Current Issues in the Management of Advanced Hodgkin’s Disease

G. Bonadonna,

A. Santoro

SUMMA R Y. During the past two decades, the standard drug regimen has been tbe MOPP program and its variants MVPP or CWPP. The search for less toxic cbemotberapy in terms of decrersed sterility and myelodysplasia-acute aon-lympbocytk leukemia prompWl the design of ABVD. Recent data from dilferent countries indicate that ad&my&kbaaed combinations as ABVD or MOPP alternating with ABM) appear very useful to improve treatment outcome compared TVMOPP alone. The combiestien of ckmotberapy and radiation has been utilized by many institutions in practically all stages of Hodgkin’s disease. The intent is to optimize the cure rate and with the tbeory tbat less intensive therapy of both modalities may carry a lower risk of iatrogenic complkatiom without compnwising treatment outcome. In patienta relap&g from curative radiotherapy, combination chemotherapy such as ABVD or MOPP/ABVD is recommended as the most elfectlve salvage regime% associated to further irradiation if t&&ally feasible. In patients ckmotherapy, clinicians have first to take into con&kration whether the re -primnry duration of tlrst complete remission is longer than 12 months. In this case, retreatment witb tbe same drug regimen remains the treatment of choice. In patients with progre&ve lympbana while on primary chemotherapy or showing remission duration lesser than 12 mo~&~, IKDWXNSresktant chemotherapy or high dose therapy plus autologous bone marrow traqlantation are indicated.

The term advanced Hodgkin’s disease is not clearly defined and may encompass various disease presentations or prognostic subsets requiring the use of chemotherapy, either alone or combined with radiotherapy. In this review, within the term advanced Hodgkin’s disease we shall include all clinical presentations of untreated lymphoma extending beyond pathologic stage IA-IIA without bulky adenopathy’p2 as well as all patients showing disease relapse or progression following first and second line treatments. As for early stages, the goal of treating advanced Hodgkin’s disease is to achieve an optimal level of cure while minimizing iatrogenic complications. The C. Bon&mm, MD, A. Stotoro, MD, Division of Medical Oncology, Instituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy. Bkwd Reviews (1990) 4, 69-73 0 1990 Longman GroupUK Ltd

central issues involving modem treatment of advanced Hodgkin’s disease include: (1) an optimal chemotherapy program with or without alternating or hybridized regimens; (2) the role of combined chemotherapy-radiotherapy; (3) an optimal salvage regimen after primary treatment failure including the place for high dose chemotherapy with autologous bone marrow transplantation. Effective Chemotherapy Regimens During the past two decades, the standard drug regimen for advanced Hodgkin’s disease has been the MOPP program or its variant MVPP where vinblastine is substituted for vincristine (Table 1). The superimposable incidence of complete remission as well as the long term benefits of MOPP and MVPP are well 0268-960x/90/0004-0069




Table 1


MOPP and ABVD regimens


Dose (mg/m’) and route

Days of treatment

MOPP” Mechlorethamine Vincristine Procarbazine Prednisone*

6 i.v. 1.4 i.v. 100 orally 40 orally

1, 8 1, 8 l-14 l-14

ABVD Doxorubicin Bleomycin Vinblastine Dacarbazine

25 iv. 10 i.v. 6 i.v. 315 i.v.

1, 1, 1, 1,

Frequency Q 28 D

Q 28 D 15 15 15 15

*On cycles I, 4, and 7 l*MVPP = vinblastine (6 mg/m’) is substituted for vincristine ChlVPP= chlorambucil (6 mg/mZ P.O. days l-14) is substituted for mechlorethamine and vinblastine (6 mg/m2) for vincristine

