can choose orchiectomy or leuprolide, but not both. The addition of androgen receptor blockers, including flutamide or bicalutamide, is of uncertain additional benefit in extending overall response duration; the combined use of orchiectomy or leuprolide plus flutamide is referred to as total androgen blockade. Enzalutamide also binds to the androgen receptor and antagonizes androgen action in a mechanistically distinct way. Somewhat analogous to inhibitors of aromatase, agents have been derived that inhibit testosterone and other androgen synthesis in the testis, adrenal gland, and prostate tissue. Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP 17A1) and has been shown to be active in prostate cancer patients experiencing progression despite androgen blockade.


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InternalMed_Harrison. Tumors that respond to a primary hormonal manipulation may frequently respond to second and third hormonal manipulations. Thus, breast tumors that had previously responded to tamoxifen have, on relapse, notable response rates to withdrawal of tamoxifen itself or to subsequent addition of an aromatase inhibitor or progestin. Likewise, initial treatment of prostate cancers with leuprolide plus flutamide may be followed after disease progression by response to withdrawal of flutamide. These responses may result from the removal Chapter 103e Principles of Cancer Treatment of antagonists from mutant steroid hormone receptors that have come to depend on the presence of the antagonist as a growth-promoting influence.


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InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment of antagonists from mutant steroid hormone receptors that have come to depend on the presence of the antagonist as a growth-promoting influence. Additional strategies to treat refractory breast and prostate cancers that possess steroid hormone receptors may also address adrenal capacity to produce androgens and estrogens, even after orchiectomy or oophorectomy, respectively. Thus, aminoglutethimide or ketocon azole can be used to block adrenal synthesis by interfering with the enzymes of steroid hormone metabolism. Administration of these agents requires concomitant hydrocortisone replacement and additional glucocorticoid doses administered in the event of physiologic stress.


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InternalMed_Harrison. Humoral mechanisms can also result in complications from an underlying malignancy producing the hormone. Adrenocortical carcinomas can cause Cushing’s syndrome as well as syndromes of androgen or estrogen excess. Mitotane can counteract these by decreasing synthesis of steroid hormones. Islet cell neoplasms can cause debilitating diarrhea, treated with the somatostatin analogue octreotide. Prolactin-secreting tumors can be effectively managed by the dopaminergic agonist bromocriptine.


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InternalMed_Harrison. DiAgNosticAlly guiDeD therApy The basis for discovery of drugs of this type was the prior knowledge of the importance of the drugs’ molecular target to drive tumors in different contexts. Figure 103e-4 summarizes how FDA-approved targeted agents act. In the case of diagnostically guided targeted chemotherapy, prior demonstration of a specific target is necessary to guide the rational use of the agent, while in the case of targeted agents directed at oncogenic pathways, specific diagnosis of pathway activation is not yet necessary or in some cases feasible, although this is an area of ongoing clinical research. Table 103e-5 lists currently approved targeted chemotherapy agents, with features of their use.


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InternalMed_Harrison. In hematologic tumors, the prototypic agent of this type is imatinib, which targets the ATP binding site of the p210bcr-abl protein tyrosine kinase that is formed as the result of the chromosome 9;22 translocation producing the Philadelphia chromosome in CML. Imatinib is superior to interferon plus chemotherapy in the initial treatment of the chronic phase of this disorder. It has lesser activity in the blast phase of CML, where the cells may have acquired additional mutations in p210bcr-abl itself or other genetic lesions. Its side effects are relatively tolerable in most patients and include hepatic dysfunction, diarrhea, and fluid retention. Rarely, patients receiving imatinib have decreased cardiac function, which may persist after discontinuation of the drug. The quality of response to imatinib enters into the decision about when to refer patients with CML for consideration of transplant approaches. Nilotinib is a tyrosine protein kinase inhibitor with a similar spectrum of


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InternalMed_Harrison. to imatinib enters into the decision about when to refer patients with CML for consideration of transplant approaches. Nilotinib is a tyrosine protein kinase inhibitor with a similar spectrum of activity to imatinib, but with increased potency and perhaps better tolerance by certain patients. Dasatinib, another inhibitor of the p210bcr-abl oncoproteins, is active in certain mutant variants of p210bcr-abl that are refractory to imatinib and arise during therapy with imatinib or are present de novo. Dasatinib also has inhibitory action against kinases belonging to the src tyrosine protein kinase family; this activity may contribute to its effects in hematopoietic tumors and suggest a role in solid tumors where src kinases are active. The T315I mutant of p210bcr-abl is resistant to imatinib, nilotinib, bosutinib, and dasatinib; ponatinib has activity in patients with this p210bcr-abl variant, but ponatinib has noteworthy associated thromboembolic toxicity. Use of this class of targeted


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InternalMed_Harrison. nilotinib, bosutinib, and dasatinib; ponatinib has activity in patients with this p210bcr-abl variant, but ponatinib has noteworthy associated thromboembolic toxicity. Use of this class of targeted agents is thus critically guided not only by the presence of the p210bcr-abl tyrosine kinase, but also by the presence of different mutations in the ATP binding site.


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InternalMed_Harrison. All-trans-retinoic acid (ATRA) targets the PML-retinoic acid receptor (RAR) α fusion protein, which is the result of the chromosome 15;17 translocation pathogenic for most forms of APL. Administered orally, it causes differentiation of the neoplastic promyelocytes to mature granulocytes and attenuates the rate of hemorrhagic complications. Adverse effects include headache with or without pseudotumor cerebri and gastrointestinal and cutaneous toxicities. In epithelial solid tumors, the small-molecule epidermal growth factor (EGF) antagonists act at the ATP binding site of the EGF receptor


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InternalMed_Harrison. FIGuRE 103e-4 Targeted chemotherapeutic agents act in most instances by interrupting cell growth factor-mediated signaling pathways. After a growth factor binds to is cognate receptor (1), in many cases there is activation of tyrsosine kinase activity particularly after dimerization of the receptors (2). This leads to autophosphorylation of the receptor and docking of “adaptor” proteins. One important pathway activated occurs after exchange of GDP for GTP in the RAS family of proto-oncogene products (3). GTP-RAS activates the RAF proto-oncogene kinase (4), leading to a phosphorylation cascade of kinases (5, 6) that ultimately impart signals to regulators of gene function to produce transcripts which activate cell cycle progression and increase protein synthesis. In parallel, tyrosine phosphorylated receptors can activate the phosphatidylinositol-3-kinase to produce the phosphorylated lipid phosphatidyl-inositol-3phosphate (7). This leads to the activation of the AKT kinase(8) which in


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InternalMed_Harrison. receptors can activate the phosphatidylinositol-3-kinase to produce the phosphorylated lipid phosphatidyl-inositol-3phosphate (7). This leads to the activation of the AKT kinase(8) which in turn stimulates the mammalian “Target of Rapamycin” kinase (mTOR), which directly increases the translation of key mRNAs for gene products regulating cell growth. Erlotinib and afatinib, are examples of Epidermal Growth Factor receptor tyrosine kinase inhibitors; imatinib can act on the nonreceptor tyrosine kinase bcr-abl or c-KIT membrane bound tyrosine kinase. Vemurafenib and Dabrafenib act on the B isoform of RAF uniquely in melanoma, and c-RAF is inhibited by sorafenib. Trametinib acts on MEK. Temsirolimus and everolimus inhibit mTOR kinase to downregulate translation of oncogenic mRNAs.


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InternalMed_Harrison. tyrosine kinase. In early clinical trials, gefitinib showed evidence of responses in a small fraction of patients with non-small-cell lung cancer (NSCLC). Side effects were generally acceptable, consisting mostly of rash and diarrhea. Subsequent analysis of responding patients revealed a high frequency of activating mutations in the EGF receptor. Patients with such activating mutations who initially responded to gefitinib but who then had progression of the disease then acquired additional mutations in the enzyme, analogous functionally to mutational variants responsible for imatinib resistance in CML. Erlotinib is another EGF receptor tyrosine kinase antagonist with a superior outcome in clinical Chapter 103e Principles of Cancer Treatment Temsirolimus Renal cell carcinoma, second line or poor prognosis Stomatitis Thrombocytopenia Nausea Anorexia, fatigue Metabolic (glucose, lipid)


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InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment Temsirolimus Renal cell carcinoma, second line or poor prognosis Stomatitis Thrombocytopenia Nausea Anorexia, fatigue Metabolic (glucose, lipid) Abbreviations: APL, acute promyelocytic leukemia; ALL, acute lymphocytic leukemia; CHF, congestive heart failure; CML, chronic myeloid leukemia; EGFR, epidermal growth factor receptor; GI, gastrointestinal; mTOR, mammalian target of rapamycin kinase; NSCLC, non-small-cell lung cancer; PDGFR, platelet-derived growth factor receptor; Pgp, P-glycoprotein; VEGFR, vascular endothelial growth factor receptor.


