Combined Modality Management of
Advanced Stage Hodgkin's Disease:
The Indian Perspective

SIDDHARTH S LASKAR,1 VIMAL N SANGHAVI,1 MARYANN A MUCKADEN,1
SURESH H ADVANI,2 TAPAN K SAIKIA,2 KETAYUN A DINSHAW1
1 DEPARTMENT OF RADIATION ONCOLOGY AND 2DEPARTMENT OF MEDICAL ONCOLOGY,
Tata Memorial Hospital, Mumbai, India

Abstract
Optimal treatment for advanced stage Hodgkin's disease is still evolving. From 1983 to 1992 at the Tata Memorial Hospital, Mumbai, India, 375 patients with Hodgkin's disease were treated with cyclophosphamide, vincristine, procarbazine, prednisolone or adriamycin, bleomycin, vinblastine, dacarbazine, or alternating regimens with or without radiation therapy. 296 patients (78.9%) received a combination of chemotherapy and radiation therapy, while 79 patients (21.1%) received chemotherapy alone. The complete response rate for the whole group was 90.7% and the partial response rate was 5.1%. When the groups were compared according to the chemotherapy regimen, the complete response rate was 90.9% for patients receiving cyclophosphamide, vincristine, procarbazine, and prednisolone, 87.7% for those receiving adriamycin, bleomycin, vinblastine, and dacarbazine, and 91.3% for patients given the combination regimen
(p = 0.882). The complete response rates for the group receiving chemotherapy alone versus the group receiving combined chemoradiotherapy were 88.6% and 91.2%, respectively (p = 0.507). Progression-free survival and overall survival at 10 years (median follow-up, 45 months) was 64% and 82%, respectively. Progression-free survival among the groups receiving cyclophosphamide, vincristine, procarbazine, prednisolone or adriamycin, bleomycin, vinblastine, dacarbazine, and alternating regimens were 62%, 62%, and 66% (p = 0.461) and overall survival was 74%, 91%, and 81% (p = 0.223), respectively. Histologic type (p = 0.000), treatment modality (p = 0.000), stage (p = 0.002), bone marrow involvement (p = 0.000), and response to therapy (p = 0.000) were found to be statistically significant factors influencing progression-free survival. Stage (p = 0.055) and response to therapy (p = 0.000) were statistically significant factors influencing overall survival. Cyclophosphamide, vincristine, procarbazine, and prednisolone, which is a more cost-effective regimen, combined with involved field radiation therapy, could be considered an effective alternative for countries such as India, where financial constraints greatly influence the choice of treatment.

Key Words: Combined modality therapy, Hodgkin's disease, Radiation therapy


Introduction

Prior to the 1960s, advanced stage Hodgkin's disease was treated using single-agent chemotherapy, resulting in an extremely poor median survival of approximately 1 year.1 The introduction of the 4-drug combination chemotherapy programme of MOPP (metchlorethamine/nitrogen mustard, vincristine, procarbazine, prednisone) by the National Cancer Institute (NCI) in 1964 was an important landmark demonstrating the principles and success of combination chemotherapy.2 The long-term results achieved with MOPP revealed that approximately 80% of patients had complete remission, although approximately one-third of patients in complete remission relapsed. These results also revealed that tumour bulk,3 performance status, associated systemic symptoms, age, and dose intensity of the active agent4-7 influenced remission and relapse rates. MOPP was also found to have substantial long-term toxic effects, including sterility, immunosuppression, secondary myelodysplasia, and acute leukaemia.8-10

In 1973, Bonadona et al from the Milan Cancer Institute introduced a regimen composed of drugs differing in structure, toxicity, and activity.11 This regimen, ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) was introduced as a second-line chemotherapy regimen for patients for whom MOPP had failed.11 It was noted, however, that ABVD was not associated with sterility or treatment-induced leukaemia or myelodysplasia.12-13 The efficacy of ABVD was prospectively compared with MOPP in previously untreated patients with stage IIB, III, and IV Hodgkin's disease and in those undergoing first relapse after radiotherapy in randomised trials.11 The results revealed complete remission rates of 80% and 71% for ABVD and MOPP, respectively. After 10 years, the results in terms of freedom from progression (FFP) and overall survival (OS) were 63% and 54%, respectively, for ABVD and 50% and 39%, respectively, for MOPP.