documented.3*4 Vomiting induced by mechlorethamine and peripheral neuropathy related to vincristine may limit the effectiveness of MOPP because many clinicians are tempted to reduce doses to ameliorate some of the above effects. For this reason, British investigators5*6 have designed a MOPP-derived regimen, known as ChlVPP where chlorambucil is substituted for mechlorethamine and vinblastine for vincristine. With this regimen treatment results look equivalent to any MOPP series while vomiting, neuropathy and hair loss are minimal. The search for less toxic chemotherapy in terms of decreased sterility and myelodysplasia-acute nonlymphocytic leukemia prompted the design of ABVD (Table 1) at the Milan Cancer Institute.’ ABVD is composed of drugs not contained in the MOPP combination and has therefore provided an alternative combination program for Hodgkin’s disease resistant to the MOPP regimen. Through prospective randomised trials, the Italian investigators have demonstrated that ABVD is at least as effective as MOPP (if not superior in patients with systemic B symptoms) and non-cross resistant to MOPP when used as a salvage program.8 These clinical observations formed the rationale to include ABVD in an alternating program with MOPP in the treatment of stage IV and subsequently of stage II (with bulky disease or B symptoms) and of stage IIIA-IIIB. Table 2 shows the consistency of findings related to the superiority of MOPP/ABVD delivered through different sequences (alternating monthly program, i.e. MM/AA or hybrid Table 2

monthly program, i.e. MA/MA) in stage IV Hodgkin’s disease. ‘*lo It is also important to point out that the same results were achieved by decreasing in the new prospective study the number of treatment cycles from 12 to 8. Thus the administration of two equally effective and non-cross resistant regimens has shown to be superior to MOPP alone in stage IV Hodgkin’s disease, either in patients previously untreated or relapsing in extranodal sites after primary irradiation. In both alternating or hybrid programs, we recommend chemotherapy for as many cycles as required to achieve a well documented complete remission followed by 2 additional cycles as treatment consolidation (minimum 6 cycles). The adriamycin-containing regimens were also successfully tested in advanced Hodgkin’s disease by Canadian investigators in Vancouver’ ’ through the delivery of a hybrid regimen without decarbazine (MOPP/ABV) as well as by investigators of the Cancer and Leukemia Group B.” The co-operative American group by randomly testing MOPP, ABVD and MOPP/ABVD in a large series of patients reported a higher response rate and a statistically significant improvement in time-to-treatment failure for the adriamycin-containing regimens. The basis for these findings may lie in the fact that repeated cycles of MOPP, as already noticed by the Italian investigators, led to a greater compromise of bone marrow reserve with successively lower doses of myelosuppressive drugs (i.e. mechlorethamine and procarbazine) being given, as compared to ABVD. At present, the follow-up period of the American study is still too short to demonstrate a significant survival advantage, but it is of interest that ABVD alone for 6-8 monthly cycles was almost equivalent to the alternating program. Therefore, recent data from different countries indicate that adriamycin-based combinations appear very useful to improve treatment outcome, i.e. costbenefit ratio, in advanced Hodgkin’s disease. Combined Chemotherapy-Radiotherapy During the past two decades the combination of chemotherapy and radiation has been utilized by many institutions in practically all stages of Hodgkin’s disease. The intent was to optimize the cure rate and with the theory that less intensive therapy of both modalities may carry a lower risk of iatrogenic complications without compromising treatment outcome. In advanced lymphoma the vast

Five-year results (%) with alternating regimens in stage IV Hodgkin’s disease

Complete remission Freedom from progression Relapse-free survival

First study MOPP (43 patients)

MOPP/ABVD (45 patients)

Second study MM/AA (28 patients)

MA/MA (28 patients)

74 40 50

89 66 14

86 66 73

89 71 15


majority of clinicians now prefer to start treatment with chemotherapy particularly in the presence of bulky disease. With this strategy, radiation therapy can be utilized at lower doses and reduced fields to eradicate microscopic residual lymphoma, or to convert a good partial response into a complete remission. In other words, radiotherapy represents an effective modality to kill drug resistant tumor cells. For many years a controversial issue has been the balance between using the type of chemotherapy and number of cycles required to achieve the maximum response with minimal delayed morbidity. Up to a few years ago, MOPP and its variants were the standard regimens. The use of chemotherapy including alkylating agents and procarbazine has consistently been associated with a high incidence of acute leukemia, but in recent years the availability of drug regimens, such as ABVD and VBM (vinblastine, bleomycin and methotrexate) indicates that this major long term side-effect is not necessarily a consequence of successful therapy. lw4 Since bleomycincontaining regimens present the hazard of pulmonary fibrosis, the total dose of this drug should not exceed 100 mg/m’. Mediastinal irradiation should be limited to minimise toxicity 35 Gy. An alternative to 3 cycles of ABVD prior to irradiation could be the delivery of alternating MOPP/ABVD for a total of 4 cycles which can reduce the important side-effects of both regimens and probably optimize the cure rate. This could be the recommended combined treatment of stage II (A and B) presenting with large mediastinalhilar adenopathy extending below the carena, as well as in the management of stage 111,A (involvement of upper abdominal nodes). In patients with more extensive nodal disease (stage III,), with or without systemic symptoms, drug therapy (e.g. MOPP/ABVD or hybrid MOPP/ABV) should include for most patients a total of 6-8 cycles. In these stages the addition of involved field radiotherapy (35 Gy) can improve the continuous relapsefree survival particularly in patients presenting with bulky disease. In patients with stage IV treated with the previously mentioned chemotherapy, radiotherapy is usually recommended in complete responders limited to the region(s) presenting with bulky adenopathy. In stage IIA-IIB bulky and in stage III combined modality approach can yield a j-year relapse-free survival rate in over 75%. Results can be lo-15% inferior when all three B symptoms are present. Salvage Treatments This important topic remains the source of many controversies as far as optimal treatment is concerned. Prognosis and treatment selection will largely depend upon primary treatment. In patients relapsing from curative radiotherapy, after proper restaging, combination chemotherapy such as ABVD or MOPP/ABVD is recommended as the most effective


