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.

Fig. 1.

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

Fig. 1.

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

Close modal

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.

Table 1.

Staging Classification of HD

Stage I.  Involvement of a single lymph node region or lymphoid structure (spleen, thymus, Waldeyer’s ring), or involvement of a single extralymphatic site (IE).  
Stage II. Involvement of two or more lymph node regions on the same side of the diaphragm (II) which may be accompanied by localized contiguous involvement of an extralymphatic organ or site (IIE). The number of anatomic sites may be indicated by a numerical subscript. 
Stage III.  Involvement of lymph node regions on both sides of the diaphragm (III) which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of an extralymphatic organ or site (IIIE).  
Stage IV. Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement. 
Stage I.  Involvement of a single lymph node region or lymphoid structure (spleen, thymus, Waldeyer’s ring), or involvement of a single extralymphatic site (IE).  
Stage II. Involvement of two or more lymph node regions on the same side of the diaphragm (II) which may be accompanied by localized contiguous involvement of an extralymphatic organ or site (IIE). The number of anatomic sites may be indicated by a numerical subscript. 
Stage III.  Involvement of lymph node regions on both sides of the diaphragm (III) which may also be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of an extralymphatic organ or site (IIIE).  
Stage IV. Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement. 

Notes: (1) The absence or presence of fever (>38°C) and/or unexplained weight loss (>10% of body weight) in the preceding 6 months are denoted by the suffix letters A and B, respectively. (2) If staging laparotomy/splenectomy has been performed the designation is pathological stage (PS), if not clinical stage (CS). (3) Stage III may be subdivided into III1 to designate involvement of only the upper abdominal nodes and/or spleen, and III2 to designate involvement of the paraaortic and/or pelvic nodes. (4) A mediastinal mass >13maximum chest diameter or a lymphoid mass >10 cm in diameter may be designated by the subscript “x.”

Data from Carbone et al,6 Lister et al,7 and Gobbi et al.8 

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 (Table2) 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 

Table 2.

REAL Classification of HD

Lymphocyte predominance (LPHD)  
Classical HD  
 Nodular sclerosis  
 Mixed cellularity  
 Lymphocyte depletion 
 Lymphocyte-rich classical HD* 
Anaplastic large cell lymphoma Hodgkin’s-like 
Lymphocyte predominance (LPHD)  
Classical HD  
 Nodular sclerosis  
 Mixed cellularity  
 Lymphocyte depletion 
 Lymphocyte-rich classical HD* 
Anaplastic large cell lymphoma Hodgkin’s-like 
*

Provisional subtype.

Subtype of NHL.

Data from Harris et al.20 

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).

Table 3.

Primary Treatment of HD

Clinical Stage Primary Treatment
I and II  
 Very favorable  
  Female; IA, IIA NSHD or ≤3 nodal sites and <26 yr   Male; IA LPHD, neck or groin   Age 11-60 yr   ESR <50   No restrictions listed below  EF RT Consider:  Mantle (IF) RT after negative lap; ABVD ×6 for smokers and females <27 
 Favorable  
  ≤3 nodal sites   ESR <50   No restrictions listed below  EF RT after negative lap, or ABVD ×6 + RT to residual3-150disease, Consider:  ABVD ×4 + mantle (IF) RTABVD ×6 for smokers and females <27 
 Unfavorable  
  >3 nodal sites   LMA or bulky (≥10 cm) adenopathy   ESR >50  Fever and/or weight loss   Bilateral hilar adenopathy   Involvement of pericardium, pleura, lung or bone   Gross lymphatic permeation and obstruction ABVD3-151 ×6 + RT to residual3-150 disease, or ABVD3-151×6-8 + mantle for LMA Consider:  ABVD ×4 + mantle (IF) RT 
IIIA  ABVD ×6-8 + RT to residual3-150disease Consider lap for equivocal CT and LAG only  
IIIB and IV  ABVD3-151 ×6-8 + RT to limited residual3-150disease 
Clinical Stage Primary Treatment
I and II  
 Very favorable  
  Female; IA, IIA NSHD or ≤3 nodal sites and <26 yr   Male; IA LPHD, neck or groin   Age 11-60 yr   ESR <50   No restrictions listed below  EF RT Consider:  Mantle (IF) RT after negative lap; ABVD ×6 for smokers and females <27 
 Favorable  
  ≤3 nodal sites   ESR <50   No restrictions listed below  EF RT after negative lap, or ABVD ×6 + RT to residual3-150disease, Consider:  ABVD ×4 + mantle (IF) RTABVD ×6 for smokers and females <27 
 Unfavorable  
  >3 nodal sites   LMA or bulky (≥10 cm) adenopathy   ESR >50  Fever and/or weight loss   Bilateral hilar adenopathy   Involvement of pericardium, pleura, lung or bone   Gross lymphatic permeation and obstruction ABVD3-151 ×6 + RT to residual3-150 disease, or ABVD3-151×6-8 + mantle for LMA Consider:  ABVD ×4 + mantle (IF) RT 
IIIA  ABVD ×6-8 + RT to residual3-150disease Consider lap for equivocal CT and LAG only  
IIIB and IV  ABVD3-151 ×6-8 + RT to limited residual3-150disease 

