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Journal of Clinical Oncology, Vol 25, No 3 (January 20), 2007: pp. 332-337 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.4772 Final Results of a Prospective Clinical Trial With VAMP and Low-Dose Involved-Field Radiation for Children With Low-Risk Hodgkin's Disease
From the Stanford University Medical Center, Stanford, CA; Dana-Farber Cancer Institute and the Massachusetts General Hospital, Boston, MA; Barbara Bush Children's Hospital at Maine Medical Center, Portland, ME; and St Jude Children's Research Hospital, Memphis TN Address reprint requests to Sarah S. Donaldson, MD, Department of Radiation Oncology, Cancer Center, 875 Blake Wilbur Dr, G-226, Stanford, CA 94305-5847; e-mail: sarah2{at}stanford.edu
PURPOSE: To evaluate outcome and assess complications in children and adolescents with low-risk Hodgkin's disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low-dose, involved-field radiation therapy (IFRT). PATIENTS AND METHODS: One hundred ten children with low-risk Hodgkin's disease were treated with four cycles of VAMP and 15 Gy IFRT for those who achieved a complete response (CR) or 25.5 Gy for those with a partial response after two cycles of VAMP. RESULTS: With median follow-up of 9.6 years (range, 1.7 to 15.0), 5- and 10-year overall survival were 99.1% and 96.1%, respectively, and 5-and 10-year event-free survival (EFS) were 92.7% and 89.4%. Factors contributing to 10-year EFS were: early CR (P = .02), absence of B symptoms (P = .01), lymphocyte predominant histologic subtype (P = .04), and less than three initial sites of disease (P = .02). Organ toxicity has been limited to correctable hypothyroidism in 42% of irradiated patients, and one case of cardiac dysfunction. Seventeen healthy babies have been born to 106 survivors. There have been two malignant tumors: one thyroid cancer within the radiation therapy field and one Ewing's sarcoma outside the radiation therapy field. CONCLUSION: Risk-adapted, combined-modality therapy using VAMP chemotherapy with radiation is effective and well tolerated. Pediatric patients with low-risk Hodgkin's disease can be cured with therapy without an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiotherapy. Thus, these children are expected to retain normal fertility, organ function, and be at low risk of a second malignant tumor.
Risk-adapted treatment for children with Hodgkin's disease is directed toward high survival, minimal toxicity, and optimal quality of life. We previously published early results in children with low-risk disease using four cycles of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy, and low-dose, involved-field radiation (IFRT),1 a study based on our prior experience using low-dose IFRT with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).2,3 We now report the mature results of this prospective trial.
Study Population and Eligibility Criteria This study enrolled patients from September 30, 1990 to February 28, 2000 after institutional review board approval. The objectives were to retain the survival rates achieved in prior protocols and to decrease treatment-related toxicity. Low risk was defined as: Ann Arbor stage I-II,4 mediastinal mass smaller than one third of the intrathoracic diameter, absence of extranodal lesions, and peripheral nodal disease smaller than 6 cm. Other criteria included: age younger than 21 years, histologic confirmation of Hodgkin's disease,5 no prior treatment for Hodgkin's disease, and informed consent. In July 1998, the protocol eligibility was modified to exclude patients with systemic symptoms.
