Pharmacology_Katzung

Pharmacology_Katzung. Capecitabine is used in the treatment of metastatic breast cancer either as a single agent or in combination with other anti-cancer agents, including docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab. It is also approved for use in the adjuvant therapy of stage III and high-risk stage II colon cancer, and used in the treatment of metastatic CRC as monotherapy or in combination with other active cytotoxic agents, including irinotecan and oxaliplatin. The capecitabine/oxaliplatin (XELOX) regimen is now widely used for the first-line treatment of metastatic CRC as well as in the adjuvant setting for patients with stage III and high-risk stage II colon cancer. The main toxicities of capecitabine include diarrhea and the hand-foot syndrome. While myelosuppression, nausea and vomiting, mucositis, and alopecia are also observed with capecitabine, their incidence is significantly less than that observed with intravenous 5-FU.


Pharmacology_Katzung

Pharmacology_Katzung. TAS-102 is an oral fluoropyrimidine analog approved in 2015 by the U.S. Food and Drug Administration (FDA) for the treatment of progressive, refractory metastatic CRC. As with 5-FU, TAS-102 is inactive in its parent form. It is made up of trifluridine, a fluorinated pyrimidine nucleoside analog, and tipiracil, a thymidine phosphorylase (TP) inhibitor, in a 1/0.5 ratio. Trifluridine is metabolized to the monophosphate form, which inhibits TS, albeit a much weaker TS inhibitor than FdUMP, and also to the triphosphate form, which is directly incorporated into DNA, leading to inhibition of DNA synthesis and function. The role of tipiracil is to inhibit TP, a key enzyme that degrades trifluridine to inactive forms. Thus, tipiracil allows for higher levels of trifluridine, which can then be activated to the active metabolite forms. The advantages of TAS-102 are that it retains clinical activity in 5-FU resistant tumors and it displays similar clinical activity in the setting of wild-type


Pharmacology_Katzung

Pharmacology_Katzung. to the active metabolite forms. The advantages of TAS-102 are that it retains clinical activity in 5-FU resistant tumors and it displays similar clinical activity in the setting of wild-type and mutant RAS colorectal cancer. The main dose-limiting toxicity is myelosuppression, with neutropenia more commonly observed than anemia and thrombocytopenia. The other adverse effects commonly observed with this oral fluoropyrimidine are GI toxicity with diarrhea and nausea/vomiting, fatigue, and anorexia.


Pharmacology_Katzung

Pharmacology_Katzung. Cytarabine (ara-C) is an S phase–specific antimetabolite that is converted by deoxycytidine kinase to the 5′-mononucleotide (ara-CMP). Ara-CMP is further metabolized to the diphosphate and triphosphate metabolites, and the ara-CTP triphosphate is thought to be the main cytotoxic metabolite. Ara-CTP competitively inhibits DNA polymerase-α and DNA polymerase-β, thereby resulting in blockade of DNA synthesis and DNA repair, respectively. This metabolite is also incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA. The cellular retention of ara-CTP appears to correlate with its lethality to malignant cells.


Pharmacology_Katzung

Pharmacology_Katzung. After intravenous administration, the drug is cleared rapidly, with most of an administered dose being deaminated to inactive forms. The stoichiometric balance between the level of activation and catabolism of cytarabine is important in determining its eventual cytotoxicity. The clinical activity of cytarabine is highly schedule-dependent and, because of its rapid degradation, it is usually administered via continuous infusion over a 5-to 7-day period. Its activity is limited exclusively to hematologic malignancies, including acute myelogenous leukemia and non-Hodgkin’s lymphoma. This agent has absolutely no activity in solid tumors. The main adverse effects associated with cytarabine therapy include myelosuppression, mucositis, nausea and vomiting, and neurotoxicity when high-dose therapy is administered.


Pharmacology_Katzung

Pharmacology_Katzung. Gemcitabine is a fluorine-substituted deoxycytidine analog that is phosphorylated initially by the enzyme deoxycytidine kinase to the monophosphate form and then by other nucleoside kinases to the diphosphate and triphosphate nucleotide forms. The antitumor effect is considered to result from several mechanisms: inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for DNA synthesis; inhibition by gemcitabine triphosphate of DNA polymerase-α and DNA polymerase-β, thereby resulting in blockade of DNA synthesis and DNA repair; and incorporation of gemcitabine triphosphate into DNA, leading to inhibition of DNA synthesis and function.


Pharmacology_Katzung

Pharmacology_Katzung. In contrast to cytarabine, which has no activity in solid tumors, gemcitabine has broad-spectrum activity against both solid tumors and hematologic malignancies. In fact, this nucleoside analog was initially approved for use in advanced pancreatic cancer and is now widely used to treat a broad range of malignancies, including NSCLC, bladder cancer, ovarian cancer, soft tissue sarcoma, and non-Hodgkin’s lymphoma. Myelosuppression in the form of neutropenia is the principal dose-limiting toxicity. Nausea and vomiting occur in 70% of patients, and a flu-like syndrome has also been observed. In rare cases, renal microangiopathy syndromes, including hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported.


Pharmacology_Katzung

Pharmacology_Katzung. 6-Mercaptopurine (6-MP) was the first of the thiopurine analogs found to have clinical efficacy in cancer therapy. This agent is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine, is used as an immunosuppressive agent (see Chapter 55). As with other thiopurines, 6-MP is inactive in its parent form and must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form the monophosphate nucleotide 6-thioinosinic acid, which in turn, inhibits several enzymes of de novo purine nucleotide synthesis (Figure 54–6). The monophosphate form is eventually metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA. Significant levels of thioguanylic acid and 6-methylmercaptopurine ribotide (MMPR) also are formed from 6-MP. These metabolites may contribute to its cytotoxic action.


Pharmacology_Katzung

Pharmacology_Katzung. 6-Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia.


Pharmacology_Katzung

Pharmacology_Katzung. 6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important difference because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50–75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol.


Pharmacology_Katzung

Pharmacology_Katzung. The thiopurines are also metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring. Patients who have a pharmacogenetic syndrome involving partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities in the form of myelosuppression and gastrointestinal toxicity with mucositis and diarrhea.


Pharmacology_Katzung

Pharmacology_Katzung. Fludarabine phosphate is rapidly dephosphorylated to 2-fluoroarabinofuranosyladenosine and then phosphorylated intra-cellularly by deoxycytidine kinase to the monophosphate, which is eventually converted to the triphosphate. Fludarabine triphosphate interferes with the processes of DNA synthesis and DNA repair through inhibition of DNA polymerase-α and DNA polymerase-β. The triphosphate form can also be directly incorporated into DNA, resulting in inhibition of DNA synthesis and function. The diphosphate metabolite of fludarabine inhibits ribonucleotide reductase, leading to inhibition of essential deoxyribonucleotide triphosphates. Finally, fludarabine induces apoptosis in susceptible cells through as yet undetermined mechanisms. This purine nucleotide analog is used mainly in the treatment of low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL). It is given parenterally, and up to 25–30% of parent drug is excreted in the urine. The main dose-limiting toxicity is


Pharmacology_Katzung

Pharmacology_Katzung. of low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL). It is given parenterally, and up to 25–30% of parent drug is excreted in the urine. The main dose-limiting toxicity is myelosuppression. This agent is a potent immunosuppressant with inhibitory effects on CD4 and CD8 T cells. Patients are at increased risk for opportunistic infections, including fungi, herpes, and Pneumocystis jiroveci pneumonia (PCP). Patients should receive PCP prophylaxis with trimethoprim-sulfamethoxazole (double strength) at least three times a week, and this should continue for up to 1 year after stopping fludarabine therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with high specificity for lymphoid cells. Inactive in its parent form, it is initially phosphorylated by deoxycytidine kinase to the monophosphate form and eventually metabolized to the triphosphate form, which can then be incorporated into DNA. The triphosphate metabolite can also interfere with DNA synthesis and DNA repair by inhibiting DNA polymerase-α and DNA polymerase-β, respectively. Cladribine is indicated for the treatment of hairy cell leukemia, with activity in other low-grade lymphoid malignancies such as CLL and low-grade non-Hodgkin’s lymphoma. It is normally administered as a single continuous 7-day infusion; under these conditions, it has a very manageable safety profile with the main toxicity consisting of transient myelosuppression. As with other purine nucleoside analogs, it has immunosuppressive effects, and a decrease in CD4 and CD8 T cells, lasting for over 1 year, is observed in patients.


Pharmacology_Katzung

Pharmacology_Katzung. The vinca alkaloids inhibit the process of tubulin polymerization, which disrupts assembly of microtubules, especially those involved in the mitotic spindle apparatus. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Thus, the vinca alkaloids work in the M phase of the cell cycle. Microtubules also play an important role in maintaining cell shape and cellular motility, and they facilitate the intracellular transport of cellular proteins. As such, inhibition of microtubule formation has important consequences that can lead to cell death. The main adverse effects are outlined in Table 54–4, and they include nausea and vomiting, bone marrow suppression, and Vinblastine is an alkaloid derived from the periwinkle plant alopecia. This agent is also a potent vesicant, and care must


Pharmacology_Katzung

Pharmacology_Katzung. Vinblastine is an alkaloid derived from the periwinkle plant alopecia. This agent is also a potent vesicant, and care must Vinca rosea. Vinblastine and other vinca alkaloids are metabo be taken in its administration. It has clinical activity in the lized by the liver P450 system, and the majority of the drug treatment of Hodgkin’s and non-Hodgkin’s lymphomas, breast is excreted in feces via the hepatobiliary system. As such, dose cancer, and germ cell cancer. modification is required in the setting of liver dysfunction. TABLE 54–4 Natural product cancer chemotherapy drugs: Clinical activity and toxicities. Drug Mechanism of Action Clinical Applications Acute Toxicity Delayed Toxicity Bleomycin Oxygen free radicals bind Hodgkin’s and non-Hodgkin’s Allergic reactions, Skin toxicity, pulmoto DNA causing singleand lymphoma, germ cell cancer, head fever, hypotension nary fibrosis, mucositis, double-strand DNA breaks and neck cancer alopecia


Pharmacology_Katzung

Pharmacology_Katzung. Daunorubicin Oxygen free radicals bind AML, ALL Nausea and vomit-Cardiotoxicity (see to DNA causing singleand ing, fever, red urine text), alopecia, double-strand DNA breaks; Doxorubicin Oxygen free radicals bind to DNA causing singleand double-strand DNA breaks; inhibits topoisomerase II; intercalates into DNA Etoposide Inhibits topoisomerase II Breast cancer, non-small cell lung Hypersensitivity Neurotoxicity, fluid retencancer, prostate cancer, gastric cancer, tion, myelosuppression head and neck cancer, ovarian cancer, Breast cancer, Hodgkin’s and non-Hodg-Nausea, red urine Cardiotoxicity (see text), kin’s lymphoma, soft tissue sarcoma, (not hematuria) alopecia, myelosuppresovarian cancer, non-small cell and small sion, stomatitis cell lung cancer, thyroid cancer, Wilms’ tumor, neuroblastoma ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia.


