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© 2002 American Society for Clinical Oncology Treatment of Unfavorable Childhood Hodgkin’s Disease With VEPA and Low-Dose, Involved-Field RadiationByFrom the Massachusetts General Hospital, Boston, MA; St Jude Children’s Research Hospital, Memphis, TN; and Stanford University Medical Center, Stanford, CA. Address reprint requests to Alison M. Friedmann, MD, Pediatric Hematology/Oncology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114; email: afriedmann{at}partners.org
PURPOSE: Between January 1990 and April 1993, 56 pediatric patients with Hodgkin’s disease were treated on a single-arm trial at three institutions with a regimen designed to maintain high cure rates while minimizing the potential late effects of treatment, such as infertility, second malignant neoplasms, and cardiopulmonary injury. PATIENTS AND METHODS: The regimen used combined-modality therapy with six cycles of vinblastine, etoposide, prednisone, and doxorubicin (VEPA) chemotherapy and low-dose, involved-field radiation. Unfavorable features comprised bulky presentations of localized (stage I or II) disease or advanced (stage III or IV) Hodgkin’s disease. RESULTS: Of 56 patients enrolled, 26 (46%) had unfavorable presentations of stage I/II disease and 30 (54%) had advanced (stage III/IV) disease. Seventy-nine percent of the patients are alive without disease at a median follow-up time of 8.9 years from diagnosis. Nineteen patients had events at a median of 1.5 years (range, 0.4 to 7.9 years) from diagnosis; 17 patients relapsed, one died of cardiomyopathy, and one died of accidental injuries. Survival and event-free survival (EFS) estimates at 5 years for the entire cohort were 81.9% (SE, 5.2%) and 67.8% (SE, 6.3%), respectively. Five-year EFS by stage was 100% for stage I, 79.2% (SE, 8.3%) for stage II, 70% (SE, 14.5%) for stage III, and 49.5% (SE, 11.3%) for stage IV patients. CONCLUSION: Combined-modality therapy with VEPA chemotherapy and low-dose, involved-field radiation is adequate for disease control of early-stage patients with unfavorable features, but it is inferior to other standard regimens for advanced-stage patients.
THE MAJORITY of children and adolescents with Hodgkin’s disease have an excellent prognosis with currently available therapy.1 Because of the high curability and the expectation that most children treated for Hodgkin’s disease will become long-term survivors, minimizing the late effects of treatment has become a major goal of current clinical research efforts. In particular, an alarmingly high incidence of second malignant neoplasms and male infertility has been reported among survivors exposed to high doses of radiation and alkylating agent chemotherapy.2-5 Cardiac and pulmonary toxicities have also been reported after regimens containing radiation plus high cumulative doses of anthracycline-based chemotherapy and bleomycin. Current treatment strategies use combination chemotherapy and low-dose, involved-field radiation in an attempt to minimize these long-term complications.6-9 With the objective of reducing cardiopulmonary, gonadal, and neoplastic treatment complications, investigators at Stanford University Medical Center, St Jude Children’s Research Hospital, and the Dana-Farber Cancer Institute initiated a collaborative study of risk-adapted therapy for childhood Hodgkin’s disease in 1990. We report here the results of a trial using an etoposide-based chemotherapy regimen that eliminated alkylating agents and bleomycin, combined with low-dose, involved-field irradiation in high-risk patients. An alternative chemotherapy regimen was used in low-risk patients; the results of that trial will be reported separately.
Study Design Between January 1990 and April 1993, 56 patients younger than 19 years of age were enrolled at three institutions (Stanford University Medical Center, St Jude Children’s Research Hospital, and the Dana-Farber Cancer Institute). Informed consent was obtained for all patients, and the protocol was approved by institutional review boards at the collaborating centers. Eligible patients had histologically confirmed Hodgkin’s disease, no prior treatment, and complete clinical staging. Patients with unfavorable disease included those with Ann Arbor stage III and IV disease, as well as those with stage I and II bulky disease, defined as a mediastinal mass to intrathoracic cavity ratio of one third or greater on chest radiograph, or peripheral lymph node disease greater than 6 cm. The required clinical staging evaluation included history and physical examination, complete blood count with differential, erythrocyte sedimentation rate, routine renal and hepatic chemistries, thyroid function tests, chest radiographs, thoracic computed tomography scan with contrast, computed tomography or magnetic resonant imaging scan of abdomen and pelvis, and bone marrow biopsy. Gallium scan and lymphangiogram were optional, as was surgical staging.