Staging, Restaging, Treatment, and Assessment of Outcome Treatment included four 28-day chemotherapy cycles and radiotherapy. VAMP was administered as: vinblastine 6 mg/m2 intravenously (IV) on days 1 and 15; doxorubicin 25 mg/m2 IV on days 1 and 15; methotrexate 20 mg/m2 IV on days 1 and 15; and prednisone 40 mg/m2 orally on days 1 through 14. Prednisone was omitted after mediastinal radiation. Chemotherapy was repeated every 4 weeks as permitted by count recovery. After the second chemotherapy cycle, patients were evaluated for response and radiation was given to initially involved sites. The axilla was treated only if initially involved; fields were designed to shield the breast. Radiation dose was determined by the chemotherapy response, with 15 Gy for those achieving a complete response (CR) and 25.5 Gy for those achieving a partial response (PR). After radiation, the last two cycles of chemotherapy were given. After therapy, patients were reevaluated every 3 months the first year, every 4 months the second and third years, every 6 months the fourth year, and annually thereafter. Follow-up examinations included physical examination, imaging and laboratory studies, including annual measurement of thyroid function for those receiving neck or upper mediastinal radiation. Restaging studies including CT scans were recommended 1 and 2 years off therapy, with additional examinations performed as indicated. Assessment of organ function and measurements of growth were performed annually. Pulmonary function studies were obtained for patients treated with chest radiation and echocardiogram for all patients. Reproductive monitoring included history of menstrual function, pregnancy attempts, and outcomes. Girls were taught breast self-examination. Breast screening imaging was recommended beginning 8 years after therapy if radiation involved the thorax or axilla. Patients with findings suspicious for relapse underwent restaging examinations; biopsy confirmation of disease progression or relapse and histologic review of second tumors were required. Patients who experience relapse were observed for survival and given retrieval therapy by investigator preference.
Statistical Methods
One hundred ten children were enrolled onto this trial, representing 34% of all consecutive patients seen during the study period, with 66% not eligible for this study with intermediate-high risk disease. This analysis reflects data as of May 8, 2006, providing median follow-up of 9.6 years (range, 1.7 to 15.0); 95% of patients have been observed for 5 years or longer, 57% were observed for 10 years or longer. The patient characteristics with survival data are presented in Table 1. While 91 (83%) were white, there were also 12 African American, five Hispanic, and two Asian children. The median age was 13.3 years (range, 3.6 to 21); only six patients were younger than 6. Seventy-seven patients had classical Hodgkin's disease, including 58 (53%) nodular sclerosis subtype, 18 (16%) mixed cellularity, and one unclassifiable. Thirty-three patients had nodular lymphocyte predominant Hodgkin's disease (LPHD). There were 36 stage IA and 74 stage II, five of whom had systemic symptoms. Twenty eight of 33 with LPHD (84%) and 23 of 76 with classical HD (30%) received 15 Gy. In 105 patients the disease was supradiaphragmatic. Thirty-four patients had one Ann Arbor site of disease, 46 had two sites, and 30 had three to six sites of disease.
Response to Treatment and Outcome All patients responded to the initial two cycles of chemotherapy, 49 achieving a CR. Eight patients relapsed, seven after the planned therapy while one developed progressive disease on therapy. Three of those who relapsed died of progressive Hodgkin's disease. Two patients developed a second malignancy after treatment; one of these was fatal. The projected actuarial OS and EFS at 5 years were 99.1% (LCL, 97.6) and 92.7% (LCL, 88.6), while at 10 years they were 96.1% (LCL, 91.8) and 89.4% (LCL, 82.5) and stable (Fig 1). Patients achieving a CR after two cycles of VAMP had a 95% 10-year EFS, while those with a PR had only a 84.5% 10-year EFS (P = .02). The OS differences were of marginal significance (P = .07). Although there were only five patients on study with B symptoms before the eligibility criteria were revised, we analyzed these five versus the remaining 105 patients without B symptoms. As predicted, the outcome was better for those without B symptoms, P = .01 (Table 1).
Because 30% of the cohort had nodular LPHD, we compared their outcome with those of patients with classical HD. The actuarial 10-year EFS for the LPHD cohort was 100%, while for those patients with classical HD it was 85.4% (SE, 5.4; P = .04; Fig 2).
While the number of involved sites was not restricted on this study, we analyzed outcome as a function of number of initially involved Ann Arbor sites at time of diagnosis. The 10-year EFS for those with one, two, and three to six sites was: 89.2% (SE, 6.7), 96.2% (SE, 4.3), and 80.0% (SE, 10.3), respectively, (P = .02). Their 10-year OS was 97.3% (SE, 3.9), 100%, and 89.2% (SE, 7.8), respectively, (P = .07; Fig 3).
