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Blood, Vol. 93 No. 3 (February 1), 1999: pp. 761-779

REVIEW ARTICLE

Problems in Hodgkin's Disease Management

By Alan C. Aisenberg

From the Hematology/Oncology Unit, Massachusetts General Hospital, Boston.


    INTRODUCTION
Top
Introduction
References

INSPECTION OF the Hodgkin's disease (HD) mortality curve (Fig 1) gives cause for satisfaction with the progress of the past 30 years. United States mortality, which remained above 1.8 per 100,000 per year in the 1950s and early 1960s, had decreased to 0.47 by 1994.1 The most recent 5-year survival figure is 81%.2 Whereas HD accounted for 30% of total lymphoma deaths in 1950, it accounted for only 6% (1,440 US deaths) in 1994. 


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  		Fig 1. HD mortality in white males and females in the United States from 1950-1994. (Reprinted from Ries et al.1)


    MANAGEMENT

The management of the disorder is undergoing a paradigm shift in the final years of the millenium as a result of the variety of drug regimens available that induce complete remission, the possibility of effective salvage of advanced HD with peripheral stem cell transplantation, better understanding of prognostic variables, economic constraints that now influence health care, and, most important, realization of the magnitude of late treatment mortality.

Movement away from staging laparotomy has been a prominent feature of the paradigm shift. With the advent of more effective and less toxic combination chemotherapy, and with the recognition of surrogate clinical markers of abdominal lymphoma, the role of surgical staging has diminished. Introduced in the late 1960s,3 staging laparotomy profoundly altered knowledge of the patterns of HD distribution at the time of diagnosis.4,5 Knowledge of abdominal spread so gained allowed appropriate application of the therapy then available, and was particularly useful in explaining the frequent failure of irradiation. One fourth of those patients without symptoms in clinical stage (CS) IA and IIA (Table 1) on the basis of a normal bipedal lymphangiogram and/or abdominal and pelvic computed tomography (CT) scan proved to be in pathological stage (PS) IIIA or IVA when surgically staged, and one third of those patients with systemic symptoms (CS IB and IIB) proved to be in PS IIIB or IVB.4,5 Surgical staging made possible the identification of PS IA and IIA patients who enjoyed greater than 80% relapse-free survival with less than 10% disease mortality 10 to 15 years after extended field irradiation.5,9 Although it is a brave oncologist who advocates a staging laparotomy in 1999, the procedure is still justified when it permits more effective treatment or significantly reduces treatment-associated mortality.

                              
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  		Table 1. Staging Classification of HD

It was a historical accident that radiation therapy was the only curative treatment modality for HD10-12 for the two decades before the introduction of MOPP (nitrogen mustard [mechlorethamine], vincristine, prednisone, procarbazine) in the late 1960s.13 The less toxic and arguably more effective ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) combination was not widely used until the mid 1970s, nearly a decade later.14 The result of this timing is that many studies with extended (>20 years) follow-up address the effectiveness of irradiation with and without MOPP, but comparatively few of similar longevity evaluate MOPP alone and even fewer ABVD alone. It is also unfortunate that accurate disease assessment through pathological staging is being abandoned at the same time that the long overdue reassessment of the role of radiation therapy and less toxic chemotherapy and combined regimens is under way.

A diagnostic workup including review of an adequate biopsy specimen by an expert hematopathologist, a history eliciting systemic complaints (particularly, unexplained weight loss and fever), a physical examination, hemogram and blood chemistries, CT of the chest, abdomen and pelvis, and bone marrow (BM) biopsy in those with systemic symptoms, is posited. Because of its greater sensitivity in the paraaortic and pelvic regions, a bipedal lymphangiogram is useful in patients in whom CT of the abdomen and pelvis is negative (particularly in those with groin presentations being considered for radiation),15 and a gallium scan can provide a baseline against which the treatment response of bulky tumors, particularly in the mediastinum, can be judged.15,16 In selected cases, magnetic resonance imaging (MRI) provides better visualization of the extent of lymphoma, especially in relation to the mediastinum, spinal cord, and BM.15,17 The full potential of positron emission tomography (PET),18,19 particularly in detecting abdominal HD, remains to be defined.

The REAL (Revised European-American Classification of Lymphoid Neoplasms) classification of Hodgkin's disease20,21 (Table 2) contains two modifications of the older Rye system of importance to clinicians. The lymphocyte predominance (paragranuloma) subtype (LPHD) closely resembles a low-grade B-cell lymphoma in clinical behavior and Reed-Sternberg cell phenotype. Most patients with LPHD present with early disease (CS IA, IB, or IIA) and enjoy an excellent prognosis despite a propensity for local relapse.22,23 Because treatment-induced mortality has been a more frequent cause of death than HD in large LPHD series, present opinion favors conservative HD management (limited radiation) for these individuals. However, advanced-stage LPHD requires conventional chemotherapy. Hematologists treating HD should also be familiar with the newly described provisional non-Hodgkin's lymphoma (NHL) subtype termed anaplastic large cell lymphoma Hodgkin's-like because of the poor response reported with conventional HD chemotherapy: regimens suitable for aggressive NHLs have been reported to be more satisfactory.20,24

                              
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  		Table 2. REAL Classification of HD

Early Stage (Clinical Stage I and II)

For prognostic and therapeutic considerations, HD patients are conveniently divided into those with early stage (CS I and II) and those with advanced-stage (CS III and IV) disease at presentation (Table 1). Most patients who die of the disorder today present with stage IIIB or IV disease, or are over age 60 at the time of diagnosis. The predominant need in early presentations is reduction of the toxicity of treatment, while in advanced disease there remains a need for more effective therapy.

In the past, radiation therapy has been the primary treatment modality for early disease and chemotherapy for advanced disease. However, the two major prospective studies comparing single modality treatment of early HD with irradiation and MOPP reached different conclusions. A National Cancer Institute investigation compared, prospectively and randomly, extended field/total nodal irradiation with MOPP chemotherapy in PS IB, IIA, and IIB patients25: overall survival was similar (85% for radiation v 90% for MOPP at 7 years). A second prospectively randomized study, a multi-institution Italian investigation of PS IA and IIA patients, reported superior survival for extended field irradiation over MOPP (93% v 56% at 8 years).26 The conflicting findings in the two investigations may be attributable to the poor results of primary MOPP treatment in the Italian study, worse than those attained by others in advanced-stage patients.

A recent meta-analysis of eight randomized trials involving 1974 early stage patients found more extensive radiotherapy associated with a one-third reduction in treatment failure compared with limited (mantle or involved field) radiotherapy (31% v 43% at 10 years).27 However, because of successful salvage chemotherapy, overall 10-year survival was identical in the two groups (77%). In the same analysis, the role of adjuvant chemotherapy was assessed in 13 randomized trials involving 1,688 early patients. The addition of chemotherapy to radiotherapy halved the 10-year risk of failure (16% v 33%) with a small statistically nonsignificant improvement in survival (79% v 76%): A reduction of HD deaths of borderline significance (12% v 15%) was partly counterbalanced by a nonsignificant increase in deaths from other causes (12% v 10%).

Recent re-analysis of the available dose-response data for HD has yielded no evidence of increased response to doses above 32.5 Gy.28,29 Thus, extended field irradiation (approximately 35 Gy to a mantle area and somewhat less to the abdomen with fastidious attention to treatment details30-32) remains an option for those with very favorable and favorable early disease (see below and Table 3).

                              
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  		Table 3. Primary Treatment of HD

Localized presentations of HD (CS I and II) have been divided into very favorable, favorable, and unfavorable subgroups (Table 3). The specific criteria used differ in different centers.30,31,33-35 Only 5% to 15% of CS I and II HD presents with very favorable characteristics; the remainder fall into the favorable and unfavorable categories, with the former being more frequent.

"Very Favorable" category.   A reasonable goal for the very favorable category is identification, by clinical characteristics, of individuals with an 80% to 90% relapse-free survival 10 years after extended field or more limited radiation therapy. Because undetected abdominal lymphoma is the major cause of failure in unexplored early stage patients, the clinical characteristics of those early stage individuals shown to have a very low risk of abdominal lymphoma (<10%) at staging laparotomy can serve as surrogate markers for the very favorable group. The clinical characteristics listed in Table 3 fulfill that laparotomy requirement; females in CS IA, and in IIA if under age 27 with nodular sclerosis (NSHD) histology and two or three contiguous disease sites, and males in CS IA with lymphocyte predominance histology presenting in the neck or groin.4,5

To eliminate treatment-induced abdominal neoplasms, limiting irradiation to a mantle field is being investigated in these patients. A small prospective trial of 81 patients in PS IA and IIA with negative laparotomy findings and no more than limited upper mediastinal disease continues at the Joint Center for Radiation Therapy in Boston (10-year actuarial freedom from relapse is 76% and overall survival is 91%),36 but a randomized prospective EORTC (European Organization for Research and Treatment of Cancer) study (CS IA, female, age <40, erythrocyte sedimentation rate [ESR] <50, lymphocyte predominance or nodular sclerosis histology, and no large mediastinal adenopathy) without surgical staging was terminated prematurely because the relapse-free survival rate at 6 years was only 68%.37 An earlier retrospective analysis of selected CS IA patients treated at St Bartholomew's Hospital (London, UK) with limited irradiation achieved 82% freedom from recurrence at 15 years.38

"Unfavorable" category.   Over the past two decades several groups of patients in CS I and II have been identified in which extended field irradiation yields a 10-year relapse-free survival only in the 50% range. Clinical criteria which help identify these individuals are systemic manifestations (fever or weight loss or, particularly, both),39 large mediastinal adenopathy (>= <FR><NU>1</NU><DE>3</DE></FR> of the maximum chest diameter),9,40-43 high tumor burden,35,41 >3 sites of involvement,9,42 age >50,33,42 ESR >50,42 and involvement of pericardium, pleura, lung or bone, or gross lymphatic permeation and obstruction.

Six to eight cycles of ABVD (two cycles beyond complete remission) is appropriate treatment for most unfavorable early stage patients.44 On the basis of limited data,42,43,45-47 it is generally agreed that individuals with bulky mediastinal adenopathy should receive adjuvant irradiation therapy to the mantle area. There is also evidence (discussed below under Adjuvant Radiation) that good partial remissions can be converted into durable complete remissions by irradiation of residual disease.

Combined modality treatment with reduced chemotherapy and radiotherapy is being explored in patients presenting with unfavorable CS I and II disease. The National Cancer Institute (Milan, Italy) reports excellent preliminary results (100% complete response and survival and 95% freedom from progression with median follow-up of 38 months in 103 patients) after 4 cycles of ABVD followed by 36 Gy to involved sites and 30 Gy to uninvolved sites.48 Involved field and extended field irradiation were equally effective.

Similarly, the Stanford V program, consisting of 12 weeks of intensive chemotherapy (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) followed by 36 Gy to sites of initial bulk (>5 cm) disease, was introduced to treat bulky stage II and advanced-stage HD.49 With a median follow-up of 36 months, all 28 patients with bulky mediastinal adenopathy were alive and disease-free.

"Favorable" (intermediate) category.   The largest group of early clinical stage patients is the remainder with neither very favorable nor unfavorable characteristics, usually designated as favorable, who enjoy an intermediate disease-free survival after radiation therapy. In the past, staging laparotomy was used to determine their suitability for extended field radiation therapy, and this remains a defensible choice. Alternatively, they can receive six cycles of ABVD followed by irradiation of limited residual disease without surgical staging.

Combined modality treatment with brief chemotherapy and limited radiotherapy is also being explored without surgical staging in these favorable patients. The Vancouver group used two cycles of various chemotherapy regimens (VECABOP [vinblastine, etoposide, cyclophosphamide, doxorubicin, bleomycin, and vincristine] or cyclophosphamide (C)OPP/ABV hybrid in most, and ABVD in a handful) followed by involved field radiotherapy in CS IA and IIA patients without bulky mediastinal disease.50 With a median followup of 31 months, no relapses have been seen in 91 patients.

In a Stanford-Permanente trial, 78 favorable patients without laparotomy were randomized to receive either extended field irradiation or involved field irradiation after vinblastine, bleomycin, methotrexate (VBM), chemotherapy.51 With a median follow-up of 4 years, 92% of the extended field group and 87% of the combined treatment group were free of HD progression.

The promising novel combined treatment programs for very favorable, favorable, and unfavorable early stage HD outlined above are not appropriate for general application without prospective trial against standard treatment. The duration of follow-up is short to assess the durability of response in indolent early stage HD let alone the long-term complication rate, and comparatively few patients have been treated.

Advanced Stage (Clinical Stage III and IV)

Advanced stage HD consists of patients in CS III with involvement of lymph nodes above and below the diaphragm, and those in CS IV with multiple sites of involvement of nonlymphoid organs, predominantly liver, lung or bone, in addition to lymph nodes (Table 1). CS III is usually diagnosed by positive lymphangiogram and/or abdominal and pelvic CT study. CS IIIA constitutes a category of intermediate malignancy between the more indolent CS IA and IIA and the more aggressive CS IIIB and IV. When laparotomy data are available, CS III is readily divided into III1, abdominal disease limited to the upper abdominal lymph nodes and/or spleen, and III2 in which lymph nodes of the lower abdomen are diseased. The spleen is involved in approximately 90% of stage III patients; it frequently is the only site of abdominal involvement and is difficult to detect without staging laparotomy.4,5 The less aggressive behavior of CS III1 is recognized in the Cotswold staging classification which separates those with more slowly evolving HD restricted to spleen, or splenic hilar or portal lymph nodes from nodes from those with disease in the lower abdomen (Table 1).7

Treatment with chemotherapy alone.   The dramatic report more than three decades ago of the effectiveness of MOPP in advanced HD remains a landmark in HD treatment.52 MOPP is still a benchmark against which newer alternatives can be judged. Of the original 188 patients (later vetted for contaminating [incorrectly diagnosed] diffuse large cell lymphomas), 84% achieved a complete remission, and 54% were disease-free and 48% alive at 15 years.53 More recently, it has become clear that MOPP alone is inferior to either alternating MOPP and ABVD44,54-57 or the MOPP/ABV hybrid57,58 in the control of HD, and probably to ABVD alone44,54 and other alternating non-cross-resistant regimens59-66 (Table 4).