Treatments in italics are supported by limited or indirect data. See text for details.

Abbreviations: EF, extended field; IF, involved field; LAG, lymphangiogram; Lap, laparotomy; LMA, large mediastinal adenopathy (≥13 chest diameter); PET, positive emission tomography; RT, radiation therapy; MOPP, nitrogen mustard 6 mg/m2 and vincristine 1.4 mg/m2 (maximum 2 mg) intravenous (IV) days 1 and 8, procarbazine 100 mg/m2orally days 1-10, prednisone 40 mg/m2 orally days 1-14; 28-day cycles; ABVD, doxorubicin 25 mg/m2, vinblastine 6 mg/m2 bleomycin 15 U and DTIC (immidazole carboxamide) 375 mg/m2 all IV; days 1 and 14 of a 28-day cycle; MOPP/ABVD, alternating 28-day cycles of MOPP and ABVD.

F3-150

Residual radiographic abnormalities on CT scan without gallium or PET positivity are not considered residual disease.

F3-151

Consider MOPP/ABVD × 6-8 in those <40 years with poor prognostic features.

Localized presentations of HD (CS I and II) have been divided intovery 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 (≥13 of the maximum chest diameter),9,40-43 high tumor burden,35,41 >3 sites of involvement,9,42 age >50,33,42ESR >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 (Table1).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.52MOPP 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 (Table4).

Table 4.

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

Study (reference) Stage Follow-up (yr) Patients (no.) Treatment (cycles) CR (%) FFS (%)OS (%) Toxic Deaths (%)
NCI53 III, IV  15  188  MOPP (6-12)  84  54  48 
CALBG44,54  IIIA2, IIIB, IV  123 115 123  MOPP (6-8) ABVD (6-8) MOPP/ABVD (6 + 6)  66 82 83 37 52 50  664-151 734-151 754-151 3 3 2  
Milan55 IV   43  45  MOPP (12) MOPP/ABVD (6 + 6) 74 89  45 64  64 84  0 0  
NCI Canada574-150 IIIB, IV  148 153  MOPP/ABVD (8) MOPP/ABV (8) 76 80  67 71  83 81  1 3  
ECOG Inter58 IIIA2, IIIB, IV  8  344 347  MOPP/ABVD Seq (6 + 3) MOPP/ABV (8-12)  75 79  54 64  71 79  1 2  
BNLI594-150 IIB, III, IV  295 299  LOPP (8) LOPP/EVAP (4 + 4) 65 75  52 72  66 75  1 3  
Christie/St Barts614-150 I-IIB/bulk, III, IV  5  208 211  MVPP (8) ChlVPP/EVA (4 + 4)  55 68  66 80  71 80  4 1  
CALBG Inter62 III, IV  428 428  ABVD (8-10) MOPP/ABV (8-10) 71 73  65 67  87 85  2 4 
Study (reference) Stage Follow-up (yr) Patients (no.) Treatment (cycles) CR (%) FFS (%)OS (%) Toxic Deaths (%)
NCI53 III, IV  15  188  MOPP (6-12)  84  54  48 
CALBG44,54  IIIA2, IIIB, IV  123 115 123  MOPP (6-8) ABVD (6-8) MOPP/ABVD (6 + 6)  66 82 83 37 52 50  664-151 734-151 754-151 3 3 2  
Milan55 IV   43  45  MOPP (12) MOPP/ABVD (6 + 6) 74 89  45 64  64 84  0 0  
NCI Canada574-150 IIIB, IV  148 153  MOPP/ABVD (8) MOPP/ABV (8) 76 80  67 71  83 81  1 3  
ECOG Inter58 IIIA2, IIIB, IV  8  344 347  MOPP/ABVD Seq (6 + 3) MOPP/ABV (8-12)  75 79  54 64  71 79  1 2  
BNLI594-150 IIB, III, IV  295 299  LOPP (8) LOPP/EVAP (4 + 4) 65 75  52 72  66 75  1 3  
Christie/St Barts614-150 I-IIB/bulk, III, IV  5  208 211  MVPP (8) ChlVPP/EVA (4 + 4)  55 68  66 80  71 80  4 1  
CALBG Inter62 III, IV  428 428  ABVD (8-10) MOPP/ABV (8-10) 71 73  65 67  87 85  2 4 