A pattern of failure analysis identified eight patients with progression or recurrence (Table 2). Two patients presented with B symptoms; seven of eight achieved only a PR to induction chemotherapy; and three of eight relapsed outside the radiation therapy field. All had classical HD. Five patients remained disease free after successful retrieval therapy.
Complications Treatment was well tolerated and without significant toxicity. All chemotherapy was given as outpatient therapy. Patients received full doses of chemotherapy with occasional delays for low blood counts. Partial alopecia was temporary. Patients experienced occasional muscle pain, mucositis, and nausea managed by supportive therapy.
Routine Screening Assessment Identified the Following Long-Term Toxicities Musculoskeletal. Soft tissue hypoplasia was recorded in three children. Osteopenia and/or osteoporosis was identified in 13 children, which may represent an underestimate since bone density studies were not routinely preformed. Metabolic. Weight gain and/or obesity was recorded in 16 children, with body mass index values of 26.4 to 41.2. The weight gain often occurred during the prednisone in the chemotherapy program. Pulmonary. Mild asymptomatic changes in pulmonary volumes, diffusion, or both were recorded in 34% of tested patients, with forced vital capacity values ranging from 74% to 101%, total lung capacity from 74% to 101%, and diffusion capacity from 68% to 98%. Diffusion capacity percentiles less than 75% were observed in children who admitted to smoking. Cardiac. One girl had a decline in left ventricular fractional shortening, which dropped to less than 25% 3 years after diagnosis. She had signs of cardiac failure coinciding with pregnancy. The etiology of the cardiomyopathy was complicated by a history of substance abuse, in addition to doxorubicin (cumulative dose, 200 mg/m2) and modified mantle radiation (25.5 Gy). Fertility. All girls of pubertal age had normal menses. One boy with pelvic and para-aortic nodal involvement received 25 Gy pelvic/15 Gy para-aortic/splenic radiation which delivered 289 cGy/3.5 weeks to the testicles. A follow-up semen analysis 13 years later demonstrated azoospermia. Among 106 surviving patients, there have been 18 healthy babies born: 14 to 12 mothers and four to three fathers. There have been three additional pregnancies which ended in abortions: one therapeutic and two spontaneous. Second tumors. Two patients developed a new second tumor. One patient was diagnosed with follicular thyroid cancer, 8 years after 25.5 Gy to a field that included the thyroid gland, presumably radiation induced. This patient is disease free and believed cured after subtotal thyroidectomy and [I131] thyroid ablation. The second patient developed Ewing's sarcoma 4 years after Hodgkin's disease treatment, outside and unrelated to his prior radiation field of 25.5 Gy to the high cervical nodal chain. He died of refractory metastatic sarcoma. Four girls, routinely screened for breast disease, have undergone breast biopsies; all revealed a benign tumor. Two additional patients had thyroid nodules detected during routine follow-up which represented benign adenomas.