                              
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  		Table 4. Chemotherapy Only as Primary Treatment of Advanced HD or After Relapse Following Radiation Therapy

An early study at the Milan Cancer Institute limited to stage IV patients randomized between 12 cycles of MOPP or alternating MOPP and ABVD showed a 15% to 20% advantage favoring the alternating combinations55 (Table 4). In the recently updated54 multi-institution CALGB study of 361 patients in stages IIIA2, IIIB, and IV,44 8-year freedom from progression was 37% for MOPP, 52% for ABVD, and 50% for alternating MOPP and ABVD: A significant difference in overall survival had not emerged. A 3% incidence of fatal febrile neutropenia in the MOPP group was balanced by a similar incidence of fatal pulmonary toxicity with ABVD, and 1% incidence of each after alternating MOPP/ABVD.

A National Cancer Institute of Canada trial (Table 4) compared alternating cycles of MOPP and ABVD with the MOPP/ABV hybrid in advanced HD.57 Both programs produced excellent results in previously untreated individuals, but the hybrid was inferior in patients treated for radiation relapse. Life-threatening febrile neutropenia and stomatitis were more frequent problems in the hybrid group, leading to a lowering of the upper age limit from 65 to 55 in midstudy.

Febrile neutropenia associated with the hybrid was also one cause of the premature closing of a CALGB Intergroup trial comparing the hybrid with ABVD62 (Table 4). Three percent of the 856 patients died of acute toxicity, 16 with the hybrid and 9 with ABVD. The majority of deaths were due to pulmonary toxicity or sepsis; 17 in patients over age 55. After 3 years of observation, complete remission rate, freedom from relapse, and overall survival were similar in the two treatment programs. Another reason for the premature closing of this study was a higher incidence of ANLL (acute nonlymphocytic leukemia)/MDS (myelodysplastic syndrome) (6 cases) and second solid neoplasms (6 cases) in the hybrid arm, a finding at odds with the ECOG Intergroup study in which 9 cases of ANLL/MDS were reported in the sequential arm and only 1 in the hybrid arm58 (Table 4).

Thus, alternating MOPP/ABVD is superior to MOPP alone.44,54,55 Alternating MOPP/ABVD and the MOPP/ABV hybrid are equally effective,57,58,63 but grave infectious, and, perhaps, pulmonary complications are greater with the hybrid57,58,62 (Table 4). The CALGB study thus far suggests that ABVD alone is as effective as alternating MOPP/ABVD,44,54 a conclusion with little independent support other than indirect data from the preliminary CALGB Intergroup report.62 ANLL/MDS data are still preliminary, and second solid-tumor risk, primarily dependent on the radiation component of combined treatment, can only be surmised from indirect data.

ABVD alone is the treatment of choice in those with advanced disease pending additional data, with MOPP/ABVD a reasonable alternative for some younger individuals (<age 40) with poor prognostic features (such as CS IVB with fever and weight loss, or multiple extranodal sites). It should be noted that the advantage of ABVD and alternating MOPP/ABVD over MOPP alone in the CALGB study44,54 (Table 4) is attributable to the subsets of patients of advanced age (>age 50) or with two or more extranodal sites. MOPP is difficult to use in the elderly because of acute and chronic marrow toxicity.

To address the continued high rate of treatment failure in advanced HD with conventional regimens, escalation of dose is again under investigation.64,65 The escalated BEACOPP (cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisone, vincristine, and bleomycin with granulocyte colony-stimulating factor) program achieved 89% freedom from treatment failure with median follow-up of 30 months and tolerable toxicity in a small cohort of patients.66 Most intensified regimens follow chemotherapy with radiation to residual or prior bulk disease.

Adjuvant radiation therapy for advanced disease.   On a priori reasoning, there was ample ground to add radiation therapy to chemotherapy in the treatment of advanced HD. Very soon after MOPP was introduced, it became clear that the majority of chemotherapy relapses occur at sites of initial disease, particularly nodal sites and sites of bulky tumor.67,68 It was also clear that adjuvant irradiation markedly reduced the frequency of those recurrences, and increased the rates of complete remission and disease-free survival.69,70 Moreover, adjuvant radiation therapy, particularly in the 15 to 25 Gy range frequently advocated, was well tolerated after chemotherapy.69,70 Because of these considerations, adjuvant irradiation was widely adopted without demonstration of which if any HD subsets enjoy improved overall survival (Table 5). However, with growing awareness of the second tumor risk associated with irradiation, a minor issue is now a major concern of radiotherapists and chemotherapists.75,76

                              
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  		Table 5. Combined Treatment With Chemotherapy and Adjuvant Radiation for Advanced-Stage HD

As mentioned earlier, there is general agreement of the need for combined treatment in the 25% to 30% of patients presenting with mediastinal masses ><FR><NU>1</NU><DE>3</DE></FR> of the chest diameter at the T5-6 level43,45-47,75,76: disease-free survival of 80% to 90% after combined treatment is nearly twice that reported after MOPP or radiation alone. Radiation therapy also consolidated good partial remissions in 122 patients in an ongoing EORTC trial of stage III/IV disease74 (Table 5): 42 months after 30 to 40 Gy to sites in partial remission and 24 Gy to sites of complete remission, 87% were alive and 75% progression-free.

In a Southwest Oncology Group (SWOG) study (Table 5), 278 adults in complete remission following MOP-BAP chemotherapy (mechlorethamine, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine) were randomized to receive low-dose irradiation to previously involved sites (10 to 20 Gy) or no further treatment.73 The 5-year remission duration estimate of 79% for irradiated patients was not significantly different from the 68% observed in those not treated (P = .09). Although low-dose radiation improved 5-year remission duration more in the subgroups with nodular sclerosis (82% v 60%, P = .002) and bulky disease (75% v 57%, P = .05), overall 5-year survival was not improved in any subgroup.

Groups at Yale, Duke, and at Memorial Sloan-Kettering strongly espouse low-dose adjuvant irradiation (15 to 30 Gy) to previously involved sites for patients in remission after chemotherapy. In a cohort of 184 Yale patients with either newly diagnosed stage IIIB or IV disease, or disease recurrent after irradiation, overall survival was 66% at 10 years, and 54% at 15 years.69 However, an unacceptable incidence of second neoplasms was observed in those whose radiation recurrence was treated by combined modality; 41% at 20 years as compared with 12% in the newly diagnosed patients.77 In a similar analysis of 270 patients at Memorial Sloan-Kettering, the actuarial 10-year overall survival and progression-free survival were 74% and 70%, respectively.70 Second malignancy incidence was only 4%, but the median length of observation was too short to address this crucial issue. A recent German investigation showed that while 20 Gy is sufficient to control initial sites of nonbulky disease or uninvolved sites following two double cycles of COPP/ABVD, relapse patterns indicate that patients destined to relapse need more systemic rather than local treatment.78

Other studies that fail to show a major role for adjuvant irradiation include an ECOG study of patients in partial or complete remission after a MOPP variant randomized to consolidation with either ABVD or low-dose irradiation.79 Irradiation converted two thirds of partial remissions into durable complete ones, but freedom from progression and overall survival were significantly longer in those consolidated with ABVD. A second ECOG study found no improvement in overall or progression-free survival 6 years after randomized patients received low-dose irradiation consolidation after induction with an MOPP variant.80 Finally, a randomized study from GATLA (Grupo Argentino de Tratamiento de Leucemia Aguda) is difficult to evaluate because of poor survival in the chemotherapy arm,81 while others use small patient groups, complex study design, or omit control groups.82,83

A recently published meta-analysis based on 1,740 individual patient records from 14 controlled adjuvant irradiation clinical trials is very instructive.84 In trials in which radiation added to chemotherapy was compared with the same chemotherapy alone (additional radiation therapy design), tumor control was improved 11% but overall survival was unchanged. However, more significant results emerged from trials in which added radiation was compared to added chemotherapy (parallel radiation therapy/chemotherapy design). In the parallel studies there was no difference in tumor control in the two arms if an appropriate number of drug cycles was administered, but overall survival was 8% better in the chemotherapy-only patients because of fewer late treatment-related deaths. Adjuvant radiation was recommended only for a few specific indications such as bulky mediastinal disease.

Novel, intense combined regimens such as the Stanford V study, which has produced excellent early results in advanced HD (93% survival and 89% freedom from progression with median follow-up of 3 years), will require two decades before the second tumor risk can be fully appreciated.49

The goal of primary treatment is to maximize HD cure with minimum cardiac toxicity and inadvertent mutational damage to normal tissue (second malignancy). The available data support the strategy of salvage with high-dose therapy and stem cell support or with drugs alone for the fraction relapsing after chemotherapy, over indiscriminate primary adjuvant irradiation. With the recognition that adjuvant irradiation poses an added hazard for most patients with HD, the conservative hematologist will restrict this treatment to patients with bulky mediastinal disease at diagnosis and to some in good partial remission after chemotherapy with limited and residual tumor. Its documented use for sites of initial tumor bulk is arguable.

Relapse and Salvage Treatment

Salvage for relapse after radiation therapy of early stage disease.   The survival of patients treated with chemotherapy after radiation relapse of pathologically staged early disease is at least equal to that of advanced stage patients initially treated with chemotherapy. Indeed, an apparent survival advantage of radiation relapses over the primary treatment group has been attributed to a more favorable patient mix in the latter with fewer stage IVB individuals. Overall and disease-free survival range from 60% to 80%.85

Stage at relapse is an important prognostic variable in radiation failures. At Stanford, the 10-year disease-free survival was 88%, 58%, and 34%, respectively, for those in stage IA, stage IIA, and IIIA, and in stage IV or with B symptoms at the time of relapse.86 Patients with lymphocyte predominance or nodular sclerosis histology fared better than those with mixed cellularity or lymphocyte depletion87,88: 10-year freedom from relapse for favorable histologies was 67% versus 44% for the unfavorable ones at the Joint Center for Radiation Medicine.88 Advanced age was a negative prognostic variable in the largest series studied,88 although a short free interval (<12 months) did not have the negative import noted in patients relapsing after chemotherapy for advanced disease (see below). From the available evidence, ABVD exhibits the same superiority over MOPP for radiation recurrence that it does in initial treatment of advanced disease44,54,89: The Milan Cancer Institute observed a disease-free survival of 81% with ABVD variants compared to 54% with MOPP.89

Chemotherapy salvage for relapse after primary chemotherapy of advanced or bulky disease.   The National Cancer Institute studies provide important insight into relapse and salvage after primary chemotherapy.90,91 Derived primarily from investigations involving relapses after MOPP and MOPP variants, the conclusions are relevant to other chemotherapy programs. Chemotherapy failures could be divided into three groups of equal size on the basis of prognoses: (1) patients who never achieved a complete remission, all of whom died within 8 years; (2) patients whose complete remission lasted less than a year, of whom less than 20% survived 5 years and whose projected 20-year survival was 11%; and (3) patients whose complete remission lasted more than a year, of whom 44% survived 5 years and whose projected 20-year survival was 24%. Unfortunately, the 24% survival of the most favorable group was all that was realized from a remarkable 20-year 45% disease-free survival because of secondary leukemia and other treatment-related mortality. MOPP was as effective as alternate drug regimens in the reinduction of patients with long initial remissions.

The Milan Cancer Institute group reported on ABVD salvage of 56 MOPP-resistant patients (induction failure or relapse within 1 year of complete response).92 Twenty-two (46%) achieved a second complete response of whom one half were still alive 5 years later. Second complete responses were achieved in 65% of those with an initial complete response compared to 33% for induction failures. In a second study, 85% of those with an initial complete remission more than 1 year in duration experienced a second complete remission with a 51% 5-year disease-free survival.93

Inferior results with ABVD or B-CAVe (ABV-CCNU) salvage were observed at Stanford in 110 MOPP-failures (induction failure or relapse), many of whom had also received prior irradiation, a second course of MOPP, or single ABVD drugs before salvage.94 Forty-one achieved a complete remission, and only 50% of these were free of progression 4 years later. Complete remission rates were 63% and 35%, respectively, for those with initial remissions greater and less than 1 year. In a similar study with the ABVD variant ABDIC (ABD-CCNU, prednisone), the overall complete response rate in MOPP-resistant patients (induction failure or short remission) was only 35%, but second complete remissions were achieved in six of seven complete initial responders.95

In the CALBG study quoted earlier,44 only 17 of 48 (35%) patients receiving ABVD after failing MOPP realized a complete remission, and their actuarial failure-free survival rate was only 20% at 4 years. However, less than one third of the patients receiving ABVD-salvage had achieved a complete response from the prior MOPP. MOPP afforded more effective salvage for ABVD-relapses than ABVD did for MOPP-relapses.

The Milan group also reported their long-term experience with 115 refractory (n = 39) and relapsed (n = 76) patients from a cohort of 415 treated with MOPP/ABVD and 25 to 30 Gy to bulky sites.96 The overall survival rate was 27% after 8 years, 8% for induction failures and 28% and 54%, respectively, for those with initial remissions less and more than 1 year.

Other recent investigations document the important prognostic variables in patients who relapse after a complete chemotherapy-induced remission. Vancouver identified a free interval of less than 1 year, stage IV disease at initial diagnosis, and B symptoms at relapse, as important adverse factors in a cohort of 71 patients97: 5-year actuarial freedom from second failure was 82% for those lacking all three (n = 22), and 17% for those in whom one or more was present (n = 49). A three-part index based on two adverse prognostic factors, free interval of less than 1 year, and the presence of stage III/IV disease at relapse was developed by a group of French investigators98: of 187 relapsing complete responders (median follow-up, 31 months), survival was 87% and survival without second relapse was 62% in those with neither adverse factor (n = 48), 59% and 47%, respectively, for those with one risk factor (n = 96), and 44% and 32% for those with both (n = 43).

