Abstract
Dose intensity (DI) of chemotherapy affects prognosis of diffuse large B cell lymphoma (DLBCL). Myelotoxicity is the major dose-limiting toxicity (DLT) of most cytotoxic agents for hematological malignancies, whereas DLT of vincristine (VCR) is mainly neurological toxicity. Although VCR is a key drug and its combination with other cytotoxic agents needs consideration, studies focused on relative DI (RDI) of VCR have not been done before. We retrospectively analyzed 86 cases of DLBCL that received six or more cycles of cyclophosphamide (CPM), doxorubicin (DXR), VCR, prednisolone, and rituximab [R-CHOP] and calculated RDI of each cytotoxic agent to analyze its influence on treatment outcome. The median RDI of CPM, doxorubicin, and VCR was 80.0, 81.7, and 78.4 %, respectively (p = 0.002). The average RDI (ARDI) of these three agents was 80.0 %. The overall survival was significantly worse in the low ARDI (<85 %) than in the high ARDI (>85 %) group (2-year survival rate 67.2 vs 93.4 %, p = 0.011). The survival rate with low RDI VCR (<85 %) was lower than that with high RDI VCR (>85 %), even when the remaining two agents had high ARDI (2-year survival rate 74.3 vs 95.8 %, p = 0.047). In conclusion, VCR dose tended to be reduced compared with CPM and DXR in R-CHOP. Lower ARDI of cytotoxic agents and lower RDI of VCR could lead to poor prognosis in the treatment of DLBCL with R-CHOP. We thought these observations should be confirmed in a prospective study.
Similar content being viewed by others
References
Swerdlow SH, International Agency for Research on Cancer, World Health Organization (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. World Health Organization classification of tumours, 4th edn. International Agency for Research on Cancer, Lyon, France
Aoki R, Karube K, Sugita Y, Nomura Y, Shimizu K, Kimura Y, Hashikawa K, Suefuji N, Kikuchi M, Ohshima K (2008) Distribution of malignant lymphoma in Japan: analysis of 2260 cases, 2001–2006. Pathol Int 58(3):174–182. doi:10.1111/j.1440-1827.2007.02207.x
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346(4):235–242. doi:10.1056/NEJMoa011795, 346/4/235 [pii]
A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project (1993). N Engl J Med 329 (14):987–994. doi:10.1056/NEJM199309303291402
Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM (2007) The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109(5):1857–1861. doi:10.1182/blood-2006-08-038257
Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, Vanderplas A, Zelenetz AD, Abel GA, Rodriguez MA, Nademanee A, Kaminski MS, Czuczman MS, Millenson M, Niland J, Gascoyne RD, Connors JM, Friedberg JW, Winter JN (2014) An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123(6):837–842. doi:10.1182/blood-2013-09-524108
Terada Y, Nakamae H, Aimoto R, Kanashima H, Sakamoto E, Aimoto M, Inoue E, Koh H, Nakane T, Takeoka Y, Ohsawa M, Koh KR, Yamane T, Nakao Y, Ohta K, Mugitani A, Teshima H, Hino M (2009) Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R-CHOP) on survival in diffuse large B-cell lymphoma. J Exp Clin Cancer Res 28:116. doi:10.1186/1756-9966-28-116
Hirakawa T, Yamaguchi H, Yokose N, Gomi S, Inokuchi K, Dan K (2010) Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma. Ann Hematol 89(9):897–904. doi:10.1007/s00277-010-0956-7
Borel C, Lamy S, Compaci G, Recher C, Jeanneau P, Nogaro JC, Bauvin E, Despas F, Delpierre C, Laurent G (2015) A longitudinal study of non-medical determinants of adherence to R-CHOP therapy for diffuse large B-cell lymphoma: implication for survival. BMC Cancer 15(1):288. doi:10.1186/s12885-015-1287-9
Gutierrez A, Bento L, Bautista-Gili AM, Garcia F, Martinez-Serra J, Sanchez B, Martorell C, Gines J, Garcia L, Gimeno E, Ferraro M, Del Campo R, Bargay J, Perez A, Vercher J, Scaff M, Pacheco A, Ballester C, Garcia F, Ramos R, Salar A, Besalduch J (2015) Differential impact of relative dose-intensity reductions in diffuse large B-cell lymphoma treated with R-CHOP21 or R-CHOP14. PLoS One 10(4):e0123978. doi:10.1371/journal.pone.0123978
Carbone PP, Bono V, Frei E 3rd, Brindley CO (1963) Clinical studies with vincristine. Blood 21:640–647
Jackson DV Jr, Sethi VS, Spurr CL, Willard V, White DR, Richards F 2nd, Stuart JJ, Muss HB, Cooper MR, Homesley HD, Jobson VW, Castle MC (1981) Intravenous vincristine infusion: phase I trial. Cancer 48(12):2559–2564
Haim N, Epelbaum R, Ben-Shahar M, Yarnitsky D, Simri W, Robinson E (1994) Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer 73(10):2515–2519
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance AL, Lymphoma G, Eastern Cooperative Oncology G, European Mantle Cell Lymphoma C, Italian Lymphoma F, European Organisation for R, Treatment of Cancer/Dutch Hemato-Oncology G, Grupo Espanol de Medula O, German High-Grade Lymphoma Study G, German Hodgkin’s Study G, Japanese Lymphorra Study G, Lymphoma Study A, Group NCT, Nordic Lymphoma Study G, Southwest Oncology G, Southwest Oncology G, United Kingdom National Cancer Research I (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32(27):3059–3068. doi:10.1200/JCO.2013.54.8800
