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© 1999 American Society for Clinical Oncology Mantle Irradiation Alone for Clinical Stage I-II Hodgkin's Disease: Long-Term Follow-Up and Analysis of Prognostic Factors in 261 PatientsFrom the Division of Radiation Oncology, Peter MacCallum Cancer Institute, Melbourne; Statistical Centre, Peter MacCallum Cancer Institute, Melbourne; Geelong Hospital, Geelong; Alfred Hospital, Prahran; and Repatriation Hospital, Melbourne, Australia. Address reprint requests to Dr. Andrew Wirth, Division of Radiation Oncology, Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne 3002, Australia; Email awirth{at}petermac.unimelb.edu.au
PURPOSE: To evaluate mantle radiotherapy (MRT) alone as the initial therapy of patients with clinical stage (CS) I-II Hodgkin's disease (HD). PATIENTS AND METHODS: We performed a retrospective study of patients treated with MRT alone for CS I-II supradiaphragmatic HD between 1969 and 1994. Prognostic factor analysis was performed for progression-free survival (PFS) and overall survival (OS). Outcome was also assessed in favorable cohorts defined in the literature. RESULTS: There were 261 eligible patients. The median follow-up period for surviving patients was 8.4 years (range, 1.8 to 27.4 years). The 10-year OS rate was 73%. Multifactor analysis for OS showed that age was the only important prognostic factor. The 10-year PFS rate was 58%. On multifactor analysis for PFS, the most important prognostic factors were clinical stage, B symptoms, histology, number of sites, and tumor bulk. The 10-year PFS rate for lymphocyte-predominant disease was 81% for stage I and 78% for stage II. In favorable patient cohorts defined in the literature, the 10-year PFS rate ranged from 70% to 73% for the whole group and from 71% to 90% in patients with favorable stage I disease, but only from 48% to 57% in patients with favorable stage II disease. On competing-risks analysis, the cumulative 10-year incidence of first site of failure in the para-aortic/splenic region alone was 10.5%. Sixty percent of relapsed patients remain progression-free at 10 years after chemotherapy salvage. CONCLUSION: These results support the use of MRT alone in patients with favorable CS I HD and CS I-II HD with lymphocyte-predominant histology. The remainder of patients with CS I-II HD require more intensive treatment.
THE MAJORITY OF PATIENTS with early-stage Hodgkin's disease can be cured with radiotherapy and/or chemotherapy.1 A major goal of current treatment strategies is to minimize both early and late treatment-related morbidity while maintaining cure rates, particularly in patients with favorable prognostic factors.2 The use of staging laparotomy has declined over recent years, both in Europe and in North America.3,4 Treatment approaches for clinically staged patients include radiotherapy alone, chemotherapy alone, and combined modality treatment.5 In clinically staged patients, it is generally considered necessary to treat potential occult abdominal disease, either by using extended-field radiotherapy or by adding chemotherapy to limited radiotherapy. Subtotal nodal irradiation has been used as the control arm in several recent randomized clinical trials for early-stage Hodgkin's disease.6 Eliminating infradiaphragmatic radiation has the potential to reduce acute and late toxicity, and the use of prognostic factors may allow the selection of clinically staged patients who are optimally suited for limited radiotherapy.7 It has recently been suggested that patients with lymphocyte-predominant (LP) histology may constitute a group particularly suited to limited-volume irradiation.8 There are, however, few reports of clinically staged patients treated with mantle radiotherapy (MRT) and no large series reporting the outcome of clinically staged patients with LP disease treated with MRT alone.9-12 In this study, we present the results of MRT in a large series of patients with clinical stage (CS) I-II supradiaphragmatic Hodgkin's disease (HD) and evaluate the impact of a number of clinical prognostic factors, including histology.
