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Dr West

Risk/Benefit from Adjuvant Chemo for Early Stage NSCLC: Maturing Data Help Us Discriminate Likely Beneficiaries

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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

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

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.


6 Responses to Risk/Benefit from Adjuvant Chemo for Early Stage NSCLC: Maturing Data Help Us Discriminate Likely Beneficiaries

  • ts says:

    This is really interesting. It seems that there are many people with early stage LC who request chemo after surgery, “just in case”. (I can’t imagine wanting that! A life without chemo sure sounds attractive to me.) They may be doing themselves harm. This is quite significant.

  • Dr Pennell
    Dr Pennell says:

    In my experience, most patients have to be talked into agreeing to adjuvant chemo, and are very happy when I tell them I don’t think it will help. I don’t think anyone has ever asked for it even if I felt it was not indicated.

  • mo wanchuk says:

    Dr. West:

    Thank you again for another informative and comprehensible article. Three years ago, I was initially staged with 1B nsclc with a 4 cm. tumor in the right lower lobe. I underwent 4 cycles of adjuvant carbo/taxol after a bilobectomy. Whether this was a mistake or waste of time and energy, I’m not sure as a spinal lesion was discovered 9 months later. Nevertheless, I have to wonder if the the adjuvant chemo is a reason I’ve been able to survive asymptomatically stage iv nsclc for this time period.

  • Dr West
    Dr West says:

    Mo,

    One point I’d make is that we are learning new things all the time, and we can only do the best we can with the information available. I’ve recommended adjuvant chemotherapy for patients with stage IB tumors, and even a rare patient with a stage IA tumor, based on the information available then. I’d also say that even with the information we have now, plenty of oncologists would recommend adjuvant chemo for a 4 cm tumor. It’s not as if there’s something magical about 4.0 cm, where treatment is detrimental for a 3.9 cm tumor but helpful for a 4.1 cm tumor. It’s really a continuum where the larger the tumor, the greater the risk of recurrence. Factors such as the health of the patient and (very likely in the next few years) molecular variables are also relevant to the discussion of whether to pursue post-operative chemo. And even when it’s given, it’s going to help some, and not help (and potentially even harm) some others.

    I’m glad you’ve done so well since the cancer recurred.

    -Dr. West

  • NL says:

    Dear Dr. West,

    Thank you so much for all the wonderful expertise you provide us with on this website. You have no idea how helpful it is to us and how much we appreciate it.

    This article is of particular interest to me. I notice that you posted it in 2009, so I am wondering if there have been any further developments on benefits/detriments of chemo for Stage 1B, since that time?

    Secondly, in regards to graph #2, I’m wondering if the group “Tumour less than 4cm” included people with visceral pleura invasion, lymph-vascular invasion, or other such prognostic factors? To what extent do these or other factors play a role in recommending/not recommending chemo in stage 1B?

  • Dr West
    Dr West says:

    I don’t think there are any new data to speak to this question; my perspective is essentially the same today.

    To answer your question about other factors such as visceral pleural invasion or poorly differentiated cancer, these factors do increase risk to a modest degree, controlling for the size of the tumor, but the analysis by size included all of these factors and still emerged showing that smaller tumors just don’t get the benefit. These are complex enough issues that we still debate these points at my own tumor boards, and there are sometimes proponents of chemo for smaller tumors based on other negative prognostic features, but I would have to say that this is not the data-driven conclusion right now.

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