Primary treatment of Hodgkin s disease

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1 DOI: /annonc/mdf653 Primary treatment of Hodgkin s disease G. P. Canellos Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Introduction Therapeutic research in human tumors has followed the lead from the early trials of combination chemotherapy for the treatment of advanced Hodgkin s disease (HD). The 1960s saw the introduction of new drugs and radiation equipment that were useful in the treatment of lymphoma in general. Chemotherapy given as single agents in moderate doses to patients previously treated with steroids and radiation therapy was the standard of the day. After anti-tumor activity was established, it remained to use them in combination in previously untreated patients with measurable, advanced disease. The precedent was already being set in the treatment of childhood acute lymphoblastic leukemia with encouraging preliminary results. The National Cancer Institute s (NCI) Medicine Branch group pioneered the effective use of combined chemotherapy in the form of combination chemotherapy composed of nitrogen mustard, vincristine, procarbazine and prednisone (known as MOPP). This regimen could achieve a high order of response with prolonged duration of complete remission that continued indefinitely in a significant number of patients [1, 2]. Table 1 is an outline of alkylating agent-containing regimens commonly used in the treatment of HD [3, 4]. These other variant regimens also confirmed their effectiveness in clinical trials. Initial trials demonstrated that MOPP could not only cure previously untreated patients but also patients in relapse from radiation therapy [5]. Maintenance therapy with intermittent MOPP beyond 6 8 monthly courses of MOPP did not increase the cure rate. There was some suggestion that the regimen was possibly as effective as radiation alone in localized disease [6]. The long-term toxicity of alkylating agents contained in combined MOPP-like regimens primarily affected bone marrow stem cells resulting in myelodysplasia leukemia and germ cells resulting in sterilization thus prompting a search for less toxic but equally effective treatments [7 9]. The combination of doxorubicin, vinblastine, bleomycin and dacarbazine (ABVD) was introduced by the NCI Milan group and proved an effective substitute which led to its acceptance as the current standard in the USA. Many of the newer and more intensive regimens are currently being compared with ABVD. A variety of active non-alkylating agent-containing regimens are shown in Table 2. They exist in phase II trials but have not been compared with one another in phase II trials [10 12]. In recent years, regimens have been changed to include the following: alternating combinations of active drugs; hybridized regimens; dose intensification per se and addition of other agents. Hybridized or alternating regimens showed some superiority to MOPP (or variant) alone in response and progression-free survival [13 15]. The move to replace or decrease the amount of radiation therapy given to young patients in order to reduce long-term radiation-induced secondary malignancies has given momentum to the use of chemotherapy alone in earlier stages. The ABVD regimen provided the means to do so with its relative safety as a systemic treatment. Many prospective trials have shown a superiority in relapse-free survival for combined modality over radiation therapy alone, although overall survival was not necessarily improved. Combined modality therapy for localized disease in recent series can be expected to generate a 5-year freedom from progression of 85% with an overall survival in the range of >80% [16, 17]. The inclusion of chemo- Table 1. Alkylating agent-containing regimens active in the treatment of Hodgkin s disease Regimen [reference] Dose (mg/m 2 ) Days MOPP [2] Mechlorethamine 6 1, 8 Vincristine 1.4 1, 8 Procarbazine Prednisone MVPP [3] Mechlorethamine 6 1, 8 Vinblastine 100 1, 8 Procarbazine Prednisone ChlVPP [4] Chlorambucil 6 (total) p.o Vinblastine 6 (max. 10) 1, 8 Procarbazine Prednisone European Society for Medical Oncology

