Chapter 081. Principles of Cancer Treatment (Part 19)

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Solid Tumors Small-molecule epidermal growth factor (EGF) antagonists act at the ATP binding site of the EGF receptor tyrosine kinase. In early clinical trials, gefitinib showed evidence of responses in a small fraction of patients with non-small cell lung cancer. Side effects were generally acceptable, consisting mostly of rash and diarrhea. Gefitinib was found to have antitumor activity mainly in the subset of patients with tumors containing activating mutations in the EGF receptor. Often patients who developed resistance to gefitinib have acquired additional mutations in the enzyme, similar to what was seen in imatinib-resistant CML. Erlotinib is another EGF receptor...

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Chapter 081. Principles of Cancer Treatment (Part 19) Solid Tumors Small-molecule epidermal growth factor (EGF) antagonists act at the ATP binding site of the EGF receptor tyrosine kinase. In early clinical trials, gefitinib showed evidence of responses in a small fraction of patients with non-small cell lung cancer. Side effects were generally acceptable, consisting mostly of rash and diarrhea. Gefitinib was found to have antitumor activity mainly in the subset of patients with tumors containing activating mutations in the EGF receptor. Often patients who developed resistance to gefitinib have acquired additional mutations in the enzyme, similar to what was seen in imatinib-resistant CML. Erlotinib is
another EGF receptor tyrosine kinase antagonist with somewhat superior activity to gefitinib in clinical trials in non-small cell lung cancer. Even patients with wild- type EGF receptors may benefit from erlotinib treatment. Lapitinib is a combined EGF receptor and erbB2 tyrosine kinase antagonist with activity in breast cancers refractory to anti-erbB2 antibodies. In addition to the p210bcr-abl kinase, imatinib also has activity against the c- kit tyrosine kinase, activated in gastrointestinal stromal sarcoma, and the platelet derived growth factor receptor (PDGF-R), activated by translocation in certain sarcomas. Imatinib has found clinical utility in these neoplasms previously refractory to chemotherapeutic approaches. "Multitargeted" kinase antagonists are small-molecule ATP site-directed antagonists that inhibit more than one protein kinase. Drugs of this type with prominent activity against the vascular endothelial growth factor receptor (VEGF- R) tyrosine kinase have activity in renal cell carcinoma. Sorafenib is a VEGF-R antagonist with activity against the raf serine-threonine protein kinase as well. Sunitinib has anti-VEGF-R as well as anti-PDGF-R and anti-c-kit activity. It causes prominent responses as well as stabilization of disease in renal cell cancers and gastrointestinal stromal tumors. Side effects for both agents are mostly acceptable, with fatigue and diarrhea encountered with both agents. The "hand- foot syndrome" with erythema and desquamation of the distal extremities, in some cases requiring dose modification, may be seen with sorafenib. Temsirolimus, an
mTOR inhibitor, has activity in renal and breast cancer. It produces some hyperlipidemia (10%), myelosuppression (10%), and rare lung toxicity. Acute Complications of Cancer Chemotherapy Myelosuppression The common cytotoxic chemotherapeutic agents almost invariably affect bone marrow function. Titration of this effect determines the MTD of the agent on a given schedule. The normal kinetics of blood cell turnover influence the sequence and sensitivity of each of the formed elements. Polymorphonuclear leukocytes (PMNs; t1/2 = 6–8 h), platelets (t1/2 = 5–7 days), and red blood cells (RBCs; t1/2 = 120 days) respectively have most, less, and least susceptibility to usually administered cytotoxic agents. The nadir count of each cell type in response to classes of agents is characteristic. Maximal neutropenia occurs 6–14 days after conventional doses of anthracyclines, antifolates, and antimetabolites. Alkylating agents differ from each other in the timing of cytopenias. Nitrosoureas, DTIC, and procarbazine can display delayed marrow toxicity, first appearing 6 weeks after dosing. Complications of myelosuppression result from the predictable sequelae of the missing cells' function. Febrile neutropenia refers to the clinical presentation of fever (one temperature ≥38.5°C or three readings ≥38°C but ≥38.5°C per 24 h) in a neutropenic patient with an uncontrolled neoplasm involving the bone marrow
or, more usually, in a patient undergoing treatment with cytotoxic agents. Mortality from uncontrolled infection varies inversely with the neutrophil count. If the nadir neutrophil count is >1000/µL, there is little risk; if
ciprofloxacin or moxifloxacin, or amoxicillin plus clavulinic acid. A less favorable prognostic group are patients with expected prolonged neutropenia, evidence of sepsis, and end-organ compromise, particularly pneumonia. These patients clearly require tailoring of their antibiotic regimen to their underlying presentation, with frequent empirical addition of antifungal agents if fever persists for 7 days without identification of an adequately treated organism or site.