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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Pre-Operative Chemotherapy as an Alternative to Post-Operative Chemo: Evidence of Stage-Dependent Survival Benefit
Sun, 07/13/2008 - 08:08
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

In contrast with post-operative chemotherapy, which has become a standard treatment approach to reduce the probability of recurrence of resected stage II and IIIA NSCLC (still pretty controversial for stage IB), pre-operative chemotherapy (also known as neoadjuvant, or induction chemotherapy) is less well studied and isn’t a typical approach. However, a recent study called ChEST, the Chemotherapy in Early Stages Trial, was presented at ASCO (abstract here) and showed a borderline positive survival benefit with neoadjuvant chemotherapy, despite the fact that the trial was stopped very early. As a trial of chemo followed by surgery vs. initial chemo followed by surgery, and post-operative chemotherapy had been shown in several trials to improve survival in this population, the Data Safety Monitoring Board felt it was unethical to continue a trial in which half the patients receive no opportunity for chemo either before or after surgery.

As shown below, the trial enrolled 270 of an initially planned 700 patients before closing early, and these patients were randomized to receive upfront surgery or three cycles of cisplatin/gemcitabine followed by surgery:

ChEST Schema

Importantly, more than half of the patients enrolled had stage IB or IIA disease. As you’d expect, this group has a better prognosis than patients who have stage IIB or IIIA resected NSCLC, and therefore potentially less to gain from chemo.

You’d presume that giving chemo is at least as beneficial in treating micrometastatic disease before compared with the same target of 3-4 cycles after surgery. In fact, not only are you able to administer chemo 6-8 weeks earlier, which might help by treating potential circulating tumor cells earlier, but you’d imagine that it’s easier to get your intended chemo into patients who aren’t still recovering from a major surgery. In fact, nearly all of the adjuvant chemotherapy trials show that only about 65-75% of patients get at least 3 cycles of intended chemo into them. In this trial, three cycles of preoperative chemo were able to be given as intended to about 85% of patients. This suggests that there may be a meaningful advantage of pre-operative vs. post-operative chemo in this regard.

Another potential advantage of neoadjuvant chemo is that you can get a sense of how well your treatment worked by assessing the cancer with a repeat CT, and it’s possible that patients can undergo a less extensive surgery if their tumor shrinks from pre-operative chemo: specifically, that some patients who would otherwise need an entire lung removed (pneumonectomy) will have enough tumor shrinkage that they can now just have a lung lobe removed (lobectomy). This trial showed that three cycles of cisplatin/gemcitabine was associated with a 35% response rate; importantly, the pneumonectomy rate was reduced from 24% with upfront surgery to 10% with chemotherapy beforehand.

Despite enrolling only 270 patients instead of 700, the trial showed a good trend toward improved progression-free survival in the recipients of pre-operative chemo:

ChEST PFS Curve

Neoadjuvant chemotherapy was associated with a more convincing improvement in overall survival (p = 0.053), which was 7% higher with chemo than with surgery alone:

ChEST OS Curve

These results are in the same ballpark of benefit as we’ve seen with adjuvant (post-operative) chemotherapy. But I was struck by the remarkably difference between the results for the better risk patients (stage IB and IIA) compared with those of the higher risk patients (stage IIB and IIIA). The benefits for both progression-free and overall survival were completely limited to those patients with higher risk:

ChEST PFS by stage

ChEST OS by Stage

And as we’ve covered in my last post, it looks like there may even be a detrimental effect of treating the earlier stage patients with chemotherapy.

At this point, even if neoadjuvant chemotherapy provides a clinical benefit as great as that with post-operative chemotherapy, it probably needs to emerge as significantly better than adjuvant chemotherapy to become a standard approach. There is a Spanish trial that is directly comparing pre-operative carbo/taxol to post-operative carbo/taxol (the NATCH trial, which stands for Neoadjuvant vs. Adjuvant Taxol/Carbo Hope). But just as I suspect that pre-operative chemo is at least as good as post-operative chemo, I’d really be surprised if giving the same chemo a couple of months earlier is actually going to be significantly better. So for now, pre-operative chemo for early stage NSCLC is a reasonable option but really isn’t considered a standard at this point.

Interestingly, stage IIIA NSCLC with N2 node involvement in North American is more typically treated with neoadjuvant therapy. I believe that’s partly because the benefits of neoadjuvant therapy with at least chemo were established more than a decade ago, so it is the standard that hasn’t been displaced by the new upstart of post-operative chemo. Another important factor, I believe, is that many experts recognize that many patients who go to surgery never end up getting to chemo, due to complications. In stage IIIA NSCLC, we feel that chemo is so important that you need to ensure you get it along with surgery, while in earlier stage lung cancer, the surgery is much more important than the chemo that is perhaps a modest modifier. If patients have surgical complications that preclude them from getting chemo for stage I or II disease, they’ve still gotten the treatment approach that is most critical for their potential cure.

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