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Originally published as JCO Early Release 10.1200/JCO.2007.15.4773 on March 10 2008 © 2008 American Society of Clinical Oncology. Involved-Field Radiotherapy Before High-Dose Therapy and Autologous Stem-Cell Rescue in Diffuse Large-Cell Lymphoma: Long-Term Disease Control and Toxicity
From the Lymphoma Disease Management Team and the Departments of Radiation Oncology, Medical Oncology, Pathology, and Epidemiology & Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY Corresponding author: Joachim Yahalom, MD, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10165; e-mail: yahalomj{at}mskcc.org
Purpose To analyze outcome, prognostic factors, and toxicities in patients with diffuse large-cell lymphoma (DLCL) who received involved-field radiotherapy (IFRT) before high-dose chemotherapy with autologous stem-cell rescue (ASCR). Patients and Methods Between January 1990 and August 2006, 164 patients with relapsed or refractory DLCL received IFRT at Memorial Sloan-Kettering Cancer Center (New York, NY) before high-dose chemotherapy and ASCR. IFRT was delivered to involved sites measuring more than 5 cm or to sites with residual disease more than 2 cm. Radiotherapy was administered in 1.5-Gy fractions twice daily to a total dose of 30 Gy. Progression-free survival and overall survival were calculated, and short- and long-term toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (version 2.0). Median follow-up was 60 months (range, 2 to 187 months). Results Two- and 5-year progression-free survival was 62% and 53%; 2- and 5-year overall survival was 67% and 58%, respectively. Sixty-seven patients relapsed; only 10 patients relapsed completely within the radiotherapy field. There were seven early treatment-related mortalities and 11 secondary cancers (including four myelodysplastic syndromes), one of which occurred within the IFRT site and five after total-body irradiation. Conclusion Minimal treatment-related mortality and morbidity resulted from short, intensive, involved-field radiotherapy before high-dose chemotherapy and ASCR, which was incorporated into a salvage regimen for patients with relapsed/refractory DLCL. This chemoradiotherapy salvage regimen resulted in a low local relapse rate that could potentially translate into an improved total outcome.
Initial therapy with anthracycline-containing chemotherapy regimens cures approximately 50% of patients with diffuse large-cell lymphoma (DLCL).1,2 Those who do not respond to first-line chemotherapy or who relapse often benefit from a comprehensive second-line, high-dose therapy strategy.3 Most have not received radiation therapy (RT) with initial treatment, and integrating involved-field radiation therapy (IFRT) into their salvage program addresses the likelihood of relapse within the nonirradiated relapsed or refractory site(s).4-8 Yet, concerns regarding toxicity and doubts over the benefit from IFRT have been raised.9-11 Indeed, RT in the salvage setting has rarely been studied. Furthermore, the sparse retrospective data available are biased by patient selection, especially when IFRT is dictated by the presence of residual or originally bulky disease and the patient's ability to tolerate additional therapy. With no clear recommendations regarding the role of IFRT in the salvage setting, the timing of IFRT administration (before or after high-dose therapy [HDT]), the RT schedule, and the dose have been poorly defined. Most reported series include a variety of indications, schedules, field sizes, and doses.7-13 For more than two decades at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY), IFRT has been incorporated into a salvage program in all refractory and relapsed patients with DLCL who meet integration criteria. After reinduction of standard-dose chemotherapy and stem-cell collection, IFRT is delivered in a hyperfractionated accelerated manner to reduce late toxicities while minimizing time lag to HDT and autologous stem-cell rescue (ASCR). In this study, we report outcomes and toxicities of patients with DLCL treated at MSKCC with IFRT before HDT and ASCR during the last 17 years.
