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Toward a Safer Cure for Low-Risk Hodgkin Lymphoma in Children

Toward a Safer Cure for Low-Risk Hodgkin Lymphoma in Children Currently children and adolescents diagnosed with Hodgkin lymphoma have 5-year overall survival rates greater than 90%.1,2 Therapeutic approaches to Hodgkin lymphoma have evolved, from high-dose extended-field radiation to dose-intensive combination chemotherapy regimens (which relied heavily on alkylating agent exposure), to the current standard of care for all stages of disease in children using multiagent chemotherapy combined with low-dose involved field radiation therapy (IFRT).1 This evolution has been driven by recognition that these curative regimens have been accompanied by significant late treatment–related complications, including secondary malignancies, cardiovascular disease, pulmonary fibrosis, thyroid dysfunction, and gonadal toxicity.2-4 These late effects significantly influence the quality of life for survivors of Hodgkin lymphoma. The current trend in both adult and pediatric oncology is to design therapy with the goal of maintaining disease-free survival, while at the same time decreasing the risk of serious treatment-related complications. To this end, several approaches to treatment have been taken in Hodgkin lymphoma, including decreasing or omitting radiation, adjusting chemotherapy agents, and tailoring therapy to the disease response. The benefit of including radiation therapy in the treatment regimen was advocated by the Children's Cancer Group (CCG) from a study (CCG 5942) initiated nearly 20 years ago.5 Results of this study demonstrated that all risk groups experienced a benefit in event-free survival with the addition of IFRT following 4 cycles of cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin, and vinblastine (COPP-ABV). In a German cooperative group study, Dorffel et al6 eliminated radiation for low-risk patients who were in a complete response after 2 cycles of vincristine, prednisone, procarbazine, and doxorubicin (OPPA) for girls or procarbazine replaced by etoposide (OEPA) for boys with a resultant 2-year event-free survival of 84%.6 Subsequently, Donaldson et al7 demonstrated that low-risk patients (defined as stage I-IIA, no bulky mediastinal disease, and no extranodal extension) could maintain excellent 5- and 10-year event-free survival (93% and 89%) using a regimen of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy with low-dose IFRT, thereby decreasing the risk of secondary leukemia, gonadal dysfunction, and pulmonary toxicity by eliminating alkylating agents, epipodophyllotoxin, and bleomycin. These 3 studies highlight the changing approach to the treatment of Hodgkin lymphoma with the goal of ensuring high rates of complete response while minimizing complications. In this issue of JAMA, Metzger et al8 report on the outcome of a prospective, nonrandomized, phase 2 clinical trial to treat low-risk childhood and adolescent Hodgkin lymphoma by tailoring and, in some cases, minimizing therapy by assessing response following 2 courses of chemotherapy. Eighty-eight patients were enrolled at 5 participating centers over approximately 9 years. Patients received 2 cycles of VAMP and then underwent early disease response evaluation by computed tomographic and functional imaging with either gallium or positron emission tomographic scans. Those who were found to be early complete responders (determined by negative functional imaging and at least 75% reduction of measurable disease) received 2 more courses of VAMP chemotherapy without subsequent IFRT, whereas those with less than complete response after 2 cycles received further chemotherapy followed by IFRT. Patients were then followed up for disease recurrence and late complications of treatment, for a mean follow-up of 6.9 years. The main results are that overall and event-free survival were similar in low-risk patients with Hodgkin lymphoma treated with VAMP alone vs those treated with VAMP plus IFRT. Two-year event-free survival was 91% with no significant difference between the 47 patients (89%) with an early complete response who did not receive IFRT and the 41 patients (93%) who did not achieve complete response and received IFRT. The estimated 5-year event-free survival was 89% for those not treated with radiation vs 89% for those who received radiation, with an overall survival at 5 years of 100%. Importantly, all 5 nonirradiated patients who experienced relapse responded to salvage therapy involving further chemotherapy and IFRT, without the need for autologous stem cell transplant. The regimen was generally well tolerated in the acute setting, and follow-up for late complications has shown no occurrence of second malignancies and minimal reports of asymptomatic endocrine, pulmonary, and cardiac complications. These findings highlight the continued commitment to reduce complications in the treatment of childhood malignancies and add to the growing body of evidence detailing the utility of early response–adapted therapy. Response-based regimens have been used for patients enrolled in studies of high-risk and low-risk Hodgkin lymphoma. With the advent of minimal residual disease testing, these regimens similarly play a large role in childhood leukemia treatment.9,10 The emphasis on minimizing therapy when possible is especially important in the treatment of childhood malignancies, for which the consequences of late complications is well documented. However, any attempt to decrease therapy to minimize late effects must be balanced with the risk of relapse because the primary cause of death the first 10 years after diagnosis remains recurrent disease.2 Even though the outcomes reported by Metzger et al are encouraging, these results must be corroborated in larger, randomized studies because earlier attempts to decrease both