We conducted a retrospective study of patients with CS I-II supradiaphragmatic HD who had been treated with MRT alone. Patients eligible for this study had not undergone prior staging laparotomy. No patient had received infradiaphragmatic irradiation (defined as irradiation below the 12th thoracic vertebra) or chemotherapy as part of first-line treatment. All patients had a histologic diagnosis of Hodgkin's disease. In 191 cases (73%), pathology was reviewed by an experienced tumor pathologist at our institution at the time of treatment. In 27% of these cases, the pathology review led to a change of subclassification; the revised subclassification was used in the present analysis. Stage classification was derived from a review of case notes.13 Staging investigations varied during the study period. Computerized tomography and Gallium scanning largely replaced chest x-ray, inferior venacavography, intravenous pyelography, bipedal lymphangiography, and nasopharyngiography during the 1980s. Quality control of data retrieval from case records required that data be checked independently by at least two of the investigators. In addition, both initial and follow-up data were cross-checked with coding from an earlier retrospective study. When involvement of a site was uncertain on the basis of case notes, the site was considered to be uninvolved. When staging was uncertain, the patient was allocated to the lower of two possible stages. Patients were classified as having B symptoms only if symptoms appeared to be unequivocal on chart review. Bulky disease was considered to be present when tumor size was larger than 10 cm or one third of the transverse thoracic diameter or, if measurements were not recorded, when masses were described as "bulky" or "large." When infradiaphragmatic imaging was performed, the results were classified as either normal or equivocal in cases where minor abnormalities were noted, but were not considered diagnostic of infradiaphragmatic disease. Patients with equivocal imaging results were included in the analysis. In general, patients were simulated and treated at a focus-incident distance of 130 cm, using 4- or 6-MeV linear accelerators. The upper border of the field was a line extending from the tip of the mastoid to 2 cm below the vermilion border of the lip. The lower border was at or above the lower level of the 10th thoracic vertebra in 82% of 159 cases for which the level could be determined. The field width was sufficient to cover the axillae with an adequate margin. The minimum mediastinal field width was 8 to 10 cm. In 29 patients, part of the mantle field was omitted. From 1975 onward, individually shaped lung blocks were used instead of standard lung blocks. The upper level of the lung blocks extended to the inferior border of the posterior fourth rib. Shielding was generally used for the larynx and the heads of humeri, as well as for the posterior cervical cord; from 1985 onward, subcarinal blocks were introduced to limit the cardiac dose to 30 Gy. The prescribed central axis dose varied from 30 to 38 Gy, with 20% of patients receiving 32 Gy and 67% receiving 36 Gy. Routine compensation for contours was not used, which resulted in a typical dose to the neck and supraclavicular region of 39 to 41 Gy. Both anterior and posterior fields were treated daily, 5 days a week, at 1.8 to 2 Gy per fraction. Verification films became standard in the latter part of the study. Follow-up data were obtained from clinical case records, mailed questionnaires, and telephone contact with patients and their doctors. Details of disease progression, toxicity, and cause of death were sought. Information about sites of relapse was obtained where possible, and relapse was classified as in field, out of field, or marginal. The type of salvage treatment and the duration of second remission were documented. Causes of death were classified as being due to HD, complications of treatment, or unrelated causes. Cause-of-death data were supplemented by inquiries to the Victorian Cancer Registry. Patients were regarded as lost to follow-up if their date of last contact was before January 1, 1995. Overall survival, progression-free survival (PFS), and time to second failure were analyzed using the Kaplan-Meier product-limit method. Overall survival was measured from commencement of radiotherapy. Deaths from all causes were included. Progression-free survival was measured from commencement of radiotherapy until disease progression or last contact. Patients whose disease had not progressed were censored at last contact whether they were alive or dead. Time to second failure was measured from commencement of salvage treatment until second failure or last contact. Patients who remained free from second failure were censored at last contact whether they were alive or dead. The Mantel-Cox log-rank test was used to test the difference between subgroups, and a test for trend was used when the categories of a factor followed a particular order. Each factor was examined for its significance in a unifactor analysis. Those factors found to be significant were examined further in a multifactor analysis using the Cox proportional hazards model. A stepwise regression procedure was used to enter factors in the model. At each step, the factor with the smallest P value less than .05 was entered, and factors already in the model could be removed if their P value was greater than .05, after adjustments were made for other factors in the model. The likelihood ratio test was used