High cure rates are now expected in children with low-risk Hodgkin's disease, with 5-year EFS reports in more than 90%, although definitions of low risk have varied. Emphasis is now on minimizing treatment for appropriate risk groups, while retaining high EFS rates. We report here the long-term results of VAMP and low-dose IFRT, and provide follow-up of these low-risk patients. This treatment was selected to avoid high-dose, extended-field radiation, and chemotherapy agents and doses previously associated with untoward toxicity. The previously reported 5-year outcome data demonstrated excellent EFS and OS of 93% and 99%, without demonstrated late effects.1 Mature results at 10 years now demonstrate a decline in EFS to 89.4%, with only a marginal decrease in OS to 96.1%, which should be contrasted with the low incidence of serious or life-threatening treatment-related complications and the preservation of fertility among the cohort. There are many acceptable treatment approaches for favorable presentations of Hodgkin's disease.8-12 Variations in pediatric studies include the definition of risk group, and the different opinions of minimal required therapy. Some define low risk as stage I-II A with no bulky and no extranodal disease.8 Others consider stage I-II A, nonbulky disease with less than three sites of disease to be low risk.9 Our initial definition of low risk was stage I-II A and B, nonbulky mediastinal disease and/or peripheral nodal disease smaller than 6 cm, which we discovered was inappropriate when we observed two early relapses in patients with stage II B disease.1 We now consider stage II B to be high-risk disease. One approach to risk-based therapy is to evaluate response to initial therapy to determine those in need of additional treatment. This approach did not work well in the Children's Cancer Group 5942 study where patients received four cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid chemotherapy; those who achieved a CR were then randomly assigned to receive receive 21 Gy IFRT.9 The study was closed to random assignment prematurely because of inferior EFS in the nonirradiated children. However, the estimated 3-year EFS was still very good for the favorable-risk patients treated with chemotherapy alone (89% ± 2.9%), although clearly superior in children treated with combined-modality therapy (100%). OS did not differ by treatment. Further follow-up will be important to establish if the EFS advantage persists or if retrieval therapy contributes an excess risk of morbidity and mortality that may impact OS. A slightly different approach was taken by the GPOH-HD 95 investigators who gave two cycles of vincristine, procarbazine, prednisone, doxorubicin (OPPA) chemotherapy for girls and vincristine, etoposide, prednisone, doxorubicin (OEPA) for boys and then reassessed response.8 Children failing to achieve a CR received 20 Gy IFRT; radiation doses were escalated to 35 Gy in those with suboptimal responses to chemotherapy. This approach also resulted in inferior EFS for the intermediate- and high-risk patients, whereas the low-risk patients had a 94% EFS at 38 months median follow-up. The study was closed before late toxicity could be addressed.8 Although our study was not randomized, we did observe a significant advantage in 10-year EFS in patients who achieved a CR versus a PR after two cycles of chemotherapy (P = .02), but no difference in OS. While the goal of studies of risk-adapted therapy in pediatric Hodgkin's disease is to define the least amount of therapy with the fewest long-term complications, controversy exists regarding minimal required therapy for these low-risk patients. We chose to build on our prior experience using low-dose radiation therapy interdigitated between six cycles of MOPP or MOPP/ABVD,2,3 by reducing the number of cycles and number of agents, while using drugs we believed would confer little risk of infertility, cardio/pulmonary dysfunction, or leukemia, and to combine them with response based, IFRT at dose levels of 15 to 25.5 Gy. We have insufficient data to determine the optimal dose between 15 and 25.5 Gy or the optimal timing of radiation therapy. This study confirms 10-year OS of 96.1% and EFS of 89.4% which are as high as those reported by other groups, but achieved with a regimen that does not include alkylating agents, epipodophyllotoxins, or bleomycin and lower radiation