Patient Characteristics Between January 1990 and August 2006, 164 patients with DLCL received IFRT at MSKCC before HDT. The median age of the patients before salvage therapy was 46 years (range, 17 to 73 years). Patients were predominantly male (59%; n = 97) and white (92%; n = 151). During the study period, ASCR was offered to patients with transformed (low-grade lymphoma at initial diagnosis with DLCL at relapse), "high-risk" (receiving ASCR as part of up-front therapy protocol on initial diagnosis of stage IV bulky or high International Prognostic Index [IPI] score DLCL), refractory (biopsy-proven disease progression during first-line therapy or within 30 days of finishing this therapy), or relapsed lymphoma (biopsy-proven disease > 30 days after first-line therapy). Patients met basic health requirements based on the protocol at the time. Histopathology was initially classified according to the International Working Formulation, with subsequent retrospective classification (by hematopathologist D.F.) according to the WHO system. All patients were restaged by the Ann Arbor system before salvage therapy. Age-adjusted IPI score based on Eastern Cooperative Oncology Group (ECOG) performance status of at least 2, lactate dehydrogenase (LDH) more than 200 U/L, and stage III or IV disease before starting salvage therapy (sAAIPI), was calculated for all patients with sufficient information (n = 148). Patient characteristics are listed in Table 1.
First-line therapy was influenced by the protocols at that time. One hundred thirty-three patients (81%) received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like chemotherapy, 29 (18%) received other doxorubicin-based regimens, and two patients were administered unknown regimens. Sixteen patients (10%) received IFRT as part of first-line therapy. All patients had chemosensitive disease after second-line chemotherapy, and 90% (n = 147) received an ifosfamide, carboplatin, etoposide (ICE)-based regimen. IFRT, limited to no more than two anatomically involved lymph node regions,14 was administered before HDT for disease measuring at least 5 cm before salvage therapy or to sites with residual nodal masses of at least 2 cm after salvage therapy. IFRT was delivered in 1.5-Gy fractions twice daily to a total dose of 30 Gy over 10 days if administered alone (54%; n = 89), or to a dose of 18 Gy over 6 days if followed by total-body irradiation (TBI) of 12 Gy in 1.5-Gy fractions delivered twice daily as part of a pretransplant conditioning regimen (46%; n = 75). The median total dose to IFRT sites (Table 2) was 30 Gy (range, 21 to 45 Gy). The median time from start of IFRT until transplant was 21 days (range, 12 to 98 days); 90% of patients underwent transplant within 1 month of starting IFRT.
HDT depended on the protocol at the time, and, accordingly, included either a TBI- or a non–TBI-containing regimen (Table 2). ASCR was generally performed using collected bone marrow (BM) until 1994, and afterward with peripheral-blood stem cells (PBSCs). Treatment characteristics are listed in Table 2.
Toxicity
Follow-Up
Statistical Analysis
Outcomes With a median follow-up of 5 years for surviving patients (range, 2 to 187 months), the 2- and 5-year OS was 67% and 58%, respectively (Fig 1). At last follow-up, 93 patients (57%) were alive, 56 patients (34%) had died as a result of disease, 10 patients (6%) died as a result of treatment-related complications, three (2%) died as a result of unknown causes but were free of disease at last follow-up, and two patients (1%) died as a result of other causes, including liver failure from hepatitis C and sepsis in an intravenous drug abuser.
Two- and 5-year PFS was 62% and 53%, respectively (Fig 1). At last follow-up, 67 patients (41%) had relapsed. In 10 (15%), failure sites were completely within the radiation field. In 27 patients (40%), failures were outside the radiation field, and in 29 patients (43%) they occurred both inside and outside the radiation field. The site was not determined in one patient. Relapse pattern was similar regardless of TBI.
Early Toxicities
Late Toxicities Late toxicities are also reported in Table 3. Two patients developed asymptomatic radiation fibrosis on imaging. Seven patients developed cough or mild dyspnea on exertion several months after undergoing transplantation; two received IFRT to the mediastinum. One patient who received IFRT to the para-aortic nodes developed recurrent pericarditis, and one who received IFRT to the mediastinum developed mediastinitis; both were successfully treated with steroids. Four patients developed hemorrhagic cystitis from HDT, which was treated with continuous irrigation. Symptoms resolved in one patient, resulted in grade 2 chronic renal failure (CRF) in two patients, and resulted in grade 4 CRF requiring dialysis in one patient (who received TBI with IFRT). Two patients who received TBI developed cataracts, which were treated surgically. One patient developed moderate hearing impairment (grade 3) requiring a hearing aid, thought to be a result of the HDT. Patients receiving TBI with IFRT did not have increased rates of late toxicities (Table 3).