Treatment Strategy
For patients with stages I, II, and IIIA disease, chemotherapy was alternated with involved-field radiotherapy in the following fashion: two cycles of chemotherapy, radiation to the most bulky site, two cycles of chemotherapy, radiation to an additional site if indicated, final two cycles of chemotherapy, and radiation to an additional site if indicated. Patients with stages IIIB and IV disease received consolidative radiotherapy after completion of all six cycles of chemotherapy. The radiation dose was 25.5 Gy in 1.5-Gy fractions to initially bulky sites, peripheral lymph node disease 3 cm or greater, and sites with a PR; it was 15 Gy to nonbulky sites and those with a CR after the first two cycles of chemotherapy. Radiation therapy was given to all fields involved excluding the bone marrow in patients with stage IV disease.
Statistical Analysis
Patient Characteristics Patient characteristics are listed in Table 1. The median age of the 56 patients enrolled was 15 years (range, 8 to 18 years). Thirty-four patients (61%) were male. The histologic classification was lymphocyte predominant in two cases, nodular sclerosis in 47, mixed cellularity in six, and unclassified in one. With respect to stage, stage II disease was the most common (24 patients). There were two children with stage IA bulky disease, 10 with stage III, and 20 with stage IV disease. Twenty-two patients presented with constitutional B symptoms (fever, night sweats, and weight loss), and 25 had extranodal tumor extension (E lesions). Concurrently, 38 patients were entered onto an early-stage, favorable study; thus the advanced, unfavorable group constituted 60% of our combined institutional experience with Hodgkin’s disease in children.
Response to Treatment and Outcome Of 56 patients enrolled onto the trial, 54 received the protocol-prescribed therapy. One patient requested removal from the study and treatment with standard-dose radiation after an outside review of his staging studies indicated a favorable presentation of localized disease. Another patient developed severe cholestasis during the first cycle of chemotherapy. Chemotherapy was discontinued and she was treated with standard-dose total nodal radiation. She subsequently relapsed and died of refractory disease. These patients are included in the survival analyses. After two cycles of VEPA, 52 (96.3%) of 54 patients had a partial response and two patients (3.7%) had a CR. Subsequently, three patients who initially had a PR never achieved a CR. The first patient, who had stage IVA disease, developed progressive disease after five cycles of chemotherapy before initiation of radiation therapy. He remains in long-term remission (10 years from his original diagnosis) after salvage therapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy and involved-field radiation. Two other patients, both with stage IVB disease, died of progressive disease 9 months after diagnosis. At a median follow-up interval of 9 years (range, 2.9 to 10.3 years), 19 of 56 patients have experienced adverse events. Two patients died in first remission, one of cardiomyopathy that developed after completion of 5.5 cycles of chemotherapy (cumulative doxorubicin dose 275 mg/m2) and mantle radiation (25.5 Gy) and the second of accidental injuries related to domestic violence. Of the 51 patients who received the VEPA regimen and ultimately achieved a complete remission, 13 relapsed at a median time of 18 months from initial diagnosis (range, 9 to 35 months). Seven of the 13 patients with recurrent disease died; three developed fatal complications related to their bone marrow transplant conditioning, and four died of progressive Hodgkin’s disease (Table 2). The other six patients remain alive without disease after receiving salvage therapy. At 5 years, the OS and EFS rates were 81.9% (± 5.2%) and 67.8% (± 6.2%), respectively (Fig 2). The study was terminated in May 1993, when an interim analysis of the first 56 patients indicated inferior results compared with historical results achieved at the collaborating institutions.
Figure 3 shows EFS by stage. The 5-year EFS was 100% for stage I patients, 79.2% (± 8.3%) for stage II, 70% (± 14.5%) for stage III, and 49.5% (± 11.3%) for stage IV. Stage IV patients had a significantly worse 5-year EFS compared with all other patients, 49.5% (± 11.3%) versus 77.8% (± 6.9%), P = .017 (Fig 4). Similarly, advanced-stage patients (stages III and IV) had significantly worse 5-year EFS compared with unfavorable early-stage patients (stages I and II), 56.5% (± 9.1%) versus 81.8% (± 7.7%), P = .046 (Fig 5).
