Dose Dense CHOP: Not for Everybody

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: Dose-dense CHOP chemotherapy was compared with standard CHOP for patients with aggressive non-Hodgkin lymphoma. For young patients with low-intermediate risk disease there was improvement in response rate and survival. However, for other groups, no advantage was demonstrated. Toxicity was greater in the dose dense regimen, but treatment related mortality was comparable.

Source: Verdonck LF, et al. Blood. 2007;2759-2766.

There had been sustained efforts over the past few decades to enhance overall response and cure rates for patients with non-Hodgkin's lymphoma (NHL) by modifying the standard CHOP chemotherapy approach. Verdonck and colleagues in the Dutch Belgian Hemato-Oncology Cooperative Group (HOVON) report the results of one such effort, a phase III trial of dose intensified cyclophosphamide and doxorubicin with added granulocyte colony stimulating factor (G-CSF) in young patients with intermediate risk aggressive NHL. For this, previously untreated patients between 16 and 65 years of age (N = 513) with untreated aggressive NHL according to the intermediate or high-grade Working Formulation (groups D, E, F, G, and H) and an intermediate risk profile according to the HOVON criteria, were included in the study. The intermediate risk profile was defined as either stage II disease with serum lactate dehydrogenase (LDH) levels greater than 1.5 times the upper limit of normal, or as stage III or IV disease with LDH levels less than 1.5 times the upper limit of normal. The patients were randomized to receive either standard CHOP (CHOP 21) or the intensified CHOP regimen (I-CHOP). The standard regimen included cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (2 mg) on day one and prednisone (100 mg orally) given on days one to five. The patients were treated every three weeks for a total of eight cycles. The experimental intensive approach included cyclophosphamide (1000 mg/m2), doxorubicin (70 mg/m2), and vincristine (2 mg) on day one and prednisone (100 mg orally) given on days one to five. G-CSF at a dose of 5 mcg/kg was given subcutaneously from days two to 11 in the intensive arm only. The patients were treated every two weeks for six cycles. The treatment was designed to offer the same total amount of cyclophosphamide and doxorubicin in 12 weeks in the intensive regimen compared with 24 weeks in the standard regimen, thus doubling dose intensity without increasing cumulative dose. A standardized dose modification scheme was implemented as well. Although there was a tendency in favor of the intensive regimen for better overall, disease-free and event-free survival, the differences did not reach a level of statistical significance. However, when the intermediate risk group was divided into low-intermediate and high-intermediate risk according to the International Prognostic Index (IPI), low intermediate risk patients had improved six-year overall survival (67% vs 52%; P = 0.05), disease free survival (58% vs 45%; P = 0.06), and event-free survival (41% vs 30%; P = 0.21) when they were treated with intensive regimen compared with standard. In contrast, those in the high intermediate risk received no benefit from the intensive regimen. The toxicity was greater in the intensive regimen; however, treatment-related mortality was similar.

Commentary

CHOP chemotherapy has been the standard approach for aggressive NHL for close to three decades, but over this period there have been efforts to improve upon the regimen to gain better response rates and cures. These efforts, however, have not met with much success, with the exception of the addition of anti-CD20 (rituximab) to CHOP, which has been demonstrated to enhance response rates and overall survival in elderly patients.1 The current trial, which recruited patients before rituximab became standard, examined the popular notion that shortening the overall treatment time by making cycles more frequent and at higher dose (ie, increasing dose density) would be associated with more favorable outcomes. These data suggest that I-CHOP might be preferable to standard CHOP for a subset of patients with aggressive NHL (ie, younger patients with low-intermediate-risk2). This is similar to the study conducted in Germany and reported by Pfreundschuh et al3 in which dose density was achieved by comparing shortened CHOP interval (21 day vs 14 day) but using standard drug doses. As with the current study, a survival advantage was demonstrated for young patients with low-intermediate risk NHL when treated on the more intensive schedule.

Thus, it appears that the more intensive (dose dense) CHOP regimen may be the optimal choice for this particular subset of patients. However, it remains to be demonstrated whether dose density favorably influences rituximab-CHOP (R-CHOP) to the same extent. Trials currently underway will soon provide the answer. In the meantime, standard R-CHOP remains the standard. It's been difficult to improve responses beyond what this regimen achieves.

References

1. Coiffier B, et al. N Engl J Med. 2002;346:235-242.

2. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329:987-994.

3. Pfreundschuh M, et al. Blood. 2004;104:634-641.