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© 1999 American Society for Clinical Oncology High Cure Rates and Reduced Long-Term Toxicity in Pediatric Hodgkin's Disease: The German-Austrian Multicenter Trial DAL-HD-90From the Department of Pediatric Hematology and Oncology, University Children's Hospital; Department of Radiotherapy and Radiooncology, University of Münster, Münster; Paracelsus Radiation Hospital, Osnabrück; II. Children's Hospital, Berlin-Buch; Department of Pediatric Hematology and Oncology, University Children's Hospital, Düsseldorf; Children's Hospital of the Medical School, Hannover; University Children's Hospital, Dresden; Institute for Hematopathology and Lymph Node Registry of the German Association of Pathologists, University of Kiel, Kiel; Municipal Institute for Pathology, Dortmund, Germany; Department of Radiotherapy, University of Vienna; and the St Anna Children's Hospital, Vienna, Austria. Address reprint requests to Günther Schellong, MD, Univ.-Kinderklinik, Albert-Schweitzer-Straße 33, D-48129 Münster, Germany; email schellon{at}uni-muenster.de
PURPOSE: To further reduce therapy-related late effects in patients with pediatric Hodgkin's disease (HD) while maintaining the high cure rates achieved with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or OPPA/cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) chemotherapy and involved-field radiotherapy. The risk of testicular dysfunction was addressed by substituting etoposide for procarbazine (OEPA) in the induction therapy for boys. Radiation doses and fields were further reduced. PATIENTS AND METHODS: Three hundred nineteen boys and 259 girls younger than 18 years with previously untreated HD, enrolled onto the study between 1990 and 1995, were allocated to treatment group (TG)1 (early stages), TG2 (intermediate stages), or TG3 (advanced stages). All groups underwent two cycles of OEPA (boys) or OPPA (girls) for induction chemotherapy. TG2 and TG3 continued on additional two or four cycles, respectively, of COPP. Low-dose radiotherapy was given to the initially involved sites, ie, reduced involved fields. RESULTS: Initial response to OPPA or OEPA induction was virtually identical. Eight of 578 patients experienced early progression of HD. Thirty-seven relapses, three secondary tumors, and no secondary leukemias have been recorded, with a median follow-up duration of 5.1 years (maximum, 8.1 years). Thirteen of 578 patients died. The probability of 5-year event-free survival/overall survival is 91%/98% in the total group, 94%/97% with OPPA, and 89%/98% with OEPA induction therapy. Risk factor analysis showed two significant prognostic factors: histologic subtype NS2 and "B" symptoms. OEPA induction therapy, large mediastinal tumor, and age were not significant. Preliminary studies of testicular function indicate a lower risk of germ cell damage than previously documented with OPPA. CONCLUSION: OEPA is a satisfactory alternative to OPPA. Radiotherapy can be confined to involved sites when combined with appropriate chemotherapy. The DAL-HD-90 regimen represents a comprehensive treatment program for all stages of pediatric HD and offers a favorable benefit/risk ratio, combining excellent disease control, moderate acute toxicity, and reduced long-term toxicity.
