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 isanother EGF receptor...
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Chapter 081. Principles of Cancer Treatment (Part 19) Chapter 081. Principles of Cancer Treatment (Part 19) Solid Tumors Small-molecule epidermal growth factor (EGF) antagonists act at the ATPbinding site of the EGF receptor tyrosine kinase. In early clinical trials, gefitinibshowed evidence of responses in a small fraction of patients with non-small celllung cancer. Side effects were generally acceptable, consisting mostly of rash anddiarrhea. Gefitinib was found to have antitumor activity mainly in the subset ofpatients with tumors containing activating mutations in the EGF receptor. Oftenpatients who developed resistance to gefitinib have acquired additional mutationsin the enzyme, similar to what was seen in imatinib-resistant CML. Erlotinib isanother EGF receptor tyrosine kinase antagonist with somewhat superior activityto 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 combinedEGF receptor and erbB2 tyrosine kinase antagonist with activity in breast cancersrefractory 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 plateletderived growth factor receptor (PDGF-R), activated by translocation in certainsarcomas. Imatinib has found clinical utility in these neoplasms previouslyrefractory to chemotherapeutic approaches. Multitargeted kinase antagonists are small-molecule ATP site-directedantagonists that inhibit more than one protein kinase. Drugs of this type withprominent activity against the vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase have activity in renal cell carcinoma. Sorafenib is a VEGF-Rantagonist 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. Itcauses prominent responses as well as stabilization of disease in renal cell cancersand gastrointestinal stromal tumors. Side effects for both agents are mostlyacceptable, with fatigue and diarrhea encountered with both agents. The hand-foot syndrome with erythema and desquamation of the distal extremities, in somecases requiring dose modification, may be seen with sorafenib. Temsirolimus, anmTOR inhibitor, has activity in renal and breast cancer. It produces somehyperlipidemia (10%), myelosuppression (10%), and rare lung toxicity. Acute Complications of Cancer Chemotherapy Myelosuppression The common cytotoxic chemotherapeutic agents almost invariably affectbone marrow function. Titration of this effect determines the MTD of the agent ona given schedule. The normal kinetics of blood cell turnover influence thesequence and sensitivity of each of the formed elements. Polymorphonuclearleukocytes (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 tousually administered cytotoxic agents. The nadir count of each cell type inresponse to classes of agents is characteristic. Maximal neutropenia occurs 6–14days 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 6weeks after dosing. Complications of myelosuppression result from the predictable sequelae ofthe missing cells function. Febrile neutropenia refers to the clinical presentationof 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 marrowor, more usually, in a patient undergoing treatment with cytotoxic agents.Mortality from uncontrolled infection varies inversely with the neutrophil count. Ifthe nadir neutrophil count is >1000/µL, there is little risk; if ciprofloxacin or moxifloxacin, or amoxicillin plus clavulinic acid. A less favorableprognostic group are patients with expected prolonged neutropenia, evidence ofsepsis, and end-organ compromise, particularly pneumonia. These patients clearlyrequire tailoring of their antibiotic regimen to their underlying presentation, withfrequent empirical addition of antifungal agents if fever persists for 7 days withoutidentification of an adequately treated organism or site.