the Leukemia/Bone Marrow Transplant Program of British Columbia
    the Divisions of Hematology, Hematopathology, Radiation Oncology, and Medical Oncology of the British Columbia Cancer Agency, Vancouver General Hospital, and the University of British Columbia, Vancouver, British Columbia, Canada

    ABSTRACT

    PURPOSE: To determine the incidence of second malignancies among patients with Hodgkin's lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence.

    PATIENTS AND METHODS: We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT.

    RESULTS: The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age  35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged  35 years (P = .03) and stage III/IV (P = .04).

    CONCLUSION: Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.

    INTRODUCTION

    High-dose chemotherapy/radiotherapy and autologous hematopoietic stem-cell transplantation (AHSCT) is well recognized as a potentially curative treatment strategy for patients with relapsed or refractory Hodgkin's lymphoma (HL) after conventional chemotherapy/radiotherapy.[1,2] Approximately 50% to 70% of patients with relapsed HL and up to 30% of patients with refractory disease are long-term disease-free survivors after AHSCT.[1,2] However, as more patients survive their disease and the early post-transplant period, it has become apparent that there are potential long-term complications. One such complication that raises great concern is the development of a second (new) malignancy after successful treatment of HL. Indeed, there are an increasing number of reports in the literature documenting an increased incidence of second malignancies for patients undergoing AHSCT for a variety of hematologic malignancies, including HL.[3,4]

    There have also been several reports in the literature during the last 20 years documenting an increased incidence of second malignancies for patients with HL treated with conventional therapy alone.[5-14] These malignancies belong to three main categories: therapy-induced myelodysplastic syndrome (tMDS) and therapy-induced acute myeloid leukemia (tAML), non-Hodgkin's lymphoma (NHL), and solid tumors. This increased risk of developing a second cancer among patients with HL is likely multifactorial, related to the carcinogenic effects of chemotherapy and radiotherapy as well as possible enhanced susceptibility to cancer development related to underlying immunologic deficiencies impairing cancer surveillance.[3] Chemotherapeutic agents (particularly alkylating agents and nitrosoureas contained in mechlorethamine, vincristine, procarbazine, and prednisone [MOPP] and similar regimens) and radiotherapy have been associated with an increased incidence of tAML/tMDS and solid tumors, respectively.[5,6,8-16] Furthermore, several studies have shown that older age at diagnosis, multiple cycles of combination chemotherapy (particularly with alkylating agents), combined-modality therapy, and radiotherapy alone have all been linked to a higher risk of second malignancy.[4,8,10,11,17-21] What remains controversial, however, is the potential contribution of AHSCT to second cancer development, and whether such treatment increases the risk further compared with standard-dose treatment alone. To establish the incidence of second malignancies among patients with HL treated with AHSCT compared with patients undergoing conventional therapy, and to identify potential risk factors for their occurrence, we retrospectively studied a large cohort of patients with HL treated at our center during a 26-year period.

    PATIENTS AND METHODS

    Patient Characteristics

    Between January 1976 and December 2001, 1,732 consecutive patients with HL (age at diagnosis  65 years) were diagnosed and treated throughout British Columbia under the treatment guidelines of the British Columbia Cancer Agency or British Columbia's Children's Hospital. January 1976 was chosen because multiagent chemotherapy, wide-field irradiation, and staging with at least lymphangiography had become standard practice in British Columbia by that date. From this patient cohort, 1,530 patients were treated with conventional therapy alone and 202 patients underwent AHSCT after failure of conventional therapy. Patient characteristics are listed in [Table 1]. All patients provided informed consent for treatment and all research studies were approved by the University of British Columbia and institutional research ethics boards.

    Conventional Therapy

    All 1,732 patients diagnosed with HL were treated initially with combination chemotherapy and/or radiotherapy. Specific treatment practices including the indications for combined-modality therapy and individual chemotherapeutic regimens varied during the time course of the study. For each patient, total courses of chemotherapy and radiotherapy administered were examined and data recorded included the type of regimen: MOPP; doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or others. Patients treated with MOPP/ABV hybrid or alternating MOPP and ABVD, or those receiving more than one treatment regimen that included MOPP, were included in the MOPP category. All other chemotherapy regimens including ABVD were pooled and classified as other. The total number of lines of therapy was recorded for each patient and classified as follows: one line of therapy and  two lines of therapy; the number of individual cycles of chemotherapy regimens was not recorded. One line of therapy consisted of chemotherapy alone, chemotherapy plus planned irradiation, or irradiation alone.

