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© 2001 American Society for Clinical Oncology Results of a Prospective Trial of Mantle Irradiation Alone for Selected Patients With Early-Stage Hodgkin’s DiseaseFrom the Department of Radiation Oncology, Brigham and Women’s Hospital, Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; and Department of Radiation Oncology, Duke University, Durham, NC. Address reprint requests to Peter M. Mauch, MD, Department of Radiation Oncology, Brigham and Women’s Hospital, ASB1-L2, 75 Francis St, Boston, MA 02115; email: pmauch{at}lroc.harvard.edu
PURPOSE: To determine the efficacy of mantle radiation therapy alone in selected patients with early-stage Hodgkin’s disease.
PATIENTS AND METHODS: Between October 1988 and June 2000, 87 selected patients with pathologic stage (PS) IA to IIA or clinical stage (CS) IA Hodgkin’s disease were entered onto a single-arm prospective trial of treatment with mantle irradiation alone. Eighty-three of 87 patients had RESULTS: The 5-year actuarial rates of freedom from treatment failure (FFTF) and overall survival were 86% and 100%, respectively. Eleven of 83 patients relapsed at a median time of 27 months. Nine of the 11 relapses contained at least a component below the diaphragm. All 11 patients who developed recurrent disease were alive without evidence of Hodgkin’s disease at the time of last follow-up. The 5-year FFTF in the 43 stage I patients was 92% compared with 78% in the 40 stage II patients (P = .04). Significant differences in FFTF were not seen by histology (P = .26) or by European Organization for Research and Treatment of Cancer H-5F eligibility (P = .25). CONCLUSION: Mantle irradiation alone in selected patients with early-stage Hodgkin’s disease is associated with disease control rates comparable to those seen with extended field irradiation. The FFTF is especially favorable among stage I patients.
A NUMBER OF therapeutic options are available in the treatment of early-stage Hodgkin’s disease. Mantle and para-aortic-splenic pedicle irradiation after a negative laparotomy, or mantle, para-aortic, and splenic irradiation without a laparotomy or, in some cases, a combination of chemotherapy and radiation therapy has traditionally been the standard treatment in early-stage Hodgkin’s disease. Another option for selected patients with early-stage disease is radiation treatment to a mantle field alone after a negative staging laparotomy.1-4 The advantages of such an approach are that with the more limited radiation field, the long-term risks of bowel complications and second malignancies are reduced.5-9 Patients are also spared the toxicity of chemotherapy, and they benefit from a higher probability of successful salvage if a relapse were to occur.10,11 Furthermore, compared with extended field irradiation or combined-modality therapy, mantle radiation therapy alone for pathologically staged, early-stage disease is generally associated with fewer acute side effects and requires shorter treatment time, with treatment typically completed within 5 weeks. This strategy may be less expensive to society, both in terms of direct medical costs and costs due to lost productivity. However, staging laparotomy may not be 100% accurate in establishing absence of occult disease in the abdomen, as evidenced by the higher risk of abdominal relapse observed in patients treated with a mantle field alone despite a negative staging laparotomy. Moreover, the reliance on staging laparotomy and splenectomy in the selection of patients for mantle radiation therapy alone exposes patients to the risks of both surgery and infection due to the lack of a spleen,5,12-15 although these risks have been reduced with modern surgical techniques and routine administration of effective polysaccharide-conjugate vaccines against encapsulated micro-organisms.16-19 The current study was designed to evaluate the efficacy of mantle radiation therapy alone in selected patients with pathologic confirmation of absence of disease below the diaphragm and in patients with low risk of occult disease in the abdomen.
