Targeted therapies have significantly changed the treatment of cancer and are now considered to be a component of care for a number of common malignancies, including breast, colorectal, and lung cancers. In particular, they have significantly improved outcomes for patients with metastatic renal cell carcinoma (mRCC) and advanced gastrointestinal stromal tumors (GIST).
However, optimizing treatment for these patients presents many challenges, according to experts who participated in a Pfizer-sponsored satellite symposium here at the 33rd European Society for Medical Oncology Congress. Targeted therapies have improved survival in mRCC, but to achieve these benefits, it is important to avoid interruptions in therapy and dose reductions, explained Alain Ravaud, MD, professor of medical oncology and coordinator of the cancer care department at Bordeaux University Hospital, in France. Treating adverse events early and proactively is essential to maintaining patient compliance and optimizing outcomes and quality of life. Although they are generally well tolerated, targeted therapies have been associated with adverse events that are different from those seen with cytokines or chemotherapeutic agents. Commonly reported adverse events are fatigue, asthenia, hand and foot syndrome, and mucositis. In addition, targeted therapies can also cause hypothyroidism and hypertension.
The onset of adverse events can cause treatment interruption or dose reduction, and Dr. Ravaud emphasized the importance of maintaining patients at the optimal dose. Because targeted therapies are considered to be cytostatic, as opposed to cytotoxic, sustaining adequate levels is important to maintaining disease control. In studies with sunitinib, longer time to progression and overall survival was observed in patients with the highest sunitinib exposure. “When you begin treatment, start with the right dose,” said Dr. Ravaud. Early identification of adverse events and timely intervention will greatly help patient compliance. Some interventions need to start before therapy begins, he explained.
For example, blood pressure should be stabilized and antihypertensives added as needed. Pretreatment hyroid-stimulating hormone (TSH), tri-iodothyronine (T3), and thyroxine (T4) levels should be considered for patients starting sorafenib (Nexavar), because it is associated with the greatest risk for hypothyroidism. “The patient also needs to understand the disease and treatment,” said Dr. Ravaud. “Comprehensive patient education is very important.” In addition to patient education, other strategies for optimizing compliance are stabilizing comorbidities before treatment and providing intensive support during the first 2 treatment cycles to avoid early-onset adverse events. New Protocols Needed in mRCC Optimizing treatment benefits for patients with mRCC is the primary goal in developing new therapies and protocols. “The targets are well established, but we are still not curing our patients or getting a complete response,” said panelist Joaquim Bellmunt, MD, an assistant professor at the Universitat Autonoma de Barcelona, in Spain. There are a number of strategies under investigation, including the use of targeted therapies in the adjuvant and neoadjuvant settings, and in combination or sequence. There is also a need for the development of novel therapies. Current and planned trials, explained Dr. Bellmunt, are evaluating the efficacy, safety, and tolerability of combination therapies. One study is comparing the investigational agent enzastaurin plus sunitinib (Sutent) with sunitinib plus placebo in patients with mRCC. Two other studies, both of which were presented at the American Society of Clinical Oncology 44th Annual Meeting, combined sorafenib with bevacizumab (Avastin) and bevacizumab with everolimus (RAD001). Other clinical trials are evaluating sequencing therapies, including 1 phase 2 trial that is evaluating axitinib in patients who are refractory to front-line therapy, and another phase 2 trial comparing temsirolimus with sorafenib in patients who are refractory to sunitinib. “One of the benefits of sequencing is that you don’t have increased toxicity,” said Dr. Bellmunt. “But there are challenges. We don’t know which agent to use first or second, and we don’t know if we are building resistance.” Other studies are looking at targeted therapies in adjuvant and neoadjuvant settings, and the role of nephrectomy is being evaluated with sunitinib as a first-line therapy. Outcomes Improved in GIST The use of targeted agents has also dramatically changed the prognosis and outcome for GIST over the past decade. Imatinib mesylate (Glivec) is now first-line therapy for unresectable and/or metastatic GIST tumors that express stem cell factor receptor (KIT). However, most patients will eventually develop resistance to imatinib, usually because of the development of secondary mutations in the KIT gene. The second-line treatment, explained Jean-Yves Blay, MD, professor medicine at the Claude Bernard University, in Lyon, France, will depend on a number of factors, including the primary resistant genotype, mutational status, and treatment tolerability. “Mutational testing may help optimize treatment; it is important to know the primary mutation as well as secondary mutations that can develop during treatment,” Dr. Blay said. Patients who have GIST tumors with KIT exon 11 mutations are often sensitive to standard-dose imatinib, whereas those with KIT 9 mutations might respond to a higher dose (800 mg/day) of imatinib. Secondary KIT mutations in exon 13 or 14 might be responsive to sunitinib, which has shown activity against GIST tumors in patients who experienced disease progression while on standard-dose imatinib. Sunitinib has been approved for the treatment of imatinib-resistant GIST, and for patients who are intolerant to imatinib. In addition, said Dr. Blay, ongoing studies are evaluating the roles of imatinib and sunitinib in the adjuvant and neoadjuvant settings. 33rd European Society of Medical Oncology (ESMO) Congress. Satellite Symposium: Expanding the boundaries of clinical practice: building on experience with targeted therapies.
Presented September 12, 2008. Reviewed by Ramaz Mitaishvili, MD
