Original Articles. Etoposide, vinblastine, adriamycin and prednisolone (EVAP) combination chemotherapy as first-line treatment for Hodgkin s disease

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1 RUPALI et al. : AETIOLOGY OF PROLONGED FEVER IN HIV-INFECTED ADULTS Original Articles 189 Etoposide, vinblastine, adriamycin and prednisolone (EVAP) combination chemotherapy as first-line treatment for Hodgkin s disease VINOD RAINA, ATUL SHARMA, BIDHU K. MOHANTI, RAJIVE KUMAR, RAMESH DAWAR, GOURA K. RATH ABSTRACT Background. Mechlorethamine, vincristine, procarbazine, prednisolone (MOPP) and doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) are well established first-line chemotherapy protocols for the treatment of Hodgkin s disease. The aim of this study was to try a new combination of drugs that individually have a proven efficacy in Hodgkin s disease but have less incidence of severe nausea, vomiting, pulmonary toxicity and sterility. Methods. This prospective, single-arm study enrolled 66 newly diagnosed, previously untreated patients of Hodgkin s disease with stages IA (bulky) IVB disease. They were given 6 8 courses of etoposide, vinblastine, doxorubicin and prednisolone (EVAP) as first-line chemotherapy between January 1992 and December Radiotherapy (RT) was given to the involved fields of those patients who had bulky (³ cm) stages I or II disease at presentation. The end-points were (i) complete and overall response; (ii) disease-free and overall survival; and (iii) toxicity. Results. Complete response was seen in 78.8% and partial response in 12.2% of patients; the overall response rate was 91%. The median follow up was 48 months. The 5-year overall and disease-free survivals were 72% and 62%, respectively. There were 3 episodes of grade IV neutropenia requiring hospitalization. One patient developed avascular necrosis of the femur. There All India Institute of Medical Sciences, Ansari Nagar, New Delhi 129, India VINOD RAINA, ATUL SHARMA Department of Medical Oncology BIDHU K. MOHANTI, GOURA K. RATH Department of Radiation Oncology RAJIVE KUMAR Department of Laboratory Oncology RAMESH DAWAR Department of Pathology Correspondence to ATUL SHARMA; atul1@hotmail.com The National Medical Journal of India 3 were 2 deaths during treatment, one due to chemotoxicity, and another due to progressive disease. Conclusion. The overall and complete responses were fractionally inferior to the recently published hybrid MOPP/ ABV combination and that of ABVD chemotherapy. The advantages of the EVAP combination are absence of pulmonary toxicity, markedly lower incidence of sterility and nausea and vomiting. EVAP is an attractive option and a randomized trial is warranted to assess its efficacy against established protocols. Natl Med J India 3;16:199 3 INTRODUCTION Mechlorethamine, vincristine, procarbazine and prednisolone (MOPP), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) are well established first-line chemotherapy protocols for the treatment of Hodgkin s disease. 1 3 In randomized trials, ABVD has better response rates and disease-free survival as well as a reduced risk of sterility compared to MOPP. 3,4 Also, MOPP has adverse effects (severe nausea, vomiting and sterility) in the vast majority of patients, and on long term follow up secondary cancers occur in a small proportion. This has led to ABVD becoming the standard protocol. However, this combination is not free from cardiac and pulmonary toxicities which are due to doxorubicin and bleomycin, especially if the patient also receives radiotherapy. Almost half the patients with Hodgkin s disease are below the age of years and, hence, concerns about sterility and other long term adverse effects are important. A recent trial of a hybrid protocol of MOPP/ABV has shown a small but significant superiority over 6 cycles of MOPP followed by 3 cycles of ABVD in advanced Hodgkin s disease in terms of complete response (CR) and overall (OS) and disease-free survival (DFS). 5 As the long term results of ABVD and the sequential MOPP/ABV protocols are not markedly different, attempts are now directed towards reducing the toxicity. 3