Between October 1988 and June 2000, 87 patients were entered onto a single-arm prospective trial. Entrance criteria included the following: pathologic stage (PS) IA to IIA or clinical stage (CS) IA Hodgkin’s disease, no B symptoms, absence of large mediastinal adenopathy (defined as > one-third the maximum thoracic diameter on a standing posterior-anterior chest radiograph), and negative radiographic staging of the abdomen by computed tomographic (CT) scanning or lymphangiography. Patients with subcarinal or hilar lymph node disease were excluded. Age more than 40 and stage IIA without upper mediastinal involvement or elevated sedimentation rates (ESR) were not criteria for exclusion. Although there were no specific limits on age and number of sites of disease, none of the patients entered onto this study were more than 54 years of age, and all had fewer than four involved sites at presentation. Thoracic CT and gallium scans were required to document the extent of Hodgkin’s disease above the diaphragm. Before 1995, only patients with nodular sclerosis (NS) or lymphocyte predominant (LP) histology were eligible for the trial, and all patients required a negative staging laparotomy. Since then, several modifications were made to the entrance criteria. The trial became open to patients with PS IA mixed cellularity (MC) Hodgkin’s disease. In addition, all patients with CS IA LP and female patients with CS IA NS Hodgkin’s disease became eligible for the trial without a staging laparotomy. This study was an institutional review board–approved protocol and informed consents were obtained on all enrolled patients. Eighty-three of 87 patients were monitored for  1 year after completion of mantle irradiation and are included for analysis in this study. No patients have been lost to follow-up. The trial has been closed to further accrual. The standard lower border of the mantle field was modified according to the presence or absence of mediastinal disease. For patients without mediastinal involvement, the mantle field included the hilar and subcarinal regions and excluded most of the heart (bottom border at T8 or T9). For patients with upper mediastinal disease, the field was extended to include the low central cardiac nodes (bottom border at T10 or T11). The dose to the mantle field ranged between 30.6 Gy and 40 Gy, and the total dose to the mediastinum was between 30.6 Gy and 44 Gy. At 30 Gy, a subcarinal block was inserted to protect the lower heart. Patient characteristics are listed in Table 1. Of the 77 patients who were pathologically staged, 37 had PS IA and 40 had PS IIA disease. The remaining six patients had CS IA disease with either LP or NS histology. Histologic distribution was as follows: 64 patients had NS, 15 had LP, three had MC, and one patient had Hodgkin’s disease without further subclassification. Compared with the 215 patients with PS IA, PS IIA, and CS IA Hodgkin’s disease seen at our institution between 1988 and 1997, there were more PS IA patients but fewer CS IA patients enrolled onto this trial. Of the total of 215 patients seen during this time period, 61 patients (28%) presented with PS IA disease, 109 patients (51%) presented with PS IIA disease, and 45 patients (21%) presented with CS IA disease. On completion of treatment, patients were observed every 3 months for the first 2 years, every 4 months in the third year, twice a year in the fourth and fifth years, and once a year thereafter. At each follow-up visit, a history and physical examination, complete blood count, thyroid function tests, and chest radiography were obtained. Gallium and/or abdominal pelvic CT scans were obtained every 6 to 12 months for the first 5 years. The median follow-up time was 61 months.
The actuarial freedom from first relapse and survival from the end of mantle irradiation were calculated using the Kaplan-Meier technique. Freedom from first relapse was calculated scoring only initial relapses as events. Survival was calculated scoring death from all causes as events. Comparisons between curves were made using a two-tailed log-rank test. P values  .05 were considered statistically significant.
The 5-year actuarial rates of freedom from treatment failure (FFTF) and overall survival for the 83 patients included for analysis were 86% and 100%, respectively ( Fig 1). Eleven of 83 patients relapsed. The timing and sites of relapse, treatment, and outcome for the 11 patients are summarized in Table 2. The median time to first relapse from the end of initial treatment was 27 months (range, 5 to 62 months). Nine of the relapses involved one or more sites below the diaphragm, but only two were limited to sites that would have been covered by a para-aortic field. Among the 11 patients who relapsed, six were treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone, and five received six cycles of ABVD followed by involved field radiation therapy. One patient had a second recurrence, underwent high-dose chemotherapy and autologous stem-cell rescue, and is currently living without Hodgkin’s disease 7 months after her transplant. The 5-year actuarial rate of freedom from second relapse was 89%. All 11 patients who developed recurrent disease were alive without evidence of Hodgkin’s disease at the time of follow-up.
Actuarial FFTF was calculated for selected subgroups based on established prognostic factors. Patients were separated according to whether they met the European Organization for Research and Treatment of Cancer (EORTC) H-5F trial eligibility criteria.20 The H-5F trial included all patients with CS I or CS II with mediastinal involvement. Only patients with NS or LP histology, age 40 years, an ESR 70, and a negative staging laparotomy were included. The 5-year actuarial FFTF for the 63 patients who were EORTC H-5F eligible was 83%, compared with 94% for the 20 patients who were EORTC H-5F ineligible (P = .25) ( Fig 2). No significant difference in FFTF was seen between patients with LP histology (n = 15, 5-year FFTF, 100%) and patients with NS, MC, or unclassifiable histology (n = 68, 5-year FFTF, 82%, P = .26) ( Fig 3). The 43 patients with stage IA disease had a FFTF at 5 years of 92%, compared with 78% for the 40 patients with stage IIA disease (P = .04) ( Fig 4).
