Over the last 5 years, it’s become standard to consider and often recommend post-operative chemotherapy to patients with higher risk, early stage lung cancer in order to reduce the risk of it recurring and increase the cure rate. In that time, we’ve also seen that there are subgroups of patients who may be harmed by chemo. This may be because their risk of recurrence is not high enough to justify the potentially detrimental effects of adjuvant chemotherapy, or because they are relatively resistant to chemo, or a combination of these issues.

One of the most influential messages from a trial in which carbo/taxol was given to patients with resected stage IB lung cancer is that the patients with tumors 4 cm and larger seemed to benefit from chemo, while those with tumors smaller than 4 cm did not. This is still a controversial point: another important trial, known as BR.10, was led by NCI-Canada gave cisplatin/navelbine to patients with stage IB and II resected NSCLC and showed a 15% improvement in 5-year survival, but the publication showed that the benefit was only in the patients in the stage II category. Stage IB patients didn’t get the benefit with post-operative chemotherapy.

This past ASCO included a presentation of the longer-term, updated results for that BR.10 trial of adjuvant chemo vs. observation alone. These updated reports are really relevant, because we need to care about long-term survival, and more mature follow up of the IALT trial and some other work has shown that some of the early survival benefits may weaken with longer-term follow-up. In contrast, the more mature analysis from BR.10, with a median follow-up of 9 years, shows that the advantage with chemotherapy is still significant over time, with 5-year survival at 67% vs. 56%.

BR.10 Trial Mature OS Results

(Click on figure to enlarge)

What I found more interesting was the breakdown of the results within the stage IB category. As in the US-based CALGB study, there was a clear difference in outcomes for patients with tumors of 4 cm or larger compared to those for patients with smaller tumors.

BR10 Trial Stage IB OS by Tumor Size

The results aren’t statistically significant, but the study wasn’t designed to test differences in subgroups (tumor size) of subgroups (stage: IB vs. II). But living in the real world, we need to make treatment recommendations in which there are potentially harmful consequences of overtreatment as well as undertreatment. In other words, we can’t necessarily rely on the comfort of statistics to tell us exactly what to do and actually need to interpret the results ourselves. One very concerning factor is that in the BR.10 trial, not only was there no benefit for stage IB patients with smaller tumors, but there was actually a nearly significant detrimental effect of chemo. This is worse than was seen in the CALGB trial, in which the effect of chemo in this group was neutral. As in the CALGB trial, there was a very strong trend of a benefit in the stage IB patients with larger tumors on the BR.10 study.

We are coming to recognize increasingly that there are also molecular variables that may help us differentiate higher risk from lower risk cancers, independent of clinical stage, and more work is emerging on the biological discriminators. But in the meantime, exact stage and tumor size are emerging as consistent factors that should arguably impact our recommendations for adjuvant chemotherapy, and we are seeing that more treatment is not always better and in fact may be worse.

Overall, then, this is another example of the important ongoing theme of personalizing treatment recommendations to provide the most benefit for every individual patient. But I would now be very wary about recommending chemotherapy for a patient with a stage IB tumor that is smaller than 4 cm, at least outside of a clinical trial.