Annals of Oncology Advance Access originally published online on June 1, 2006
Annals of Oncology 2006 17(8):1290-1295; doi:10.1093/annonc/mdl094
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© 2006 European Society for Medical Oncology
A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients
1 Hematology Center, Department of Medicine, Karolinska University Hospital and Institutet, Solna, Stockholm, Sweden; 2 Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA; 3 Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA; 4 Department of Pathology, Karolinska University Hospital and Institutet, Solna, Stockholm, Sweden
* Correspondence to: Dr O. Landgren, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Bldg. EPS/Room 7110, Bethesda, MD 20892–7236, USA. Tel: +1 (301) 496-5786; Fax: +1 (301) 402-4489; E-mail: landgreo{at}mail.nih.gov
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Abstract |
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Background: Combined modality treatment has reduced the risk of relapse among younger early-stage Hodgkin lymphoma (HL) patients. Older HL patients may not tolerate chemotherapy and their prognosis is less favorable. We conducted a population-based study to evaluate long-term follow-up outcome in older early-stage HL patients initially treated with radiotherapy (RT) alone.
Patients and methods: We included 308 consecutive patients (22% were 
60 years) diagnosed 1972–1999 (median follow-up 20 years; range 1–28). Using Cox regression models we defined risk of relapse and survival in relation to clinical factors.
Results: 272/308 (88%) patients obtained complete remission following first-line RT alone. Among these, 42% relapsed within a median of 21 months. The relapse rate was independent of gender and age at diagnosis (median age 32 years, range 14–85); however, lymphocyte-predominant HL was associated with borderline (P = 0.049) 56% decreased risk of relapse. Among patients <60 years and 60 years, we observed 29 (median latency 10 years, range 2–25) and 11 (median latency 3 years, range 1–10) second tumors, respectively.
Conclusions: Older age (60 years) was not associated with an increased risk of relapse following RT alone. Given the risks of iatrogenic morbidity/mortality of chemotherapy in older patients, RT alone could be an alternative first-line therapy in early-stage older HL patients.
Key words: elderly, Hodgkin lymphoma, late complications, radiotherapy, relapse
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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In general, older patients with Hodgkin lymphoma (HL) have a less favorable prognosis than younger patients, in part related to a decreased tolerance of chemotherapy [1
–5]. In early-stage HL disease, treatment strategies include radiotherapy (RT), chemotherapy or a combined modality approach incorporating both [2, 6]. Issues underlying the treatment decisions include not only initial toxicity and the risk of recurrence, but also an estimate of the probability of successful salvage after relapse [1, 6–10]. In long-term follow-up studies, 10-year relapse-free survival-rates of 75% to 85% have been reported for laparotomy-staged early stage HL [11, 12] patients with good prognostic profile treated with extensive subtotal nodal RT alone. However, patients presenting with an unfavorable prognostic profile are at increased risk of relapse [13–15]. To decrease the risk of failure of RT treatment, combined-modality approaches have been applied, leading to a response rate of approximately 90% and a relapse-free survival of approximately 75% among early stage HL patients including those with adverse prognostic factors [8, 16]. Although the various combined approaches tested to date have resulted in a better prognosis compared with RT alone in terms of superior short-term disease-free survival, few studies could (due to effective salvage chemotherapy) demonstrate an improved long-term overall survival [17, 18]. Furthermore, combined-modality as first-line therapy in early-stage HL increases the risk of iatrogenic morbidity/mortality relative to the use of anticancer drugs [1, 2].
Many patients, particularly older and those with high neck lymphocyte predominance [LP] histopathology have been and are treated initially with RT alone. Relapse treatment in this clinical setting still remains a clinical issue. The aim of this population-based cohort study with a long-term follow-up was to evaluate relapse rate, outcome and predictors of prognosis in consecutive early-stage HL patients initially treated with RT alone, with special reference to older (60 years) patients.
