CHOP CHEMOTHERAPY OF INTERMEDIATE AND HIGH-GRADE NON-HODGKIN S LYMPHOMA

Transcription

1 Aria Oncologicu Vol., No. 8, pp , 1994 CHOP CHEMOTHERAPY OF INTERMEDIATE AND HIGH-GRADE NON-HODGKIN S LYMPHOMA MARTA LLANOS, JOSEP TABERNERO, JOAN BRUNET, MARGARITAMENEDO, CINTA PALLARES, LUIS DE ANDRES and JUAN JOSE LOPEZ The results of CHOP treatment in 6 patients with intermediate and high-grade non-hodgkin s lymphoma (Working Formulation D to I), Ann Arbor stage I to IV were analyzed. The response rate was 87%, 71% complete remission and 16% partial remission with a mean duration of 22 months. The 5-year actuarial survival was 61% (95% confidence interval, 51-70%). The treatment was well tolerated and no deaths due to acute toxicity were observed. Poor prognostic factors in univariate analysis were: high-grade histology, stages I11 and IV, B symptoms, 24 affected lymph node regions, Karnofsky index < 70, erythrocyte sedimentation rate (ESR) > 60 mm, haemoglobin < 100 g/l and elevated lactic dehydrogenase (LDH). Poor prognostic factors in multivariate analysis were: high-grade histology, stages 111 and IV, haemoglobin < 100 g/l and elevated LDH. In summary, good results were obtained with CHOP chemotherapy, without severe toxicity. During the past decade, development of curative chemotherapy for aggressive non-hodgkin s lymphoma has been one of the major successes of cancer therapy. The first-generation regimens (C-MOPP. BACOP, COMLA, and CHOP) produce complete response rates of 45 to 55% and long-term survival rates of 0 to 5% (I, 2). Among these first-generation regimens, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been extensively studied in cooperative-group trials with complete response rates of 5 to 57% and 10 to 12 years survival rates of 0% (, 4). A variety of alternative regimens has been developed, increasing either the number of drugs or/and the dose intensity, in an effort to improve the results. For new intensive third-generation regimens (m-bacod, Pro- MACE-CytaBOM, and MACOP-B) increased complete Received 18 March Accepted 9 June From the Department of Oncology, Hospital de Sant Pau. Universitat Autonoma de Barcelona, Barcelona, Spain. Correspondence to: Dr Josep Tabernero, Department of Oncology, Hospital de Sant Pau, Av. S. Antoni M. Claret, 167, E Barcelona, Spain. remission rates of 78-84% and survival rates of 55-65% (5-7). were initially reported but follow-up was short (2 years). On the negative side these new schedules were more difficult to administer, more toxic, and more costly. Sequential phase I1 trials with these three regimens (8) showed complete remission rates similar to CHOP (65 vs 57%) and after longer follow-up the survival rates became similar to those obtained with CHOP. We have retrospectively analyzed our results in aggressive non-hodgkin s lymphoma treated with CHOP chemotherapy. Material and Methods Patients. From January 1985 to December 1989, 6 patients with intermediate and high-grade non-hodgkin s lymphoma (Working Formulation D through I), Ann Arbor stages I to IV, were treated with CHOP chemotherapy. All patients were studied with physical examination, complete blood cell count, liver and renal function tests, chest roentgenogram, abdominal CT and unilateral bone marrow needle core biopsy from the iliac crest. Upper gastrointestinal contrast radiography was performed in patients with primary involvement of the Waldeyer s ring. The histological diagnosis was confirmed Q Scandinavian University Press ISSN X 95

2 96 M. LLANOS ET AL. in all instances by a pathologist with lymphoma classification experience. The patients characteristics are shown in Table 1. The median age was 59 years (range 29 to 79 years). The original site was lymph nodes in 1 patients (49%) and extranodal in 2 (51%). According to the Ann Arbor classification, I1 patients (18%) had stage I, 19 (0%) stage 11, 14 (22%) stage 111 and 19 (0%) stage IV. The histologic classification according to the International Table 1 Patients characteristics n (%$ No. of patients 6 Age, years < (46) 60 4 (54) Sex Men 40 (6) Women 2 (7) Histology (WF) Intermediate 51 (90) D 