the intensity of chemotherapy and to omit radiation in select low-risk patients have not been as promising. For instance, the Children's Oncology Group (COG) study AHOD0431 involving patients with low-risk Hodgkin lymphoma included 3 cycles of chemotherapy and omitted IFRT for those with complete response based on computed tomographic and functional imaging with either positron emission tomography or gallium after completion of chemotherapy. This resulted in a 2-year event-free survival of 84%, suggesting that complete response status after 3 cycles of chemotherapy may not optimally identify patients for whom therapy may be decreased, and that intensification of therapy by either IFRT or further chemotherapy may be required.11 In addition, the outcomes data presented by Metzger et al for the subset of patients diagnosed with lymphocyte-predominant Hodgkin lymphoma (15% relapse rate in nonirradiated patients) were not as encouraging compared with data published by Donaldson et al7 using VAMP combined with IFRT for which no treatment failures were noted. Lymphocyte-predominant Hodgkin lymphoma have traditionally had good outcomes even with minimal therapy; therefore, these findings warrant further consideration of radiation, particularly in patients with stage II disease. The COG has also recently completed phase 3 studies for patients with intermediate- (AHOD0031) and high-risk (AHOD0831) Hodgkin lymphoma that minimize or omit IFRT in patients with early favorable responses, and data should be forthcoming shortly. In an earlier Childhood Cancer Survivor Study (CCSS) report, Oeffinger et al12 documented that approximately two-thirds of adult survivors of a childhood or adolescent malignancy have at least 1 chronic medical condition related to their diagnosis or treatment, with 28% surviving with a severe or life-threatening condition. Mariotto et al13 found that there are currently 31 500 survivors of childhood Hodgkin lymphoma in the United States, with this population increasing annually. A recent CCSS report2 focusing on morbidity and mortality among survivors of childhood Hodgkin lymphoma found a significant increased overall excess risk of death due in part to second malignant neoplasms and cardiovascular disease. In addition, 70% of survivors reported at least 1 chronic health condition, with 44% having 2 or more health conditions, and 28% reporting more than 3 morbidities. The cumulative incidence of these late effects continues to increase without an apparent plateau, emphasizing the need for ongoing assessment of childhood cancer survivors. Radiation therapy is associated with both increased risk of secondary cancers, especially breast cancer in women,14 and cardiovascular disease, including stroke and congestive heart failure. Thus, identifying a patient population in which radiation can be safely eliminated or minimized should decrease the risk of serious late complications and improve quality of life.1 Finally, it is imperative to recognize that complications of therapy may occur after years and sometimes decades, underscoring the importance of continued follow-up for survivors of Hodgkin lymphoma. Back to top Article Information Corresponding Author: Frederick D. Goldman, MD, University of Alabama at Birmingham, 1600 Seventh Ave S, Birmingham, AL 35233 (fgoldman@peds.uab.edu). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association. References 1. Hodgson DC, Hudson MM, Constine LS. Pediatric hodgkin lymphoma: maximizing efficacy and minimizing toxicity. Semin Radiat Oncol. 2007;17(3):230-24217591570PubMedGoogle ScholarCrossref 2. Castellino SM, Geiger AM, Mertens AC, et al. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood. 2011;117(6):1806-181621037086PubMedGoogle ScholarCrossref 3. Adams MJ, Constine LS, Lipshultz SE. Late effects of therapy for Hodgkin's lymphoma. Curr Hematol Malig Rep. 2007;2(3):143-15020425363PubMedGoogle ScholarCrossref 4. Schwartz CL. Special issues in pediatric Hodgkin's disease. Eur J Haematol Suppl. 2005;75(66):55-6216007870PubMedGoogle ScholarCrossref 5. Nachman JB, Sposto R, Herzog P, et al; Children's Cancer Group. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol. 2002;20(18):3765-377112228196PubMedGoogle ScholarCrossref 6. Dörffel W, Lüders H, Rühl U, et al. Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook. Klin Padiatr. 2003;215(3):139-14512838937PubMedGoogle ScholarCrossref 7. Donaldson SS, Link MP, Weinstein HJ, et al. Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease. J Clin Oncol. 2007;25(3):332-33717235049PubMedGoogle ScholarCrossref 8. Metzger ML, Weinstein HJ, Hudson MM, et al. Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable risk Hodgkin lymphoma. JAMA. 2012;307(24):joc1200292609-2616Google ScholarCrossref 9. Brepoels L, Stroobants S. PET scanning and prognosis in Hodgkin's lymphoma. Curr Opin Oncol. 2008;20(5):509-51619106652PubMedGoogle ScholarCrossref 10. Borowitz MJ, Devidas M, Hunger SP, et al; Children's Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood. 2008;111(12):5477-548518388178PubMedGoogle ScholarCrossref 11. Keller FG, Nachman J, Constine L, et al. A phase III study for the treatment of children and adolescents with newly diagnosed low risk Hodgkin lymphoma (abstract). Presented at: the 52nd American Society of Hematology; November 2010; Los Angeles, CA 12. Oeffinger KC, Mertens AC, Sklar CA, et al; Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572-158217035650PubMedGoogle ScholarCrossref 13. Mariotto AB, Rowland JH, Yabroff KR, et al. Long-term survivors of childhood cancers in the United States. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1033-104019336557PubMedGoogle ScholarCrossref 14. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290(4):465-47512876089PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Toward a Safer Cure for Low-Risk Hodgkin Lymphoma in Children