Thirty patients (36%) had an elevated thyroid-stimulating hormone level and/or clinical hypothyroidism that required supplemental thyroid medication ( Table 3). The median time to thyroid dysfunction was 21 months (range, 5 to 115 months). One patient, who relapsed 5 months after initial treatment and received salvage treatment of six cycles of ABVD followed by para-aortic irradiation, developed cardiomyopathy 29 months after the salvage therapy. Her cardiac function is currently within normal range on medications, and she is living disease-free 38 months after her initial diagnosis of Hodgkin’s disease. One woman, age 36 at the time of diagnosis, developed ductal carcinoma-in-situ with microinvasion of the breast 27 months after mantle irradiation. Another patient, age 28 at diagnosis, developed invasive carcinoma of the breast 91 months after initial radiation therapy. Both patients underwent modified radical mastectomy, and are living without disease. One patient, age 17 at diagnosis and with a known history of cocaine abuse, had a myocardial infarction 40 months after mantle irradiation and subsequently developed a stroke, which was believed to be a result of his continued cocaine use. He is living without disease 61 months from treatment but has severe sequelae from his cerebral vascular accident.
The role of prophylactic abdominal irradiation in patients with early-stage Hodgkin’s disease after a negative staging laparotomy has been addressed by a number of investigators. The EORTC conducted a prospective randomized trial comparing mantle and para-aortic-splenic pedicle irradiation with mantle irradiation alone in selected PS I to II patients.4 Eligibility criteria for the H5-F study included NS or LP histology, age 40, all PS I, PS II if mediastinal adenopathy was present, and an ESR of less than 70. The 9-year disease-free survival rates for the mantle radiation therapy alone arm and the mantle and para-aortic-splenic pedicle irradiation arm were 69% and 70%, respectively. The overall survival rates were 94% and 91%, respectively. At 15 years of follow-up, there were no statistically significant differences in relapse rates or overall survival rates between the two treatment groups.21 Of note, the overall disease-control rates in both arms were low compared with results from single-institution studies, possibly reflecting the difficulty in maintaining uniform treatment quality in large multi-institutional trials.1,2,22 Our current trial was conducted in a single tertiary care center, where the staging laparotomies were performed by experienced surgeons and the radiation oncology techniques were administered by a limited number of physicians given treatment guidelines. Careful follow-up was maintained. Unlike the EORTC trial, our study did not exclude patients who were over the age of 40, and all patients with PS II disease were included regardless of the presence or absence of mediastinal disease. In the current study, these did not seem to be adverse features. In addition, we detailed the anatomic definition of mediastinal involvement as part of the eligibility criteria to more precisely define a group of early-stage patients with a favorable prognosis for whom this treatment might be appropriate. There have also been several retrospective studies looking at mantle radiation treatment only in patients with pathologically staged, early-stage disease. At St Bartholomew’s Hospital in London, cases of PS IA Hodgkin’s disease treated with mantle (n = 62) and inverted-Y (n = 4) irradiation alone were retrospectively reviewed.22 All histologic subtypes, including MC histology, were included in the study. Nine of the 66 patients relapsed, yielding a 15-year actuarial freedom-from-relapse rate of 80%. The 15-year actuarial cause-specific survival rate was more than 90%, with only one of the nine patients who relapsed dying of Hodgkin’s disease. These results support the premise that outcome is favorable with mantle radiation treatment alone in selected patients with early-stage disease. Another retrospective study from M.D. Anderson Cancer Center (Houston, TX) on 146 patients with PS I or II Hodgkin’s disease was recently reported in abstract form.23 In