CHILDREN AND adolescents with Hodgkin's disease (HD) have an excellent chance of definitive cure from their malignancy with modern treatment strategies.1,2 Therefore, in many pediatric studies, high priority has been given to the objective of reducing therapy-related late effects.1-11 Combined chemotherapy/radiotherapy has become the preferred treatment approach because it enables a considerable reduction of the intensity of both modalities. One important step was replacing high-dose extended-field radiotherapy with low-dose involved-field (IF) radiotherapy. Possible late sequelae of high-dose radiotherapy include growth impairment of bones and soft tissues; ovarian dysfunction after pelvic irradiation; impairment of lung function; coronary heart disease; hypothyroidism; and secondary solid tumors, especially breast cancer (in females) and thyroid cancer.3,4,12-20 Chemotherapy may also cause late effects: six cycles of mechlorethamine, oncovine, procarbazine, and prednisone (MOPP)21 are followed by azoospermia in the majority of male patients,12,22,23 and by a 2% to 6% risk of secondary leukemias mainly caused by mechlorethamine,4,24-26 whereas doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)27 is associated with a risk of chronic cardiomyopathy and pulmonary dysfunction, especially in children.10-13 Severity and frequencies of these late effects are related to the cumulative total doses of the critical drugs and, in part, combination with radiotherapy.10-12,28 Here we report on the fifth German-Austrian multicenter trial (DAL-HD-90) for pediatric HD. The general objectives of this trial and the previous studies since 1978 have been to reduce the extent of chemotherapy and radiotherapy within a combined-modality treatment, and to develop a chemotherapeutic regimen of high efficacy and low long-term toxicity.2,6,8 From the first study onward, mechlorethamine in MOPP has been replaced by doxorubicin (OPPA) in the two induction cycles and by cyclophosphamide (COPP) in the later courses. The extent of chemotherapy has been limited to two cycles in stages I and IIA, four cycles in stages IIB and IIIA, and six cycles in stages IIIB and IV disease. High-dose extended-field radiotherapy in the first study was later replaced by IF radiotherapy with progressively reduced doses.2,6,8 In addition, the relevance of exploratory laparotomy and splenectomy has been reevaluated, and the frequency markedly reduced.2,6,29 Although the disease control with the OPPA and OPPA/COPP regimens was very favorable, the short- and long-term toxicity was moderate.6,8 The main late effect has been testicular dysfunction in boys, predominantly caused by procarbazine.28 Study HD-85 set out to eliminate procarbazine completely from chemotherapy.6,8 Unfortunately, the frequency of treatment failures was unacceptably high, whereas the overall survival (OS) rate (98%) was not affected. With study HD-90, a second attempt was made to reduce the exposure to procarbazine in boys by replacing this drug in the two induction cycles (OPPA) with etoposide (OEPA). The girls received OPPA again, because they do not suffer gonadal dysfunction with this combination.6,30 The second objective of the study was to diminish further the risk potential for radiotherapy-related sequelae by reducing radiation doses and fields.
All children and adolescents younger than 18 years who were diagnosed with primary, previously untreated HD in the participating hospitals were to be registered with the trial center and enrolled onto the study. Patients with HD as a second malignancy were not included, nor were patients suffering from a preexisting chronic disease that precluded treatment according to protocol.
Diagnostic Work-Up Imaging procedures. Minimal requirements were chest radiographs; ultrasonography of the neck, axillae, abdomen, and pelvis; and computed tomography of the chest, abdomen, and pelvis. Exploratory laparotomy was performed selectively, when equivocal or unequivocal diagnostic imaging abnormalities were found that suggested intraabdominal/retroperitoneal involvement, but splenectomy was omitted. Bone marrow biopsy was mandatory, except in patients with stages IA and IIA disease. When bone involvement was suspected, the following examinations were performed: bone scan, computed tomography or magnetic resonance imaging and radiographs of suspicious sites, as well as biopsy of at least one bony focus. Most of the radiographs and computed tomography and magnetic resonance imaging scans were reviewed by the study center in Münster, Germany, where proposals for radiotherapy of the individual patients were prepared. The Ann Arbor classification was used for the definition of disease stages.33 However, the differentiation between E stages (E lesions) and stage IV was defined in more detail: extralymphatic infiltrations continuing from involved lymphatic structures were classified as E lesions, whereas noncontiguous spread led to the diagnosis of stage IV. Clinical restaging to determine the response was performed after two, four, and six cycles of chemotherapy 6 weeks after completion of radiotherapy. Follow-up examinations were performed quarterly during the first 2 years, semiannually during the third to fifth year, and annually thereafter. Biopsy confirmation of any suspected recurrence was mandatory before salvage therapy was initiated.
Treatment
Radiotherapy was administered to the initially involved areas. However, the classical IF definition as described in the 1960s3 was abandoned for patients in whom lymphomas were initially located only in part of the fields.34 In these instances, radiation was applied only to the involved sites, eg, upper or lower neck, supraclavicular region, upper mediastinum, upper axilla, or upper paraaortic region (details to be published separately). The standard total dose administered was 25 Gy in TG1 and TG2, and 20 Gy in TG3. A boost up to 25 to 35 Gy total dose was given to sites with residual lymphoma that exceeded a volume of 50 mL and/or of 25% of the initial tumor volume after completion of chemotherapy. Initially involved extralymphatic organs (except bone marrow) were irradiated with a dose adapted to the tolerance of the respective normal tissue (eg, 12 Gy to the lungs and kidneys, 15 Gy to the liver). Lungs and kidneys were not irradiated if initially observed foci in these organs disappeared completely after two chemotherapy cycles. Radiotherapy was applied at a dose per fraction of 1.5 to 2.0 Gy (five times per week), usually with linear accelerators, rarely with a cobalt-60 radiation unit. Salvage therapy after disease progression during therapy or first recurrence also consisted of combination treatment.35 High-dose chemotherapy followed by autologous bone marrow transplantation or peripheral stem-cell support was confined to patients with early disease progression/early relapse and second recurrence.