    Data regarding irradiation included the field(s) (involved field, mantle, inverted Y, total-body irradiation [TBI], and so on), and administration times (as part of conditioning [TBI], post-AHSCT irradiation, and at relapse). These data were pooled and classified as follows: mantle field, inverted Y, whole abdominal irradiation, or TBI was classified as extended field; any other field less than that classified under extended field was classified as involved field.

    After completion of each course of therapy, the disease status was evaluated for each patient and categorized as complete response (CR; absence of all measurable disease), unconfirmed CR (residual masses of unknown significance), partial response (regression of  50% of measurable disease), or refractory disease (regression of < 50% of measurable disease or progression during therapy). Evidence of disease progression after CR or unconfirmed CR was classified as disease relapse.

    Stem-Cell Transplantation

    Of the 1,732 patients initially treated with conventional therapy, 202 subsequently underwent AHSCT. Transplantation details are listed in [Table 2]. All 202 patients had documented relapsed or refractory disease before transplantation. Patients typically received a short course of salvage chemotherapy before stem-cell collection, although chemosensitivity was not a requirement for proceeding to AHSCT. The conditioning regimen was chemotherapy based in 201 patients (cyclophosphamide, carmustine, and etoposide ± cisplatin [n = 197]; etoposide and cyclophosphamide ± other [n = 2]; carmustine, etoposide, melphalan, and cytarabine [n = 1]; ifosfamide, cisplatin, and etoposide [n = 1]). One patient received TBI (12 Gy) with etoposide and cyclophosphamide ([Table 2]). All doses were based on the lesser of corrected body weight [0.5 (ideal body weight + actual body weight)] or actual body weight. The stem-cell source varied over the time period of the study, as listed in [Table 2]. Patients with a history of prior pelvic irradiation or bone marrow contamination with HL preferentially underwent blood stem-cell collections. In all other patients, stem cells were collected according to institutional protocol and patient or physician preference. Stem-cell purging was not undertaken. Standard supportive care techniques were used as described previously.[2]

    Second Malignancy Diagnosis

    After completion of conventional therapy or AHSCT, patients were routinely observed by their oncologist and referring physician. At a minimum and more frequently during the first 5 years after therapy, recommended evaluations included yearly physical examinations with special attention to skin, thyroid gland (if previously irradiated), and nodal sites; cervical cytologic (Papanicolaou) smears for all females; mammography for all females starting at age 40 years or 10 years after the diagnosis of HL, whichever came sooner; careful investigation of any new symptoms suggesting specific organ dysfunction; complete blood counts, thyroid-stimulating hormone level (if thyroid was previously irradiated), and blood tests of renal and liver function. Chest radiographs were performed once per year for those patients with a previous history of intrathoracic involvement with HL through 10 years of follow-up.

    To identify all second neoplasms, including those not routinely reported to the original oncologist, the records of all patients with a diagnosis of HL were electronically crosslinked with the independent records of the British Columbia Cancer Registry, which is maintained separately and to which all pathologically verified neoplastic diagnoses in British Columbia are reported. To avoid potential under-reporting, nonmelanomatous skin cancer was not included as a second neoplasm. Likewise, to avoid overestimation of risk, uterine cervical carcinoma-in-situ was not included in this analysis. All second malignancies were confirmed where possible by central review of the histopathology specimens by an appropriate reference pathologist. The time at risk for the development of a second malignancy was calculated from the date of end of initial HL treatment or the date of ASCT (as appropriate) to either the date of death, date of second neoplasm, the date of last follow-up, or to the end of the period of analysis (December 31, 2002). All second cancers developing before the completion of initial therapy were excluded from this analysis.

