Dr. Ganti and colleagues from the University of Nebraska provide a thorough review of the management of patients with follicular lymphoma, including many recent additions to the therapeutic armamentarium. The field is rapidly changing, and this article will be an enduring resource both for clinicians currently managing these patients and for anyone in the future who wants to understand what the state of the art was in 2004. Follicular lymphoma accounts for about one-third of non- Hodgkin's lymphomas in the United States, making it likely that an individual oncologist will see one to three patients with follicular lymphoma each year. As the authors point out, numerous active agents have been developed for use in patients with follicular lymphoma over the past 5 years and additional promising new therapeutic agents and novel approaches (eg, vaccination) are in the development pipeline. The Ganti et al review is thorough, scholarly, and up-to-date. It avoids controversy by not making strong recommendations. The authors' position is appropriate because nothing resembling a consensus exists in the management of patients with follicular lymphoma. However, I would like to address several of the current controversies directly and assess whether the new therapeutic options speak to them. In other words, how much progress have we actually made? Treatment and Survival
Does treatment improve the survival of patients with follicular lymphoma? This would seem to be the first and most straightforward question that needs to be addressed in the treatment of any type of cancer. However, after more than 40 years of concentrated efforts from many of the cleverest minds and most talented research groups in oncology, I do not believe that anyone has shown unequivocally that treating follicular lymphoma improves survival. Of course, we all believe our interventions are altering the natural history of disease. But objective proof is not easy to come by. Circumstantial evidence can be marshaled to defend treatment. For example, several studies cited by Ganti et al show that patients who receive combination chemotherapy plus interferon- alfa have longer overall survivals than patients who receive combination chemotherapy without interferon. These results imply a treatment effect. However, no prospective randomized study has compared a watch-and-wait approach (with palliative symptom-driven intervention) to primary aggressive therapy and shown a survival advantage for efforts to eradicate the disease. In our own study conducted at the National Cancer Institute (NCI), ostensibly comparing primary aggressive treatment with a watch-and-wait approach, the two arms in fact represent immediate vs delayed aggressive treatment, which is not at all the same as adopting and adhering to a palliative approach throughout the disease course. When we last updated that study in 1997, with a median followup of 13 years, there were no differences in overall survival between patients randomly assigned to aggressive treatment and those assigned to an initial watch-and-wait approach. About 75% of the patients assigned to aggressive treatment who were alive had been continuously free of cancer throughout the period of follow-up. By contrast, 75% of the patients in the watch-and-wait arm were alive with lymphoma. We are now updating the study again with a median of 20 years of follow-up. However, even if there is now a survival difference, the results demonstrate that it is possible to keep patients with follicular lymphoma alive with disease for many years. We have known this to be true since at least the 1970s. In my training, I saw patients who had received intermittent CVP chemotherapy (cyclophosphamide [Cytoxan, Neosar], vincristine, prednisone) for 25 to 35 cycles and had been progression-free for many years. This same approach is being employed now with rituximab (Rituxan), only with less concern for long-term complications. (I hope that lack of concern is justified.) None of us were under the delusion that the disease was eradicated, but both the patients and doctors were happy keeping the disease at clinically undetectable levels. What was unclear then remains unclear now: Does the act of keeping the disease at clinically undetectable levels translate to an improvement in survival? We don't know. And given all the treatment options now available (some of which interfere minimally with quality of life) and rising patient expectations, I do not believe that a controlled study can or will ever be conducted that addresses this fundamental question. Disease Curability
Are patients with follicular lymphoma curable? Most experts would likely answer this question with a "no." However, even experts who are skeptical of curability must acknowledge that some subsets of patients experience remissions of extraordinary duration. Ganti et al cite the impressively durable remissions of half of patients with stage I/II follicular lymphoma treated with radiation therapy. To this group must be added a similar subset of patients with pathologically documented stage III disease who had long remissions after total nodal irradiation treated by Glatstein and colleagues at Stanford in the early 1970s. It seems clear that radiation therapy is capable of killing follicular lymphoma cells if you can encompass all of those cells in the radiation field. Similarly, while the diagnostic criteria utilized have been both variable and inconsistently applied, many groups find that patients with advanced-stage follicular mixed lymphoma (or follicular lymphoma, grade 2) and even those with follicular large-cell lymphoma (or follicular lymphoma, grade 3) can achieve long-lasting, possibly permanent complete remissions in response to combination chemotherapy. Thus, at least some subsets of patients with follicular lymphoma are curable. In addition, the length of remission in follicular lymphoma patients is clearly increasing with the use