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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2520-2526 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.5823 Hodgkin's Lymphoma in Adolescents
From the Division of Hematology, Leukemia/Bone Marrow Transplant Program of British Columbia; Division of Medical Oncology of the British Columbia Cancer Agency; and the University of British Columbia, Vancouver, British Columbia, Canada Address reprint requests to Joseph M. Connors, MD, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, BC, Canada V5Z 4E6; e-mail: jconnors{at}bccancer.bc.ca
PURPOSE: To compare the clinical presentation, response to treatment, and long-term outcome of Hodgkin's lymphoma (HL) presenting in adolescents and young adults. PATIENTS AND METHODS: The British Columbia Cancer Agency Lymphoid Cancer database was used to identify adolescents (16 years to 21 years) and young adults (22 years to 45 years) receiving primary treatment for HL between 1981 and 2004. All patients were treated using adult protocols. RESULTS: The study population included 259 adolescents and 890 young adults. There were no significant differences in histologic subtypes, sex, stages, or presence of B symptoms or bulky disease between adolescents and adults. Equal proportions of adolescents and adults were treated with radiation alone (38% v 35%), chemotherapy alone (13% v 15%), or combined-modality programs (49% v 50%). There was no difference in progression-free survival (PFS) or overall survival (OS) between adolescents and adults, with 10-year PFS rates of 77% versus 80% (P = .67) and 10-year OS rates of 91% versus 89% (P = .42). In limited stage disease, 10-year PFS was 89% for adolescents and 89% for adults and OS 96% and 96%, respectively. In advanced stage disease, 10-year PFS was 71% for adolescents and 75% for adults and OS 88% and 86%, respectively. Actuarial risk of second malignancy for adolescents and adults was not different (P = .68). CONCLUSION: Adolescents and young adults with HL have similar baseline characteristics and achieve similar outcomes when treated with the same protocols. The use of adult treatment protocols is a safe and effective strategy for treating adolescents with HL.
Hodgkin's lymphoma (HL) is an uncommon malignancy with an annual incidence in North America of 2.4 per 100,000.1 The age distribution at diagnosis of HL is bimodal with peak incidences between 15 years and 30 years and at ages older than 55 years.2
HL is highly responsive to both chemotherapy and radiotherapy. Treatment strategies have been developed to improve disease-related outcomes while minimizing the risk of late therapy related complications in survivors. Adults with limited stage disease (Ann Arbor stage IA or IIA without any bulky masses [ In the pediatric population, chemotherapy regimens have been developed to minimize exposure to alkylating agents due to the risk of leukemia and male infertility. The German-Austrian Pediatric Hodgkin's Disease Study Group found no difference in the outcome between vincristine, prednisone, procarbazine, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine (OPPA/COPP) given to girls and etoposide substituted for procarbazine (OEPA/COPP) given to boys.6 The combined advanced stage group, treated with six cycles of chemotherapy and IFRT had a 5-year EFS of 86%. Limited stage patients received two to four cycles of chemotherapy and IFRT and had an EFS of 93%. Ongoing pediatric studies are evaluating treatment strategies based on risk stratification by early response. In adult Hodgkin's lymphoma, age 45 years or older has been identified as an adverse prognostic feature and is incorporated in the International Prognostic Factors Project score8; however, the prognostic significance of adolescent age is unknown. Adolescents are treated with either adult or pediatric protocols depending on center specific policies and referral patterns. Thus, in various prospective trials they have been treated with either adult or pediatric protocols; however, the outcomes of this subgroup have rarely been reported separately.7 A few reports have indicated that outcome of treatment for HL may be different depending on age group but no studies have had sufficient numbers of patients evaluated and treated with uniform policies to examine this question with confidence.7 In British Columbia, Canada, individuals older than the age of 15 are routinely evaluated and treated according to adult protocols affording us the opportunity to examine the clinical characteristics and treatment outcomes of all adolescent patients in comparison with adult patients. In this study we review the characteristics at initial presentation, response to treatment, and long-term outcomes of adolescents with HL treated with modern adult protocols.