It is difficult to escape the dismal long-term results experienced by patients who receive salvage chemotherapy for chemotherapy failure. A fraction (no more than one quarter96 to one third91) with a free interval of more than a year realize a high rate of second remission and a disease-free survival approaching 50% at 20 years, but, even in this favorable group, treatment complications reduce overall survival by half.91 Overall survival of the entire cohort was 27% at 8 years after MOPP/ABVD relapse,96 and 12% at 20 years after MOPP relapse.91 High-dose salvage regimens without stem cell support have been associated with excessive toxicity.99,100

Radiation therapy for relapse after combination chemotherapy.   There are several reports of long-term disease-free survival after irradiation salvage of small groups of patients with advanced HD treated initially with chemotherapy.97,101-105 These patients were highly selected for favorable prognostic criteria: long free intervals, the absence of extranodal sites and B symptoms at relapse, the feasibility of encompassing all disease sites in the radiation ports, and, frequently, other criteria. Extensive irradiation was usually administered. Although radiation salvage can rarely be recommended in practice, its capacity to salvage any relapses after systemic chemotherapy provides insight into the biology of HD.

Autologous BM/Stem Cell Transplantation (ASCT) in HD

The high mortality (20% to 25%) experienced in the early years of autologous BM transplantation for HD was largely the result of the poor general condition of patients transplanted late in the course of the condition, and fatal pulmonary toxicity associated with prior mediastinal irradiation, and bleomycin and BCNU (carmustine) chemotherapy.106 With a movement toward earlier transplantation and away from preparative programs with fractionated total body irradiation (FTBI) in those at risk for pulmonary complications, most centers now perform ASCT with a 5% to 10% early mortality (Table 6). Frequently used non-FTBI regimens include CBV (cyclophosphamide, BCNU, and etoposide) and BEAM (BCNU, etoposide, cytarabine, and melphalan). The lesser pulmonary toxicity of CCNU (lomustine) may prove useful.115

                              
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  		Table 6. Autologous BM/Stem Cell Transplantation in HD

Autologous peripheral stem cells are the donor cell of choice when obtainable in adequate number, as is usually possible after chemotherapy- and/or cytokine-mobilization.116 In most circumstances, allogeneic BM transplants from HLA-identical siblings are not recommended for patients with HD117-119: reduced relapse associated with a graft-versus-tumor effect is offset by lethal graft-versus-host toxicity.

Adjuvant involved field irradiation is widely used either before or after marrow/stem cell transplantation. There is evidence that posttransplant adjuvant irradiation can control limited residual disease. Thus, the University of Chicago group converted 10 of 21 patients with residual disease after high-dose chemotherapy to complete remission status with involved field irradiation.120 The progression-free and cause-specific survivals of patients so-converted to complete remission status was similar to those achieving a complete response with high-dose chemotherapy alone, a second instance of the chemotherapy-induced conversion of disseminated (radiation-incurable) HD into a localized (radiocurable) disorder.

Table 6 lists selected results from some of the larger, recent ASCT series with longer follow-up. Event-free survival (survival without relapse or toxic or intercurrent death) of 40% to 50% at 4 to 5 years has been realized in several clinics. Negative risk factors include chemotherapy-resistant disease (induction failure and resistant relapse),106,121 two failed chemotherapy regimens,109,114 bulky residual disease at transplant,110,111 B symptoms at relapse,110,112 extranodal disease at relapse,110,112,114 poor performance status,107,109 and duration of complete remission of less than 1 year. Some centers do not recommend ASCT for patients who never achieved complete remission after three chemotherapy programs.106 Stanford subdivides transplant candidates into four prognostic categories on the basis of three risk factors (B symptoms at relapse, extranodal disease involving lung or BM at relapse, and bulk disease at transplant),110 and Vancouver similarly divides transplant candidates who relapse after a complete response (B symptoms at relapse, extranodal disease at relapse, and initial remission duration <1 year).113

The patients in most published transplant series (Table 6) comprise a mixture of induction failures, and first and later relapses and remissions, who are at varying points in the evolution of HD of varying initial aggressiveness. The result is that patient selection based on arbitrary criteria is often the principal arbiter of survival, and the crucial questions of the place of ASCT versus other forms of salvage and the optimum time for its usage are difficult to judge.122 Two studies address this problem.

The BNLI (British National Lymphoma Investigation) undertook a prospective randomized study of autologous BM transplantation using the BEAM preparative regimen versus salvage chemotherapy with reduced-dose mini-BEAM in high-risk HD (induction failure, or relapse <1 year after 7- or 8-drug programs, or MOPP with other adverse features).123 The 3-year actuarial event-free survival was 53% for the transplanted group and 10% for the salvage chemotherapy group (P = .025). Because of inferior results in the conventional-dose salvage group, the trial was terminated after only 20 patients were entered into each arm. Overall survival was not significantly different at 3 years.

A different approach to the problem was used at Stanford.124 Sixty HD patients in first relapse or with refractory disease treated with high-dose therapy and autografting between 1988 and 1993 were compared with a matched group of 109 similar individuals treated with conventional salvage between 1976 and 1989 when doxorubicin was available. Overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) all favored the high-dose group (OS: 54% v 47%, P = .25; EFS: 53% v 27%, P < .01; PFS: 62% v 32%, P < .01). The benefit of high-dose therapy was most pronounced in patients with less favorable prognostic factors (refractory disease or complete remission of <1 year), but improved outcomes were seen even in those with the most favorable characteristics.

An important problem, perhaps the most important unsolved problem, in the application of ASCT to HD (and to NHL) is the recently recognized distressing incidence of ANLL/MDS (9% to 18% actuarially calculated at 5 to 7 years)116,124-128 (Table 7). The pathogenesis of ANLL/MDS in this context is complex, with essential roles alotted to both prior lymphoma treatment and the preparative regimen for transplantation. The complication is very infrequent following allogeneic marrow transplantation for aplastic anemia.129,130 A short interval between transplantation and MDS is consistent with an important contribution of latent cytogenetic damage from prior lymphoma therapy (see Table 7). Nonetheless, in a City of Hope study of 10 patients who developed clonal chromosomal abnormalities after autologous marrow transplantation, the transplanted marrow was morphologically and cytogenetically normal in all cases.131 Thus, excluding patients with cytogenetically abnormal marrow from transplantation129 will not eliminate the problem. In the Nebraska series, FTBI preparation was linked to ANLL/MDS only in patients autotransplanted for NHL.125 The remarkably high incidence of ANLL/MDS observed in NHL patients, whose primary treatment was FTBI (without ASCT) and whose subsequent therapy included alkylating agent chemotherapy, is of interest in this connection.132,133 Second solid cancers are not yet an important problem following ASCT of patients with Hodgkin's or non-Hodgkin's lymphoma.134,135

                              
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  		Table 7. MDS/ANLL After High-Dose Treatment With Autografting for HD and NHL

The lethal consequences, both immediate and delayed, of high-dose therapy with autografting is one reason for a lack of enthusiasm for its use as part of primary therapy in poor prognosis HD. Difficulty in establishing criteria that define a group at sufficiently high risk provides a second reason.136,137 A recent international study analyzed 20 prognostic factors in more than 5,000 patients with advanced HD.138 Seven significant negative factors were identified: hemoglobin level <10.5/dL, albumin level <4 mg/dL, age >= 45, male sex, stage IV disease, white blood cell (WBC) count >= 15,000/µL, and lymphocyte count <600/µL. Tumor control at 5 years was 74% in patients with 0-2 factors and 55% in those with 3-7. Nonetheless, a pilot trial of 21 patients with high-risk HD transplanted in first remission has been undertaken: 70% experienced progression-free survival at 28 months.139 An unusual high-dose program of effective drugs administered singly and sequentially has been used at the Milan Cancer Institute in 48 untreated CS IIB-IV patients with a 75% complete response rate.140

At the present time ASCT is an appropriate option for those who fail induction chemotherapy or whose remission is less than a year.106,115,116 Because of early and late procedure-associated mortality, ASCT is a less clear choice over competing salvage strategies for individuals with longer initial remissions, and is not recommended today for consolidating initial complete remissions in patients presenting with adverse prognostic features. However, the acute mortality of the procedure will likely diminish further with time, and patients transplanted earlier in the course of their disease with less prior mutational damage may exhibit a lower incidence of secondary malignancy. It is unlikely that these difficult strategic choices can be resolved without prospectively randomized trials comparing high-dose/ASCT with conventional salvage chemotherapy.


    TREATMENT-INDUCED MORTALITY

Unfortunately, the high price in treatment-related mortality exacted by the dramatic improvement in HD cure is still insufficiently appreciated. This is graphically illustrated in Fig 2, adapted from an illustration describing the Stanford experience.141 Fifteen years after diagnosis the mortality from causes other than HD had overtaken HD deaths. Because the median age of this cohort 15 years after treatment was only 44 years,141 mortality from causes other than HD at this time point was overwhelmingly treatment-related. Furthermore, few additional HD-related deaths occur beyond 15 years, while late treatment deaths are still accumulating. Similar observations have been reported from other clinics.142-148 Thus, critical analysis of treatment-related mortality is an essential part of a discussion of HD management. Deaths from second malignancies are the most important cause of death other than HD itself (Table 8).


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  		Fig 2. Actuarial risk of death from HD (curve B) or other causes (curve A) in 2,498 patients treated for HD at Stanford University from 1960-1995. (Modified and reprinted with kind permission from Kluwer Academic Publishers, Annals of Oncology 8 (Suppl 1), p. 116, fig. 1, 1997, Hoppe.141)


                              
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  		Table 8. Causes of Death in Treated HD

ANLL

ANLL was the first neoplasm noted following HD therapy and the most extensively characterized. Cases of this devastating and otherwise uncommon disorder were recognized within a decade of the introduction of MOPP chemotherapy.149,150 Chromosome 5 and 7 deletions are characteristic and approximately half are preceded by MDS.151 Although patients presenting with MDS have been cured by stem cell transplantation,152 few with overt ANLL are salvaged.153

The first cases appear several years after the administration of MOPP, reach a peak in the second half of the first decade, and decline in the first half of the second with few cases reported beyond the second decade.143-147,154 Although ANLL is observed after radiation therapy alone, the relative risk is an order of magnitude less than that following alkylating agents and demonstrable only in very large series. The entire class of alkylating agents are leukemogenic149,150,154,155; cyclophosphamide is significantly less so than mechlorethamine, chlorambucil, melphalan, lomustine (CCNU), or thiotepa. The leukemia risk is linearly related to total alkylating agent dose.155 However, repeated courses of drug (treatment of relapse) are particularly undesirable: in one series a 40-fold higher leukemia risk was associated when the same amount of alkylating agent was administered in two or more separate time periods.154

Drug-induced ANLL is also related to age at time of treatment.150,154,155 Individuals 40 and older exhibit a threefold to fourfold increased cumulative leukemia risk over younger patients.149 The increased cumulative risk reflects the increasing baseline (general population) incidence of ANLL with advancing age.

The leukemia risk after a single course of MOPP chemotherapy is modest (2% to 3% at 10 to 15 years).156-162 Maintenance cycles of MOPP or nitosureas add to this without increasing cure.161 The addition of involved field irradiation increases the risk from MOPP alone little if at all, but combined treatment with aggressive (total nodal or extended field) irradiation results in a threefold increase (6% to 9% at 10 to 15 years).158-163 Relapsed HD requiring salvage with additional courses of alkylating agent chemotherapy is associated with particularly high rates of ANLL (10% to 15%),154,161 and the cumulative risks are multiplied further in individuals age 40 and older. Thus, a low ANLL risk is possible after MOPP chemotherapy by avoidance of the following: (1) combined treatment with total nodal or aggressive extended field irradiation, (2) patients aged 40 and above, and (3) the subset of patients in stage IIIB and IV with a higher (35%) probability of relapse requiring salvage therapy.

The important issue of whether combined modality treatment with chemotherapy and irradiation confers a significantly higher leukemia risk over chemotherapy alone is particularly problematic. Some investigators find the leukemia risk equal in the two groups,146,148,150,154,156,157 while others report it several-fold greater following combined treatment.145,158-164 The sources of disagreement most plausibly lie in differing modes of patient acquisition (population-, registry-, multiinstitution- or single institution-based, or cohort case-control design, all with associated age, stage, and treatment biases), and different methods of analysis. Combined therapy could be linked to some of the variables discussed in the preceding paragraph. Some, but not all, observers have identified splenectomy as a risk factor for ANLL,155,165 another observation subject to confounding, contingent variables.159

The leukemia risk after ABVD, either alone (based on few patients with extended follow-up) or combined with extensive irradiation, is much less than that following MOPP (15-year cumulative risks of 0.7% and 9.5%, respectively).158,159 Additionally, the Netherlands Cancer Institute reports a lower ANLL risk in the 1980s, when alternating or combined MOPP and ABV(D) regimens were introduced, than in the 1970s when only MOPP was available (10-year cumulative risks of 2.1% and 6.4%, respectively).148 Recently, topoisomerase II inhibitors, particularly the epipodophyllotoxins, have been implicated in a clinically (median latent period only 2 to 3 years usually without preceding MDS) and cytogenetically [balanced t(11q23;21q22)] distinct type of ANLL.166

Second NHLs

The relationship of secondary NHLs167 to the preceding HD is complex and poorly understood.168 The risk curve of second NHLs is unusual for radiation-induced solid neoplasms in exhibiting increased risk even in the first 5 years after HD treatment, with subsequent levels remaining elevated or increasing further according to different observers.143-146, 148 Relative risks are high (8.1 to 34),169 with absolute risks similar to those reported for ANLL (Table 9): the cumulative risk of NHL at the Netherlands Cancer Institute was 4.1% after 20 years compared with an ANLL/MDS risk of 4.0%.148 Like ANLL, the cumulative risk of secondary NHL appears to plateau by the middle of the second decade after treatment.

