Curability of Advanced Indolent or Low-Grade Follicular Lymphomas: Time for a New Paradigm?

As oncologists, we have for decades accepted two major paradigms that have shaped our management of non-Hodgkin lymphomas (NHLs): the current incurability of advanced indolent or low-grade NHL and the potential curability of most types of histologically aggressive NHL.Essentially all working oncologists have been raised under these precepts to the point that they have become our operational doctrine and sometimes our practicing dogma.After so many years, it is fitting to examine the basis for these two paradigms.The first paradigm in essence tells us that advanced low-grade NHLs are incurable disorders marked by multiple relapses in which the average patient survives for 6 to 9 years.With the advent of rituximab, their average survival has been lengthened to Ն 10 years.This paradigm is the basis for the watch-and-wait approach first promulgated by the Stanford group, 1,2 the origins of which stem from the fact that if the disease behaves indolently and is incurable, why treat it?Indeed, a few randomized trials that have attempted to look at early intervention have failed to prove superiority in survival over watch and wait. 3,4he second paradigm states that aggressive NHLs are potentially curable, and if a patient survives disease free beyond 2 years, he or she can be considered cured.The source of this practice standard can be traced back to a report by De Vita et al, 5 entitled "Diffuse Histiocytic Lymphoma, a Potentially Curable Disease," published in Lancet in 1974.It described a total of 27 patients with what used to be called diffuse histiocytic lymphoma, which is now designated diffuse largecell lymphoma (DLCL).Of these 27 patients, 10 achieved complete remission, and of these 10, only one experienced relapse.On the basis of these nine so-called cured patients, they concluded that "survival free of disease beyond two years from the end of treatment may be considered tantamount to cure." 5(p248) Having summarized the basis and origins of these two paradigms, it is now appropriate to examine their legitimacy.Because these paradigms have shaped our thinking throughout decades, these issues are not of merely academic significance.If we accept that indolent NHLs are indeed incurable, then the research questions that we will ask, as well as the therapeutic goals that we will set, can be fogged by this concept of incurability.The primary goals of phase II trials can then become response rate and progressionfree survival; cure can turn into a nonissue, thus leading to discovery of multiple new active agents but not to the development of an integrated curative strategy.