salvage regimen. I5 Further irradiation can be delivered, only if technically feasible, to patients with marginal or true recurrence. The results in patients relapsing from radiation therapy are usually slightly superior to previously untreated patients with advanced Hodgkin’s disease and indicate that 75-80% remain continuously disease-free from second relapse. Factors which negatively influence treatment outcome include extranodal disease and systemic symptoms. In patients relapsing from primary chemotherapy, clinicians have first to take into consideration whether the duration of first complete remission is longer than 12 months. In this case, retreatment with the same drug regimen (MOPP or one of its variants, MOPP/ ABVD or one of its variants) remains the treatment of choice for it can yield a second complete response in 70-80% and in 60-80% of cases remission is durable. I6 In patients wi th progressive lymphoma while on primary chemotherapy or showing remission duration lesser than 12 months, non-cross resistant chemotherapy is indicated. In MOPP resistant patients, ABVD remains today the most widely used salvage regimen. The complete response rate is about 50%, and the likelihood of attaining complete remission is higher or lower in relation to A or B symptoms as well as to the anatomic extent of disease. Approximately 20% of all MOPP resistant patients remain disease-free at 5 or more years. Comparable results are being obtained with other adriamycincontaining regimens such as B-CAVe (bleomycin, CCNU, adriamycin and vinblastine) or ABDIC (adriamycin, bleomycin, decarbazine, CCNU, and prednisone) if salvage chemotherapy is promptly instituted at the time of recurrent or progressive lymphoma.“8 As a third-line chemotherapy CEP (CCNU, etoposide and prednimustine) or MIME (methyl-GAG, ifosfamide, methotrexate, and etoposide) can be utilized. Complete remission can be achieved in 25-35% and the 5-year survival is about 20%.’ 7 In patients with short remission duration following alternating MOPP/ABVD or its hybrid version salvage cannot be achieved with any known regimen, although patients may survive a number of months and even years in various states of relapse. Thus these patients are candidates for high dose therapy plus autologous bone marrow transplantation (ABMT). The important issues in ABMT include selection of optimal conditioning regimen, the role of total body irradiation (TBI) or involved field radiotherapy, the usefulness of peripheral stem cell reinfusion as well as the administration of growth factors. Last but not least, which is the proper timing for ABMT. Modem ABMT-conditioning regimens used for Hodgkin’s disease include multiple drugs such as cyclophosphamide, etoposide and BCNU (CBV) or, as in the Milan Cancer Institute experience, two alkylating agents (cyclophosphamide and melphalan), vincristine, high dose methotrexate plus leucovorin and cisplatin. In MOPP/ABVD resistant patients this