Abbreviations: CR, complete remission; FFS, failure-free survival; OS, overall survival; NCI, National Cancer Institute; CALBG, Cancer and Acute Leukemia Group B; Milan, Milan Cancer Institute; ECOG, Eastern Cooperative Oncology Group; Inter, Intergroup; BNLI, British National Lymphoma Investigation; St Barts, St Bartholomew’s Hospital; MOPP (mechlorethamine, vincristine, prednisone, procarbazine); ABVD, (doxorubicin, bleomycin, vinblastine, dacarbazine); MOPP/ABVD, alternating 28-day cycles of MOPP and ABVD; MOPP/ABV, MOPP/ABV hybrid (7 drugs over 14 days of each 28-day cycle); MOPP/ABV Seq, 6 cycles of MOPP followed by 3 cycles of ABVD; LOPP, (chlorambucil, vincristine, prednisone procarbazine); EVAP, (etoposide, vinblastine, doxorubicin, prednisone); MVPP, (mechlorethamine, vinblastine, prednisone, procarbazine); ChlVPP (chlorambucil, vinblastine, prednisone, procarbazine); EVA, (etoposide, vincristine, doxorubicin).

F4-150

Radiation to residual disease permitted.

F4-151

Five-year survival.

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 

Table 5.

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

Study (reference) Stage Treatment (cycles)Patients (no.) Follow-up (yr) CR (%)FFS (%) OS (%) Toxic Deaths (%)
Milan71,72  IIB, IIIA/B  MOPP/EFRT/MOPP (3 + 3) 114  10  81  62  64  3  
  ABVD/EFRT/ABVD (3 + 3)  118   92  81  71  
Milan63 IIA, B/bulky & III & IV  MOPP/ABVD (6-8) + RT (bulky)  427  10  90  68  73  
Yale69 IIIB & IV  MOPP, MVVPP or MOPP/ABVD + LDIF  184  10 15  82  695-150 675-150 66 54  
SKI70 IIB/bulky III & IV MOPP/ABVD (6-8) + LDIF  270  10  82  70  74 
SWOG735-151 III, IV in CR  MOP-BAP (6) MOP-BAP (6) + LDIF  130 104  5  NA NA 66 74  79 86  
EORTC745-151 III, IV in PR MOPP/ABV (6) + LDIF  122  3.5  NA  75  87 
Study (reference) Stage Treatment (cycles)Patients (no.) Follow-up (yr) CR (%)FFS (%) OS (%) Toxic Deaths (%)
Milan71,72  IIB, IIIA/B  MOPP/EFRT/MOPP (3 + 3) 114  10  81  62  64  3  
  ABVD/EFRT/ABVD (3 + 3)  118   92  81  71  
Milan63 IIA, B/bulky & III & IV  MOPP/ABVD (6-8) + RT (bulky)  427  10  90  68  73  
Yale69 IIIB & IV  MOPP, MVVPP or MOPP/ABVD + LDIF  184  10 15  82  695-150 675-150 66 54  
SKI70 IIB/bulky III & IV MOPP/ABVD (6-8) + LDIF  270  10  82  70  74 
SWOG735-151 III, IV in CR  MOP-BAP (6) MOP-BAP (6) + LDIF  130 104  5  NA NA 66 74  79 86  
EORTC745-151 III, IV in PR MOPP/ABV (6) + LDIF  122  3.5  NA  75  87 

Abbreviations: PR, partial remission; EFRT, extended field radiation therapy; LDIF, low-dose involved field radiation therapy; RT (bulky), radiation therapy to bulky disease; SKI, Memorial/Sloan-Kettering Cancer Institute, SWOG, Southwestern Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; MVVPP, (methclorethamine, vincristine, vinblastine, prednisone, procarbazine); MOP-BAP, (mechlorethamine, vincristine, prednisone, bleomycin, doxorubicin, procarbazine); NA, not applicable; see Table 4.