of more aggressive and more active treatments. Rituximab certainly increases remission duration following CHOP chemotherapy (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone). Remissions lasting many years can be obtained from high-dose therapy and hematopoietic stem cell transplantation. Some remissions from radioimmunotherapy may be long-lasting. How long does a remission need to last for a patient to be considered cured? Clearly, this threshold varies with the tumor. Nearly all patients with acute lymphoid leukemia who are going to relapse do so within 5 years of achieving a remission, but that is not true of breast cancer and melanoma. No threshold for cure has been established in follicular lymphoma. But does it make sense to watch a patient with clinical stage I/II disease progress to a more advanced stage when involved-field radiation therapy has a 50% chance of producing long-term disease-free survival? We cannot say with certainty that survival would be improved, and it is possible that radiation therapy could produce unwanted late effects that could be life-threatening. However, most patients I see would prefer a 50:50 chance of being rid of the disease over watching the disease progress to an incurable stage. At the least, the 15% of patients with early-stage disease should be offered the option of treatment. Tumor-Related Translocation
What is the clinical relevance of cells in the peripheral blood that bear the t(14;18) translocation? More and more studies are employing molecular monitoring of patients, and a new remission criterion-elimination of t(14;18)-bearing cells-has been used to establish a new definition of molecular remission. It seems reasonable to assume that a remission state in which cells bearing a tumor-related translocation are absent or undetectable should be more durable than a remission state in which persistent abnormal cells are detectable. But the data simply do not support this notion. Why might it be that the presence of cells bearing the t(14;18) translocation is not a harbinger of relapse? First, as cited by Ganti et al, these cells can be found in normal people who never develop lymphoma. Nevertheless, their presence should be more ominous in someone who has actually had lymphoma that contains the translocation, shouldn't it? The detection of such cells does not mean that the cells that are the source of the signal are alive and well or capable of division and expansion. Some of these cells may be damaged and incapable of dividing. They may be sufficiently rare that they are below a threshold that can be controlled by host defense mechanisms. Other factors may explain why they are present but not a threat. They may not be able to find a niche in which to adhere and expand. It is especially dangerous to use the elimination of t(14;18) cells as a clinical end point when its meaning has not been defined. A therapy cannot be judged as superior on the basis of a higher rate of eliminating t(14;18)-bearing cells. The presence of t(14;18)-bearing cells cannot become a surrogate marker for a therapeutic end point until it is shown to accurately predict disease-free and/or overall survival, and we certainly aren't there yet. Histologic Transformation
Is histologic transformation inevitable? It is striking that autopsy series of patients with follicular lymphoma show that over 90% of patients dying with the disease have undergone histologic transformation to diffuse large B-cell lymphoma. Past studies have suggested that this transformation occurs at a rate of about 7% per year whether the patient is managed expectantly or treated aggressively. This transformation is an intrinsic biologic property of the tumor, not a treatment-related effect. It is accompanied by an accumulation of genetic lesions, including mutations in p53, that seem to be the result of the inherent mutability of a follicular center B cell. However, the rate of histologic transformation needs to be assessed again in large series of patients treated with CHOP plus rituximab (or some of the other new therapies) and followed over a period of at least 5 to 10 years. In the NCI study, patients randomly assigned to aggressive primary therapy at diagnosis had a significantly lower rate of histologic progression than patients assigned to a watch-and-wait approach. It is possible that as treatments improve, an important justification for treatment will be to reduce the risk of histologic transformation. Conclusions
We have a burgeoning number of treatment options in the clinic and a growing body of information emanating from the laboratory on the patterns of gene expression that lead to follicular lymphoma. We have not yet been able to put together these two bodies of knowledge to design therapies that target particular molecular vulnerabilities in follicular lymphoma cells, but the day when that will be possible is not far off. If a new therapy or a combination of old and new therapies represents a true treatment advance, it will likely take us at least a decade to recognize it. Follicular lymphoma treatment is not a field of research upon which an ambitious young investigator should hang his or her hopes. The impressive ability we have to employ a wide range of therapies to keep people alive (with both disease we can see and disease we can't see) serves to cloud the most persuasive end point-overall survival. We cannot yet be sure that our current therapies are actually improving survival. However, when we develop a therapy that produces long-term remission of the disease, we will know it. Most of our patients would prefer survival without disease to survival with disease if the price they pay in treatment side effects is well-defined and limited.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Glatstein E, Fuks Z, Goffinet DR, et al: Non-Hodgkin’s lymphomas of stage III extent. Is total lymphoid irradiation appropriate treatment? Cancer 37:2806-2812, 1976.