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InternalMed_Harrison. VEGFR, vascular endothelial growth factor receptor. trials in NSCLC; an overall survival advantage was demonstrated in subsets of patients who were treated after demonstrating progression of disease and who also had not been preselected for the presence of activating mutations. Thus, although even patients with wild-type EGF receptors may benefit from erlotinib treatment, the presence of EGF receptor tyrosine kinase mutations has recently been shown to be a basis for recommending erlotinib and afatinib for first-line treatment of advanced NSCLC. Likewise, crizotinib targeting the alk protooncogene fusion protein has value in the initial treatment of alk-positive NSCLC. Lapatinib is a tyrosine kinase inhibitor with both EGF receptor and HER2/neu antagonist activity, which is important in the treatment of breast cancers expressing the HER2/neu oncoprotein.


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InternalMed_Harrison. In addition to the p210bcr-abl kinase, imatinib also has activity against the c-kit tyrosine kinase (the receptor for the steel growth factor, also called stem cell factor) and the platelet-derived growth factor receptor (PDGFR), both of which can be expressed in gastrointestinal stromal sarcoma (GIST). Imatinib has found clinical utility in GIST, a tumor previously notable for its refractoriness to chemotherapeutic approaches. Imatinib’s degree of activity varies with the specific mutational variant of kit or PDGFR present in a particular patient’s tumor.


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InternalMed_Harrison. The BRAF V600E mutation has been detected in a notable fraction of melanomas, thyroid tumors, and hairy cell leukemia, and preclinical models supported the concept that BRAF V600E drives oncogenic signaling in these tumors. Vemurafenib and dabrafenib, with selective capacity to inhibit the BRAF V600E serine kinase activity, were each shown to cause noteworthy responses in patients with BRAF V600E– mutated melanomas, although early relapse occurred in many patients treated with the drugs as single agents. Trametinib, acting downstream of BRAF V600E by directly inhibiting the MEK serine kinase by a non-ATP binding site mechanism, also displayed noteworthy responses in BRAF V600E–mutated melanomas, and the combination of trametinib and dabrafenib is even more active, by targeting the BRAF V600E– driven pathway at two points in the pathway leading to gene activation.


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InternalMed_Harrison. oNcogeNicAlly ActivAteD pAthwAys This group of agents also targets specific regulatory molecules in promoting the viability of tumor cells, but they do not require the diagnostically verified presence of a particular target or target variant at this time.


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InternalMed_Harrison. “Multitargeted” kinase antagonists are small-molecule ATP site-directed antagonists that inhibit more than one protein kinase and have value in the treatment of several solid tumors. Drugs of this type with prominent activity against the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase have activity in renal cell carcinoma. Sorafenib is a VEGFR antagonist with activity against the raf serine-threonine protein kinase, and regorafenib is a closely related drug with value in relapsed advanced colon cancer. Pazopanib also prominently targets VEGFR and has activity in renal carcinoma and soft tissue sarcomas. Sunitinib has anti-VEGFR, anti-PDGFR, and anti-c-kit activity. It causes prominent responses and stabilization of disease in renal cell cancers and GISTs. Side effects for agents with anti-VEGFR activity prominently include hypertension, proteinuria, and, more rarely, bleeding and clotting disorders and perforation of scarred gastrointestinal lesions. Also


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InternalMed_Harrison. effects for agents with anti-VEGFR activity prominently include hypertension, proteinuria, and, more rarely, bleeding and clotting disorders and perforation of scarred gastrointestinal lesions. Also encountered are fatigue, diarrhea, and the hand-foot syndrome, with erythema and desquamation of the distal extremities, in some cases requiring dose modification, particularly with sorafenib.


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InternalMed_Harrison. Temsirolimus and everolimus are mammalian target of rapamycin (mTOR) inhibitors with activity in renal cancers. They produce stomatitis, fatigue, and some hyperlipidemia (10%), myelosuppression (10%), and rare lung toxicity. Everolimus is also useful in patients with hormone receptor–positive breast cancers displaying resistance to hormonal inhibition and in certain neuroendocrine and brain tumors, the latter arising in patients with sporadic or inherited mutations in the pathway activating mTOR.


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InternalMed_Harrison. In hematologic neoplasms, bortezomib is an inhibitor of the proteasome, the multisubunit assembly of protease activities responsible for the selective degradation of proteins important in regulating activation of transcription factors, including nuclear factor-κB (NF-κB) and proteins regulating cell cycle progression. It has activity in multiple myeloma and certain lymphomas. Adverse effects include neuropathy, orthostatic hypotension with or without hyponatremia, and reversible thrombocytopenia. Carfilzomib is a proteasome inhibitor chemically unrelated to bortezomib without prominent neuropathy, but with evidence of a cytokine release syndrome, which can be a cardiopulmonary stress. Other agents active in multiple myeloma and certain other hematologic neoplasms include the immunomodulatory agents related to thalidomide, including lenalidomide and pomalidomide. All these agents collectively inhibit aberrant angiogenesis in the bone marrow microenvironment, as well as influence


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InternalMed_Harrison. agents related to thalidomide, including lenalidomide and pomalidomide. All these agents collectively inhibit aberrant angiogenesis in the bone marrow microenvironment, as well as influence stromal cell immune functions to alter the cytokine milieu supporting the growth of myeloma cells. Thalidomide, although clinically active, has prominent cytopenic, neuropathic, procoagulant, and CNS toxicities that have been somewhat attenuated in the other drugs of the class, although use of these agents frequently entails concomitant anticoagulant prophylaxis.


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InternalMed_Harrison. Ibrutinib is representative a novel class of inhibitors directed at Bruton’s tyrosine kinase, which is important in the function of B cells. Initially approved for use in mantle cell lymphoma, it is potentially applicable to a number of B cell neoplasms that depend on signals through the B cell antigen receptor. Janus kinases likewise function downstream of a variety of cytokine receptors to amplify cytokine signals, and Janus kinase inhibitors including ruxolitinib have approved activity in myelofibrosis to ameliorate splenomegaly and systemic symptoms. Vorinostat is an inhibitor of histone deacetylases, which are responsible for maintaining the proper orientation of histones on DNA, with resulting capacity for transcriptional readiness. Acetylated histones allow access of transcription factors to target genes and therefore


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InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment increase expression of genes that are selectively repressed in tumors. The result can be differentiation with the emergence of a more normal cellular phenotype, or cell cycle arrest with expression of endogenous regulators of cell cycle progression. Vorinostat is approved for clinical use in cutaneous T cell lymphoma, with dramatic skin clearing and very few side effects. Romidepsin is a distinct molecular class of his-tone deacetylase inhibitor also active in cutaneous T cell lymphoma. An active retinoid in cutaneous T cell lymphoma is the synthetic retinoid X receptor ligand bexarotene.


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InternalMed_Harrison. DNA methyltransferase inhibitors, including 5-aza-cytidine and 2´-deoxy-5-azacytidine (decitabine), can also increase transcription of genes “silenced” during the pathogenesis of a tumor by causing demethylation of the methylated cytosines that are acquired as an “epigenetic” (i.e., after the DNA is replicated) modification of DNA. These drugs were originally considered antimetabolites but have clinical value in myelodysplastic syndromes and certain leukemias when administered at low doses.


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InternalMed_Harrison. CANCER BIOLOGIC THERAPY Principles The goal of biologic therapy is to manipulate the host– tumor interaction in favor of the host, potentially at an optimum biologic dose that might be different than the MTD. As a class, biologic therapies may be distinguished from molecularly targeted agents in that many biologic therapies require an active response (e.g., reexpression of silenced genes or antigen expression) on the part of the tumor cell or on the part of the host (e.g., immunologic effects) to allow therapeutic effect. This may be contrasted with the more narrowly defined antiproliferative or apoptotic response that is the ultimate goal of molecularly targeted agents discussed above. However, there is much commonality in the strategies to evaluate and use molecularly targeted and biologic therapies.