to assess the significance of each factor. The BMDP statistical package14 was used to perform the above analysis. The pattern of failure was assessed by a competing-risks analysis performed using the S-PLUS statistical package.15,16 Five sets of prognostic criteria were abstracted from previous publications and assessed in our study population. Favorable groups were defined as follows: Princess Margaret Hospital defined patients as favorable if they had CS IA-IIA disease, were younger than 50 years old, had an erythrocyte sedimentation rate (ESR) of less than 40, had LP or nodular sclerosis histology, and had no bulky mediastinal mass or extranodal involvement.11 The European Organization for Research and Treatment of Cancer (EORTC) included patients in their very favorable (EORTC-VF) prognostic group if they had CS IA disease, were female, were younger than 40 years old, had an ESR of less than 50, had LP or nodular sclerosis histology, and had no bulky mediastinal mass.17,18 Patients in the EORTC's favorable (EORTC-F) prognostic group were 50 years old or younger, had three or fewer involved sites, had an ESR of 50 or less without B symptoms or an ESR of 30 or less with B symptoms, had no bulky mediastinal mass, and did not fit criteria for the EORTC-VF group.17,18 In the Harvard "mantle" series, favorable patients were those who had CS IA or IIA disease and LP or nodular sclerosis histology, with no involvement of the hilum.19 (This definition of a favorable patient was modified from the original reference, in which patients had no subcarinal disease and all but three patients had staging laparotomy; in the series presented here, all patients were clinically staged and the position of the mediastinal disease was not always recorded.) In the Harvard "prognostic factor" series, favorable patients were female and had CS IA disease or were male and had CS IA disease with LP histology or upper neck disease.20 The Stanford series defined the favorable patient as either (i) female with CS I disease or CS I with mediastinal disease only, (ii) male with CS I disease and LP or interfollicular histology, or (iii) female with CS II disease, and younger than 27 years old with two to three sites of involvement.21
Patient Characteristics A comprehensive review of databases identified 261 eligible patients treated at public hospitals in Victoria, Australia, between January 1969 and December 1994: 253 patients were from the Peter MacCallum Cancer Institute and eight were from the Geelong, Alfred, and Repatriation Hospitals (which commenced radiotherapy services after 1991). During this period, an additional 208 patients received radiotherapy after laparotomy staging, and seven patients received subtotal nodal irradiation. None of these patients are included in this report. Characteristics of the 261 eligible patients are listed in Table 1.
Overall Survival
Progression-Free Survival
Subset analyses of PFS were performed separately within each stage. Within stage I, the site of involvement appeared to influence PFS. The 10-year PFS rate was 79% ± 11% for patients who had axillary disease only (n = 20) and 78% ± 6% for patients with upper neck involvement only (n = 68), but it was only 56% ± 9.5% when the lower neck was involved (n = 49). All four patients with nonbulky mediastinal disease were progression-free at 10 years. Because of the poor overall 10-year PFS rate (43%) for stage II, an exploratory analysis was performed to identify possible favorable subsets. The 10-year PFS rate in patients with LP histology (n = 9) was 78% ± 14% versus 38% ± 6% for nodular sclerosis (n = 83) and 45% ± 12% for mixed cellularity (n = 22) (P = .09). Patients with a normal abdominal CT scan (n = 42) had a 59% ± 8% 10-year PFS rate compared with 39% ± 16% for patients with CT findings that were equivocal (n = 13) (P = .5)
Evaluation of Published Prognostic Groups
The favorable groups defined by the Harvard mantle series, EORTC, Princess Margaret Hospital, and Stanford criteria included favorable subsets of patients with both stage I and II disease. Given the poor overall results for patients with stage II disease, we evaluated PFS in favorable stage I and II separately. Depending on the definition used, stage I patients who met the favorable criteria represented 23% to 49% of the study population and had an estimated 10-year PFS rate of 71% to 90%. For patients with stage II disease who fulfilled the same criteria, the estimated 10-year PFS rate was only 48% to 57%. Illustrative results based on the EORTC criteria are shown in Figure 4, demonstrating PFS according to EORTC category and stage. Patients with unfavorable stage I disease had a higher PFS than patients with favorable stage II disease. Because unifactor analysis suggested a possible impact of equivocal abdominal CT on PFS, we repeated this analysis on the 31 stage II patients who had a completely normal abdominal CT scan. Patients with EORTC-F stage II disease and normal abdominal CT scans (n = 18) had an estimated 10-year PFS rate of 72% ± 11%.
Pattern of Relapse and Salvage Treatment Ninety-three of 94 patients who relapsed underwent salvage treatment, which consisted of chemotherapy in 65 patients, radiotherapy in 15 patients, both chemotherapy and radiotherapy in 12 patients, and surgery in one patient. The estimated percentage of patients who remained free from second failure at 10 years was 52% ± 6%. After chemotherapy-containing salvage treatment, an estimated 60% ± 6% remained free from second failure at 10 years.