doses. Results provide convincing evidence of the curability of children with favorable, low-risk Hodgkin's disease, and confirm that the treatment does not carry unanticipated toxicity. It also emphasizes the importance of continual assessment, as one of our most favorable patients (patient 8; Table 2) relapsed 10 years after therapy. The follow-up of this cohort indicates the risk of secondary leukemia is negligible. The risk of secondary solid tumor requires very long follow-up. However, we anticipate the risk of solid tumor after VAMP and low-dose IFRT will be considerably lower than rates observed with protocols prescribing larger radiation treatment volumes and doses. While some patients receiving neck/mediastinal radiation will be at risk for thyroid cancer, this malignancy is highly curable and unlikely to affect survival. Eliminating radiation of the uninvolved axilla should likewise reduce the incidence of breast cancer because axillary involvement, the site which contributes radiation to the breast, is rare in low-risk disease presentation. We lack sufficient follow-up to adequately address the incidence of breast cancer in this cohort. We do not believe our case of Ewing's sarcoma can be explained by the treatment of this study. All of our female patients have maintained normal menses and most who have attempted pregnancy have been successful. While one male treated with pelvic radiation was azoospermic on initial testing, his measured testicular radiation dose was within the range where recovery of spermatogenesis has been reported.13,14 Subdiaphragmatic presentation of HD is rare, and thus few boys will be at similar risk. While hypothyroidism following neck and mediastinal radiation is reported from 21% to 43% depending on race, this can be easily corrected with replacement thyroid. Thus we recommend routine thyroid testing and replacement therapy when appropriate.15 It is also important to routinely examine the thyroid gland for nodules, the majority of which represent benign adenomas. Based on investigations in childhood leukemia, we anticipate that a cumulative doxorubicin dose of 200 mg/m2 will not predispose to clinically significant cardiac injury,16 yet the combination of anthracycline chemotherapy with mediastinal radiation may confer additive risks of cardiotoxicity. This is of particular importance for females who may experience increased cardiac stress during pregnancy and delivery. We recommend periodic monitoring as recommended by the Children's Oncology Group.17,18 Accurate assessment of musculoskeletal abnormalities including soft tissue asymmetry is difficult because of lack of comparison norms and such abnormalities are subtle and usually go unreported.19 Other late effects, which are not commonly reported, but may be of significant consequence, include osteoporosis and osteopenia. Psychosocial issues are also important and often not adequately addressed by caregivers. The number of sites of disease involvement is an important characteristic in the definition of risk group, as there is a decrement of EFS and OS at follow-up in patients with three or more sites of disease. This supports the theory that the degree of tumor burden, as shown in mediastinal mass measurement, needs to be considered in addition to stage.20 Using our current definition of low risk as stage I-II A, nonbulky mediastinal disease, involving fewer than three sites of disease, four cycles of VAMP and 15 to 25.5 Gy IFRT is projected to result in OS at 5 and 10 years of 100% and 98.6% (SE, 1.9), and 5- and 10-year EFS of 97.3% (SE, 1.9) and 92.7% (SE, 4.2), respectively (Fig 4). Using this definition of low risk, four cycles of VAMP and low-dose IFRT provides therapy against which new protocols can be compared.
The authors indicated no potential conflicts of interest.
