Adding high-dose tamoxifen to CHOP does not influence response or survival in aggressive non-Hodgkin's lymphoma: an interim analysis of a randomized phase III trial
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CHOP is the standard regimen currently used in the management of the majority of patients with aggressive non-Hodgkin's lymphoma (NHL). However, CHOP only produces 30–35% long-term survival. We hypothesized that adding high-dose tamoxifen, which is known to have multiple drug resistance-modulatory effects, to the CHOP regimen could increase the response rate, and consequently enhance the survival of patients with NHL.
Patients and Methods
In a prospective, controlled, and randomized study, eligible adult patients with aggressive NHL were randomized between CHOP only (Group I), or CHOP plus high-dose tamoxifen (Group II). The primary aim was to assess the effect of tamoxifen on complete response (CR) rate, with the secondary evaluation of tamoxifen potential impact on survival. The interim analysis of this study is presented.
Fifty-one and forty-seven evaluable patients were randomized to Group I and Group II, respectively. The median age of all patients was 53y (range 18–78y). The two groups had comparable distributions of the pretreatment prognostic variables. The CR for patients in Group I was 80% (41 patients) as compared with 74% (35 patients) in Group II (P=0.48). Likewise, there was no apparent difference in the partial remission rates between the two groups (6% vs 15%, respectively). Of patients who initially attained CR, 15 (37%) and 10 (29%) subsequently relapsed in Groups II and I respectively (P=0.45). The NHL International Prognostic Index (IPI) was the only factor that predicted attaining CR. At the time of this interim analysis, the actuarial-estimated overall survival (OS) probability (±S.E.) for the entire population at 5 y was 58% (±6) with no survival difference between the two groups (P=0.51). Only attaining CR and the IPI predicted OS probability. The probability of remaining event-free at 5 y (±SE) for those achieving CR was 72% (±9), and there was no significant difference between the two treatment groups (P=0.68). Toxicity profile was similar in the two groups.
Based on this interim analysis, combining high-dose tamoxifen, as used in this study, with the CHOP regimen has failed to have any favorable effect on the outcome of patients with aggressive NHL, and therefore cannot be recommended for future trials.
- Coltman Jr ACet al. CHOP is curative in thirty per cent of patients with large cell lymphoma: A twelve year Southwest Oncology Group follow-up. In: Skarin A (ed).Update on Treatment for Diffuse Large Cell Lymphoma. Park Row: New York, 1986, pp 71–77.
- Coleman M. Chemotherapy for large cell lymphoma: optimism and caution.Ann Intern Med 1985;103: 140–141.
- Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large cell lymphoma.Ann Intern Med 1985;102: 596–602.
- Fisher RIet al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma.N Engl J Med 1993;328: 1002–1006. CrossRef
- Cooper IAet al. Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma.J Clin Oncol 1994;12: 769–778.
- Yuen AR, Sikic BI. Multidrug resistance in lymphomas.J Clin Oncol 1994;11: 2453–2459.
- Fojo Aet al. Reduced drug accumulation in multiple drug resistance human KB carcinoma cell lines.Cancer Res 1985;45: 3002–3007.
- Inaba M. Biochemical mechanism for resistance to anthracycline antibiotics.Prog Clin Bio Res 1986;223: 35–44.
- Sorris AHet al. Cyclosporin A does not reverse clinical resistance to paclitaxel in patients with relapsed non-Hodgkin's lymphoma.J Clin Oncol 1996;14: 233–239.
- Wilson WHet al. Reversal of Multidrug resistance (mdr-1) with R-verapamil and analysis of mdr-1 expression in patients with lymphoma refractory to EPOCH chemotherapy.Proc Am Assoc Cancer Res 1993;34: 212, (abstract).
- Ramu A, Glaubiger D, Fuks Z. Reversal of acquired resistance to doxorubicin MP 388 murine leukemia cells by tamoxifen and triparanol.Cancer Res 1984;44: 4392–4395.
