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Dose dense CHOP: When more is not always better!

One of the fundamental tenets of medical oncology is derived from studies conducted on tumor bearing animals. The dose response curve implies that in order to obtain the maximum benefit from cytotoxic drugs, we need to administer these agents at or close to their maximum tolerated dose (MTD). To exploit this concept, investigators have aimed at delivering doses above the MTD by utilizing supportive care methods such as growth factors and autologous stem cell transplant (ASCT). Efforts to intensify the dose of CHOP used in lymphomas have been going on even before colony stimulating factors and transplantation were introduced. The first such study was designed by Bodey et al. at MD Anderson in the 1970s and included the use of escalating doses of CHOP given in a sterile PE unit (‘‘protected environment’’) [1]. It was a randomized study in which one half of the patients received three courses inside a PE unit with prophylactic antibiotics and the other half were treated with high doses but outside of a PE. This somewhat heroic effort was essentially unsuccessful. Patients treated inside the PE were able to tolerate dose escalations better and received more intense therapy but the overall survival and disease free survival were the same in both arms of the study and not any better than historical controls treated at standard doses. Subsequent attempts at delivering higher doses of chemo had to wait until autologous transplants became established as a feasible means of escalating doses. The first and only randomized study performed in the salvage setting was published by Philip et al. and is known as the Parma trial. It randomized between the high dose BEAC/ABMT regimen and standard dose DHAP for patients with recurrent histologically aggressive NHL. The results were clearly in favor of the high dose arm. Subsequently, at least five prospective randomized studies have been published in which high dose chemotherapy with autologous stem cell transplant (ASCT) was moved to the front line setting mostly for patients with aggressive histologies with at least one adverse prognostic feature. Of these, only two studies are positive [2,3] and the remainder did not show any significant difference in outcome. In addition, there are two randomized trials in which up front high dose chemotherapy/ASCT was used for patients who achieved a partial response as their best response to first line therapy[4, 5]. Both were negative trials. In addition there is one study which looked at a subset of 94 partial responders out of 759 patients entered on a GELA protocol (LNH 87-2). This was a retrospectively selected group of patients entered on a prospective randomized trial. It showed improved survival for the high dose chemotherapy arm. In this issue of Leukemia Lymphoma, Peterson et al. present the results of a study conducted by CALGB from 1994 – 96 [6]. It is a phase II trial performed in patients ranging in age from 18 – 65 with diffuse large cell NHL and poor prognostic features, i.e., International Prognostic Index (IPI) 2 – 5. The goal was to determine the response rate, toxicity and feasibility of escalated doses of cyclophosphamide and doxorubicin as part of the CHOP regimen. Support with G-CSF and prophylactic antibiotics were routinely administered. The complete response rate was only 36% and two-year failure free survival 39%. These results were disappointing enough to discourage the investigators from pursuing this approach further. Several details about the study need to be highlighted. The total number of CHOP courses planned was four instead of the usual six or eight. This translates into a theoretical total dose of cyclophosphamide of 16 g/M2 and doxorubicin