F5-150

Progression-free survival.

F5-151

All patients in CR after MOP-BAP (SWOG) or in PR after MOPP/ABV (EORTC). See text for details.

As mentioned earlier, there is general agreement of the need for combined treatment in the 25% to 30% of patients presenting with mediastinal masses >13 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% v57%, 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.90,91Derived 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 

Table 6.

Autologous BM/Stem Cell Transplantation in HD

Center (reference) Patients (no.) Follow-up (yr)Toxic Deaths (%) OS (%) EFS (%) Risk Factors
St Louis, Cleveland, Duke107 26  23  38  38  Performance status, disease duration 
UCL108 155  5  10  55  50  Bulk >10 cm, >2 lines of treatment, female sex 
Nebraska/MDA109 128  4  9  45  25 Performance status, >1 chemotherapy regimen 
Stanford110  0 RF  1 RF  2 RF  3 RF  119 23 39 23 6  4  9  52 77 56-64 35-53 17  44 71 47-54 23-29  7  B symptoms at relapse, extranodal disease in lung or BM, bulk disease at transplant 
Toronto111 73  4  10   39  
 23    68  No disease at transplant  
 44    26  No bulk at transplant  
     0  Bulk at transplant  
Vancouver 
 IF112 30  3.6  17   486-150 Bleomycin lung toxicity  
 CR113   ≥1 yr   <1 yr  58 23 35  2.3  5  72  646-150 856-150 486-150 Duration of remission, B symptoms at relapse, extranodal disease at relapse  
City of Hope114 85  2  13  67  52  No prior chemotherapy, extranodal disease at transplant 
Center (reference) Patients (no.) Follow-up (yr)Toxic Deaths (%) OS (%) EFS (%) Risk Factors
St Louis, Cleveland, Duke107 26  23  38  38  Performance status, disease duration 
UCL108 155  5  10  55  50  Bulk >10 cm, >2 lines of treatment, female sex 
Nebraska/MDA109 128  4  9  45  25 Performance status, >1 chemotherapy regimen 
Stanford110  0 RF  1 RF  2 RF  3 RF  119 23 39 23 6  4  9  52 77 56-64 35-53 17  44 71 47-54 23-29  7  B symptoms at relapse, extranodal disease in lung or BM, bulk disease at transplant 
Toronto111 73  4  10   39  
 23    68  No disease at transplant  
 44    26  No bulk at transplant  
     0  Bulk at transplant  
Vancouver 
 IF112 30  3.6  17   486-150 Bleomycin lung toxicity  
 CR113   ≥1 yr   <1 yr  58 23 35  2.3  5  72  646-150 856-150 486-150 Duration of remission, B symptoms at relapse, extranodal disease at relapse  
City of Hope114 85  2  13  67  52  No prior chemotherapy, extranodal disease at transplant 

Abbreviations: CR, complete remission; IF, induction failure; RF, risk factors; MDA, MD Anderson Tumor Institute; UCL, University College London.

F6-150

Progression-free survival.

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 (Table7). 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.131Thus, 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 

Table 7.

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

Institution (reference) Patients (no.) MDS/ANLL (no.) Actuarial IncidenceMedian Time From Autografting (yr)
(%) (yr)
Nebraska125 511  12  8-10  3.7  
Dana-Farber126 262  20  18  2.6  
Minnesota127 206  9  14.5  2.8  
City of Hope128 275  10  9  1.4 
Institution (reference) Patients (no.) MDS/ANLL (no.) Actuarial IncidenceMedian Time From Autografting (yr)
(%) (yr)
Nebraska125 511  12  8-10  3.7  
Dana-Farber126 262  20  18  2.6  
Minnesota127 206  9  14.5  2.8  
City of Hope128 275  10  9  1.4 

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.