Conception and design: Sarah S. Donaldson, Michael P. Link, Howard J. Weinstein, Shesh N. Rai, Larry E. Kun, Nancy J. Tarbell, Melissa M. Hudson Administrative support: Sarah S. Donaldson, Melissa M. Hudson Provision of study materials or patients: Sarah S. Donaldson, Michael P. Link, Howard J. Weinstein, Amy L. Billett, Craig A. Hurwitz, Matthew Krasin, Larry E. Kun, Karen C. Marcus, Nancy J. Tarbell, Jeffrey A. Young, Melissa M. Hudson Collection and assembly of data: Sarah S. Donaldson, Michael P. Link, Howard J. Weinstein, Shesh N. Rai, Sam Brain, Amy L. Billett, Craig A. Hurwitz, Larry E. Kun, Nancy J. Tarbell, Jeffrey A. Young, Melissa M. Hudson Data analysis and interpretation: Sarah S. Donaldson, Howard J. Weinstein, Shesh N. Rai, Sam Brain, Amy L. Billett, Matthew Krasin, Larry E. Kun, Karen C. Marcus, Nancy J. Tarbell, Jeffrey A. Young, Melissa M. Hudson Manuscript writing: Sarah S. Donaldson, Michael P. Link, Howard J. Weinstein, Shesh N. Rai, Sam Brain, Amy L. Billett, Matthew Krasin, Larry E. Kun, Karen C. Marcus, Melissa M. Hudson Final approval of manuscript: Sarah S. Donaldson, Michael P. Link, Howard J. Weinstein, Shesh N. Rai, Sam Brain, Amy L. Billett, Craig A. Hurwitz, Matthew Krasin, Larry E. Kun, Karen C. Marcus, Nancy J. Tarbell, Jeffrey A. Young, Melissa M. Hudson
Supported by St Jude Children's Research Hospital Cancer Center (CORE) Grant No. CA 21765 from the National Cancer Institute and the American Lebanese Syrian Associated Charities (ALSAC). Presented in part at the 47th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, Denver, CO, October 17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Donaldson SS, Hudson MM, Lamborn KR, et al: VAMP and low-dose, involved-field radiation for children and adolescents with favorable, early-stage Hodgkin's disease: Results of a prospective clinical trial. J Clin Oncol 20:3081-3087, 2002 2. Donaldson SS, Link MP: Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin's disease. J Clin Oncol 5:742-749, 1987 3. Hunger SP, Link MP, Donaldson SS: Long-term results of ABVD/MOPP and low dose involved field radiotherapy in pediatric Hodgkin's disease. J Clin Oncol 12:2160-2168, 1994 4. Carbone PP, Kaplan HS, Musshoff K, et al: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31:1860-1861, 1971 5. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361, 1994 6. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 7. Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52:650-653, 1965 8. Dorffel W, Luders H, Ruhl 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 215:139-145, 2003[CrossRef][Medline] 9. Nachman JB, Sposto R, Herzog P, et al: 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 20:3765-3771, 2002 10. Schellong G, Bramswig JH, Hornig-Franz I, et al: Hodgkin's disease in children: Combined modality treatment for stages IA, IB, and IIA –results in 356 patients of the German/Austrian Pediatric Study Group. Ann Oncol 5:113-115, 1994 11. Schellong G, Hornig-Franz I, Rath B, et al: Reducing radiotherapy dosage to 20-30 Gy in combined chemo-/radiotherapy of Hodgkin's disease in childhood: A report of the cooperative DAL-HD-87 study. Klin Padiatr 206:253-262, 1994[Medline] 12. Landman-Parker J, Pacquement H, Lebanc T, et al: Localized childhood Hodgkin's disease: Response adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low dose radiation therapy: Results of the French Society of Pediatric Oncology study MDH90. J Clin Oncol 18:1500-1507, 2000 13. Pedrick TJ, Hoppe RT: Recovery of spermatogenesis following pelvic irradiation for Hodgkin's disease. Int J Radiat Oncol Biol Phys 12:117, 1986[Medline] 14. Griffin JE, Wilson JD: Disorders of the testes and the male reproductive tract, in Wilson JD, Foster DW (eds): Williams Textbook of Endocrinology. Philadelphia, PA, WB Saunders, 1992, pp 799-852 15. Metzger ML, Hudson MM, Somes GW, et al: White race as a risk factor for hypothyroidism after treatment for pediatric Hodgkin's lymphoma. J Clin Oncol 24:1516-1521, 2006 16. Sorensen K, Levitt GA, Bull C, et al: Late anthracycline cardiotoxicity after childhood cancer: A prospective longitudinal study. Cancer 97:1991-1998, 2003[CrossRef][Medline] 17. Children's Oncology Group: Long-term follow-up guidelines for survivors of childhood, adolescent and young adult cancers. www.survivorshipguidelines.org 18. Landier W, Bhatia S, Eshelman DA, et al: Development of risk-based guidelines for pediatric cancer survivors: The Children's Oncology Group long-term follow-up guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 22:4979-4990, 2004 19. Merchant TE, Nguyen L, Nguyen D, et al: Differential attenuation of clavicle growth after asymmetric mantle radiotherapy. Int J Radiat Oncol Biol Phys 59:556-561, 2004[CrossRef][Medline] 20. Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early-stage Hodgkin's disease. Cancer 42:1039-1045, 1978[CrossRef][Medline] Submitted July 28, 2006; accepted October 17, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
