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Originally published as JCO Early Release 10.1200/JCO.2004.12.170 on June 15 2004 © 2004 American Society of Clinical Oncology. ABVD Plus Subtotal Nodal Versus Involved-Field Radiotherapy in Early-Stage Hodgkin's Disease: Long-Term ResultsFrom the Department of Medical Oncology, Department of Radiotherapy, and Department of Anesthesiology and Emergency Patient Care, Istituto Nazionale Tumori, Milano, Italy Address reprint requests to Gianni Bonadonna, MD, FRCP, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milano, Italy; e-mail: gianni.bonadonna{at}istitutotumori.mi.it
PURPOSE: Radiation therapy (RT) alone can cure more than 80% of all patients with pathologic stage IA, IB, and IIA Hodgkin's disease, but some prognostic factors unfavorably affect treatment outcome. Combined-modality approaches improved results compared with RT, but the optimal extent of RT fields when combined with chemotherapy warranted additional evaluation. PATIENTS AND METHODS: In February 1990, we activated a prospective trial in patients with early, clinically staged Hodgkin's disease to assess efficacy and tolerability of four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by either subtotal nodal plus spleen irradiation (STNI) or involved-field radiotherapy (IFRT). RESULTS: Main patient characteristics were fairly well balanced between the two arms. Complete remission was achieved in 100% and in 97% of patients, respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to 100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT, whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94% (95% CI, 89% to 100%), respectively. Apart from three patients who developed second malignancies in the STNI arm, treatment-related morbidities were mild. CONCLUSION: Present long-term findings suggest that, after four cycles of ABVD, IFRT can achieve a worthwhile outcome. The limited size of our patient sample, however, had no adequate statistical power to test for noninferiority of IFRT versus STNI. Despite this, ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkin's disease with both favorable and unfavorable presentation.
Long-term follow-up of laparotomy-staged patients treated with extensive subtotal nodal radiation therapy (RT) alone have reported a 10-year relapse-free survival of 75% to 85% for early stages of Hodgkin's disease.1-3 Patients presenting with unfavorable indicators (such as bulky disease, pulmonary hilus involvement, and extranodal lesions) remain at risk of experiencing local and distant relapses despite extensive irradiation.4-7 To decrease the risk of failure of RT treatment, a combined-modality approach with both RT and chemotherapy was proposed, particularly in patients with unfavorable prognostic factors. With this approach, approximately 90% of patients can be cured of their disease; even in less favorable settings, combined-modality therapy can achieve a relapse-free survival of approximately 75%.8,9 Although the various combined approaches tested so far have resulted in a superior outcome compared with RT alone in terms of disease-free survival improvement, few studies could demonstrate a long-term survival advantage. In fact, patients experiencing disease relapse from RT alone could be successfully treated with salvage chemotherapy.10-12 A major argument against the use of combined modality as first-line therapy in early-stage Hodgkin's disease seems to be an increased risk of iatrogenic morbidity and mortality relative to the use of anticancer drugs, especially alkylating agents, associated with extensive irradiation. The occurrence of iatrogenic sequelae probably could be prevented by avoiding the need of staging laparotomy and splenectomy, using less toxic but effective combination regimens to control occult sites of the disease, and reducing the doses and fields of RT. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy currently is considered the gold standard for Hodgkin's disease and it is associated with a significantly lower potential for leukemogenesis and gonadal toxicity.13-16 In February 1990, we chose to use this regimen and activated a prospective study in patients with clinical stages (CS) IA, IB, and IIA disease testing four cycles of ABVD chemotherapy followed by subtotal nodal plus spleen irradiation (STNI) versus four cycles of ABVD followed by involved-field radiotherapy (IFRT). The aim of this article is to present the final results in terms of both treatment efficacy and iatrogenic sequelae.
Patient Eligibility and Study Design Since February 1990, consecutive patients aged between 16 and 70 years, with untreated early-stage (I unfavorable, IIA), biopsy-confirmed Hodgkin's disease were eligible for this randomized study. Eligibility assessment included medical history and physical examination; routine laboratory tests with CBC and leukocyte differential; and renal and liver function tests. Procedures to define CS included chest x-ray; chest, abdominal, and pelvic computed tomography (CT) or magnetic resonance imaging (MRI); bipedal lymphangiogram; gallium scan; and bilateral posterior iliac crest bone marrow biopsies. On completion of staging procedures, eligible patients were stratified according to CS and disease presentation (ie, CS I unfavorable, CS IIA favorable, and CS IIA unfavorable). The unfavorable group included at least one of the following characteristics: bulky disease (defined as mediastinal mass greater than one third of the thoracic diameter and/or nodal disease > 10 cm), pulmonary hilus involvement, contiguous extranodal extent and, limited to stage I patients, presence of systemic symptoms (ie, fever, night sweats, or weight loss greater than 10% of baseline body weight).