2 1 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 16, NO. 4, 3 Doxorubicin (adriamycin), vinblastine and prednisolone have proven efficacy as individual agents in Hodgkin s disease and are part of the ABVD and MOPP regimens. Etoposide (VP-16) has been demonstrated to have an efficacy of % % in refractory Hodgkin s disease and is commonly used in this disease for highdose chemotherapy with bone marrow/stem cell rescue. 6,7 The Cancer and Leukemia Group B (CALGB) has reported a 67% clinical response rate in patients with relapse of Hodgkin s disease with the combination of EVA. 8 In India, cost is a major factor. The EVAP protocol is almost half as expensive as ABVD. In view of the efficacy of all these drugs individually and their major cost advantage, we used this combination as a first-line therapy in newly diagnosed patients with Hodgkin s disease. METHODS Previously untreated patients with a histologically proven diagnosis of Hodgkin s disease [stages IA (bulky) to IVB] were enrolled in the study after taking written informed consent. Bulky disease was defined as any nodal mass > cm or mediastinal/thoracic ratio of more than 1/3. Staging procedures included complete blood counts, liver and kidney function tests, bone marrow biopsy and touch preparation, X-ray chest and CT scan or ultrasound of the abdomen (because of logistical problems a CT scan of the abdomen could not be done in all patients). Staging laparotomy and lymphangiogram were not done. The study period was from January 1992 to December Sixty-six patients were recruited and the cut-off date for follow up was June 1. The chemotherapy protocol is shown in Table I. All patients received 6 courses but those who had liver or bone marrow involvement were given 8 cycles. Assessment was done after 3 and 6 courses had been completed. At the end of chemotherapy, radiotherapy was given to the involved fields that originally had bulky disease (25 Gy). Toxicity was graded as per WHO criteria. Patients having a platelet count <75 9 /L and an absolute neutrophil count of <1.5 9 /L had their chemotherapy postponed by one week. Response assessment and analysis Complete response (CR) was defined as complete disappearance of all clinical, radiological, pathological and biochemical abnormalities for at least 4 weeks. Partial response (PR) was defined as >% reduction in the sum of the products of two diameters of all measurable lesions. Patients who had <% response were categorized as having stable disease and those who developed new lesions or in whom the total sum of all lesions increased by ³25% were classified as having progressive disease. The main objectives were assessment of OS and DFS. OS was calculated from the date of entry into the trial till death or the date on which the patient was last seen alive, and DFS from the date of complete remission till relapse. The survival curves were plotted using the SPSS statistical programme with the Kaplan Meier method. Test of significance was determined by the log rank test. RESULTS Table II shows the age, sex and histological subtypes of the patients. Response evaluation was done in 64 patients (1 patient died of chemotoxicity after one cycle and another of disease within 2 weeks). The most common histological type was mixed cellularity in 48 patients (72.7%). The commonest stage was IIIB in 22 (33%) followed by IIIA. Fifty-two patients (78.8%) achieved CR and 8 (12.2%) achieved PR (Table III). Four patients had either no response or progressive disease and were TABLE I. Chemotherapy protocol Drug Dose Days Etoposide mg/m 2 i.v. infusion 1 3 Vinblastine 6 mg/m 2 i.v. bolus 1 and 8 Doxorubicin 25 mg/m 2 i.v. infusion 1and 8 Prednisolone mg/m 2 orally 1 14 Each cycle was of 28 days duration and 6 8 cycles were given to all the patients TABLE II. Patient characteristics (n=66) Characteristic n Age < years 52 ³ years 14 Gender Men 54 Women 12 Histology Mixed cellularity 48 Nodular sclerosis 9 Lymphocyte predominance 5 Lymphocyte depletion 3 Unclassified 1 TABLE III. Response evaluation Stage n Complete Partial No response/ Early response response progressive death disease IA 3 3 IIA IIB 6 5 IIIA 5 5 IIIB IVA+B (78.8%) 8 (12.2%) 4 2 given salvage chemotherapy. At months, the OS and DFS were 72% and 62%, respectively (Figs. 1 and 2). Among those who achieved CR there were 18 relapses (34%), 9 within one year and the rest after one year. Eleven patients were lost to follow up; of these, 5 had CR and 6 had relapse. Since the number of patients in stages I and IV were small for survival analysis, stage I patients were clubbed with stage II (n=28) and stage III with stage IV patients (n=38). The -month OS for patients with stages I and II disease was 85%, and for stages III and IV it was 65% (Fig. 3). The DFS for stages I and II and stages III and IV disease was 75% and 55%, respectively (p=.1; Fig. 4). For patients without and with B symptoms, the OS was 82% and 68%, respectively (p=.1; Fig. 5), and the DFS was % and 48%, respectively (p=.9). Patients without bulky disease had a better OS (95%) than those with bulky disease (61%; p=.1; Fig. 6), and the DFS was 78% v. 55% (p=.1), respectively. There were 15 deaths (23%), 7 each died of progressive disease and relapse, and 1 died of chemotoxicity. Toxicity Chemotherapy was generally well tolerated. Grade III or IV toxicity was noted in 6 patients. Three patients required reduction in the dose of vinblastine after 2 cycles because of subacute intestinal obstruction. Grade III gastrointestinal toxicity was seen in 2 patients and 1 patient with grade IV gastrointestinal toxicity died at another hospital. Three patients had grade IV neutropenia