Late Toxicity
A shift in management strategy for Hodgkin's disease occurred during the 1980s, when it became clearer that staging laparotomy did not contribute to improved overall survival but did add to early and late morbidity.3 With greater understanding of clinical prognostic factors, the use of laparotomy has markedly diminished in North America and Europe.3,4 In clinically staged patients, subtotal nodal irradiation is the standard approach in many centers for low- to intermediate-risk patients; it produces a PFS rate of 80% to 90%.11,12,22 Long-term follow-up of patients cured of HD has shown an increased incidence of late toxicity, including second malignancy, that seems to be related, at least in part, to wide-field irradiation.23,24 This has led to strategies aimed at reducing the size of the radiotherapy field. One increasingly common strategy is the use of low-dose, involved-field irradiation combined with chemotherapy.6 Combined-modality treatment improves failure-free survival but has not been shown to improve overall survival in two meta-analyses.25,26 Furthermore, the incorporation of chemotherapy may increase acute treatment-related morbidity, may make salvage more difficult, and has a poorly defined impact on long-term toxicity.27-30 The use of chemotherapy alone is also being explored, but at present, long-term results in large series of patients treated with modern chemotherapy are unavailable.5,28,31-34 An alternative approach is the use of MRT alone. By omitting para-aortic and splenic irradiation, MRT reduces the duration and acute toxicity of treatment, reduces radiation exposure of the left kidney, lung and cardiac apex, and potentially reduces the patient's risk of developing second malignancy.35-37 During the 1960s, results from Stanford University and the EORTC suggested that the use of MRT alone in clinically staged patients led to an unacceptably high rate of relapse, with most relapses occurring in the abdomen.18,38 This experience led to the use of staging laparotomy and the routine application of subdiaphragmatic irradiation. Subsequently, some investigators have limited the use of MRT to favorable, laparotomy-staged patients.19 In the present study, MRT was used in patients staged without laparotomy. The estimated 10-year overall survival rate was 73%, which is lower than might be expected in this group of patients.1 However, 15% of patients were 60 years or older and had a 10-year estimated survival rate of only 10%. The overall survival rate at 10 years for patients younger than 60 years was 83%. It is possible that in our population, patients were selected for treatment without staging laparotomy because of medical comorbidity, which may have contributed to mortality. When assessed in favorable groups, our results for overall survival are comparable to those in previous reports (see Tables 4 and 5). The estimated 10-year PFS rate for the entire group was 58%. This rate is comparable to the long-term outcome obtained using limited radiotherapy in clinically staged patients in early studies from Stanford and the EORTC.18,38 The present study aimed to assess previously published prognostic factors and to refine selection criteria for clinically staged patients who may have acceptable PFS after MRT. Several groups have recognized prognostic factors that allow the identification of favorable subsets of patients who may be suitable for less intensive treatment after clinical staging.20,21,39,40 Using a multifactor analysis, we have confirmed the prognostic importance of clinical stage, B symptoms, number of involved sites, histology, and disease bulk in patients treated with MRT. Our data are consistent with the favorable outcome associated with special sites in stage I disease, such as the upper neck, axilla, and mediastinum. The uncommon presentation of Hodgkin's disease limited to the mediastinum has been reported to have a good prognosis.41 In our series, all four patients with nonbulky mediastinal disease remained progression-free after MRT. To our knowledge, the present study contains the largest reported group of clinically staged patients with LP histology treated by MRT alone. In 1973, the first EORTC study of early-stage HD reported a 5-year PFS rate of approximately 70% in 19 patients with CS I-II LP histology who were treated with mantle irradiation alone.42 In the present series, patients with LP histology had a 10-year PFS rate of approximately 80%, in stages I and II (Fig 3). No other individual factor was associated with a high PFS rate among stage II patients. It is now understood that LP disease shares a number of clinical and biologic features with low-grade, B-cell non-Hodgkin's lymphoma.43,44 Thus, the role of limited-field irradiation in LP Hodgkin's disease may be analogous to that in early-stage, low-grade non-Hodgkin's lymphoma.45 Limited-volume irradiation may be even more suitable for CS I-II, LP Hodgkin's disease, because of its relatively low incidence of marrow, mediastinal, and occult abdominal involvement.8 The low incidence of mediastinal involvement may allow fields even less than a full mantle to produce acceptable PFS.8 This would provide a further opportunity to reduce late morbidity. Unlike some investigators, we did not