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 Fig2, 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).

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)

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)

Close modal
Table 8.

Causes of Death in Treated HD

Stanford1418-150Joint Center1428-151
Patients Deaths (%)Patients Deaths (%)
(no.) (%)(no.) (%)
Total patients  2,498  100  794  100  
Total deaths  754  30.2  100  124 15.6  100  
 HD  333  13.3  44  56  7.0  45 
 Second malignancy  160  6.5  21  36  4.5  29 
 Cardiovascular  117  4.8  16  15  1.9  12 
 Pulmonary  50  2.0  7  1  0.1  
 Infectious  31  1.3  4  8  1.0  
 Accidental  14  0.6  2  3  0.4  2  
 Other 49  2.0  7  4  0.5  
Stanford1418-150Joint Center1428-151
Patients Deaths (%)Patients Deaths (%)
(no.) (%)(no.) (%)
Total patients  2,498  100  794  100  
Total deaths  754  30.2  100  124 15.6  100  
 HD  333  13.3  44  56  7.0  45 
 Second malignancy  160  6.5  21  36  4.5  29 
 Cardiovascular  117  4.8  16  15  1.9  12 
 Pulmonary  50  2.0  7  1  0.1  
 Infectious  31  1.3  4  8  1.0  
 Accidental  14  0.6  2  3  0.4  2  
 Other 49  2.0  7  4  0.5  
F8-150

All stages treated from 1960-1995: estimated mean follow-up, 12 years.

F8-151

Laparotomy stage IA-IIIB only treated from 1969-1988: mean follow-up, 11 years.

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%.148Like ANLL, the cumulative risk of secondary NHL appears to plateau by the middle of the second decade after treatment.

Table 9.

Risk of Second Malignancies After HD Treatment

Site or Type Relative Risk Absolute Excess Risk9-150 (per 10,000 patients per yr)
All malignancies  3.5  56.2  
ANLL 70.8  15.5  
NHL  18.6  10.7  
Solid tumors  2.4 29.3  
 Lung  4.2  13.5  
 Breast  2.5  11.3 
 GI  2.5  5.8  
 Sarcoma  7.0  1.0  
 Thyroid 4.7  0.5  
 Melanoma  4.2  1.6 
Site or Type Relative Risk Absolute Excess Risk9-150 (per 10,000 patients per yr)
All malignancies  3.5  56.2  
ANLL 70.8  15.5  
NHL  18.6  10.7  
Solid tumors  2.4 29.3  
 Lung  4.2  13.5  
 Breast  2.5  11.3 
 GI  2.5  5.8  
 Sarcoma  7.0  1.0  
 Thyroid 4.7  0.5  
 Melanoma  4.2  1.6 

Abbreviation: GI, gastrointestinal tract.

F9-150

Absolute (excess) risk per 10,000 patient years = [observed events −  expected events/person-years] × 10,000. The absolute risk divided by 100 is the percentage likelihood of an event per year of follow-up for an individual patient.

Data derived from reference 155, except for GI tumor data derived from reference 171.

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,146,148,168although 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.192For 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.194This 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 

Cardiovascular complications of mantle irradiation comprise the second most frequent cause of treatment-related mortality in HD patients followed through the second decade (Table8).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).

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 

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.