                              
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  		Table 9. Risk of Second Malignancies After HD Treatment

The role of irradiation is unclear. In some series the risks after chemotherapy and irradiation are similar,146,156 while in others the risk is lowest in patients treated with irradiation alone and highest in those receiving intense combined modality therapy.145,148,168 Increasing age at HD treatment is a potent predictor of secondary NHL risk as it is of ANLL.144,145 The great majority of NHL after HD treatment is of intermediate- or high-grade histology,146,148,168 although occasional low-grade tumors are reported. The proportion of T-cell neoplasms may be increased, and some observers note a comparatively favorable response to treatment.142 A high incidence of primary involvement of the gastrointestinal tract has been observed.172

In view of the disparate pathogenic mechanisms involved in the various primary NHLs,20,173,174 it is probable that the lymphomas following HD also have multiple causes. One group, about one third in the BNLI study,146 plausibly represent the natural evolution (transformation) of nodular lymphocyte predominant HD,175 a disorder closely resembling a low-grade B-lineage NHL at the outset.20

Immunological deficiency or perturbation related to HD and/or its treatment can be invoked as a possible cause of the remaining, larger group of secondary NHLs.173,176,177 The spectrum of NHL seen after HD treatment and that associated with inherited or acquired immunosuppression share common features.178-182 A single report identified Epstein-Barr virus (EBV) in two post-HD NHLs,183 but systematic study is required to unravel this complex problem.

Second Solid Neoplasms

Second neoplasms other than ANLL and NHL are the most frequent obstacles to the cured HD patient realizing his or her normal longevity. Relative risks of ANLL and NHL are far greater, but absolute risks are smaller (Table 9). Some of these second solid tumors are common neoplasms (lung, breast, gastrointestinal tract) in which modest increases (several-fold) in relative risk lead to major absolute risks. The 20-year cumulative risk of solid tumors in the Netherlands Cancer Institute series was 13.1% compared with 8.1% for ANLL and NHL combined.148 Furthermore, while the excess risks of ANLL and NHL are largely dissipated by the middle of the second decade after treatment, the solid cancer risk continues well into the third with no indication of when, if ever, it abates.141,142,144-146,148,155,184

Most investigators of second solid cancers after HD treatment attribute the major carcinogenic role to irradiation.145,146,148,156,169,184,185 The solid cancers reported to occur in excess (carcinomas of lung, breast, stomach, pancreas and thyroid, and sarcomas of bone and soft tissues) are those that have been observed in other radiation-exposed populations.155,186-188 Usually after a latent period of at least 5 to 10 years, the solid tumor risk appears with a multiplicative relationship to its underlying incidence in the population; ie, the risk is proportional to the background risk of the neoplasm.

Approximately two thirds (65% to 90%) of second solid tumors arise within or at the edge of treatment fields155-159; the remaining third plausibly reflects baseline tumor incidence. Few second solid tumors have been reported after chemotherapy alone, although comparatively few individuals with very long follow-up (>20 years) have been treated with drugs alone. Data from some combined modality treatment studies raise the possibility that radiation carcinogenicity is potentiated by chemotherapy or that chemotherapy plays a lesser independent role, but the findings could be accounted for by confounding variables. If chemotherapy plays any role in second solid tumors, available data suggest that ABVD and MOPP are equally culpable.159

Carcinoma of the lung.   A twofold to eightfold excess risk of lung cancer (compared with the risk in the general population) is observed 5 or more years after HD treatment and persists through the second decade (the longest observed patients).145,148,169 In view of the frequency of lung cancer in the general population, an increase in relative risk of this magnitude makes lung cancer the most important cause of second solid tumor deaths in treated HD (Table 9).146,148 There is general agreement of the excess risk after irradiation and combined regimens containing alkylating agents.145,146,148,156,189,190

A recent European investigation shows a direct relationship between lung cancer risk and dose to the previously irradiated lung segments.190 A positive smoking history, particularly continued smoking after the diagnosis of HD, markedly increases the risk. This more than multiplicative effect of smoking resembles earlier observations in uranium191 and tin miners.192 For the HD patient anticipating mantle irradiation, abstinence from smoking is essential. A negative smoking history is even better.

Breast carcinoma.   Carcinoma of the breast is arguably the best studied solid neoplasm that follows HD treatment.157,170,193,194 The increased incidence of this tumor in atomic bomb survivors and following iatrogenic irradiation provided ample warning of the risk of mantle radiation.

The excess risk of breast carcinoma is almost completely restricted to women irradiated before the age of 30. Those treated in the second decade and first half of the third decade of life are subject to the maximum cumulative risk, with shoulders of the risk peak extending into the second half of both the first and third decades.194 This risk curve is consistent with current understanding of breast carcinogenesis which posits a window of risk when breast epithelium, before its terminal differentiation, is susceptible to the carcinogenic effect of unbalanced estrogen stimulation.195 The first breast carcinomas appear at the end of the first decade after HD irradiation and continue to appear in the longest observed women (three decades). In one series, actuarial calculation predicted a 34% incidence of breast cancer 25 years after irradiation in those treated before age 20.194 These second tumors appear within or at the edge of treatment fields.157,170,193 Stanford data raise the possibility that alkylating agents potentiate the radiation breast cancer risk,170 but confounding variables may explain the modest increase in risk ratio observed with added chemotherapy.196 It is early to assess the effectiveness of efforts to moderate the breast cancer risk through dose and field reduction.197

Other second solid neoplasms.   In the three decades of modern HD treatment, the remaining second tumors have constituted less important causes of mortality. With the exception of melanoma, these other neoplasms (carcinomas of stomach, pancreas and thyroid, and sarcomas of bone and soft tissue) exhibit the latency and in-field characteristics of radiation-induced carcinogenesis noted above.

Carcinomas of the stomach and pancreas are a concern even though much less attention has been paid to them in the HD literature. That concern arises from their lethal character, frequency both in the normal population and following abdominal irradiation for testicular carcinoma,198 and absolute risk which is still rising in the third decade after HD treatment.171,199 In pediatric HD patients, an increase in colorectal cancer has also been reported.157,193

Sarcomas of bone and soft tissue are infrequently encountered in the general population, but deserve attention because of their often unfavorable outcome when observed after HD irradiation.183,194 These tumors constitute a particularly important group of treatment-induced neoplasms in pediatric and adolescent HD populations.157,200,201 Thyroid carcinoma is also more frequent in children after HD treatment,157,193,202,203 but fortunately more amenable to therapy. The pathogenesis of the melanomas that follow HD is unclear204: immune deficiency related to chemotherapy or to HD itself has been invoked, but a multifactoral causation is more likely.148,179,204


    CARDIAC COMPLICATIONS OF MANTLE IRRADIATION

Cardiovascular complications of mantle irradiation comprise the second most frequent cause of treatment-related mortality in HD patients followed through the second decade (Table 8).141,142,205 Cardiac deaths have been responsible for approximately one quarter of the mortality from causes other than HD itself, and 2% to 5% of the mortality in the entire HD population.141,142 Although the relative risk of cardiac death is modest (2.2 to 3.1),145,206 the absolute risk is high (9.3 to 28/10,000 patients/yr)145,206 because of the frequency of cardiac death in the general population. The higher risk of cardiac death in men in the general population accounts for their much greater cumulative risk of cardiac mortality after HD treatment (23% for males after 22 years of observation versus 8% for females).206 Although the relative risk of cardiac death is greatest in irradiated children and adolescents, the absolute risk increases with increasing age at the time of irradiation, at least up to the sixth decade.206 The relative risk of cardiac death is already elevated in the initial 5 years after treatment with a slowly continuing increase in patients observed more than 20 years.206

Cardiac deaths after HD treatment are conveniently divided into those resulting from myocardial infarction secondary to radiation damage to the coronary arteries, and deaths from other manifestations of radiation injury to the heart; ie, pericardial disease, diffuse myocardial disease (pancarditis and cardiomyopathy), valvular defects, and conduction abnormalities.207,208

Myocardial Infarction

While appreciated later and encountered less frequently than some other forms of radiation damage to the heart, myocardial infarction exacts more than two thirds of the cardiac mortality observed in irradiated HD patients.141,142,205,208-211 In the Stanford series, 22-year Kaplan-Meier projected cumulative mortality was 15.5% for males and 3.5% for females.67 Further, unlike other manifestations of radiation damage to the heart, myocardial infarction deaths have not been substantially reduced by refinement of radiation technique (introduction of equal anterior and posterior fractions, reduced fraction size, and routine left ventricular and subcarinal blocking to limit dosage to the entire cardiac silhouette). The 18-year actuarially calculated cumulative mortality was 4.5% for patients treated after 1972 when radiation technique was improved, and 5% before that date.206 Individuals at high risk of myocardial infarction because of prior mantle irradiation require careful cardiac monitoring.206,211,212

Other Cardiac Deaths

Radiation damage to the pericardium, the myocardium, and heart valves213 frequently follows mantle irradiation. Unfortunately, many early and late cardiac deaths from these treatment complications accompanied the early phases of the learning curve of HD irradiation in the 1960s and early 1970s. However, the risk of cardiac deaths from causes other than myocardial infarction is markedly diminished with modern radiation technique and the availability of chemotherapy as a viable treatment alternative. The relative risk of nonmyocardial infarction cardiac deaths at Stanford was reduced to 1.4 after 1972 when refined irradiation practices were adopted and combination chemotherapy was available, from 5.3 before that date.211 Our institutional experience supports published reports211 of the value of expert cardiac intervention (surgical and medical).


    OTHER CAUSES OF TREATMENT-RELATED MORTALITY

A miscellaneous group of other treatment-related complications with fatal consequences requires enumeration. The many significant nonfatal complications, including male and female sterility and psychosocial problems, are not addressed here.

Bleomycin-Induced Pulmonary Toxicity

Risk factors for fatal bleomycin-induced lung toxicity include prior or concomitant mediastinal irradiation, total drug dose in excess of 300 to 400 U, age greater than 70, and subsequent high-dose oxygen therapy.214,215 However, fatal toxicity can be seen at all dose levels at all ages even in carefully monitored patients. Bleomycin-related mortality after 6 cycles of ABVD chemotherapy is estimated at 1% to 3%,44,71,216 but attention to risk factors and meticulous monitoring of pulmonary symptoms, signs, and function can reduce that risk. In contrast to bleomycin, doxorubicin in the dose used in ABVD has been responsible for only sporadic deaths in patients who enter treatment with satisfactory cardiac function.44,71,216

Mortality From Infectious and Other Complications After Chemotherapy and Laparotomy

With hematopoietic growth factors available, the mortality from infection and bleeding associated with MOPP chemotherapy in patients without complicating disease is less than 2% in experienced hands.44,71 Mortality from staging laparotomy, both immediate and that associated with fulminant postsplenectomy sepsis, is less than 1% in experienced centers using bacterial vaccines preoperatively and avoiding treatment programs that include total nodal irradiation.4,5,142,211,217


    CONCLUSION

In view of the litany of treatment-induced catastrophes, it is important to recall that the new problems are a consequence of one of the triumphs of cancer management. Even a grave treatment complication in middle or late life is preferable to death from HD 20, 30, or more years earlier. Moreover, it is likely that the projected mortality of HD treatment is overestimated today as it was underestimated in the past. Many of the earliest treated patients, whose complications constitute the principal basis of extrapolating future mortality, were treated when knowledge of the variables controlling carcinogenesis and HD cure was rudimentary. Furthermore, background risks of common epithelial malignancies unrelated to HD treatment become important confounding factors as these patients enter their fifties and sixties.

One response to the residue of uncured HD and the frequent treatment complications has been a recourse to novel combined treatment programs applied to large fractions of patients. Past experience suggests that, barring dramatic new therapeutic advances, incremental improvement of proven treatment strategies based on the individual patient's HD prognostic factors and his or her risk factors for treatment complications is more likely to improve survival. Available clinical observations already give an indication of the contributions of radiation therapy, chemotherapy, and age to treatment complications, and the specific temporal sequences often defined by relapse which place the patient in greatest jeopardy. Epidemiology should eventually provide a detailed description of the variables controlling second neoplasms to further guide treatment strategy.

Although HD therapy cannot be reduced to a few overarching principles today, patient management can be based on a large body of reliable data, albeit of more limited application. Thus, treatment risks that can be justified in patients presenting with still lethal stage IIIB and IV disease are not appropriate for those with more indolent stage I and IIA. Similarly, the use of adjuvant radiation or high-dose therapy with ASCT, each of which carry substantial treatment-related mortality (10% to 20% at 20 to 25 years), demand comparable gains in HD cure. Mantle irradiation should be avoided when possible in smokers and young women because of lung and breast cancer risks, respectively. Older individual (above age 50) do poorly with MOPP because of acute and chronic (ANLL/MDS) marrow toxicity, and with the MOPP/ABV hybrid. While all relapses after systemic chemotherapy markedly increase the risk of second neoplasms, relapses within a year are infrequently controlled without high-dose therapy and PSCT. From restricted observations such as these and similar ones discussed in the body of this review, it is possible to arrive at a coherent treatment strategy for most patients today. A pressing need remains for trials that evaluate novel combined treatment programs.


    FOOTNOTES

Submitted April 17, 1998; accepted September 29, 1998.

Address reprint requests to Alan C. Aisenberg, MD, PhD, Massachusetts General Hospital, 75 Blossom Ct, Boston, MA 02114.


    REFERENCES
Top
Introduction
References

1. Ries LAG, Miller BA, Hankey BF, Kosary CL, Harras A, Edwards BK (eds): SEER Cancer Statistics Review, 1973-1994, National Cancer Institute. NIH Pub. No. 97-2789. Bethesda, MD, NIH, 1997.