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InternalMed_Harrison. Immune Cell–Mediated Therapies Tumors have a variety of means of avoiding the immune system: (1) they are often only subtly different from their normal counterparts; (2) they are capable of downregulating their major histocompatibility complex antigens, effectively masking them from recognition by T cells; (3) they are inefficient at presenting antigens to the immune system; (4) they can cloak themselves in a protective shell of fibrin to minimize contact with surveillance mechanisms; and (5) they can produce a range of soluble molecules, including potential immune targets, that can distract the immune system from recognizing the tumor cell or can kill or inactivate the immune effector cells. Some of the cell products initially polarize the immune response away from cellular immunity (shifting from TH1 to TH2 responses; Chap. 372e) and ultimately lead to defects in T cells that prevent their activation and cytotoxic activity. Cancer treatment further suppresses host immunity. A


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InternalMed_Harrison. (shifting from TH1 to TH2 responses; Chap. 372e) and ultimately lead to defects in T cells that prevent their activation and cytotoxic activity. Cancer treatment further suppresses host immunity. A variety of strategies are being tested to overcome these barriers.


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InternalMed_Harrison. Cell-Mediated Immunity The strongest evidence that the immune system can exert clinically meaningful antitumor effects comes from allogeneic bone marrow transplantation. Adoptively transferred T cells from the donor expand in the tumor-bearing host, recognize the tumor as being foreign, and can mediate impressive antitumor effects (graft-versus-tumor effects). Three types of experimental interventions are being developed to take advantage of the ability of T cells to kill tumor cells.


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InternalMed_Harrison. 1. Transfer of allogeneic T cells. This occurs in three major settings: in allogeneic bone marrow transplantation; as purified lymphocyte transfusions following bone marrow recovery after allogeneic bone marrow transplantation; and as pure lymphocyte transfusions following immunosuppressive (nonmyeloablative) therapy (also called minitransplants). In each of these settings, the effector cells are donor T cells that recognize the tumor as being foreign, probably through minor histocompatibility differences. The main risk of such therapy is the development of graft-versus-host disease because of the minimal difference between the cancer and the normal host cells. This approach has been highly effective in certain hematologic cancers. 2.


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InternalMed_Harrison. Transfer of autologous T cells. In this approach, the patient’s own T cells are removed from the tumor-bearing host, manipulated in several ways in vitro, and given back to the patient. There are three major classes of autologous T-cell manipulation. First, tumor antigen–specific T cells can be developed and expanded to large numbers over many weeks ex vivo before administration. Second, the patient’s T cells can be activated by exposure to polyclonal stimulators such as anti-CD3 and anti-CD28 after a short period ex vivo, and then amplified in the host after transfer by stimulation with IL-2, for example. Short periods removed from the patient permit the cells to overcome the tumor-induced T cell defects, and such cells traffic and home to sites of disease better than cells that have been in culture for many weeks. In a third approach, genes that encode for a T cell receptor specific for an antigen expressed by the tumor along with genes that facilitate T cell activation can be


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InternalMed_Harrison. been in culture for many weeks. In a third approach, genes that encode for a T cell receptor specific for an antigen expressed by the tumor along with genes that facilitate T cell activation can be introduced into subsets of a patient’s T cells, which, after transfer back into the patient, allow homing of cytotoxic T cells to tumor cells expressing the antigen.


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InternalMed_Harrison. 3.


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InternalMed_Harrison. Tumor vaccines aimed at boosting T cell immunity. The finding that mutant oncogenes that are expressed only intracellularly can be recognized as targets of T cell killing greatly expanded the possibilities for tumor vaccine development. No longer is it difficult to find something different about tumor cells. However, major difficulties remain in getting the tumor-specific peptides presented in a fashion to prime the T cells. Tumors themselves are very poor at presenting their own antigens to T cells at the first antigen exposure (priming). Priming is best accomplished by professional antigen-presenting cells (dendritic cells). Thus, a number of experimental strategies are aimed at priming host T cells against tumor-associated peptides. Vaccine adjuvants such as granulocytemacrophage colony-stimulating factor (GM-CSF) appear capable of attracting antigen-presenting cells to a skin site containing a tumor antigen. Such an approach has been documented to eradicate microscopic residual


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InternalMed_Harrison. factor (GM-CSF) appear capable of attracting antigen-presenting cells to a skin site containing a tumor antigen. Such an approach has been documented to eradicate microscopic residual disease in follicular lymphoma and give rise to tumor-specific T cells. Purified antigen-presenting cells can be pulsed with tumor, its membranes, or particular tumor antigens and delivered as a vaccine. One such vaccine, Sipuleucel-T, is approved for use in patients with hormone-independent prostate cancer. In this approach, the patient undergoes leukapheresis, wherein mononuclear cells (that include antigen-presenting cells) are removed from the patient’s blood. The cells are pulsed in a laboratory with an antigenic fusion protein comprising a protein frequently expressed by prostate cancer cells, prostate acid phosphatase, fused to GM-CSF, and matured to increase their capacity to present the antigen to immune effector cells. The cells are then returned to the patient in a well-tolerated treatment.


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InternalMed_Harrison. acid phosphatase, fused to GM-CSF, and matured to increase their capacity to present the antigen to immune effector cells. The cells are then returned to the patient in a well-tolerated treatment. Although no objective tumor response was documented in clinical trials, median survival was increased by about 4 months. Tumor cells can also be transfected with genes that attract antigen-presenting cells.


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InternalMed_Harrison. Another important vaccine strategy is directed at infectious agents whose action ultimately is tied to the development of human cancer. Hepatitis B vaccine in an epidemiologic sense prevents hepatocellular carcinoma, and a tetravalent human papillomavirus vaccine prevents infection by virus types currently accounting for 70% of cervical cancer. Unfortunately, these vaccines are ineffective at treating patients who have developed a virus-induced cancer.


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InternalMed_Harrison. Antibody-Mediated Therapeutic Approaches In general, antibodies are not very effective at killing cancer cells. Because the tumor seems to influence the host toward making antibodies rather than generating cellular immunity, it is inferred that antibodies are easier for the tumor to fend off. Many patients can be shown to have serum antibodies directed at their tumors, but these do not appear to influence disease progression. However, the ability to grow very large quantities of high-affinity antibody directed at a tumor by the hybridoma technique has led to the application of antibodies in the treatment of cancer. In this approach, antibodies are derived where the antigen-combining regions are grafted onto human immunoglobulin gene products (chimerized or humanized) or derived de novo from mice bearing Drug Target Indications and Features of Use


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InternalMed_Harrison. Drug Target Indications and Features of Use Rituximab CD20 B cell neoplasms (also emerging role in autoimmune disease); chimeric antibody with frequent mouse-derived sequences; frequent infusion reactions, particularly on initial doses; reactivation of infections, Ofatumumab CD20 active in CLL; fully human antibody with distinct binding site compared to rituximab; decreased intensity infusion reactions; Trastuzumab HER2/neu Active in breast cancer and GI cancers expressing HER2/neu; cardiotoxicity, particularly in setting of prior anthracyclines, requires monitoring; infusion reactions Pertuzumab HER2/neu Breast cancer; targets distinct binding site from trastuzumab, inhibiting dimerization of HER2 family members; infusion Cetuximab EGFR Colorectal cancers with wild-type Ki-ras oncoprotein; head and neck cancers with radiation; rash, diarrhea, infusion reactions


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InternalMed_Harrison. Cetuximab EGFR Colorectal cancers with wild-type Ki-ras oncoprotein; head and neck cancers with radiation; rash, diarrhea, infusion reactions Panitumumab EGFR Colorectal cancers with wild-type Ki-ras oncoprotein; fully humanized; decreased infusion reactions; different IgG subtype Bevacizumab VEGF Metastatic colorectal cancer and non-small-cell lung cancer (nonsquamous) with chemotherapy; renal cancer and glioblastoma as single agents; prominent HBP, proteinuria, GI perforations, hemorrhage, thrombosis (venous and arterial) adverse events Abbreviations: CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; GI, gastrointestinal; HBP, high blood pressure; VEGF, vascular endothelial growth factor.


