Getting back to the issue of differences in side effects and efficacy of treatments based on differences in individuals and populations, let’s continue the story of how different populations appear to have significant differences in how the do on the same treatment regimen. In a recent prior post I described the SWOG-Japanese research collaboration to compare treatment with the carbo/taxol combination for patients with previously untreated advanced NSCLC and the same eligibility requirements – these results demonstrated superior survival despite significantly greater hematologic toxicity in Japanese compared with North American patients. Is this an isolated occurrence, and do we have any potential explanations for why we might see population-based differences?

When we look for it, we can also see racial/population-based differences in the setting of extensive disease SCLC. In fact, racial differences may be very relevant, because several years ago a Japanese trial by Noda and colleagues was published in the New England Journal of Medicine (abstract here) as a potential change in the standard of care. This study closed early, with only 154 patients enrolled, after showing highly significant improvements in response rate and, more importantly, survival for recipients of cisplatin/irinotecan vs. the older standard of cisplatin/etoposide (see prior post for further discussion). Following this publication, the cisplatin/irinotecan combination for ED-SCLC was widely considered to be a standard of care, an appropriate option, but many and probably most US-based oncologists wanted to learn whether the superior results with cisplatin-irinotecan would hold true in a North American trial. This wasn’t due to xenophobia, but rather a recognition that a trial with just 154 patients that stopped early is pretty small to change the standard of care for more than a decade, and irinotecan might be more challenging and/or less effective outside of Japan. This could be based on the longer experience of Japanese oncologists with irinotecan – the drug was developed there – or it could be from population-based differences.

In fact, a subsequent industry-sponsored US-based trial (abstract here) of cisplatin/etoposide vs. cisplatin-irinotecan failed to demonstrate an improvement in survival on the irinotecan arm, but it changed the doses and schedule of chemo from the Japanese trial in order to make the treatment more user-friendly. The true test would be from a US-based trial conducted by SWOG that would recapitulate the same doses and schedules of cisplatin/etoposide and cisplatin/irinotecan that were used in the Japanese ground-breaking trial:

This trial that will serve as a tie-breaker completed enrollment over a year ago, but survival results were too immature for the results to be presented at ASCO last year. Instead, we learned some side effect results and await the final, survival results, which should be presented at ASCO 2008, in early June.

Dr. Primo Lara from the University of California at Davis presented the side effect analysis of the SWOG 0124 trial at ASCO 2007 (abstract here). This report was quite interesting, as we saw that Japanese patients again had significantly more of a drop in their neutrophil counts (white blood cells that fight bacterial infections) and also their leukocyte counts (white blood cells that help fight viruses); Japanese patients also had far more significant than US-based patients who received the same chemo regimens, but there weren’t significant differences irinotecan-induced diarrhea, which can be serious enough to require patients to be hospitalized. Interestingly, the differences in blood counts between Japanese and American patients were observed for both the cisplatin/irinotecan and cisplatin/etoposide arms:

In order to understand why these differences may exist, the leaders of this collaboration between the Southwest Oncology Group (SWOG) and Japanese researchers have been looking at single nucleotide polymorphisms, or SNPs (pronounced “snips”). A nucleotide is the smallest unit of DNA coding, and these SNPs are very small differences in the DNA of several important genes, many of which are very important in drug uptake, metabolism, and receptor binding. So these SNPs produce much of the normal variability we see in the world in drug handling, both within populations and between one broad population and another.

There are certain SNPs, producing varying degrees of gene function, that have been found to be associated now with longer progression-free and overall survival, higher response rate, and greater degree of neutropenia or diarrhea when analyzing the results of a broad range of SNPs.

The actual names for all of these variables are complex (such as CYP3A4*1B), and the data are very complex but not as important as the general idea. In addition, this work is still very investigational, so it isn’t time yet start testing blood of individual patients to look at these profiles in order to predict whether a treatment will be more or less effective, or particularly toxic. But I hope this gives a sense of where the field is going, and also why it may be possible for various chemotherapy drugs, in addition to the EGFR inhibitors, to behave very differently in different parts of the world, both in terms of efficacy and tolerability.