Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer: Report of Cancer and Leukemia Group B (CALGB) Protocol 9633

Reviewer: S. Jack Wei, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2004

Presenter: Gary M. Strauss
Presenter's Affiliation: Cancer and Leukemia Group B
Type of Session: Scientific

Background

The role of adjuvant chemotherapy for early stage non-small cell lung cancer (NSCLC) has been controversial
Recently reported studies regarding the role of adjuvant chemotherapy with completely resected NSCLC have been conflicting
The International Adjuvant Lung Trial (IALT) showed a small, but significant overall survival benefit with adjuvant cisplatin-based chemotherapy for stage IA to III NSCLC
The Adjuvant Lung Project Italy (ALPI) failed to demonstrate a benefit of cisplatin-based chemotherapy for similarly staged patients
In particular, for stage I patients, there is no convincing randomized data regarding the benefit of adjuvant chemotherapy
However, large numbers of stage I lung cancer patients continue to recur and die after complete resection
This study was designed to examine the role of adjuvant chemotherapy for high-risk stage I NSCLC (defined as T2N0 (Stage IB))

Materials and Methods

Patients with T2N0M0 stage IB NSCLC who underwent complete resection were randomized within 4-8 weeks of surgery between September 1996 and November 2003 to adjuvant chemotherapy (Arm 1) or observation (Arm 2)
Patients were stratified by histology (squamous vs. other), grade (poorly differentiated vs. other), and mediastinoscopy (yes vs. no)
All patients underwent lymph node sampling at the time of surgery and received either a lobectomy or pnemonectomy
The overall accrual goal was 384 patients (previously revised downward from 700 patients due to poor accrual); however at a planned interim analysis, accrual was terminated after 344 patients due to a significant benefit seen for the adjuvant chemotherapy arm
344 patients were randomized with 14 patients found ineligible leaving 330 patients treated, though all 344 patients were included in the analysis
Median follow-up was 34 months
Chemotherapy consisted of carboplatin (AUC = 6) and paclitaxel (200 mg/m2) q3wks x 4 cycles
Patient groups were well balanced with regards to age, gender, ethnicity, performance status, weight loss, histology, grade, presence of symptoms, tumor diameter, surgery extent, and mediastinoscopy

Results

4-year overall survival (OS): 71% (Arm 1) vs. 59% (Arm 2) (p=0.028)
The hazard ratio (HR) for death was 0.62 (95% CI 0.41-0.95)
4-year failure free survival (FFS): 61% (Arm 1) vs. 50% (Arm 2) (p=0.035)
HR for failure was 0.69 (95% CI 0.48-0.98)
24% of patients receiving chemotherapy experienced primary lung failures
Adjuvant chemotherapy was well tolerated with no treatment-related toxic deaths
Grade 3 or 4 neutropenia was seen in 36% of patients receiving chemotherapy
85% of patients received all four cycles of chemotherapy with 55% of patients receiving 4 cycles of full dose chemotherapy
A competing risk analysis showed no difference between study arms with regards to death from other causes with ~50% reduction in lung cancer mortality with the addition of adjuvant chemotherapy
Multivariate analysis showed that only treatment with chemotherapy resulted in reduced mortality

Author's Conclusions

Adjuvant chemotherapy reduces both lung cancer and all-cause mortality in patients with completely resected stage IB NSCLC
The chemotherapy in this trial was very well tolerated
This trial is the first randomized trial to show efficacy for carboplatin-based chemotherapy and the first to use a single TNM stage group of patients
Carboplatin/paclitaxel x 4 is now an evidence-based option for adjuvant treatment of completely resected stage IB NSCLC

Clinical/Scientific Implications

This study combined with the NCIC trial which was also presented at this conference provide convincing evidence that adjuvant chemotherapy for early stage completely resected NSCLC improves survival. Aside from the OS improvement, this study shows for the first time that a well-tolerated chemotherapy (in the form of carboplatn/paclitaxel) results in a significant survival advantage. A large advantage of carboplatin-based therapy compared to cisplatin-based therapy is the higher rate of tolerance to treatment with carboplatin. This is evidenced by the much higher rate of patients receiving full dose chemotherapy in this trial compared to other adjuvant lung cancer trials. It is possible that the higher rate of chemotherapy completion played a role in the improved results from this trial compared to previous trials. Importantly, there were no treatment-toxicity related deaths in this study. This stands in contrast to the IALT study which had a 0.8% rate of treatment-related mortality. It is unclear what other factors may have played a role in the improved results of this study compared to previous studies. Regardless, this study, in conjunction with the NCIC and IALT trials have established adjuvant chemotherapy as the standard of care for completely resected early stage NSCLC.

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