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InternalMed_Harrison. human immunoglobulin gene loci. Three general strategies have emerged using antibodies. Tumor-regulatory antibodies target tumor cells directly or indirectly to modulate intracellular functions or attract immune or stromal cells. Immunoregulatory antibodies target antigens expressed on the tumor cells or host immune cells to modulate primarily the host’s immune responsiveness to the tumor. Finally, antibody conjugates can be made with the antibody linked to drugs, toxins, or radioisotopes to target these “warheads” for delivery to the tumor. Table 103e-6 lists features of currently used or promising antibodies for cancer treatment.


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InternalMed_Harrison. tumor-regulAtory ANtiboDies Humanized antibodies against the CD20 molecule expressed on B cell lymphomas (rituximab and ofatumumab) are exemplary of antibodies that affect both signaling events driving lymphomagenesis as well as activating immune responses against B cell neoplasms. They are used as single agents and in combination with chemotherapy and radiation in the treatment of B cell neoplasms. Obinutuzumab is an antibody with an altered glycosylation that enhances its ability to fix complement; it is also directed against CD20 and is of value in chronic lymphocytic leukemia. It seems to be more effective in this setting than rituximab.


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InternalMed_Harrison. The HER2/neu receptor overexpressed on epithelial cancers, especially breast cancer, was initially targeted by trastuzumab, with noteworthy activity in potentiating the action of chemotherapy in breast cancer as well as some evidence of single-agent activity. Trastuzumab also appears to interrupt intracellular signals derived from HER2/ neu and to stimulate immune mechanisms. The anti-HER2 antibody pertuzumab, specifically targeting the domain of HER2/neu responsible for dimerization with other HER2 family members, is more specifically directed against HER2 signaling function and augments the action of trastuzumab.


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InternalMed_Harrison. EGF receptor (EGFR)-directed antibodies (such as cetuximab and panitumumab) have activity in colorectal cancer refractory to chemotherapy, particularly when used to augment the activity of an additional chemotherapy program, and in the primary treatment of head and neck cancers treated with radiation therapy. The mechanism of action is unclear. Direct effects on the tumor may mediate an antiproliferative effect as well as stimulate the participation of host mechanisms involving immune cell or complement-mediated response to tumor cell–bound antibody. Alternatively, the antibody may alter the release of paracrine factors promoting tumor cell survival.


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InternalMed_Harrison. The anti-VEGF antibody bevacizumab shows little evidence of antitumor effect when used alone, but when combined with chemotherapeutic agents, it improves the magnitude of tumor shrinkage and time to disease progression in colorectal and nonsquamous lung cancers. The mechanism for the effect is unclear and may relate to the capacity of the antibody to alter delivery and tumor uptake of the active chemotherapeutic agent. Ziv-aflibercept is not an antibody, but a solubilized VEGF receptor VEGF binding domain, and therefore may have a distinct mechanism of action with comparable side effects.


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InternalMed_Harrison. Unintended side effects of any antibody use include infusion-related hypersensitivity reactions, usually limited to the first infusion, which can be managed with glucocorticoid and/or antihistamine prophylaxis. In addition, distinct syndromes have emerged with different antibodies. Anti-EGFR antibodies produce an acneiform rash that poorly responds to glucocorticoid cream treatment. Trastuzumab (anti-HER2) can inhibit cardiac function, particularly in patients with prior exposure to anthracyclines. Bevacizumab has a number of side effects of medical significance, including hypertension, thrombosis, proteinuria, hemorrhage, and gastrointestinal perforations with or without prior surgeries; these adverse events also occur with small-molecule drugs modulating VEGFR function.


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InternalMed_Harrison. immuNoregulAtory ANtiboDies Purely immunoregulatory antibodies stimulate immune responses to mediate tumor-directed cytotoxicity. First-generation approaches sought to activate complement and are exemplified by antibodies to CD52; these are active in chronic lymphoid leukemia and T cell malignancies. A more refined understanding of the tumor–host interface has defined that cytotoxic tumor-directed T cells are frequently inhibited by ligands upregulated in the tumor cells. The programmed death ligand 1 (PD-L1; also known as B7-homolog 1) was initially recognized as an entity that induced T cell death through a receptor present on T cells, termed the PD receptor (Fig 103e-5), which physiologically exists to regulate the intensity of the immune response. The PD family of ligands and receptors also regulates macrophage function, present in tumor stroma. These actions raised the hypothesis that antibodies directed against the PD signaling axis (both anti-PD-L1 and anti-PD) might be useful


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InternalMed_Harrison. also regulates macrophage function, present in tumor stroma. These actions raised the hypothesis that antibodies directed against the PD signaling axis (both anti-PD-L1 and anti-PD) might be useful in cancer treatment by allowing reactivation of the immune response against tumors. Indeed, nivolumab and lambrolizumab, both anti-PD antibodies, have shown evidence of important immune-mediated actions against certain solid tumors, including melanoma and lung cancers.


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InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment


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InternalMed_Harrison. FIGuRE 103e-5 Tumors possess a microenvironment (tumor stroma) with immune cells including both helper T cells, suppressor T cells (both “regulatory” of other immune cell function), macrophages, and cytotoxic T cells. Cytokines found in the stroma and deriving from macrophawsges and regulatory T cells modulate the activities of cytotoxic T cells, which have the potential to kill tumor cells. Antigens released by tumor cells are taken up by Antigen Presenting Cells (APCs), also in the stroma. Antigens are processed by the APCs to peptides presented by the Major Histocompatibility Complex to T-cell antigen receptors, thus providing an (+) activation signal for the cytotoxic tumor cells to kill tumor cells bearing that antigen. Negative (–) signals inhibiting cytoxic T cell action include the CTLA4 receptor (on T cells), interacting with the B7 family of negative regulatory signals from APCs, and the PD receptor (on T cells), interacting with the PD-L1 (–) signal coming from tumor cells


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InternalMed_Harrison. CTLA4 receptor (on T cells), interacting with the B7 family of negative regulatory signals from APCs, and the PD receptor (on T cells), interacting with the PD-L1 (–) signal coming from tumor cells expressing the PD-1 ligand (PD-l1). As both CTLA4 and PD1 signals attenuate the anti-tumor T cell response, strategies which inhibit CTLA4 and PD1 function are a means of stimulating cytotoxic T cell activity to kill tumor cells. Cytokines from other immune cells and macrophages can provide both (+) and (–) signals for T cell action, and are under investigation as novel immunoregulatory therapeutics.


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InternalMed_Harrison. Already approved for clinical use in melanoma is ipilimumab, an antibody directed against the anti-CTLA4 (cytotoxic T lymphocyte antigen 4), which is expressed on T cells (not tumor cells), responds to signals from antigen-presenting cells (Fig. 103e-5), and also down-regulates the intensity of the T cell proliferative response to antigens derived from tumor cells. Indeed, manipulation of the CTLA4 axis was the first demonstration that purely immunoregulatory antibody strategies directed at T cell physiology could be safe and effective in the treatment of cancer, although it acts at a very early stage in T cell activation and can be considered somewhat nonspecific in its basis for T cell stimulation. Pembrolizumab, an anti-PD ligand blocking agent was also approved for melanoma, with a similar spectrum of potential adverse events, but acting in the tumor microenvironment. Indeed, prominent activation of autoimmune hepatic, endocrine, cutaneous, neurologic, and gastrointestinal


InternalMed_Harrison

InternalMed_Harrison. a similar spectrum of potential adverse events, but acting in the tumor microenvironment. Indeed, prominent activation of autoimmune hepatic, endocrine, cutaneous, neurologic, and gastrointestinal responses is a basis for adverse events with the use of ipilimumab; the emergent use of glucocorticoids may be required to attenuate severe toxicities, which unfortunately can cause potential attenuation of antitumor effect. Importantly for the general internist, these events may occur late after exposure to ipilimumab while the patient may otherwise be enjoying sustained control of tumor growth owing to the beneficial actions of ipilimumab.


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InternalMed_Harrison. Another class of immunoregulatory antibody is the “bispecific” antibody blinatumomab, which was constructed to have an anti-CD19 antigen combining site as one valency of an antibody with anti-CD3 binding site as the other valency. This antibody thus can bring T cells (with its anti-CD3 activity) close to B cells bearing the CD19 determinant. Blinatumomab is active in B cell neoplasms such as acute lymphocytic leukemia, which may not have prominent expression of the CD20 targeted by rituximab.