Epelbaum R, Haim N, Ben-Shahar M, Ron Y, Cohen Y (1988) Dose-intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma. Isr J Med Sci 24(9–10):533–538
Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR et al (1994) Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330(18):1253–1259. doi:10.1056/NEJM199405053301801
Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C (1995) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 332(14):901–906. doi:10.1056/NEJM199504063321401
Lyman GH, Dale DC, Friedberg J, Crawford J, Fisher RI (2004) Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol 22(21):4302–4311. doi:10.1200/JCO.2004.03.213
Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458. doi:10.1038/bmt.2012.244
Kwak LW, Halpern J, Olshen RA, Horning SJ (1990) Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: results of a tree-structured survival analysis. J Clin Oncol 8(6):963–977, RDI of CHOP
Lee KW, Kim DY, Yun T, Kim DW, Kim TY, Yoon SS, Heo DS, Bang YJ, Park S, Kim BK, Kim NK (2003) Doxorubicin-based chemotherapy for diffuse large B-cell lymphoma in elderly patients: comparison of treatment outcomes between young and elderly patients and the significance of doxorubicin dosage. Cancer 98(12):2651–2656. doi:10.1002/cncr.11846
Bosly A, Bron D, Van Hoof A, De Bock R, Berneman Z, Ferrant A, Kaufman L, Dauwe M, Verhoef G (2008) Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann Hematol 87(4):277–283. doi:10.1007/s00277-007-0399-y
Epelbaum R, Faraggi D, Ben-Arie Y, Ben-Shahar M, Haim N, Ron Y, Robinson E, Cohen Y (1990) Survival of diffuse large cell lymphoma. A multivariate analysis including dose intensity variables. Cancer 66(6):1124–1129
Yamaguchi H, Hirakawa T, Inokuchi K (2011) Importance of relative dose intensity in chemotherapy for diffuse large B-cell lymphoma. J Clin Exp Hematop 51(1):1–5
Lyman GH, Dale DC, Culakova E, Poniewierski MS, Wolff DA, Kuderer NM, Huang M, Crawford J (2013) The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol 24(10):2475–2484. doi:10.1093/annonc/mdt226
Balducci L, Mo M, Abella E, Saven A (2014) Retrospective analysis of relative dose intensity in patients with non-Hodgkin lymphoma receiving CHOP-based chemotherapy and pegfilgrastim. Am J Clin Oncol 37(6):603–610. doi:10.1097/COC.0000000000000141
Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328(14):1002–1006. doi:10.1056/NEJM199304083281404
Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP (1994) A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin’s lymphoma: results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol 5(2):91–95
Sertoli MR, Santini G, Chisesi T, Congiu AM, Rubagotti A, Contu A, Salvagno L, Coser P, Porcellini A, Vespignani M et al (1994) MACOP-B versus ProMACE-MOPP in the treatment of advanced diffuse non-Hodgkin’s lymphoma: results of a prospective randomized trial by the non-Hodgkin’s Lymphoma Cooperative Study Group. J Clin Oncol 12(7):1366–1374
Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquieres H, Hacini M, Fruchart C, Ysebaert L, Ferme C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A (2013) Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 14(6):525–533. doi:10.1016/S1470-2045(13)70122-0
Silverman JA, Reynolds L, Deitcher SR (2013) Pharmacokinetics and pharmacodynamics of vincristine sulfate liposome injection (VSLI) in adults with acute lymphoblastic leukemia. J Clin Pharmacol 53(11):1139–1145. doi:10.1002/jcph.155
Thomas DA, Kantarjian HM, Stock W, Heffner LT, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Pierce S, Lu B, Deitcher SR, O’Brien S (2009) Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia. Cancer 115(23):5490–5498. doi:10.1002/cncr.24632
O’Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H (2013) High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol 31(6):676–683. doi:10.1200/JCO.2012.46.2309
Hagemeister F, Rodriguez MA, Deitcher SR, Younes A, Fayad L, Goy A, Dang NH, Forman A, McLaughlin P, Medeiros LJ, Pro B, Romaguera J, Samaniego F, Silverman JA, Sarris A, Cabanillas F (2013) Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo(®)) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas. Br J Haematol 162(5):631–638. doi:10.1111/bjh.12446
Acknowledgments
We would like to thank all the patients who took part in this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Formal consent is not required for this type of study.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Utsu, Y., Takaishi, K., Inagaki, S. et al. Influence of dose reduction of vincristine in R-CHOP on outcomes of diffuse large B cell lymphoma. Ann Hematol 95, 41–47 (2016). https://doi.org/10.1007/s00277-015-2514-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-015-2514-9