2 154 Table 2. Non-alkylating combination chemotherapy regimens Regimen [reference] Dose (mg/m 2 ) Days ABVD [10] Doxorubicin 25 i.v. 1, 15 Bleomycin 10 units 1, 15 Vinblastine 6 1, 15 Dacarbazine 375 1, 15 EVA [11] Etoposide 100 1, 2, 3 Vinblastine 6 1 Doxorubicin 50 1 q. 28 days NOVP [12] Mitoxantrone 10 1 Vincristine q. 21 days Vinblastine 6 1 Prednisone therapy in the combined modality approach and improved radiographic staging for localized disease has obviated the need for staging laparotomy. These include the use of and radionuclide scanning with 67 gallium and positron emission tomography with 18 F-fluoro-deoxyglucose to evaluate the status of residual masses. Nodular lymphocyte predominant HD represents a unique variant of the disease and a different philosophy of management. It has the immunophenotypic and genetic features of a low-grade B-cell lymphoma, often presenting as localized disease. Radiation therapy alone is usually sufficient to control or cure the disease [18]. Alkylating agent-containing regimens may be more effective for advanced stages of this unique group which represents only 5% of patients. The treatment of advanced disease is not optimal and requires improvement since there is a 30 40% likelihood of relapse following 6 8 cycles of any of the standard regimens. The challenge to improve therapeutic results has to be balanced by the risk of increased drug-induced toxicity that results from agents, such as etoposide or alkylating agents, when used in higher doses. Dose intensity is relevant since escalated or intensive dose regimens tend to have a higher response rate, but whether a real survival advantage ensues remains uncertain. Further, escalated doses used with autologous peripheral stem cell or bone marrow transplantation can cure patients who relapse from conventional dose therapy, which further suggests a dose response effect in Hodgkin s disease. Management of localized disease Several long-term follow-up series of laparotomy-staged patients treated with extensive radiation alone have demonstrated a 10-year relapse-free survival of 76 83% for stages I or I/II in three series of 699 patients. The late toxicity of ischemic heart disease (16%) and second tumors (10%) was noted in long-term follow-up. The radiation fields usually included the mantle field of the mediastinum/neck/axillae and extension to the upper para-aortic nodes. The average dose was 35 Gy with a boost to the involved field up to 44 Gy. The dose to uninvolved nodal sites need not exceed 30 Gy. In general, the rate of clinical hypothyroidism is 14%. The in-field disease control rate exceeded 95% [19 21]. Using the European Organization for Research and Treatment of Cancer (EORTC) favorable criteria, young women <26 years of age presenting with clinical stage I asymptomatic disease, and especially patients with lymphocyte predominant nodular or nodular sclerosis histology, can be treated with radiation alone to a mantle field without a laparotomy with excellent outcomes; however, the issue of the risk of irradiationinduced breast cancer would be expected to be highest in young females. The long-term progression-free rate approaches 80% for this subgroup [22]. Mantle-only radiation therapy in localized classical HD staged without laparotomy has only a 58% 10-year progression-free survival [23]. In classical HD, laparotomy staging selected patients for mantle only radiation resulted in a 76% disease-free rate at 10 years [24]. The major concern now is the potential for an increasing radiationinduced complication rate with even longer follow-up. The clinical criteria which define the risk for subsequent dissemination or relapse in patients with unfavorable localized presentations have been presented by the EORTC (Table 3). Bulky mediastinal presentations (mass of >10 cm or >33% of the thoracic diameter) have been shown to have at least a 50% chance of recurrence when radiation therapy alone has been used [25]. This has been reduced considerably to 20% or less when systemic therapy is followed by localized irradiation [26]. Unfavorable features also include B symptoms and an ESR >30 mm, no symptoms but an ESR >50 mm, and >2 nodal areas. A series of randomized trials have shown a consistent superiority of combined modality therapy over extensive nodal irradiation alone in relapse-free survival [16, 17]. The issue of the elimination of radiation therapy in patients with Table 3. Unfavorable risk factors in localized disease (EORTC) a Mediastinal mass ( 33% thoracic diameter) Age >50 years Elevated erythrocyte sedimentation rate (ESR) a Ιnvolved sites 4 with the same side of diaphragm Mixed cellularity histology a Unfavorable entails ESR 50 or 30 with B symptoms. Any one of these factors in clinical stage I/II is unfavorable (Carde et al. [25]). EORTC, European Organisation for Research and Treatment of Cancer.