Pharmacology_Katzung

Pharmacology_Katzung. ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia. Vincristine is another alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action, mechanism of resistance, and clinical pharmacology are identical to those of vinblastine. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and safety profile, which results, in large part, from its higher affinity for axonal microtubules. Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children. It is also active in various hematologic malignancies such as Hodgkin’s and non-Hodgkin’s lymphomas, and multiple myeloma, and in several pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, and Wilms’ tumor.


Pharmacology_Katzung

Pharmacology_Katzung. The main dose-limiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction with orthostatic hypotension, urinary retention, and paralytic ileus or constipation, cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression occurs, it is generally milder and much less significant than with vinblastine. The other adverse effect that may develop is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).


Pharmacology_Katzung

Pharmacology_Katzung. Vinorelbine is a semisynthetic derivative of vinblastine whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. This agent has activity in NSCLC, breast cancer, and ovarian cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but other adverse effects include nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH. Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This promotion of microtubule assembly by paclitaxel results in inhibition of mitosis and cell division. As such, paclitaxel and the other taxanes work in the M phase of the cell cycle.


Pharmacology_Katzung

Pharmacology_Katzung. Paclitaxel has significant activity in a broad range of solid tumors, including ovarian, advanced breast, NSCLC and small cell lung cancer (SCLC), head and neck, esophageal, prostate, and bladder cancers, as well as AIDS-related Kaposi’s sarcoma. It is metabolized extensively by the liver P450 system, and nearly 80% of the drug is excreted in feces via the hepatobiliary route. Dose reduction is required in patients with liver dysfunction. The primary dose-limiting toxicities are listed in Table 54–4. Hypersensitivity reactions may be observed in up to 5% of patients, but the incidence is significantly reduced by premedication with dexamethasone, diphenhydramine, and an H2 blocker.


Pharmacology_Katzung

Pharmacology_Katzung. An albumin-bound paclitaxel nanoparticle formulation (Abraxane) is approved for several solid tumors, including breast cancer, pancreatic cancer, and non-small cell lung cancer. In contrast to paclitaxel, this nanoparticle formulation is not associated with hypersensitivity reactions, and premedication to prevent such reactions is not required. Moreover, this agent has significantly reduced myelosuppressive effects compared with paclitaxel, and the neurotoxicity that results appears to be more readily reversible than is typically observed with paclitaxel.


Pharmacology_Katzung

Pharmacology_Katzung. Docetaxel is a semisynthetic taxane derived from the European yew tree. Its mechanism of action, metabolism, and elimination are identical to those of paclitaxel. It is approved for use as second-line therapy in advanced breast cancer and NSCLC, and it also has major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer. Its major toxicities are listed in Table 54–4.


Pharmacology_Katzung

Pharmacology_Katzung. Cabazitaxel is a semisynthetic taxane and its mechanism of action, metabolism, and elimination are identical to those of the other taxanes. However, unlike other taxanes, cabazitaxel is a poor substrate for the multidrug resistance P-glycoprotein efflux pump and may, therefore, be useful for treating multidrug-resistant tumors. It is approved for use in combination with prednisone in the second-line therapy of hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Its major toxicities include myelosuppression, neurotoxicity, and allergic reactions.


Pharmacology_Katzung

Pharmacology_Katzung. Ixabepilone is a semisynthetic epothilone B analog, not a taxane, that functions as a microtubule inhibitor and binds directly to β-tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. As such, it is active in the M phase of the cell cycle. This agent is presently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy.


Pharmacology_Katzung

Pharmacology_Katzung. Eribulin is a synthetic analog of halichondrin B, and it inhibits microtubule function, leading to a block in the G2-M phase of the cell cycle. This agent appears to be less sensitive to the multidrug resistance-mediated P-glycoprotein efflux pump, and one of the advantages of this agent is that it has activity in drug-resistant tumors that overexpress P-glycoprotein. It is presently approved for the treatment of patients with metastatic breast cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Etoposide is a semisynthetic derivative of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum). Intravenous and oral formulations of etoposide are approved for clinical use in the USA. Oral bioavailability is about 50%, requiring oral dosage to be twice that of intravenous dosage. Up to 30–50% of an administered dose of drug is excreted in the urine, and dose reduction is required in patients with renal dysfunction. Etoposide forms a complex with topoisomerase II, the enzyme responsible for cutting and religating double stranded DNA, and DNA, leading to inhibition of the functional activity of topoisomerase II with inhibition of DNA synthesis and function. Etoposide has clinical activity in germ cell cancer, small cell and NSCLC, Hodgkin’s and non-Hodgkin’s lymphomas, and gastric cancer. Major toxicities are listed in Table 54–4.


Pharmacology_Katzung

Pharmacology_Katzung. The camptothecins are natural products derived from the Camptotheca acuminata tree originally found in China; they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA damage. Topotecan and irinotecan are the two camptothecin analogs used in clinical practice in the USA. Although they both inhibit the same molecular target, their spectrum of clinical activity is quite different.


Pharmacology_Katzung

Pharmacology_Katzung. Topotecan is indicated in the treatment of advanced ovarian cancer as second-line therapy following initial treatment with platinum-based chemotherapy. It is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and dosage must be adjusted in patients with renal impairment. Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracilbased therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin, and this combination is known as FOLFIRI.


Pharmacology_Katzung

Pharmacology_Katzung. colorectal cancer who had failed fluorouracilbased therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin, and this combination is known as FOLFIRI. Myelosuppression and diarrhea are the two most common adverse events (Table 54–4). There are two forms of diarrhea: an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2–10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases.


Pharmacology_Katzung

Pharmacology_Katzung. Liposomal irinotecan is approved in combination with 5-FU and leucovorin for the treatment of metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. The main adverse effects associated with the liposomal formulation are myelosuppression and GI toxicity with diarrhea and nausea and vomiting. Relatively little is known about the clinical pharmacology and metabolism of this liposomal formulation of irinotecan.


Pharmacology_Katzung

Pharmacology_Katzung. Screening of microbial products led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both; cause DNA strand scission; and interfere with cell replication. All of the anti-cancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin.


Pharmacology_Katzung

Pharmacology_Katzung. The anthracycline antibiotics, isolated from Streptomyces peucetius var caesius, are among the most widely used cytotoxic anti-cancer drugs. The structures of the two original anthracyclines, doxorubicin and daunorubicin, are shown below. Several other anthracycline analogs have entered clinical practice, including idarubicin, epirubicin, and mitoxantrone. The anthracyclines exert their cytotoxic action through four major mechanisms: (1) inhibition of topoisomerase II; (2) generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process; (3) high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission; and (4) binding to cellular membranes to alter fluidity and ion transport. While the precise mechanisms by which the anthracyclines exert their cytotoxic effects remain to be defined in particular tumors, the free radical mechanism is well-established to


Pharmacology_Katzung

Pharmacology_Katzung. and ion transport. While the precise mechanisms by which the anthracyclines exert their cytotoxic effects remain to be defined in particular tumors, the free radical mechanism is well-established to be the cause of the cardiotoxicity associated with the anthracyclines (Table 54–4).


Pharmacology_Katzung

Pharmacology_Katzung. R: Anthracyclines are administered via the intravenous route. They are metabolized extensively in the liver, with reduction and hydrolysis of the ring substituents. The hydroxylated metabolite is an active species, whereas the aglycone is inactive. Up to 50% of drug is eliminated in the feces via biliary excretion, and dose reduction is required in patients with liver dysfunction. Although anthracyclines are usually administered on an every-3-week schedule, alternative schedules such as low-dose weekly or 72to 96-hour continuous infusions have been shown to yield equivalent clinical efficacy with reduced toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Doxorubicin is one of the most important anti-cancer drugs in clinical practice, with major clinical activity in cancers of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas; and in several childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. It also has clinical activity in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and Hodgkin’s and non-Hodgkin’s lymphomas. It is generally used in combination with other anti-cancer agents (eg, cyclophosphamide, cisplatin, and 5-FU), and clinical activity is improved with combination regimens as opposed to single-agent therapy. Daunorubicin was the first agent in this class to be isolated, and it is still used in the treatment of acute myeloid leukemia. In contrast to doxorubicin, its efficacy in solid tumors is limited.


