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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.

Japanese Study Demonstrates Elderly Patients Benefit from Post-Operative Chemo
Mon, 08/04/2008 - 20:30
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

In Japan, a different chemotherapy approach than cisplatin doublet chemo has been used in the post-operative setting. In contrast to the North American and European approach of 3-4 cycles of platinum-based chemo, in Japan they have studied an oral chemotherapy called UFT, a combination of uracil and tegafur. This combination is in the same family as an old chemo drug called 5-FU that is still used in various settings today, although not commonly in lung cancer. Nevertheless, this oral chemotherapy, which isn't and probably won't become available in the US and several other parts of the world, has been studied in a Japanese population and actually shown to improve survival in patients with stage I NSCLC. And this year we saw an analysis of the benefit of chemotherapy on the basis of patient age in this trial (abstract here).

The original trial enrolled just under 1000 patients with stage I adenocarcinomas (a remarkably common presentation in Japan, where they really do see a fundamentally different lung cancer biology than we see in North America and Europe, at least). This focus on patients with adeno NSCLC is based on earlier work that indicated this drug worked preferentially in adenocarcinoma tumors, and randomized patients with stage I tumors to observation or up to two years of daily oral chemotherapy after surgery (abstract here). As shown in the curves below, there was a modest but significant survival benefit, and nearly all of that benefit was seen in patients with larger, higher risk T2 cancers, rather than the smaller T1 cancers with the lowest risk for recurrence and death:

Tsuboi kato overview

Interestingly, this is really the most conclusive survival benefit we've ever seen for stage I NSCLC, and in the curve for the overall trial population (left curve), the separation of the curves that signifies a survival benefit from treatment doesn't occur until four years out. Unfortunately, this is with a drug not available in the US and was a benefit seen only in patients with stage IB adeno NSCLC: we haven't been able to do another study with UFT to confirm this, but it's currently a standard treatment in Japan.

As is typical for every large study of post-operative chemotherapy thus far, the clear majority of patients were relatively young. In the analysis presented at ASCO this year (abstract here), the investigators divided patients into three groups: the young patients were under 65, and comprised 56% of the trial population, a 65 -69 year-old group that comprised 25% of the patients, and patients 70 and older, who constituted the remaining 19%.

What they found was that the older patients actually derived more of the benefit than the younger patients, as illustrated by the clear separation of the curves in the figure on the right, below, while the younger patients (middle and left figures) received less of a benefit from the post-operative UFT:

Tsuboi UFT analysis by age

One of the other interesting aspects of this analysis is mentioned in the lower part of the slide here. Just as with IV chemo, people dropped off of treatment as it continued. Although this was a relatively mild oral chemotherapy, patients of all ages were increasingly likely to report not taking the drug consistently as the time on study continued, so that by 2 years out, only about 60% of patients reported taking the drug as directed. And older patients were more likely to drop off than younger patients at every six month time point, so that by the two year end of the study, less than half of the older population remained on the study drug. This was largely due to patient preference, although the side effects in older patients were a bit more severe, primarily in terms of liver function test abnormalities and diminished appetite and oral intake.

These results may sound familiar. In fact, in the retrospective analysis of older patients on the adjuvant chemtherapy trial led by NCI-Canada and comparing cisplatin/navelbine for four post-operative cycles vs. monitoring and supportive care alone, older patients also received less chemo overall but had a numerically greater benefit from the chemo they did receive (as reviewed in prior post here). So now we have results with both IV and oral chemo, from both North America and Japan, all showing the same results of a clear survival benefit that even appears to be more pronounced than in younger patients, despite older patients experiencing more side effects and being more likely to come off of treatment earlier. While it's important to remember that these patients are likely fairly selected as good candidates to go on a clinical trial with aggressive anticancer therapy, there is certainly no evidence to say that fit older patients don't benefit from and shouldn't be offered adjuvant therapy to improve their likelihood of prolonged survival from early stage NSCLC.

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