Adding Radiotherapy to CHOP Improves Results for Early- or Limited-Stage NHL

ORLANDO, Florida-Updated data from two separate studies ratify earlier results showing that following CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)) with radiation improves results for patients with early- or limited-stage non-Hodgkin's lymphoma (NHL), according to data reported at the 43rd Annual Meeting of the American Society of Hematology (abstract 3023) . The final results of E1484 showed that radiotherapy was successful in converting patients with limitedstage diffuse aggressive NHL who had achieved partial response following treatment with CHOP to complete response. In a trial conducted by the Southwest Oncology Group (SWOG), patients with early- stage aggressive NHL receiving CHOP plus radiotherapy continued to realize survival advantages superior to patients receiving CHOP alone at greater doses. New Results, Old System In reporting the final results of E1484, Sandra J. Horning, MD, of Stanford University in California noted that the study had "the advantage of mature follow-up, but the disadvantage of outdated classification," having been done before the International Prognostic Index (IPI) or the WHO and REAL classifications became standard. Patient accrual and randomization ran from October 1984 to September 1992. "The objectives of this study," Dr. Horning explained, "were to determine the complete response rate and the toxicity of CHOP for early-stage diffuse aggressive lymphoma, to compare the effect of involved field radiotherapy after a CHOP-induced remission with end points of duration of response, survival, sites of relapse, and toxicity, and lastly to determine the ability of radiotherapy to convert partial responders to complete responders." Predominantly Diffuse Large-Cell Lymphomas Most patients in the study (82%) had diffuse large-cell lymphoma. To be eligible, patients had to be in stage IE/II/IIE, or to have mediastinal, retroperitoneal, or bulky disease, defined as ≥ 10 cm if stage I. The vast majority of patients had a performance status of 0 to 1 and slightly less than one-third had bulky disease. A total of 81% of patients had fewer than three disease sites, according to the Ann Arbor classification. Stage I disease was present in 31% (14% stage I, 17% stage IE) and the remainder had stage II disease. Extranodal disease was present in 47% of patients (and in this study the spleen was considered an extranodal site). The median age of participants was 59 years. Patients were initially stratified based on performance status, tumor mass, and number of disease sites. "Randomization was up front," Dr. Horning said. "Patients in both arms of the study received a full eight cycles of CHOP. Those in arm 1 who achieved a complete response were observed, whereas those in arm 2 received 30 Gy of involved field radiation. Partial responders in either arm received 40 Gy of radiation." Among the 324 patients who completed all eight cycles of chemotherapy, the only four deaths were due to CHOP toxicity. Among the worst toxicities, 33% were grade 3 and 45% were grade 4. Almost all toxicities were restricted to neutropenia. Conversions From Partial to Complete Response Among patients for whom response data were available, "215, or 61%, achieved a complete remission as defined in the protocol, with relatively narrow confidence intervals," Dr. Horning reported. "Note that 28% of patients converted from partial response to complete response with the addition of radiation therapy," she added. A smaller subset of patients actually received consolidation treatment. These were the 79 patients in arm 2 who achieved complete response and went on to receive 30 Gy of involved field radiation. In arm 1 there were 93 patients who achieved complete response and were then observed. Partial responders numbered 71. Among those receiving consolidation therapy, there was a 17% increase in failure-free survival at 5 years and 15% at 15 years, Dr. Horning reported. Time-to-progression data showed only one relapse after 6 years of treatment in either arm of the study. "I think it is notable that 78% of the patients in the radiation therapy arm are still in remission or estimated to be in remission at 15 years," Dr. Horning stated. Multiple regression analysis showed performance status of 2 to 4 and more than three involved sites to be statistically significant adverse factors for time to progression. "Bulk, stage, extranodal disease, age, and gender were not statistically significant," Dr. Horning said. Curves for overall survival diverged, came together, and again separated somewhat at 15 years. There were no statistical differences in overall survival. "This study does suffer from a small number of patients," Dr. Horning acknowledged. "In conclusion, the complete response rate in this study was 61% after eight cycles of CHOP therapy. We found that 28% of partial responders converted to complete responders with 40 Gy of involved field radiotherapy. Overall, induction CHOP of eight cycles was relatively well tolerated," Dr. Horning said. Important Difference Between the Two Trials Updated data from the SWOG trial found that survival advantages shown at 4.4 years median followup for CHOP(3) (three cycles of CHOP) plus radiation compared to CHOP(8) (eight cycles of CHOP) alone were essentially unchanged at about 8.2 years. Overall survival rates were 82% for CHOP(3) plus radiation vs 74% for CHOP(8). Failure- free survival rates were 76% for CHOP(3) plus radiation vs 67% for CHOP(8). Patients eligible for the SWOG trial had biopsy-proven intermediate- or high-grade NHL, except lymphoblastic, according to Thomas P. Miller, MD, of Arizona Cancer Center in Tucson. "The important difference between this trial and the one presented by Dr. Horning is that nonbulky stage II and IIE, that is, patients with a single mass measuring 10 cm or greater than one-third chest diameter, were ineligible, presuming three cycles of CHOP would be inadequate therapy."