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InternalMed_Harrison. ANtiboDy coNjugAtes Conjugates of antibodies with drugs and isotopes have also been shown to be effective in the treatment of cancer and have the intent of increasing the therapeutic index of the drug or isotope by delivering the toxic “warhead” directly to the tumor cell or tumor microenvironment. Ado-trastuzumab is a conjugate of the HER2/neu-directed trastuzumab and a highly toxic microtubule targeted drug (emtansine), which by itself is too toxic for human use; the antibody-drug conjugate shows valuable activity in patients with breast cancer who have developed resistance to the “naked” antibody. Brentuximab vedotin is an anti-CD30 antibody drug conjugate with a distinct microtubule poison with activity in neoplasms such as Hodgkin’s lymphoma where the tumor cells frequently express CD30. Radioconjugates targeting CD20 on lymphomas have been approved for use (ibritumomab tiuxetan [Zevalin], using yttrium-90 or 131I-tositumomab). Toxicity concerns have limited their use.


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InternalMed_Harrison. Cytokines There are >70 separate proteins and glycoproteins with biologic effects in humans: interferon (IFN) α, β, and γ; interleukin (IL) 1 through 29 (so far); the tumor necrosis factor (TNF) family (including lymphotoxin, TNF-related apoptosis-inducing ligand [TRAIL], CD40 ligand, and others); and the chemokine family. Only a fraction of these has been tested against cancer; only IFN-α and IL-2 are in routine clinical use.


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InternalMed_Harrison. About 20 different genes encode IFN-α, and their biologic effects are indistinguishable. IFN induces the expression of many genes, inhibits protein synthesis, and exerts a number of different effects on diverse cellular processes. The two recombinant forms that are commercially available are IFN-α2a and -α2b. Interferon is not curative for any tumor but can induce partial responses in follicular lymphoma, hairy cell leukemia, CML, melanoma, and Kaposi’s sarcoma. It has been used in the adjuvant setting in stage II melanoma, multiple myeloma, and follicular lymphoma, with uncertain effects on survival. It produces fever, fatigue, a flulike syndrome, malaise, myelosuppression, and depression and can induce clinically significant autoimmune disease. IFN-α is not generally the treatment of choice for any cancer.


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InternalMed_Harrison. IL-2 exerts its antitumor effects indirectly through augmentation of immune function. Its biologic activity is to promote the growth and activity of T cells and natural killer (NK) cells. High doses of IL-2 can produce tumor regression in certain patients with metastatic melanoma and renal cell cancer. About 2–5% of patients may experience complete remissions that are durable, unlike any other treatment for these tumors. IL-2 is associated with myriad clinical side effects, including intravascular volume depletion, capillary leak syndrome, adult respiratory distress syndrome, hypotension, fever, chills, skin rash, and impaired renal and liver function. Patients may require blood pressure support and intensive care to manage the toxicity. However, once the agent is stopped, most of the toxicities reverse completely within 3–6 days.


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InternalMed_Harrison. Ligand Receptor–Directed Constructs High-affinity receptors for cytokines have led to the design of cytokine-toxin recombinant fusion proteins, such as IL-2 expressed in frame with a fragment of diphtheria toxin. A commercially available construct has activity against certain T cell lymphomas. Likewise, the high-affinity folate receptor is the target for folate conjugated to chemotherapeutic agents. In both cases, the drug’s utility derives from the internalization of the targeted receptor and cleavage of the active drug or toxin moiety.


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InternalMed_Harrison. Although total-body irradiation has a role in preparing a patient to received allogeneic stem cells, and antibodies as described above can specifically target radioisotopes, systemically administered isotopes of iodide salts have an important role in the treatment of thyroid neoplasms, owing to the selective upregulation of the iodide transporter in the tumor cell compartment. Likewise, isotopes of samarium and radium have been found useful in the palliation of symptoms from advanced bony metastases of prostate cancer owing to their selective deposition at the tumor–bone matrix interface, thereby potentially affecting the function of both tumor and stromal cells in the progressive growth of the metastatic deposit.


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InternalMed_Harrison. Resistance mechanisms to the conventional cytotoxic agents were initially characterized in the late twentieth century as defects in drug uptake, metabolism, or export by tumor cells. The multidrug resistance (mdr) gene defined in vitro in cell lines exposed to increasing concentrations of drugs led to the definition of a family of transport proteins that, when overexpressed, result in the facile transport of a variety of hydrophobic drugs out of the cancer cell. Although efforts to manipulate this transporter to promote drug residence in tumor cells have been pursued, none are clinically useful at this time. Drug-metabolizing enzymes such as cytidine deaminase are upregulated in resistant tumor cells, and this is the basis for so-called “high-dose cytarabine” regimens in the treatment of leukemia. Another resistance mechanism defined during this era involved increased expression of a drug’s target, exemplified by amplification of the dihydrofolate reductase gene, in patients who had


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InternalMed_Harrison. leukemia. Another resistance mechanism defined during this era involved increased expression of a drug’s target, exemplified by amplification of the dihydrofolate reductase gene, in patients who had lost responsiveness to methotrexate, or mutation of topoisomerase II in tumors that relapsed after topoisomerase II modulator treatment.


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InternalMed_Harrison. A second class of resistance mechanisms involves loss of the cellular apoptotic mechanism activated after the engagement of a drug’s target by the drug. This occurs in a way that is heavily influenced by the biology of the particular tumor type. For example, decreased alkylguanine alkyltransferase defines a subset of glioblastoma patients with the prospect of greatest benefit from treatment with temozolomide, but has no predictive value for benefit from temozolomide in epithelial neoplasms. Likewise, ovarian cancers resistant to platinating agents have decreased expression of the proapoptotic gene bax. These types of findings have prompted the idea that responsive tumors to chemotherapeutic agents are populated by cells that express drug-related cell death controlling genes, creating in effect a state of “synthetic lethality” of the drug (Chap. 102e) with the genes expressed in responsive tumors, analogous to the existence in yeast of mutations that are well tolerated in the absence


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InternalMed_Harrison. effect a state of “synthetic lethality” of the drug (Chap. 102e) with the genes expressed in responsive tumors, analogous to the existence in yeast of mutations that are well tolerated in the absence of a physiologic stressor but become lethal in the presence of that stressor. In the case of tumors, the chemotherapy inducing the cell death response is the analogous physiologic stressor.


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InternalMed_Harrison. A third class of resistance mechanisms emerged from sequencing of the targets of agents directed at oncogenic kinases. Thus, patients with CML resistant to imatinib have acquired mutations in the ATP binding domain of p210bcr-abl in some cases, leading to the screening and design of agents with activity against the mutant proteins. Entirely analogous resistance mechanisms have emerged in patients with lung cancer treated with the EGFR antagonists gefitinib and erlotinib.


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InternalMed_Harrison. A final category of tumor resistance mechanisms to targeted agents includes the upregulation of alternate means of activating the pathway targeted by the agent. Thus melanomas initially responsive to BRAF V600E antagonists such as vemurafenib may reactivate raf signaling by upregulating isoforms that can bypass the variant blocked by the drug. Likewise, inhibition of HER2/neu signaling in breast cancer cells can lead to the emergence of variants with distinct oncogenic signaling pathways such as PI3 kinase. Analogously in NSCLC, EGFR inhibitor treatment leads to the emergence of cells with a predominance of c-met protooncogene–dependent signaling in the resistant tumors.


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InternalMed_Harrison. The susceptibility of a tumor to different treatments as a function of its expression of potential drug targets or their mutational profile has led to efforts to define the dominant pathways driving a patient’s tumor by genomic techniques including whole exome sequencing. The difficulty with applying such data to patient treatment is recognizing that these pathways may change during the natural history of a tumor and that different sites in a single patient may have tumors with different patterns of gene mutation.