demonstrate an impact of age and sex on PFS, even on unifactor analysis.7 The reason for this is unclear. Our data suggest that peripheral sites of bulk disease are associated with poor PFS, a factor that is not usually included in the selection of favorable patients.46 This factor remained significant on multifactor analysis. Mediastinal bulk and high ESR have generally been found to be adverse prognostic factors.7,47 In the present study, mediastinal bulk and high ESR were adverse factors for PFS on unifactor analysis; however, they were not significant on multifactor analysis. Progression-free survival was lower in the patient cohort treated from 1969 to 1984, and the worst PFS was in patients treated before 1975. To explore the possibility that this observation may have been contributed to by improvements in treatment technique over the study period (such as the introduction of shaped lung shielding in 1975), the treatment era was included in a multifactor analysis. After adjustments were made for other significant factors, the effect of treatment era on PFS could not be demonstrated (P = .38). This suggests that other factors, possibly related to patient characteristics, may have been more important in determining PFS. A combination of individual prognostic factors may allow the identification of patient subsets suitable for treatment with MRT alone, with acceptable PFS. Several investigators have attempted to define favorable groups, and we found that several published definitions were useful in identifying favorable cohorts within our study population (Table 4). For comparison, we tabulated results from previous reports of favorable clinically staged patients (Table 5). In the Swedish and Norwegian series, treatment was chosen according to prognostic factors.9,10 In the former series, only patients with CS I disease received MRT, whereas the Norwegian series used MRT for selected patients with CS I-II. In both reports, the PFS rate was 78%. It should be noted that in the Harvard series, almost all patients were laparotomy-staged, and in the EORTC series, subtotal nodal and splenic irradiation was used. Despite the reduced extent of staging and treatment in our series, our results were generally comparable to those previous reports (Table 4).
The EORTC criteria (see Patients and Methods) were developed by analyzing outcome in a series of large, prospective, randomized trials.7 One hundred eighty patients in our series had their pretreatment ESR documented and could therefore be analyzed according to EORTC criteria. Twelve patients were in the EORTC-VF group and had a 10-year PFS rate of 86%. In the EORTC-F group, MRT produced a 71% 10-year PFS rate. When we analyzed patients with stage I and stage II disease separately, we found that the 50 EORTC-F patients with stage I disease had an 86% PFS rate at 10 years and so might be added to the EORTC-VF group in an expanded definition of patients suitable for MRT. Thus, 34% of patients analyzed using EORTC criteria were potentially suitable for mantle radiotherapy (6% VF and 28% stage I F). Our results in EORTC-VF (and favorable stage I) patients seem to be superior to what might be expected on the basis of the recent EORTC results in the H7-VF (mantle) and H7-F (subtotal nodal irradiation) study arms.12 Although patient numbers were smaller in our series, our data provide support for the use of MRT in these patient groups. Patients with stage II disease had a poor PFS rate. Unifactor analysis of patients with stage II disease identified patients with LP disease (10-year PFS rate, 78%) and patients with normal infradiaphragmatic imaging (10-year PFS rate, 59%) as the most favorable groups. No combination of factors in published prognostic groups identified a cohort of stage II patients with a 10-year PFS rate of more than 57%. Because the unifactor analysis suggested a negative impact of equivocal changes on abdominal CT imaging, we repeated our analysis in patients with normal CT scans. This exploratory subset analysis suggested that a slightly more favorable group of stage II patients could be identified. For example, patients who were stage II favorable (EORTC criteria) and had normal abdominal imaging had a 72% 10-year PFS rate. Such findings in small, retrospectively defined subsets require confirmation in a prospective series. However, these data do highlight the importance of meticulous assessment of imaging, in addition to prognostic factor evaluation, in the selection of patients for limited-volume irradiation. The disadvantage of MRT compared with subtotal nodal and splenic irradiation is the greater potential for relapse caused by untreated occult disease in the para-aortic nodes and spleen. In the present series, the percentage of patients with first failure in these sites alone was 10.5% at 10 years, which represents 25% of all failures at this time. If it is assumed that the same pattern of failure would hold in a favorable group with a 30% overall relapse rate, the addition of infradiaphragmatic radiotherapy might only be expected to reduce the total relapse rate by 7% to 8%. In the H7 trial, the EORTC reported an 81% PFS rate at 6 years in the favorable group, after subtotal nodal and splenic irradiation. We found a 74% 5-year