    Statistical Analysis

    The cumulative incidence of developing any second malignancy, tAML/tMDS, NHL, or solid tumor after conventional therapy or AHSCT was determined using the competing risks method of Kalbfleisch and Prentice.[22] The incidence for those patients who underwent AHSCT was compared to the incidence for patients treated with conventional therapy alone using the Gray test. The following were analyzed as potential risk factors for the development of second malignancy after therapy for HL: age at diagnosis of HL, sex, stage at diagnosis (I/II v III/IV), presence of "B" symptoms at diagnosis, type of therapy (chemotherapy v radiotherapy v both), type of chemotherapy (MOPP v other), radiotherapy (none v any), extent of radiotherapy (extended field v involved field), year of diagnosis (before 1991 v 1991 or later), and whether the patient underwent AHSCT. Risk factors were evaluated for association with the development of second cancer by univariate and multivariate analysis utilizing a Cox proportional-hazards regression model.[23] The same risk factors were evaluated for association with the development of tAML/tMDS or solid tumors.

    To determine whether the patients studied were at increased risk of developing a second malignancy, comparisons were made with age- and sex-specific population data collected by the British Columbia Cancer Registry. The risk ratio (RR) was calculated by comparing second malignancy rates that would be expected based on the registry data. The overall survival from diagnosis of HL for patients receiving conventional therapy or AHSCT and the overall survival for patients developing a second malignancy was calculated using the methods of Kaplan and Meier.[24]

    RESULTS

    Treatment Outcome

    At the time of the analysis, the study cohort had accumulated a follow-up of 16,225 patient-years. The median follow-up was 9.8 years (range, 0.03 to 25.5 years) for the whole cohort; 683 patients (39%) had more than 10 years and 366 patients (21%) had more than 15 years of follow-up. The median follow-up was 9.7 years (range, 0.03 to 25.5 years) for those patients who received conventional therapy alone and 7.8 years (range, 0.2 to 17.4 years) from AHSCT for those patients who underwent AHSCT. At present, 1,406 of the 1,732 patients are alive, with a 15-year overall survival (OS) from diagnosis of HL of 77% (95% CI, 74% to 79%). The 15-year OS from the diagnosis of HL for the patients receiving conventional therapy alone compared with the patients undergoing AHSCT was 80% (95% CI, 77% to 83%) and 53% (95% CI 45% to 60%), respectively (P < .0001). In all, 282 patients have experienced a relapse/progression of HL after conventional therapy alone (n = 203) or AHSCT (n = 79). Of the 202 patients who underwent AHSCT, eight patients died as a result of early AHSCT-related toxicity (pneumonitis, n = 7; sepsis, n = 1), seven patients died as a result of a second malignancy, one patient died as a result of late pulmonary fibrosis, and one patient died in a motor vehicle accident. The 15-year probability of death not due to a second neoplasm for patients treated with conventional therapy alone compared with the patients undergoing AHSCT was 14% (95% CI, 12% to 16%) and 43% (95%, CI 35% to 50%), respectively (P = .002).

    Second Neoplasms

    In total, 136 second malignancies developed among 1,732 patients; two of these second malignancies were diagnosed before completion of initial therapy and were excluded from this analysis. Of the remaining 134 second malignancies, there were 18 tAML/tMDS, 98 solid tumors, 13 NHL, one Langerhans cell histiocytosis, one multiple myeloma, one chronic lymphocytic leukemia, one chronic myeloid leukemia, and one polycythemia vera. One hundred twenty-two second malignancies developed after conventional therapy alone and 12 developed after AHSCT ([Table 3]). These second cancers developed at a median of 10.3 years (range, 0.4 to 25.4 years) from the diagnosis of HL. Of the 134 patients who developed a second malignancy, 55 had received both chemotherapy and radiotherapy, 36 had been treated with chemotherapy alone, and 43 received only radiotherapy. The cumulative number of lines of therapy for the patients developing a second neoplasm was one (n = 98) and  two (n = 36). Only 55 of the 134 patients diagnosed with a second malignancy are alive, with a median survival from the diagnosis of the second neoplasm of 1.2 years ([Fig 1]).

    Probability of Second Cancer

    The 15-year cumulative incidence of developing a second malignancy was 9% (95% CI, 7% to 11%). The 15-year cumulative incidence of developing a second malignancy for patients receiving conventional therapy alone or AHSCT was 10% (95% CI, 8% to 12%) and 8% (95%, CI 4% to 14%), respectively (P = .48; [Fig 2]). Compared with age- and sex-adjusted cancer rates in the general population of British Columbia, the RR of a second malignancy occurring in patients after therapy for HL was 3.5 (95% CI, 2.9 to 4.1; P < .001). The RR for those patients receiving conventional therapy alone and AHSCT was 3.3 (95% CI, 2.8 to 3.9; P < .001) and 6.17 (95% CI, 3.2 to 10.8; P < .001), respectively.