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InternalMed_Harrison. The common cytotoxic chemotherapeutic agents almost invariably affect bone marrow function. Titration of this effect determines the MTD of the agent on a given schedule. The normal kinetics of blood cell turnover influences the sequence and sensitivity of each of the formed elements. Polymorphonuclear leukocytes (PMNs; t1/2 = 6–8 h), platelets (t = 5–7 days), and red blood cells (RBCs; t = 120 days) have most, less, and least susceptibility, respectively, to usually administered cytotoxic agents. The nadir count of each cell type in response to classes of agents is characteristic. Maximal neutropenia occurs 6–14 days after conventional doses of anthracyclines, antifolates, and antimetabolites. Alkylating agents differ from each other in the timing of cytopenias. Nitrosoureas, DTIC, and procarbazine can display delayed marrow toxicity, first appearing 6 weeks after dosing.


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InternalMed_Harrison. Complications of myelosuppression result from the predictable sequelae of the missing cells’ function. Febrile neutropenia refers to the clinical presentation of fever (one temperature ≥38.5°C or three readings ≥38°C but ≤38.5°C per 24 h) in a neutropenic patient with an uncontrolled neoplasm involving the bone marrow or, more usually, in a patient undergoing treatment with cytotoxic agents. Mortality from uncontrolled infection varies inversely with the neutrophil count. If the nadir neutrophil count is >1000/μL, there is little risk; if <500/μL, risk of death is markedly increased. Management of febrile neutropenia has conventionally included empirical coverage with antibiotics for the duration of neutropenia (Chap. 104). Selection of antibiotics is governed by the expected association of infections with certain underlying neoplasms; careful physical examination (with scrutiny of catheter sites, dentition, mucosal surfaces, and perirectal and genital orifices by gentle palpation);


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InternalMed_Harrison. of infections with certain underlying neoplasms; careful physical examination (with scrutiny of catheter sites, dentition, mucosal surfaces, and perirectal and genital orifices by gentle palpation); chest x-ray; and Gram stain and culture of blood, urine, and sputum (if any) to define a putative site of infection. In the absence of any originating site, a broadly acting β-lactam with anti-Pseudomonas activity, such as ceftazidime, is begun empirically. The addition of vancomycin to cover potential cutaneous sites of origin (until these are ruled out or shown to originate from methicillin-sensitive organisms) or metronidazole or imipenem for abdominal or other sites favoring anaerobes reflects modifications tailored to individual patient presentations. The coexistence of pulmonary compromise raises a distinct set of potential pathogens, including Legionella, Pneumocystis, and fungal agents that may require further diagnostic evaluations, such as bronchoscopy with bronchoalveolar


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InternalMed_Harrison. raises a distinct set of potential pathogens, including Legionella, Pneumocystis, and fungal agents that may require further diagnostic evaluations, such as bronchoscopy with bronchoalveolar lavage. Febrile neutropenic patients can be stratified broadly into two prognostic groups. The first, with expected short duration of neutropenia and no evidence of hypotension or abdominal or other localizing symptoms, may be expected to do well even with oral regimens, e.g., ciprofloxacin or moxifloxacin, or amoxicillin plus clavulanic acid. A less favorable prognostic group is patients with expected prolonged neutropenia, evidence of sepsis, and end organ compromise, particularly pneumonia. These patients require tailoring of their antibiotic regimen to their underlying presentation, with frequent empirical addition of antifungal agents if fever and neutropenia persists for 7 days without identification of an adequately treated organism or site.


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InternalMed_Harrison. Transfusion of granulocytes has no role in the management of febrile neutropenia, owing to their exceedingly short half-life, mechanical fragility, and clinical syndromes of pulmonary compromise with leukostasis after their use. Instead, colony-stimulating factors (CSFs) are used to augment bone marrow production of PMNs. Early-acting factors such as IL-1, IL-3, and stem cell factor have not been as useful clinically as late-acting, lineage-specific factors such as granulocyte colony-stimulating factor (G-CSF) or GM-CSF, erythropoietin (EPO), thrombopoietin, IL-6, and IL-11. CSFs may easily become overused in oncology practice. The settings in which their use has been proved effective are limited. G-CSF, GM-CSF, EPO, and IL-11 are currently approved for use. The American Society of Clinical Oncology has developed practice guidelines for the use of G-CSF and GM-CSF (Table 103e-7).


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InternalMed_Harrison. Primary prophylaxis (i.e., shortly after completing chemotherapy to reduce the nadir) administers G-CSF to patients receiving cytotoxic Chapter 103e Principles of Cancer Treatment With the first cycle of chemotherapy (so-called primary CSF administration) Use if the probability of febrile neutropenia is ≥20% Age >65 years treated for lymphoma with curative intent or other tumor Dose-dense regimens in a clinical trial or with strong evidence of benefit With subsequent cycles if febrile neutropenia has previously occurred (so-called secondary CSF administration) Afebrile neutropenic patients No evidence of benefit Febrile neutropenic patients No evidence of benefit May feel compelled to use in the face of clinical deterioration from sepsis, pneumonia, or fungal infection, but benefit unclear In bone marrow or peripheral blood stem cell transplantation Use to mobilize stem cells from marrow Use to hasten myeloid recovery In acute myeloid leukemia G-CSF of minor or no benefit


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InternalMed_Harrison. Use to mobilize stem cells from marrow Use to hasten myeloid recovery In acute myeloid leukemia G-CSF of minor or no benefit GM-CSF of no benefit and may be harmful In myelodysplastic syndromes Use intermittently in subset with neutropenia and recurrent infection What Dose and Schedule Should Be Used? G-CSF: 5 mg/kg per day subcutaneously GM-CSF: 250 mg/m2 per day subcutaneously Pegfilgrastim: one dose of 6 mg 24 h after chemotherapy When Should Therapy Begin and End? When indicated, start 24–72 h after chemotherapy Continue until absolute neutrophil count is 10,000/μL Do not use concurrently with chemotherapy or radiation therapy Abbreviations: CSF, cerebrospinal fluid; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor. Source: From the American Society of Clinical Oncology: J Clin Oncol 24:3187, 2006.


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InternalMed_Harrison. regimens associated with a 20% incidence of febrile neutropenia. “Dose-dense” regimens, where cycling of chemotherapy is intended to be completed without delay of administered doses, may also benefit, but such patients should be on a clinical trial. Administration of G-CSF in these circumstances has reduced the incidence of febrile neutropenia in several studies by about 50%. Most patients, however, receive regimens that do not have such a high risk of expected febrile neutropenia, and therefore most patients initially should not receive G-CSF or GM-CSF. Special circumstances—such as a documented history of febrile neutropenia with the regimen in a particular patient or categories of patients at increased risk, such as patients older than age 65 years with aggressive lymphoma treated with curative chemotherapy regimens; extensive compromise of marrow by prior radiation or chemotherapy; or active, open wounds or deep-seated infection—may support primary treatment with G-CSF or GM-CSF.


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InternalMed_Harrison. curative chemotherapy regimens; extensive compromise of marrow by prior radiation or chemotherapy; or active, open wounds or deep-seated infection—may support primary treatment with G-CSF or GM-CSF. Administration of G-CSF or GM-CSF to afebrile neutropenic patients or to patients with low-risk febrile neutropenia is not recommended, and patients receiving concomitant chemoradiation treatment, particularly those with thoracic neoplasms, likewise are not generally recommended for treatment. In contrast, administration of G-CSF to high-risk patients with febrile neutropenia and evidence of organ compromise including sepsis syndrome, invasive fungal infection, concurrent hospitalization at the time fever develops, pneumonia, profound neutropenia (<0.1 × 109/L), or age >65 years is reasonable.


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InternalMed_Harrison. Secondary prophylaxis refers to the administration of CSFs in patients who have experienced a neutropenic complication from a prior cycle of chemotherapy; dose reduction or delay may be a reasonably considered alternative. G-CSF or GM-CSF is conventionally started 24–72 h after completion of chemotherapy and continued until a PMN count of 10,000/μL is achieved, unless a “depot” preparation of G-CSF such as pegfilgrastim is used, where one dose is administered at least 14 days before the next scheduled administration of chemotherapy. Also, patients with myeloid leukemias undergoing induction therapy may have a slight reduction in the duration of neutropenia if G-CSF is commenced after completion of therapy and may be of particular value in elderly patients, but the influence on long-term outcome has not been defined. GM-CSF probably has a more restricted utility than G-CSF, with its use currently limited to patients after autologous bone marrow transplants, although proper head-to-head


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InternalMed_Harrison. has not been defined. GM-CSF probably has a more restricted utility than G-CSF, with its use currently limited to patients after autologous bone marrow transplants, although proper head-to-head comparisons with G-CSF have not been conducted in most instances. GM-CSF may be associated with more systemic side effects.