At the Tata Memorial Hospital in India, patients with Hodgkin's disease account for 7.5% of all patients.14 The policy for the treatment of advanced stage Hodgkin's disease at the Tata Memorial Hospital has been combined modality management using combination chemotherapy with or without adjuvant radiation therapy. Chemotherapy consisted of COPP (cyclophosphamide, vincristine, procarbazine, and prednisolone), or ABVD or a combination in the form of an alternating COPP/ABVD regimen. Involved field radiation therapy (IFRT) was delivered to the site of initial disease for patients with a tumour size more than 7 cm and for patients with tumour less than 7 cm with residual disease after chemotherapy. Cyclophosphamide was used instead of nitrogen mustard because nitrogen mustard is not available in India. In this article, we review the results of patients treated with these regimens from 1983 to 1992 at the Tata Memorial Hospital.


Patients and Methods

All patients with histopathologically proven Hodgkin's disease, with clinical or pathological stage IB, IIB, III, or IV according to the Ann Arbor criteria,15 were included in this study. All patients had not received any prior therapy. A careful clinical examination with documentation of all sites of involvement was undertaken prior to treatment. Staging investigations consisted of complete blood counts, blood biochemistry including lactate dehydrogenase, bone marrow aspiration and biopsy, chest X-ray, ultrasonography of the abdomen, and computed tomography (CT) scan/magnetic resonance imaging as and when indicated. Patients were evaluated in the lymphoma joint clinic by radiation oncologists, medical oncologists, and pathologists prior to starting therapy.

The chemotherapy regimens were COPP, ABVD, or alternating COPP/ABVD, as follows: COPP

  • cyclophosphamide 600 mg/m2, intravenous (IV) infusion on days 1 and 8
  • vincristine 1.4 mg/m2, slow IV push on days 1 and 8
  • procarbazine 100 mg/m2, orally (O) from days 1 to 14
  • prednisolone 40 mg /m2, O from days 1 to 14.

This regimen was repeated every 28 days for 6 cycles. ABVD

  • adriamycin 25 mg/m2, slow IV injection on days 1 and 15
  • bleomycin 10 mg/m2, slow IV push on days 1 and 15
  • vinblastine 6 mg/m2 slow IV push on days 1 and 15
  • dacarbazine 375 mg/m2, IV infusion on days 1 and 15.

This regimen was repeated every 28 days for 6 cycles. COPP/ABVD consisted of alternating monthly cycles of each regimen as per the schedule.

Radiotherapy was planned to the site of the initial disease. Patients were treated with megavoltage radiation at doses ranging from 20 Gy to 45 Gy for 2 to 5 weeks at 1.8 Gy to 2.0 Gy per fraction. The chemotherapy regimen, site of initial bulky disease, and age of the patient determined the total dose and the radiotherapy portal.


Response Evaluation

Response to treatment was evaluated 3 months after completion of prescribed therapy. Patients were evaluated every 6 months for the first 3 years after therapy and every year thereafter. A complete physical examination with accurate documentation of any measurable disease was made at every follow-up visit. The relevant haematological parameters were also evaluated. Chest X-ray, ultrasonogram of the abdomen and pelvis, and CT scan was done, as required, to assess the response to therapy.

Response was evaluated 3 months after completion of therapy and graded according to the WHO response evaluation criteria, as follows:16

  • complete response (CR) the disappearance of all measurable disease
  • partial response (PR) 50% reduction of all measurable disease
  • stable disease (SD) <50% reduction in the total tumour size or <25% increase in the size of 1 or more measurable lesions
  • progressive disease (PD ) 25% increase in the size of 1 or more measurable lesions or the appearance of new lesions confirmed by biopsy.


Survival Analysis

Progression-free survival (PFS) was defined as the interval from registration to the date of progression from a partial remission or the date of relapse after complete remission. OS was defined as the interval from the date of registration to the date of documented death from any cause.


