A Look in the Mirror

Prospective clinical trials can be difficult to conduct, starting with the basic first step of enrollment. Without the structure of a clinical trial, default off-protocol option(s) can be relatively straightforward in some diseases, such as the choice of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or a variant in diffuse large B-cell lymphoma (DLBCL). Conversely, the report by Friedberg et al in the current issue indicates that the options exercised in the United States in follicular lymphoma (FL) are so diverse as to seem chaotic. We should not be surprised. Published guidelines, such as those of the National Comprehensive Cancer Network, show that there is indeed no single standard of care. There are numerous effective options for patients with advanced stage FL, and none is the clear winner (ie, there is no curative option). Hence, a variety of options are selected. The unpleasant surprise is that motivated practitioners, both in community and academic settings, are content to treat FL patients off protocol, rather than seek out pertinent clinical trials that can generate answers about the relative benefits of these various treatment strategies. The problem is not unique to the United States: a report from Germany by Dreyling et al indicates that only 10% of German patients are enrolled on clinical trials, not much better than the 6% rate reported by Friedberg et al. What are the issues? Is data collection a deterrent to clinical trial participation? The LymphoCare project shows that many physicians in private practice are motivated to collect information, and are willing to take a self-critical look at their own practice patterns. To be sure, the LymphoCare project shows that some important and relevant data (eg, some of the components of the Follicular Lymphoma International Prognostic Index [FLIPI] prognostic model) and even key information for basic Ann Arbor stage assignment, are not routinely collected. A disparity between academic and community physicians with respect to stage assignment is noted in the Friedberg et al 2 report, which in part relates to a lower frequency of marrow sampling in the community as opposed to the academic setting. Even among academics, marrow sampling was omitted 36% of the time. Why? Perhaps partly because models such as FLIPI and the International Prognostic Index 6 lump together stages III and IV: if the stage assignment is already stage III, the importance of sampling the bone marrow is downplayed. But opting out of performing a baseline bone marrow analysis is a bad idea, for many reasons. First, prognostic models come and go, and get refined. For instance, an eight-factor preliminary version of the FLIPI model included bone marrow involvement. A new prospective FL prognostic factor project also emphasizes the importance of marrow involvement, as well as the role of beta-2 microglobulin (B2M). B2M data were not reported in the Friedberg et al 2 project, but B2M is another parameter that deserves to be considered as a standard baseline test. B2M is a simple, quantitative, and important predictor that was recognized in the univariate analyses in both the International Prognostic Index and FLIPI projects, and possibly would have been incorporated in the models if more patients’ B2M data had been available. A second reason to sample the bone marrow is that the nuance of stage III versus stage IV is important with respect to radiation therapy, which can sometimes be a valid option in stage III, but is seldom appropriate in stage IV situations. Third, the presence of bone marrow involvement and its extent is important if radioimmunotherapy (RIT) is a treatment consideration, since extensive marrow involvement would be a contraindication to this approach. This is not just an academic issue. There is encouraging recent literature about the effectiveness of incorporating RIT into first-line therapy programs for FL. A questionably significant observation in the Friedberg et al report is the different frequency of grade 3 disease at academic sites compared with community practice. There was no slide review in the LymphoCare project, so this perceived difference should probably be discounted. But the histopathology issue deserves comment, and the grade issue is a convenient starting point, since patients with follicular lymphoma, grade 3 (at least those with grade 3b), should be treated aggressively. The clinician, the hematopathologist, and the surgeon have to work together to ensure that adequate biopsy material is obtained. The Friedberg et al article does not report whether their patients’ FL diagnoses were based on fine needle aspirate, core biopsy, or excisional biopsy, and this in an important issue. It is also important that the diagnostic biopsy come not necessarily from the most expedient or easy site to biopsy, but from a clinically pertinent site (eg, a growing or bulky site), or one with high metabolic activity if a PET scan is done. One of the most startling findings of the Friedberg et al report is the common choice of deferral of therapy for approximately 25% of patients with stage I/II disease. One of the cornerstones of the “watch and wait” argument is the incurability of advanced stage FL. Stage I/II FL is a conspicuous exception, since cure is possible in almost half of patients with stage I/II FL with involved field radiation therapy. Promising attempts have been made to improve the cure rate by the use of combined-modality therapy. Of course, deferral of therapy can be done, sometimes for years. But if progression occurs as disseminated disease, the opportunity to offer potentially curative therapy has been squandered. The National Comprehensive Cancer Network guidelines suggest that, in stage I/II FL, deferral be considered mainly when there are extenuating circumstances. Concerning the general topic of deferral of therapy for patients with advanced stage FL, the Friedberg et al report makes an interesting geographic observation. Practitioners in the northeastern United JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 8 MARCH 1