Pharmacology_Katzung

Pharmacology_Katzung. Daunorubicin was the first agent in this class to be isolated, and it is still used in the treatment of acute myeloid leukemia. In contrast to doxorubicin, its efficacy in solid tumors is limited. Idarubicin is a semisynthetic anthracycline glycoside analog of daunorubicin, and it is approved for use in combination with cytarabine for induction therapy of acute myeloid leukemia. When combined with cytarabine, idarubicin appears to be more active than daunorubicin in producing complete remissions and in improving survival in patients with acute myelogenous leukemia. Epirubicin is an anthracycline analog whose mechanism of action and clinical pharmacology are identical to those of all other anthracyclines. It was initially approved for use as a component of adjuvant therapy in early-stage, node-positive breast cancer but is also used in the treatment of metastatic breast cancer and gastroesophageal cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Mitoxantrone (dihydroxyanthracenedione) is an anthracene compound whose structure resembles the anthracycline ring. It binds to DNA to produce strand breakage and inhibits both DNA and RNA synthesis. It is currently used in the treatment of advanced, hormone-refractory prostate cancer and low-grade non-Hodgkin’s lymphoma. It is also indicated in breast cancer and in pediatric and adult acute myeloid leukemias. Myelosuppression with leukopenia is the dose-limiting toxicity, and mild nausea and vomiting, mucositis, and alopecia also occur. Although the drug is thought to be less cardiotoxic than doxorubicin, both acute and chronic cardiac toxicities are observed. A blue discoloration of the fingernails, sclera, and urine is observed 1–2 days after drug administration.


Pharmacology_Katzung

Pharmacology_Katzung. The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2–3 days and presents as arrhythmias and conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and in most cases is asymptomatic. The chronic form is a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of oxygen free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 400–450 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce


Pharmacology_Katzung

Pharmacology_Katzung. infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. The anthracyclines can also produce a “radiation recall reaction,” with erythema and desquamation of the skin observed at sites of prior radiation therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Mitomycin (mitomycin C) is an antibiotic isolated from Streptomyces caespitosus. It undergoes metabolic activation through an enzyme-mediated reduction to generate an alkylating agent that cross-links DNA. Hypoxic tumor stem cells of solid tumors exist in an environment conducive to reductive reactions and are more sensitive to the cytotoxic effects of mitomycin than normal cells and oxygenated tumor cells. This agent is active in all phases of the cell cycle and is the best available drug for use in combination with radiation therapy to attack hypoxic tumor cells. Its clinical use is mainly limited to the treatment of squamous cell cancer of the anus in combination with 5-FU and radiation therapy. One special application of mitomycin has been in the intravesical treatment of superficial bladder cancer. Because virtually none of the agent is absorbed, there is little to no systemic toxicity when used in this way.


Pharmacology_Katzung

Pharmacology_Katzung. The common adverse events of mitomycin are outlined in Table 54–4. Hemolytic-uremic syndrome, manifested as microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, as well as occasional instances of interstitial pneumonitis have been reported. Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. It acts by binding to DNA, which results in single-and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations. Bleomycin is a cell cycle– specific drug that causes accumulation of cells in the G2 phase of the cell cycle.


Pharmacology_Katzung

Pharmacology_Katzung. Bleomycin is indicated for the treatment of Hodgkin’s and non-Hodgkin’s lymphomas, germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva. One advantage of this agent is that it can be administered subcutaneously, intramuscularly, or intravenously. Elimination of bleomycin is mainly via renal excretion, and dose modification is recommended in patients with renal dysfunction. Pulmonary toxicity is dose-limiting for bleomycin and usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray.


Pharmacology_Katzung

Pharmacology_Katzung. Pulmonary toxicity is dose-limiting for bleomycin and usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray. The incidence of pulmonary toxicity is increased in patients older than 70 years of age, in those who receive cumulative doses greater than 400 units, in those with underlying pulmonary disease, and DRUGS in those who have received prior mediastinal or chest irradiation. A large number of anti-cancer drugs that do not fit traditional In rare cases, pulmonary toxicity can be fatal. Other toxicities are categories have been approved for clinical use; they are listed in listed in Table 54–4. Table 54–5. TABLE 54–5 Miscellaneous anti-cancer drugs: Clinical activity and toxicities. 1See text for acronyms.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 54–5 Miscellaneous anti-cancer drugs: Clinical activity and toxicities. 1See text for acronyms. Imatinib is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9:22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent also inhibits other receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), and c-kit.


Pharmacology_Katzung

Pharmacology_Katzung. Imatinib is well absorbed orally, and it is metabolized in the liver, with elimination of metabolites occurring mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior IFN-α therapy. Imatinib is also effective in the treatment of gastrointestinal stromal tumors (GIST) expressing the c-kit tyrosine kinase. The main adverse effects are listed in Table 54–5. Dasatinib is an oral inhibitor of several tyrosine kinases, including Bcr-Abl, Src, c-kit, and PDGFR-α. It differs from imatinib in that it binds to the active and inactive conformations of the Abl kinase domain and overcomes imatinib resistance resulting from mutations in the Bcr-Abl kinase. It is approved for use in CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to imatinib therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Nilotinib is a second-generation phenylamino-pyrimidine molecule that inhibits Bcr-Abl, c-kit, and PDGFR-β tyrosine kinases. It has a higher binding affinity (up to 20to 50-fold) for the Abl kinase when compared with imatinib, and it overcomes imatinib resistance resulting from Bcr-Abl mutations. It was originally approved for chronic phase and accelerated phase CML with resistance or intolerance to prior therapy that included imatinib and was recently approved as first-line therapy of chronic phase CML. Bosutinib is a potent inhibitor of the Bcr-Abl tyrosine kinase, and it retains activity in 16 of 18 imatinib-resistant Bcr-Abl mutations. However, it is not effective against T315I and V299L mutations, which reside within the ATP-binding domain of the Abl tyrosine kinase. It is currently approved for the treatment of adult patients with chronic, accelerated, or blast phase Ph chromosome– positive CML with resistance or intolerance to prior therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Ponatinib is a potent inhibitor of the Bcr-Abl tyrosine kinase, and it inhibits all known mutant forms of BCR-ABL, including the gatekeeper mutation T315I. It inhibits other kinases, including members of VEGF-R, PDGF, FGF, Flt3, TIE-2, Src family kinases, Kit, TET, and EPH. This agent is currently FDA-approved for adult patients with chronic, accelerated, or blast phase CML that is resistant or intolerant to prior TKI therapy and also approved for Ph+ ALL that is resistant or intolerant to prior TKI therapy.


Pharmacology_Katzung

Pharmacology_Katzung. Imatinib and the other TKIs are metabolized in the liver, mainly by the CYP3A4 liver microsomal enzymes and then eliminated in feces via the hepatobiliary route. It is also important to review the patient’s current list of prescription and nonprescription drugs because these agents have potential drug-drug interactions, especially with those that are also metabolized by the CYP3A4 system. In addition, patients should avoid grapefruit products, starfruit, and pomelos, as they may inhibit the metabolism of these small molecule inhibitors, leading to increased drug levels and toxicity (see Chapter 4). Cetuximab, Panitumumab, & Necitumumab


Pharmacology_Katzung

Pharmacology_Katzung. Cetuximab, Panitumumab, & Necitumumab The epidermal growth factor receptor (EGFR) is a member of the erb-B family of growth factor receptors, and it is overexpressed in a number of solid tumors, including colorectal cancer, head and neck cancer, NSCLC, and pancreatic cancer. Activation of the EGFR signaling pathway results in downstream activation of several key cellular events involved in cellular growth and proliferation, invasion and metastasis, and angiogenesis. In addition, this pathway inhibits the cytotoxic activity of various anti-cancer agents and radiation therapy, presumably through suppression of key apoptotic mechanisms, thereby leading to the development of cellular drug resistance.


Pharmacology_Katzung

Pharmacology_Katzung. Cetuximab is a chimeric monoclonal antibody directed against the extracellular domain of the EGFR, and it is presently approved for use in combination with irinotecan for metastatic colon cancer in the refractory setting or as monotherapy in patients who are deemed to be irinotecan-refractory. Because cetuximab is of the G1 isotype, its antitumor activity may also be mediated, in part, by immunologic-mediated mechanisms. There is growing evidence that cetuximab can be effectively and safely combined with irinotecanand oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer as well. Of note, the efficacy of cetuximab is restricted to only those patients whose tumors express the wild-type RAS gene, which includes both KRAS and NRAS. Combination regimens of cetuximab with cytotoxic chemotherapy may be of particular benefit in the neoadjuvant therapy of patients with liver-limited disease. Although this antibody was initially approved to be administered


Pharmacology_Katzung

Pharmacology_Katzung. cetuximab with cytotoxic chemotherapy may be of particular benefit in the neoadjuvant therapy of patients with liver-limited disease. Although this antibody was initially approved to be administered on a weekly schedule, pharmacokinetic studies have shown that an every-2-week schedule provides the same level of clinical activity as the weekly schedule. This agent is also approved for use in combination with radiation therapy in patients with locally advanced head and neck cancer. Cetuximab is well tolerated, with the main adverse effects being an acneiform skin rash, hypersensitivity infusion reaction, and hypomagnesemia. However, when cetuximab is combined with radiation therapy for head and neck cancer, there is a very low but real increased risk (1%) of sudden death, which has resulted in a black-box warning for the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Panitumumab is a fully human monoclonal antibody directed against the EGFR and works through inhibition of the EGFR signaling pathway. In contrast to cetuximab, this antibody is of the G2 isotype and, as such, would not be expected to exert any immunologic-mediated effects. Panitumumab was originally approved for patients with refractory metastatic CRC who have been treated with all other active agents. However, it is now also approved for use in combination with FOLFOX chemotherapy in the front-line treatment of metastatic CRC. As with cetuximab, this antibody is only effective in patients whose tumors express wild-type RAS. Recent clinical studies have shown that this antibody can also be effectively and safely combined with irinotecanbased chemotherapy in the second-line treatment of metastatic CRC. Acneiform skin rash and hypomagnesemia are the two main adverse effects associated with its use. Despite being a fully human antibody, infusion-related reactions can still be observed,


Pharmacology_Katzung

Pharmacology_Katzung. CRC. Acneiform skin rash and hypomagnesemia are the two main adverse effects associated with its use. Despite being a fully human antibody, infusion-related reactions can still be observed, although much less commonly than cetuximab.