1
Ries
LAG
Miller
BA
Hankey
BF
Kosary
CL
Harras
A
Edwards
BK
SEER Cancer Statistics Review, 1973-1994, National Cancer Institute. NIH Pub. No. 97-2789.
1997
NIH
Bethesda, MD
2
Landis
SH
Murray
T
Bolden
S
Wingo
PA
Cancer statistics 1998.
CA Cancer J Clin
48
1998
6
3
Glatstein
E
Guernsey
JM
Rosenberg
SA
Kaplan
HS
The value of laparotomy and splenectomy in the staging of Hodgkin’s disease.
Cancer
24
1969
709
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
1989
81
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
1990
257
6
Carbone
PP
Kaplan
HS
Musshoff
K
Smithers
DW
Tubiana
M
Report of the Committee on Hodgkin’s Disease Staging Classification.
Cancer Res
31
1971
1860
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
1989
1630
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
1985
2874
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
1982
455
10
Gilbert
R
Radiotherapy in Hodgkin’s disease (malignant lymphogranulomatosis).
Am J Roentgenol
41
1939
198
11
Peters
MV
A study of survival in Hodgkin’s disease treated radiologically.
Am J Roentgenol
63
1950
299
12
Kaplan
HS
The radical radiotherapy of regionally localized Hodgkin’s disease.
Radiology
78
1962
553
13
DeVita
VT
Sepick
AA
Carbone
PP
Combination chemotherapy for advanced Hodgkin’s disease.
Ann Intern Med
73
1970
881
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
1996
131
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
1997
518
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
1997
1754
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
1997
S57
(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
1997
795
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
1994
1361
21
Ferry
JA
Harris
NL
The pathology of Hodgkin’s disease: What’s new?
Semin Radiat Oncol
6
1996
121
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
1996
S61
(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
1997
3060
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
1996
955
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
1991
906
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
1992
378
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
1998
830
28
Vijayakumar
S
Myrianthopoulos
LC
An updated dose-response analysis of Hodgkin’s disease.
Radiother Oncol
24
1992
1
29
Brinker
H
Bentzen
SM
A re-analysis of available dose-response and time-dose data in Hodgkin’s disease.
Radiother Oncol
30
1994
227
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
1992
859
31
Mauch
PM
Management of early stage Hodgkin’s disease: The role of radiation therapy and/or chemotherapy.
Ann Oncol
7
1996
S79
(suppl 4)
32
Hoppe
RT
Radiation therapy in the management of Hodgkin’s disease.
Semin Oncol
17
1990
704
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
1993
2258
35
Specht
L
Prognostic factors in Hodgkin’s disease.
Semin Radiat Oncol
6
1996
141
36
Jones
E
Mauch
P
Limited radiation therapy for selected patients with pathological stage IA and IIA Hodgkin’s disease.
Semin Radiat Oncol
6
1996
161
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
1997
565a
(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
1990
314
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
1987
1041
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
1988
1576
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
1988
1719
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
1992
1847
43
Mauch
PM
Controversies in the management of early stage Hodgkin’s disease.
Blood
83
1994
319
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
1992
1478
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
1980
809
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
1991
227
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
1993
771
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
1996
415
(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
1996
S105
(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
1996
S21
(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
1997
1736
52
DeVita
VT
Jr
Serpick
A
Combination chemotherapy in the treatment of Hodgkin’s disease.
Proc Am Assoc Cancer Res
8
1967
13
(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
1986
1295
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
1996
S68
(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
1986
739
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
1994
279
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
1997
1638
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
1998
19
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
1992
1252
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
1998
2704
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
1995
2379
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
1997
12a
(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
1996
1421
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
1996
S95
(suppl 4)
65
Reuss
K
Enger
A
Tesch
H
Diehl
V
Current clinical trials in Hodgkin’s disease.
Ann Oncol
7
1996
S109
(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
1997
143
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
1973
376
68
Young
RC
Canellos
GP
Chabner
BA
Hubbard
SM
DeVita
VT
Patterns of relapse in advanced Hodgkin’s disease.
Cancer
42
1978
1001
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
1988
603
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
1991
2193
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
1987
27
72
Bonadonna
G
Modern treatment of Hodgkin’s disease: A multidisciplinary approach?
Ann Oncol
5
1994
S5
(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
1994
903
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
1997
S111
(suppl 1)
75
Longo
DL
The case against the routine use of radiation therapy in advanced stage Hodgkin’s disease.
Cancer Invest
14
1996
353
76
Prosnitz
LR
Wu
JJ
Yahalom
J
