A focused update to the 2009 ASCO Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer reflects new evidence on maintenance therapy in patients with response or stable disease after four cycles of first-line cytotoxic chemotherapy.1 The 2009 update recommendation (recommendation A6) stated that cytotoxic chemotherapy should be stopped at progression or after four cycles in patients without response and evidence that did not support (1) continuation of cytotoxic chemotherapy until disease progression or (2) initiation of a different chemotherapy before disease progression in patients with stable disease or response to first-line therapy.2
New 2011 Recommendation
The 2011 focused update states that for patients with stable disease or response after four cycles, “immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxelin unselected patients, or erlotinib in unselected patients may be considered [italics added].” The recommendation also states that because of limitations of the data in this area, a break from cytotoxic chemotherapy in patients with response or stable disease after a fixed course of first-line therapy is also an acceptable option, with second-line treatment being delayed until disease progression.
It continues to be recommended that first-line cytotoxic chemotherapy be stopped at disease progression or after four cycles in patients not responding and that two-drug cytotoxic combinations be given for no more than six cycles.
‘Switch Maintenance’ Trials
The focused update is based on review of data from seven phase III trials involving immediate non–cross-resistant alternative therapy (“switch maintenance”) in patients with response or stable disease after first-line treatment. The trials using docetaxel, pemetrexed (Alimta, in patients with non–squamous cell carcinoma), erlotinib (Tarceva), gefitinib (Iressa), and gemcitabine as switch maintenance therapy showed increased progression-free survival with maintenance therapy, with one of the two trials using erlotinib and the trial using pemetrexed also showing statistically significant increases in overall survival. These gains were accompanied by acceptable toxicity.
Key findings from these trials included the following:
ASCO guidelines indicate that patients with radiologic response after four cycles of first-line cytotoxic chemotherapy may be considered for continuation of treatment for two additional cycles. In line with this recommendation are data on switch maintenance therapy indicating better response with the cytotoxic agents docetaxel and gemcitabine in patients with response vs stable disease after four cycles of platinum-based first-line treatment.
Toxicity and Chemotherapy Breaks
The ASCO panel notes that the clinical trial data used for establishing the guidelines for duration of first-line chemotherapy involve drugs that are associated with cumulative toxicity and that the advent of new drugs without cumulative toxicity, as well as biomarkers for their effectiveness, will “complicate and perhaps diminish the importance of the question of optimal duration of therapy.”
The panel also notes that it would be of interest to analyze why some of the patients in the control arms of the reviewed studies, whose treatment had resulted in disease control after four cycles of first-line treatment, did not receive second-line treatment. In this regard, the panel states, “Until the time of further [overall survival] benefit shown in studies in which there was sufficient second-line therapy offered to participants in the control arm, and given the limitations of current data, the panel accepts as viable the traditional approach of allowing patients a break from cytotoxic chemotherapy after a fixed course of first-line therapy, with initiation of second-line chemotherapy at disease progression.”
Important considerations in implementing the focused update include the following:
1. Azzoli CG, Temin S, Aliff T, et al: 2011 focused update of 2009 American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol. September 6, 2011 (early release online).
2. Azzoli CG, Baker S Jr, Temin S, et al: American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non–small-cell lung cancer. J Clin Oncol 27:6251-6266, 2009.
Before the discovery of predictive molecular tests (eg, EGFR mutation and ALK rearrangement), each chemotherapy drug for stage IV non–small cell lung cancer had about the same chance of success. Progress was made as more drugs were discovered. Patients lived longer with second- and third-line...