3 155 early stages but without bulk disease has been raised based on the preliminary observations. ABVD alone has been shown to have a low relapse rate when given to such patients in a single pilot trial [27]. The EORTC and NCI (Canada) are addressing this question in prospective trials. A relatively modest randomized trial in stage I, II patients without bulk of disease comparing ABVD alone versus the same ABVD regimen but with mantle or involved field radiation showed an equivalent result at 3 years of follow-up [28]. Since the long-term risk of second neoplasms exceeds 20 25% at years based on the techniques/doses of radiation used in the past, systemic therapy alone or that combined with very localized (limited) irradiation is being considered for most patients with nonbulky localized disease. What is unknown is whether these reduced radiation fields will have a commensurate reduction in second radiation-induced cancers. The latter include inthe-field sarcoma, epithelial aerodigestive cancers and breast cancer [29 31]. There is no uniform standard, but four cycles of ABVD plus involved field irradiation of at least 30 Gy to the involved field is commonly used for patients presenting with favorable prognosis localized HD. Treatment of recurrence from localized disease Localized disease treated with radiation alone will have a recurrence rate which varies from 20% to 30% for patients without negative prognostic features and carefully staged by laparotomy to >40% for clinically staged patients with either bulky mediastinal masses, elevated sedimentation rate, multiple nodal area involvement or extranodal extension. The majority of relapses will be detected in extranodal or nodal sites not previously irradiated and usually occur within the first 3 years following initiation of irradiation. Late relapses are rare with 5% at 4 years and 3.4% at 5 years in two series [32, 33]. Patients relapsing from primary radiation therapy can achieve an excellent response to combination chemotherapy. Patients who were originally in pathologic stage I/IIA can expect a chemotherapy-induced complete response (CR) rate of 80 90% with a 60 70% 10-year survival [34]. Disseminated recurrence following radiation alone has a second CR rate of 70% with a 58% 10-year survival [35]. The current use of combined modality, especially if a full six cycles of chemotherapy is given, has reduced the relapse rate, but the potential for drug resistance is still a factor. Second-line therapy is needed similar to patients who relapsed after chemotherapy alone for stage III or IV disease if patients had received combined modality therapy as primary treatment. Treatment of advanced disease The vast majority of patients presenting in stage III or IV are treated with combination chemotherapy. Over the passage of time, the regimens have varied in both their composition and Table 4. Prognostic factors which predict relapse of advanced disease a Stage IV Serum albumin <4 g Male gender Hemoglobin <10 g Age 45 years WBC >15 000/mm 3 Absolute lymphocyte count <600/mm 3 No. of factors (% of patients) Relapse-free survival at 6 years (%) None (7) 85 1 (22) (29) (23) (12) (7) a Treated with systemic therapy alone or combined with irradiation (adapted from Hasenclever and Diehl [38]). the schedules of drugs used and, in addition, some regimens have been used with radiation therapy. At the time of writing, the general standard in the USA and many centers in Europe, outside of a clinical trial, is ABVD for six to eight cycles. The Cancer and Leukemia Group B has conducted two trials where ABVD has been prospectively compared (see below) with MOPP alone; 12 months of MOPP alternating with ABVD; and MOPP/ABV hybrid [36, 37]. Long-term follow-up of these trials have shown that ABVD was equivalent or superior in progression-free survival without the toxicity of alkylating agents namely, more profound myelosuppression, sterility and leukemogenesis. However, the overall survival showed no difference due to the ability of second-line therapy to salvage relapsed patients. In general, combination chemotherapy, including ABVD, used for stage III/IV disease should achieve a clinical CR rate in the 70 80% range with an approximately 20 30% relapse rate over time. The outcome is directly influenced by the number of negative prognostic factors (Table 4) [38]. The majority of patients present with two to three of these negative factors. When five or more are present, there is an overall 5-year survival that is somewhat <50%. These poor risk patients represent only 7% of cases. In addition to clinical prognostic factors in advanced disease, there may be biological factors that correlate with response to chemotherapy. They include presence of Epstein Barr viral latent antigen (LMP-1) positivity exerting a favorable outcome [39]. The presence of tissue eosinophilia and elevated serum IL-10 levels have been associated with an inferior failure-free survival [40, 41]. With a salvage rate of 30 50%, an overall survival at 5 years could be in the range of 80%. The potential cure rate is in the range of 70%. With conventional dose chemotherapy regimens,

