In this issue of ONCOLOGY, Solomon,Mitchell, and Bunn providean excellent review on adjuvanttherapy for resected non–smallcelllung cancer (NSCLC). Theauthors have thoroughly reviewed therecent literature and highlight severalimportant areas for discussion. Theauthors appropriately frame the importanceof the clinical issue at hand.
In this issue of ONCOLOGY, Solomon, Mitchell, and Bunn provide an excellent review on adjuvant therapy for resected non-smallcell lung cancer (NSCLC). The authors have thoroughly reviewed the recent literature and highlight several important areas for discussion. The authors appropriately frame the importance of the clinical issue at hand. Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death. Moreover, in the United States, lung cancer is the leading cause of cancer-related death in both men and women. For patients with operable NSCLC (the most common subtype of lung cancer), surgery offers the best hope for cure. However, recurrence following surgery is all too common, and overall survival rates following complete resection are disappointing. At present, pathologic staging and histologic subsets provide our best estimation of recurrence, while biologic and molecular parameters that may more accurately predict recurrence and survival are an area of ongoing research. Renewed interest in adjuvant therapy for NSCLC followed the results of a meta-analysis reported in 1995. In this meta-analysis, postoperative cisplatin-based chemotherapy was associated with a 5% absolute improvement in 5-year overall survival and a 13% reduction in the risk of death compared to no postoperative therapy. These differences, although encouraging, did not achieve statistical significance (P = .08). Since the time of the meta-analysis, additional randomized trials have been conducted and now reported. Taken as a whole, these studies have clearly established the benefit of postoperative chemotherapy in resected NSCLC. ALPI and IALT
The authors have reviewed these apparently conflicting large trials in great detail. The Italian trial (ALPI) randomized 1,088 evaluable patients to three cycles of postoperative mitomycin, vindesine, and cisplatin chemotherapy or control with slightly more than 40% of patients receiving postoperative thoracic irradiation. The larger IALT study randomized 1,867 patients to a cisplatin-based two-drug adjuvant regimen and 27% received radiation. Although only the IALT trial found a statistically significant survival benefit with chemotherapy, the 3% (ALPI) vs 4% (IALT) improvements in 5-year overall survival are within the same range of benefit. Differences in the two trials which likely accounted for the differing statistical outcomes include number of patients studied, frequency of postoperative radiation, chemotherapy regimen (two vs three drugs), and more early deaths in the ALPI study. NCIC JBR10, CALGB 9633, and ANITA
Results from the National Cancer Institute of Canada (NCIC) JBR10 and Cancer and Leukemia Group B (CALGB) 9633 trials were presented initially at the American Society of Clinical Oncology (ASCO) annual meeting in 2004. Both of these trials were strongly positive in favor of postoperative chemotherapy, with a 12% to 15% improvement in overall survival (at 4 or 5 years) and a 30% to 38% reduction in the risk of death. These two studies differed from previous adjuvant trials in several aspects of trial design-both focused on a narrow surgical subset of patients (stage IB/IIA and stage IB, respectively), both used modern or "third-generation" chemotherapy (vinorelbine/cisplatin and paclitaxel/ carboplatin), and neither trial used postoperative thoracic irradiation. The compelling results of these two trials led to a paradigm shift in the treatment of completely resected NSCLC patients with good performance status. At ASCO 2005, confirmatory results of the benefits of postoperative chemotherapy for NSCLC were presented. The Adjuvant Navelbine International Trialist Association (ANITA) study randomized 840 stage IB, II, or IIIA patients to four cycles of vinorelbine plus cisplatin or to observation. No postoperative radiation was given. With a median follow-up of more than 70 months, the 5-year and 7-year overall survival rates were improved by 8% (43% vs 51% and 37% vs 45%) and the risk of death was reduced by 21% (P = .0131). Current Controversies
The studies reported to date support the use of a two-drug, platin-based adjuvant chemotherapy regimen in completely resected NSCLC patients with good performance status. However, there remain several areas of controversy. Several of these are as follows:
1.Should all stages receive adjuvant treatment?-Stage IA: There is insufficient data concerning the efficacy of chemotherapy in stage IA patients. Very few patients with this surgical subset have been studied.
Stage IB: Both the JBR10 and ANITA trials performed subgroup analyses by stratification variables. In contrast to the findings of CALGB 9633, JBR10 and ANITA did not find statistically significant survival benefits for the stage IB patients. A metaanalysis may clarify the efficacy of adjuvant chemotherapy in these patients. As the JBR10 and ANITA analyses were performed on subset patient populations, these findings should be interpreted with caution.
Stage IIIA: Should patients with stage IIIA disease be treated? Although Solomon and colleagues recommended adjuvant chemotherapy only for stages IB and II patients, the greatest benefit in the IALT study was seen in the stage IIIA patients; the ANITA trial found a significant 16% improvement in 5-year survival for these patients. The data support the use of adjuvant chemotherapy in stage IIIA patients who undergo surgical resection as initial treatment. Other controversies in stage IIIA patients include whether postoperative irradiation should be administered and which patients should be treated with a multimodality program including surgery vs definitive radiation.
2.Other patient variables affecting treatment recommendations- Age: In all the studies conducted to date, there have been only a handful of patients treated who were over the age of 75. Although age has not affected outcome in good performance status patients treated for metastatic disease, patients of advanced age have not been studied sufficiently in the adjuvant setting to make firm recommendations.
Elapsed time from surgery: There is no information about whether adjuvant chemotherapy initiated more than 3 months following surgery is efficacious. Patients who have prolonged postoperative recovery or other delays prior to presentation for adjuvant therapy should be counseled that the efficacy of therapy beginning several months or longer following surgery is unknown.
Performance status: All studies reported to date have only included patients who recovered quickly from surgery, had excellent performance status, and did not have significant comorbid illnesses. Future trials will need to evaluate the efficacy of tolerable regimens in poor performance status patients.
3.UFT-As reviewed by Solomon, Mitchell, and Bunn, uracil/ tegafur (UFT) has been found to improve survival in Japanese patient populations with minimal toxicity. Unfortunately, there are no confirmatory data from other countries and this agent is not available in the United States. With the proven benefit of postoperative adjuvant platin-based chemotherapy, trials comparing UFT to no treatment in the adjuvant setting are no longer appropriate. Use of UFT or other oral fluoropyrimidines outside of a clinical trial are not recommended as adjuvant therapy at present.
4. Targeted Therapies-The NCIC-CTG BR19 trial randomizing completely resected NSCLC patients to oral gefitinib (Iressa) or placebo following complete resection (postoperative chemotherapy and radiation were stratification variables and permitted) was prematurely closed in April 2005. This decision was based on data from the Southwest Oncology Group S0023 study. S0023 randomized locally advanced/inoperable patients to oral gefitinib or placebo following definitive chemotherapy and radiation. A preliminary analysis found a clear lack of efficacy of gefitinib, to the extent that a deleterious effect could not be excluded. Future trials evaluating other targeted agents in combination with systemic chemotherapy are likely.
5. Induction or Adjuvant Chemotherapy?- As discussed by Solomon and colleagues, there are several trials documenting a survival benefit of preoperative chemotherapy in stage IIIA disease, while two studies trend in favor of induction chemotherapy in stage IB to IIIA patients. Collectively, these studies further support the role of chemotherapy in the treatment of patients with operable NSCLC. What is not established is whether chemotherapy is better administered before or after surgical resection. Only large, randomized trials will adequately answer this question.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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