Radiation therapy for stage III follicular lymphoma-often ignored, but still effective.

Almost a quarter of all non-Hodgkin’s lymphomas are pathologically characterized by the presence of a follicular architecture. The follicular lymphomas are commonly composed of small cleaved cells (Grade 1), may contain a mix of small cleaved and large cells (Grade 2), or less commonly, only large cells (Grade 3). These lymphomas, called “nodular” in the past and later termed “follicular follicle center cell lymphomas” by the REAL classification, or simply “follicular lymphomas” (FL) by the new WHO classification, originate from the lymphatic germinal center B-cells (1). They typically contain a translocation between chromosomes 14 and 18 that is associated with over-expression of BCL2—the antiapoptotic protein. The follicular lymphomas present a clinical challenge. Paradoxically, although indolent in nature and initially responsive to different treatments (radiotherapy, chemotherapy, and immunotherapy), patients often relapse and are considered by most to be incurable. Adding to the confusion of both patients and physicians dealing with FL is the wide range of treatment options, ranging from a “watch and wait” policy to high-dose therapy with autologous, and even allogeneic, stem cell transplantation (2, 3). Further, many patients with FL present with Stage IV disease, often because, in addition to their nodal disease, a patient’s bone marrow biopsy will disclose aggregates of lymphoid cells that rarely interfere with bone marrow function. The staging classification for follicular lymphomas, as for all other lymphomas, is the Ann Arbor staging system that was originally (1971) designed for Hodgkin’s disease and was influenced by the radiation-field options available at that time. In recent years, as for Hodgkin’s disease, most studies condensed the four Ann Arbor stages into two categories: early-stage (Stages I–II), comprising about 20% of all FL, and advanced-stage (Stages III–IV), involving the majority of patients. Although the proportion in different series may vary, it appears that in the British Lymphoma Investigation Group studies approximately half of the patients with “advanced-stage” had Stage III disease (4, 5). The grouping into earlyand advanced-stage was driven by the notion that most patients with early-stage were considered appropriate candidates for local therapy—radiation. On the other hand, the advanced-stage patients were deemed incurable, and the treatment strategy for them was primarily palliative, centered on systemic, relatively nonaggressive chemotherapy (2). Patients with “advanced-stage” low-burden disease are also prime candidates for the watchful waiting approach (3). Clearly, lumping Stage III and Stage IV patients into the same treatment category does not allow a distinction: Stage III disease is still clinically limited to nodal sites and is thus encompassable by standard radiation fields, whereas Stage IV lymphoma involves extranodal sites (primarily the bone marrow) and thus standard radiotherapy is not a curative option. Does this approach, in which Stage III and Stage IV are combined into one category, limit the chance of some patients with Stage III disease being cured? The impressive long-term results from Stanford University of patients with Stage III disease treated with primary radiotherapy, published in this issue of the Red Journal, suggest that it might (6). The follicular lymphomas are highly sensitive to ionizing radiation, and relapse in an irradiated site is quite unusual (7). Almost half of patients with Stage I or II follicular lymphomas remain free of relapse 10 and 15 years after treatment with radiation alone (8), and relapse after 10 years is a rare event (9). Follicular lymphoma in early stages is thus a curable disease for a substantial number of patients (4). It is of interest that no difference in outcome between Stages I and II was detected in series of patients for whom relatively large fields of radiation were used (9). Stage determination of lymphomas has changed over the last four decades. The Stanford series of Stages I–II and the updated Stage III study used lymphangiography for all patients and staging laparotomy for approximately half of the cohort. These two staging tools are rarely used today. Yet, there was no difference in outcome between patients who were staged by laparotomy and those who were clinically staged. Most patients today are staged on the basis of modern, high-resolution computerized tomography, and it is conceivable that more patients are considered to be clinically Stage III (or “advanced-stage”) than in the past. Over the last decade, the availability of molecular techniques (PCR) to detect the t(14; 18) translocation not only in the biopsy specimen, but also in peripheral blood or bone marrow cells, added a new facet to assessing the clinical behavior, prognosis, and response to treatment of FL. Although the clinical significance of the molecular findings is still questionable, the emerging information is challenging. For example, the significance of detecting circulating cells with t(14; 18) in patients in continuous clinical remission for longer than 10 years after the diagnosis of advancedstage FL(10), and even in patients in remission after radiotherapy for early-stage disease, is unclear, and its effect on prognosis is yet to be determined (11, 12). Yet, recent data suggest that patients who achieve a molecular response and sustain it had better failure-