10 (16) E 1 (20) F 14 (22) G 20 (2) High 6 (10) H 5 (8) I I (2) Stage I 11 (18) I1 19 (0) (22) IV 19 (0) Nodal 1 (49) Extranodal 2 (51) Head and neck 19 (0) Gastrointestinal 1 (11) Other 6 (10) Lymph node regions <4 42 (67) >4 21 () Bulky disease 21 (4) Bone marrow disease 1 (21) Mediastinal disease 12 (19) Systemic symptoms A 40 (6) B 2 (7) Karnofsky PS Q (27) > (7) Elevated ESR ( > 60 mm) 1 (21) Elevated LDH 21 () Haemoglobin < 100 g/l 10 (16) Albumin < 50 g/1 16 (25) Abbreviations: WF = Working Formulation. PS = performance status. ESR =erythrocyte sedimentation rate. LDH = lactate dehydrogenase. Working Formulation was intermediate grade in 57 patients (90%) and high grade in 6 (10%). The median follow-up was 44 months (range 20 to 8 months). Therapy. The treatment regimen included cyclophosphamide 750 mg/m2 intravenously (i.v.), doxorubicin 50 mg/m2 i.v., vincristine 1.4 mg/m2 i.v. (maximum single dose, 2 mg) on day 1 and prednisone 125 mg parenterally for 5 consecutive days. This sequence was repeated at 21-day intervals. The median number of treatment cycles administered was 6 (range 1 to 9). Initial debulking surgery, without remaining clinical evidence of disease, was performed in 8 patients (12%) due to gastrointestinal lesions and 1 (2%) patient due to lymphadenopathy. Adjuvant radiotherapy (0-5 Gy) was administered due to bulky disease in 19 patients (0%) with complete remission and 1 patient (2%) with residual minimal disease. Response criteria. All patients underwent repeated staging after therapy. Complete remission (CR) was defined as the disappearance of all clinical evidence of active tumour for a minimum of 4 weeks, remission was verified by repeating all tests previously yielding positive findings. Partial remission (PR) was defined as more than a 50% decrease in the sum of the products of the maximal perpendicular diameters of the measured lesions, lasting at least 4 weeks. Disease progression was defined as the appearance of new lesions or an increase of 225% of the size of preexisting lesions. Toxicity. Chemotherapy toxicity was evaluated according to the WHO grading. The maximum toxicity during chemotherapy was registered. Statistical methods. All patients were considered eligible. Remission duration and survival were calculated from the first day of treatment until relapse or death respectively, and were plotted by the technique of Kaplan-Meier (9), and compared using the log rank test ( 10). All univariate comparisons were made using an adjusted x2 test (1 I), whereas the multivariate regression analyses in survival were performed using a stepwise selection procedure and a proportional hazards regression model ( 12). Results The chemotherapy responses are detailed in Table 2. The response rate was 87%, 71% complete remission (CR) and 16% partial remission (PR) with a mean duration of 22 months (range 1 to 5). The CR rate was in stage I loo%, in stage I1 84%, in stage % and in stage IV 7%. It was 68% in patients with nodal disease and 75% in those with extranodal disease. In intermediate grade lymphomas the CR rate was 75% and in high grade lymphomas %. After a median follow-up of 44 months the relapse rate was 17%. The 5-year actuarial survival (Fig. 1) was 61% (95% confidence interval: 51-70%) and disease-free survival (Fig. 2) was 45% (95% CI: 29-61%). In stages I, I1 and 111 the 4.5-year survival rates were 91,

3 CHOP IN NON-HODGKIN'S LYMPHOMA 97 Table 2 Response to CHOP chemotherapy Table CHOP ckemotherupy roxiriiy n ('Xj) Type* (%) I I V CR 45 (71) PR 10 (16) Total 55 (87) CR according to stage I II (100) I1 16 (84) (78) IV 7 (7) CR according to origin site Nodal 21 (68) Extranodal 24 (75) CR according to grade Intermediate 4 (75) High 2 () Abbreviations: n = number of patients. CR =complete response. PR =partial response. 