Statistical Analysis

Rates of response were compared between treatment groups and according to patient characteristics, with the chi-square test for contingency tables.17 Time to event distributions (PFS and OS) was estimated by the product-limit method of Kaplan and Meier.18 The statistical significance of differences observed in the distributions of time to event was assessed with the log-rank test.19


Results

375 patients who had completed the planned chemotherapy and radiation therapy were considered for the final analysis. There were 294 men (78.4%) and 81 women (21.6%). The median age at presentation was 24 years (range, 3 to 74 years). The histological subtypes included mixed cellularity (55.2%), lymphocyte predominant (17.6%), nodular sclerosis (16.8%), and lymphocyte depleted (7.5%). The histological subtype was not specified for 11 patients. Most patients had stage III disease (48.5%), followed by stage IIB (24.3%), stage IV (18.4%), and stage IB (8.8%). The clinical characteristics of the patients are shown in Table 1. 295 patients (78.6%) received a combination of chemotherapy and radiation therapy, whereas 79 (21.1%) received chemotherapy alone. Of the 295 patients, 191 (50.9%) received local field, 18 (4.8%) received mantle field, 6 (1.6%) received inverted 'Y', and 80 (21.3%) patients received total nodal irradiation. Forty nine patients (13.1%) received ABVD, 222 (59.2%) received COPP, and 104 (27.7%) received COPP/ABVD.

Table 1. Patient and disease characteristics.
Abbreviations: ABVD = adriamycin, bleomycin, vinblastine, dacarbazine; COPP = cyclophosphamide, vincristine, procarbazine, prednisolone.


Induction of Remission

The CR rate for the entire group was 90.7% (340/375), while 5.1% of patients (19/375) had a PR, 1.3% (5/375) had SD, and 0.5% (2/375) had PD. The CR rates for individual treatment groups were 90.9% of patients (202/222), 87.7% (43/49), and 91.3% (95/104) for COPP, ABVD, and COPP plus ABVD, respectively.

The radiation dose used for each group was similar. There was no statistically significant difference in the response rates between the 3 groups (p = 0.882). Stage of disease (p = 0.002) and visceral involvement (p = 0.000) were significant prognostic factors that influenced response rates. The differences in response rates amongst the various prognostic groups are highlighted in Table 2

Table 2. Response rates.
Abbreviations: ABVD = adriamycin, bleomycin, vinblastine, dacarbazine; COPP = cyclophosphamide, vincristine, procarbazine, prednisolone.

 

Progression-Free Survival

After a median follow-up of 45 months (range, 6 to 166 months), the overall PFS was 64% at 10 years for the whole group. Among the 3 treatment groups, the relapse rates after therapy were 52/222 patients (23.4%), 8/49 (16.3%), and 22/104 (21.1%) for COPP, ABVD, and alternating COPP/ABVD, respectively. The overall rate of relapse was 82/375 patients (21.9%). After 10 years, the PFS for the group receiving chemotherapy alone was 45% and for the group receiving a combination of chemotherapy and radiotherapy was 68% (Figure 1). There was no statistically significant difference observed in PFS amongst the 3 treatment groups 62% for COPP, 62% for ABVD, and 66% for alternating COPP/ABVD (p = 0.461) [Figure 2]. The evaluation of the influence of various prognostic factors determining PFS showed histological type, treatment (chemotherapy versus chemotherapy and radiotherapy), response rates, stage of disease, and bone marrow involvement as statistically significant. There was a significant improvement in PFS in the group receiving COPP followed by IFRT compared with the group receiving COPP alone (68% vs 36%; p = 0.0001). Among patients receiving a combination of chemotherapy and radiation therapy, PFS in the groups receiving radiation doses of 25 Gy, 26 Gy to 35 Gy, and 36 Gy were 78%, 65%, and 55%, respectively (p = 0.365). Age at presentation, sex, presence of 'B' symptoms, involvement of liver and spleen, and chemotherapy regimen did not have a statistically significant influence on PFS.

Figure 1. Kaplan Meier curve showing progression.

Figure 2. Kaplan Meier curve showing disease progression in patients receiving cyclophosphamide, vincristine, procarbazine, prednisolone (COPP) or adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), or alternating regimens.