Toxicity and Treatment Complications There was one toxic death as noted above due to congestive heart failure. One patient developed pneumonia and one patient developed osteomyelitis during chemotherapy, while two patients developed radiation pneumonitis. Varicella/zoster infection occurred in six patients. As described above, one patient developed severe cholestasis during the first cycle of chemotherapy that prohibited further chemotherapy. Immediate hypersensitivity reactions to etoposide were common, as previously reported, occurring in 23 (43%) of 54 patients, including four patients (7%) with anaphylaxis.11 Most of these reactions occurred after the first or second dose of etoposide, and all patients were rechallenged. The majority of patients tolerated subsequent etoposide infusions after premedication with diphenhydramine and/or corticosteroids. The most common late complication was hypothyroidism, which developed in 17 patients (30.9%), all of whom had received 25.5-Gy mantle radiation. Three patients had cardiac abnormalities, including the patient who died of congestive heart failure; one patient was diagnosed with mitral valve prolapse 7 years after diagnosis, and one developed a transiently decreased shortening fraction by echocardiogram during therapy. All three had received 25.5-Gy mediastinal radiation in addition to a total cumulative doxorubicin dose of 275 to 300 mg/m2. Six patients who received 25.5-Gy mediastinal radiation developed pulmonary dysfunction; all six patients had moderately decreased diffusion capacity (53% to 77% of predicted values), and two patients had mild restrictive defects by spirometric testing. Five patients (three females and two males) developed gonadal failure. Of the females, two had received 25.5-Gy pelvic radiation and the third had received MOPP chemotherapy and autologous bone marrow transplantation for recurrent disease. Of the males, one had received 15-Gy pelvic radiation and the other had received MOPP chemotherapy and 25.6-Gy pelvic radiation for recurrent disease. Three female patients have successfully carried pregnancies to term and two male patients have fathered children. There have been no second malignant neoplasms to date.
We evaluated a combined-modality treatment approach for children and adolescents with unfavorable Hodgkin’s disease using VEPA chemotherapy, an etoposide-based regimen that excluded alkylating agents and bleomycin. An unfavorable presentation was defined as advanced-stage (III or IV) disease or early-stage (I or II) disease with bulky lymphadenopathy. Compared with historical results with alkylating agent–based regimens (MOPP and doxorubicin, bleomycin, vinblastine, and dacarbazine), the VEPA regimen seems to be inferior for disease control in higher-risk patients, especially those with stage IV disease (Table 3). However, estimates of EFS among patients with stages I and II bulky disease are comparable to other series.
There has been considerable interest in using the epipodophyllotoxin etoposide for the treatment of Hodgkin’s disease. Etoposide has been used frequently in salvage regimens for patients with relapsed Hodgkin’s disease.12,13 In the last decade, several cooperative group trials have evaluated combination chemotherapy regimens including etoposide for newly diagnosed Hodgkin’s disease in both children and adults.8,14-16 Etoposide is an attractive substitute for alkylating agent chemotherapy because of its efficacy and lack of gonadal toxicity. Maintaining fertility is particularly important for patients treated during childhood and adolescence who have not yet reached their childbearing years.17 However, preservation of fertility must be balanced against the risk of secondary acute myeloid leukemia, typically observed in patients treated with high cumulative doses of etoposide or regimens combining etoposide with other chemotherapeutic agents producing DNA damage.18 Cases of secondary acute myeloid leukemia after administration of lower doses (< 2,000 mg/m2) of etoposide underscore the importance of proceeding cautiously with the use of this agent, particularly in pediatric cancer patients with historically favorable outcomes. Low-cumulative-dose, etoposide-based regimens are extremely effective for disease control in patients with early-stage Hodgkin’s disease. Over the past decade, the German-Austrian Pediatric Hodgkin’s Disease Study Group has pursued a sex-based treatment approach utilizing an etoposide-based regimen similar to VEPA, vincristine, etoposide, prednisone, and doxorubicin (OEPA) with low-dose, involved-field radiation.8 Boys with stages I and IIA disease treated with two cycles of OEPA and radiation had an excellent outcome, with a 5-year EFS of 94%. In addition, the response rate to two cycles of OEPA among boys was identical to that among girls treated with two cycles of OPPA (procarbazine substituted for etoposide). The French Society of Pediatric Oncology used four cycles of vinblastine, bleomycin, etoposide, and prednisone with involved-field radiation in children with stages I and II disease, including those with bulky disease.14 Patients with more than 70% reduction in tumor size (85% of patients) then received low-dose radiation (20 Gy), whereas those not achieving a 70% reduction were then treated with one to two cycles of OPPA followed by radiation (40 Gy). This approach produced a 5-year EFS of 91%. Treatment results using etoposide-based regimens in unfavorable Hodgkin’s disease have been less impressive. Treatment of children with vincristine, etoposide, epirubicin, and prednisolone chemotherapy alone resulted in inferior disease-free survival, particularly for patients with stage IV disease or bulky mediastinal adenopathy.19,20 Similarly, the estimated 4-year EFS was only 65% for early-stage adult patients with unfavorable features treated on a Cancer and Leukemia Group B trial using three cycles of etoposide, vinblastine, and doxorubicin with subtotal lymph node radiation.16 Finally, another group also used a VEPA regimen with low-dose radiation in 31 children with stage IIB to IV disease or stage IIA disease with bulky lymphadenopathy.21 They achieved results similar to ours, with an estimated 3-year EFS rate of 77%. In summary, these results and those of other investigators suggest that it is feasible to eliminate alkylating agents in children with early-stage Hodgkin’s disease, but this approach results in inferior disease control in those with advanced-stage disease. We do not recommend the VEPA combination for children with unfavorable Hodgkin’s disease.