Pharmacology_Katzung

Pharmacology_Katzung. Necitumumab is a fully human IgG1 monoclonal antibody directed against EGFR. Like cetuximab and panitumumab, it works through inhibition of the EGFR signaling pathway. However, as with cetuximab, necitumumab is of the G1 isotype, and as such, its antitumor activity may also be mediated, at least in part, through immunologically mediated mechanisms. It is approved for use in combination with gemcitabine and cisplatin chemotherapy for the treatment of squamous NSCLC. The main adverse effects are what have been previously described for other anti-EGFR antibodies, and both venothrombolic and arterioembolic events have also been described.


Pharmacology_Katzung

Pharmacology_Katzung. Erlotinib is a small molecule inhibitor of the tyrosine kinase domain associated with the EGFR. It is now approved as first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations and are refractory to at least one prior chemotherapy regimen. It is also approved for maintenance therapy of patients with metastatic NSCLC whose disease has not progressed after four cycles of platinum-based chemotherapy. Patients who are nonsmokers and who have a bronchoalveolar histologic subtype appear to be more responsive to these agents. In addition, erlotinib has been approved for use in combination with gemcitabine for the treatment of advanced pancreatic cancer. It is metabolized in the liver by the CYP3A4 enzyme system, and elimination is mainly hepatic with excretion in feces. Caution must be taken when using these agents with drugs that also are metabolized by the liver CYP3A4 system, such as phenytoin and warfarin, and the use of


Pharmacology_Katzung

Pharmacology_Katzung. mainly hepatic with excretion in feces. Caution must be taken when using these agents with drugs that also are metabolized by the liver CYP3A4 system, such as phenytoin and warfarin, and the use of grapefruit products should be avoided. An acneiform skin rash, diarrhea, and anorexia and fatigue are the most common adverse effects observed with these small molecules (Table 54–5).


Pharmacology_Katzung

Pharmacology_Katzung. Afatinib is a small molecule inhibitor of the tyrosine kinase domains associated with EGFR, HER2 and HER4, and causes inhibition of downstream ErbB signaling. It is approved for the first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 substitution mutations. The toxicities associated with this agent are similar to those seen with erlotinib. Osimertinib is a small molecule inhibitor approved in 2015 for the treatment of metastatic EGFR T790M mutant NSCLC following progression on or after EGFR tyrosine kinase inhibitor therapy. In addition to targeting the T790M mutant, this agent targets the L858R and exon 19 EGFR mutations. The adverse effect profile is similar to erlotinib and afatinib, but unique cardiac toxicities are associated with this agent, including QTc prolongation and cardiomyopathy. Bevacizumab, Ziv-Aflibercept, Ramucirumab, Sorafenib, Sunitinib, & Pazopanib


Pharmacology_Katzung

Pharmacology_Katzung. Bevacizumab, Ziv-Aflibercept, Ramucirumab, Sorafenib, Sunitinib, & Pazopanib Vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors. The growth of both primary and metastatic solid tumors requires an intact vasculature; thus the VEGF signaling pathway represents an attractive target for chemotherapy. Several approaches have been taken to inhibit VEGF signaling; they include inhibition of VEGF interactions with its receptor by targeting either the VEGF ligand with antibodies or soluble chimeric decoy receptors, or by direct inhibition of VEGF receptor–associated tyrosine kinase activity by small molecule inhibitors.


Pharmacology_Katzung

Pharmacology_Katzung. Bevacizumab is a recombinant humanized monoclonal antibody that targets all forms of VEGF-A. This antibody binds to and prevents VEGF-A from interacting with the target VEGF receptors. Bevacizumab can be safely and effectively combined with 5-FU-, irinotecan-, and oxaliplatin-based chemotherapy in the treatment of metastatic colorectal cancer. Bevacizumab is FDA approved as a first-line treatment for metastatic colorectal cancer in combination with any intravenous fluoropyrimidinecontaining regimen and is now also approved in combination with chemotherapy for metastatic NSCLC and breast cancer. One potential advantage of this antibody is that it does not appear to exacerbate the toxicities typically observed with cytotoxic chemotherapy. The main safety concerns associated with bevacizumab include hypertension, an increased incidence of arterial thromboembolic events (transient ischemic attack, stroke, angina, and myocardial infarction), wound healing complications, gastrointestinal


Pharmacology_Katzung

Pharmacology_Katzung. include hypertension, an increased incidence of arterial thromboembolic events (transient ischemic attack, stroke, angina, and myocardial infarction), wound healing complications, gastrointestinal perforations, and proteinuria.


Pharmacology_Katzung

Pharmacology_Katzung. Ziv-aflibercept is a recombinant fusion protein made up of portions of the extracellular domains of human VEGF receptors (VEGFR) 1 and 2 fused to the Fc portion of the human IgG1 molecule. This molecule serves as a soluble receptor to VEGFA, VEGF-B, and placental growth factor (PlGF), and it binds with significantly higher affinity to VEGF-A than bevacizumab. Presumably, binding of the VEGF ligands prevents their subsequent interactions with the target VEGF receptors, which then results in inhibition of downstream VEGFR signaling. This agent is FDA-approved in combination with the FOLFIRI regimen for patients with metastatic colorectal cancer that has progressed on oxaliplatin-based chemotherapy. The main adverse effects are similar to what has been observed with bevacizumab.


Pharmacology_Katzung

Pharmacology_Katzung. Ramucirumab is an IgG1 antibody that targets the VEGFR2 receptor. This agent inhibits binding of the VEGF ligands, VEGF-A, VEGF-C, and VEGF-D, to the target VEGF-R2 receptor, which then results in inhibition of downstream VEGFR signaling. This agent is now FDA-approved for advanced gastric or gastroesophageal junction adenocarcinoma, metastatic NSCLC, and metastatic CRC. The main adverse events are similar to those observed with bevacizumab and other anti-VEGF inhibitors. Sorafenib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), especially VEGF-R2 and VEGF-R3, platelet-derived growth factor-β (PDGFR-β), and raf kinase. It was initially approved for advanced renal cell cancer and is also approved for advanced hepatocellular cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Sunitinib is similar to sorafenib in that it inhibits multiple RTKs, although the specific types are somewhat different. They include PDGFR-α and PDGFR-β, VEGF-R1, VEGF-R2, VEGFR3, and c-kit. It is approved for the treatment of advanced renal cell cancer and for the treatment of gastrointestinal stromal tumors after disease progression on or with intolerance to imatinib. Pazopanib is a small molecule that inhibits multiple RTKs, especially VEGF-R2 and VEGF-R3, PDGFR-β, and raf kinase. This oral agent is approved for the treatment of advanced renal cell cancer.


Pharmacology_Katzung

Pharmacology_Katzung. Pazopanib is a small molecule that inhibits multiple RTKs, especially VEGF-R2 and VEGF-R3, PDGFR-β, and raf kinase. This oral agent is approved for the treatment of advanced renal cell cancer. Sorafenib, sunitinib, and pazopanib are metabolized in the liver by the CYP3A4 system, and elimination is primarily hepatic with excretion in feces. Therefore, each of these agents has potential interactions with drugs that are also metabolized by the CYP3A4 system, especially warfarin. In addition, patients should avoid grapefruit products, starfruit, pomelos, and St. John’s Wort, as they may alter the metabolism of these agents. Hypertension, bleeding complications, and fatigue are the most common adverse effects seen with these drugs. With respect to sorafenib, skin rash and the hand-foot syndrome are observed in up to 30–50% of patients. For sunitinib, there is also an increased risk of cardiac dysfunction, which in some cases can lead to congestive heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. The use of specific cytotoxic and biologic agents for each of the main cancers is discussed in the following sections.


Pharmacology_Katzung

Pharmacology_Katzung. Acute lymphoblastic leukemia (ALL) is the main form of leukemia in childhood, and it is the most common form of cancer in children. Children with this disease now have a relatively good prognosis. A subset of patients with neoplastic lymphocytes expressing surface antigenic features of T lymphocytes has a poor prognosis (see Chapter 55). A cytoplasmic enzyme expressed by normal thymocytes, terminal deoxycytidyl transferase (terminal transferase), is also expressed in many cases of ALL. T-cell ALL also expresses high levels of the enzyme adenosine deaminase (ADA). This led to interest in the use of the ADA inhibitor pentostatin (deoxycoformycin) for treatment of such T-cell cases. Until 1948, the median length of survival in ALL was 3 months. With the advent of methotrexate, the length of survival was greatly increased. Subsequently, corticosteroids, 6-mercaptopurine, cyclophosphamide, vincristine, daunorubicin, and asparaginase all have been found to be active against this disease. A


Pharmacology_Katzung

Pharmacology_Katzung. survival was greatly increased. Subsequently, corticosteroids, 6-mercaptopurine, cyclophosphamide, vincristine, daunorubicin, and asparaginase all have been found to be active against this disease. A combination of vincristine and prednisone plus other agents is currently used to induce remission. More than 90% of children enter complete remission with this therapy with only minimal toxicity. However, circulating leukemic cells often migrate to sanctuary sites located in the brain and testes. The value of prophylactic intrathecal methotrexate therapy for prevention of central nervous system leukemia (a major mechanism of relapse) has been clearly demonstrated. Intrathecal therapy with methotrexate should therefore be considered as a standard component of the induction regimen for children with ALL.


