Lymphoma: Many Questions, Too Few Answers

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The successful treatment of malignant lymphoma has been one of the great achievements in medical oncology, but certainly more work is needed to define key biologic targets as well as molecular markers for a more accurate definition of prognosis following therapy. In day-to-day practice, unanswered questions arise in the management of these diseases. Nevertheless, a profusion of new agents is emerging from the biotechnology industry, requiring clinical assessment for safety and efficacy. Meanwhile, we encounter clinical situations for which there are still no answers as to the appropriate therapy, balancing risks and benefits.

George P. Canellos, MD

George P. Canellos, MD

Clinical Trials Needed

I am prompted to enumerate situations where appropriate clinical (preferably prospective randomized) trials could have or should have been done to facilitate clinical decisions. To mention just a few issues that have arisen recently:

A form of extranodal lymphoma called mediastinal large cell lymphoma, which occurs in younger patients, has biologic and clinical similarities to Hodgkin lymphoma. As with localized Hodgkin lymphoma, there is a propensity to add mediastinal radiation therapy following chemotherapy. Also as in Hodgkin lymphoma, however, it is unclear whether the addition of radiation adds anything for a patient achieving an excellent response to chemotherapy including a negative positron-emission tomography (PET) status.

The rarity of the disease would require a broad multigroup, multi-institutional effort to assess the need for radiation therapy in a randomized trial. These generally young patients would be at risk for the well-recorded, long-term complications of radiation therapy already known to occur in Hodgkin lymphoma survivors. Further, the optimal chemotherapy is unknown. Well-published Italian studies advocated MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, plus bleomycin) given over 3 months.1 With the addition of rituximab to our armamentarium, it would appear that CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, plus rituximab) may be as effective.2 This uncertainty could be solved by an appropriate clinical trial.

Other Unanswered Questions

Another issue arises in elderly patients with lymphoma requiring systemic therapy. Because of age and/or cardiac problems, there is a concern that anthracyclines pose a threat of cardiac toxicity. Liposomal encapsulated doxorubicin has not been shown to penetrate cardiac muscle. Whether this anthracycline, in reality, allows for chemotherapy with a CHOP-R–type regimen in older patients is unknown. A prospective trial could compare CHOP-R to CHOP-R (liposomal) in elderly patients with large cell lymphoma, but surprisingly this has never been done. As a result, patients might receive increasingly reduced doses or alternative regimens that might be inferior.

Orally administered chemotherapeutic agents have potential appeal for patient convenience in avoiding hospital infusion visits. Oral fludarabine has FDA approval and is used widely in Britain and Canada but has had minimal exposure in the United States. In the emerging era of cost-saving in cancer care, this issue will come to the fore if oral drug pricing is realistic and less than infusional therapy.

The daily practice of lymphoma medicine is often determined by phase II trials conducted by single institutions. However, the data in such trials may reflect selection bias of investigators and unique referral patterns to institutions. A number of “standard” regimens such as CHOP or ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) had their position solidified by prospective, randomized trials.3,4 One has only to recall the impact of the Southwest Oncology Group (SWOG) trial that randomized CHOP against three more complicated regimens generated by single institutions.5 It has been noted that an increasing number of phase III randomized trials are being conducted outside the United States, given existing and emerging impediments to U.S.-based clinical trials. Although American geography and lack of centralized cancer care (as can be found in many European countries) are significant factors, NCI must seek solutions to improve the system.


A larger list of unanswered questions in daily practice abuts the issues of cost and lack of scientific evidence—for example, what is the overall survival value of rituximab maintenance for follicular lymphoma, and does CNS prophylaxis in large cell lymphoma significantly decrease the incidence of CNS relapse? Clinical trials have done a great deal to formulate the practice of lymphoma oncology. With the introduction of new agents and new targets, the clinical trials process needs to be expanded and supported by NCI and other independent funding mechanisms. The cancer clinical trials system has been described as a “chronic but curable crisis.”6 The Institute of Medicine’s recommendations for changes in the system need timely implementation.7


1. Zinzani PL, Martelli M, Bertini M, et al: Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: A retrospective multi-national study on 426 previously untreated patients. Haematologica 87:1258-1264, 2002.

2. Savage KJ, Al-Rajhi N, Voss N, et al: Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: The British Columbia experience. Ann Oncol 17:123-130, 2006.

3. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992.

4. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: Report of an Intergroup trial. J Clin Oncol 21:607-614, 2003.

5. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

6. Young RC: Cancer clinical trials—a chronic but curable crisis. N Engl J Med 363:306-309, 2010.

7. Nass SJ, Moses HL, Mendelsohn J (eds): A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Institute of Medicine. Washington, DC, National Academies Press, 2010.

Dr. Canellos is William Rosenberg Professor of Medicine, Harvard Medical School, and Dana-Farber Cancer Institute, Boston.