The case for adjuvant radiation therapy in advanced Hodgkin’s disease.
Cancer Invest
14
1996
361
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
1995
2016
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
1997
2275
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
1987
91
(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
1990
350a
(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
1992
533
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
1990
535
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
1991
1983
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
1998
818
85
Yuen
AR
Horning
SJ
Hodgkin’s disease: Management of first relapse.
Oncology
10
1996
233
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
1990
623
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
1993
2613
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
1994
805
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
1986
343
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
1979
761
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
1992
21
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
1991
9
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
1990
123
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
1984
440
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
1983
423
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
1997
528
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
1991
2292
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
1996
1293
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
1992
1096
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
1994
580
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
1983
27
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
1987
550
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
1993
207
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
1987
38
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
1994
965
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
1993
S21
(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
1989
2086
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
1993
1137
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
1993
767
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
1997
801
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
1993
704
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
1995
451
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
1994
1193
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
1995
1381
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
1995
1354
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
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
1993
2342
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
1996
1291
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
1996
57
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
1995
261
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
1996
1272
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
1992
200
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
1993
1051
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
1997
814
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
1994
2527
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
1994
2535
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
1994
3780
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
1994
957
129
Rohatiner
A
Myelodysplasia and acute myelogenous leukemia after myeloablative therapy with autologous stem-cell transplantation.
J Clin Oncol
12
1994
2521
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
1992
169a
(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
1991
1575
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
1989
67
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
1996
565
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
1996
3633
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
1997
897
136
Carde
P
Who are the high-risk patients with Hodgkin’s disease?
Leukemia
10
1996
S62
(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
1997
110
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
1998
1506
139
Carella
AM
The place of high-dose therapy with autologous stem cell transplantation in primary treatment of Hodgkin’s disease.
Ann Oncol
4
1993
S15
(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
1993
889
141
Hoppe
RT
Hodgkin’s disease: Complications of therapy and excess mortality.
Ann Oncol
8
1997
S115
(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
1995
33
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
1987
571
144
Somers
R
Henry-Amar
M
Meerwaldt
JT
Carde
P
Treatment strategy in Hodgkin’s disease.
Colloque INSERM/John Libbey Eurotext Ltd
196
1990
357
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
1992
S117
(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
1992
1137
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
1994
25
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
1994
312
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
1982
965
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
1990
7
151
Kantarjian
HM
Keating
MJ
Therapy-related leukemia and myelodysplastic syndromes.
Semin Oncol
14
1987
435
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
1995
2973
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
1987
731
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
1994
1063
155
Van Leeuwen
FE
Adverse effects of treatment: Second cancers
Cancer: Principles and Practice of Oncology
ed 5
DeVita
VT
Jr
Hellman
S
Rosenberg
SA
1997
2773
Lippincott
Philadelphia, PA
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
1988
76
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
1996
745
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
1986
830
159
Valagussa
P
Bonadonna
G
Carcinogenic effects of cancer treatment