that study, 65% of the patients had PS II disease, and 5% had B symptoms at the time of presentation. All histologic subtypes were included in the analysis. At a median follow-up of 12 years, the 10-year actuarial freedom-from-progression rate was 75%, and the 10-year actuarial overall survival rate was 89%. The higher relapse rate observed in this study emphasizes the need to identify subgroups of patients in whom the radiation treatment to the para-aortic region can be safely omitted. With the diminishing use of staging laparotomy in Hodgkin’s disease, the identification of patients who can be treated with mantle radiation therapy alone without a staging laparotomy is of increasing importance. Earlier trials examining use of mantle irradiation alone in clinically staged patients have been disappointing, showing unacceptably high relapse rates. In the EORTC H1 trial, in which CS I and II patients were randomized to mantle radiation therapy alone versus mantle radiation followed by 2 years of weekly vinblastine, the 15-year disease-free survival rates of the two arms were 38% and 60% (P < .001), and the 15-year overall survival rates were 58% and 65% (P = .15), respectively.4 The high relapse rates observed in both treatment arms reflect the inadequacy of limited field radiation therapy in unselected patients. However, careful selection using prognostic criteria to predict a low risk of occult abdominal involvement may yield a subset of patients for whom radiation to a mantle field alone without a staging laparotomy is adequate treatment. A retrospective study from Princess Margaret Hospital in Toronto, Canada, of 130 CS I and II patients treated with mantle or inverted-Y irradiation alone showed 10-year freedom-from-relapse rates in CS IA (n = 37), IIA (n = 84), and I-IIB (n = 9) of 81%, 54%, and 67%, respectively, suggesting a reasonable disease-control rate in patients with stage I disease.22 This subject has been explored prospectively by the EORTC H7-VF and H8-VF trials in which a selected group of favorable patients, defined as women younger than 40 years of age with CS IA LP or NS histology, and an ESR less than 50 mm, were treated with mantle radiation therapy alone without pathologic staging. Results on 40 patients enrolled onto the H7-VF trial showed 6-year event-free survival, relapse-free survival, and overall survival rates of 66%, 73%, and 96%, respectively.24 The relapse rate was thought to be unacceptably high and this trial has been closed. Whether a relapse rate of 27% is high enough to justify the premature discontinuation of the trial, especially given the minimal initial therapy and the high rate of survival, is debatable. The trial also did not capture other potential advantages of this treatment approach, including improved patient quality of life and reduced late toxicities. Based on data estimating the likelihood of upstaging in relation to clinical characteristics, our current practice is to treat patients with a low risk of occult abdominal disease, including patients with CS IA LP disease, CS IA females, and CS IA males with high neck disease, with mantle irradiation alone without a staging laparotomy.25,26 Among the various treatment options for selected early-stage Hodgkin’s disease, radiation therapy to a mantle field alone entails the shortest treatment duration, results in the fewest acute and likely long-term side effects, and has a high salvage potential in cases of relapse. Results of our prospective study showed that treatment with mantle irradiation alone in a well-defined group of patients with early-stage Hodgkin’s disease yielded a disease-control rate comparable to that of extended field radiation therapy. The freedom from relapse was especially favorable among patients with stage I disease. The pattern of relapse shows predominance of recurrent disease below the diaphragm as at least a component of the failure. However, given follow-up surveillance with patient visits every 3 to 4 months for 3 years and every 6 months in the fourth and fifth year, and abdominal-pelvic CT scans and/or gallium scans every 6 to 12 months for the first 5 years, relapses have been detected quickly and salvage therapy has been successful.
