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.
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 setting of progressive disease following first-line chemotherapy.
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 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.
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.