4 156 the overall survival outcome is likely to be similar regardless of regimen. The major differences in the follow-up will be in the toxicity. Although the standard is ABVD, there is certainly a need for newer regimens that might offer the potential for an improved outcome. The German Hodgkin s Lymphoma Study Group (GHSG) pioneered the development of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), a regimen based on a model which proposed to increase the failure-free survival by 10 20% by modest dose intensification. They also tested an escalated version given every 21 days which increased the doxorubicin 20% (from 25 to 30 mg/m 2 ); cyclophosphamide 90% (from 650 to 1200 mg/m 2 ) and etoposide 100% (from 100 to 200 mg/m 2 ) and required growth factor support. It was compared with regular dose BEACOPP and cyclophosphamide, vincristine, procarbazine and prednisone (COPP)/ABVD as the standard in a prospective randomized trial. With a median follow-up of 56 months, the freedom from treatment failure rate was 87%, 76% and 69%, respectively. The overall survival at five years was 91%, 88% and 83%, respectively [42]. The escalated BEACOPP was significantly superior in overall survival to COPP/ABVD but not the standard BEACOPP. The escalated BEACOPP was also associated with greater hematological toxicity. Nine leukemias out of 466 patients were noted in the escalated group compared with 4 of 469 with standard BEACOPP and 1 of 260 in COPP/ABVD. The BEACOPP regimen (standard dose) is now being compared with ABVD in a prospective randomized trial. Stanford V is a combined modality program which entails 3 months of weekly chemotherapy and steroids followed by irradiation (36 44 Gy) to initial bulky and residual radiographic sites. The most recent analysis in 142 patients demonstrated an 89% freedom from progression at a median of 5.4 years with an overall survival of 96%. These excellent results need confirmation but it should be noted that 32% of patients had bulky (>33% intrathoracic diameter) stage I or II. There were no treatment deaths or apparent sterilization. The vast majority (91%) in the series received radiation therapy [43]. The Milan NCI group piloted VEBEP (etoposide, epirubicin, bleomycin, cyclophosphamide, and prednisolone), a regimen given for eight cycles and followed with complementary radiotherapy to sites of prior disease. The complete remission rate was high (94%) with 78% freedom from progression at 6 years [44]. These excellent results were associated with gonadal damage, although this was reversible in half of the men. This again illustrates the toxic risks associated with more intensified treatment. It is possible that a relatively small fraction of patients (10 20%) will be spared the necessity of salvage therapy when higher dose alkylating agents or etoposidecontaining regimens are used compared with ABVD or ABVD-like regimens (with or without radiotherapy). This means that 60 70% of patients are exposed to the potential of a variety of unnecessary toxic risks. If salvage therapy is effective in that 10 20% group as opposed to de novo refractory or induction failures, then the group of patients treated with the less toxic regimen could show an equivalent survival with less overall toxicity. This emphasizes the importance of prognostic factors. However, it still remains to be seen whether more cytotoxic regimens will prove superior to ABVD in overall disease-related survival in patients with clinical factors predicting a poorer overall survival. Many trials including BEACOPP and VEBEP trials have been combined with radiation and do not permit an assessment of the impact of chemotherapy alone. A recent EORTC trial tested the value of complementary involved field radiotherapy in stage III/IV patients in CR after completing 6 8 cycles of MOPP/ABV in a randomized trial. After 6 years of follow-up, the relapse-free and overall survival for the radiation group was 85% versus 82%, 82% versus 88% for the radiated and non-irradiated groups, respectively [45]. All partial remissions received irradiation with an outcome similar to CR patients. Radionuclide scans to determine the status of residual mass in partial remission patients were not performed. It is conceivable that some of the PR patients may have been in a pathological CR as well. The major toxicity of the ABVD regimen is myelosuppression, but hair loss is common. Sterility is uncommon, but sperm banking can be recommended as an extra precaution. The pulmonary toxicity of bleomycin alone or with radiation therapy is usually mild but is a toxic consideration and monitoring of clinical symptoms as well as periodic carbon monoxide diffusion (DLCO) in selected patients may be warranted. There is often a transient decrease in pulmonary function. Similarly, cardiac dysfunction in the absence of prior left ventricular irradiation is unusual [46, 47]. Six cycles of the ABVD regimen contains doxorubicin 300 mg/m 2 which is below the known total dose that has the potential for cardiac toxicity. Myelosuppression is reversible in almost all cases and prolonged myeloid stem cell compromise or myelodysplasia is very rare. References 1. DeVita VT Jr, Simon RM, Hubbard SM et al. Curability of advanced Hodgkin s disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med 1980; 92: DeVita VT Jr, Serpick AA, Carbone PP. 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