Cancer care in the province of British Columbia is coordinated by the British Columbia Cancer Agency (BCCA). All patients must be registered with the BCCA before receiving radiotherapy or chemotherapy. A central pharmacy coordinates dispensing of chemotherapeutic agents. Physicians are expected to follow the BCCA treatment guidelines, which are designed to promote a uniform standard of care. The BCCA Lymphoid Cancer Database is a comprehensive clinical database of all lymphoma patients registered with the BCCA. Baseline data are entered at diagnosis and follow-up data are collected prospectively from oncology clinical records, family physicians, and death certificates. Independent of this database all malignancies diagnosed in British Columbia are captured by a comprehensive British Columbia Cancer Registry. By crosslinking our HL database with the independent data in the cancer registry, we have been able to ensure accurate documentation of all second malignancies. Additional data regarding second malignancies were obtained from death certificates, but all cases agreed with data in the cancer registry. All second malignancies were confirmed histologically. The BCCA lymphoma database was used to identify all 1,221 patients age 16 years to 45 years, inclusive, who were diagnosed with HL and received primary treatment in British Columbia between January 1981 and November 2004. All patients had a histologically confirmed diagnosis of HL. Sixty-nine patients were excluded due to coincident pregnancy (n = 13); HIV/AIDS (n = 11); coincident or previously diagnosed major second malignancy (n = 6); or other severe comorbid illness (n = 39) leading to inability to complete standard staging tests and deliver primary therapy. Three patients were excluded due to incomplete records or staging evaluations. For purposes of this study we defined adolescence as age 16 years to 21 years, inclusive. The adolescent group was compared with the group of younger adults aged 22 to 45 years inclusive. Patients older than 45 years were excluded from the comparison group because age older than 45 years is a known adverse prognostic feature for Hodgkin's lymphoma.8 The research protocol was approved by the University of British Columbia BCCA research ethics board.
Staging and Treatment In British Columbia, all patients 16 years or older are treated by oncologists who treat adults and who employ adult treatment protocols. Limited stage disease was treated with extended field radiotherapy (1981 to 1988), two cycles of ABVD and extended field radiotherapy (1989 to 1996), or two cycles of ABVD and IFRT (1997 to 2004). Advanced stage disease was treated with six to eight cycles (two cycles past maximal response) of MOPP/ABV hybrid chemotherapy (1981 to 1988) or ABVD (1989 to 2004). Patients with bulky disease received IFRT after completion of chemotherapy. Patients who did not respond to primary treatment or who relapsed following chemotherapy were offered high-dose chemotherapy and autologous stem cell transplant. The ABVD regimen consisted of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, bleomycin 10 U/m2, and dacarbazine 375 mg/m2 intravenously on days 1 and 15, repeated at 28 day intervals for six to eight cycles, two cycles past maximal response. The MOPP/ABVD regimen alternated cycles of MOPP with ABVD at 28-day intervals for six to eight cycles, two cycles past maximal response. The MOPP cycle consisted of mechlorethamine 6 mg/m2 and vincristine 1.4 mg/m2 intravenously on day 1 and day 8 with procarbazine 100 mg/m2 and prednisone 40 mg/m2 orally on days 1 to 14. Radiation therapy consisted of 36 Gy in 20 daily fractions. Extended field radiation consisted of a mantle field for supradiaphragmatic disease or an inverted Y field including the spleen for infradiaphragmatic disease. IFRT consisted of radiation to the nodal region containing the abnormal lymph nodes. Patients were observed after diagnosis according to the BCCA management guidelines, which recommend clinical assessment with physical examination, imaging studies, and laboratory testing every 3 months for 2 years, then every 6 months until 5 years, then every 12 months thereafter. With respect to surveillance for second malignancies, patients were encouraged to perform regular breast self-examination and skin examination. Pap smears were recommended annually. Annual mammography was recommended at either 10 years after diagnosis of HL or age 40, whichever happened first.
Statistical Methods
Frequencies of occurrence of specific characteristics in adolescent and adult patients were compared using the Pearson
The study cohort consisted of 259 adolescents age 16 years to 21 years and 890 adults age 22 years to 45 years diagnosed with HL between January 1981 and November 2004. Baseline demographics and primary treatment regimens were similar between the groups (Table 1). There was a trend towards increased frequency of the nodular sclerosis subtype in the adolescent group (85% v 76%; P = .054). Sixty-seven percent of adolescents and 66% of adults had advanced stage disease.
Median follow-up was 8.5 years for adolescents and 7.8 years for adults, with a similar proportion of patients lost to follow-up in both groups (Table 2). Of the patients eventually lost to follow-up, over 70% were accurately observed for at least 5 years. Between the adolescent and adult groups, there was no difference in incidence of primary refractory disease, relapse, frequency of stem cell transplant, or treatment-related mortality (Table 2). PFS was not significantly different between groups with 10-year PFS of 77% in adolescents and 80% in adults (P = .67; Table 3 and Fig 1). Ten-year overall survival (OS) was 91% in adolescents and 89% in adults (P = .42; Fig 2). In patients with limited stage disease, 10-year PFS was 89% for adolescents and 89% for adults (Fig 3) and OS was 96% and 96% (Fig 4). In advanced disease, 10-year PFS was 71% for adolescents and 75% for adults (Fig 5) and OS was 88% and 86% (Fig 6).