Treatment-Related Mortality
Second Malignancy Eleven malignancies (excluding basal cell carcinoma of the skin) were diagnosed during follow-up. Two patients died as a result of a second malignancy, including one patient who developed myelodysplastic syndrome (MDS) that progressed to acute myelogenous leukemia (AML) and died 74 months after non-TBI HDT/ASCR. One patient developed esophageal cancer 51 months after TBI and IFRT to the mediastinum and died 6 months later. MDS was diagnosed in three patients 1 to 2 years after ASCR (two received TBI); however, two relapsed and died as a result of progression of DLCL, whereas the other underwent an allotransplant and is alive at 175 months without DLCL or MDS. Another two patients who received TBI developed Hodgkin's lymphoma outside of the IFRT field 4 years after transplant; both were successfully treated with local therapy. Four other solid tumors developed outside the IFRT field, including a superficial bladder cancer, non–small-cell lung cancer, and two prostate cancers, all of which were successfully treated with local therapy.
Prognostic Factors
Advanced stage (III to IV) before salvage therapy was a significant independent adverse factor for both PFS and OS. Using BM for rescue (compared with PBSC) was an adverse factor only for OS.
Although HDT followed by ASCR has become the standard of care in patients with relapsed or refractory DLCL,15 the implications of adding IFRT have not been fully analyzed. In this study, we evaluated a prospectively designed second-line hyperfractionated accelerated IFRT program delivered immediately before HDT/ASCR in a cohort of 164 consecutive patients with DLCL. To the best of our knowledge, this is the largest study on the consequences of incorporating IFRT into the salvage treatment of DLCL. Our analysis indicates the addition of pre-HDT IFRT is safe and effective in reducing relapses in sites most prone to relapse. Some studies suggest that adding IFRT to HDT/ASCR is associated with an unacceptable rate of treatment-related mortality (TRM). Tsang et al11 observed 33% TRM (eight of 24) in patients receiving IFRT to the thorax before BMT for recurrent/refractory Hodgkin's disease between 1986 and 1992, likely because of extended fields and long treatment periods. Fenske et al16 described five patients (18%) who received IFRT before HDT/ASCR for non-Hodgkin's lymphoma and who had a TRM compared with one patient (2%) who did not receive IFRT in a historical group. These studies and others suggest delivering IFRT after transplant, if necessary. However, in our program, TRM and morbidity substantially decreased since the early 1990s. The decreasing toxicity coincides with our switch in 1994 from BM-collected cells to PBSCs. This change, important in itself, was also most likely a surrogate for improvements in supportive care and in radiation planning and delivery methods. Geisler et al17 also reported less TRM with PBSC compared with BM (P = .001), possibly related to shorter time of engraftment with PBSC compared with BM, and therefore quicker neutrophil recovery and shorter hospital stays, or better supportive care over time.18,19 Indeed, since 1994, TRM in our salvage programs dropped from 28% to 2%; since 2000, there has not been a single TRM in 64 consecutive patients. In our study, after evaluation by both the treating radiation oncologist and medical oncologist, IFRT likely played a role in only three acute TRMs (Table 5), whereas non-IFRT related causes (including TBI) could be implicated in the remaining patients. Furthermore, if we limit the analysis to patients who received PBSC transplants, IFRT seems to contribute to only 1 TRM. Regarding the association of pulmonary toxicity and IFRT, a large proportion of patients who received IFRT to the mediastinum developed acute but mild grade 1 or 2 pulmonary symptoms. More significant grade 3 or 4 pulmonary toxicities occurred infrequently (4% of patients) and equally, regardless of whether IFRT was administered to the mediastinum or whether the patient received TBI. Accordingly, we continue to recommend thoracic IFRT before ASCR when patients have bulky mediastinal disease or residual disease after salvage therapy. Pulmonary toxicity is reduced with mediastinal IFRT, using post–salvage-chemotherapy disease volumes, and employing precise imaging and intensity-modulated radiation therapy (IMRT).20 Some argue that the addition of pretransplant IFRT will cause delays in transplant that can lead to relapses, and that there may be less toxicity if IFRT is administered after ASCR.8,21,22 In our experience, we found that a short, intensive course of IFRT (administered within 10 days) does not delay the time