2. Landis SH, Murray T, Bolden S, Wingo PA: Cancer statistics 1998. CA Cancer J Clin 48:6, 1998[Abstract]

3. Glatstein E, Guernsey JM, Rosenberg SA, Kaplan HS: The value of laparotomy and splenectomy in the staging of Hodgkin's disease. Cancer 24:709, 1969[Medline] [Order article via Infotrieve]

4. Leibenhaut MH, Hoppe RT, Efron S, Halpern J, Nelson T, Rosenberg SA: Prognostic indicators of laparotomy findings in clinical stage I-II supradiaphragmatic Hodgkin's disease. J Clin Oncol 7:81, 1989[Abstract]

5. Mauch P, Larson D, Osteen R, Silver B, Yeap B, Canellos G, Weinstein H, Rosenthal D, Pinkus G, Jochelson M, Coleman CN, Hellman S: Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 8:257, 1990[Abstract]

6. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31:1860, 1971[Free Full Text]

7. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswold Meeting. [published erratum appears in J Clin Oncol 8:1602, 1990.] J Clin Oncol 7:1630, 1989[Abstract]

8. Gobbi PG, Cavelli C, Gendarini A, Crema A, Ricevuti G, Federico M, Di Prisco U, Ascari E: Revaluation of prognostic symptoms in Hodgkin's disease. Cancer 56:2874, 1985[Medline] [Order article via Infotrieve]

9. Hoppe RT, Coleman CN, Rosenberg SA, Kaplan HS: The management of stage I-II Hodgkin's disease with irradiation alone or combined modality treatment: The Stanford experience. Blood 59:455, 1982[Abstract/Free Full Text]

10. Gilbert R: Radiotherapy in Hodgkin's disease (malignant lymphogranulomatosis). Am J Roentgenol 41:198, 1939

11. Peters MV: A study of survival in Hodgkin's disease treated radiologically. Am J Roentgenol 63:299, 1950

12. Kaplan HS: The radical radiotherapy of regionally localized Hodgkin's disease. Radiology 78:553, 1962

13. DeVita VT, Sepick AA, Carbone PP: Combination chemotherapy for advanced Hodgkin's disease. Ann Intern Med 73:881, 1970

14. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C: Combination chemotherapy of Hodgkin's disease with Adriamycin, bleomycin, vinblastine and imadazole carboxamide versus MOPP. Cancer 252, 1975

15. Mendenhall NP: Diagnostic procedures and guidlines for the evaluation and follow-up of Hodgkin's disease. Semin Radiat Oncol 6:131, 1996[Medline] [Order article via Infotrieve]

16. Salloum E, Brandt DS, Caride VJ, Zelteram D, Schubert W, Mannino T, Cooper DL: Gallium scan in the management of patients with Hodgkin's disease. A study of 101 patients. J Clin Oncol 15:518, 1997[Abstract/Free Full Text]

17. Altehoefer C, Blum U, Bathmann J, Wustenberg C, Uhrmeister J, Lange W, Schwarzkopf J, Moser E, Langer M: Comparative diagnostic accuracy of magnetic resonance imaging and immunoscintigraphy for detection of bone marrow involvement in patients with malignant lymphoma. J Clin Oncol 15:1754, 1997[Abstract/Free Full Text]

18. de Wit M, Baumann D, Beyer W, Herbst K, Clausen M, Hossfeld DK: Whole-body positron emission tomography for diagnosis of residual mass in patients with lymphoma. Ann Oncol 8:S57, 1997[Abstract] (suppl 1)

19. Moog F, Bangerter M, Diederichs CG, Guhlmann A, Kotzerke J, Merkle E, Kolokythas O, Herrmann F, Reske SN: Lymphoma: Role of whole body 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) PET in nodal staging. Radiology 203:795, 1997[Abstract/Free Full Text]

20. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsol G, De Wolf-Peeters C, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink H-K, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA: A revised European-American classification of malignant lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361, 1994[Free Full Text]

21. Ferry JA, Harris NL: The pathology of Hodgkin's disease: What's new? Semin Radiat Oncol 6:121, 1996[Medline] [Order article via Infotrieve]

22. Sextro M, Diehl V, Franklin J, Handsmann H-L, Agnagostopoulos I, Marafioti T, Stein H: Lymphocyte predominant Hodgkin's disease: A workshop report. European Task Force on Lymphoma. Ann Oncol 7:S61, 1996 (suppl 4)

23. Bodis S, Kraus MD, Pinkus G, Silver B, Kadin ME, Canellos GP, Shulman LN, Tarbell NJ, Mauch PM: Clinical presentation and outcome in lymphocyte predominant Hodgkin's disease. J Clin Oncol 15:3060, 1997[Abstract]

24. Zinzani PL, Benandi M, Martelli M, Falini B, Sabattini E, Amadori S, Gherlinzoni F, Martelli MF, Mandelli F, Tura S, Pileri S: Anaplastic large-cell lymphoma: Clinical and prognostic evaluation in 90 adult patients. J Clin Oncol 14:955, 1996[Abstract/Free Full Text]

25. Longo DL, Glatstein E, Duffey PL, Young RC, Hubbard SM, Urba WJ, Wesley MN, Raubitschek A, Jaffe ES, Wiernik PH, DeVita VT Jr: Radiation therapy versus combination chemotherapy in the treatment of early stage Hodgkin's disease: Seven-year results of a prospective randomized trial. J Clin Oncol 9:906, 1991[Abstract]

26. Biti GP, Cimino G, Cartoni C, Mangini SM, Anselmo AP, Maurizi Enrici RM, Bellisi GP, Bosi A, Papa A, Giannarelli D, Ponticelli P, Papi MGH, Rossi Ferrini PL, Biagini C, Mandelli F: Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: Eight-year update of an Italian prospective randomized trial. J Clin Oncol 10:378, 1992[Abstract/Free Full Text]

27. Specht L, Gray RG, Clarke MJ, Peto R, for the International Hodgkin's Disease Collaborative Group: Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcone of early-stage Hodgkin's disease: A meta-analysis of 23 randomized trials involving 3,888 patients. J Clin Oncol 16:830, 1998[Abstract]

28. Vijayakumar S, Myrianthopoulos LC: An updated dose-response analysis of Hodgkin's disease. Radiother Oncol 24:1, 1992[Medline] [Order article via Infotrieve]

29. Brinker H, Bentzen SM: A re-analysis of available dose-response and time-dose data in Hodgkin's disease. Radiother Oncol 30:227, 1994[Medline] [Order article via Infotrieve]

30. Gospodorowicz MK, Sutcliffe SB, Clark RM, Dembo AJ, Fitzpatrick PJ, Munro AJ, Bergsagel DE, Patterson BJ, Tsang R, Chua T, Bush RS: Analysis of suprsdiaphragmatic clinical stage I and II Hodgkin's disease treated with radiation alone. Int J Radiat Oncol Biol Phys 22:859, 1992[Medline] [Order article via Infotrieve]

31. Mauch PM: Management of early stage Hodgkin's disease: The role of radiation therapy and/or chemotherapy. Ann Oncol 7:S79, 1996 (suppl 4)

32. Hoppe RT: Radiation therapy in the management of Hodgkin's disease. Semin Oncol 17:704, 1990[Medline] [Order article via Infotrieve]

33. Sutcliffe SB, Gospodarowicz MK, Bergsagel DE, Bush RS, Alison RE, Bean HA, Brown TC, Chua T, Clark RM, Curtis JE, Dembo AJ, Fitzpatrick PJ, Hasselback RH, Rideout DF, Sturgeon JFG, Quirt I, Yeoh L, Peters MV: Prognostic groups for management of localized Hodgkin's disease. J Clin Oncol 393, 1985

34. Carde P, Hagenbeek A, Hayat M, Monconduit M, Thomas J, Burgers MJV, Noordijk EM, Tanguy A, Meervaldt JH, Le Fur R, Somers R, Kluin-Nelemans HC, Busson A, Breed WP, Bron D, Holdrinet A, Rutten EHJM, Michiels JJ, Regnier R, Debusscher L, Musella R, Fargeot P, Thyss A, Cattan A, Rigol-Huguet F, Roth S, Caillou B, Dupouy N, Henry-Amar M: Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: The H6 twin randomized trials for the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 11:2258, 1993[Abstract/Free Full Text]

35. Specht L: Prognostic factors in Hodgkin's disease. Semin Radiat Oncol 6:141, 1996

36. Jones E, Mauch P: Limited radiation therapy for selected patients with pathological stage IA and IIA Hodgkin's disease. Semin Radiat Oncol 6:161, 1996

37. Hagenbeek A, Carde P, Noordijk E, Thomas J, Tirelli U, Misconduit M, Eghbali H, Mandard AM, Henry-Amar M: Prognostic factor tailored treatment of early stage Hodgkin's disease. Results of a prospective randomized Stage III clinical trial in 762 patients (H7 study). Blood 90:565a, 1997 (abstr, suppl 1)

38. Ganesan T, Wrigley P, Murray P, Stansfield AG, d'Ardenne AJ, Arnott S, Jones A, Shant WS, Malpas JS, Lister TA: Radiotherapy for stage I Hodgkin's disease. 20 years experience at St Bartholomew's Hospital. Br J Cancer 3:314, 1990

39. Crnkovich MJ, Leopold K, Hoppe RT, Mauch PM: Stage IB to IIB Hodgkin's disease: The combined experience at Stanford University and the Joint Center for Radiation Therapy. J Clin Oncol 5:1041, 1987[Abstract/Free Full Text]

40. Mauch P, Tarbell N, Weinstein H, Silver B, Goffman T, Osteen R, Zajac A, Coleman C, Canellos G, Rosenthal D: Stage IA and IIA supradiaphragmatic Hodgkin's disease: Prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation. J Clin Oncol 6:1576, 1988[Abstract/Free Full Text]

41. Specht L, Nordentoft A, Cold S, Clausen N, Nissen N: Tumor burden as the most important prognostic factor in early stage Hodgkin's disease. Relations to other prognostic factors and implications for choice of treatment. Cancer 61:1719, 1988[Medline] [Order article via Infotrieve]

42. Cosset JM, Henry-Amar M, Meervaldt JH, Carde P, Noordijk EM, Thomas J, Burgers JMV, Somers R, Hayat M, Tubiana M, on behalf of the EORTC Lymphoma Cooperative Group: The EORTC trials for limited stage Hodgkin's disease. Eur J Cancer 28A:1847, 1992

43. Mauch PM: Controversies in the management of early stage Hodgkin's disease. Blood 83:319, 1994

44. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478, 1992[Abstract]

45. Prosnitz LR, Curtis AM, Knowlton AH, Peters LM, Farber LR: Supradiaphragmatic Hodgkin's disease: Significance of large mediastinal masses. Int J Radiat Oncol Biol Phys 6:809, 1980[Medline] [Order article via Infotrieve]

46. Longo DL, Russo A, Duffey PL, Hubbard SM, Glatstein E, Hill JB, Jaffe E, Young RS, DeVita VT: Treatment of advanced stage massive mediastinal Hodgkin's disease: The cases for combined modality treatment. J Clin Oncol 9:227, 1991[Abstract]

47. Behar RA, Horning SJ, Hoppe RT: Hodgkin's disease with bulky mediastinal involvement: Effective management with combined modality therapy. Int J Radiat Oncol Biol Phys 25:771, 1993[Medline] [Order article via Infotrieve]

48. Santoro A, Bonfante V, Viviani S, Devizzi L, Zanini M, Soncini F, Gaaspanini M, Valagussa P, Bonadonna G: Subtotal nodal versus involved field irradiation after 4 cycles of ABVD in early stage Hodgkin's disease. Proc Am Soc Clin Oncol 15:415, 1996 (abstr)

49. Horning SJ, Rosenberg SA, Hoppe RT: Brief chemotherapy (Stanford V) and adjuvant radiotherapy for bulky or advanced Hodgkin's disease: An update. Ann Oncol 7:S105, 1996 (suppl 4)

50. Klasa RJ, Connors JM, Fairey R, Gascoyne R, Hoskin's P, O'Reilly S, Shenkier T, Voss N, Wilson K: Treatment of early stage Hodgkin's disease: Improved outcome with brief chemotherapy and radiotherapy without staging laparotomy. Ann Oncol 7:S21, 1996 (abstr, suppl 3)

51. Horning SJ, Hoppe RT, Mason J, Brown BW, Hancock SL, Baer D, Rosenberg SA: Stanford-Kaiser Permanente G1 study for clinical stage I and IIA Hodgkin's disease: Subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation. J Clin Oncol 15:1736, 1997[Abstract/Free Full Text]

52. DeVita VT Jr, Serpick A: Combination chemotherapy in the treatment of Hodgkin's disease. Proc Am Assoc Cancer Res 8:13, 1967 (abstr)

53. Longo DL, Young RC, Wesley M, Hubbard AM, Duffey PL, Jaffe ES, DeVita VT Jr: Twenty years of MOPP therapy for Hodgkin's disease. J Clin Oncol 4:1295, 1986[Abstract/Free Full Text]

54. Canellos GP: Is ABVD the standard regimen for Hodgkin's disease based on randomized CALGB comparison of MOPP, ABVD and MOPP alternating with ABVD? Leukemia 10:S68, 1996 (suppl 2)

55. Bonadonna G, Valagussa P, Santoro A: Alternating non-cross-resistant combination chemotherapy or MOPP in Stage IV Hodgkin's disease. Ann Intern Med 104:739, 1986

56. Somers R, Corde P, Henry-Amar M, Tarayre M, Thomas J, Hagenbeek A, Monconduit M, De Pauw BE, Breed WPM, Verdonck L, Burgers JMV, Eghbali H, Zittoun R: A randomized study in Stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alternation of MOPP with ABVD: A European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial. J Clin Oncol 12:279, 1994[Abstract]

57. Connors JM, Klimo P, Adams G, Burns BF, Cooper I, Meyer RM, O'Reilly SE, Pater J, Quirt I, Sadura A, Shustik C, Skillings J, Sutcliffe S, Verma S, Yoshida S, Zee B: Treatment of advanced Hodgkin's disease with chemotherapy---Comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: A report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 15:1638, 1997[Abstract]

58. Glick JH, Young ML, Harrington D, Schilsky RL, Beck T, Neiman R, Fisher RI, Peterson BA, Oken MM: MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: The 8-years results of the Intergroup trial. J Clin Oncol 16:19, 1998[Abstract/Free Full Text]

