Tuesday, December 21, 2010

Are Survival Statistics for Follicular Lymphoma Changing?

As I have warned before, survival statistics for cancer, especially for indolent cancers like follicular lymphoma, can be highly misleading. Median figures say little about where most people actually fall on a curve. And it is still a curve -- there's no way to say where on that curve your particular data point sits. Plus, that curve applies only to historical patients, not (necessarily) to current ones. The 5-year survival curve published today applies only to patients diagnosed 5 years ago.

One historical problem is clear in follicular lymphoma, though: it's easy to induce a partial remission with chemotherapy, and fiendishly difficult to actually extend lifespan with effective treatment. This is one of the basic realizations that informs the "watch & wait" strategy of today: hold off on the hard drugs, because early treatment doesn't really help much. Alkalating agent-based protocols, like CHOP, had only modest effects on overall survival.

Then rituximab came along. Actually, that particular anti-CD20 monoclonal antibody was simply the first in a series of revolutionary new lymphoma drugs, but it has resulted in massive change in the statistical picture. The question now is how much overall survival has changed in the past decade, and whether that means altering our understanding of how follicular lymphoma should be treated. Which is why studies like the recent immediate-maintenance-rituximab trial get press despite their obvious flaws. So how far have we come, anyways?

Over the past five years, several retrospective studies have started trying to answer that question. Most of them take the form of statistical analyses, either of consecutive trials at single institutions or of large quantitative databases like America's SEER. Patients are grouped into periods or eras defined by a handful of widely accepted treatment protocols, and then survival estimates between those groups are compared. The results are interesting, and show that survival rates are increasing not just in one country or in one subset of patients, but across the board. Not that the task is over, of course, but there are always grounds for optimism.

Two single-institution studies provide a useful review of the available evidence, although both of them are now old enough that they don't show the real long-term benefits, if any, of the rituximab era. In the first, a 2006 study in the Journal of Clinical Oncology, Qi Liu et al. examined clinical trials of Stage IV follicular lymphoma patients at the M.D. Anderson Cancer Centre in Texas from 1972 to 2002. 580 patients over the full thirty-year span had a median life expectancy of 12 years, they reported, which already sounds above average and may indicate carefully selected populations for the clinical trials. Another pre-rituximab survey, published in 1993, estimated that the median (50%) survival rate was 9 years.

In that span of time, the best trials at Anderson (which I assume is the ones they hand-picked) went from CHOP combined with Bleomycin (1972-1982), to CHOP-Bleomycin followed by interferon-a maintenance (1982-1988), to alternating treatments with IFN-a maintenance (1988-1992), to fludarabine-based combinations (1992-1997), to fludarabine- and rituximab-based combinations (1997-2002). In that same time, 5-year survival rates jumped upwards from a dismal 64% to an encouraging 95%.

The Anderson review is corroborated by a similar review of patients at the Oncology Institute of Southern Switzerland, between 1979 and 2007. Annarita Conconi et al. classified 281 patients into three eras of treatment: alkylating agents (to 1989), aggressive combination regimens (1990-1999), and the "rituximab era" (2000-2007). This study looked at cause-specific survival rather than overall survival -- meaning they counted only those deaths which were directly linked to the underlying disease. In this group of patients, survival improved from 80% to 91%. A third review, of trials in the Southwestern Clinical Oncology Group, also found that 4-year overall survival rates increased from 70% after CHOP to 91% after R-CHOP.

In short, the development of new therapies, especially rituximab, seems to have cut the risk of death over 5 years at least in half, and quite possibly more. As we anticipate the next generation of anti-CD20 antibodies and, beyond that, a wide range of exciting new inhibitors, there is therefore reason to be hopeful.

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