to ASCR (90% underwent ASCR within 1 month of starting IFRT), and is also safe. Furthermore, the preference at MSKCC has been to administer IFRT before transplant to obtain as minimal disease state as possible before ASCR, because this can determine a long-term PFS.4,15,23,24 Also, by administering IFRT before ASCR, patients are ensured that they will receive IFRT as part of their treatment regimen. This is not the case in patients planning to receive post-ASCR IFRT, because relapse shortly after transplant or significant hematologic or pulmonary toxicities after ASCR could prevent the delivery of IFRT.25 Furthermore, we hypothesize that a higher likelihood of MDS/leukemia could occur in patients receiving IFRT after transplant compared with before transplant because of exposing newly infused stem cells to radiation. This is avoided with pretransplant IFRT. Thus far, we have witnessed a relatively low number of associated second malignancies (including MDS and AML), and only one patient developed a solid tumor within the IFRT field. However, treatment-related MDS and AML have been associated with IFRT in other studies. Kalaycio et al reported on 20 patients26 (4% of those transplanted) who developed treatment-related MDS/AML. They found that IFRT was a significant prognostic factor. Friedberg et al10 reported 13% of IFRT patients developed secondary MDS compared with 6.5% not receiving IFRT (P = .02). Our results contradict these findings; only 2% of patients developed MDS or AML, similar to the number found in studies without IFRT.27 Furthermore, half of those patients who developed MDS relapsed and died as a result of DLCL. Other factors, including prior exposure to alkylating agents and more extensive use of radiation, may explain the conflicting results. Although 49% of our patients have been observed for more than 5 years, longer follow-up is still necessary. Our comprehensive, combined-modality treatment approach resulted in 5-year OS of 57% and PFS of 52%. These outcomes compare favorably with other large studies of patients with relapsed or refractory lymphoma undergoing HDT/ASCR.6-11,13,15,16,21,28-35 Nevertheless, these results should be viewed with caution, since they are limited to the particular patients who received IFRT before HDT/ASCR. Arguments can be made that these patients had more limited disease with less extranodal site involvement, which could be safely irradiated,33 but they also had more bulky and/or residual disease, or primary refractory disease—all associated with an inferior outcome.4-8,13,21,27,29,33 The pattern of recurrence after ASCR in patients with relapsed or refractory lymphoma has consistently been shown to occur primarily within a prior involved site of disease if IFRT is not administered.5,7,8,15,32,35 However, when IFRT has been added to the treatment, fewer in-field relapses have occurred.7,8,15,30,32,34,36 Our results are consistent with these findings, with only 15% of patients relapsing solely within the irradiated site. This suggests that IFRT effectively controls the areas at high risk for relapse. In summary, IFRT before HDT/ASCR offers good local control for patients with relapsed/refractory DLCL. IFRT does not seem to increase the rate of MDS/AML when compared with other non–IFRT-containing ASCT regimens. Important prognostic factors include patient stage before salvage therapy. The way to show the benefits of IFRT in a salvage regimen is with a properly powered, prospectively randomized study. Unfortunately, a study designed by the National Cancer Institute of Canada Clinical Trials Group (Study LY8) closed because of poor accrual (R. Tsang, personal communication, June 2007). Although recognizing the limitations of retrospective data, we nonetheless recommend that patients with bulky or residual disease limited to one or two sites after standard-dose salvage chemotherapy should be strongly considered for pre-HDT IFRT to safely reduce their risk for relapse.
The author(s) indicated no potential conflicts of interest.
Conception and design: Craig H. Moskowitz, Joachim Yahalom Administrative support: Craig H. Moskowitz, Andrew D. Zelenetz, Joachim Yahalom Collection and assembly of data: Bradford S. Hoppe, Daniel A. Filippa, Tarun Kewalramani, Andrew D. Zelenetz, Joachim Yahalom Data analysis and interpretation: Bradford S. Hoppe, Chaya S. Moskowitz, Joachim Yahalom Manuscript writing: Bradford S. Hoppe, Joachim Yahalom Final approval of manuscript: Bradford S. Hoppe, Craig H. Moskowitz, Daniel A. Filippa, Chaya S. Moskowitz, Tarun Kewalramani, Andrew D. Zelenetz, Joachim Yahalom
We thank Carol Pearce, Memorial Sloan-Kettering Cancer Center writer/editor, for her review of this article.