Pharmacology_Katzung

Pharmacology_Katzung. Acute myelogenous leukemia (AML) is the most common leukemia in adults. The single most active agent for AML is cytarabine; however, it is best used in combination with an anthracycline, which leads to complete remissions in about 70% of patients. While there are several anthracyclines that can be effectively combined with cytarabine, idarubicin is preferred.


Pharmacology_Katzung

Pharmacology_Katzung. Patients often require intensive supportive care during the period of induction chemotherapy. Such care includes platelet transfusions to prevent bleeding, the granulocyte colony-stimulating factor filgrastim to shorten periods of neutropenia, and antibiotics to combat infections. Younger patients (eg, age < 55) who are in complete remission and have an HLA-matched donor are candidates for allogeneic bone marrow transplantation. The transplant procedure is preceded by high-dose chemotherapy and total body irradiation followed by immunosuppression. This approach may cure up to 35–40% of eligible patients. Patients over age 60 respond less well to chemotherapy, primarily because their tolerance for aggressive therapy and resistance to infection are lower. Once remission of AML is achieved, consolidation chemotherapy is required to maintain a durable remission and to induce cure.


Pharmacology_Katzung

Pharmacology_Katzung. Chronic myelogenous leukemia (CML) arises from a chromosomally abnormal hematopoietic stem cell in which a balanced translocation between the long arms of chromosomes 9 and 22, t(9:22), is observed in 90–95% of cases. This translocation results in constitutive expression of the Bcr-Abl fusion oncoprotein with a molecular weight of 210 kDa. The clinical symptoms and course are related to the white blood cell count and its rate of increase. Most patients with white cell counts greater than 50,000/μL should be treated. The goals of treatment are to reduce the granulocytes to normal levels, to raise the hemoglobin concentration to normal, and to relieve disease-related symptoms. The tyrosine kinase inhibitor imatinib is considered as standard first-line therapy in previously untreated patients with chronic phase CML. Nearly all patients treated with imatinib exhibit a complete hematologic response, and up to 40–50% of patients show a complete cytogenetic response. As described previously,


Pharmacology_Katzung

Pharmacology_Katzung. with chronic phase CML. Nearly all patients treated with imatinib exhibit a complete hematologic response, and up to 40–50% of patients show a complete cytogenetic response. As described previously, this drug is generally well tolerated and is associated with relatively minor adverse effects. Initially, dasatinib and nilotinib were approved for patients who were intolerant or resistant to imatinib; each shows clinical activity, and both are now also indicated as first-line treatment of chronic phase CML. In addition to these tyrosine kinase inhibitors, other treatment options include IFN-α, busulfan, other oral alkylating agents, and hydroxyurea.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with early-stage chronic lymphocytic leukemia (CLL) have a relatively good prognosis, and therapy has not changed the course of the disease. However, in the setting of high-risk disease or in the presence of disease-related symptoms, treatment is indicated.


Pharmacology_Katzung

Pharmacology_Katzung. Chlorambucil and cyclophosphamide are the two most widely used alkylating agents for this disease. Chlorambucil is frequently combined with prednisone, although there is no clear evidence that the combination yields better response rates or survival compared with chlorambucil alone. In most cases, cyclophosphamide is combined with vincristine and prednisone (COP), or it can also be given with these same drugs along with doxorubicin (CHOP). Bendamustine is the newest alkylating agent to be approved for use in this disease, either as monotherapy or in combination with prednisone. The purine nucleoside analog fludarabine also is effective in treating CLL. This agent can be given alone, in combination with cyclophosphamide and with mitoxantrone and dexamethasone, or combined with rituximab. Monoclonal antibody targeted therapies are being widely used in CLL, especially in relapsed or refractory disease. Rituximab is an anti-CD20 antibody that has documented clinical activity in this


Pharmacology_Katzung

Pharmacology_Katzung. Monoclonal antibody targeted therapies are being widely used in CLL, especially in relapsed or refractory disease. Rituximab is an anti-CD20 antibody that has documented clinical activity in this setting. This chimeric antibody appears to enhance the antitumor effects of cytotoxic chemotherapy and is also effective in settings in which resistance to chemotherapy has developed. Ofatumumab is a fully human IgG1 antibody that binds to a different CD20 epitope than rituximab. Of note, it maintains activity in rituximab-resistant tumors, and it is presently approved for CLL that is refractory to fludarabine and alemtuzumab therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The treatment of Hodgkin’s lymphoma has undergone dramatic evolution over the last 40 years. This lymphoma is now widely recognized as a B-cell neoplasm in which the malignant Reed-Sternberg cells have rearranged VH genes. In addition, the Epstein-Barr virus genome has been identified in up to 80% of tumor specimens.


Pharmacology_Katzung

Pharmacology_Katzung. Complete staging evaluation is required before a definitive treatment plan can be made. For patients with stage I and stage IIA disease, there has been a significant change in the treatment approach. Initially, these patients were treated with extended-field radiation therapy. However, given the well-documented late effects of radiation therapy, which include hypothyroidism, an increased risk of secondary cancers, and coronary artery disease, combined-modality therapy with a brief course of combination chemotherapy and involved field radiation therapy is now the recommended approach. The main advance for patients with advanced stage III and IV Hodgkin’s lymphoma came with the development of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy in the 1960s. This regimen resulted initially in high complete response rates, on the order of 80–90%, with cures in up to 60% of patients. More recently, the anthracycline-containing regimen termed ABVD (doxorubicin,


Pharmacology_Katzung

Pharmacology_Katzung. regimen resulted initially in high complete response rates, on the order of 80–90%, with cures in up to 60% of patients. More recently, the anthracycline-containing regimen termed ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been shown to be more effective and less toxic than MOPP, especially with regard to the incidence of infertility and secondary malignancies. In general, four cycles of ABVD are given to patients. An alternative regimen, termed Stanford V, utilizes a 12-week course of combination chemotherapy (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone), followed by involved radiation therapy.


Pharmacology_Katzung

Pharmacology_Katzung. With all of these regimens, over 80% of previously untreated patients with advanced Hodgkin’s lymphoma (stages III and IV) are expected to go into complete remission, with disappearance of all disease-related symptoms and objective evidence of disease. In general, approximately 50–60% of all patients with Hodgkin’s lymphoma are cured of their disease. Non-Hodgkin’s lymphoma is a heterogeneous disease, and the clinical characteristics of non-Hodgkin’s lymphoma subsets are related to the underlying histopathologic features and the extent of disease involvement. In general, the nodular (or follicular) lymphomas have a far better prognosis, with a median survival up to 7 years, compared with the diffuse lymphomas, which have a median survival of about 1–2 years.


Pharmacology_Katzung

Pharmacology_Katzung. Combination chemotherapy is the treatment standard for patients with diffuse non-Hodgkin’s lymphoma. The anthracycline-containing regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been considered the best treatment in terms of initial therapy. Randomized phase III clinical studies now have shown that the combination of CHOP with rituximab results in improved response rates, disease-free survival, and overall survival compared with CHOP chemotherapy alone.


Pharmacology_Katzung

Pharmacology_Katzung. The nodular follicular lymphomas are low-grade, relatively slow-growing tumors that tend to present in an advanced stage and are usually confined to lymph nodes, bone marrow, and spleen. This form of non-Hodgkin’s lymphoma, when presenting at an advanced stage, is considered incurable, and treatment is generally palliative. To date, there is no evidence that immediate treatment with combination chemotherapy offers clinical benefit over close observation and “watchful waiting” with initiation of chemotherapy at the onset of disease symptoms. This plasma cell malignancy is one of the models of neoplastic disease in humans, as it arises from a single tumor stem cell. Moreover, the tumor cells produce a marker protein (myeloma immunoglobulin) that allows the total body burden of tumor cells to be quantified. Multiple myeloma principally involves the bone marrow and bone, causing bone pain, lytic lesions, bone fractures, and anemia as well as an increased susceptibility to infection.


Pharmacology_Katzung

Pharmacology_Katzung. Most patients with multiple myeloma are symptomatic at the time of initial diagnosis and require treatment with cytotoxic chemotherapy. Treatment with the combination of the alkylating agent melphalan and prednisone (MP protocol) has been a standard regimen for nearly 30 years. About 40% of patients respond to the MP combination, and the median duration of remission is 2–2.5 years. In patients who are considered candidates for high-dose therapy with stem cell transplantation, melphalan and other alkylating agents are to be avoided, as they can affect the success of stem cell harvesting.


Pharmacology_Katzung

Pharmacology_Katzung. Thalidomide is a well-established agent for treating refractory or relapsed disease, and about 30% of patients will achieve a response to this therapy. More recently, thalidomide has been used in combination with dexamethasone, and response rates approaching 65% have been observed. Studies are now under way to directly compare the combination of vincristine, doxorubicin, and dexamethasone (VAD protocol) with the combination of thalidomide and dexamethasone. In some patients, especially those with poor performance status, single-agent pulse dexamethasone administered on a weekly basis can be effective in palliating symptoms. Lenalidomide and pomalidomide are two immunomodulatory analogs (IMiDs) of thalidomide. Lenalidomide is approved in combination with dexamethasone for multiple myeloma patients who have received at least one prior therapy, and clinical data show that this combination is effective as first-line therapy. Pomalidomide is the most recent IMiD to receive approval, and


Pharmacology_Katzung

Pharmacology_Katzung. patients who have received at least one prior therapy, and clinical data show that this combination is effective as first-line therapy. Pomalidomide is the most recent IMiD to receive approval, and this drug may be able to overcome resistance to thalidomide and lenalidomide. The side-effect profiles of these IMiDs appear to be similar, although neurotoxicity is observed more commonly with thalidomide, somewhat less often with pomalidomide, and rarely with lenalidomide.