JAMA , Volume 307 (24) – Jun 27, 2012

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Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2012.6975
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Abstract

Currently children and adolescents diagnosed with Hodgkin lymphoma have 5-year overall survival rates greater than 90%.1,2 Therapeutic approaches to Hodgkin lymphoma have evolved, from high-dose extended-field radiation to dose-intensive combination chemotherapy regimens (which relied heavily on alkylating agent exposure), to the current standard of care for all stages of disease in children using multiagent chemotherapy combined with low-dose involved field radiation therapy (IFRT).1 This evolution has been driven by recognition that these curative regimens have been accompanied by significant late treatment–related complications, including secondary malignancies, cardiovascular disease, pulmonary fibrosis, thyroid dysfunction, and gonadal toxicity.2-4 These late effects significantly influence the quality of life for survivors of Hodgkin lymphoma. The current trend in both adult and pediatric oncology is to design therapy with the goal of maintaining disease-free survival, while at the same time decreasing the risk of serious treatment-related complications. To this end, several approaches to treatment have been taken in Hodgkin lymphoma, including decreasing or omitting radiation, adjusting chemotherapy agents, and tailoring therapy to the disease response. The benefit of including radiation therapy in the treatment regimen was advocated by the Children's Cancer Group (CCG) from a study (CCG 5942) initiated nearly 20 years ago.5 Results of this study demonstrated that all risk groups experienced a benefit in event-free survival with the addition of IFRT following 4 cycles of cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin, and vinblastine (COPP-ABV). In a German cooperative group study, Dorffel et al6 eliminated radiation for low-risk patients who were in a complete response after 2 cycles of vincristine, prednisone, procarbazine, and doxorubicin (OPPA) for girls or procarbazine replaced by etoposide (OEPA) for boys with a resultant 2-year event-free survival of 84%.6 Subsequently, Donaldson et al7 demonstrated that low-risk patients (defined as stage I-IIA, no bulky mediastinal disease, and no extranodal extension) could maintain excellent 5- and 10-year event-free survival (93% and 89%) using a regimen of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy with low-dose IFRT, thereby decreasing the risk of secondary leukemia, gonadal dysfunction, and pulmonary toxicity by eliminating alkylating agents, epipodophyllotoxin, and bleomycin. These 3 studies highlight the changing approach to the treatment of Hodgkin lymphoma with the goal of ensuring high rates of complete response while minimizing complications. In this issue of JAMA, Metzger et al8 report on the outcome of a prospective, nonrandomized, phase 2 clinical trial to treat low-risk childhood and adolescent Hodgkin lymphoma by tailoring and, in some cases, minimizing therapy by assessing response following 2 courses of chemotherapy. Eighty-eight patients were enrolled at 5 participating centers over approximately 9 years. Patients received 2 cycles of VAMP and then underwent early disease response evaluation by computed tomographic and functional imaging with either gallium or positron emission tomographic scans. Those who were found to be early complete responders (determined by negative functional imaging and at least 75% reduction of measurable disease) received 2 more courses of VAMP chemotherapy without subsequent IFRT, whereas those with less than complete response after 2 cycles received further chemotherapy followed by IFRT. Patients were then followed up for disease recurrence and late complications of treatment, for a mean follow-up of 6.9 years. The main results are that overall and event-free