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Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633.

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 3 de junio del 2006

Presenter: G.M. Strauss
Presenter's Affiliation: CALGB
Type of Session: Scientific

Background

• Lung cancer is the number one cause of cancer death in America.
• A meta-analysis published in 1995 demonstrated a marginally significant survival benefit with adjuvant cisplatin based chemotherapy in patients who received surgery for their diagnosis of non-small cell lung cancer (NSCLC).
• Since then, many investigators have conducted clinical trials with various adjuvant chemotherapeutic regimens for resected lung cancer patients.
• The CALGB 9633 trial randomized patients with stage IB NSCLC to either carboplatin/paclitaxel or no further therapy.
• Preliminary results of CALGB 9633 were reported at ASCO 2004 (median f/u 34 months), and the study was stopped early by the data safety monitoring committee because of a significant survival advantage seen in the chemotherapy arm (HR 0.62, 95%CI 0.41-0.95, p=0.028).
• However, two other large trials of adjuvant chemotherapy in resected NSCLC patients failed to demonstrate a benefit with chemotherapy in patients with stage IB disease.
• Thus, there has been considerable interest in having the results of this trial updated.

Materials and Methods

• CALGB 9633 randomized patients with completely resected T2N0M0 NSCLC four to eight weeks following surgery to either 4 cycles of carboplatin (AUC 6) and paclitaxel (200mg/m²) or observation.
• Patients had to be at least 18 years old with biopsy confirmed NSCLC.
• All patients had to have either a lobectomy or pneumonectomy with lymph nodes sampled via medistinoscopy and/or surgery.
• With 384 patients enrolled, 155 events were needed to provide a type I error (1 sided) of 0.05 with a power of 80%.
• Overall survival was the primary endpoint.
• Median follow-up is 54 months.
• 344 patients (90%) had been randomized at the time of early closure.
• 14 patients eventually proved to be ineligible or cancelled, but all 344 patients were included in an intent to treat analysis.
• Patient and disease related variables were well balanced between both arms.

Results

• Adjuvant chemotherapy was well tolerated, and there were no toxic deaths related to chemotherapy.
• The most common grade 3/4 toxicity was neutropenia (35%).
• With a median follow-up of 54 months, the updated analysis no longer demonstrates a significant difference in overall survival between the 2 treatment arms (chemotherapy-63% vs. observation-57.3%, p=0.10).
• A significant overall survival benefit with chemotherapy was seen at both 2 years (90% vs 84%, p=0.05) and 3 years (79% vs 71%, p=0.043), but did not persist at 5 years (59% vs 57%, p=0.375).
• Failure free survival was significantly improved in the chemotherapy arm (57.2% vs. 48%, p=0.030).
• An unplanned exploratory subgroup analysis demonstrated an overall survival benefit with chemotherapy in 74 patients with tumors > 4cm (HR 0.66, 95%CI 0.45-0.97, p=0.04.
• This benefit did not hold when examining patients with tumors <4 cm in size (HR 1.02, 95%CI 0.67-1.55, p=0.51).

Author's Conclusions

• The updated analysis no longer shows a significant overall survival advantage for adjuvant chemotherapy in patients with stage IB NSCLC.
• CALGB 9633 can be interpreted as a negative study.
• Adjuvant chemotherapy did improve both disease free survival and survival in the early years.
• Chemotherapy was well tolerated.
• The study did not have the statistical power to detect smaller survival differences that are nonetheless clinically important.
• The advantages in 2 and 3 years survival and disease free survival raise the possibility that adjuvant chemotherapy may delay recurrence, even if does enhance curability.
• The exploratory analysis suggests that the benefit of chemotherapy may be limited to patients with tumors >4cm in size.
• The results of CALGB 9633 do not mandate the use of adjuvant chemotherapy in patients with stage IB NSCLC.

Clinical/Scientific Implications

The authors presented an update of a well designed phase III randomized clinical trial of adjuvant chemotherapy for patients with resected stage IB NSCLC. Unfortunately, the initial excitement over this trial has proven to have been somewhat premature. The authors are correct when they state that adjuvant chemotherapy is not indicated in patients with stage IB NSCLC. This conclusion stems from the results of this study and other clinical trials and meta-analyses that have failed to demonstrate a survival benefit in stage IB patients. The unplanned exploratory analysis regarding tumors > 4 cm is certainly intriguing, but must be viewed as hypothesis generating rather than conclusive evidence. There may actually be a benefit to adjuvant chemotherapy in stage IB patients, however, the effect is probably too small to be discerned without very large numbers of patients being studied. Finally, other studies have suggested that cisplatin containing regimens are superior to carboplatin containing regimens. There is a possibility that a more active regimen could produce a durable survival advantage in stage IB patients. However, until evidence surfaces to suggest otherwise, chemotherapy should not routinely be employed for completely resected stage IB NSCLC patients.