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patients and methods |
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patient selection
This study was approved by the Karolinska Ethics committee. Consecutive patients with newly diagnosed early-stage HL during the years 1972–1999 in the Stockholm area, scheduled to receive RT alone, were referred to the major regional center at Karolinska to receive treatment. In total, 308 patients were included (median age 36 years, range 14–90 years) (Table 1). Older patients (
60 years) accounted for 22% of the total number of patients. Since all participating patients during the 30-year study-period were referred to, seen, and treated with RT at one major center, a limited number of clinicians were involved in decisions/applications of types of RT given. Most patients (approximately 90%) received RT as part of the current guidelines and clinical routines of that time [19]. Thirty-three patients participated in a clinical trial evaluating the value of early splenectomy [20] and were given total nodal irradiation as part of that trial. Four patients received involved field irradiation purely as palliation due to old age, and one patient due to pregnancy. Details of radiation fields and doses (Gy) are shown in Table 2. The median observation time at follow-up for surviving patients was long compared to most other studies (20 years, range 1–28 years), reflecting the fact that this is a population-based cohort that will provide information about characteristics of HL in patients seen outside clinical trials.
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diagnostic and staging procedures
As described previously [1
], diagnostic biopsies were reviewed to confirm the diagnosis and classified according to the REAL nomenclature [21] (Table 1). When necessary, complementary immunostaining for CD15, CD30, CD 20, LN-1, CD79a, CD3, UCHL-1, and EMA (avidin-biotin-peroxidase complex technique) were performed. Patients were staged according to the Ann Arbor staging classification [22]. For further details see our previous reports [1, 19].
prognostic markers
The following variables were tested in univariate and multivariate analysis: age, gender, histological subtype, time to relapse, stage, B-symptoms at relapse, and laboratory tests at relapse including erythrocyte sedimentation rate (ESR), hemoglobin, and white blood cell count.
statistical methods
Complete remission (CR) was defined as total regression of all palpable or histologically documented tumors and resolution of all radiographic and biochemical abnormalities due to HL for a minimum of three months [1, 19]. Overall survival was defined as the time from diagnosis to death, irrespective of cause. In those with CR, disease-free survival was defined as the time from last day of treatment to relapse or death from HL or death judged to be related to treatment of the disease (infections, certain second malignancies and cardiovascular events). Observations were censored by end of follow-up or death without signs of HL. Survival curves were constructed by the Kaplan-Meier procedure. Differences in the survival for categorical factors were tested with a Wilcoxon test appropriate for censored data [23]. Cox regression analyses were used for univariate analyses of factors and for multivariate analyses. Chi-square tests were used for contingency tables. All calculations were performed using SAS 8.2 (SAS Institute, Cary, NC, USA).
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results |
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A total of 272/308 (88%) patients obtained CR following first-line RT alone with a border-line significant difference (P = 0.05) between patients
60 (n = 54/67, 82%) and <60 years (n = 218/241, 90%).
The relapse rates for patients aged 60 and those <60 years at initial diagnosis were virtually the same (overall 42%, n = 114). However, a borderline (relative risk [RR] = 0.44, P = 0.049) decreased risk for relapse was found among patients with LP (versus other) histological subtype (Table 3). Median time to relapse was 21 months (range 3–165 months) with a majority (92%) occurring within the first 5 years.
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For relapsing patients, rescue treatment types were: RT (12%), chemotherapy (86%), and combined-modality treatment (2%). As shown in Table 4, the percentages did not vary by age. The rates of second complete remission (CR2) differed significantly (Chi-square, P < 0.0001) between patients
60 years (43%) and patients <60 years (85%). In univariate analysis, poor overall survival was significantly associated with the following characteristics at relapse: age 60 years (RR = 11.78, P < 0.0001), occurrence of B-symptoms (RR = 2.19, P = 0.007), anemia (per unit) (RR = 1.02, P = 0.037), and increased ESR (per unit) (RR = 1.01, P = 0.033). In multivariate analyses, however, only older age was an independent predictor (Table 4).
Subsequent to first-line RT treatment, no RT related deaths were observed. A total of 40 (13%) patients developed second malignancies; 29 (12%) were diagnosed with HL at age <60 years, and 11 (16%) were diagnosed with HL at age 60 (Table 5). The site-specific burden of cancer varied according to age at HL diagnosis. For younger patients (<60 years), breast cancer (patients 1–5) and lung cancer (patients 6–12) were the most frequently observed second malignancies. Median latency, i.e. the time between completed first-line RT and an observed second cancer, in the younger patient group was 10 years (range 2–25 years). As shown in Table 5, for a majority of the younger patients there was an association between applied RT field and second tumor site.