Chemotherapy Treatment
RT Treatment Daily fractionation, for treatments either above or below the diaphragm, was 0.90 + 0.90 Gy for 5 days per week, and was given through anteroposterior and posteroanterior equally weighted portals, usually using a 6-MV linear accelerator for the supradiaphragmatic irradiation and a 6- or 18-MV linear accelerator, depending on the thickness of the area, for the infradiaphragmatic treatments. Source-to-skin distance was 110 to 120 cm for supradiaphragmatic RT, and 120 cm or more for infradiaphragmatic RT. Portal films were obtained at the treatment unit on day 1 and during treatment. Personalized immobilization devices were used for each patient requiring supradiaphragmatic irradiation. Target volumes were defined on the basis of postchemotherapy nodal dimensions and delineation was obtained on standard x-ray. No CT simulation or computerized treatment plans were performed. After setup was planned at a conventional simulator, personalized shields were obtained in all the patients with more than one site to be treated, using 10-cm-thick personalized blocks (corresponding to five half-value layers). In patients allocated to received IFRT, irradiation was to be administered to all initially involved regions with one single field, whenever possible. In Hodgkin's disease limited to the neck, the upper limit of the field was 1 cm above the apex of the mastoid and the lower margin was designated above sternoclavicular joint. When the supraclavicular region was involved, the whole homolateral neck was treated. Irradiation of the mediastinum was extended to both hilar nodes, the upper limit was the top of T1 and the lower limit usually was placed at T8-9. The limits of the lung blocks were at 4 to 5 cm from the lower border of the clavicle, 1 cm inside the inner margin of the ribs, and at 1 to 2 cm laterally to the hilar regions. In patients presenting with involvement of mediastinum, neck, and axillae, mantle irradiation was planned. A two-dimensional map of the dose distribution was prepared to calculate different thickness in several points (two for neck, two for mediastinum, and one for axilla) and daily dose was calculated to be given at the midplane in the central axis. During the treatment, when the prescribed dose was reached at one or more sites, the sites were excluded from irradiation either by the use of external blocks or by the creation of a new personalized shield. The thoracic spinal cord was never shielded, whereas the irradiation to the cervical cord was blocked after 23.4 Gy, from C1 to the lower margin of C7, and in the posteroanterior field only when the planned dose to the neck was 36 Gy or higher. Subcarinal blocks for heart shielding were never used. In patients presenting with subdiaphragmatic disease, only the involved nodal regions were to be irradiated. The upper limit of the para-aortic field was tailored by leaving a gap of one vertebral body from the lower limit of the mediastinal field; the lower limit included L4. Daily dose was calculated at the midplane of the patient's thickness measured on the central axis. Personalized shields were adopted. In patients allocated to receive STNI, mantle RT, as previously described, was started first and was followed by irradiation to the subdiaphragmatic region, which included the para-aortic nodes and the spleen. Pelvic nodes were irradiated only if involved at diagnosis.
Toxicity Evaluation
Follow-Up Evaluation and Response Assessment Treatment response was assessed clinically and by repeating all CT, MRI, and gallium scans that were positive at diagnosis; these tests were performed within 4 weeks from the completion of ABVD chemotherapy and, if still positive, they were repeated 1 month from the end of RT or until normalization. Residual radiographic abnormalities, particularly in the mediastinum, were noted frequently at the conclusion of chemotherapy and RT by chest x-ray, CT, and/or MRI. In these patients, assessment of remission according to the Cotswold’s criteria17 was performed using additional findings achieved with gallium scan evaluation.
Percentage of Optimal Dose and Dose-Intensity of ABVD The rate of administration was calculated by dividing the actual number of weeks of treatment by the planned number of weeks (ie, 10 weeks from day 1 of cycle 1 to day 15 of cycle 4). Received dose-intensity was calculated by dividing the percentage of optimal drug dosage by the rate of drug treatment.