Oxford Textbook of Oncology.
Peckham
M
Pinedo
H
Veronesi
U
1995
2348
Oxford University Press
Oxford, UK
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
1984
762
161
Young
RC
Bookman
MA
Longo
DL
Late complications of Hodgkin’s disease.
J Natl Cancer Inst Monogr
10
1990
55
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
1991
432
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
1985
501
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
1990
1148
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
1993
925
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
1993
209
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
1979
452
168
Zarrabi
MH
Rosner
F
Second neoplasms in Hodgkin’s disease: Current controversies.
Hematol Oncol Clin North Am
3
1989
303
169
Tucker
MA
Solid second cancers following Hodgkin’s disease.
Hematol Oncol Clin North Am
7
1993
389
170
Hancock
SL
Tucker
MA
Hoppe
RT
Breast cancer after Hodgkin’s disease treatment.
J Natl Cancer Inst
85
1993
25
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
1997
67
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
1984
459
173
Aisenberg
AC
Coherent view of non-Hodgkin’s lymphoma.
J Clin Oncol
13
1995
2656
174
Gaidano
G
Dalla-Favera
R
Lymphoma: Molecular biology
Cancer: Principles and Practice of Oncology
ed 5
DeVita
VT
Jr
Hellman
S
Rosenberg
SA
1997
2131
Lippincott
Philadelphia, PA
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
1995
2312
176
Louie
S
Daoust
PR
Schwartz
RS
Immunodeficiency and the pathogenesis of non-Hodgkin’s lymphoma.
Semin Oncol
7
1980
267
177
List
AF
Greco
FA
Vogler
LB
Lymphoproliferative diseases in immunocompromised hosts: The role of Epstein-Barr virus.
J Clin Oncol
5
1987
1673
178
Filipovich
AH
Heinitz
KJ
Robison
LL
Frizzera
G
The Immunodeficiency Cancer Registry: A research resource.
Am J Ped Hematol Oncol
9
1987
183
179
Penn
I
Cancers complicating organ transplantation.
N Engl J Med
323
1990
1767
180
Ferry
JA
Harris
NL
Atlas of Lymphoid Hyperplasia and Lymphoma.
1997
214
Saunders
Philadelphia, PA
181
Salloum
E
Tallini
G
Levy
A
Cooper
DL
Burkitt’s lymphoma-leukemia in patients treated for Hodgkin’s disease.
Cancer Invest
14
1996
527
182
Jarrett
AF
Armstrong
AA
Alexander
E
Epidemiology of EBV and Hodgkin’s lymphoma.
Ann Oncol
7
1996
S5
(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
1986
668
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
1996
3625
185
Young
RC
Bookman
MA
Longo
DL
Late complications of Hodgkin’s disease management.
J Natl Cancer Inst Monogr
10
1990
55
186
National Research Council
Health Effects of Exposure to Low Levels of Ionizing Radiation (BEIR V).
1990
National Academy Press
Washington, DC
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.
1994
United Nations
New York, NY
188
Boice
JD
Jr
Carcinogenesis: A synopsis of human experience with external exposure in medicine.
Health Phys
121
1990
120
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
1992
677
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
1995
1530
191
Thomas
D
Pagoda
J
Langholz
B
Mack
W
Temporal modifiers of the radon-smoking interaction.
Health Phys
67
1994
675
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
1994
326
193
Sankila
R
Garwicz
S
Olsen
JH
Dollner
H
Hertz
H
Kreuger
A
Langmark
F
Lanning
M
Moller
T
Tulinius
H
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
1996
1442
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
1997
1203
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
1983
767
196
Boice
JD
Jr
Second cancer after Hodgkin’s disease—The price of success?
J Natl Cancer Inst
85
1993
4
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
1991
1343
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
1993
415
199
Dietrich
PY
Belleqih
S
Henry-Amar
M
Cosset
JM
Hayat
M
Linitis plastica after Hodgkin’s disease.
Lancet
342
1993
57
200
Wolden
SL
Lamborn
KR
Cleary
SF
Tate
DJ
Donaldson
SS
Second cancers following pediatric Hodgkin’s disease.
J Clin Oncol
16
1998
536
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
1997
588
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
1991
2885
203
Hancock
SL
Cox
RS
McDougall
IR
Thyroid diseases after treatment of Hodgkin’s disease.
N Engl J Med
325
1991
599
204
Tucker
MA
Misfeldt
D
Coleman
N
Clark
WH
Jr
Rosenberg
SA
Cutaneous malignant melanoma after Hodgkin’s disease.
Ann Intern Med
102
1985
37
205
Henry-Amar
M
Joly
F
Late complications after Hodgkin’s disease.
Ann Oncol
7
1996
S115
(suppl 4)
206
Hancock
SL
Tucker
MA
Hoppe
RT
Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease.
JAMA
270
1993
1949
207
Stewart
JR
Fajardo
LF
Radiation-induced heart disease: An update.
Prog Cardiovasc Dis
27
1984
173
208
Stewart
JR
Fajardo
LF
Gillette
SM
Constine
LS
Radiation injury to the heart.
Int J Radiat Oncol Biol Phys
31
1995
1205
209
Boivin
J-F
Hutchison
GB
Lubin
JH
Mauch
P
Coronary artery disease mortality in patients treated for Hodgkin’s disease.
Cancer
69
1992
1241
210
Hancock
SL
Donaldson
SS
Hoppe
RT
Cardiac disease following treatment of Hodgkin’s disease in children and adolescents.
J Clin Oncol
11
1993
1208
211
Hancock
SL
Hoppe
RT
Long-term complications of treatment and causes of mortality after Hodgkin’s disease.
Semin Radiat Oncol
6
1996
225
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
1991
447
213
Carlson
RG
Mayfield
WR
Norman
S
Alexander
JA
Radiation-associated valvular disease.
Chest
99
1991
538
214
Ginsberg
SJ
Comis
RL
The pulmonary toxicity of antineoplastic agents.
Semin Oncol
9
1982
34
215
Jules-Elysee
K
White
DA
Bleomycin-induced pulmonary toxicity.
Clin Chest Med
11
1990
1
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
1996
1297
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
1994
615

Author notes

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

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