Statistical Methods
Patient Characteristics A total of 588 children and adolescents younger than 18 years with primary HD were enrolled onto the study by 71 hospitals between October 1990 and July 1995. Ten patients had to be excluded because the diagnosis was revised (n = 5) or they had a serious preexisting disease (congenital immunodeficiency syndrome in four patients and previous liver transplantation in one patient). The characteristics of the 578 study patients (319 boys and 259 girls; median age, 13.0 years) are listed in Table 2.
A total of 191 of 578 patients (33%) underwent laparotomy; seven patients (1.2%) underwent splenectomy at the discretion of the surgeons. Eleven of 191 laparotomized patients (5.8%) developed an obstructive ileus that required a second laparotomy after 4 days to 6 years. Other serious postoperative complications were not reported. Eight patients (five boys and three girls) with localized involvement of one to two lymph nodes (stage IA) that were completely removed at biopsy (lymphocyte predominance in seven cases, nodular sclerosis in one) did not receive further therapy, according to the experience of Hansmann et al.41 Two of these boys (lymphocyte predominance) relapsed locally after 23 and 24 months and were then treated according to TG1. All eight patients have been in complete remission for 13 to 76 months, six without any therapy after biopsy.
Twenty-one percent of all patients received a radiation boost of
Treatment Results
In the total group of 578 patients, the probability of EFS and OS at 5 years is 91% and 98%, respectively (Fig 2 and Table 4); in the 259 girls (OPPA induction therapy), those values were 94% and 97%, respectively, and in the 319 boys (OEPA induction therapy), they were 89% and 98%, respectively (Fig 3 and Table 4). The slight difference in EFS is not significant. In TG1, the 5-year EFS probabilities are 95% in girls and 94% in boys (P = .70). There are minor, statistically nonsignificant differences in EFS values in favor of the girls in TG2 (5-year probabilities, 96% v 90%; P = .14) and TG3 (89% v 84%; P = .28). The results by total treatment groups, stages, symptoms, histology, and age groups are listed in Table 4. The values of all of these subgroups (EFS of patients with histologic subtype NS2 excepted) vary in a small range at a high level (EFS, 86% to 99%; OS, 90% to 99.6%). To identify potential prognostic factors that indicate progression/relapse, Cox regression analyses involving 14 parameters were performed. By multivariate analysis, only two parameters remained independent significant risk factors: histologic subtype NS2 (relative risk, 2.8; 95% confidence interval, 1.4 to 5.4; P = .002) and "B" symptoms (relative risk, 2.1; 95% confidence interval, 1.1 to 3.8; P = .002). All other tested factors were not significant, including age, sex (type of induction chemotherapy), stages, TG, and large mediastinal mass.