survival were similar in low-risk patients with Hodgkin lymphoma treated with VAMP alone vs those treated with VAMP plus IFRT. Two-year event-free survival was 91% with no significant difference between the 47 patients (89%) with an early complete response who did not receive IFRT and the 41 patients (93%) who did not achieve complete response and received IFRT. The estimated 5-year event-free survival was 89% for those not treated with radiation vs 89% for those who received radiation, with an overall survival at 5 years of 100%. Importantly, all 5 nonirradiated patients who experienced relapse responded to salvage therapy involving further chemotherapy and IFRT, without the need for autologous stem cell transplant. The regimen was generally well tolerated in the acute setting, and follow-up for late complications has shown no occurrence of second malignancies and minimal reports of asymptomatic endocrine, pulmonary, and cardiac complications. These findings highlight the continued commitment to reduce complications in the treatment of childhood malignancies and add to the growing body of evidence detailing the utility of early response–adapted therapy. Response-based regimens have been used for patients enrolled in studies of high-risk and low-risk Hodgkin lymphoma. With the advent of minimal residual disease testing, these regimens similarly play a large role in childhood leukemia treatment.9,10 The emphasis on minimizing therapy when possible is especially important in the treatment of childhood malignancies, for which the consequences of late complications is well documented. However, any attempt to decrease therapy to minimize late effects must be balanced with the risk of relapse because the primary cause of death the first 10 years after diagnosis remains recurrent disease.2 Even though the outcomes reported by Metzger et al are encouraging, these results must be corroborated in larger, randomized studies because earlier attempts to decrease both the intensity of chemotherapy and to omit radiation in select low-risk patients have not been as promising. For instance, the Children's Oncology Group (COG) study AHOD0431 involving patients with low-risk Hodgkin lymphoma included 3 cycles of chemotherapy and omitted IFRT for those with complete response based on computed tomographic and functional imaging with either positron emission tomography or gallium after completion of chemotherapy. This resulted in a 2-year event-free survival of 84%, suggesting that complete response status after 3 cycles of chemotherapy may not optimally identify patients for whom therapy may be decreased, and that intensification of therapy by either IFRT or further chemotherapy may be required.11 In addition, the outcomes data presented by Metzger et al for the subset of patients diagnosed with lymphocyte-predominant Hodgkin lymphoma (15% relapse rate in nonirradiated patients) were not as encouraging compared with data published by Donaldson et al7 using VAMP combined with IFRT for which no treatment failures were noted. Lymphocyte-predominant Hodgkin lymphoma have traditionally had good outcomes even with minimal therapy; therefore, these findings warrant further consideration of radiation, particularly in patients with stage II disease. The COG has also recently completed phase 3 studies for patients with intermediate- (AHOD0031) and high-risk (AHOD0831) Hodgkin lymphoma that minimize or omit IFRT in patients with early favorable responses, and data should be forthcoming shortly. In an earlier Childhood Cancer Survivor Study (CCSS) report, Oeffinger et al12 documented that approximately two-thirds of adult survivors of a childhood or adolescent malignancy have at least 1 chronic medical condition related to their diagnosis or treatment, with 28% surviving with a severe or life-threatening condition. Mariotto et al13 found that there are currently 31 500 survivors of childhood Hodgkin lymphoma in the United States, with