The comprehensive review by Drs. Gaynor and Fischer details the historical and prospective data on conventional doxorubicin-based chemotherapy in advanced-stage intermediate grade lymphoma. However, it does not address the question of dose intensity in the era of growth-factor and stem-cell support. As the authors carefully document, modest increases in the dose intensity of conventional agents has translated into little objective gain in curative outcome. The pivotal Intergroup study  has emphasized the value of prospective compararative trials and has established CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone) as the gold standard of conventional chemotherapy.
What Is the Appropriate Dose Intensity?
But these data beg the question of dose intensity in intermediate-grade lymphoma. Several important studies recently presented in abstract form are the basis for concluding that maximally increasing dose intensity with stem-cell transplantation can result in higher rates of durable complete remissions compared to conventional chemotherapy. This success must be tempered by the increase in patient toxicity and the potential risks of serious morbidity and mortality. Therefore, the question is not whether increasing dose intensity to autologous transplant levels improves complete response, but rather, what is the appropriate dose intensity in a given patient.
The Parma study  prospectively compared conventional DHAP (dexamethasone, high-dose cytarabine, and cisplatin) chemotherapy with autologous transplantation as salvage therapy for relapsed intermediate-grade lymphoma. Significant improvements in event-free survival (46% vs 12%) and overall survival (53% vs 32%) at 5 years were achieved with autologous transplantation. This study is now the basis for the routine use of autologous transplantation in relapsed intermediate-grade lymphoma, as it clearly demonstrates the value of dose intensity and its appropriate application.
In the setting of previously untreated patients, a prospective trial of high-dose sequential chemotherapy with autologous transplantation has been compared to conventional MACOP-B (methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin) . The autologous transplantation group had a significantly higher complete response rate than the group receiving MACOP-B (94% vs 61%) and also had a significantly higher remission duration (93% vs 68% at 43 months). However, autologous transplantation did not improve survival (73% vs 62%). In the previously untreated patient, therefore, the potential curative advantage of autologous transplantation was counterbalanced by its increased toxicity and mortality; another factor was the ability to cure patients with conventional chemotherapy and reserve autologous transplantation for salvage if relapse occurs.
Dose Intensity Most Critical in High-Risk Patients
The recently published International Prognostic Index  permits the identification of high-risk patients whose expectation of curative outcome with conventional chemotherapy is low (less than 25%). It is in this subset that autologous transplantation may be appropriately studied in the future.
The majority of patients with advanced intermediate-grade lymphomas have low- or intermediate-risk presentations, according to the International Prognostic Index. The question of appropriate dose intensity is most critical in these groups. Conventional chemotherapy can achieve a curative outcome in more than 40% of such patients. Can moderate increases in dose intensity (as achieved with growth-factor support alone, without stem-cell transfusion) result in significant improvement in disease-free survival without resulting in excessive toxicity? Can overall survival be significantly improved with initial growth factor-supported intensification, as compared with conventional chemotherapy followed by salvage autologous transplantation when relapse occurs? Prospective comparisons are clearly needed to answer these important questions.
In summary, Gaynor and Fischer document the limitations of single-arm phase II studies. Their emphasis on prospective comparison and the CHOP gold standard is essential for the development of future clinical trials. However, the question of dose intensity has been answered at the level of autologous transplantation; data show that a higher cure rate is achievable. Two unresolved questions remain: (1) When is autologous transplantation appropriate? (2) Are escalated regimens without stem-cell transplantation more effective than conventional chemotherapy?
1. 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, 1993.
2. Philip T, Guglieimi C, Chauvin F, et al: Autologous bone marrow transplantation (ABMT) versus conventional chemotherapy (DHAP) in relapsed non-Hodgkin lymphoma (NHL): Final analysis of the Parma randomized study (216 patients) (abstract). Proc Am Soc Clin Oncol 14:390, 1995.
3. Gianni AM, Bregni S, Siena C, et al: 5-Year update of the Milan Cancer Institute randomized trial of high-dose sequential (HDS) vs MACOP-B therapy for diffuse large-cell lymphomas (abstract). Proc Am Soc Clin Oncol 13:373, 1994.
4. The International Non-Hodgkin's Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 329:987-995, 1993.