84 and 56% respectively. In stage IV the 2.5-year survival was 44% (Fig. ). Toxicity. Treatment was well tolerated and no deaths due to acute toxicity were observed. The CHOP regimen toxicity, according to WHO classification, was (Table ): haematological toxicity, grade 111 in 4 patients and IV in 5; oral toxicity grades I1 and TI1 in patients; cardiac toxicity grade 111 in 1 and neurotoxicity grades I1 and 111 in 4 patients. Chemotherapy had to be stopped in 4 patients because of toxicity. The treatment schedule was modified in 14 patients: the drug doses were decreased in 6. one drug was omitted in 5 and in patients the treatment had to be delayed. Prognostic factors. Clinical and biological parameters at diagnosis were studied by univariate analysis: age, systemic symptoms, Karnofsky index, stage, grade, nodal or extranodal involvement, number of nodal regions involved, Haematological 5 (8) 7 (11) 4 (6) 5 (8) Oral 2 () 2 () 1 (1) - Cardiac 1 (1) - 1 (1) - Neurological 7 (11) 2 () 2 () - *WHO classification. erythrocyte sedimentation rate (ESR), lactic dehydrogenase (LDH), haemoglobin and serum albumin. Significant poor prognostic factors were Karnofsky index < 70 (p < 0.001), elevated LDH (p < 0.001), haemoglobin < 100 g/1 (p < O.OOl), high-grade histology (p = 0.005), stages I11 and IV (p = 0.008), B symptoms (p = 0.00), ESR >60 mm (p = 0.0), and involvement of 24 lymph node regions (p = 0.0). Multivariate analysis identified four independent variables significantly associated with poor prognosis: high-grade histology (p < 0.001), stages 111 and IV (p = 0.002), haemoglobin < 100 g/l (p = 0.004) and elevated LDH (p = 0.004) (Table 4). loo 75 - I L Time, months Fig. 2. Disease-free survival of the entire group..st L I Time, months Fig. 1. Survival of the entire group Time, month8 Fig.. Survival according to stage. Stage I -; Stage I1 -; Stage ; Stage IV

4 M LLANOS ET AL Table 4 Results of multivariate analysis Characteristic Relative 95% CI risk p-value High grade histology < 0.00 I Elevated LDH Stages 111-IV 7.14 I Haemoglobin < 100 g/l ~ Abbreviations: 95% CI = 95%) confidence interval. LDH = lactate dehydrogenase. Discussion The treatment of choice for aggressive non-hodgkin s lymphoma is combination chemotherapy. A variety of regimens has been developed, often called first, second, and third generation regimens, with increasing number of drugs and/or increasing dose intensity aimed at improving complete remission and survival rates. During the past decade CHOP has been considered standard treatment, with good complete remission and survival rates observed in several studies (Table 5) (, 4, 1-18). Our results showed a high CR rate, 71%, and a 5-year survival of 61%. Several factors must be taken into account, such as the inclusion of a relatively high frequency of stages I and 11 (48%); 70% of our cases with stages I and I1 were of extranodal origin, which contrasts with a US report in which extranodal lymphomas constituted only one-quarter of the total material (2). Nine of our patients (14%) had no remaining clinical disease after the initial debulking surgery. These factors may explain the relatively high CR and survival rates in our study. With the new intensive third-generation regimens, initially increased complete remission and survival rates were reported but randomized trials comparing standard treatment, such as CHOP with these new regimens revealed no significant differences. Cooper et al. (15) compared CHOP with MACOP-B, Montserrat et al. (16). CHOP with Pro- Table 5 CHOP chemotherapy treatment results in non-hodgkin s 1.vmphoma Ref. n CR (X,) s ( X) FOIIOW-UP years MACE-CytaBOM, Gordon et al. (17) CHOP with m- BACOD, and Fisher et al. (18) compared CHOP, m- BACOD, ProMACE-CytaBOM, and MACOP-B in a phase 111 study. In these studies no significant differences were observed in partial or complete response rates, time to treatment failure, or survival. However, serious toxicity differed significantly, CHOP and ProMACE-CytaBOM being less toxic than the other regimens. Many factors such as dose intensity, toxicity, and different distribution of prognostic factors may explain these results. The intensive regimens were generally more toxic and so the dose often had to be reduced because of myelosuppresion. Recent studies (19. 