1. Hudson MM, Donaldson SS: Treatment of pediatric Hodgkin’s lymphoma. Semin Hematol 36: 313-323, 1999[Medline]
2. Bhatia S, Robison LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 334: 745-751, 1996 3. Papadakis V, Vlachopapadopoulou E, Van Syckle K, et al: Gonadal function in young patients successfully treated for Hodgkin disease. Med Pediatr Oncol 32: 366-372, 1999[CrossRef][Medline] 4. Viviani S, Santoro A, Ragni G, et al: Gonadal toxicity after combination chemotherapy for Hodgkin’s disease: Comparative results of MOPP vs. ABVD. Eur J Cancer Clin Oncol 21: 601-605, 1985[CrossRef][Medline] 5. Wolden SL, Lamborn KR, Cleary SF, et al: Second cancers following pediatric Hodgkin’s disease. J Clin Oncol 16: 536-544, 1998[Abstract]
6. Hunger SP, Link MP, Donaldson SS: ABVD/MOPP and low-dose involved-field radiotherapy in pediatric Hodgkin’s disease: The Stanford experience. J Clin Oncol 12: 2160-2166, 1994 7. Hutchinson RJ, Fryer CJH, Davis PC, et al: MOPP or radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin’s disease in children: Results of the Children’s Cancer Group phase III trial. J Clin Oncol 16: 897-906, 1998[Abstract]
8. Schellong G, Potter R, Bramswig J, et al: High cure rates and reduced long-term toxicity in pediatric Hodgkin’s disease: The German-Austrian multicenter trial DAL-HD-90. J Clin Oncol 17: 3736-3744, 1999 9. Weiner MA, Leventhal B, Brecher ML, et al: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2. IIIB, and IV Hodgkin’s disease in pediatric patients: A Pediatric Oncology Group study. J Clin Oncol 15: 2769-2779, 1997[Abstract] 10. Kaplan ES, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 456-480, 1958
11. Hudson MM, Weinstein HJ, Donaldson SS, et al: Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin’s disease. J Clin Oncol 11: 1080-1084, 1993
12. Chopra R, McMillan AK, Linch DC, et al: The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin’s disease: A single-center eight-year study of 155 patients. Blood 81: 1137-1145, 1993
13. Jagannath S, Dicke KA, Armitage JO, et al: High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin’s disease. Ann Intern Med 104: 163-168, 1986
14. Landman-Parker J, Pacquement H, Leblanc 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 15. Tebbi C, Leventhal BG, Chauvenet A, et al: Treatment of stage I, IIA, and IIIA pediatric Hodgkin’s disease with Adriamycin, bleomycin, vincristine, etoposide (ABVE) and low-dose radiation with option to eliminate laparotomy. Proc Am Soc Clin Oncol 13: 392, 1994 (abstr 1335) 16. Wasserman TH, Petroni GF, Millard FE, et al: Sequential chemotherapy (etoposide, vinblastine, and doxorubicin) and subtotal lymph node radiation for patients with localized Hodgkin disease and unfavorable prognostic features: A phase II Cancer and Leukemia Group B study (9051). Cancer 86: 1590-1595, 1999[CrossRef][Medline] 17. Gerres L, Gramswig JH, Schlegel W, et al: The effects of etoposide on testicular function in boys treated for Hodgkin’s disease. Cancer 83: 2217-2222, 1998[CrossRef][Medline]
18. Smith MA, Rubinstein L, Anderson JR, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17: 569-577, 1999 19. Ekert H, Toogood I, Downie P, et al: High incidence of treatment failure with vincristine, etoposide, epirubicin, and prednisolone chemotherapy with successful salvage in childhood Hodgkin disease. Med Pediatr Oncol 32: 255-258, 1999[CrossRef][Medline] 20. Shankar AG, Ashley S, Atra A, et al: A limited role for VEEP chemotherapy in childhood Hodgkin’s disease. Eur J Cancer 34: 2058-2063, 1998[Medline] 21. Kavan P, Kabickova E, Koutecky J, et al: Treatment of Hodgkin’s disease in children with VAMP and VEPA. Pediatr Hematol Oncol 16: 141-148, 1999[CrossRef][Medline]
22. Oberlin O, Leverger G, Pacquement H, et al: Low-dose radiation therapy and reduced chemotherapy in childhood Hodgkin’s disease: The experience of the French Society of Pediatric Oncology. J Clin Oncol 10: 1602-1608, 1992 Submitted March 11, 2002; accepted April 25, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