The acute toxicity of the chemotherapy was generally comparable to that of similar conventional regimens. Nearly all patients developed complete but temporary alopecia. Myelosuppression was mostly mild to moderate. Nadir values corresponding to World Health Organization grades 3 and 4 were recorded after 4.5% and 1.0%, respectively, of all chemotherapy cycles for WBCs, after 1.5% and 0% for platelets, and after 2.4% and 0.3% for hemoglobin. Only less than 1% of patients received hematopoietic growth factors, and less than 1% required transfusions. The beginning of 4.1% of cycles two to six was delayed by
Design and results of the DAL-HD-90 study have arisen from a long-term collaboration of nearly all pediatric oncology departments in Germany and Austria. This study included more than 90% of the children with HD in the two countries (and a considerable number of the adolescents). Hence, the results of the study reflect the standard of patient care in pediatric HD in both countries. The probability of OS and EFS at 5 years in the total group of 578 patients is 98% and 91%, respectively. The median follow-up duration in this comparatively large cohort exceeds 5 years (maximum, 8.1 years). Because most recurrences after combination therapy of childhood HD tend to occur within 2.5 to 3 years,1,2,4-11 the long-term outcome will not change considerably. The treatment results in the girls clearly confirm the previously demonstrated high efficacy of the OPPA and OPPA/COPP regimens,2,6,8 now combined with further reduced radiotherapy. Replacing the two OPPA cycles with OEPA led to similar results in the boys. The slight differences between the sex groups did not reach statistical significance. Considering also the virtually identical initial response, it may be concluded that OEPA is a satisfactory alternative to OPPA induction therapy, and that radiotherapy combined with appropriate chemotherapy can be confined to the involved sites rather than fields and to a standard total dose of 20 to 25 Gy. These favorable results were obtained using a fairly short chemotherapy regimen. Sixty-nine percent of all patients received only two or four cycles; 31% (with the most advanced stages of disease) received six cycles. In stages I and IIA, our study group has successfully used only two cycles of therapy for 20 years.42 The results in TG1, which comprises nearly 50% of the total patient cohort, with the minimized therapy (two cycles of OEPA or OPPA plus low-dose radiotherapy to reduced involved fields), are as favorable as those for early- and favorable-stage disease in other studies using equivalent (eg, three cycles of ABVD)43 or much more intensive therapy.4,5,7,9,11 In the group of patients with advanced-stage disease, ie, mainly stage IIIB/IV (TG3), two cycles of OPPA or OEPA plus four cycles of COPP and low-dose IF radiotherapy led to results (EFS, 86%; OS, 94%) similar to those reported by a Pediatric Oncology Group study that used eight alternating MOPP/ABVD cycles with or without low-dose total nodal radiotherapy,44 and those of the St. Jude Hospital study that used four to five cycles of COP(P) plus three to four cycles of ABVD and low-dose IF radiotherapy.10 Although several multicenter studies reported a particularly poor prognosis in patients with stage IV disease,1,7,9,45 the first German-Austrian studies, HD-78 and HD-82, observed EFS rates exceeding 80%. This was the motivation to initiate an international stage IV study using the described regimen (two cycles of OPPA plus four of COPP and 20-Gy IF radiotherapy). The 7-year EFS rate in 115 patients of this study was 85%.46 An Italian group (Associazione Italiana Ematologia ed Oncologia Pediatrica) confirmed these results with the same treatment regimen in stages IIIB and IV disease and experienced an improved outcome compared with the previous trial with six alternating cycles of MOPP/ABVD plus IF radiotherapy.43 The multivariate analysis of potential prognostic factors indicating progression/relapse showed significant results only for two parameters: histologic subtype NS2 and B symptoms. However, the relative risks do not exceed 3.1 and 2.3, respectively. All other parameters tested were not significant, including age, type of induction chemotherapy, stage, and TG. It may be concluded from these results that the overall treatment concept successfully reduced the impact of most of the known prognostically unfavorable factors.47 In summary, a multitude of data indicate very favorable disease control by the OPPA, OEPA, OPPA/COPP, and OEPA/COPP regimens that might be explained by the relatively high dose-intensity of the two cycles of OPPA or OEPA during the first 8 weeks of therapy. The cumulative total dose of doxorubicin is analogous to three cycles of ABVD, and the total dose of procarbazine, prednisone, and vincristine