Going Beyond CHOP in Advanced Large-Cell Lymphoma

LUGANO, Switzerland—Although a decade’s worth of phase II studies in advanced large-cell lymphoma have suggested that new, multidrug regimens could nearly double both the complete response rate and the proportion of long-term survivors, appearances can be deceiving, Richard Fisher, MD, Coleman Professor of Oncology, Loyola University Medical Center, Maywood, Illinois, said at the VII International Conference on Malignant Lymphoma.

Dr. Fisher underscored this contention with new long-term follow-up data from the 1993 SWOG/ECOG 8516 trial, which compared CHOP with three intensive chemotherapy regimens, m-BACOD, Pro-MACE-CytaBOM, and MACOP-B. After 7 years, progression-free survival was 33% to 38% and overall survival was 45% to 46%, with none of the third-generation regimens exhibiting any significant advantage over CHOP.

The misleadingly favorable results of earlier phase II studies, Dr. Fisher said, are probably attributable to the inadvertent inclusion of more low-risk patients in nonrandomized trials.

“Although CHOP remains the standard, as good as any with the least toxicity, it is unacceptable for the long term because it fails to cure more than half of patients,” Dr. Fisher stressed.

Four New Strategies

At least four strategies are being explored in an attempt to boost the disappointing cure rates in lymphoma. Whether doubling the dose intensity of CHOP with the use of cytokines will be enough to modify the natural history of lymphoma was the focus of the just-completed SWOG 9349 trial.

Another approach that has aroused considerable interest is to surmount drug resistance with chemosensitizing agents. “However,” Dr. Fisher said, “the efficacy of drug resistance modification has not yet been borne out in the clinic.”

Since the CD20 antibody is expressed in about 85% of large-cell lymphomas, it represents a logical target for monoclonal antibody treatment. “As a single agent, rituximab [Rituxan] yields a response rate of about 33%,” Dr. Fisher noted. However, preliminary results have suggested that when this monoclonal antibody is coupled with CHOP, the complete response rate may be as high as 73%. Prospective randomized studies using rituximab are now being conducted by ECOG, CALGB, and SWOG.

Role of Transplantation

Dr. Fisher called ablative chemotherapy with bone marrow or peripheral blood stem cell support “the glass that’s half full and half empty.” He reminded the audience of the PARMA study, which showed that transplant clearly prolonged survival in patients who achieved a complete response, subsequently relapsed, and remained sensitive to chemotherapy. “While this strategy is effective for the individual who meets these criteria, it will not have a statistically major impact on overall survival,” he maintained.

In contrast, Dr. Fisher said, the study of Verdonck and colleagues failed to show any advantage of transplant over CHOP in slow responders. A small study from the Milan group, on the other hand, indicated that high-dose sequential chemotherapy was superior to MACOP-B in terms of both freedom from progression and overall survival.

“Retrospective subset analysis in several prospective studies has suggested that the benefits of high-dose chemotherapy with transplant may be limited to high-risk patients,” Dr. Fisher said. He acknowledged, nonetheless, that this finding has not been universal and that the picture is complicated.

“The hypothesis that I would generate for you is that intermediate-risk and high-risk patients with aggressive lymphoma who receive full-course standard induction therapy will benefit from the addition of a high-dose therapy program,” Dr. Fisher said.

To test this hypothesis, a US cooperative intergroup study will be randomizing patients with high-intermediate risk and high-risk lymphoma who have responded to five cycles of CHOP to receive either one additional cycle of CHOP followed by high-dose chemotherapy with autologous stem cell rescue (early transplant) or three additional cycles of CHOP, with salvage transplant carried out in cases of relapse (late transplant).

In nonbulky early-stage large-cell lymphoma, a large-scale SWOG trial has demonstrated that three cycles of CHOP followed by involved-field radiation is superior to standard-dose, full-course chemotherapy alone. A companion study conducted by ECOG has obtained similar results in patients with bulky early-stage disease.

“I believe that we should vary the amount of chemotherapy based on tumor bulk and use involved-field consolidation in all early-stage patients,” Dr. Fisher said. He pointed out that the cure rate in early-stage disease is in the range of 80% to 90%, comparable to that achieved in Hodgkin’s lymphoma.