Statistical Analysis Freedom from progression was considered as the time elapsed from the date chemotherapy was started to the first documented treatment failure, whereas event-free survival also included second malignancies and deaths unrelated to Hodgkin's disease and its treatment. Death from all causes was taken as the end point for total survival, which was also measured from the date chemotherapy was started. The patterns of freedom from progression and total survival were estimated by means of the Kaplan-Meier product limit method.18 Assessment of differences in respiratory test values before and after treatment and during follow-up was made by use of the t test for paired samples. All data relative to the study herein reported were managed and analyzed according to the standard operating procedures of the Operations Office of the Istituto Nazionale Tumori (Milan, Italy). This analysis was carried out on data available as of Octo-ber 31, 2003. Only one patient in complete clinical remission was lost to follow-up after 8 months.
Patient Population and Disease Extent From February 1990 to July 1996, a total of 140 consecutive patients were entered onto this trial and 136 eligible patients are assessable after a median follow-up of 116 months (range, 1 to 157 months). Four patients were not considered eligible because of stage III and IV disease (two patients) and refusal to be treated in our institute (two patients). According the randomization, in 66 patients RT consisted of subtotal nodal plus spleen irradiation (STNI), whereas in 70 patients RT was limited to the previous involved sites only (IFRT). Table 1 shows the main characteristics according to the two treatment groups. Overall, the majority of patients were younger than 40 years and the median age was 29 years (range, 17 to 64 years). Nodular sclerosis histology accounted for 73% and 80% of patients in the STNI versus IFRT arm, respectively. In CS I, only three (4.5%) and five (7%) patients in each group had systemic symptoms (CS IB); there were three (4.5%) and four (6%) patients in each group with CS IA unfavorable disease, respectively. The great majority of patients had CS IIA with a favorable presentation (59% and 60%, respectively). The supradiaphragmatic presentation was the rule; in fact, subdiaphragmatic disease was documented in only two patients in each treatment group (3% and 3%, respectively). Extranodal sites of disease included lung, pleura, and pericardium.
Complete Remission All of the 66 patients allocated to extensive irradiation received STNI as planned and achieved complete remission at the end of the combined-modality treatment; the rate of complete remission was 91% after ABVD alone. One of the 70 patients allocated to ABVD followed by IFRT died as a result of a myocardial infarction during the second ABVD cycle and the autopsy revealed a complete disappearance of all sites of the lymphoma. All other patients received IFRT as planned and the rate of complete remission after combined-modality treatment was 97%, 86% of which were documented after ABVD alone. One patient achieved a partial response during ABVD, but showed disease progression while receiving RT. A second patient was classified as a partial responder at the end of combined therapy, but normalization of all radiologic signs was documented during the follow-up. Overall, ABVD alone was able to achieve clinical complete remission in 89% of the patients; in one third of the patients, complete remission was documented within the third cycle.
Long-Term Treatment Outcome
Table 2 shows freedom from progression related to the two treatment groups and to patient characteristics and disease presentation. As shown in Figure 2, a total of six patients have died within 12 years from starting treatment (four in the group given limited irradiation and two in the group given extensive RT), for a total survival rate of 94% and 96%, respectively. In the IFRT arm, two patients died as a result of lymphoma progression and one patient died as a result of myocardial infarction during the second ABVD cycle; the remaining patient died as a result of fatal hepatitis. In the STNI arm, one patient died as a result of lymphoma progression and the other patient died as a result of acute leukemia while in complete remission.
Second Malignancies Three patients in the STNI arm (4.5%) developed second malignancies while in complete remission. One patient developed acute leukemia 18 months from the start of ABVD and died 39 months later. The other two patients presented sigmoid adenocarcinoma (22 months after the start of chemotherapy) and breast cancer (105 months after the start of ABVD) and at present are alive and in complete remission.
Treatment Compliance and Acute Toxicity Weekly assessments of blood cell counts performed during irradiation showed that acute toxicity was mild and no treatment interruptions were required. Median duration of the combined treatment was 7 months (range, 6 to 9 months) for patients enrolled in the STNI arm, whereas it was 6 months (range, 5 to 9 months) for the patients enrolled in the IFRT arm.