Overall Survival

After a median follow-up of 45 months (range, 6 to 166 months), the OS for the whole group was 82% at 10 years. OS for the groups receiving COPP, ABVD, and COPP/ABVD were 74%, 91%, and 80%, respectively (Figure 3). The post-therapy response rates and stage of disease were the only statistically significant factors that influenced overall survival (p < 0.0001 and p < 0.002, respectively). Patients with CR had an OS of 80% versus 50% and 49% for patients with PR and PD, respectively. Patients receiving a combination of chemotherapy and radiation therapy had an OS of 80% whereas the group receiving chemotherapy alone had an OS of 75% at 10 years (Figure 4). Other prognostic factors such as age at presentation, sex, presence of B symptoms, involvement of liver and spleen, and chemotherapy regimen did not have a statistically significant influence on OS.

Figure 3. Kaplan Meier curve showing overall survival in patients receiving cyclophosphamide, vincristine, procarbazine, prednisolone (COPP) or adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), or alternating regimens.

Figure 4. Kaplan Meier curve showing overall survival in patients receiving chemotherapy alone versus a combination of chemotherapy and radiation therapy.

 

Salvage Therapy

Of the 82 patients (21.8%) who relapsed, 65 (79.2) received salvage therapy. Amongst those who received salvage therapy, 53 patients (64.4%) received chemotherapy only, 7 (8.5%) received radiotherapy only, and 5 (6.1%) received a combination of radiotherapy and chemotherapy. After salvage therapy, 16 patients (24.6%) had CR, 3 (4.6%) had PR, 4 (6.1%) had SD, and 10 (15.3%) had PD. ABVD was found to be the most effective of the chemotherapy regimens used for salvage therapy. The CR rate with ABVD when used as salvage therapy was 33.3%. The rest of the chemotherapy regimens used for salvage had CR rates of less than 15%.

Data for complications were available for 367/375 patients (97%). Fifty-two patients (14%) developed significant treatment-related complications. The overall complication rate recorded was 18% for COPP, 12.2% for ABVD, and 5% for alternating COPP/ABVD. Grade 2 pneumonitis was recorded in 9/52 patients (17.3%) patients. The incidence of grade 2 pneumonitis in the groups receiving COPP, ABVD, and COPP/ABVD was 12% (6/52), 2% (1/52), and 4% (2/52), respectively. Haematological complications were greatest in the patients receiving COPP (4.5%).


Discussion

A review of 441 patients with Hodgkin's disease treated at the Tata Memorial Hospital from 1975 to 1978 has been reported earlier.20 In this study, the results of 375 patients with advanced-stage Hodgkin's disease treated at the Tata Memorial Hospital for a period of 9 years, from 1983 to 1992 are reviewed. Comparison of the efficacy of COPP, ABVD, and alternating COPP/ABVD with or without radiation therapy did not reveal a statistically significant difference in the response rates between the 3 treatment groups. The CR rates were 90.3% for COPP, 87.7% for ABVD, and 91.3% for the alternating COPP/ABVD regimen. These results are comparable to those published by the NCI, which reported an 81% CR rate with MOPP.21 The Eastern Cooperative Oncology Group (ECOG) studied MOPP in 1 group in a randomised trial of patients with advanced Hodgkin's disease and reported a CR rate of 73%.22 Bonadonna et al compared the efficacy of MOPP versus ABVD in a prospective randomised trial.11 The complete response rates favoured ABVD over MOPP (80% versus 71%). The Cancer and Acute Leukemia Group B (CALGB) also reported superior complete remission rates with ABVD and alternating COPP/ABVD compared with MOPP in advanced-stage Hodgkin's disease.23

The PFS at 10 years for patients in the groups receiving COPP, ABVD, and alternating COPP/ABVD were 62%, 62%, and 66%, respectively. Histopathologic type, stage of disease, treatment type, and response to initial therapy were statistically significant prognostic factors that influenced PFS. There was no dose response relationship seen for patients receiving a radiotherapy dose ranging from 25 Gy to 35 Gy. The NCI study reported a PFS rate of 52% at 10 years for patients treated with MOPP.21 In the randomised trial reported by the CALGB, the failure-free survival rates at 10 years were 38% for MOPP, 55% for ABVD, and 50% for MOPP/ABVD.23 Bonadonna et al reported a superior rate of freedom from progression of 53% for MOPP versus 65% for ABVD at 4 years.11