3 RAINA et al. : EVAP AS FIRST-LINE TREATMENT FOR HODGKIN S DISEASE FIG 1. Overall and disease-free survival at 5 years FIG 2. Disease-free survival at 5 years Stages I and II Stages III and IV Stages I and II Stages III and IV FIG 3. Comparison of 5-year overall survival in stages I and II with stages III and IV disease Survival No B symptoms B symptoms Fig 4. Comparison of 5-year disease-free survival in stages I and II with stages III and IV disease Survival No bulky disease Bulky disease FIG 5. Comparison of 5-year overall survival in patients with and without B symptoms FIG 6. Comparison of 5-year overall survival in patients with and without bulky disease

4 192 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 16, NO. 4, 3 TABLE IV. Comparison of results of different chemotherapy protocols for Hodgkin s disease Study Regimen n Complete Survival rates (%) Follow up (Overall) Disease- Failure Overall response free free Bonadonna et al. 4 MOPP years Canellos et al. 3 ABVD Glick et al. 5 MOPP/ABV Not stated years Brizel et al. 13 EVA+IFRT Not stated Canellos et al. 8 EVA* 45 (73) Not stated years (median) Our study EVAP (91) years * Relapse/Refractory patients requiring hospitalization and intravenous antibiotics. None of the patients required platelet transfusion. One patient developed avascular necrosis of the head of the left femur one year after treatment; this was thought to be due to prednisolone. Cost The cost (drugs only) of 6 courses of ABVD at our centre was approximately Rs (US$ ), whereas the cost of EVAP was approximately Rs 25 (US$ ). DISCUSSION This single-arm study was carried out using a combination of drugs whose efficacy in the treatment of Hodgkin s disease is proven. Three of the drugs, i.e. adriamycin, vinblastine and prednisolone, are used either in MOPP or ABVD. We added etoposide, which has proven efficacy in Hodgkin s disease when used as first-line therapy in salvage and high dose settings with transplants. 6,7,9 We wanted to avoid alkylating agents and bleomycin. This combination was almost % cheaper than ABVD. We included stage I patients with only bulky disease as they have a poorer prognosis, akin to the prognosis in patients with the mixed cellularity variety (the predominant histological variety in our patients). Previous publications from India have also reported a higher incidence of the mixed cellularity subtype (% 68.5%).,11 Moreover, we did not do a staging laparotomy, and it is well known that understaging can occur to the extent of % 15% if one relies only on CT scans for this. A combination of etoposide, vinblastine and adriamycin (EVA) was used by Canellos et al. in patients who relapsed for the first time after MOPP therapy. 8 In a trial on 45 patients they reported an overall response rate of 73% with % CR and 33% PR. At a median follow up of 42 months, 31 patients were disease-free. They concluded that EVA was an effective second-line treatment. The MOPP variant chlorambucil, vincristine, procarbazine and prednisone (LOPP)+EVAP was compared with LOPP alone as part of the British National Lymphoma Investigation trial by Hancock et al. 12 The combination was found to be superior to LOPP alone. Etoposide, vinblastine and doxorubicin have also been used in previously untreated patients by Brizel et al. from the USA. 13 In a pilot study of 26 previously untreated patients, they also used local involved field radiation. However, the results were disappointing with only 54% of patients showing CR and a 2-year OS of 86%. 13 Except the trial by Hancock et al., 12 the protocol used by all other investigators who have used this combination is different from ours as they used adriamycin and vinblastine on day 1 only. In our protocol and that of Hancock et al., adriamycin and vinblastine were used on days 1 and 8. This might be responsible for the differences in the results. In a recent study, Schellong et al. have reported that in paediatric Hodgkin s disease, replacement of procarbazine with etoposide not only equates the survival with the standard chemotherapy protocols but also reduces testicular damage. 14 Our results are comparable (Table IV) to those of ABVD and the recently published hybrid MOPP/ABV trial. 