- Chatterjee M, Harris AL. Reversal of acquired resistance to adriamycin in CPO cells by tamoxifen and 4-hydroxy tamoxifen: roller drug interaction with alpha-1 acid glycoprotein.Br J Cancer 1990;62: 712–717.
- Horgan Aet al. Inhibition of protein kinase C mediated signal transduction by tamoxifen. Importance for antitumor activity.Biochem Pharm 1986;35: 4463–4465. CrossRef
- Lamb HY. Tamoxifen as a calmodulin antagonist in the activation of cAMP phosphodiesterase.Biochem and Biophys Res Commun 1984;118: 27–32. CrossRef
- Colletti RBet al. Effects of tamoxifen on plasma insulin like growth factor I in patients with breast cancer.Cancer Res 1989;49: 1882–1884.
- Colletta AAet al. Anti-estrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts.Br J Cancer 1990;62: 405–409.
- Stuart NSet al. High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical and in vitro assessment in p-glycoprotein expressing cell line.Br J Cancer 1992;66: 833–839.
- Figueredo Aet al. Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer: a phase I/II study.Cancer 1990;65: 1895–1902. CrossRef
- Trump OLet al. High-dose oral tamoxifen, a potential multi-drug resistance-reversal agent: phase I trial in combination with vinblastin.Journal of National Cancer Institute 1992;84: 1811–1816. CrossRef
- El-Yazigi Aet al. Effect of tamoxifen on the pharmacokinetics of doxorubicin in patients with non-Hodgkin's lymphoma.Ther Drug Monit 1997;19: 632–636. CrossRef
- The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classification of non-Hodgkin's lymphoma: Summary and description of a working formulation for clinical usage.Cancer 1982;49: 2112–2135.
- Oken MM, Creech RH, Tormey DC. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol 1982;5: 649–655. CrossRef
- Carbone PPet al. Report of the Committee on Hodgkin's Disease's Staging Classification.Cancer Res 1971;31: 1860–1861.
- Freedman LS. Tables of the number of patients required in clinical trials using the log rank test.Statist Med 1982;1: 121–129. CrossRef
- Cox DR, Snell EJ.Analysis of Binary Data. London: Chapman & Hall, 1989.
- Kaplan EL, Meier P. Nonparametric estimation from incomplete observations.J Am Statist Assoc 1958;53: 457–481. CrossRef
- Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration.Cancer Chemother Rep 1966;50: 163–170.
- Cox DR, Oakes D. Regression models and life tables (with discussion).J R Statist Soc 1972;B34: 187–220.
- Dixon WJet al. BMDP Statistical Software. Berkeley: University of California Press, 1990.
- 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.
- Miller T Pet al. P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil.J Clin Oncol 1991;9: 17–24.
- Millward MJet al. High-dose (480 mg/day) tamoxifen with etoposide: a study of a potential multi-drug resistance modulator.Oncology 1994;51: 79–83. CrossRef
- Feller WK. Statistical aspects of extra-sensory perception.J Parapsychol 1940;4: 271–298.
- McPherson K. Interim analysis and stopping rules. In: Buyse ME (ed.)Cancer Clinical Trials: Methods and Practice. Oxford: Oxford University Press, 1988, pp 407–422.
- Haioun Cet al. Comparison of autologous bone marrow transplantation with sequential chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphoma in first complete remission: a study of 464 patients. Groupe d'Etude des Lymphomes de l'Adulte.J Clin Oncol 1994;12: 2543–2551.
- Weaver CHet al. High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma.J Clin Oncol 1994;12: 2559–2566.
- Pettengell Ret al. Survival benefit from high-dose therapy with autologous blood progenitor-cell transplantation in poor-prognosis non-Hodgkin's lymphoma.J Clin Oncol 1996;14: 586–592.
- Adding high-dose tamoxifen to CHOP does not influence response or survival in aggressive non-Hodgkin's lymphoma: an interim analysis of a randomized phase III trial
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