The OS at 10 years was 74% for patients receiving COPP, 91% for those receiving for ABVD, and 80% for those with alternating COPP/ABVD (p = 0.223). The improvement in OS was mainly due to the high salvage rates for patients who relapsed. Seventy nine percent of patients who relapsed received salvage therapy. The NCI study reported an OS rate of 50% at 10 years for patients treated with MOPP.21 Bonadonna et al reported OS rates of 88% for MOPP and 90% for ABVD at 4 years.11 The CALGB reported overall survival rates of 58% for MOPP, 68% for ABVD, and 65% for MOPP/ABVD at 10 years.23

The theoretical basis for the use of multidrug regimens is the predicted advantage of the earliest possible introduction of all active agents to address the heterogeneous tumour cell population. The first clinical trial using a hybrid regimen was conducted by the Southwest Oncology Group (SWOG).24 These researchers used the MOP-BAP (metchlorethamine/ nitrogen mustard, vincristine, procarbazine, bleomycin, adriamycin and prednisone) regimen. A higher complete remission rate and OS and significantly less thrombocytopenia was reported for the MOP-BAP regimen compared with MOPP. A hybrid regimen was developed by the group from Milan,25 who tested MOPP-ABVD given in a hybrid fashion versus alternating MOPP/ABVD in a randomised trial of 427 patients with advanced stage Hodgkin'ss disease.25 After 10 years, there was no difference in PFS between the hybrid (69%) and alternating (67%) regimens.

The German Hodgkin's Study Group (GHSG) developed the BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen based on mathematical modelling that suggested that modest dose-intensification would yield a 10% to 20% increase in failure-free survival.26,27 The GHSG designed a 3-group study comparing COPP/ABVD, standard BEACOPP, and escalated BEACOPP.28 Interim analysis revealed superior freedom from failure with escalated BEACOPP (89%) versus BEACOPP (81%) and COPP/ABVD (72%). There was no significant difference in OS amongst the 3 treatment groups. Escalated BEACOPP was associated with greater haematological toxicity, however. The use of alkylating agents may be associated with an increased incidence of sterility and second malignancies at longer follow-up. The aggressive regimen designed by the Stanford group, Stanford V (doxorubicin, vinblastine, mechlorethamine, bleomycin, vincristine, etoposide, prednisone) revealed an 8-year PFS of 89% and OS of 96% after a median follow-up of 4.5 years.29,30

In an earlier publication, the rate of testicular dysfunction in 92 male patients treated with 6 to 10 cycles of COPP chemotherapy at the Tata Memorial Hospital between 1970 and 1978 was reported.31 After a median follow-up of 6 years (range, 1 to 17 years), testicular atrophy was observed at physical examination in 96.7% patients. All patients remained azoospermic during the follow-up period. The testosterone levels did not differ before and after treatment. Testicular biopsy performed for 19 patients showed germinal aplasia in all patients. Thyroid dysfunction after radiotherapy, and the results of treatment in the paediatric age group have been reported earlier.32,35

When the cost of treatment was taken into account, COPP was found to be the most economical regimen. At the Tata Memorial Hospital, 6 cycles of COPP, ABVD, or COPP/ABVD would cost US$125, US$625, and US$375, respectively. The course of radiation therapy would cost approximately US$208. It was further noticed that the addition of IFRT significantly improved the PFS. This improvement in PFS with the addition of IFRT was most pronounced in the group receiving COPP.


Conclusion

This study of combined modality management of advanced Hodgkin's disease using chemotherapy and radiotherapy resulted in response and survival rates comparable to those published in the recent literature. Although the current standard at the Tata Memorial Hospital is to use ABVD for all patients who can afford it, there remains a large proportion of patients who cannot afford to pay for expensive chemotherapy regimens. In a country such as India, and other developing countries where financial constraints greatly influence the choice of treatment, COPP combined with involved field radiation therapy could be considered an effective alternative for the management of advanced-stage Hodgkin's disease. This option is feasible and effective, with the known adverse effects of alkylating agents having been taken into consideration.


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    Address for Correspondence

    Dr Siddharth Laskar
    Consultant Radiation Oncologist
    Tata Memorial Hospital
    Dr Ernest Borges Marg
    Parel, Mumbai 400012
    India
    Tel: (91 22) 414 6750
    Fax: (91 22) 414 6937
    E-mail:




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