Pharmacology_Katzung

Pharmacology_Katzung. Bortezomib was first approved for use in relapsing or refractory multiple myeloma and is now widely used as first-line therapy. This agent is thought to exert its main cytotoxic effects through inhibition of the 26S proteosome, resulting in downregulation of the nuclear factor kappa B (NF-κB) signaling pathway, which is thought to be a major signaling pathway for this disease. Of note, inhibition of NF-κB has also been shown to restore chemosensitivity. One potential advantage of bortezomib is that it can be administered by the intravenous or subcutaneous route. Carfilzomib is an epoxyketone 26S proteosome inhibitor that is approved for patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent. This agent is important as it is able to overcome resistance to bortezomib, and preclinical and clinical studies suggest that it has broad-spectrum activity in hematologic malignancies and solid tumors. Ixazomib is the


Pharmacology_Katzung

Pharmacology_Katzung. as it is able to overcome resistance to bortezomib, and preclinical and clinical studies suggest that it has broad-spectrum activity in hematologic malignancies and solid tumors. Ixazomib is the newest proteosome inhibitor to be approved in multiple myeloma, and in contrast to the other proteosome inhibitors, it is orally administered with good oral bioavailability. This agent can cause peripheral sensory neuropathy, but it is also associated with GI toxicity in the form of diarrhea and nausea and vomiting, thrombocytopenia, and hepatotoxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The management of primary breast cancer has undergone a remarkable evolution as a result of major efforts at early diagnosis (through encouragement of self-examination as well as through the use of cancer detection centers) and the implementation of combined modality approaches incorporating systemic chemotherapy as an adjuvant to surgery and radiation therapy. Women with stage I disease (small primary tumors and negative axillary lymph node dissections) are currently treated with surgery alone, and they have an 80% chance of cure.


Pharmacology_Katzung

Pharmacology_Katzung. Women with node-positive disease have a high risk of both local and systemic recurrence. Thus, lymph node status directly indicates the risk of occult distant micrometastasis. In this situation, postoperative use of systemic adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF protocol) or of fluorouracil, doxorubicin, and cyclophosphamide (FAC) has been shown to significantly reduce the relapse rate and prolong survival. Alternative regimens with equivalent clinical benefit include four cycles of doxorubicin and cyclophosphamide and six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Each of these chemotherapy regimens has benefited women with stage II breast cancer with one to three involved lymph nodes. Women with four or more involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premenopausal women who have been treated


Pharmacology_Katzung

Pharmacology_Katzung. involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premenopausal women who have been treated aggressively with multiagent combination chemotherapy. The results from three randomized clinical trials clearly show that the addition of trastuzumab, a monoclonal antibody directed against the HER-2/neu receptor, to anthracyclineand taxane-containing adjuvant chemotherapy benefits women with HER-2-overexpressing breast cancer with respect to disease-free and overall survival.


Pharmacology_Katzung

Pharmacology_Katzung. Breast cancer was the first neoplasm shown to be responsive to hormonal manipulation. Tamoxifen is beneficial in postmenopausal women when used alone or in combination with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection. Longer durations of tamoxifen therapy do not appear to offer additional clinical benefit. Postmenopausal women who complete 5 years of tamoxifen therapy should be placed on an aromatase inhibitor such as anastrozole for at least 2.5 years, although the optimal duration is unknown. In women who have completed 2–3 years of tamoxifen therapy, treatment with an aromatase inhibitor for a total of 5 years of hormonal therapy is now recommended (see Chapter 40).


Pharmacology_Katzung

Pharmacology_Katzung. Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35–50% over 15 years), this risk can be further reduced with adjuvant therapy.


Pharmacology_Katzung

Pharmacology_Katzung. The approach to women with advanced breast cancer remains a major challenge, as current treatment options are only palliative. Combination chemotherapy, endocrine therapy, or a combination of both results in overall response rates of 40–50%, but only a 10–20% complete response rate. Breast cancers expressing estrogen receptors (ER) or progesterone receptors (PR) retain the intrinsic hormonal sensitivities of the normal breast—including the growth-stimulatory response to ovarian, adrenal, and pituitary hormones. Patients who show improvement with hormonal ablative procedures also respond to the addition of tamoxifen. The aromatase inhibitors anastrozole and letrozole are now approved as first-line therapy in women with advanced breast cancer whose tumors are hormone receptor–positive. In addition, these agents and exemestane are approved as second-line therapy following treatment with tamoxifen.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with significant involvement of the lung, liver, or brain and those with rapidly progressive disease rarely benefit from hormonal maneuvers, and initial systemic chemotherapy is indicated in such cases. For the 25–30% of breast cancer patients whose tumors express the HER-2/neu cell surface receptor, trastuzumab, is available for therapeutic use alone or in combination with cytotoxic chemotherapy. Other agents that target HER-2/neu signaling include pertuzumab, ado-trastuzumab emtansine, and the small molecule lapatinib. Pertuzumab is a humanized IgG1 antibody that targets a different epitope on the HER-2/neu receptor than trastuzumab, and this antibody inhibits heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. This drug is used in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer in patients who have not previously received anti-HER chemotherapy for metastatic disease. Ado-trastuzumab emtansine is an


Pharmacology_Katzung

Pharmacology_Katzung. with trastuzumab and docetaxel for HER2-positive metastatic breast cancer in patients who have not previously received anti-HER chemotherapy for metastatic disease. Ado-trastuzumab emtansine is an antibody-drug conjugate composed of trastuzumab and the small molecule microtubule inhibitor DM1; it is approved for women with HER2-positive metastatic breast cancer who have received prior therapy with trastuzumab and taxane-based chemotherapy. Finally, lapatinib is a small molecule inhibitor of the tyrosine kinases associated with EGFR (ErbB1) and HER2 (ErbB2), resulting in inhibition of downstream signaling. This agent is used in combination with the oral fluoropyrimidine capecitabine for metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy with an anthracycline, a taxane, and trastuzumab.


Pharmacology_Katzung

Pharmacology_Katzung. About 50–60% of patients with metastatic disease respond to initial chemotherapy. A broad range of anti-cancer agents have activity in this disease, including the anthracyclines (doxorubicin, mitoxantrone, and epirubicin) and the taxanes (docetaxel, paclitaxel, and albumin-bound paclitaxel), along with the microtubule inhibitor ixabepilone, navelbine, capecitabine, gemcitabine, cyclophosphamide, methotrexate, and cisplatin. The anthracyclines and the taxanes are two of the most active classes of cytotoxic drugs. Combination chemotherapy has been found to induce higher and more durable remissions in up to 50–80% of patients, and anthracycline-containing regimens are now considered the standard of care in first-line therapy. With most combination regimens, partial remissions have a median duration of about 10 months and complete remissions have a duration of about 15 months. Unfortunately, only 10–20% of patients achieve complete remissions with any of these regimens, and as noted,


Pharmacology_Katzung

Pharmacology_Katzung. duration of about 10 months and complete remissions have a duration of about 15 months. Unfortunately, only 10–20% of patients achieve complete remissions with any of these regimens, and as noted, complete remissions are usually not long-lasting.


Pharmacology_Katzung

Pharmacology_Katzung. Prostate cancer was the second cancer shown to be responsive to hormonal manipulation. The treatment of choice for patients with metastatic prostate cancer is elimination of testosterone production by the testes through either surgical or chemical castration. Bilateral orchiectomy or estrogen therapy in the form of diethylstilbestrol was previously used as first-line therapy. Presently, the use of luteinizing hormone-releasing hormone (LHRH) agonists—including leuprolide and goserelin agonists, alone or in combination with an antiandrogen (eg, flutamide, bicalutamide, or nilutamide)— is the preferred approach (see Chapter 40). There appears to be no survival advantage of total androgen blockade using a combination of LHRH agonist and antiandrogen agent compared with single-agent therapy. Abiraterone, an inhibitor of steroid synthesis (see Chapter 39), has recently been approved. Hormonal treatment reduces symptoms—especially bone pain—in 70–80% of patients and may cause a significant


Pharmacology_Katzung

Pharmacology_Katzung. Abiraterone, an inhibitor of steroid synthesis (see Chapter 39), has recently been approved. Hormonal treatment reduces symptoms—especially bone pain—in 70–80% of patients and may cause a significant reduction in the prostate-specific antigen (PSA) level, which is now widely accepted as a surrogate marker for response to treatment in prostate cancer. Although initial hormonal manipulation is able to control symptoms for up to 2 years, patients usually develop progressive disease. Second-line hormonal therapies include aminoglutethimide plus hydrocortisone, the antifungal agent ketoconazole plus hydrocortisone, or hydrocortisone alone.


Pharmacology_Katzung

Pharmacology_Katzung. Unfortunately, nearly all patients with advanced prostate cancer eventually become refractory to hormone therapy. A regimen of mitoxantrone and prednisone is approved in patients with hormone-refractory prostate cancer because it provides effective palliation in those who experience significant bone pain. Estramustine is an antimicrotubule agent that produces an almost 20% response rate as a single agent. However, when used in combination with either etoposide or a taxane such as docetaxel or paclitaxel, response rates are more than doubled to 40–50%. The combination of docetaxel and prednisone was recently shown to confer survival advantage when compared with the mitoxantroneprednisone regimen, and this combination has now become the standard of care for hormone-refractory prostate cancer.


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Pharmacology_Katzung. Colorectal cancer (CRC) is the most common type of gastrointestinal malignancy. Nearly 150,000 new cases are diagnosed each year in the USA; worldwide, nearly 1.2 million cases are diagnosed annually. At the time of initial presentation, only about 40–45% of patients are potentially curable with surgery. Patients presenting with high-risk stage II disease and stage III disease are candidates for adjuvant chemotherapy with an oxaliplatin-based regimen in combination with 5-FU plus leucovorin (FOLFOX) or with oral capecitabine (XELOX) and are generally treated for 6 months following surgical resection. Treatment with this combination regimen reduces the recurrence rate after surgery by 35% and clearly improves overall patient survival compared with surgery alone.


