The demonstration that adjuvant cisplatin-based chemotherapy significantly improves survival for patients with resected stage II and IIIA NSCLC represents an important advance in the management of this malignancy. The randomized, phase III trials showing a survival benefit for adjuvant chemotherapy were initially reported with median-follow-up times of 56 months, 5.1 years and 76 months for IALT, JBR.10, and Adjuvant Navelbine International Trialist Association, respectively. Long-term follow-up of patients in these trials is critical to assess whether chemotherapy is associated with a sustained survival benefit and to identify any late toxicities that may be attributable to adjuvant therapy. For example, in trials of adjuvant therapy for breast cancer the survival benefit is maintained or amplified over time.12
The data reported here from the updated survival analysis of patients on JBR.10 represents the longest reported follow-up data from any of the recent adjuvant NSCLC trials. Most importantly, with median follow-up of longer than 9 years, a significant survival benefit for adjuvant cisplatin and vinorelbine is maintained with an absolute improvement in 5-year survival of 11%. Furthermore, no significant increase in death from other causes or from other primary malignancies was observed in the patients receiving adjuvant chemotherapy.
These results differ from recent survival updates from other NSCLC adjuvant trials. CALGB 9633 initially reported a survival advantage for adjuvant carboplatin and paclitaxel in stage IB patients with median follow-up of only 2.8 years. Mature results of this study with follow-up of 74 months no longer show a survival benefit for adjuvant chemotherapy. However, there was a trend for longer OS with a HR of 0.83 and so the lack of significance may be related to a lack of statistical power for this study to detect a survival advantage in this relatively good risk population with only 344 patients and 155 events.
The positive survival advantage reported in IALT with a median follow-up of 56 months was no longer evident after 90 months.8
This appeared to be related to an increase in noncancer deaths in the chemotherapy arm after 5 years. An important finding of our updated survival analysis of JBR.10 is that deaths due to causes other than NSCLC were not increased in the chemotherapy arm. In particular, the number of deaths from cardiac or vascular causes was low in both arms.
The reasons for the difference seen in the IALT and our results are not obvious. One possibility may be related to the smoking status of the patients in the two trials. In JBR.10, 84% of patients were no longer smoking at the time of random assignment. This information is not reported from IALT. Current smoking has been reported as an independent predictor of survival in patients with NSCLC after surgical resection.13,14
Alternatively, this may be related to the relatively low incidence of comorbidity in the JBR.10 patients (28%). The Charlson Comorbidity Index score was used to assess comorbidity. Comorbidity has also been reported to be an independent predictor of survival in early-stage NSCLC.15,16
Information on the comorbidities of the IALT patients is not available. Other explanations might be the difference in chemotherapy used in the two trials or possibly the exclusion of postoperative radiation in JBR.10. Finally, there were 33 patients lost to follow-up in JBR.10, 15 in the observation arm and 18 in the chemotherapy arm. However, the likelihood of this impacting the results is remote.
Similar to our initial report, a survival advantage for adjuvant cisplatin and vinorelbine continues to be seen primarily in stage II patients. Median survival was almost double in the chemotherapy patients (3.6 v 6.8 years) with an absolute improvement in 5-year survival of 15%. Overall, patients with IB disease did not benefit (HR, 1.03; P = .87).
The analysis of stage IB patients based on primary tumor size was an unplanned analysis testing reports that primary tumor size appeared to be important in CALGB 9633.17
In JBR.10, IB patients with tumors 4 cm or greater in size did appear to derive a clinically meaningful benefit, with a similar HR of 0.66 (v
HR 0.68 in stage II patients). The lack of statistical significance may be due to the small sample size, with only 99 and 120 patients in the less than 4 cm and 4 cm or greater subgroups respectively. While this analysis by size within the stage IB subset is only exploratory, the results provide support for a similar exploratory subgroup from CALGB 9633. This study was restricted to stage IB disease and a statistically significant improvement in survival for adjuvant chemotherapy was seen for patients with tumors 4 cm or greater (P
= .043), with a HR (HR, 0.69) similar to that seen in this JBR.10 updated analysis.
However, both of these analyses were posthoc and caution should be exercised in interpreting their significance.
The original report of JBR.10 suggested a trend toward a differential effect of adjuvant chemotherapy based on the presence or absence of RAS
mutation, although the interaction term for RAS
was not significant (P
In our current analysis we were not able to demonstrate a significant interaction with chemotherapy for either OS or DSS. Interestingly, the HR for RAS
wild-type patients did show apparent benefit for chemotherapy on DSS, which was not seen in patients who were RAS
mutation positive. Two previous adjuvant trials, ECOG 459218
and the Adjuvant Lung Project Italy,19
assessed only K-RAS
and found no association with treatment effect.
Second primary malignancies (SPM) of any site were seen in 11% of the study population over the 9 years of follow-up and were similar in the two arms. This is similar to previous reports of risk of SPM in lung cancer survivors. Keller et al20
reported a cumulative SPM risk of 6.1% after 73 months of follow-up of patients in the ECOG 3590 study. In stage I patients surviving longer than 5 years after lobectomy, Kim et al21
found a 9.5% cumulative risk of SPM. Second primary lung cancers were infrequent, and more often seen in the observation arm of our study. This is lower than the 13% to 20% cumulative risk of second primary lung cancers or smoking-related cancers reported by Johnson22
in an earlier review of the literature. This may possibly be explained by the high smoking cessation rate of 84% in our trial, since the development of a second primary lung cancer has been associated with continued exposure to tobacco products in previous reports.23
In summary, this updated analysis with more than 9 years of follow-up confirms a significant survival benefit for adjuvant chemotherapy in early-stage NSCLC. The survival benefit is seen in the stage II patients. No evidence of unexpected late toxicity or increase in second malignancies from adjuvant chemotherapy was observed.