latter regimen has induced complete remission in 82% with a 3-year actuarial relapse-free survival of 70%. ’ 8 In the Milan experience granulocyte-macrophage colony-stimulating factor (GM-CSF), given to accelerate recovery from cytopenia induced by high dose (7 g/m’) cyclophosphamide, reproducibly brought about a dramatic increase (up to lOOO-fold) in the number of peripheral blood granulocyte-macrophage colony-forming units (CFU-GM). These circulating progenitors were harvested by leucapheresis and, when reinfused together with autologous bone marrow cells after TBI and melphalan, induced complete hemopoietic recovery in all transplanted patients in a very short time. This approach promises to increase the therapeutic index of high dose chemoradiotherapy regimens and to widen their role as treatment for chemoradiosensitive tumors.lg On this basis, we can foresee the early use of ABMT, i.e. following conventional MOPP/ABVD in poor prognostic subsets such as those with massive adenopathy extending into the lung, pericardium, or chest wall. In fact, there is general consensus that treatment outcome following ABMT is best when high dose chemotherapy is delivered to patients in first complete remission. Evaluation of Response Advances in radiographic technology are resulting in a number of patients with residual abnormalities characterized by mediastinal widening and anteroposterior window fullness after primary therapy. A number of investigators including those from Christie Hospital in Manchester 2o demonstrated that residual shadows do not necessarily represent residual lymphoma but rather necrosis or fibrosis and may persist for months to several years before returning to normal. Thus the presence of residual mediastinal abnormality following radiotherapy does not predict for relapse since in most patients it does not represent partial remission. However, for the patients treated by chemotherapy alone a residual abnormality is associated with a significantly higher risk of relapse. Computed axial tomography of the thorax helps identifying patients with bulky mediastinum limited largely above the carena and thus mostly manageable with radiation therapy alone. Furthermore, investigators from Boston”’ have demonstrated that high dose 67 gallium-citrate scintigraphy, especially when used Table 3

with single photon emission computed tomography (SPECT), can provide additional information in identifying sites of active tumor and can be valuable in treatment determination. Late Side-effects The most serious consequence of successful curative therapy for Hodgkin’s disease is the emergence of second malignancies. Most common among these are acute non-lymphocytic leukemia, myelodysplastic syndromes including preleukemia and high grade non-Hodgkin’s lymphomas. Following radiotherapy alone, secondary leukemia is extremely rare. In patients treated with MOPP or one of its variants, the risk of leukemia within lo-15 years varies in relation to whether chemotherapy is administered along or combined with radiotherapy as primary treatment or it is given as salvage therapy (Table 3). The risk of leukemia is also increased in patients older than 40 years (> 15%) compared to young adults (< 10%). The possible association between staging laparotomy with splenectomy and leukemia has been evaluated but caution is needed in the claim of such an association because of the possible existence of other concomitant risk factors (e.g. age greater than 40 years and/or salvage MOPP). The peak incidence of therapy-related leukemia is 6 years from initial treatment, but it has been recently reported that the risk decreases after 9- 10 years. This may be true for the vast majority of patients, but additional follow-up is required. In fact, cases of leukemia were documented more than lo-15 years from initial therapy.22*23 The risk for developing leukemia after ABVD is 0.7°h.22 The overall risk of non-Hodgkin’s lymphomas is about 2% while the risk of developing secondary solid tumors is continuing to increase beyond 10 years and it is highest in older patients; approximately two thirds of tumors have occurred so far in the radiation therapy field.22*23 Gonadal dysfunction represents another important iatrogenic toxicity. 7~13,23However, permanent azoospermia and amenorrhea were seen only after MOPP or MOPP-like chemotherapy and not after ABVD or VBM. Other delayed side-effects include myocardial toxicity following high dose radiotherapy (> 40 Gy) or adriamycin when the total dose exceeds 500 mg/m2. As previously mentioned, bleomycin can

Frequency at lo-15 years of second leukemia in three major cases series

Research center National Cancer Institute (USA) Stanford University Milan Cancer Institute RT: Radiotherapy