59. Hancock BW, Vaughan Hudson G, Vaughn Hudson B, Bennett MH, MacLennan KA, Haybittle JL, Anderson L, Linch DC: 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 10:1252, 1992[Abstract/Free Full Text]

60. Gobbi PG, Pieresca C, Ghirardelli ML, Di Renzo N, Federico M, Merli F, Iannitto E, Pitini V, Grignani G, Donelli A, Carotenuto M, Silingardi V, Ascari E: Long-term results of MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease. Blood 91:2704, 1998[Abstract/Free Full Text]

61. Radford JA, Crowther D, Rohatiner AZS, Ryder WDJ, Gupta RK, Oza A, Deakin DP, Arnott S, Wilkinson PM, James RD, Johnson RJ, Lister TA: Results of a randomized trial comparing MVPP chemotherapy with a hybrid regimen, Ch1VPP/EVA, in the initial treatment of Hodgkin's disease. J Clin Oncol 13:2379, 1995[Abstract/Free Full Text]

62. Duggan D, Petroni G, Johnson J, Hanson K, Glick J, Connors R, Chemy R, Barcos M, Peterson BA, for CALBG: MOPP/ABV versus ABVD for advanced Hodgkin's disease---A preliminary report of CALBG 8952 (with SWOG, ECOG, NCIC). Proc Am Soc Clin Oncol 16:12a, 1997 (abstr)

63. Viviani V, Bonadonna G, Santoro A, Bonafante V, Zanini M, Devizzi L, Soncini F, Valagussa P: Alternating versus hybrid MOPP and ABVD combinations in advanced Hodgkin's disease: Ten-year results. J Clin Oncol 14:1421, 1996[Abstract/Free Full Text]

64. Hasenclever D, Loeffler M, Diehl V, for the German Hodgkin's Lymphoma Study Group: Rationale for dose escalation of first line conventional chemotherapy in advanced Hodgkin's disease. Ann Oncol 7:S95, 1996 (suppl 4)

65. Reuss K, Enger A, Tesch H, Diehl V: Current clinical trials in Hodgkin's disease. Ann Oncol 7:S109, 1996 (suppl 4)

66. Diehl V, Sieber M, Ruffer U, Lathan B, Hasenclever D, Pfreundschuh M, Loeffler M, Lieberz D, Koch P, Adler M, Tesch H, for the German Hodgkin's Lymphoma Study Group: BEACOPP: An intensified chemotherapy regimen in advanced Hodgkin's disease. Ann Oncol 8:143, 1997[Abstract/Free Full Text]

67. Frei E III, Luce JK, Gamble G, Coltman CA Jr, Constanzi JJ, Talley RW, Monto RW, Wilson HE, Hewlett JS, Delaney FC, Gehan EA: Combination chemotherapy in advanced Hodgkin's disease: Induction and maintenance of remission. Ann Intern Med 79:376, 1973

68. Young RC, Canellos GP, Chabner BA, Hubbard SM, DeVita VT: Patterns of relapse in advanced Hodgkin's disease. Cancer 42:1001, 1978[Medline] [Order article via Infotrieve]

69. Prosnitz LR, Farber LR, Kapp DS, Scott J, Bertino JR, Fischer JJ, Cadmen EC: Combined modality therapy for advanced stage Hodgkin's disease: 15-year follow-up data. J Clin Oncol 6:603, 1988[Abstract]

70. Yahalom J, Ryu J, Straus DJ, Gaynor JJ, Meyers J, Caravelli J, Clarkson BD, Fuks Z: Impact of adjuvant radiation on the patterns and rate of relapse in advanced-stage Hodgkin's disease treated with alternating chemotherapy combinations. J Clin Oncol 9:2193, 1991[Abstract]

71. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F, Pagnani AM, Bonafante V, Musumeci R, Crippa F, Tess JDT, Banfi A: Long-term results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: Superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 5:27, 1987[Abstract]

72. Bonadonna G: Modern treatment of Hodgkin's disease: A multidisciplinary approach? Ann Oncol 5:S5, 1994 (suppl 3)

73. Fabian CJ, Mansfield CM, Dahlberg S, Jones SE, Miller TP, Van Slyck E, Grozea PN, Morrison FS, Coltman CA Jr, Fisher R: Low-dose involved field radiation after chemotherapy in advanced Hodgkin's disease. Ann Intern Med 120:903, 1994[Abstract/Free Full Text]

74. Raemaekers J, Burgers M, Henry-Amar M, Pinna A, Mandard A, Monfardini S, Hagenbeek A, Breed W, Carde P, Vovk M, van Hoof A, Thomas J, Noordijk E, for the EORTC Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie: Patients with stage III/IV Hodgkin's disease in partial remission after MOPP/ABV chemotherapy have excellent prognosis after additional involved-field radiotherapy: Interim results from the ongoing EORTC-LCC and GPMC phase III trial. Ann Oncol 8:S111, 1997[Abstract] (suppl 1)

75. Longo DL: The case against the routine use of radiation therapy in advanced stage Hodgkin's disease. Cancer Invest 14:353, 1996[Medline] [Order article via Infotrieve]

76. Prosnitz LR, Wu JJ, Yahalom J: The case for adjuvant radiation therapy in advanced Hodgkin's disease. Cancer Invest 14:361, 1996[Medline] [Order article via Infotrieve]

77. Doria R, Holford T, Farber LR, Prosnitz LR, Cooper DL: Second solid malignancies after combined modality therapy of Hodgkin's disease. J Clin Oncol 13:2016, 1995[Abstract/Free Full Text]

78. Loeffler M, Diehl V, Pfreundschuh M, for the German Hodgkin's Lymphoma Study Group: Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin's disease. J Clin Oncol 15:2275, 1997[Abstract/Free Full Text]

79. Glick J, Rubin P, Tsiatis A, Graves R, Bennett J: Hodgkin's disease stage IIB & IV: Failure of radiation consolidation to improve survival compared to B-MOPP-ABVD: An ECOG study. Int J Radiat Oncol Biol Phys 13:91, 1987 (abstr, suppl 1)

80. Glick J, Tsiatis A, Chen M, Rassiga A, Mann R, O'Connell M: Improved survival with MOPP-ABVD compared to BCVPP ± radiotherapy (RT) for advanced Hodgkin's disease: 6-year ECOG results. Blood 76:350a, 1990 (abstr, suppl 1)

81. Pavlovsky S, Santarelli MT, Sackmann F, Muriel I, Fernandez I, Garcia I, Schwartz L, Montero C, Lobo Sanahuja F, Magnasco H, Costa A, Corrado C, Rana R, Bezares R: Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage III-IV Hodgkin's disease. Ann Oncol 3:533, 1992[Abstract/Free Full Text]

82. Brizel DM, Winer EP, Prosnitz LR, Scott J, Crawford J, Moore JO, Gockerman JP: Improved survival in advanced Hodgkin's disease. Int J Radiat Oncol Biol Phys 19:535, 1990[Medline] [Order article via Infotrieve]

83. Yelle Y, Bergsagel D, Basco V, Brown T, Bush R, Gillies J, Israels L, Miller A, Rideout D, Whitelaw D, Willan A, Pater J: Combined modality therapy of Hodgkin's disease: 10-year results of National Cancer Institute of Canada Clinical Trials Group multicenter clinical trial. J Clin Oncol 9:1983, 1991[Abstract/Free Full Text]

84. Loeffler M, Hasenclever D, Sextro M, Assouline D, Bartolucci AA, Cassileth PA, Diehl V, Fisher RI, Hoppe RT, Jacobs P, Pater JL, Pavlovsky S, Thompson E, Wiernik P, for the International Database on Hodgkin's Disease Overview Study Group: Meta-analysis of chemotherapy versus combined treatment trials in Hodgkin's disease. J Clin Oncol 16:818, 1998[Abstract]

85. Yuen AR, Horning SJ: Hodgkin's disease: Management of first relapse. Oncology 10:233, 1996[Medline] [Order article via Infotrieve]

86. Roach M III, Brophy N, Varghese A, Hoppe RT: Prognostic factors for patients relapsing after radiotherapy for early-stage Hodgkin's disease. J Clin Oncol 8:623, 1990[Abstract]

87. Healey EA, Tarbell NJ, Kalish LA, Silver B, Rosenthal DS, Marcus K, Shulman LN, Coleman CN, Canellos G, Weinstein H, Mauch P: Prognostic factors for patients with Hodgkin's disease in first relapse. Cancer 71:2613, 1993[Medline] [Order article via Infotrieve]

88. Specht L, Horwich A, Ashley S: Salvage of relapse of patients with Hodgkin's disease in clinical stages I or II who were staged with laparotomy and initially treated with radiotherapy alone. A report for the International Database on Hodgkin's Disease. Int J Radiat Oncol Biol Phys 30:805, 1994[Medline] [Order article via Infotrieve]

89. Santoro A, Viviani S, Villarreal CJR, Bonofante V, Delfino A, Valagussa P, Bonadonna G: Salvage chemotherapy in Hodgkin's disease irradiation failure: Superiority of doxorubicin-containing regimens over MOPP. Cancer Treat Rep 70:343, 1986[Medline] [Order article via Infotrieve]

90. Fisher RI, DeVita VT Jr, Hubbard SP, Simon R, Young RC: Prolonged disease-free survival in Hodgkin's disease with MOPP reinduction after first relapse. Ann Intern Med 90:761, 1979

91. Longo DL, Duffey PL, Young RC, Hubbard SM, Ihde DC, Glatstein E, Phares JC, Jaffe ES, Urba WJ, DeVita VT Jr: Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: The low probability of cure. J Clin Oncol 10:21, 1992[Abstract]

92. Bonadonna G, Santoro A, Gianni AM, Viviani S, Siena S, Bregni M, Zucali R, Lombardi F, Bonafanti V, Gianni L: Primary and salvage chemotherapy in advanced Hodgkin's disease: The Milan Cancer Institute experience. Ann Oncol 1:9, 1991

93. Viviani S, Santoro A, Negretti E, Bonafanti V, Valagussa P, Bonadonna G: Salvage chemotherapy in Hodgkin's disease: Results in patients relapsing more than twelve months after complete remission. Ann Oncol 1:123, 1990[Abstract/Free Full Text]

94. Harker WG, Kushlan P, Rosenberg SA: Combination chemotherapy for advanced Hodgkin's disease after failure of MOPP:ABVD and B-CAVe. Ann Intern Med 101:440, 1984

95. Tannir N, Hagemeister F, Velasquez W, Cabanillas F: Long term follow-up with ABDIC salvage chemotherapy of MOPP-resistant Hodgkin's disease. J Clin Oncol 1:423, 1983

96. Bonefante V, Santoro A, Viviani S, Devizzi S, Balzarotti M, Soncini F, Zanini M, Valagussa P, Bonadonna G: Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD. Ann Clin Oncol 15:528, 1997

97. Lohri A, Barnett M, Fairey RN, O'Reilly SE, Phillips GL, Reece D, Voss N, Connors JM: Outcome of treatment of first relapse of Hodgkin's disease after primary chemotherapy: Identification of risk factors from the British Columbia experience. Blood 77:2292, 1991[Abstract/Free Full Text]

98. Brice P, Bastion Y, Divine M, Nedellec G, Ferrant A, Gabarre J, Reman O, Lepage E, Ferme C: Analysis of prognostic factors after the first relapse of Hodgkin's disease in 187 patients. Cancer 78:1293, 1996[Medline] [Order article via Infotrieve]

99. Tourani J-M, Levy R, Colonna P, Desablens B, Leprise P-Y, Guilhot F, Brahimi SB, Belhani M, Ifrah N, Sensebe L, Lemevel A, Lotz J-P, Le Maignan C, Andrieu J-M: High-dose salvage chemotherapy without bone marrow transplantation for adult patients with refractory Hodgkin's disease. J Clin Oncol 10:1096, 1992

100. Pfreundschuh MG, Rueffer U, Lathan B, Schmitz N, Brosteanu O, Hasenclever D, Haas R, Kirchner H, Koch P, Kuse R, Loeffler M, Diehl V: Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: A trial of the German Hodgkin's Disease Study Group. J Clin Oncol 12:580, 1994[Abstract]

101. Diehl LF, Perry DJ, Terebelo P, Baldwin PE, Hurwitz M, Kimball DB, Dorn RV: Radiation as salvage therapy for patients with Hodgkin's disease relapsing after MOPP (mechorethamine, vincristine, prednisone and procarbazine) chemotherapy. Cancer Treat Rep 67:27, 1983[Medline] [Order article via Infotrieve]

102. Roach M III, Kapp DS, Rosenberg SA, Hoppe RT: Radiotherapy with curative intent: An option in selected patients relapsing after chemotherapy for advanced Hodgkin's disease. J Clin Oncol 5:550, 1987[Abstract/Free Full Text]

103. Uematsu M, Tarbell NJ, Silver B, Coleman NS, Rosenthal DS, Shulman LN, Canellos G, Weinstein H, Mauch P: Wide-field radiation therapy with or without chemotherapy for patients with Hodgkin's disease in relapse after initial combination chemotherapy. Cancer 72:207, 1993[Medline] [Order article via Infotrieve]

104. Fox KA, Lippman SM, Cassady JR, Heusinveld RS, Miller TP: Radiation therapy salvage of Hodgkin's disease following chemotherapy failure. J Clin Oncol 5:38, 1987[Abstract]

105. Pezner RD, Lipsett JA, Vora N, Forman SJ: Radical radiotherapy as salvage treatment for relapse of Hodgkin's disease initially treated by chemotherapy alone: Prognostic significance of the disease-free interval. Int J Radiat Oncol Biol Phys 30:965, 1994[Medline] [Order article via Infotrieve]

106. Goldstone AH, McMillan AK: The place of high-dose therapy with haemopoietic stem cell transplanation in relapsed and refractory Hodgkin's disease. Ann Oncol 4:S21, 1993[Abstract] (suppl 1)