published online ahead of print at www.jco.org on March 10, 2008. Supported by the Lymphoma Foundation and the Sports Foundation against Cancer. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 2. Fisher RI, Gaynor ER, Dahlberg S, et al: A phase III comparison of CHOP vs m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin's lymphoma: Results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study. Ann Oncol 5:91-95, 1994 (suppl)[Medline] 3. Philip T, Chauvin F, Armitage J, et al: Parma international protocol: Pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation. Blood 77:1587-1592, 1991 4. Philip T, Armitage JO, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 316:1493-1498, 1987[Abstract] 5. Takvorian T, Canellos GP, Ritz J, et al: Prolonged disease-free survival after autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma with a poor prognosis. N Engl J Med 316:1499-1505, 1987[Abstract] 6. Nademanee A, Molina A, Dagis A, et al: Autologous stem-cell transplantation for poor-risk and relapsed intermediate- and high-grade non-Hodgkin's lymphoma. Clin Lymphoma 1:46-54, 2000[Medline] 7. Wendland MM, Smith DC, Boucher KM, et al: The impact of involved field radiation therapy in the treatment of relapsed or refractory non-Hodgkin lymphoma with high-dose chemotherapy followed by hematopoietic progenitor cell transplant. Am J Clin Oncol 30:156-162, 2007[CrossRef][Medline] 8. Mundt AJ, Williams SF, Hallahan D: High dose chemotherapy and stem cell rescue for aggressive non-Hodgkin's lymphoma: Pattern of failure and implications for involved-field radiotherapy. Int J Radiat Oncol Biol Phys 39:617-625, 1997[CrossRef][Medline] 9. Emmanouilides C, Asuncion DJ, Wolf C, et al: Localized radiation increases morbidity and mortality after TBI-containing autologous stem cell transplantation in patients with lymphoma. Bone Marrow Transplant 32:863-867, 2003[CrossRef][Medline] 10. Friedberg JW, Neuberg D, Monson E, et al: The impact of external beam radiation therapy prior to autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma. Biol Blood Marrow Transplant 7:446-453, 2001[CrossRef][Medline] 11. Tsang RW, Gospodarowicz MK, Sutcliffe SB, et al: Thoracic radiation therapy before autologous bone marrow transplantation in relapsed or refractory Hodgkin's disease: PMH Lymphoma Group, and the Toronto Autologous BMT Group. Eur J Cancer 35:73-78, 1999[CrossRef][Medline] 12. Jules-Elysee K, Stover DE, Yahalom J, et al: Pulmonary complications in lymphoma patients treated with high-dose therapy autologous bone marrow transplantation. Am Rev Respir Dis 146:485-491, 1992[Medline] 13. Rodriguez J, Caballero MD, Gutierrez A, et al: Autologous stem-cell transplantation in diffuse large B-cell non-Hodgkin's lymphoma not achieving complete response after induction chemotherapy: The GEL/TAMO experience. Ann Oncol 15:1504-1509, 2004 14. Yahalom J, Mauch P: The involved field is back: Issues in delineating the radiation field in Hodgkin's disease. Ann Oncol 13:79-83, 2002 (suppl) 15. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1545, 1995 16. Fenske TS, Kahl BS, Eickhoff J, et al: Excessive toxicity of the high dose thiotepa and etoposide regimen when combined with radiation: Long-term autologous transplantation experience in follicular and mantle cell lymphoma. Leuk Lymphoma 46:1441-1448, 2005[CrossRef][Medline] 17. Geisler CH, Hansen MM, Andersen NS, et al: BEAM+autologous stem cell transplantation in malignant lymphoma: 100 consecutive transplants in a single centre—Efficacy, toxicity and engraftment in relation to stem-cell source and previous treatment. Eur J Haematol 61:173-182, 1998[Medline] 18. Schmitz N, Linch DC, Dreger P, et al: Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 347:353-357, 1996[CrossRef][Medline] 19. Puig N, de la Rubia J, Remigia MJ, et al: Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation. Leuk Lymphoma 47:1488-1494, 2006[CrossRef][Medline] 20. Goodman KA, Toner S, Hunt M, et al: Intensity-modulated radiotherapy for lymphoma involving the mediastinum. Int J Radiat Oncol Biol Phys 62:198-206, 2005[CrossRef][Medline] 21. Rapoport