We also performed an exploratory analysis within the group of adolescent patients to see if there was any difference in outcomes between those in the younger age range, 16 years to 18 years, compared with those in the older range, 19 years to 21 years. The outcomes of younger adolescents were not different from older adolescents (PFS, P = .25; OS, P = .44) The actuarial risk of second malignancy was similar between the groups (Fig 7). Four percent of adolescents (11 of 259) and 5% of adults (42 of 890) developed second malignancies with one adult developing two malignancies (Table 4). Breast carcinoma represented 45% of the malignancies (5 of 11) in adolescents, but only 14% in adults (6 of 43), whereas hematologic malignancies accounted for 9% in adolescents (1 of 11), but 37% in adults (16 of 43). Seventy-three percent of adolescents (8 of 11) and 70% of adults (30 of 43) with second malignancies had received radiation treatment for Hodgkin's lymphoma. These observations should be interpreted with caution because the duration of follow-up, although quite sufficient to allow confident projection of likelihood of cure of the HL and risk of development of leukemia, myelodysplasia and non-Hodgkin's lymphoma, is still too short to allow accurate prediction of the probability of developing secondary solid tumors.
We describe a population-based cohort study of the largest series of adolescents with HL uniformly treated with adult treatment protocols reported to date. Although adolescents have been included in both pediatric and adult treatment trials for Hodgkin's lymphoma, outcomes of the adolescent subgroup have rarely been reported in detail. In a recent literature review, Mottl et al7 identified only four trials (three pediatric and one adult) reporting adolescent-specific outcomes. We detected no differences in the baseline characteristics of adolescents and young adults with Hodgkin's lymphoma. In particular, we found that the frequency of histologic subtypes, male sex, individual and grouped stages (limited and advanced), B symptoms, bulky disease, and performance status did not differ significantly between adolescents and adults strongly suggesting that the biology of the lymphoma is the same in these two populations. Importantly, there was no difference in PFS or OS between the adolescent and young adult populations. Similar outcomes were also seen within the subgroups of limited and advanced disease. Because the definition of adolescence as age 16 years to 21 years was arbitrary, we also compared the younger adolescents (16 years to 18 years) with older adolescents (19 years to 21 years) and again found no difference in outcome. In our study, both adolescents and adults with limited stage disease had a 5-year OS of 99%, comparable with previously published reports in adult and pediatric populations.1 In advanced stage disease, both adolescents and adults had 5-year PFS of 76% and 5-year OS of 92% and 93%, respectively. Studies in the adult population with MOPP/ABVD or ABVD regimens have found 5-year PFS of 61% to 66% and OS of 73% to 82%.3 The better outcome in our study population likely reflects exclusion of patients older than 45 years, who are known to have a poorer prognosis.8 Superior outcomes were also reported in a pediatric study of MOPP/ABVD in advanced stage disease with a 5-year event-free survival of 79%.11 Poorer outcomes were noted in a retrospective study of adolescents treated with adult protocols in the United Kingdom from 1970 to 1997 with a 5-year EFS of only 50%.12 However, most patients in this study were treated with extended field radiation or MOPP chemotherapy whereas most of our patients received ABVD or hybrid regimens. The population-based approach of our study provides important information regarding long-term clinical outcomes of adolescents and adults with HL outside the carefully regulated clinical trial setting. A limitation inherent with this approach is the change in treatment regimens over the 23-year span of the study, most notably the change from radiation-based to combined-modality therapy for limited stage disease. However, with the centralization of cancer therapy protocols in British Columbia, the treatment change occurred simultaneously for both the adolescent and adult populations, facilitating comparison of these groups. Patients with advanced disease received either MOPP/ABVD hybrid or ABVD, regimens with similar efficacy throughout the duration of the study period. We found that the incidence of second malignancies was similar between the adolescent and adult groups. Previous studies have consistently demonstrated an increased relative risk (RR) and absolute excess risk (AER) of leukemia, non-HL, and solid tumors in patients treated for HL.13-16 For breast cancer, age at time of HL treatment appears to be an important risk factor. Children younger than 10 years of age may not be at increased risk of breast cancer, presumably due to lack of breast tissue development at the time of treatment. Pediatric studies have shown increased RR of breast cancer in patients treated between the ages of 10 years to 16 years, whereas adult studies have shown elevated RR and AER in patients younger than 20 to 30 years of age.13,15 In our study, breast cancer represented a higher proportion of second malignancies in the adolescent compared with the adult population, supporting