Cardiac and Pulmonary Toxicity
Respiratory function parameters were assessed before therapy, and repeated after completion of irradiation and after a median follow-up of 42 months (range, 21 to 61 months) from the end of all therapies (Table 3). Radiotherapy to the mediastinum was delivered in a total of 86% of the patients assessed for pulmonary toxicity. The time course of spirometric parameters and DLCO showed a significant decrease between baseline values and post-treatment values (P < .001), but at the last follow-up examination significant differences from baseline were detected only for total lung capacity (P = .03) or DLCO (P = .004); these tests are indicative of a subclinical restrictive syndrome. Asymptomatic decline in DLCO
Fourteen patients (seven in each treatment group) had pulmonary symptoms; 10 developed dry cough and four had mild dyspnea on exertion. Two patients were treated with low doses of corticosteroids and none of the patients developed chronic symptomatic pulmonary disease. Radiologic findings of interstitial fibrosis were present in 19 patients and were grade 1 (slight radiographic appearances) in 10 patients and grade 2 (patchy radiographic appearances) in nine patients.
Gonadal Toxicity
In the early 1990s, when this study was designed and activated, conventional treatment for patients with early-stage Hodgkin's disease still consisted of laparotomy and extensive irradiation to include the mantle field and para-aortic area.19 The fairly high rate of disease recurrence after this treatment modality, especially in patients with unfavorable prognostic features, prompted some investigators to assess the effectiveness of chemotherapy or combined chemoradiotherapy in this subset of patients.20 Despite a significantly improved disease-free survival, no apparent effects could be demonstrated on overall survival because recurrence after RT alone could be cured by salvage chemotherapy. As patients began to survive longer after the successful treatment of Hodgkin's disease, other problems were documented in these patients at a greater frequency than one would expect in an age-matched population. Apart from late sepsis in splenectomized patients who also could suffer from complications of abdominal surgery, other major problems associated with RT and specific drug therapy were second malignancies, heart and lung disease, and sterility.22-24 In an attempt to avoid (or at least decrease) the occurrence of these sequelae, less extensive irradiation was proposed and the well-known mechlorethamine, vincristine, procarbazine, and prednisone regimen was replaced by less toxic and potentially nonleukemogenic combinations.20 In contrast to the results reported in the meta-analysis published by Specht et al,9 in which less extensive RT was associated to a higher risk of recurrence (43%) than more extensive irradiation (31%), in our case series the risks of recurrence were 6% (95% CI, 0% to 12%) after four cycles of ABVD followed by IFRT and 7% (95% CI, 0% to 17%) after four cycles of ABVD followed by STNI. Our treatment results compare favorably with other reported series. In fact, patients with stage I to II disease treated with the Stanford V regimen (vinblastine, doxorubicin, vincristine, bleomycin, nitrogen mustard, etoposide, and prednisone) could achieve a 5-year freedom from progression of approximately 97% at the expense of minimal late toxicity.24 However, in contrast with the Stanford V regimen, none of the patients treated with ABVD and irradiation required either hospitalization or supportive therapy with granulocyte colony-stimulating factor. In the large case series of patients with early-stage unfavorable Hodgkin's disease treated in the German Hodgkin's lymphoma study,25 5-year freedom from treatment failure (98.5% v 97.2%) and overall survival (90.8% v 92.4%) revealed no difference after four courses of cyclophosphamide, vincristine, procarbazine, and prednisone + ABVD followed respectively by extended-field RT or IFRT. In the German study, however, the 5-year incidence of second malignancies was 2.8% after IFRT, whereas we failed to observe any occurrence of second tumors after ABVD followed by IFRT at a median period of observation as long as 9.7 years. Finally, an abstract format the Canadian Study Group26 reported that in early-stage disease, two cycles of ABVD and irradiation had superior 5-year therapeutic results (93%) compared with single-modality ABVD (87%). Additional details and a longer follow-up are required to assess the true therapeutic ratio of the two treatment modalities. In our study, iatrogenic sequelae other than second malignancies also were rare. Apart from the patient who died because of an acute myocardial infarction after the second cycle of ABVD, one other patient presented infarction during the follow-up, whereas decreases in LVEF were transient and asymptomatic. Similarly, pulmonary late toxicity was low; the vast majority of patients were asymptomatic or presented mild symptoms of grade 1 to 2 lung fibrosis. Abnormalities in respiratory function tests were mainly transient and only DLCO and total lung capacity (ie, tests showing a minor restrictive disease) continued to be abnormal during the follow-up in a minority of patients who, however, remained asymptomatic. Present long-term findings suggest that after four cycles of ABVD, IFRT can achieve a worthwhile outcome. The limited size of our patient sample, however, had no adequate statistical power to test for noninferiority of IFRT versus STNI. Despite this, ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkin's disease with both favorable and unfavorable presentation.
