The last 5 years have seen a dramatic shift in the standard of care regarding adjuvant chemotherapy of NSCLC. Beginning with the report of a significant survival difference from IALT, five multi-institutional RCTs have been reported that demonstrate statistically significant survival advantages associated with adjuvant chemotherapy for early-stage NSCLC.
These five positive RCTs include the preliminary 2004 report of CALGB 9633.1
This was the only RCT designed specifically for stage IB NSCLC. However, stage IB patients were eligible to participate in each trial. Although mature results of CALGB 9633 no longer demonstrate a significant OS advantage for adjuvant chemotherapy across the entire cohort, the other four RCTs have retained significance in the entire study population. Because stage IB patients were eligible to participate in each positive trial, one question is whether sufficient evidence exists to routinely recommend adjuvant chemotherapy for patients with stage IB NSCLC, despite the results reported here. The answer would appear to be no.
Three of these four RCTs utilized a cisplatin-based doublet as the adjuvant chemotherapy. In IALT, patients were randomly assigned either to observation or to three or four cycles of cisplatin (Platinol; Bristol-Myers Squibb) combined with either vinorelbine (Navelbine; GlaxoSmithKline, Research Triangle Park, NC), vinblastine (Velban; Eli Lilly & Co, Indianapolis, IN), vindesine, or etoposide (Vepesid; Bristol-Myers Squibb). All resectable patients (including stages IA to IIIB) were eligible to participate in IALT.2
In both NCIC-CTG-JBR-10 and ANITA, patients were randomly assigned either to observation or to four cycles of cisplatin/vinorelbine. Eligibility in NCIC-CTG-JBR-10 included stages IB and II NSCLC,4
whereas stagesIB, II, and IIIA were eligible in in ANITA.6
The fourth RCT was the Japan Lung Cancer Research Group (JLCRG) study, in which patients with stage IA or IB lung adenocarcinoma were randomly assigned to 2 years of adjuvant chemotherapy with oral uracil/tegafur (UFT) or observation.3
Although each study showed a significant OS advantage for chemotherapy, no cisplatin-based RCT demonstrated a significant OS advantage for the stage IB subset. In IALT, there was no survival advantage among 681 stage I patients (HR, 0.95; 95% CI, 0.74 to 1.23), 73% of whom had stage IB NSCLC.2,25
ANITA demonstrated a significant OS advantage for adjuvant cisplatin/vinorelbine among all patients and among patients in the stages II and IIIA subsets, although not in the stage IB subset (HR, 1.10; 95% CI, 0.76 to 1.67).6
Similarly, NCIC-CTG-JBR-10 demonstrated a significant OS advantage for adjuvant cisplatin/vinorelbine in all patients and in the stage II subset.4
However, there was no survival advantage in stage IB disease (P
The only other multi-institutional RCT that did show benefit in stage IB disease is JLCRG, which utilized adjuvant UFT in stage I lung adenocarcinoma. Results indicate a significant survival improvement for all 979 patients with stage IA or IB disease (HR, 0.71; 95% CI, 0.52 to 0.98).3
Among the 27% of participants with stage IB disease, there was a significant survival advantage (HR, 0.48; 95% CI, 0.29 to 0.81). In contrast, there was no benefit for UFT within the much larger stage IA subset (HR, 0.97; 95% CI, 0.64 to 1.46). There is no experience with adjuvant UFT outside Japan, and this agent is not available in Europe or North America for NSCLC.
The only other data that supports efficacy for adjuvant chemotherapy in stage IB NSCLC comes from a small, single-institutional RCT from Italy.26
In this trial, 140 stage IB patients were randomly assigned after resection to six cycles of adjuvant cisplatin/etoposide or observation. Results demonstrate large and significant OS/DFS advantages in the adjuvant arm. Five-year, 10-year, and median survivals were 62%, 44%, and 84.8 months versus 42%, 20%, and 41.6 months, respectively (P
= .02). Although impressive, the small sample size and the large effect size introduce questions about the reproducibility of these findings.
