Adjuvant Chemotherapy for Resected Non–Small-Cell Lung Cancer
Adjuvant Chemotherapy for Resected Non–Small-Cell Lung Cancer
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.
International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 350:3351-3360, 2004.
Kato H, Ichinose Y, Ohta M, et al: A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713-1721, 2004.
Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311:899-909, 1995.
Pisters KMW: Adjuvant chemotherapy for non-small-cell lung cancer—The smoke clears. N Engl J Med 352(25):2640-2642, 2005. Pisters KMW, Le Chevalier T: Adjuvant chemotherapy in completely resected non-small cell lung cancer. J Clin Oncol 23:3270-3278, 2005.
Scagliotti GV, Fossati R, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, II or IIIA non-small cell lung cancer. J Natl Cancer Inst 95:1453- 1461, 2003.
Strauss GM, Herndon J, Maddaus MA, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633 (abstract 7019). J Clin Oncol 22(July 15 suppl 14S):621s, 2004.
Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. Report of National Cancer Institute of Canada Clinical Trials Group and National Cancer Institute of the United States Intergroup JBR.10. N Engl J Med 352(25):2589-2597, 2005.