Combined-Modality Therapy for Early-Stage Diffuse Large B-Cell Lymphoma: Knowing When to Quit

In his recent memoir entitled Do No Harm, the London neurosurgeon Henry Marsh recounts an anecdote of a man on whom he operated who had a tumor in the brainstem. The operation began at 9:00 am and was still going on at midnight. He had successfully removed almost all of the tumor in a most risky area. Mistakes in the brainstem can be fatal or permanently damaging. Surgery on the brainstem has been likened to defusing a bomb. After a pause, he decided to continue the operation because he wanted to be able to tell the family he had removed the tumor entirely. But when he resumed the procedure, he nicked a blood vessel. In gainingcontrolof thebleeding, thebrainstembecamedeprivedofoxygen and the man never woke up. The problem for Dr Marsh with this patient was knowing when to quit. This anecdote reflects a major dilemma in cancer therapy. When have we given enough therapy to cure a person? All of our treatments have the capacity to cause harm. When is the use of these therapies of so little additional benefit that their risks outweigh those benefits? This question is the polar opposite of asking when therapy is futile at the end of life, but like many facets of medicine, the issues are similar. Futile is a label that can apply to therapy at both ends of the treatment response spectrum. Deciding when enough therapy is enough is a high-stakes question. If we stop treatment when the tumor appears to be eradicated but is not, the outcome is likely to be recurrence and death, an outcome that might have been avoided had therapy continued. Curable may become incurable, or a lot more risky treatment might be needed for cure. The question is relevant in a growing number of clinical settings, including childhood leukemia, Hodgkin lymphoma, diffuse large B-cell lymphoma, testicular cancer, and adjuvant therapy of breast cancer. Are there subsets of patients with these cancers who can be cured with less therapy? And if so, how do we identify them? Early-stage diffuse large B-cell lymphoma is one of the settings in which it has seemed that the question has been definitively answered. Historically, outcomes were excellent when multiagent chemotherapy and radiation therapy were combined. However, randomized trials have shown that the use of combined-modality therapy in patients with stage I and II diffuse large B-cell lymphoma does not improve overall survival compared with chemotherapy alone (reviewed in Sehn). The International Extranodal Lymphoma Study Group has extended these data with similar results in observational studies on patients with lymphomas of particular anatomic sites that seem to have distinctive clinical features, for example, lymphoma of the head and neck. The consensus seems to be that it is no longer justifiable to treat every patient with combination chemotherapy plus involvedfield radiation therapy. Consensus is probably the wrong word here because some radiation oncologistscontinuetoargueforaroleforradiationtherapyintheroutine management of every patient with early-stage diffuse large B-cell lymphoma. They raise the point that the randomized trials were conducted before rituximab was added to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Addition of rituximab improves the efficacy of CHOP, so now we have to go back and compare rituximab plus CHOP (R-CHOP) plus radiation therapy versus R-CHOP alone. For many of us, however, that logic is difficult to justify. Is there any reason to believethatanineffective interventionwillbeusefulwhenretestedwithan improved partner therapy? Is the idea that radiation therapy will be more effective when it has less to accomplish? The role of radiation therapy in diffuse large B-cell lymphoma has been controversial. Unlike follicular lymphoma where there is a clear dose-response curve, no dose-response curve exists for radiation effects in diffuse large B-cell lymphoma. A randomized trial showed that 30 Gy of radiation was similar to 40 to 45 Gy in local control. A retrospective study at Duke Cancer Institute involving 105 patients with stage I to IV diffuse large B-cell lymphoma irradiated to 214 sites after achieving a chemotherapy-induced complete response also found no dose-response relationship for a range of doses between 12 and 40 Gy. The local recurrence rate was low regardless of dose. The local recurrence rate after no radiation therapy was not reported. Although randomized trials have not supported its continued routine use in every patient, certain clinical situations seem to benefit from involved-field radiation therapy. Patients who achieve a partial response to chemotherapy can be converted to long-term disease-free survivors by radiating a specific site of persistent disease. Patients with bulky masses may benefit from radiation therapy, but there is no real agreement on how big a tumor needs to be to be labeled bulky. Prospective randomized studies in patients more likely to benefit from adjuvant radiation therapy are sorely needed. Our treatment recommendations are influenced by many things, including our past experience, our clinical judgment, and, wherever possible, objective data. Not all data are equally strong or persuasive. The data in which we have the highest level of confidence are those obtained from prospective randomized trials. Retrospective observational data may serve to suggest hypotheses, but their conclusions cannot be viewed as establishing fact given the potential that unmeasured biases in selecting patients for one intervention or another JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 32 NOVEMBER 1