AP, Lifton R, Constine LS, et al: Autotransplantation for relapsed or refractory non-Hodgkin's lymphoma (NHL): Long-term follow-up and analysis of prognostic factors. Bone Marrow Transplant 19:883-890, 1997[CrossRef][Medline] 22. Toren A, Nagler R, Nagler A: Involved field radiation post autologous stem cell transplantation in lymphoma patients is associated with major haematological toxicities. Med Oncol 15:113-118, 1998[Medline] 23. Gulati S, Yahalom J, Acaba L, et al: Treatment of patients with relapsed and resistant non-Hodgkin's lymphoma using total body irradiation, etoposide, and cyclophosphamide and autologous bone marrow transplantation. J Clin Oncol 10:936-941, 1992[Abstract] 24. Vose JM, Anderson JR, Kessinger A, et al: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11:1846-1851, 1993 25. Rapoport AP, Guo C, Badros A, et al: Autologous stem cell transplantation followed by consolidation chemotherapy for relapsed or refractory Hodgkin's lymphoma. Bone Marrow Transplant 34:883-890, 2004[CrossRef][Medline] 26. Kalaycio M, Rybicki L, Pohlman B, et al: Risk factors before autologous stem-cell transplantation for lymphoma predict for secondary myelodysplasia and acute myelogenous leukemia. J Clin Oncol 24:3604-3610, 2006 27. Stiff PJ, Dahlberg S, Forman SJ, et al: Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: Value of augmented preparative regimens—A Southwest Oncology Group trial. J Clin Oncol 16:48-55, 1998 28. Bertz H, Zeiser R, Lange W, et al: Long-term follow-up after high-dose chemotherapy and autologous stem-cell transplantation for high-grade B-cell lymphoma suggests an improved outcome for high-risk patients with respect to the age-adjusted International Prognostic Index. Ann Oncol 15:1419-1424, 2004 29. Caballero MD, Perez-Simon JA, Iriondo A, et al: High-dose therapy in diffuse large cell lymphoma: Results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group. Ann Oncol 14:140-151, 2003 30. Kahn ST, Flowers CR, Lechowicz MJ, et al: Refractory or relapsed Hodgkin's disease and non-Hodgkin's lymphoma: Optimizing involved-field radiotherapy in transplant patients. Cancer J 11:425-431, 2005[Medline] 31. Lancet JE, Rapoport AP, Brasacchio R, et al: Autotransplantation for relapsed or refractory Hodgkin's disease: Long-term follow-up and analysis of prognostic factors. Bone Marrow Transplant 22:265-271, 1998[CrossRef][Medline] 32. Mundt AJ, Sibley G, Williams S, et al: Patterns of failure following high-dose chemotherapy and autologous bone marrow transplantation with involved field radiotherapy for relapsed/refractory Hodgkin's disease. Int J Radiat Oncol Biol Phys 33:261-270, 1995[CrossRef][Medline] 33. Vose JM, Zhang MJ, Rowlings PA, et al: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: A report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19:406-413, 2001 34. Wadhwa PD, Fu P, Koc ON, et al: High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: An effective regimen with low morbidity and mortality. Biol Blood Marrow Transplant 11:13-22, 2005[Medline] 35. Wendland MM, Asch JD, Pulsipher MA, et al: The impact of involved field radiation therapy for patients receiving high-dose chemotherapy followed by hematopoietic progenitor cell transplant for the treatment of relapsed or refractory Hodgkin disease. Am J Clin Oncol 29:189-195, 2006[CrossRef][Medline] 36. Poen JC, Hoppe RT, Horning SJ: High-dose therapy and autologous bone marrow transplantation for relapsed/refractory Hodgkin's disease: The impact of involved field radiotherapy on patterns of failure and survival. Int J Radiat Oncol Biol Phys 36:3-12, 1996[CrossRef][Medline] Submitted November 23, 2007; accepted January 8, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
100 days after ASCR) toxicities were recorded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0). All severe toxicities were evaluated by medical and radiation oncologists to determine IFRT contribution to the toxicity. 
2 test among the 160 patients who had at least 100 days of follow-up, included testing the use of TBI, treatment era (before 1994 and 1994 to present), and stem-cell source. 