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InternalMed_Harrison. Dangerous degrees of thrombocytopenia do not frequently complicate the management of patients with solid tumors receiving cytotoxic chemotherapy (with the possible exception of certain carboplatincontaining regimens), but they are frequent in patients with certain hematologic neoplasms where marrow is infiltrated with tumor. Severe bleeding related to thrombocytopenia occurs with increased frequency at platelet counts <20,000/μL and is very prevalent at counts <5000/μL.


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InternalMed_Harrison. The precise “trigger” point at which to transfuse patients has been defined as a platelet count of 10,000/μL or less in patients without medical comorbidities that may increase the risk of bleeding. This issue is important not only because of the costs of frequent transfusion, but unnecessary platelet transfusions expose the patient to the risks of allosensitization and loss of value from subsequent transfusion owing to rapid platelet clearance, as well as the infectious and hypersensitivity risks inherent in any transfusion. Prophylactic transfusions to keep platelets >20,000/μL are reasonable in patients with leukemia who are stressed by fever or concomitant medical conditions (the threshold for transfusion is 10,000/μL in patients with solid tumors and no other bleeding diathesis or physiologic stressors such as fever or hypotension, a level that might also be reasonably considered for leukemia patients who are thrombocytopenic but not stressed or bleeding). In contrast, patients


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InternalMed_Harrison. stressors such as fever or hypotension, a level that might also be reasonably considered for leukemia patients who are thrombocytopenic but not stressed or bleeding). In contrast, patients with myeloproliferative states may have functionally altered platelets despite normal platelet counts, and transfusion with normal donor platelets should be considered for evidence of bleeding in these patients. Careful review of medication lists to prevent exposure to nonsteroidal anti-inflammatory agents and maintenance of clotting factor levels adequate to support near-normal prothrombin and partial thromboplastin time tests are important in minimizing the risk of bleeding in the thrombocytopenic patient.


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InternalMed_Harrison. Certain cytokines in clinical investigation have shown an ability to increase platelets (e.g., IL-6, IL-1, thrombopoietin), but clinical benefit and safety are not yet proven. IL-11 (oprelvekin) is approved for use in the setting of expected thrombocytopenia, but its effects on platelet counts are small, and it is associated with side effects such as headache, fever, malaise, syncope, cardiac arrhythmias, and fluid retention. Eltrombopag and romiplostim are thrombopoietin agonists with demonstrated efficacy in certain thrombocytopenic states, but they have not been systematically studied in chemotherapy-induced thrombocytopenia.


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InternalMed_Harrison. Anemia associated with chemotherapy can be managed by transfusion of packed RBCs. Transfusion is not undertaken until the hemoglobin falls to <80 g/L (8 g/dL), compromise of end organ function occurs, or an underlying condition (e.g., coronary artery disease) calls for maintenance of hemoglobin >90 g/L (9 g/dL). Patients who are to receive therapy for >2 months on a “stable” regimen and who are likely to require continuing transfusions are also candidates for erythropoietin (EPO). Randomized trials in certain tumors have raised the possibility that EPO use may promote tumor-related adverse events. This information should be considered in the care of individual patients. In the event EPO treatment is undertaken, maintenance of hemoglobin of 90–100 g/L (9–10 g/dL) should be the target. In the setting of adequate iron stores and serum EPO levels <100 ng/mL, EPO, 150 U three times a week, can produce a slow increase in hemoglobin over about 2 months of administration. Depot formulations


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InternalMed_Harrison. the setting of adequate iron stores and serum EPO levels <100 ng/mL, EPO, 150 U three times a week, can produce a slow increase in hemoglobin over about 2 months of administration. Depot formulations can be administered less frequently. It is unclear whether higher hemoglobin levels, up to 110–120 g/L (11–12 g/dL), are associated with improved quality of life to a degree that justifies the more intensive EPO use. Efforts to achieve levels at or above 120 g/L (12 g/dL) have been associated with increased thromboses and mortality rates. EPO may rescue hypoxemic cells from death and contribute to tumor radioresistance.


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InternalMed_Harrison. The most common side effect of chemotherapy administration is nausea, with or without vomiting. Nausea may be acute (within 24 h of chemotherapy), delayed (>24 h), or anticipatory of the receipt of chemotherapy. Patients may be likewise stratified for their risk of susceptibility to nausea and vomiting, with increased risk in young, female, heavily pretreated patients without a history of alcohol or drug use but with a history of motion or morning sickness. Antineoplastic agents vary in their capacity to cause nausea and vomiting. Highly emetogenic drugs (>90%) include mechlorethamine, streptozotocin, DTIC, cyclophosphamide at >1500 mg/m2, and cisplatin; moderately emetogenic drugs (30–90% risk) include carboplatin, cytosine arabinoside (>1 mg/m2), ifosfamide, conventional-dose cyclophosphamide, and anthracyclines; low-risk (10–30%) agents include 5FU, taxanes, etoposide, and bortezomib, with minimal risk (<10%) afforded by treatment with antibodies, bleomycin, busulfan, fludarabine,


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InternalMed_Harrison. and anthracyclines; low-risk (10–30%) agents include 5FU, taxanes, etoposide, and bortezomib, with minimal risk (<10%) afforded by treatment with antibodies, bleomycin, busulfan, fludarabine, and vinca alkaloids. Emesis is a reflex caused by stimulation of the vomiting center in the medulla. Input to the vomiting center comes from the chemoreceptor trigger zone (CTZ) and afferents from the peripheral gastrointestinal tract, cerebral cortex, and heart. The different emesis “syndromes” require distinct management approaches. In addition, a conditioned reflex may contribute to anticipatory nausea arising after repeated cycles of chemotherapy. Accordingly, antiemetic agents differ in their locus and timing of action. Combining agents from different classes or the sequential use of different classes of agent is the cornerstone of successful management of chemotherapy-induced nausea and vomiting. Of great importance are the prophylactic administration of agents and such psychological


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InternalMed_Harrison. classes of agent is the cornerstone of successful management of chemotherapy-induced nausea and vomiting. Of great importance are the prophylactic administration of agents and such psychological techniques as the maintenance of a supportive milieu, counseling, and relaxation to augment the action of antiemetic agents.


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InternalMed_Harrison. Serotonin antagonists (5-HT3) and neurokinin 1 (NK1) receptor antagonists are useful in “high-risk” chemotherapy regimens. The combination acts at both peripheral gastrointestinal and CNS sites that control nausea and vomiting. For example, the 5-HT3 blocker dolasetron, 100 mg intravenously or orally; dexamethasone, 12 mg; and the NK1 antagonist aprepitant, 125 mg orally, are combined on the day of administration of severely emetogenic regimens, with repetition of dexamethasone (8 mg) and aprepitant (80 mg) on days 2 and 3 for delayed nausea. Alternate 5-HT3 antagonists include ondansetron, given as 0.15 mg/kg intravenously for three doses just before and at 4 and 8 h after chemotherapy; palonosetron at 0.25 mg over 30 s, 30 min before chemotherapy; and granisetron, given as a single dose of 0.01 mg/kg just before chemotherapy. Emesis from moderately emetic chemotherapy regimens may be prevented with a 5-HT3 antagonist and dexamethasone alone for patients not receiving doxorubicin and


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InternalMed_Harrison. of 0.01 mg/kg just before chemotherapy. Emesis from moderately emetic chemotherapy regimens may be prevented with a 5-HT3 antagonist and dexamethasone alone for patients not receiving doxorubicin and cyclophosphamide combinations; the latter combination requires the 5-HT3/dexamethasone/aprepitant on day 1 but aprepitant alone on days 2 and 3. Emesis from low-emetic-risk regimens may be prevented with 8 mg of dexamethasone alone or with non-5-HT3, non-NK1 antagonist approaches including the following.