107. Phillips GL, Wolff SN, Herzig RH, Lazarus HM, Fay JW, Lin H-S, Shina DC, Glasgow GP, Griffith RC, Lamb CW, Herzig GP: Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation. Blood 73:2086, 1989[Abstract/Free Full Text]

108. Chopra R, McMillan AK, Linch DC, Yuklea S, Taghipour G, Pearce R, Patterson KG, Goldstone AH: The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight-year study of 155 patients. Blood 81:1137, 1993[Abstract/Free Full Text]

109. Bierman PJ, Bagin RG, Jagannath S, Vose JM, Spitzer G, Kessinger A, Dicke KA, Armitage JO: High dose chemotherapy followed by autologous hematopoietic rescue in Hodgkin's disease: Long term follow-up in 128 patients. Ann Oncol 4:767, 1993[Abstract/Free Full Text]

110. Horning SJ, Chao NJ, Negrin RS, Hoppe RT, Long GD, Hu WW, Wong RM, Brown BW, Blume KG: High-dose therapy and autologous hematopoietic progenitor cell transplantation for recurrent or refractory Hodgkin's disease: Analysis of the Stanford University results and prognostic indices. Blood 89:801, 1997[Abstract/Free Full Text]

111. Crump M, Smith AM, Brandwein J, Couture F, Sherret H, Sutton DMC, Scott JG, McCrae J, Murray C, Pantalony D, Sutcliffe SB, Keating A: High-dose etoposide and melphalan and autologous bone marrow transplantation for patients with advanced Hodgkin's disease: Importance of disease status at transplant. J Clin Oncol 11:704, 1993[Abstract]

112. Reece DE, Barnett JD, Shepherd JD, Klasa RJ, Nantel SH, Sutherland HJ, Klingemann HG, Fairey RN, Voss NJ, Connors JM, O'Reilly SE, Spinelli JJ, Phillips GL: High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with and without cisplatin (CBV ± P) and autologous transplantation for patients with Hodgkin's disease who fail to enter complete remission after combination chemotherapy. Blood 86:451, 1995[Abstract/Free Full Text]

113. Reece DE, Connors JM, Spinelli JJ, Barnett MJ, Fairey RN, Klingemann H-G, Nantel SH, O'Reilly S, Shepherd JD, Sutherland HJ, Voss N, Chan K-W, Phillips GL: Intensive therapy with cyclophosphamide, carmustine, etoposide ± cisplatin, and autologous bone marrow transplantation for Hodgkin's disease in first relapse after combination chemotherapy. Blood 83:1193, 1994[Abstract/Free Full Text]

114. Nademanee A, O'Donnell MR, Snyder DS, Schmidt GM, Parker PM, Stein AS, Smith EP, Molina A, Stepam DE, Somlo G, Margolin KA, Sniecinski I, Dagis AC, Niland J, Pezner R, Forman SJ: High-dose chemotherapy with and without total body irradiation followed by autologous bone marrow and/or peripheral stem cell transplantation for patients with relapsed or refractory Hodgkin's disease: Results in 85 patients with analysis of prognostic factors. Blood 85:1381, 1995[Abstract/Free Full Text]

115. Chao NJ, Kastrissios H, Long GD, Negrin RS, Horning SJ, Wong RM, Blaschke TF, Blume KG: A new preparatory regimen for autologous bone marrow transplantation for patients with lymphoma. Cancer 75:1354, 1995[Medline] [Order article via Infotrieve]

116. Forman SJ: Role of high-dose therapy and stem-cell transplantation in the management of Hodgkin's disease.Alexandria, VA, American Association of Clinical Oncology Educational Book, 33rd Annual Meeting, Denver, CO, May 17-20, 1997, p 244.

117. Anderson JE, Litzow MR, Appelbaum FR, Schoch G, Fisher LD, Buckner CD, Petersen FB, Crawford SW, Press OW, Sander JE, Bensinger WI, Martin PJ, Storb R, Sullivan KM, Hansen JA, Thomas ED: Allogeneic, syngeneic, and autologous marrow transplantation for Hodgkin's disease: The 21-year Seattle experience. J Clin Oncol 11:2342, 1993[Abstract/Free Full Text]

118. Milpied N, Fielding AK, Pearce RM, Ernst P, Goldstone AH, for the European Group for Blood and Marrow Transplantation: Autologous bone marrow transplantation is not better than autologous transplant for patients with relapsed Hodgkin's disease. J Clin Oncol 14:1291, 1996[Abstract/Free Full Text]

119. Gajewski JL, Phillips GL, Sobocinski KA, Armitage JO, Gale RP, Champlin RE, Herzig RH, Hurd DD, Jagannath S, Klein JP, Lazarus HM, McCarthy PL Jr, Pavlovsky S, Petersen FB, Rowlings PA, Russell JA, Silver SM, Vose JM, Wiernik PH, Bortin MM, Horowitz MM: Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease. J Clin Oncol 14:57, 1996

120. Mundt AJ, Sibley G, Williams S, Hallahan D, Nautiyal J, Weichelsbaum RR: Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin's disease. Int J Radiat Oncol Biol Phys 33:261, 1995[Medline] [Order article via Infotrieve]

121. O'Brien MER, Milan S, Cunningham D, Jones AL, Nicolson P, Hickish T, Hill M, Gore ME, Viner C: High-dose chemotherapy and autologous bone marrow transplant in relapsed Hodgkin's disease---A pragmatic prognostic index. Br J Cancer 73:1272, 1996[Medline] [Order article via Infotrieve]

122. Desch CE, Lasala MR, Smith TJ, Hillner BE: The optimal timing of autologous bone marrow transplantation in Hodgkin's disease patients after chemotherapy relapse. J Clin Oncol 10:200, 1992[Abstract]

123. Linch DC, Winfield D, Goldstone AH, Moir D, Hancock B, McMillan A, Chopra R, Milligan D, Vaughan Hudson G: Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: Results of a BNLI randomized trial. Lancet 341:1051, 1993[Medline] [Order article via Infotrieve]

124. Yuen AR, Rosenberg SA, Hoppe RT, Halpern JD, Horning SJ: Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood 89:814, 1997[Abstract/Free Full Text]

125. Darrington DL, Vose JM, Anderson JA, Bierman PJ, Bishop MR, Chan WC, Morris ME, Reed EC, Sanger WG, Tarantolo SR, Weisenberger DD, Kessinger A, Armitage JO: Incidence and characterization of secondary myeodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12:2527, 1994[Abstract/Free Full Text]

126. Stone RM, Neuberg D, Soiffer R, Takvorian T, Whelan M, Rabinowe S, Aster JC, Leavitt P, Mauch P, Freedman AS, Nadler LM: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 12:2535, 1994[Abstract/Free Full Text]

127. Miller JS, Arthur DC, Litz CE, Neglia JP, Miller WJ, Weisdorf DJ: Myelodysplastic syndrome after autologous bone marrow transplantation: An additional late complication of curative cancer therapy. Blood 83:3780, 1994[Abstract/Free Full Text]

128. Traweek ST, Slovak ML, Nademanee A, Brynes RK, Niland JC, Forman SJ: Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and non-Hodgkin's lymphoma. Blood 84:957, 1994[Abstract/Free Full Text]

129. Rohatiner A: Myelodysplasia and acute myelogenous leukemia after myeloablative therapy with autologous stem-cell transplantation. J Clin Oncol 12:2521, 1994[Free Full Text]

130. Socie G, Henry-Amar M, Bacigalupo A, Hows J, Tichelli A, Ljungman P, Gluckman E: Malignancies occurring after the treatment for aplastic anemia: A survey on 1680 patients conducted by the European Group for Bone Marrow Transplantation (EBMT)-Severe Aplastic Anemia Working Party. Blood 80:169a, 1992 (abstr, suppl 1)

131. Chao NJ, Nademanee AP, Long GD, Schmidt GM, Donlon TA, Parker P, Slovak ML, Nagasawa LS, Blume KG, Forman SJ: Importance of bone marrow cytogenetic evaluation before bone marrow transplantation for Hodgkin's disease. J Clin Oncol 9:1575, 1991[Abstract]

132. Mendenhall NP, Noyes WD, Million RR: Total body irradiation for stage II-IV non-Hodgkin's lymphoma: Ten-year follow-up. J Clin Oncol 7:67, 1989[Abstract]

133. Travis LB, Weeks J, Curtis RE, Chaffey JT, Stovall M, Banks PM, Boyce JD Jr: Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin's lymphoma. J Clin Oncol 14:565, 1996[Abstract/Free Full Text]

134. Bhatia S, Ramsay NKC, Steinbuch M, Dusenberry KE, Shapiro RS, Weisdorf DJ, Robison LL, Miller JS, Neglia JP: Malignant neoplasms following bone marrow transplantation. Blood 87:3633, 1996[Abstract/Free Full Text]

135. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, Horowitz MM, Witherspoon RP, Hoover RN, Sobocinski KA, Fraumeni JF Jr, Boyce JD Jr: Solid cancers after bone marrow transplantation. N Engl J Med 336:897, 1997[Abstract/Free Full Text]

136. Carde P: Who are the high-risk patients with Hodgkin's disease? Leukemia 10:S62, 1996 (suppl 2)

137. Lee SM, Radford JA, Ryder WDJ, Collins CD, Deakin DP, Crowther D: Prognostic factors for disease progression in advanced Hodgkin's disease: An analysis of patients aged 60 years and younger showing no progression in the first 6 months after starting chemotherapy. Br J Cancer 75:110, 1997[Medline] [Order article via Infotrieve]

138. Hasenclever D, Diehl V, for the International Prognostic Factors Project for Advanced Hodgkin's Disease: A prognostic score for advanced Hodgkin's disease. N Engl J Med 339:1506, 1998[Abstract/Free Full Text]

139. Carella AM: The place of high-dose therapy with autologous stem cell transplantation in primary treatment of Hodgkin's disease. Ann Oncol 4:S15, 1993 (suppl 1)

140. Gianni AM, Siena S, Bregni M, Lombardi F, Gandola L, DiNicola M, Magni M, Peccatori F, Valagussa P, Bonnadonna G: High-dose sequential chemotherapy with peripheral blood progenitor cell support for relapsed or refractory Hodgkin's disease---A 6-year update. Ann Oncol 4:889, 1993[Abstract/Free Full Text]

141. Hoppe RT: Hodgkin's disease: Complications of therapy and excess mortality. Ann Oncol 8:S115, 1997 (suppl 1)

142. Mauch PM, Kalish LA, Marcus KC, Shulman LN, Krill E, Tarbell NJ, Silver B, Weinstein H, Come S, Canellos GP, Coleman CN: Long-term survival in Hodgkin's disease: Relative impact of mortality, second tumors, infection and cardiovascular disease. Cancer J Sci Am 1:33, 1995[Medline] [Order article via Infotrieve]

143. Kaldor JM, Day NE, Band P, Choi NW, Clarke EA, Coleman NP, Hakama M, Koch M, Langmark F, Neal FE, Pettersson F, Pompe-Kirn V, Prior P, Storm HH: Second malignancies following testicular cancer, ovarian cancer and Hodgkin's disease: An international collaborative study among cancer registries. Int J Cancer 39:571, 1987[Medline] [Order article via Infotrieve]

144. Somers R, Henry-Amar M, Meerwaldt JT, Carde P: Treatment strategy in Hodgkin's disease. Colloque INSERM/John Libbey Eurotext Ltd 196:357, 1990

145. Henry-Amar M: Second cancer after the treatment of Hodgkin's disease: A report from the International Database on Hodgkin's Disease: Ann Oncol 3:S117, 1992[Abstract] (suppl 4)

146. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, Bennett MH, MacLennan KA: Risk of second primary cancers after Hodgkin's disease by type of treatment: Analysis of 2846 patients in the British National Lymphoma Investigation. Br Med J 304:1137, 1992

147. Biti G, Cellai E, Magrini SM, Papi MG, Ponticelli P, Boddi V: Second solid tumors and leukemias after treatment for Hodgkin's disease: An analysis of 1121 patients from a single institution. Int J Radiat Oncol Biol Phys 29:25, 1994[Medline] [Order article via Infotrieve]

148. Van Leeuwen FE, Klokman WJ, Hagenbeek A, Noyon R, van den Belt-Dusebout AW, van Kerkhoff EHM, van Heerde P, Somer R: Second cancer risk following Hodgkin's disease: A 20-year follow-up study. J Clin Oncol 12:312, 1994[Abstract]

149. Pedersen-Bjergaard J, Larsen SO: Incidence of acute non-lymphocytic leukemia, preleukemia and acute myeloproliferative syndrome up to 10 years after treatment of Hodgkin's disease. N Engl J Med 307:965, 1982[Abstract]

150. Kaldor JM, Day NE, Clarke A, Van Leeuwen FE, Henry-Amar M, Fiorentino MV, Bell J, Pedersen D, Band P, Assouline D, Koch M, Choi W, Prior P, Blair V, Langmark F, Kirn VP, Neal F, Peters D, Pfeiffer R, Karjalainen S, Cuzick J, Sutcliffe SB, Somers R, Pellae-Cosset B, Papagallo GL, Fraser P, Storm H, Stovall M: Leukemia following Hodgkin's disease. N Engl J Med 322:7, 1990[Abstract]

151. Kantarjian HM, Keating MJ: Therapy-related leukemia and myelodysplastic syndromes. Semin Oncol 14:435, 1987[Medline] [Order article via Infotrieve]

152. O'Donnell MR, Long GD, Parker PM, Niland J, Nademanee A, Amylon M, Chao N, Negrin RS, Schmidt GM, Slovak ML, Smith EP, Snyder DS, Stein AS, Traweek T, Blume KG, Forman SJ: Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia. J Clin Oncol 13:2973, 1995[Abstract]

153. Sugar M, Buckner CD, Applebaum FR, Stewart P, Deeg HJ, Weiden PL, Sullivan KM, Fefer A, Thomas ED: Marrow transplantation for acute nonlymphocytic leukemia following therapy for Hodgkin's disease. J Clin Oncol 5:731, 1987[Abstract/Free Full Text]

154. Van Leeuwen FE, Chorus AMJ, van den Belt-Dusebout AW, Hagenbeek A, Noyon R, van Kerkhoff EHM, Pinedo HM, Somers R: Leukemia risk following Hodgkin's disease: Relation to cumulative dose of alkylating agents, treatment with teniposide combinations, and bone marrow damage. J Clin Oncol 12:1063, 1994[Abstract/Free Full Text]

155. Van Leeuwen FE: Adverse effects of treatment: Second cancers, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott, 1997, p 2773.