Pharmacology_Katzung

Pharmacology_Katzung. Significant advances have been made over the past 10 years with respect to treatment of metastatic CRC. Five active cytotoxic agents have been approved during this time period—5-FU, the oral fluoropyrimidine analogs capecitabine and TAS-102, oxaliplatin, and irinotecan. In addition, 5 novel biologic agents and one small molecule inhibitor have been approved, including the anti-VEGF antibody bevacizumab; the recombinant fusion protein ziv-aflibercept, which targets VEGF-A, VEGF-B, and PlGF; the anti-VEGF-R2 antibody ramucirumab, which inhibits binding of the VEGF ligands VEGF-A, VEGF-C, and VEGF-D; the two anti-EGFR antibodies cetuximab and panitumumab; and the small molecule TKI inhibitor regorafenib. In general, a fluoropyrimidine—either intravenous 5-FU or oral capecitabine—serves as the main foundation of cytotoxic chemotherapy regimens. Recent clinical studies have shown that in tumors with wild-type KRAS and NRAS, FOLFOX/FOLFIRI regimens in combination with the anti-VEGF antibody


Pharmacology_Katzung

Pharmacology_Katzung. main foundation of cytotoxic chemotherapy regimens. Recent clinical studies have shown that in tumors with wild-type KRAS and NRAS, FOLFOX/FOLFIRI regimens in combination with the anti-VEGF antibody bevacizumab or with the anti-EGFR antibody cetuximab or panitumumab result in significantly improved clinical efficacy with no worsening of the toxicities normally observed with chemotherapy. In order for patients to derive maximal benefit, they should be treated with each of these active agents in a continuum of care approach. Regorafenib and TAS102 are approved for the chemo-refractory disease setting, but unfortunately, each drug is associated with significant toxicities and only limited clinical efficacy with very low overall response rates; median progression-free survival is about 2-months. Given all of the available treatment regimens, median overall survival for metastatic CRC is now in the 28to 30-month range and, in some cases, approaches or even exceeds 3 years.


Pharmacology_Katzung

Pharmacology_Katzung. The incidence of gastric cancer, esophageal cancer, and pancreatic cancer is much lower than for CRC, but these malignancies tend to be more aggressive and result in greater tumor-related symptoms. In most cases, they cannot be completely resected surgically, as most patients present with either locally advanced or metastatic disease at the time of their initial diagnosis. 5-FU-based chemotherapy, using either intravenous 5-FU or oral capecitabine, is generally considered the main backbone for regimens targeting gastroesophageal cancers. In addition, cisplatin-based regimens in combination with either irinotecan or one of the taxanes (paclitaxel or docetaxel) also exhibit clinical activity. Response rates in the 40–50% range are now being reported. The addition of the biologic agent trastuzumab to cisplatin-containing chemotherapy regimens provides significant clinical benefit in metastatic gastric cancer patients whose tumors overexpress the HER-2/neu receptor. At present, the


Pharmacology_Katzung

Pharmacology_Katzung. trastuzumab to cisplatin-containing chemotherapy regimens provides significant clinical benefit in metastatic gastric cancer patients whose tumors overexpress the HER-2/neu receptor. At present, the optimal fluoropyrimidine backbone has not been established, and either infused 5-FU or oral capecitabine can be combined with cisplatin plus trastuzumab. For second-line therapy, the combination of ramucirumab plus paclitaxel is recommended for patients with a good performance status and favorable comorbidity profile. In patients who are unable to tolerate more intensive therapy, single-agent ramucirumab or paclitaxel monotherapy are more appropriate treatment options.


Pharmacology_Katzung

Pharmacology_Katzung. Although gemcitabine is approved for use as a single agent in metastatic pancreatic cancer, the overall response rate is low at less than 10%, with complete responses being exceedingly rare. Intense efforts have focused on incorporating gemcitabine into various combination regimens, and currently, the most commonly used regimen for the first-line treatment of metastatic pancreatic cancer is gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel [Abraxane]). In patients who are able to tolerate a more aggressive approach, the FOLFIRINOX regimen, which includes intravenous 5-FU, irinotecan, and oxaliplatin, has become a widely used therapy. Single-agent irinotecan or liposomal irinotecan in combination with intravenous 5-FU are appropriate treatment options in the second-line setting. In patients with early-stage pancreatic cancer who have undergone successful surgical resection, adjuvant chemotherapy with either single-agent gemcitabine or 5-FU/leucovorin is


Pharmacology_Katzung

Pharmacology_Katzung. second-line setting. In patients with early-stage pancreatic cancer who have undergone successful surgical resection, adjuvant chemotherapy with either single-agent gemcitabine or 5-FU/leucovorin is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Hepatocellular cancer (HCC) has been a relatively difficult tumor to treat as it frequently occurs in the context of chronic liver disease and cirrhosis. It is usually diagnosed late in the course of chronic liver disease, and a large majority of patients have underlying poor liver function and only limited hepatic reserve. In general, HCC is considered to be a chemotherapy-resistant disease, and palliative chemotherapy is usually not recommended as first-line therapy in patients with unresectable or advanced HCC. Single-agent sorafenib therapy is currently approved for advanced or unresectable HCC, and in patients who have progressed on front-line sorafenib therapy, the small molecule tyrosine kinase inhibitor regorafenib is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Lung cancer is divided into two main histopathologic subtypes, non-small cell and small cell. Non-small cell lung cancer (NSCLC) makes up about 75–80% of all cases of lung cancer, and this group includes adenocarcinoma, squamous cell cancer, and large cell cancer, while small cell lung cancer (SCLC) makes up the remaining 20–25%. When NSCLC is diagnosed in an advanced stage with metastatic disease, the prognosis is extremely poor, with a median survival of about 8 months. It is clear that prevention (primarily through avoidance of cigarette smoking) and early detection remain the most important means of control. When diagnosed at an early stage, surgical resection results in patient cure. Moreover, recent studies have shown that adjuvant platinum-based chemotherapy provides a survival benefit in patients with pathologic stage IB, II, and IIIA disease. However, in most cases, distant metastases have occurred at the time of diagnosis. In certain instances, radiation therapy can be


Pharmacology_Katzung

Pharmacology_Katzung. benefit in patients with pathologic stage IB, II, and IIIA disease. However, in most cases, distant metastases have occurred at the time of diagnosis. In certain instances, radiation therapy can be offered for palliation of pain, airway obstruction, or bleeding and to treat patients whose performance status would not allow for more aggressive treatments.


Pharmacology_Katzung

Pharmacology_Katzung. In patients with advanced disease, systemic chemotherapy is generally recommended. Combination regimens that include a platinum agent (“platinum doublets”) appear superior to non-platinum doublets, and either cisplatin or carboplatin are appropriate platinum agents for such regimens. For the second drug, paclitaxel and vinorelbine appear to have activity independent of histology, while the antifolate pemetrexed should be used for non-squamous cell cancer, and gemcitabine for squamous cell cancer. For patients with good performance status and those with non-squamous histology, the combination of the anti-VEGF antibody bevacizumab with carboplatin and paclitaxel is a standard treatment option. In patients deemed not to be appropriate candidates for bevacizumab therapy and those with squamous cell histology, a platinum-based chemotherapy regimen in combination with the anti-EGFR antibody cetuximab is a reasonable treatment strategy. Maintenance chemotherapy with pemetrexed is now used in


Pharmacology_Katzung

Pharmacology_Katzung. cell histology, a platinum-based chemotherapy regimen in combination with the anti-EGFR antibody cetuximab is a reasonable treatment strategy. Maintenance chemotherapy with pemetrexed is now used in patients with non-squamous NSCLC whose disease has remained stable after four cycles of platinum-based first-line chemotherapy.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with advanced NSCLC should have molecular testing of their tumor. Patients whose tumors contain an actionable mutation should then receive a targeted therapy. For example, first-line therapy with erlotinib significantly improves outcomes in advanced NSCLC patients with sensitizing EGFR mutations, which include exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib is a small molecule inhibitor of EGFR, HER2, and HER4, and it is approved for the first-line treatment of metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 mutations. Osimertinib is approved for the treatment of metastatic EGFR T790M-mutant NSCLC following progression on or after EGFR TKI therapy. This small molecule is important as it is able to overcome the resistance that arises from the emergence of the T790M gatekeeper mutation either de novo or following previous EGFR TKI therapy. In NSCLC that is ALK-positive, three new small molecules have been developed: crizotinib,


Pharmacology_Katzung

Pharmacology_Katzung. from the emergence of the T790M gatekeeper mutation either de novo or following previous EGFR TKI therapy. In NSCLC that is ALK-positive, three new small molecules have been developed: crizotinib, ceritinib, and alectinib. Crizotinib is the first-generation ALK inhibitor, while ceritinib and alectinib have clinical efficacy in patients whose disease has progressed on or who have become intolerant to crizotinib.


Pharmacology_Katzung

Pharmacology_Katzung. Squamous cell NSCLC makes up approximately 30% of NSCLC. This form of NSCLC is responsive to platinum-based chemotherapy with either cisplatin or carboplatin in combination with gemcitabine. Recent studies have shown superior clinical activity when cisplatin and gemcitabine are combined with the anti-EGFR antibody necitumumab when compared to the cisplatin-gemcitabine combination in the first-line treatment of metastatic disease. In 2015, the immune checkpoint inhibitor nivolumab was approved to treat metastatic squamous cell NSCLC whose cancer has progressed during or after standard platinum-based chemotherapy. This agent binds to the PD-1 receptor and inhibits the PD-1 immune signaling pathway, which then leads to activation and proliferation of T cells as well as inhibition of T-regulatory cells.