PFS rate when we used MRT in a cohort matched to the EORTC-F group, which fits well with the incremental benefit expected from infradiaphragmatic irradiation.12 This finding is supported by data from Toronto, which showed only a 7% difference in the 10-year PFS rate for their favorable patient group treated with either MRT or subtotal nodal irradiation.11 Weighed against this small benefit, infradiaphragmatic irradiation adds to acute and late toxicity and the duration and technical complexity of treatment. Acute toxicity was mild in our series. All but one patient completed treatment, and only 5% required treatment interruption of more than 1 week (data not shown). Late toxicity is the major concern for patients with early-stage Hodgkin's disease. Two patients in our series developed acute leukemia, but in both cases, this occurred after salvage treatment with mechlorethamine, vincristine, procarbazine, and prednisone. The most common second malignancies were non-Hodgkin's lymphoma and breast cancer. Non-Hodgkin's lymphoma is generally considered to be independent of initial treatment and may be a function of impaired immunity associated with HD.37 Six cases of breast cancer were noted, and four cases occurred in women 28 years or younger at the time of mantle treatment, which is consistent with reports indicating that women irradiated under the age of 30 are at greatest risk of developing breast cancer.48 The data in our series did not allow rigorous assessment of cardiac risk. There were no cases of significant clinical pulmonary sequelae (data not shown). The reported experience with MRT for clinically staged Hodgkin's disease in the modern era is limited.9-12 Our study provides long-term results from a large cohort of patients treated with MRT after clinical staging only and includes all eligible patients treated in public hospitals in our geographic region. Great care was taken to avoid incorrect retrospective assignment of disease stage or number of involved sites. Each case record was reviewed by at least two investigators, and all discrepancies were checked. Whenever there was doubt in the interpretation of clinical stage, number of involved sites, or presence of B symptom, the more favorable classification was applied. This was done to avoid incorrect assignment to a higher stage, which would artificially improve the results in stage II disease. Thus, our results may provide a conservative estimate of the efficacy of MRT. Our report is subject to the limitations of all retrospective studies. The quality and documentation of initial patient assessments varied. Imaging and laboratory data were incomplete in some patients, and the technical quality of radiotherapy was poorer in the early part of the study period. Stage allocation was not always explicit in case notes and had to be allocated in retrospect. Finally, although we analyzed outcome in well-defined prognostic groups, this cannot entirely overcome unrecognized factors that may have affected selection of patients for MRT after clinical staging. Mantle irradiation is a brief treatment that produces low relapse rates in patients selected according to established prognostic factors. By eliminating subdiaphragmatic radiation, both acute and late toxicity may be reduced. Future improvements in imaging technology may aid in both patient selection and treatment planning.49 Recent analyses also suggest that radiotherapy dose may be reduced without loss of efficacy, possibly leading to lower toxicity rates.50,51 The treatment of early-stage Hodgkin's disease needs to be individualized, and management decisions should be made with due consideration of both expected efficacy and toxicity. Our data confirm the ability of MRT to produce long-term PFS in patients with favorable, clinically staged, early Hodgkin's disease and aid in the selection of patients suitable for this treatment option.
Presented in part at the 39th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Orlando, FL, 1997.
1. Rosenberg SA: The management of Hodgkin's disease: Half a century of change. The Kaplan Memorial Lecture. Ann Oncol 7:555-560, 1996 2. Mauch PM, Kalish LA, Marcus KC, et al: Long-term survival in HD: Relative impact of mortality, second tumors, infection, and cardiovascular disease. Cancer J Sci Am 1:33-42, 1995[Medline]
3.
Carde P, Hagenbeek A, Hayat M, et al: Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: The H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 11:2258-2272, 1993 4. Smitt MC, Buzydlowski J, Hoppe RT: Over 20 years of progress in radiation oncology: Hodgkin's disease. Semin Oncol 7:127-134, 1997
5.
Mauch PM: Controversies in the management of early stage Hodgkin's disease. Blood 83:318-329, 1994 6. Reus K, Engert H, Tesch H, et al: Current clinical trials in Hodgkin's disease. Ann Oncol 7:S109-S113, 1996 (suppl 4)
7.
Tubiana M, Henry-Amar M, Carde P, et al: Toward comprehensive management tailored to prognostic factors of patients with clinical stages I-II in Hodgkin's disease: The EORTC lymphoma group controlled clinical trials 1964-87. Blood 73:47-56, 1989 8. Bodis S, Kraus MD, Pinkus G, et al: Clinical presentation and outcome in lymphocyte-predominant Hodgkin's disease. J Clin Oncol 15:3060-3066, 1997[Abstract]
9.