5 However, as the patient populations in the two studies were different, a randomized trial comparing EAVP with ABVD or MOPP/ABV is warranted. Even with the hybrid MOPP/ABV protocol sterility due to mechlorethamine is likely to occur in some patients. Also the MOPP/ABV hybrid is more toxic than ABVD; 5% of patients developed grade III or more pulmonary toxicity, 63% of patients developed grade III or IV neutropenia, and 8 patients died of toxicity. We are aware of the recent reports of secondary leukaemias with etoposide. 15,16 All these reports were published after our trial was started. None of our patients has developed a secondary leukaemia till date. Although our objective was not to derive any conclusion regarding prognostic factors, on univariate analysis bulky disease for OS (p=.1), and B symptoms for DFS (p=.9) were significant prognostic factors. No statistically significant differences were found in patients above and below the age of years and in different stages of the disease. This could be because of the small numbers of patients in each subgroup. We had 1 death due to toxicity. This is much less than that seen with the MOPP/ ABV hybrid protocol. We did not assess the impact of EVAP on sterility as none of the drugs used is known to cause permanent sterility. The fact that some of our patients were lost to follow up might have confounded the survival end-points (particulary patients who were lost to follow up after disease relapse). In conclusion, we found the EVAP combination to be effective, less toxic and cheaper. In developing countries, where cost is a major factor in the use of ABVD, EVAP should be considered as an alternative regimen. REFERENCES 1 DeVita VT, Serpick AA, Carpone PP. Combination chemotherapy in the treatment of Hodgkin s disease. Ann Intern Med 19;73: Bonadona G, Zucali R, Monfardini S, DeLena M, Ushlenghi C. Combination chemotherapy of Hodgkin s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 1975;36: Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, et al. Chemotherapy of advanced Hodgkin s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327: Bonadonna G, Valagussa P, Santoro A. Alternating non-cross resistant combination chemotherapy or MOPP in stage IV Hodgkin s disease: A report of 8-year results. Ann Intern Med 1986;4: Glick JH, Young ML, Harrington D, Schilsky RL, Beck T, Neiman R, et al. MOPP/ ABV hybrid chemotherapy for advanced Hodgkin s disease significantly improves failure-free and overall survival: The 8-year results of the intergroup trial. J Clin Oncol 1998;16: Schmoll H. Review of etoposide single-agent activity. Cancer Treat Rev 1982;9: Taylor RE, McElwain TJ, Barrett A, Peckham MJ. Etoposide as a single agent in

5 RAINA et al. : EVAP AS FIRST-LINE TREATMENT FOR HODGKIN S DISEASE 193 relapsed advanced lymphomas: A phase II study. Cancer Chemother Pharmacol 1982;7: Canellos GP, Petroni GR, Barcos M, Duggan DB, Peterson BA. Etoposide, vinblastine and doxorubicin: An active regimen for the treatment of Hodgkin s disease in relapse following MOPP. Cancer and Leukemia Group B. J Clin Oncol 1995;13: Canellos GP, Anderson JR, Peterson BA, Gottlieb AJ. EVA: Etoposide, vinblastine, doxorubicin (adriamycin): An effective regimen for the treatment of Hodgkin s disease in relapse following MOPP: A study of the Cancer and Leukemia Group B (abstract). Proc Am Soc Clin Oncol 1991;:273. Chandi L, Kumar L, Kochupillai V, Dawar R, Singh R. Hodgkin s disease: A retrospective analysis of 15 years experience at a large referral centre. Natl Med J India 1998;11: Dinshaw KA, Advani SH, Gopal R, Nair CN, TalvalkarGV, Gangadharan P, et al. Management of Hodgkin s disease in western India. Cancer 1984;54: Hancock BW, Vaughan Hudson G, Vaughan Hudson B, Bennett MH, MacLennan KA, Haybittle JL, et al. LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin s disease: Results of a British National Lymphoma Investigation Trial. J Clin Oncol 1992;: Brizel DM, Gockerman JP, Crawford J, Hathorn JW, Moore JO, Osborne B, et al. A pilot study of etoposide, vinblastine, and doxorubicin plus involved field irradiation in advanced, previously untreated Hodgkin s disease. Cancer 1994;74: Schellong G, Potter R, Bramswig J, Wagner W, Prott FJ, Dorfell W, et al. High cure rates and reduced long-term toxicity in pediatric Hodgkin s disease: The German Austrian multicenter trial DAL-HD-. J Clin Oncol 1999;17: Pedersen-Bjergaard J, Osterlind K, Hansen M, Philip P, Pedersen AG, Hansen HH. Acute nonlymphocytic leukemia, preleukemia, and solid tumors following intensive chemotherapy of small cell carcinoma of the lung. Blood 1985;66: Bajorin DF, Motzer RJ, Rodriguez E, Murphy B, Bosl GJ. Acute nonlymphocytic leukemia in germ cell tumor patients treated with etoposide-containing chemotherapy. J Natl Cancer Inst 1993;85: 2. The National Medical Journal of India is now covered in Current Contents: Clinical Medicine, Science Citation Index, SciSearch and Research Alert. Editor