Dose Dense Chemotherapy for Lymphoma
Dear OncoLink "Ask The Experts,"
I have heard that giving CHOP chemotherapy every 2 weeks may be more effective than every 3 weeks (the standard). Can you provide any details?
Babis (Charalambos) Andreadis, MD, Assistant Professor in Medicine in the Division of Hematology/Oncology at the Abramson Cancer Center and an Associate Scholar in the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, responds:
This technique is often called dose-dense chemotherapy. The doses of chemotherapy are the same in both regimens, but the dose dense regimen is given at shorter intervals, the goal being to not allow the cancer cells to have enough time between cycles to start growing again. By using growth factors to support the patient during dose-dense chemo, the most common side effect of neutropenia can be avoided. This schedule also allows the patient to complete treatment about 1 month sooner. See our article explaining dose dense in detail. Let's review the studies of this therapy done in lymphoma.
Attempts have been made to improve first-line therapy of diffuse large B-cell lymphoma by delivering CHOP chemotherapy on a two-week rather than three-week schedule, with growth-factor support to prevent neutropenia. Two multi-institution phase II studies (one from Italy 1 and one from the southwest oncology group 2 ) have shown reasonable response rates, short-term progression-free survival, and overall survival utilizing CHOP-14 (every 14 days) or R-CHOP-14 (including Rituxan) with Neulasta (growth factor) support. There were no significant unexpected side-effects, with the exception of a high rate of interstitial pneumonitis seen in the Italian study (14%) associated with pneumocystis carinii in 6% (a type of pneumonia).
A large, randomized, phase III study completed by the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) 3 in young patients with good-prognosis, aggressive non-Hodgkin lymphoma, directly compared CHOP-21 (every 21 days) with CHOP-14 (every 14 days). Chemotherapy dose delivery was not compromised by the dose-dense schedule (meaning doses did not need to be changed or delayed due to severe side effects), and patients were able to complete treatment on the average at 76 days on CHOP-14 and 106 days on CHOP-21. Toxicity and secondary malignancies (cancers caused by the chemotherapy) were not significantly different between the two groups. The study observed statistically significantly higher complete response rates for CHOP-14 vs. CHOP-21 (76.1% vs. 60.1% respectively), as well as better 5-year event-free survival (survival with no relapses) and overall survival (survival despite relapses) rates (43.8% vs. 32.5%, and 53.3% vs. 40.6% respectively).
Even though the results of this study are significant, they were derived in the pre-rituximab era and may not hold for the combination of rituximab with CHOP. A randomized phase III study is underway by the GELA to directly compare R-CHOP-21 (every 3 weeks with Rituxan) with R-CHOP-14 (every 2 weeks with Rituxan) and address the issue of pulmonary toxicity seen in the prior phase II study.
Brusamolino E, Rusconi C, Montalbetti L, Gargantini L, Uziel L, Pinotti G, Fava S, Rigacci L, Pagnucco G, Pascutto C, Morra E, Lazzarino M. Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica. 2006 Apr; 91(4):496-502.
Blayney DW, LeBlanc ML, Grogan T, Gaynor ER, Chapman RA, Spiridonidis CH, Taylor SA, Bearman SI, Miller TP, Fisher RI; Southwest Oncology Group. Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol. 2003 Jul 1; 21(13):2466-73.
Pfreundschuh M, Trumper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rube C, Loeffler M. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL -B1 trial of the DSHNHL. Blood. 2004 Aug 1; 104(3):626-33.