20) agree on the need for a prognostic classification of non-hodgkin s lymphoma, taking into account relevant clinical and biological factors to define subgroups of patients with different response to chemotherapy and different prognosis. We found that stages TTILIV, high-grade histology, elevated LDH and haemoglobin < 100 g/l were poor prognostic factors. Treatment with more aggressive regimens could be justified in these groups. Further studies are, however. required to demonstrate that subgroups with poor prognostic signs really benefit from these intensive chemotherapy regimens. The studies of CHOP versus third-generation regimens will probably require another decade before more definite conclusions can be drawn. In the meantime, CHOP can be considered as the standard treatment of aggressive non- Hodgkin s lymphoma. ACKNOWLEDGEMENTS We are indebted to Dr. R. Bordes for kindly reviewing and classifying the histological specimens Abbreviations: Ref = Reference. n = number CR = complete response. S = survival of patients. REFERENCES I. Longo DL. DeVita VT. Jaffe ES. Mauch P. Urba WJ. Lymphocytic lymphomas. In: DeVita VT. Hellman S. Rosenberg SA. eds. Cancer: Principles & practice of oncology. 4th ed. Philadephia: J. B. Lippincott Company. 199: Aisenberg AC. Treatment of non-hodgkin s lymphoma. In: Aisenberg AC, ed. Malignant lymphoma. Pennsylvania: Lea & Febiger. 1991:

5 CHOP IN NON-HODGKIN S LYMPHOMA 99. Jones SE. Grozea PN, Miller TP, et al. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: a Southwest Oncology Group Study. J Clin Oncol 1985; : Coltman CA. Dalhberg S, Jones SE. Southwest Oncology Group studies in diffuse large cell lymphoma: a subset analysis. In: Kimura K, ed. Cancer chemotherapy: challenges for the future. Tokyo: Excerpta Medica, 1988: Skarin A, Canellos G, Rosenthal D. Moderate dose methotrexate combined bleomycin, adriamycin, cyclophosphamide. oncovin, and dexamethasone, m-bacod, in advanced diffuse histiocytic lymphoma (Abstract). Proc Am Soc Clin Oncol 198; 2: Fisher RI, DeVita VT, Hubbard SM, et al. Randomized trial of ProMACE-MOPP vs. ProMACE-CytaBOM in previously untreated, advanced stage, diffuse aggressive lymphomas (Abstract). Proc Am SOC Clin Oncol 1984; : Klimo P, Connors JM. MACOB-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med 1985; 102: Miller TP, Dana BW, Weick JK, et al. Southwest Oncology Groupclinical trials for intermediate- and high-grade non-hodgkin s lymphomas. Semin Hemato1 1988; 25 (Suppl2): Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 5: Mantel N. Evaluation of survival data and two new rank order statistics evising in its consideration. Cancer Chemother Rep 1966; 50: Armitage P. Statistical methods in medical research. Oxford; Blackwell 1971: Cox DR. Regression models and life tables. J R Stat Soc B 1972; 4: Armitage JO. Dick FR. Corder MP. Garneau SC, Platz CE, Slymen DJ. Predicting therapeutic outcome in patients with diffuse histiocytic lymphoma treated with cyclophosphamide. adriamycin, vincristine and prednisone (CHOP). Cancer 1982; 50: Harberg H, Lindelmalm C. Cavallin-Stahl E. CHOP versus CHOP-M in the treatment of high grade malignant non- Hodgkin s lymphomas in adults: a Swedish national randomized study (Abstract). Proc Am Soc Clin Oncol 1988; 7: Cooper IA, Ding JC, Matthews JP, et al. A randomized comparison of MACOP-B and CHOP in intermediate grade non-hodgkin s lymphoma (Abstract). Proc Am Soc Clin Oncol 1991; 10: Montserrat E, Garcia-Conde J, Vifiolas N. et al. ProMACE- CytaBOM vs. CHOP in the treatment of unfavorable lymphomas: a randomized trial (Abstract). Blood 1991; 27 (Suppl I): Gordon LI, Harrington D. Andersen J, et al. Comparison of a second-generation combination chemotherapeutic regimen (m-bacod) with a standard regimen (CHOP) for advanced diffuse non-hodgkin s lymphoma. N Engl J Med 1992; 27: Fisher RI. Gaynor ER. Dahlberg S. et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-hodgkin s lymphoma. N Engl J Med 199; 28: Armitage JO. Staging systems for aggressive non-hodgkin s lymphoma (Editorial). Ann Oncol 1992; : Rodriguez J, Cabanillas F. McLaughlin P, et al. A proposal for a single staging system for intermediate grade lymphoma and inmunobbastic lymphoma based on the tumor score. Ann Oncol 1992; :