Pharmacology_Katzung

Pharmacology_Katzung. Small cell lung cancer is the most aggressive form of lung cancer. It is usually exquisitely sensitive, at least initially, to platinum-based combination regimens, including cisplatin and etoposide or cisplatin and irinotecan. Unfortunately, drug resistance eventually develops in nearly all patients with extensive disease. When diagnosed at an early stage, this disease is potentially curable using combined chemotherapy and radiation therapy. Topotecan is used as second-line monotherapy in patients who have failed a platinum-based regimen.


Pharmacology_Katzung

Pharmacology_Katzung. In the majority of patients, ovarian cancer remains occult and becomes symptomatic only after it has already metastasized to the peritoneal cavity. At this stage, it usually presents with malignant ascites. It is important to accurately stage this cancer with laparoscopy, ultrasound, and CT scanning. Patients with stage I disease appear to benefit from whole-abdomen radiotherapy and may receive additional benefit from combination chemotherapy with cisplatin and cyclophosphamide. Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, carboplatin plus paclitaxel has become the treatment of choice. In patients who present with recurrent disease, topotecan, altretamine, or liposomal doxorubicin are used as single-agent monotherapy.


Pharmacology_Katzung

Pharmacology_Katzung. The introduction of platinum-based combination chemotherapy has made an impressive change in the treatment of patients with advanced testicular cancer. Presently, chemotherapy is recommended for patients with stage IIC or stage III seminomas and nonseminomatous disease. Over 90% of patients respond to chemotherapy and, depending upon the extent and severity of disease, complete remissions are observed in 70–80% of patients. More than 50% of patients achieving complete remission are cured with chemotherapy. In patients with good risk features, three cycles of cisplatin, etoposide, and bleomycin (PEB protocol) or four cycles of cisplatin and etoposide yield virtually identical results. In patients with high-risk disease, the combination of cisplatin, etoposide, and ifosfamide can be used as well as etoposide and bleomycin with high-dose cisplatin.


Pharmacology_Katzung

Pharmacology_Katzung. Malignant melanoma is curable with surgical resection when it presents locally (see also Chapter 61). However, once metastasis has occurred, it is one of the most difficult cancers to treat because of drug resistance. While dacarbazine, temozolomide, and cisplatin are the most active cytotoxic agents for this disease, the overall response rates to these agents remain low. Biologic agents, including IFN-α and interleukin 2 (IL-2), have greater activity than traditional cytotoxic agents, and treatment with high-dose IL-2 has led to cures, albeit in a relatively small subset of patients. Ipilimumab binds to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which is expressed on the surface of activated CD4 and CD8 T-cells. CTLA-4 normally acts as a brake on T-cell antitumor activity. Binding of ipilimumab results in inhibition of the interaction between CTLA-4 and its target ligands CD80/CD86 and thus enhances T-cell immune responses, which include T-cell activation and


Pharmacology_Katzung

Pharmacology_Katzung. activity. Binding of ipilimumab results in inhibition of the interaction between CTLA-4 and its target ligands CD80/CD86 and thus enhances T-cell immune responses, which include T-cell activation and proliferation. This agent is approved for the treatment of metastatic melanoma. More recently, ipilimumab is recommended as adjuvant therapy for cutaneous melanoma following complete surgical resection, with treatment for up to 3 years.


Pharmacology_Katzung

Pharmacology_Katzung. Nivolumab and pembrolizumab are IgG4 antibodies that bind to the programmed death (PD)-1 receptor, which is expressed on T cells, and they inhibit the interaction between the programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2) and the PD-1 receptor. The PD-1 signaling pathway mediates an immune escape mechanism, and inhibition of this pathway enhances T-cell immune response, leading to T cell activation and proliferation. Each of these agents is approved for unresectable or metastatic melanoma as monotherapy. In addition, nivolumab is also approved in combination with ipilimumab for BRAF V600 mutation–positive unresectable or metastatic melanoma.


Pharmacology_Katzung

Pharmacology_Katzung. The BRAF V600E mutation has been identified in the large majority of melanomas. This mutation results in constitutive activation of BRAF kinase, which then leads to activation of downstream signaling pathways involved in cell growth and proliferation. Two oral and highly selective small molecule inhibitors of BRAF V600E are approved for metastatic melanoma: vemurafenib and dabrafenib. Studies are ongoing to determine their activity in combination with other cytotoxic and biologic agents for metastatic melanoma as well as their potential role in the adjuvant and neoadjuvant therapy of early stage melanoma.


Pharmacology_Katzung

Pharmacology_Katzung. Trametinib and cobimetinib are reversible inhibitors of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and kinase 2 (MEK2), and in combination with a BRAF inhibitor molecule, they are approved for patients with metastatic melanoma whose tumors express the BRAF V600E or V600K mutation. While these agents have clinical activity as monotherapies, clinical studies suggest that the most promising clinical activity is seen when they are used in combination with a BRAF inhibitor.


Pharmacology_Katzung

Pharmacology_Katzung. In general, chemotherapy has had only limited efficacy in the treatment of malignant gliomas. Because of their ability to cross the blood-brain barrier, the nitrosoureas have historically been the most active agents in this disease. Carmustine (BCNU) has been used as a single agent, or lomustine (CCNU) can be used in combination with procarbazine and vincristine (PCV regimen). In addition, the alkylating agent temozolomide is active when combined with radiotherapy and is also used in patients with newly diagnosed glioblastoma multiforme (GBM) as well as in those with recurrent disease. The histopathologic subtype oligodendroglioma has been shown to be especially chemosensitive, and the PCV combination regimen is the treatment of choice for this disease. It is now well-established that the anti-VEGF antibody bevacizumab alone or in combination with chemotherapy has documented clinical activity in adult GBM. Bevacizumab is presently approved as a single agent for adult GBM in the


Pharmacology_Katzung

Pharmacology_Katzung. the anti-VEGF antibody bevacizumab alone or in combination with chemotherapy has documented clinical activity in adult GBM. Bevacizumab is presently approved as a single agent for adult GBM in the setting of progressive disease following first-line chemotherapy.


Pharmacology_Katzung

Pharmacology_Katzung. The development of secondary malignancies is a late complication of the alkylating agents and the epipodophyllotoxin etoposide. For both drug classes, the most frequent secondary malignancy is acute myelogenous leukemia (AML). AML develops in up to 15% of patients with Hodgkin’s lymphoma who have received radiotherapy plus MOPP chemotherapy and in patients with multiple myeloma, ovarian carcinoma, or breast carcinoma treated with melphalan. The increased risk of AML is observed as early as 2–4 years after the initiation of chemotherapy and typically peaks at 5 and 9 years. With improvements in the clinical efficacy of various combination chemotherapy regimens resulting in prolonged survival and in some cases actual cure of cancer, the issue of how second cancers may affect long-term survival assumes greater importance. Certain alkylating agents (eg, cyclophosphamide) may be less carcinogenic than others (eg, melphalan). In addition to AML, other secondary malignancies have been


Pharmacology_Katzung

Pharmacology_Katzung. survival assumes greater importance. Certain alkylating agents (eg, cyclophosphamide) may be less carcinogenic than others (eg, melphalan). In addition to AML, other secondary malignancies have been well-described, including non-Hodgkin’s lymphoma and bladder cancer, the latter most typically associated with cyclophosphamide therapy. Etoposide can give rise to an 11:23 translocation, which has been associated with the development of the M4 and M5 AML histologic subtypes.


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Pharmacology_Katzung. See Tables 54–2, –3, –4, and –5. The reader is referred to the Internet and manufacturers’ literature for the most recent information on preparations available. Abeloff MD et al: Clinical Oncology, 5th ed. Elsevier, 2014. Barakat RR et al: Principles and Practice of Gynecologic Oncology, 5th ed. Lippincott Williams & Wilkins, 2009. Chabner BA, Longo DL: Cancer Chemotherapy and Biotherapy: Principles and Practice, 5th ed. Lippincott Williams & Wilkins, 2011. Chu E, DeVita VT Jr: Cancer Chemotherapy Drug Manual 2017, 17th ed. Jones & Bartlett. DeVita VT Jr, Hellman S, Rosenberg SA: Cancer: Principles and Practice of Oncol ogy, 10th ed. Lippincott Williams & Wilkins, 2015. Harris JR et al: Diseases of the Breast, 4th ed. Lippincott Williams & Wilkins, 2009. Hoppe R et al: Textbook of Radiation Oncology, 3rd ed. Elsevier, 2010. Kantoff PW et al: Prostate Cancer: Principles and Practice. Lippincott Williams & Wilkins, 2001.


Pharmacology_Katzung

Pharmacology_Katzung. Hoppe R et al: Textbook of Radiation Oncology, 3rd ed. Elsevier, 2010. Kantoff PW et al: Prostate Cancer: Principles and Practice. Lippincott Williams & Wilkins, 2001. Kelsen DP et al: Gastrointestinal Oncology: Principles and Practices, 2nd ed. Lippincott Williams & Wilkins, 2007. Kufe D et al: Cancer Medicine, 7th ed. BC Decker, 2006. Mendelsohn J et al: The Molecular Basis of Cancer, 3rd ed. Saunders, 2008. Pass HI et al: Principles and Practice of Lung Cancer: The Official Reference Text of the International Association for the Study of Lung Cancer (IASLC), 4th ed. Lippincott Williams & Wilkins, 2010. Pizzo PA, Poplack AG: Principles and Practice of Pediatric Oncology, 6th ed. Lippincott Williams & Wilkins, 2010. Weinberg RA: Biology of Cancer, 2nd ed. Taylor & Francis, 2013. DeVita VT, Chu E: The history of cancer chemotherapy. Cancer Res 2008;68:8643. Redmond KM et al: Resistance mechanisms to cancer chemotherapy. Front Biosci 2008;13:5138.