is analogous to three cycles of MOPP or COPP (12 weeks). One primary objective of all our treatment protocols has been to reduce therapy-related late effects. Although definitive data of the long-term sequelae for study HD-90 will not be available until much later, the risk potential of this protocol can be estimated with some confidence based on the literature, results of our previous studies, and preliminary data from this trial. In 667 patients treated in the previous DAL-HD protocols, the cumulative incidence of secondary leukemias and myelodysplastic syndromes is 0.7% after 10 years and 1.1% after 15 years.48 This is clearly lower than the 2% to 6% reported in patients who received MOPP chemotherapy.4,24-26 In HD-90, which abandoned splenectomy, the incidence might be further reduced because the loss of the spleen has been identified by several investigators24,26 as an independent risk factor for the development of secondary leukemias after HD. On the other hand, introducing etoposide into the chemotherapeutic regimen for boys (OEPA) might increase the risk, although this is rather unlikely considering the total dose (1,000 mg/m2).26,48,49 Moreover, at a median follow-up duration of 5.1 years (maximum, 8.1 years), secondary leukemias and myelodysplastic syndromes have not yet been observed in the patients of this study, although the literature reports a median interval of only 2 to 3 years for leukemias to occur after administration of topoisomerase-II inhibitors such as etoposide.26,49,50 Preliminary studies of testicular function in male patients indicate a lower risk of germ cell damage when procarbazine in OPPA is replaced by etoposide in OEPA.51 All tested 27 male patients who received two cycles of OEPA chemotherapy (TG1) had normal levels of follicle-stimulating hormone and luteinizing hormone at 15 to 22 years of age. In contrast, in previous studies, 11 of 38 patients showed elevated levels of follicle-stimulating hormone after two cycles of OPPA (P = .001).28 It will be necessary to confirm these data by sperm count analyses and/or paternity. However, semen analyses were normal in 23 of 25 adults treated with higher doses of etoposide (2,400 mg/m2 intravenously or 4,800 mg/m2 orally) in a regimen of vincristine, epirubicin, etoposide, and prednisone.52 Two other patients fathered children 2 and 14 months after the final course of chemotherapy. These data demonstrate that testicular function is normal when etoposide is used in treatment protocols such as OEPA or the combination of vincristine, epirubicin, etoposide, and prednisone that do not include agents such as procarbazine, mechlorethamine, cyclophosphamide, or chlorambucil. Remarkably, in the HD-90 protocol, nearly 50% of all male patients received such a therapy of low gonadotoxicity. On the other hand, we observed elevated levels of follicle-stimulating hormone in seven of 19 boys treated with two cycles of OEPA plus two or four cycles of COPP in TG2 and TG3.51 This finding demonstrates again that the procarbazine, and perhaps the cyclophosphamide, of COPP may cause germ cell dysfunction. Because the number of procarbazine-containing cycles of chemotherapy in these patients is smaller than in the previous studies (two and four cycles instead of four and six in TG2 and TG3, respectively), against the background of earlier investigations,28 one might expect that the percentage of males with testicular dysfunction will be reduced after OEPA/COPP compared with OPPA/COPP. Among the more than 1,200 patients treated in the five DAL studies since 1978, one case of (moderate) chronic cardiomyopathy has been observed. Generally, this complication is not very likely to occur considering the total doxorubicin dose of 160 mg/m2 given with two cycles of OPPA or OEPA in the primary therapy.53 The radiotherapy-induced long-term sequelae occur much later than chemotherapy-related late effects. Thus, a long follow-up time is needed until definitive evaluations can be performed. Nevertheless, one may anticipate that the risk of radiotherapy-related late effects in the patients of this study will be considerably reduced because lower doses and smaller radiation fields were used. Moreover, reports in the literature already strongly indicate that the risk of growth impairment,14 coronary heart disease,16,17 pulmonary dysfunction,54 secondary breast cancer,18,20 and thyroid dysfunction6 is smaller when low-dose radiotherapy is given in childhood and adolescent HD. Overall, it may be concluded that the therapy regimen of the DAL-HD-90 study represents a comprehensive, risk-adapted treatment program for all patients with pediatric HD and offers a particularly favorable benefit/risk ratio considering the excellent disease control, the moderate acute toxicity, and the low-risk potential for therapy-related late effects.