The authors indicated no potential conflicts of interest.
We thank all of the patients who participated in our clinical trial. We also thank Armando Santoro, Marcello Zanini, Fulvia Soncini, and Lilli Devizzi for their invaluable advice during the planning and the conduct of the study, and Mrs. Annabella Di Florio for data management.
Supported in part by Associazione Italiana Ricerca sul Cancro, Milano, Italy. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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5. Tubiana M, Henry-Amar M, Carde P, et al: Towards comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease: The EORTC Lymphoma Group controlled clinical trials—1964-1987. Blood 73:47-56, 1989
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7. 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 8. Cosset JM, Fermé C, Noordijk EM, et al: Combined modality treatment for poor prognosis stages I and II Hodgkin's disease. Semin Radiat Oncol 6:185-195, 1996[CrossRef][Medline] 9. 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 3888 patients. J Clin Oncol 16:830-843, 1998[Abstract] 10. Zanini M, Viviani S, Santoro A, et al: Extended-field radiotherapy in favorable stage IA-IIA Hodgkin's disease (prognostic role of stage). Int J Radiat Oncol Biol Phys 30:813-819, 1994[Medline] 11. Bonfante V, Santoro A, Viviani S, et al: Early stage Hodgkin's disease: Ten-year results of a nonrandomized study with radiotherapy alone or combined with MOPP. Eur J Cancer 29A:24-29, 1992 12. 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] 13. Bonadonna G, Santoro A: ABVD chemotherapy in the treatment of Hodgkin's disease. Cancer Treat Rev 9:21-35, 1982[Medline]
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15. Valagussa P, Santoro A, Fossati-Bellani F, et al: Second acute leukemia and other malignancies following treatment for Hodgkin's disease. J Clin Oncol 4:830-837, 1986 16. Viviani S, Santoro A, Ragni G, et al: Gonadal toxicity after combination chemotherapy for Hodgkin's disease: Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 21:601-605, 1985[CrossRef][Medline] 17. Lister AT, Crowther D, Sutcliffe SB, et al: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7:1630-1636, 1989[Abstract] 18. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 19. Kaplan H: Hodgkin's Disease. Cambridge, MA, Harvard University Press, 1980 20. Connors JM, Noordijk EM, Horning SJ: Hodgkin's lymphoma: Basing the treatment on the evidence. Hematology (Am Soc Hematol Educ Program) 178-193, 2001 21. van Leeuwen FE, Klokman WJ, Hagenbeek A, et al: Second cancer risk following Hodgkin's disease: A 20-year follow-up study. J Clin Oncol 12:312-325, 1994[Abstract] 22. Valagussa P, Santoro A, Bonadonna G: Thyroid, pulmonary and cardiac sequelae after treatment for Hodgkin's disease. Ann Oncol 3:111-115, 1992 (suppl 4) 23. Schilsky RL, Lewis BJ, Sherins RJ, et al: Gonadal dysfunction in patients receiving chemotherapy for cancer. Ann Intern Med 93:109-114, 1980
24. Horning SJ, Hoppe RT, Breslin S, et al: Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630-637, 2002
25. Engert A, Schiller P, Josting A, et al: Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's Lymphoma: Results of the HD8 Trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol 21:3601-3608, 2003 26. Meyer R, Gospodarowicz M, Connors J, et al: A randomized phase II comparison of single-modality ABVD with a strategy that includes radiation therapy in patients with early-stage Hodgkin's disease: The HD-6 trial of the National Cancer Institute of Canada Clinical Trials Group (Eastern Cooperative Oncology Group Trial JHD06). Blood 102:26a, 2003 (abstr 81) Submitted December 30, 2003; accepted April 23, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
20% from baseline values was recorded in 13 patients (18.8%) allocated to IFRT and in 17 patients (25.7%) allocated to STNI. This decline was documented in 29 of the patients at the end of irradiation, whereas in the remaining two patients it was recorded during the follow-up. Recovery was documented in the vast majority of patients during subsequent examinations, but a decline of approximately 20% from baseline values persisted unchanged after 3 years in six patients who remained asymptomatic. 