Total patients 413 1507 1329

Radiotherapy alone % 0 0.6 0

Chemotherapy alone %


Salvage MOPP %




11.5 1.4

4.9 9.5

1.8 17.1


produce lung fibrosis when the total dose exceeds 150mg/m2, particularly i.n previously irradiated patients. References 1. Lister T A, Crowther D, Sutcliffe S B et al 1989 Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease. Journal of Clinical Oncology, in press 2. Mauch P, Tarbell N, Weinstein H et al 1988 Stage IA and IIA with supradiaphragmatic Hodgkin’s disease: prognostic factor in surgically staged patients treated with mantle and paraaortic irradiation. Journal of Clinical Oncology 6: 1576-1583 3. Longo D L, Young R C, Wesley M et al 1986 Twenty years of MOPP therapy for Hodgkin’s disease. Journal of Clinical Oncology 4: 1295-1306 4. Sutcliffe S B, Wrigley P F M, Peto J et al 1978 MVPP chemotherapy regimen for advanced Hodgkin’s disease. British Medical Journal 1: 679-683 5. Dady P J, McElwain T J, Austin D E, Barrett A, Peckham M J 1982 Five vears’ exnerience with ChlVPP effective low. toxicity combination chemotherapy for Hodgkin’s disease. British Journal of Cancer 45: 851-859 6. McKendrick J J, Mead G M, Sweetenham J et al 1989 ChlVPP chemotherapy in advanced Hodgkin’s disease. European Journal of Cancer and Clinical Oncology 25: 557-562 I. Bonadonna G 1982 Chemotherapy strategies to improve the control of Hodgkin’s disease. The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Research 42: 4309-4320 8. Santoro A, Bonfante V, Bonadonna G 1982 Salvage chemotherapy with ABVD in MOPP-resistant Hodgkin’s disease. Annals of Internal Medicine 96: 139-144 9. Bonadonna G, Valagussa P, Santoro A 1986 Alternating noncross-resistant combination chemotherapy or MOPP in stage IV Hodgkin’s disease A report of S-year results. Annals of Internal Medicine 104: 739-746 10. Bonadonna G 1989 Does chemotherauv fultill its expectations in cancer chemotherapy?‘Annals of Oncology, in press Il. Klimo P, Connors J M 1988 An update of the Vancouver experience in the management of advanced Hodgkin’s disease treated with the MOPP/ABV hybrid program. Seminars in Hematology 25: 34-40


12. CatteIIosGP,PmpartK:CooperRataII988MGPPvs ABVDvsMQPP&rnstingwithABvDina&#mad Hod&in’s&a+aaezap CALGBtrial. Proceedings of Amer&n Society of Chnical OncoIogy 7: 230 13. Santoro A, Bonadoma G, Valaguasa P et al 1987 Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. Journal of Clinical Oncology 5: 27-37 14. Homing S J, Hoppe R T, Hancock S L, Rosenberg S A 1988 Vinblastine, bleomycin, and methotreaxte: an effective adjuvant in favorable Hodgkin’s disease. Journal of Clinical Oncology 6: 1822-1831 15. Santoro A, Viviani S, Villareal C J R et al 1986 Salvage chemotherapy in Hodgkin’s disease irradiation failures: superiority of doxorubicin-containing regimens over MOPP. Cancer Treatment Reports 7: 344-348 16. Viviani S, Santoro A, Negretti E et al 1989 Salvage chemotherapy in Hodgkin’s disease. Results in patients relapsing after twelve months from first complete remission. Annals of Oncology, in press 17. Santoro A, Viviani S, Valagussa P, Bonfante V, Bonadonna G 1986 CCNU, etoposide, and prednimustine (CEP) in refractory Hodgkin’s disease. Seminars in Oncology 13: 23-26 18. Gianni A M, Siena S, Bmgni M et al 1989 Autologous hematopoietic stem cell transpIantation for poor prognosis Hodgkin’s disease. Proceedings of American Society of Clinical Oncology 8: 251 19. Gianni A M, Siena S. Bregni M et al 1989 Granulocytemacrophage colony-stimulating factor to harvest circulating haemopoietic stem ceils for autotransplantation. Lancet 2: 580-584 20. Radford J A, Cowan R A, Flanagan M et al 1988 The significance of residual mediastinal abnormality on the chest radiograph following treatment for Hodgkin’s disease. Journal of Clinical &ology 6: 940-9461 21. Jochelson M S. Herman T S. Stomner PC. Mauch P M. Kaplan W D 1988 Planning ‘mantle’radiation therapy in patients with Hodgkin’s disease: role of Gallium-67 scintigraphy. American Journal of Roentgenology 151: ,1229-1231 22. Valagussa P, Santoro A, Fossati-Bellani F, Banft A, Bonadonna G 1988 Hodgkin’s disease and second malignancies. Proceedings of American Society of Clinical Oncology 7: 227 23. Bookman M A, Longo D L 1986 Concomitant illness in patients treated for Hodgkin’s disease. Cancer Treatment Reviews 13: 77-l 11

Current issues in the management of advanced Hodgkin's disease.

During the past two decades, the standard drug regimen has been the MOPP program and its variants MVPP or ChlVPP. The search for less toxic chemothera...
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