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InternalMed_Harrison. Antidopaminergic phenothiazines act directly at the CTZ and include prochlorperazine (Compazine), 10 mg intramuscularly or intravenously, 10–25 mg orally, or 25 mg per rectum every 4–6 h for up to four doses; and thiethylperazine, 10 mg by potentially all of the above routes every 6 h. Haloperidol is a butyrophenone dopamine antagonist given at 1 mg intramuscularly or orally every 8 103e-25 h. Antihistamines such as diphenhydramine have little intrinsic anti-emetic capacity but are frequently given to prevent or treat dystonic reactions that can complicate use of the antidopaminergic agents. Lorazepam is a short-acting benzodiazepine that provides an anxiolytic effect to augment the effectiveness of a variety of agents when used at 1–2 mg intramuscularly, intravenously, or orally every 4–6 h. Metoclopramide acts on peripheral dopamine receptors to augment gastric emptying and is used in high doses for highly emetogenic regimens (1–2 mg/kg intravenously 30 min before chemotherapy and


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InternalMed_Harrison. h. Metoclopramide acts on peripheral dopamine receptors to augment gastric emptying and is used in high doses for highly emetogenic regimens (1–2 mg/kg intravenously 30 min before chemotherapy and every 2 h for up to three additional doses as needed); intravenous doses of 10–20 mg every 4–6 h as needed or 50 mg orally 4 h before and 8 and 12 h after chemotherapy are used for moderately emetogenic regimens. 5-9-Tetrahydrocannabinol (Marinol) is a rather weak antiemetic compared to other available agents, but it may be useful for persisting nausea and is used orally at 10 mg every 3–4 h as needed.


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InternalMed_Harrison. Regimens that include 5FU infusions and/or irinotecan may produce severe diarrhea. Similar to the vomiting syndromes, chemotherapy-induced diarrhea may be immediate or can occur in a delayed fashion up to 48–72 h after the drugs. Careful attention to maintained hydration and electrolyte repletion, intravenously if necessary, along with antimotility treatments such as “high-dose” loperamide, commenced with 4 mg at the first occurrence of diarrhea, with 2 mg repeated every 2 h until 12 h without loose stools, not to exceed a total daily dose of 16 mg. Octreotide (100–150 μg), a somatostatin analogue, or opiate-based preparations may be considered for patients not responding to loperamide.


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InternalMed_Harrison. Irritation and inflammation of the mucous membranes particularly afflicting the oral and anal mucosa, but potentially involving the gastrointestinal tract, may accompany cytotoxic chemotherapy. Mucositis is due to damage to the proliferating cells at the base of the mucosal squamous epithelia or in the intestinal crypts. Topical therapies, including anesthetics and barrier-creating preparations, may provide symptomatic relief in mild cases. Palifermin or keratinocyte growth factor, a member of the fibroblast growth factor family, is effective in preventing severe mucositis in the setting of high-dose chemotherapy with stem cell transplantation for hematologic malignancies. It may also prevent or ameliorate mucositis from radiation.


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InternalMed_Harrison. Chemotherapeutic agents vary widely in causing alopecia, with anthracyclines, alkylating agents, and topoisomerase inhibitors reliably causing near-total alopecia when given at therapeutic doses. Antimetabolites are more variably associated with alopecia. Psychological support and the use of cosmetic resources are to be encouraged, and “chemo caps” that reduce scalp temperature to decrease the degree of alopecia should be discouraged, particularly during treatment with curative intent of neoplasms, such as leukemia or lymphoma, or in adjuvant breast cancer therapy. The richly vascularized scalp can certainly harbor micrometastatic or disseminated disease.


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InternalMed_Harrison. Cessation of ovulation and azoospermia reliably result from alkylating agent– and topoisomerase poison–containing regimens. The duration of these effects varies with age and sex. Males treated for Hodgkin’s disease with mechlorethamineand procarbazine-containing regimens are effectively sterile, whereas fertility usually returns after regimens that include cisplatin, vinblastine, or etoposide and after bleomycin for testicular cancer. Sperm banking before treatment may be considered to support patients likely to be sterilized by treatment. Females experience amenorrhea with anovulation after alkylating agent therapy; they are likely to recover normal menses if treatment is completed before age 30 but unlikely to recover menses after age 35. Even those who regain menses usually experience premature


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InternalMed_Harrison. Chapter 103e Principles of Cancer Treatment menopause. Because the magnitude and extent of decreased fertility can be difficult to predict, patients should be counseled to maintain effective contraception, preferably by barrier means, during and after therapy. Resumption of efforts to conceive should be considered in the context of the patient’s likely prognosis. Hormone replacement therapy should be undertaken in women who do not have a hormonally responsive tumor. For patients who have had a hormone-sensitive tumor primarily treated by a local modality, conventional practice would counsel against hormone replacement, but this issue is under investigation.


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InternalMed_Harrison. Chemotherapy agents have variable effects on the success of pregnancy. All agents tend to have increased risk of adverse outcomes when administered during the first trimester, and strategies to delay chemotherapy, if possible, until after this milestone should be considered if the pregnancy is to continue to term. Patients in their second or third trimester can be treated with most regimens for the common neoplasms afflicting women in their childbearing years, with the exception of antimetabolites, particularly antifolates, which have notable teratogenic or fetotoxic effects throughout pregnancy. The need for anticancer chemotherapy per se is infrequently a clear basis to recommend termination of a concurrent pregnancy, although each treatment strategy in this circumstance must be tailored to the individual needs of the patient.


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InternalMed_Harrison. Treatment with EGFR-directed small molecules (e.g., erlotinib, afatinib, lapatinib), antibodies (e.g., cetuximab, panitumumab), and mTOR antagonists (e.g., everolimus, temsirolimus) reliably produces an acneiform rash that can be a source of distress to patients and can be ameliorated with topically applied clindamycin gels and low-potency corticosteroid creams. Diarrhea frequently accompanies tyrosine kinase inhibitor administration and may respond to antimotility agents such as loperamide or stool-bulking agents.


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InternalMed_Harrison. Anti-VEGFR-directed treatments, including the specific antibody bevacizumab, and the “multikinase” inhibitors with anti VEGFR activity, such as sorafenib, sunitinib, and pazopanib, reliably produce hypertension in a significant fraction of patients that typically can be treated with lisinopril, amlodipine, or clonidine alone or in combination. More difficult to treat is proteinuria with resultant azotemia; this can be a basis for discontinuing treatment depending on the clinical context. Thyroid function is prominently affected by chronic exposure to this group of multikinase inhibitors including sorafenib and pazopanib, and periodic surveillance of thyroid-stimulating hormone and thyroxine (T4) levels during treatment is reasonable. Gastrointestinal perforations, arterial thromboses, and hemorrhage likewise have no specific treatments and may be a basis to avoid this class of agents. Palmar-plantar dysesthesia (“hand-foot syndrome”) can be seen after administration of these agents


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InternalMed_Harrison. hemorrhage likewise have no specific treatments and may be a basis to avoid this class of agents. Palmar-plantar dysesthesia (“hand-foot syndrome”) can be seen after administration of these agents (as well as some cytotoxic agents including gemcitabine and liposomal preparations of doxorubicin) and is a basis for considering dose reduction if not responsive to topical emollients and analgesics.


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InternalMed_Harrison. Protein kinase antagonists as a class have been associated with poorly predicted hepatic and cardiac toxicities (imatinib, dasatinib, sorafenib, pazopanib) or cardiac conduction deficits including prolonged QT interval (pazopanib). The occurrence of new cardiac or liver abnormalities in a patient receiving treatment with a protein kinase antagonist should lead to a consideration of the risk versus benefit and the possible relation of the agent to the new adverse event. The existence of prior cardiac dysfunction is a relative contraindication to the use of certain targeted therapies (e.g., trastuzumab), although each patient’s needs should be individualized. Chronic effects of cancer treatment are reviewed in Chap. 125. of the epidermis, which allows bacteria to gain access to subcutaneous infections in patients with Cancer tissue and permits the development of cellulitis. The artificial closing of a normally patent orifice can also predispose to infection; for


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InternalMed_Harrison. Robert W. Finberg example, obstruction of a ureter by a tumor can cause urinary tract Infections are a common cause of death and an even more common cause of morbidity in patients with a wide variety of neoplasms. Autopsy studies show that most deaths from acute leukemia and half of deaths from lymphoma are caused directly by infection. With more intensive chemotherapy, patients with solid tumors have also become more likely to die of infection. Fortunately, an evolving approach to prevention and treatment of infectious complications of cancer has decreased infection-associated mortality rates and will probably continue to do so. This accomplishment has resulted from three major steps: 1.