the hypothesis that developing breast tissue is more susceptible to the carcinogenic effects of HL treatment. Radiation therapy in particular has been associated with an increased risk of breast cancer and was likely a significant contributing factor in our population as four of five adolescents and three of six adults with breast cancer had received mantle field irradiation. Hematologic malignancies, particularly non-HL, accounted for proportionally more of the malignancies in our young adult population compared with the adolescents. This is consistent with previous data suggesting increasing RR and AER of non-HL with age at HL diagnosis.13-15 While adequate for the purpose of examining the course of the HL, the median follow-up of approximately 8 years precluded a more detailed comparison of the risk of malignancy between the adolescent and adult groups, or assessment of the risk due to radiation therapy. Additional follow-up will be particularly useful in assessing the risk of solid tumors in adolescents exposed to radiotherapy. Although current adult protocols for advanced disease tend to avoid the use of radiation, many standard pediatric protocols incorporate routine consolidation with radiotherapy. Additional data documenting second malignancies associated with radiation therapy in adolescents would, in combination with our finding that outcome is the same in adolescents as in adults following typical adult treatment approaches, further support the use of adult chemotherapy only protocols in this population. In conclusion, adolescents and adults with HL have similar baseline characteristics and outcomes when treated with the same adult protocols, suggesting a uniform disease biology. The overall incidence of second malignancies was also similar between the groups. We found no evidence to support the assertion that HL presenting in adolescents differs either in its basic biology or response to curative treatment when compared with the same disease presenting in adults. Overall, this study shows that adolescents with HL can be safely and effectively treated with adult treatment protocols.
The authors indicated no potential conflicts of interest.
Conception and design: Lynda M. Foltz, Joseph M. Connors Collection and assembly of data: Lynda M. Foltz, Joseph M. Connors Data analysis and interpretation: Lynda M. Foltz, Kevin W. Song, Joseph M. Connors Manuscript writing: Lynda M. Foltz, Kevin W. Song, Joseph M. Connors Final approval of manuscript: Lynda M. Foltz, Kevin W. Song, Joseph M. Connors
We thank all of the contributing physicians throughout the province of British Columbia for their referral of patients. We also thank Randy Gascoyne, MD, Mukesh Chhanabhai, MD, Ken Lerner, MD, Hugh Pontifex, MD, Ann Worth, MD, and Brian Skinnider, MD, for expert review of pathologic material.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Yung L, Linch D: Hodgkin's lymphoma. Lancet 361:943-951, 2003[CrossRef][Medline] 2. Ekstrand BC, Horning SJ: Hodgkin's disease. Blood Rev 16:111-117, 2002[CrossRef][Medline] 3. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract] 4. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348:2386-2395, 2003 5. Horning SJ, Hoppe RT, Breslin S, et al: Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630-637, 2002 6. 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: The German-Austrian Pediatric Hodgkin's Disease Study Group. J Clin Oncol 17:3736-3744, 1999 7. Mottl AM, Fisher SG, Fisher RI, et al: Adolescents with hodgkin lymphoma treated on adult and pediatric protocols have distinct therapeutic outcome. Blood 104:312, 2004 8. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease: International prognostic factors project on advanced Hodgkin's disease. N Engl J Med 339:1506-1514, 1998 9. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Statist Assoc 53:457-481, 1958[CrossRef] 10. Peto R, Peto J: Asymptotically efficient rank invarian test procedures. J Roy Statist Soc 135:185-207, 1972 11. 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] 12. Yung L, Smith P, Hancock BW, et al: Long term outcome in adolescents with Hodgkin's lymphoma: Poor results using regimens designed for adults. Leuk Lymphoma 45:1579-1585, 2004[CrossRef][Medline] 13. Lin HM, Teitell MA: Second malignancy after treatment of pediatric Hodgkin disease. J Pediatr Hematol Oncol 27:28-36, 2005[CrossRef][Medline] 14. Swerdlow AJ, Barber JA, Hudson GV, et al: Risk of second malignancy after Hodgkin's disease in a collaborative British cohort: The relation to age at treatment. J Clin Oncol 18:498-509, 2000 15. Dores GM, Metayer C, Curtis RE, et al: Second malignant neoplasms among long-term survivors of Hodgkin's disease: A population-based evaluation over 25 years. J Clin Oncol 20:3484-3494, 2002 16. Bhatia S, Yasui Y, Robison LL, et al: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the Late Effects Study Group. J Clin Oncol 21:4386-4394, 2003 Submitted October 18, 2005; accepted March 10, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 cm]) were historically treated with extended field radiation alone. However, studies have demonstrated lower relapse rates with short course chemotherapy and involved-field radiotherapy (IFRT), with 5-year event free survivals (EFS) of greater than 90%.
2 statistic. Survival curves were plotted according to the method of Kaplan and Meier