this population increasing annually. A recent CCSS report2 focusing on morbidity and mortality among survivors of childhood Hodgkin lymphoma found a significant increased overall excess risk of death due in part to second malignant neoplasms and cardiovascular disease. In addition, 70% of survivors reported at least 1 chronic health condition, with 44% having 2 or more health conditions, and 28% reporting more than 3 morbidities. The cumulative incidence of these late effects continues to increase without an apparent plateau, emphasizing the need for ongoing assessment of childhood cancer survivors. Radiation therapy is associated with both increased risk of secondary cancers, especially breast cancer in women,14 and cardiovascular disease, including stroke and congestive heart failure. Thus, identifying a patient population in which radiation can be safely eliminated or minimized should decrease the risk of serious late complications and improve quality of life.1 Finally, it is imperative to recognize that complications of therapy may occur after years and sometimes decades, underscoring the importance of continued follow-up for survivors of Hodgkin lymphoma. Back to top Article Information Corresponding Author: Frederick D. Goldman, MD, University of Alabama at Birmingham, 1600 Seventh Ave S, Birmingham, AL 35233 (fgoldman@peds.uab.edu). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association. References 1. Hodgson DC, Hudson MM, Constine LS. Pediatric hodgkin lymphoma: maximizing efficacy and minimizing toxicity. Semin Radiat Oncol. 2007;17(3):230-24217591570PubMedGoogle ScholarCrossref 2. Castellino SM, Geiger AM, Mertens AC, et al. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood. 2011;117(6):1806-181621037086PubMedGoogle ScholarCrossref 3. Adams MJ, Constine LS, Lipshultz SE. Late effects of therapy for Hodgkin's lymphoma. Curr Hematol Malig Rep. 2007;2(3):143-15020425363PubMedGoogle ScholarCrossref 4. Schwartz CL. Special issues in pediatric Hodgkin's disease. Eur J Haematol Suppl. 2005;75(66):55-6216007870PubMedGoogle ScholarCrossref 5. Nachman JB, Sposto R, Herzog P, et al; Children's Cancer Group. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol. 2002;20(18):3765-377112228196PubMedGoogle ScholarCrossref 6. Dörffel W, Lüders H, Rühl U, et al. Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook. Klin Padiatr. 2003;215(3):139-14512838937PubMedGoogle ScholarCrossref 7. Donaldson SS, Link MP, Weinstein HJ, et al. Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease. J Clin Oncol. 2007;25(3):332-33717235049PubMedGoogle ScholarCrossref 8. Metzger ML, Weinstein HJ, Hudson MM, et al. Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable risk Hodgkin lymphoma. JAMA. 2012;307(24):joc1200292609-2616Google ScholarCrossref 9. Brepoels L, Stroobants S. PET scanning and prognosis in Hodgkin's lymphoma. Curr Opin Oncol. 2008;20(5):509-51619106652PubMedGoogle ScholarCrossref 10. Borowitz MJ, Devidas M, Hunger SP, et al; Children's Oncology Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood. 2008;111(12):5477-548518388178PubMedGoogle ScholarCrossref 11. Keller FG, Nachman J, Constine L, et al. A phase III study for the treatment of children and adolescents with newly diagnosed low risk Hodgkin lymphoma (abstract). Presented at: the 52nd American Society of Hematology; November 2010; Los Angeles, CA 12. Oeffinger KC, Mertens AC, Sklar CA, et al; Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572-158217035650PubMedGoogle ScholarCrossref 13. Mariotto AB, Rowland JH, Yabroff KR, et al. Long-term survivors of childhood cancers in the United States. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1033-104019336557PubMedGoogle ScholarCrossref 14. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290(4):465-47512876089PubMedGoogle ScholarCrossref

Journal

JAMAAmerican Medical Association

Published: Jun 27, 2012

Keywords: hodgkin's disease,child

References