Accordingly, results of CALGB 9633 remain highly relevant to the question of the effect of adjuvant chemotherapy in stage IB NSCLC. Unfortunately, with longer follow-up, our encouraging preliminary findings have not been sustained. Nonetheless, the HR of 0.83 reported in our current analysis is similar to overall HRs observed in several positive trials. For example, in IALT and in ANITA, statistically significant survival advantages for adjuvant chemotherapy indicate HRs of 0.86, and 0.80, respectively. Moreover, LACE, a pooled analysis of five RCTs, reports a significant modest OS advantage (HR, 0.89; 95% CI, 0.82 to 0.96).17
Accordingly, the 17% reduction in risk of death observed in updated results from our study is similar in magnitude to survival advantages observed in several positive trials. However, with only 344 participants, CALGB 9633 is considerably smaller than any of the other RCTs. Given the smaller sample size and the lower event rates, our study had only 31% power to demonstrate a significant survival difference with HR = 0.83. Similarly, the 28% reduction in lung cancer mortality would suggest a benefit for adjuvant chemotherapy, although with only 89 deaths as a result of lung cancer, there was insufficient power to show a statistically significant difference.
Clearly, our results do not support routine use of adjuvant chemotherapy as standard of care in stage IB NSCLC. Recent American Society of Clinical Oncology guidelines assert that “adjuvant chemotherapy is not recommended for routine use for patients with completely resected stage IB NSCLC,”27
a conclusion with which we concur.
Nonetheless, CALGB 9633 does demonstrate a trend in favor of use of adjuvant chemotherapy. Moreover, exploratory analysis suggests that the adjuvant chemotherapy significantly improves survival for patients who had tumors ≥ 4.0 cm.
Although the analysis on the basis of on tumor size represents an unplanned subgroup analysis, the finding that adjuvant chemotherapy is effective for stage IB patients with large tumors is biologically plausible,21-24
and, if confirmed, would represent an observation that could substantially impact clinical practice. In this regard, after our updated 2006 presentation,28
investigators from NCIC-CTG-JBR-10 analyzed their data and also found a significant survival advantage for stage IB patients with greater than 4-cm tumors (Frances Shepherd, personal communication, April 19, 2007). We currently are participating in a pooled analysis in the context of an expanded LACE analysis in which this observation will be further explored.
We believe that our results support consideration for adjuvant chemotherapy in stage IB patients for those who had tumors ≥ 4.0 cm, which comprised 59% of patients in our study. The finding of a significant 31% mortality reduction provides a basis for considering adjuvant treatment in this subgroup, despite the fact that this was not an a priori objective of our trial. Indeed, the vast majority of such patients would be classified as having stage II tumors on the basis of a proposed new staging system for NSCLC.23,24
In terms of treatment regimen, our results suggest that adjuvant paclitaxel/carboplatin was at least comparable to cisplatin-based combinations for stage IB disease.29
Although LACE reported a significant survival advantage for all treated patients (HR, 0.89; 95% CI, 0.82 to 0.96) and in stage II and III patients (HR, = 0.83; 95% CI, 0.73 to 0.95), there was no significant advantage in stage IB NSCLC (HR, 0.93; 95% CI, 0.78 to 1.10).17
It also should be emphasized that adjuvant paclitaxel plus carboplatin was well tolerated, and there were no chemotherapy-related toxic deaths. Although compliance with adjuvant chemotherapy has been difficult in all RCTs, it was less problematic in CALGB 9633 than in cisplatin-based trials.30,31
Accordingly, paclitaxel plus carboplatin could be considered as a treatment option in selected stage IB patients who had tumors ≥ 4.0 cm in diameter. We believe that our results support the need to at least discuss the potential role of adjuvant chemotherapy with stage IB patients who have large tumors.
At this time, our study indicates that routine use of adjuvant chemotherapy is not justified for all patients with stage IB NSCLC. Nonetheless, results of CALGB 9633 (and confirmatory findings from NCIC-CTG-JBR-10) support consideration for adjuvant chemotherapy in stage IB patients who have tumors ≥ 4.0 cm in diameter.