Participating Children Hospitals at the Universities/Medical Schools: Aachen, Berlin Charité, Bonn, Dresden, Düsseldorf, Erfurt, Erlangen, Essen, Frankfurt, Freiburg, Gießen, Göttingen, Graz (Austria), Greifswald, Halle, Hamburg, Hannover, Heidelberg, Homburg/Saar, Jena, Kiel, Köln, Leipzig, Lübeck, Magdeburg, München (Kinderklinik München-Schwabing, von Haunersches-Kinderspital, Kinderpoliklinik, Städt. Krankenhaus Harlaching), Münster, Rostock, Tübingen, Ulm, and Würzburg. Participating Children Hospitals and Departments: Kinderklinik Krankenhaus-Zweckverband Augsburg, Städtische Kinderklinik Bayreuth; Kinderklinik Klinikum Berlin-Buch, Städtische Kinderklinik Braunschweig, Prof.-Hess-Kinderklinik Bremen, Allgemeines Krankenhaus Celle, Carl-Thiem-Klinikum Cottbus, Vestische Kinderklinik Datteln, Städtische Kinderklinik Dortmund, Städtische Kinderklinik Dresden-Neustadt, Gemeinschaftskrankenhaus Herdecke, Städtische Kinderklinik Karlsruhe, Park Schönefeld Kinderklinik Kassel, Städtische Kinderklinik Kassel, Allgemeines Krankenhaus Klagenfurt (Austria), Städtisches Krankenhaus Kemperhof Koblenz, Städtische Kinderklinik Köln, Städtische Kinderklinik Krefeld, Landeskinderkrankenhaus Linz (Austria), St. Annastiftskrankenhaus Ludwigshafen, Städtische Kinderklinik Mannheim, Kinderklinik Minden, Kinderklinik Neuwerk Mönchengladbach, Friedrich-Ebert-Krankenhaus Neumünster, Cnopf'sche Kinderklinik Nürnberg, Städtische Kinderklinik Nürnberg, Kinderhospital Osnabrück, Marienhospital Osnabrück, Kinderklinik Winterbergkliniken Saarbrücken, DRK Kinderklinik Siegen, Johanniter-Kinderklinik St. Augustin, Kinderklinik Olgahospital Stuttgart, Krankenanstalten Mutterhaus der Borromäerinnen Trier, St.-Anna-Kinderspital Wien (Austria), Reinhard-Nieter-Krankenhaus Wilhelmshaven, Stadtkrankenhaus Wolfsburg, and Kinderklinikum Barmen-Wuppertal. Participating Radiotherapy Departments at the Universities/Medical Schools: Aachen, Berlin Charité, Bonn, Dresden, Düsseldorf, Erfurt, Erlangen, Essen, Frankfurt, Freiburg, Gießen, Göttingen, Graz (Austria), Greifswald, Halle, Hamburg, Hannover, Heidelberg, Homburg/Saar, Jena, Kiel, Köln, Leipzig, Lübeck, Magdeburg, Technische Universität München, Radiologische Poliklinik München, München (Städtisches Krankenhaus Harlaching), Münster, Rostock, Tübingen, Ulm, Wien (Austria), and Würzburg. Participating Hospitals: Krankenhaus-Zweckverband Augsburg, Klinikum Bayreuth, Klinikum Berlin-Buch, Städtisches Krankenhaus Moabit Berlin, Städtische Kliniken Braunschweig, Zentralkrankenhaus St.-Jürgen-Straße Bremen, Allgemeines Krankenhaus Celle, Carl-Thiem-Klinikum Cottbus, Städtische Kliniken Dortmund, Städtische Kliniken Karlsruhe, Städtische Kliniken Kassel, Allgemeines Krankenhaus Klagenfurt (Austria), Städtisches Krankenhaus Kemperhof Koblenz, Städtische Klinik Krefeld, Krankenhaus der Barmherzigen Schwestern Linz (Austria), Städtische Klinik Ludwigshafen, Städtisches Klinikum Mannheim, Klinikum Minden, Krankenhaus Maria Hilf Mönchengladbach, Städtische Klinik Nürnberg, Paracelsus-Strahlenklinik Osnabrück, Knappschaftskrankenhaus Recklinghausen, Winterbergkliniken Saarbrücken, St.-Marien-Krankenhaus Siegen, Katharinenhospital Stuttgart, Krankenanstalten Mutterhaus der Borromärinnen Trier, Reinhard-Nieter-Krankenhaus Wilhelmshaven, and Städtische Klinik Wolfsburg.
Supported by Deutsche Krebshilfe, Bonn, and Kinderkrebs-Initiative Buchholz, Germany. We thank the colleagues and data managers in the participating departments for their continuous cooperation, Burkhard Kuhne for the centralized data management, Dr Achim Heinecke for statistical advice, Dr Sharon Murphy for reviewing the manuscript, and Jutta Bietmann and Gabriele Braun-Munzinger for their assistance in preparing the manuscript.
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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
5 Gy in addition to the standard dose of 20 to 25 Gy to sites with residual lymphoma after completion of chemotherapy, resulting in cumulative local doses of 25 to 35 Gy. Only 4.8% required 35 Gy to the mediastinum. 