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For individuals diagnosed with HL at
60 years, median latency between completed first-line RT and an observed second cancer was 3 years (range 1–10 years). There was no topographic association between used RT fields and second tumor sites (Table 5). |
discussion |
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In this population-based cohort of early-stage HL patients treated with RT alone, at a median observation time of 20 years, approximately 60% of patients remained in CR without any evidence of recurrent disease. The substantial fraction of older patients (
60 years) compared to most other studies reflects HL patients seen in a population-based setting outside clinical trials. Most relapses occurred within the first five years of follow-up, similar to other reports [6]. Older patients were not at significantly increased risk for relapse compared to younger patients. In contrast to previous reports of predictors of relapse [7, 9, 24], we found a reduced risk of relapse only in those with the LP histological subtype. This may reflect the fact that the small number of patients in our study or could be due to differences in patient selection.
Approximately 90% of relapsing patients received chemotherapy-based rescue treatment. The CR2 rate differed significantly between younger and older patients. The 5-year overall survival for older patients compares favorably with our [1] previously reported 5-year survival rates for older HL patients with advanced disease initially treated with chemotherapy ± RT, as well as 5-year survival rates reported by other major study groups [2, 3, 5]. The underlying mechanism for the clinically well-known poor prognosis of older HL patients treated with chemotherapy [1–5] remains poorly understood. One hypothesis is that HL in older patients is biologically more aggressive. We found anemia, increased ESR and B-symptoms to be significantly more frequent at diagnosis among older patients, which supports the hypothesis of age-related disease differences in HL. Another hypothesis is that older patients have reduced tolerance to chemotherapy and receive decreased dose intensity. However, in the same population, we previously found that approximately 2/3 of older HL patients with advanced disease received what could be considered adequate treatment [1]. In this study, we found the same proportion among those who relapsed and received rescue chemotherapy, which further supports the concept of age-related biological differences.
A total of 40 (13%) patients developed second malignancies; 29 in the younger group and 11 in the older. The median latency between completed first-line RT and occurrence of secondary malignancies in the younger group was extended (10 years), while in the older group the latency was only 3 years. Furthermore, among the younger patients, there was a tight correspondence between previously applied RT field and site of observed second tumor. These observations are consistent with previous studies, which have reported elevated risk of second malignancies 10–15 years subsequent to RT [25, 26], and provide strong evidence for a true RT related causality in this age group. However, in contrast to the younger patients, in the older HL patients there was no association between applied RT fields and second tumors which strongly suggests that the observed malignancies were mainly due to expected surveillance effects seen in older populations, rather than RT related second tumors [26].
In our study, we included all consecutive patients with newly diagnosed early-stage HL during a 30-year period in the Stockholm area, scheduled to receive RT alone, who were referred to the major regional center at Karolinska to receive treatment. Since the early-1970s, we have consecutively identified all incident HL patients diagnosed in the Stockholm area and collected detailed demographic, clinical, diagnostic and prognostic, and follow-up information on each individual patient. As mentioned above, the median observation time at follow-up for surviving patients in our current study was long and the fraction of older patients was high, reflecting the unique population-based design of this study.
Limitations include the retrospective study-design as well as inherent variations and improvements of RT and radiation techniques introduced during the 30-year study period. Importantly, there was no acute RT related mortality and, as discussed above, most of the observed second neoplasms in the older HL group are most likely not RT related but rather due to surveillance effects seen in an older population.
In conclusion, our study shows that older patients have a highly sustained CR rate following RT alone and no evidence of an age-related increased risk of relapse. Older HL patients who relapse and receive rescue chemotherapy have a prognosis comparable with that of older patients being treated initially with chemotherapy [1]. Therefore, RT alone seems to remain an alternative approach in older HL patients [13]. The well-known increased susceptibility to RT among young patients, reflected in an increased risk of second malignancies [25, 26], is probably not as important in this older patient category. Until we have access to effective but less toxic regimens that are effective, the decision to use chemotherapy in older patients with early-stage disease should be based on individual risk profile, projected benefit versus risk of iatrogenic morbidity/mortality, and in collaboration with an informed patient [2, 3, 5, 7, 9, 24].
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Acknowledgements |
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We wish to thank Drs Margaret A. Tucker, Erik Svedmyr, and Lois B. Travis for helpful comments and critical review of the manuscript, and RN Camilla Byström for her help obtaining clinical information on study patients. This study was supported by grants from the Swedish Cancer Society, the Stockholm County Council, and Karolinska Institutet Foundations.
Received for publication June 21, 2005. Revision received March 20, 2006. Accepted for publication March 28, 2006.