Abrahamsen AF, Hannisdal E, Nome O, et al: Clinical stage I and II Hodgkin's disease: Long-term results of therapy without laparotomy. Experience at one institution. Ann Oncol 7:145-150, 1996
10.
Glimelius B, Kälkner M Enbald G, et alfor the Swedish Lymphoma Study Group: Treatment of early and intermediate stages of supradiaphragmatic Hodgkin's disease: The Swedish National Care Programme experience. Ann Oncol 5:809-816, 1994 11. Gospodarowicz MK, Sutcliffe SB, Bergsagel DE, et al for the Princess Margaret Hospital Lymphoma Group: Radiation therapy in clinical stage I and II Hodgkin's disease. Eur J Cancer 28:1841-1846, 1992 12. Noordijk EM, Carde P, Hagenbeek A, et al: Combination of radiotherapy and chemotherapy is advisable in all patients with clinical stage I-II Hodgkin's disease: Six-year results of the EORTC-GPMC controlled clinical trials "H7-VF," "H7-F," "H7-U". Int J Radiat Oncol Biol Phys 39:173, 1997 (suppl) [Medline] 13. Lister TA, Crowther D, Sutcliffe SB, et al: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: The Cotswolds meeting. J Clin Oncol 7:1630-1636, 1989[Abstract] 14. Dixon WJ, Brown MB, Engelman L, et al: BMDP Statistical Software Manual. Berkeley, CA, University of California Press, 1988 15. S-PLUS [computer program]. Version 4.0 for Windows. Seattle, WA, StatSci, a division of MathSoft, Inc., 1995 16. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley & Sons, 1980 17. Noordijk EM, Carde P, Mandard A-M, et al: Preliminary results of the EORTC-GPMC controlled clinical trial H7 in early-stage Hodgkin's disease. Ann Oncol 5:s107-s112, 1994 (suppl 2) 18. Cosset JM, Henry-Amar M, Meervaldt JH, et al: The EORTC trials for limited stage Hodgkin's disease. Eur J Cancer 28A:1847-1850, 1992 19. Mauch PM, Canellos GP, Shulman LN, et al: Mantle irradiation alone for selected patients with laparotomy-staged IA and IIA Hodgkin's disease: Preliminary results of a prospective trial. J Clin Oncol 13:947-952, 1995[Abstract] 20. Mauch P, Larson D, Osteen R, et al: Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 8:257-265, 1990[Abstract] 21. Leibenhaut MH, Hoppe RT, Efron B, et al: Prognostic indicators of laparotomy findings in clinical stage I-II supradiaphragmatic Hodgkin's disease. J Clin Oncol 7:81-91, 1989[Abstract]
22.
Horning SJ, Hoppe RT, Mason J, et al: Stanford-Kaiser Permanente G1 study for clinical stage I to IIA Hodgkin's disease: Subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation. J Clin Oncol 15:1736-1744, 1997
23.
Mauch PM, Kalish LA, Marcus KC, et al: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: Long-term analysis of risk factors and outcome. Blood 87:3625-2632, 1996 24. Hoppe RT: HD: Complications of therapy and excess mortality. Ann Oncol 8:s115-s118, 1997 (suppl 1) 25. Shore T, Nelson N, Weinerman B: A meta-analysis of stages I and II Hodgkin's disease. Cancer 65:1155-1160, 1990[Medline] 26. Specht L, Gray RG, Clarke MJ, et al: Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease: A meta-analysis of 23 randomized trials involving 3,888 patients. J Clin Oncol 16:830-843, 1998[Abstract] 27. Cimino G, Biti GP, Cartoni C, et al: Chemotherapy versus radiotherapy in early-stage Hodgkin's disease: Evidence of a more difficult rescue for patients relapsed after chemotherapy. Eur J Cancer 28:1853-1855, 1992
28.
Rueda A, Alba E, Ribelles N, et al: Six cycles of ABVD in the treatment of stage I and II Hodgkin's lymphoma: A pilot study. J Clin Oncol 15:1118-1122, 1997
29.
Hirsch A, Vander Els N Straus DJ, et al: Effect of ABVD chemotherapy with and without mantle or mediastinal irradiation on pulmonary function and symptoms in early-stage Hodgkin's disease. J Clin Oncol 14:1297-1305, 1996
30.
