Lessons from a time capsule: evolution, not revolution, in therapy for advanced non-small-cell lung cancer.

This article, selected for representation by the editors of Journal of Clinical Oncology, reports the findings of the first Cancer and Leukemia Group B (CALGB) trial for patients with advanced non–smallcell lung cancer. It creates an interesting opportunity to evaluate what has happened in 25 years of therapy for individual patients with stage IV lung cancer. On balance—not enough therapeutically. But over the same 25 years, there have been major advances in understanding the disease and in setting the foundation for important individualized therapy advances to come. And, most important and gratifying of all is worldwide attention to the root cause of the disease, tobacco use and unintended addiction, with the attendant fall in incidence and total new lung cancer cases in the United States and in many other countries world wide. Rereading the article now highlights the naive optimism of solid tumor therapy (and therapists) in the early 1980s and the decidedly primitive nature of clinical trials designs and execution processes of the period. For example, the manuscript reports a phase II trial with a planned accrual of 125 patients, far too large for such an exploratory phase II study by current standards. The methods section is devoid of any suggestion of the basis for the size selected. The popularization by Simon et al of two-stage designs for phase II trials was still years away. In addition, we failed to include all patients in the denominator for assessment of outcome data, excluding, for example, 15 patients whose therapy was marked by major protocol violations and eight additional patients because we could not get adequate data from the treatment site. Not acceptable now, but done then with the best of intentions. The entry criteria for the trial were remarkably nonrestrictive— basically a histologic or cytologic diagnosis, disease too extensive for curative surgery, selected screening labs within a reasonable but rather arbitrary range, and no prior chemotherapy. It is stunning to recollect the absence of access to routine chest computed tomography (CT) scanning and our reliance on chest radiographs and liver/spleen scans as the core anatomic staging tools. CNS evaluations were required for patients with neurologic signs or symptoms, but if brain metastases were identified by either brain scan or head CT (where available), the patients were still eligible for study (and six were included). Performance scores were recorded but there was no restriction on participation based on performance status (PS). In fact, 38% of patients had a PS of 2 to 4 including 14% either 3 or 4. Disease status was assessed every 4 weeks by physical examination, laboratory screening, and chest radiographs. Categories of response were numerous—complete response, partial response, improvement, stable, relapse/progression. This reflected our near-sighted acceptance of both the prevalent model for what was important (ie, any amount of measurable tumor shrinkage was meaningfully beneficial) and the rudimentary tools at hand for response assessment. Duration of therapy was not discussed in the Methods section or commented on in the Results or Discussion portion of the 1983 manuscript. Therapy was continued to progression or intolerance. Today, level one evidence supports a finite duration of first-line chemotherapy. Questions about the potential benefits of using sequential regimens in first-line therapy have recently re-emerged, based on preliminary findings from one large phase III trial presented at American Society of Clinical Oncology annual meeting in 2007. More follow-up of this trial is needed. But regardless of the result, almost no one expects cytotoxic therapy to progression to return as recommended management. Phase III data suggest that use of bevacizumab combined with a finite course of paclitaxel plus carboplatin followed by bevacizumab alone to progression is associated with a significant survival advantage over chemotherapy alone. However, the design of that pivotal trial does not specifically allow us to know what, if any, independent benefit to survival is provided by continuing bevacizumab maintenance. More work in this area is needed. The regimen reported by CALGB in 1983 utilized four drugs and was built on classic principles supporting combination therapy. There were responses and some patients benefited from study treatment. But neither this nor other four and five drug regimens in vogue at the time were ever tested in the phase III setting and shown to provide a survival advantage over best supportive care. Perhaps such a trial would have been positive but the toxicity costs would have raised major issues of therapeutic index. Now we have several two-drug regimens shown to produce significant survival improvement with shortened treatment durations. This strategy, plus advances in supportive care, allows patients with stage IV non–small-cell lung cancer the longer duration of quality life we are all seeking. Despite its rudimentary nature, two important observations emerging from this (and other contemporary clinical trials) are key considerations in current treatment for patients with advanced solid tumors. The first involves PS. We included patients of all PS categories, 62% with PS 0 to 1 and 38% with PS 2 to 4. Among those 36 individuals with PS 2 to 4, there was one objective responder. The median survival for all patients with poor PS was 7.3 weeks. Today, we have better supportive care, less toxic single agent or doublet JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 19 JULY 1 2008