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References |
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1. Landgren O, Algernon C, Axdorph U et al. Hodgkin's lymphoma in the elderly with special reference to type and intensity of chemotherapy in relation to prognosis. Haematologica 2003; 88: 438–444.
2. Engert A, Ballova V, Haverkamp H et al. Hodgkin's lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol 2005; 23: 5052–5060.
3. Ballova V, Ruffer JU, Haverkamp H et al. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol 2005; 16: 124–131.
4. Proctor SJ, White J, Jones GL. An international approach to the treatment of Hodgkin's disease in the elderly: launch of the SHIELD study programme. Eur J Haematol Suppl 2005; 63–67.
5. Weekes CD, Vose JM, Lynch JC et al. Hodgkin's disease in the elderly: improved treatment outcome with a doxorubicin-containing regimen. J Clin Oncol 2002; 20: 1087–1093.
6. Gustavsson A, Osterman B, Cavallin-Stahl E. A systematic overview of radiation therapy effects in Hodgkin's lymphoma. Acta Oncol 2003; 42: 589–604.[CrossRef][ISI][Medline]
7. Horwich A, Specht L, Ashley S. Survival analysis of patients with clinical stages I or II Hodgkin's disease who have relapsed after initial treatment with radiotherapy alone. Eur J Cancer 1997; 33: 848–853.[CrossRef][ISI][Medline]
8. Specht L, Gray RG, Clarke MJ, Peto R. Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group. J Clin Oncol 1998; 16: 830–843.[Abstract]
9. Healey EA, Tarbell NJ, Kalish LA et al. Prognostic factors for patients with Hodgkin disease in first relapse. Cancer 1993; 71: 2613–2620.[CrossRef][ISI][Medline]
10. Bendandi M, Pileri SA, Zinzani PL. Challenging paradigms in lymphoma treatment. Ann Oncol 2004; 15: 703–711.
11. Duhmke E, Franklin J, Pfreundschuh M et al. Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 2001; 19: 2905–2914.
12. Sears JD, Greven KM, Ferree CR, D'Agostino RB, Jr. Definitive irradiation in the treatment of Hodgkin's disease. Analysis of outcome, prognostic factors, and long-term complications. Cancer 1997; 79: 145–151.[CrossRef][ISI][Medline]
13. Bonadonna G, Bonfante V, Viviani S et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results. J Clin Oncol 2004; 22: 2835–2841.
14. Mauch P, Tarbell N, Weinstein H et al. Stage IA and IIA supradiaphragmatic Hodgkin's disease: prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation. J Clin Oncol 1988; 6: 1576–1583.
15. Carde P, Hagenbeek A, Hayat M et al. Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1993; 11: 2258–2272.
16. Cosset JM, Ferme C, Noordijk EM et al. Combined modality treatment for poor prognosis stages I and II Hodgkin's disease. Semin Radiat Oncol 1996; 6: 185–195.[CrossRef][Medline]
17. Carde P, Burgers JM, Henry-Amar M et al. Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors. J Clin Oncol 1988; 6: 239–252.[Abstract]
18. Bonfante V, Santoro A, Viviani S et al. Early stage Hodgkin's disease: ten-year results of a non-randomised study with radiotherapy alone or combined with MOPP. Eur J Cancer 1992; 29A: 24–29.
19. Bjorkholm M, Wedelin C, Holm G et al. Immune status of untreated patients with Hodgkin's disease and prognosis. Cancer Treat Rep 1982; 66: 701–709.[ISI][Medline]
20. Askergren J, Bjorkholm M, Holm G et al. Prognostic influence of early diagnostic splenectomy in Hodgkin's disease. A long-term follow-up. Acta Med Scand 1986; 219: 315–322.[ISI][Medline]
21. 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 1994; 84: 1361–1392.
22. Carbone PP, Kaplan HS, Musshoff K et al. Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 1971; 31: 1860–1861.
23. Gehan EA. A generalized two-sample Wilcoxon test for doubly censored data. Biometrika 1965; 52: 650–653.
24. Roach M, 3rd, Brophy N, Cox R et al. Prognostic factors for patients relapsing after radiotherapy for early-stage Hodgkin's disease. J Clin Oncol 1990; 8: 623–629.[Abstract]
25. Tucker MA, Coleman CN, Cox RS et al. Risk of second cancers after treatment for Hodgkin's disease. N Engl J Med 1988; 318: 76–81.[Abstract]
26. 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 2002; 20: 3484–3494.
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