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Lessons From a Time Capsule: Evolution, Not Revolution, in Therapy for Advanced Non–Small-Cell Lung Cancer

Network for Medical Communication and Research Analytics, Atlanta, GA; Medical University of South Carolina, Charleston, SC

This article,¹ 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–small-cell 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.²

Rereading the article now highlights the naïve 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 al³ 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.⁴ 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 2007.⁵ 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.⁶ 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 regimens, and an appreciation of the potential to choose care based on whether the poor PS is of recent onset due to progressing cancer rather than comorbid conditions. Selected patients with PS 2 can benefit from systemic therapy, either single agents or even platinum-based doublets. But the PS lessons from this 25-year-old CALGB trial (and the work of many others as well) remain important drivers of therapy selection.

This phase II experience also shed early light on the value of nonprogression during therapy and the utility of disease control, rather than objective response rate, as a predictor of overall outcome. In this CALGB trial, the 59 patients with good PS (0 to 1) were compared with respect to response assessment and survival. Immediate progression was bad then as it is today. But more provocative was the observation of similar survival patterns among those with less than partial response (improved or stable disease) compared with the objective responders (complete response or partial response as traditionally defined by pre Response Evaluation Criteria in Solid Tumors WHO criteria).

"Perhaps more noteworthy is the observation of no statistically significant difference in median survival [or 2-year survival] between responders (complete and partial) and patients who achieved an ‘improved’ status or ‘stable disease’ within the high performance subgroup." This remains a highly relevant observation today. In the January 20, 2008, issue of the Journal of Clinical Oncology, Lara et al⁷ reported a retrospective analysis of three randomized Southwest Oncology Group trials in advanced non–small-cell lung cancer patients exploring the predictive values of disease control rate and response rate relative to survival. Using data from 984 patients and a landmark analysis technique, they concluded that "DCR at week 8 is a more powerful predictor of subsequent survival than is the traditional tumor response rate in advanced NSCLC... . "

Another observation, chastening to say the least, comes clearly into focus during the rereading process. These data are from 1983. Yes, 40% of the CALGB study patients had only intrathoracic disease identified at study entry, an earlier stage of disease than usually included in advanced disease trials today. And, yes, the overall survival for the entire population was despairingly short at 19.7 weeks. But in contrast, there were no body CT or positron emission tomography/CT scans for meticulous staging or monitoring early progression, no options for second- or third-line management which have now been now shown to further improve survival compared with best supportive care, and very little of what we have today in terms of broad experience and attentive supportive care. Yet for the 59 patients with good PS (0 to 1) median survival was 37.9 weeks and the 1-year survival approximately 35%. These benchmarks are not so different from those just reported by Belani et al⁸ in the same January 20, 2008, issue of the Journal. There, among several hundred patients (PS 0 to 1, 88%) receiving two different schedules of first-line paclitaxel plus carboplatin chemotherapy for their wet IIIB or IV NSCLC, median survival times were 38.6 and 42.9 weeks and 1-year survival rates were 37.8% and 41.3%.

In closing the 1983 article, the CALGB investigators concluded: "A number of drugs known to produce disease regression in some lung cancer patients have been recognized. However combinations of the modestly active agents have yet to produce markedly effective drug programs. This implies that one very important thrust of ... [research in this setting] ... must remain phase II trials of new agents or of pharmacologic manipulations designed to enhance the efficacy and therapeutic ratio of agents already at hand."

We now have more agents, some more effective than those of the 1970s, more than just pharmacology to "manipulate," (eg, patients whose tumors lack gemcitabine transporters may be poor candidates for gemcitabine therapy and those whose tumors express ERCC-1 may be relatively resistant to platinum therapy), excellent capabilities for both physical and psychosocial support, and improved guidelines for selection of patients and regimens to optimize care. But if it is still "just" chemotherapy, it is not so much of an advance. For now and beyond, science must guide us to demonstrate and exploit the inevitable vulnerabilities of neoplastic tissues. These emerging insights should allow dramatic therapy advances for a much larger percentage of all NSCLC patients and the outlook for future individuals with advanced NSCLC should become far superior to what CALGB investigators were able to describe in 1983 and the better, but still far from desired, outlook available tools allow us to offer today.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Mark R. Green, Network for Medical Communication and Research Analytics (C) Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Green M, Horton C, Spaulding M, et al: Four-drug combination chemotherapy (methorexate, cyclophosphamide, hexamethylmelamine, and CCNU) for non-small cell bronchogenic carcinoma: A Cancer and Leukemia Group B Study. J Clin Oncol 1:559-565, 1983[Medline]

2. American Cancer Society Cancer Facts and Figures 2007: http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2007.asp

3. Simon R: How large should a phase II trial of a new drug be? Cancer Treat Rep 71:1079-1085, 1987[Medline]

4. Socinski MA, Baggstrom MQ, Hensing TA: Duration of therapy in advanced, metastatic non-small-cell lung cancer. Clin Adv Hematol Oncol 1:33-38, 2003[Medline]

5. Fidias P, Dakhil S, Lyss A, et al: Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: Updated report with survival. J Clin Oncol 25:388s, 2007 (suppl; abstr LBA7516)

6. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006[Abstract/Free Full Text]

7. Lara PN Jr, Redman MW, Kelly K, et al: Disease control rate at 8 weeks predicts clinical benefit in advanced non-small-cell lung cancer: Results from Southwest Oncology Group randomized trials. J Clin Oncol 26:463-467, 2008[Abstract/Free Full Text]

8. Belani CP, Ramalingam S, Perry MC, et al: Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 26:468-473, 2008[Abstract/Free Full Text]

Related Article

• Four-drug combination chemotherapy (methotrexate, cyclophosphamide, hexamethylmelamine, and CCNU) for non-small cell bronchogenic carcinoma: a Cancer and Leukemia Group B study
  M Green, C Horton, M Spaulding, RT Silver, J Berenberg, BJ Kennedy, TF Pajak, and R Comis
  JCO 1983 1: 559-565 [Abstract]

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