156. Tucker MA, Coleman CN, Cox RS, Varghese A, Rosenberg SA: Risk of second cancers after treatment for Hodgkin's disease. N Engl J Med 318:76, 1988[Abstract]

157. Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, Meadows AT: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334:745, 1996[Abstract/Free Full Text]

158. Valagussa P, Santoro A, Fossati-Bellani F, Banfi A, Bonadonna G: Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 4:830, 1986[Abstract/Free Full Text]

159. Valagussa P, Bonadonna G: Carcinogenic effects of cancer treatment, in Peckham M, Pinedo H, Veronesi U (eds): Oxford Textbook of Oncology. Oxford, UK, Oxford University Press, 1995, p 2348.

160. Tester WJ, Kinsella TJ, Waller B, Makuch RW, Kelley PA, Glatstein E, DeVita VT: Second malignant neoplasms complicating Hodgkin's disease: The National Cancer Institute experience. J Clin Oncol 2:762, 1984[Abstract]

161. Young RC, Bookman MA, Longo DL: Late complications of Hodgkin's disease. J Natl Cancer Inst Monogr 10:55, 1990

162. Cimino G, Papa G, Tura S, Mazza P, Rossi Ferrini PL, Bosi A, Amadori S, Lo Coco F, D'Arcangelo E, Giannarelli D, Mandelli F: Second primary cancer following Hodgkin's disease: Updated result of an Italian multicentric study. J Clin Oncol 9:432, 1991[Abstract]

163. Mauch PM, Canellos GP, Rosenthal DS, Hellman S: Reduction in fatal complications from combined mortality therapy of Hodgkin's disease. J Clin Oncol 3:501, 1985[Abstract]

164. Andrieu J-M, Ifrah N, Payen C, Fermanian J, Coscas Y, Flandrin G: Increased risk of secondary acute nonlymphocytic leukemia after extended-field radiation therapy combined with MOPP chemotherapy of Hodgkin's disease. J Clin Oncol 8:1148, 1990[Abstract]

165. Tura S, Fiacchini M, Zinzani PL, Brusamolino E, Gobbi PG: Splenectomy and the increasing risk of secondary acute leukemia in Hodgkin's disease. J Clin Oncol 11:925, 1993[Abstract/Free Full Text]

166. Winick NJ, McKenna RW, Shuster JJ, Schneider NR, Borowitz MJ, Bowman WP, Jacaruso D, Kamen BA, Buchanan GR: Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. J Clin Oncol 11:209, 1993[Abstract/Free Full Text]

167. Krikorian JG, Burke JS, Rosenberg SA, Kaplan HS: Occurrence of non-Hodgkin's lymphoma after therapy for Hodgkin's disease. N Engl J Med 300:452, 1979[Abstract]

168. Zarrabi MH, Rosner F: Second neoplasms in Hodgkin's disease: Current controversies. Hematol Oncol Clin North Am 3:303, 1989[Medline] [Order article via Infotrieve]

169. Tucker MA: Solid second cancers following Hodgkin's disease. Hematol Oncol Clin North Am 7:389, 1993[Medline] [Order article via Infotrieve]

170. Hancock SL, Tucker MA, Hoppe RT: Breast cancer after Hodgkin's disease treatment. J Natl Cancer Inst 85:25, 1993[Abstract/Free Full Text]

171. Birdwell SH, Hancock SL, Varghese A, Cox RS, Hoppe RT: Gastrointestinal cancer after treatment of Hodgkin's disease. Int J Radiat Oncol Biol Phys 37:67, 1997[Medline] [Order article via Infotrieve]

172. Jacquillat C, Khayat D, Desprez-Curely JP, Weil M, Brocheriou C, Auclerc G, Chamseddine N, Bernard J: Non-Hodgkin's lymphoma occurring after Hodgkin's disease: Four new cases and a review of the literature. Cancer 53:459, 1984[Medline] [Order article via Infotrieve]

173. Aisenberg AC: Coherent view of non-Hodgkin's lymphoma. J Clin Oncol 13:2656, 1995[Abstract]

174. Gaidano G, Dalla-Favera R: Lymphoma: Molecular biology, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott, 1997, p 2131.

175. Wickert RS, Weisenberger DD, Tierens A, Greiner TC, Chan WC: Clonal relationship between lymphocytic predominance Hodgkin's disease and concurrent or subsequent large-cell lymphoma of B lineage. Blood 86:2312, 1995[Abstract/Free Full Text]

176. Louie S, Daoust PR, Schwartz RS: Immunodeficiency and the pathogenesis of non-Hodgkin's lymphoma. Semin Oncol 7:267, 1980[Medline] [Order article via Infotrieve]

177. List AF, Greco FA, Vogler LB: Lymphoproliferative diseases in immunocompromised hosts: The role of Epstein-Barr virus. J Clin Oncol 5:1673, 1987[Abstract/Free Full Text]

178. Filipovich AH, Heinitz KJ, Robison LL, Frizzera G: The Immunodeficiency Cancer Registry: A research resource. Am J Ped Hematol Oncol 9:183, 1987[Medline] [Order article via Infotrieve]

179. Penn I: Cancers complicating organ transplantation. N Engl J Med 323:1767, 1990[Medline] [Order article via Infotrieve]

180. Ferry JA, Harris NL: Atlas of Lymphoid Hyperplasia and Lymphoma. Philadelphia, PA, Saunders, 1997, p 214.

181. Salloum E, Tallini G, Levy A, Cooper DL: Burkitt's lymphoma-leukemia in patients treated for Hodgkin's disease. Cancer Invest 14:527, 1996[Medline] [Order article via Infotrieve]

182. Jarrett AF, Armstrong AA, Alexander E: Epidemiology of EBV and Hodgkin's lymphoma. Ann Oncol 7:S5, 1996 (suppl 4)

183. List AF, Greer JP, Cousar JB, Stein RS, Flexner JM, Sinangil F, Davis J, Volsky DJ, Purtilo DT: Non-Hodgkin's lymphoma after treatment of Hodgkin's disease: Association with Epstein-Barr virus. Ann Intern Med 105:668, 1986

184. Mauch PM, Kalish LA, Marcus KC, Coleman CN, Shulman LN, Krill E, Come S, Silver B, Canellos GP, Tarbell NJ: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: Long-term analysis of risk factors and outcome. Blood 87:3625, 1996[Abstract/Free Full Text]

185. Young RC, Bookman MA, Longo DL: Late complications of Hodgkin's disease management. J Natl Cancer Inst Monogr 10:55, 1990

186. National Research Council: Health Effects of Exposure to Low Levels of Ionizing Radiation (BEIR V). Washington, DC, National Academy Press, 1990.

187. United Nations Scientific Committee on the Effects of Atomic Radiation: Sources and effects of ionizing radiation: UNCLEAR 1994 Report to the General Assembly With Scientific Annexes. New York, NY, United Nations, 1994.

188. Boice JD Jr: Carcinogenesis: A synopsis of human experience with external exposure in medicine. Health Phys 121:120, 1990

189. Kaldor JM, Day NE, Bell J, Clarke EA, Langmark F, Karjalainen S, Band P, Pedersen D, Choi W, Blair V, Henry-Amar M, Prior P, Assouline D, Pomp-Kirn V, Cartwright RA, Koch M, Arslan A, Fraser P, Sutcliffe SB, Host H, Hakama M, Stovall M: Lung cancer following Hodgkin's disease: A case-control study. Int J Cancer 52:677, 1992[Medline] [Order article via Infotrieve]

190. Van Leeuwen FE, Klokman WJ, Stovall M, Hagenbeek A, van den Belt-Dusebout AW, Noyon R, Boice JD Jr, Burgers JMV, Somers R: Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 87:1530, 1995[Abstract/Free Full Text]

191. Thomas D, Pagoda J, Langholz B, Mack W: Temporal modifiers of the radon-smoking interaction. Health Phys 67:675, 1994

192. Yao SX, Lubin JH, Qiao YL, Boice JD Jr, Li JY, Cai SK: Exposure to radon progeny, tobacco use and lung cancer in a case control study in southern China. Radiat Res 138:326, 1994[Medline] [Order article via Infotrieve]

193. Sankila R, Garwicz S, Olsen JH, Dollner H, Hertz H, Kreuger A, Langmark F, Lanning M, Moller T, Tulinius H, and for the Association of the Nordic Cancer Registies and the Nordic Society of Pediatric Hematology and Oncology: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: A population-based cohort study of five Nordic countries. J Clin Oncol 14:1442, 1996[Abstract/Free Full Text]

194. Aisenberg AC, Finkelstein DM, Doppke KP, Koerner FC, Boivin J-F, Willett CG: High risk of breast carcinoma after irradiation of young women with Hodgkin's disease. Cancer 79:1203, 1997[Medline] [Order article via Infotrieve]

195. Pike MC, Krailo MD, Henderson BE, Casagrande JT, Hoel DG: `Hormonal' risk factors, `breast tissue age' and the age incidence of breast cancer. Nature 303:767, 1983[Medline] [Order article via Infotrieve]

196. Boice JD Jr: Second cancer after Hodgkin's disease---The price of success? J Natl Cancer Inst 85:4, 1993[Free Full Text]

197. Zellmer DL, Wilson JF, Janjan NA: Dosimetry of the breast for determining carcinogenic risk of mantle irradiation. Int J Radiat Oncol Biol Phys 21:1343, 1991[Medline] [Order article via Infotrieve]

198. Van Leeuwen FE, Stiggelbout AM, van den Belt-Dusebout AW, Noyon R, Eliel MR, van Kerkhoff EHM, Delemarre JFM, Somer R: Second cancers following testicular cancer. J Clin Oncol 11:415, 1993[Abstract/Free Full Text]

199. Dietrich PY, Belleqih S, Henry-Amar M, Cosset JM, Hayat M: Linitis plastica after Hodgkin's disease. Lancet 342:57, 1993[Medline] [Order article via Infotrieve]

200. Wolden SL, Lamborn KR, Cleary SF, Tate DJ, Donaldson SS: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16:536, 1998[Abstract]

201. Tucker MA, D'Angio GJ, Boice JD Jr, Strong LC, Li FP, Stovall M, Stone BJ, Green DM, Lombardi F, Newton W, Hoover RN, Fraumeni JF Jr, for the Late Effects Study Group: Bone sarcomas linked to radiation and chemotherapy of children. N Engl J Med 317:588, 1997[Abstract]

202. Tucker MA, Morris Jones PH, Boice JD Jr, Robison LL, Stone BJ, Stovall M, Jenkin RDT, Lubin JH, Baum ES, Siegel SE, Meadows AT, Hoover RN, Fraumeni JF Jr, for the Late Effects Study Group: Therapeutic radiation at a young age linked to secondary thyroid cancer. Cancer Res 51:2885, 1991[Abstract/Free Full Text]

203. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325:599, 1991[Abstract]

204. Tucker MA, Misfeldt D, Coleman N, Clark WH Jr, Rosenberg SA: Cutaneous malignant melanoma after Hodgkin's disease. Ann Intern Med 102:37, 1985

205. Henry-Amar M, Joly F: Late complications after Hodgkin's disease. Ann Oncol 7:S115, 1996 (suppl 4)

206. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270:1949, 1993[Abstract/Free Full Text]

207. Stewart JR, Fajardo LF: Radiation-induced heart disease: An update. Prog Cardiovasc Dis 27:173, 1984[Medline] [Order article via Infotrieve]

208. Stewart JR, Fajardo LF, Gillette SM, Constine LS: Radiation injury to the heart. Int J Radiat Oncol Biol Phys 31:1205, 1995[Medline] [Order article via Infotrieve]

209. Boivin J-F, Hutchison GB, Lubin JH, Mauch P: Coronary artery disease mortality in patients treated for Hodgkin's disease. Cancer 69:1241, 1992[Medline] [Order article via Infotrieve]

210. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11:1208, 1993[Abstract/Free Full Text]

211. Hancock SL, Hoppe RT: Long-term complications of treatment and causes of mortality after Hodgkin's disease. Semin Radiat Oncol 6:225, 1996[Medline] [Order article via Infotrieve]

212. Cosset JM, Henry-Amar M, Pellae-Cosset B, Carde P, Girinski T, Tubiana M, Hayat M: Pericarditis and myocardial infarctions after Hodgkin's disease therapy. Int J Radiat Oncol Biol Phys 21:447, 1991[Medline] [Order article via Infotrieve]

213. Carlson RG, Mayfield WR, Norman S, Alexander JA: Radiation-associated valvular disease. Chest 99:538, 1991[Abstract/Free Full Text]

214. Ginsberg SJ, Comis RL: The pulmonary toxicity of antineoplastic agents. Semin Oncol 9:34, 1982[Medline] [Order article via Infotrieve]

215. Jules-Elysee K, White DA: Bleomycin-induced pulmonary toxicity. Clin Chest Med 11:1, 1990[Medline] [Order article via Infotrieve]

216. Hirsch A, Els NV, Straus DJ, Gomez EG, Leung D, Portlock CS, Yahalom J: Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin's disease. J Clin Oncol 14:1297, 1996[Abstract/Free Full Text]

217. Jockovich M, Mendenhall NP, Sombeck MD, Talbert JL, Copeland EM III, Bland KI: Long-term complications of laparotomy in Hodgkin's disease. Ann Surg 219:615, 1994[Medline] [Order article via Infotrieve]

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