1. Ganesan TS, Wrigley PF, Murray PA, et al: Radiotherapy for stage I Hodgkin’s disease: Twenty years’ experience at St Bartholomew’s Hospital. Br J Cancer 62: 314-318, 1990[Medline] 2. Jones E, Mauch P: Limited radiation therapy for selected patients with pathological stages IA and IIA Hodgkin’s disease. Semin Radiat Oncol 6: 162-171, 1996[Medline] 3. Mauch PM, Canellos GP, Shulman LN, et al: Mantle irradiation alone for selected patients with laparotomy-staged IA to IIA Hodgkin’s disease: Preliminary results of a prospective trial. J Clin Oncol 13: 947-952, 1995[Abstract]
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Tubiana M, Henry-Amar M, Carde P, et al: Toward comprehensive management tailored to prognostic factors of patients with clinical stages of I and II in Hodgkin’s disease: The EORTC Lymphoma Group controlled clinical trials—1964-1987. Blood 73: 47-56, 1989 5. Morris DM, Coleman JJ, Slawson RG, et al: Effect of postoperative radiotherapy on the development of small bowel obstruction in patients undergoing staging laparotomy for Hodgkin’s disease. Am J Clin Oncol 8: 463-467, 1985[Medline] 6. Swerdlow A, Barber J, Horwich A, et al: Second malignancy in patients with Hodgkin’s disease treated at the Royal Marsden Hospital. Br J Cancer 75: 116-123, 1997[Medline]
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Henry-Amar M: Second cancer after the treatment for Hodgkin’s disease: A report from the International Data Base on Hodgkin’s Disease. Ann Oncol 3: 117-128, 1992 (suppl 4) 8. Kushner B, Zauker A, Tan C: Second malignancies after childhood Hodgkin’s disease. Cancer 62: 1364-1370, 1988[Medline] 9. Biti G, Cellai E, Magrini S, 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]
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Biti GP, Cimino G, Cartoni C, et al: Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathological-stage I-IIA Hodgkin’s disease: Eight-year update of an Italian prospective randomized study. J Clin Oncol 10: 378-382, 1992 11. Healey EA, Tarbell NJ, Kalish LA, et al: Prognostic factors for patients with Hodgkin’s disease in first relapse. Cancer 71: 2613-2620, 1993[Medline] 12. Jockovich M, Mendenhall NP, Sombeck MD, et al: Long-term complications of laparotomy in Hodgkin’s disease. Ann Surg 219:615-621, discussion 621-624, 1994 13. Hays DM, Ternberg JL, Chen TT, et al: Complications related to 234 staging laparotomies performed in the Intergroup Hodgkin’s Disease in Childhood study. Surgery 96: 471-478, 1984[Medline] 14. Hays DM, Ternberg JL, Chen TT, et al: Postsplenectomy sepsis and other complications following staging laparotomy for Hodgkin’s disease in childhood. J Pediatr Surg 21: 628-632, 1986[Medline] 15. Wobbes T, Lubbers EJ, de Pauw BE: Results and complications of staging laparotomy in Hodgkin’s disease. J Surg Oncol 26: 135-137, 1984[Medline] 16. Chan C, Molrine D, George S, et al: Pneumococcal conjugate vaccine primes for antibody response to polysaccharide pneumococcal vaccine following treatment of Hodgkin’s disease. J Infect Disease 173: 256-258, 1996[Medline] 17. Molrine D, George S, Tarbell N, et al: Antibody responses to polysaccharide and polysaccharide-conjugate vaccines following treatment for Hodgkin’s disease. Ann Intern Med 123: 824-828, 1995 18. Grimfors G, Soderquist M, Holar G, et al: A longitudinal study of class and subclass of antibody response to pneumococcal vaccination in splenectomized individuals with special reference to patients with Hodgkin’s disease. Eur J Haematol 45: 101-108, 1990[Medline] 19. Siber G, Gorham C, Martin P, et al: Antibody response to pretreatment immunization and post-treatment boosting with bacterial polysaccharide vaccines in patients with Hodgkin’s disease. Ann Intern Med 104: 467-475, 1986 20. Carde P, Burgers JM, Henry-Amar M, et al: Clinical stages I and II Hodgkin’s disease: A specifically tailored therapy according to prognostic factors. J Clin Oncol 6: 239-252, 1988[Abstract] 21. Cosset JM, Henry-Amar M, Noordyk E, et al: The EORTC trials for adult patients with early-stage Hodgkin’s disease: A 1997 update. American Society for Therapeutic Radiology and Oncology Syllabus, 1997 22. 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] 23. Liao Z, Ha C, Vlachaki M, et al: Mantle irradiation alone for pathologic stage I and II Hodgkin’s disease: Long-term follow-up and patterns of failure. Proc Am Soc Ther Radiol Oncol 45: 216, 1999 (abstr, suppl 3) 24. Noordijk E, 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’ and ’H7-U’. Proc Am Soc Ther Radiol Oncol 39: 173, 1997 (abstr, suppl 2) 25. Leibenhaut M, Hoppe R, Efron B, et al: Prognostic indicators of laparotomy findings in clinical stage I-II supradiaphragmatic Hodgkin’s disease. J Clin Oncol 7: 81-85, 1989[Abstract] 26. Mauch PM, Larson D, Osteen R, et al: Prognostic factors for positive surgical staging in patients with Hodgkin’s disease. J Clin Oncol 8: 257-262, 1990[Abstract] Submitted July 25, 2000; accepted September 18, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