Steinherz LJ, Steinherz PG, Tan CTC, et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 266:1672-1677, 1991 31. Longo DL: Chemotherapy alone in the treatment of patients with early stage HD. Ann Oncol 7:s85-s89, 1996 (suppl 4) 32. Longo DL, Glatstein E, Duffey PL, et al: Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: Seven-year results of a prospective randomized trial. J Clin Oncol 9:906-917, 1991[Abstract]
33.
Biti GP, Cimino G, Cartoni C, et al: 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 study. J Clin Oncol 10:378-382, 1992
34.
Pavlovsky S, Schvartzman E, Lastiri F, et al: Randomized trial of CVPP for three versus six cycles in favorable-prognostic and CVPP versus AOPE plus radiotherapy in intermediate-prognosis untreated Hodgkin's disease. J Clin Oncol 15:2652-2658, 1997 35. Biti G, Cellai E, Magrini SM, et al: Second solid tumors and leukemia after treatment for Hodgkin's disease: An analysis of 1121 patients from a single institution. Int J Radiat Oncol Biol Phys 29:25-31, 1994[Medline] 36. Swerdlow AJ, Douglas AJ, Vaughan Hudson Get al: Risk of second primary cancers after Hodgkin's disease by type of treatment:Analysis of 2846 patients in the British National Lymphoma Investigation. Br Med J 304:1137-1143, 1992 37. Henry-Amar M: Second cancer after the treatment for Hodgkin's disease: A report from the International Database on Hodgkin's disease. Ann Oncol 3:s117-s128, 1992 38. Rosenberg SA, Kaplan HS: The evolution and summary results of the Stanford randomized clinical trials of the management of HD: 1962-1984. Int J Radiat Oncol Biol Phys 11:5-22, 1985[Medline] 39. Sutcliffe SB, Gospodarowicz MK, Bergsagel DE, et al: Prognostic groups for management of localized Hodgkin's disease. J Clin Oncol 3:393-401, 1985[Abstract] 40. Tubiana M, Henry-Amar M, van der Werf-Messing B, et al for the Radiotherapy-Chemotherapy Group of the EORTC: A multifactor analysis of prognostic factors in early stage HD. Int J Radiat Oncol Biol Phys 11:23-30, 1985[Medline] 41. Johnson DW, Hoppe RT, Cox RS, et al: Hodgkin's disease limited to intrathoracic sites. Cancer 52:8-13, 1983[Medline] 42. van der Werf-Messing B: Morbus Hodgkin's disease, stages I and II: Trial of the European Organization for Research on Treatment of Cancer. Natl Cancer Inst Monogr 36:331-386, 1973 43. Schwartz RS: Hodgkin's disease: Time for a change. N Engl J Med 337:495-496, 1997 44. Crennan E, D'Costa I Liew K, et al: Lymphocyte predominant Hodgkin's disease: A clinicopathologic comparative study of histologic and immunophenotypic subtypes. Int J Radiat Oncol Biol Phys 31:333-337, 1995[Medline] 45. Sutcliffe SB, Gospodarowicz MK, Bush RS, et al: Role of radiation therapy in localized non-Hodgkin's lymphoma. Radiother Oncol 4:211-223, 1985[Medline] 46. Bonadonna G, Valagussa P, Santoro A: Prognosis of bulky Hodgkin's disease treated with chemotherapy alone or combined with radiotherapy. Cancer Surv 4:439-458, 1985[Medline] 47. Behar RA, Horning SJ, Hoppe RT: Hodgkin's disease with bulky mediastinal involvement: Effective management with combined modality therapy. Int J Radiat Oncol Biol Phys 25:771-776, 1993[Medline]
48.
Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin's disease. J Natl Cancer Inst 85:25-31, 1993 49. Banarter M, Griesshammer M, Binder T, et al: New diagnostic imaging procedures in Hodgkin's disease. Ann Oncol 7:S55-S59, 1996 (suppl 4) 50. Moody AM, Williams MV: Radiation dose in Hodgkin's disease: Are we overtreating? Clin Oncol 9:155-157, 1997
51.
Hancock SL, Tucker MA, Hoppe RT: Factors affecting late morbidity from heart disease after treatment of Hodgkin's disease. JAMA 270:1949-1955, 1993 Submitted May 18, 1998; accepted September 3, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