    Treatment-Related AML/MDS

    Twenty-three of the 134 second neoplasms were hematopoietic (tAML/tMDS, n = 18; Langerhans cell histiocytosis, n = 1; multiple myeloma, n = 1; chronic myeloid leukemia, n = 1; chronic lymphocytic leukemia, n = 1; and polycythemia vera, n = 1). Fourteen of the 18 occurrences of tAML/tMDS were among the group of patients receiving conventional therapy alone and four occurred after AHSCT; the patient developing Langerhans cell histiocytosis had undergone AHSCT and the other four hematopoietic malignancies developed after conventional therapy alone. Of the 18 patients developing tAML/tMDS, 15 patients, including the four patients who underwent AHSCT, had previously received both radiotherapy and chemotherapy (including MOPP in 13 patients), two patients received MOPP alone, and one patient was treated with radiotherapy only. Bone marrow cytogenetic analysis was available in only six of the patients with tAML/tMDS: four had an abnormality of chromosome 5 or 7; one had an 11q23 rearrangement, and one had t(8;21). The median interval from the diagnosis of HL to the diagnosis of tAML/tMDS for all patients and for those receiving conventional therapy and AHSCT was 4.5 years (range, 2.2 to 16.6 years), 3.1 years (range, 2.2 to 16.6 years), and 7.0 years (range, 3.3 to 14.7 years), respectively (P = .33). For the patients undergoing AHSCT, the median interval from AHSCT to tAML/tMDS was 3.9 years (range, 2.1 to 4.2 years). The 15-year cumulative incidence of developing tAML/tMDS was 1.4% (95% CI, 0.8% to 2.2%) for all patients ([Fig 3]), 1.1% (95% CI, 0.6% to 1.8%) for those treated with conventional therapy alone, and 3.6% (95% CI, 0.9% to 9.6%) for those undergoing AHSCT (P = .22). Of the 18 patients with tAML/tMDS, only one patient [who had t(8;21)] is still alive in complete remission 18 months after completion of induction chemotherapy. The other 17 patients have died a median of 5.5 months (range, 0 to 18.5 months) from the diagnosis of tAML/tMDS. Compared with age- and sex-adjusted cancer rates in the general population of British Columbia, the RR of developing tAML/tMDS after therapy for HL was 19.6 (95% CI, 11.6 to 31.0; P < .001).

    Solid Tumors

    Ninety-eight solid tumors have developed (lung, n = 31; breast, n = 18; gastrointestinal, n = 16; genitourinary, n = 12; ear/nose/throat, n = 6; CNS, n = 4; melanoma, n = 4; thyroid, n = 3; sarcoma, n = 2; primary unknown, n = 2) a median of 12.0 years (range, 0.4 to 25.4 years) from the diagnosis of HL. Ninety-three of the solid malignancies occurred after conventional therapy alone and five developed after AHSCT. Seventy-eight of the 98 patients had received radiotherapy (extended field, n = 74; involved field, n = 4) before the development of the second solid neoplasm. The location of the solid tumor in relation to the radiotherapy field was not known for all patients. The median interval from the diagnosis of HL to the diagnosis of a second solid tumor was 12.2 years (range, 0.4 to 25.4 years) among the patients receiving conventional therapy alone and 9.9 years (range, 7.5 to 22.5 years) for the patients undergoing AHSCT (P = .65). For the patients undergoing AHSCT, the median interval from AHSCT to solid tumor was 3.8 years (range, 0.5 to 6.6 years). The 15-year cumulative incidence of developing a solid tumor was 7.2% (95% CI, 5.5% to 9.0%) for all patients ([Fig 3]), 7.7% (95% CI, 5.9% to 9.8%) for those patients receiving conventional therapy alone, and 3.2% (95% CI, 1.2% to 6.9%) for those undergoing AHSCT (P = .06).

    Of the 17 female patients developing breast cancer, 15 had received prior mantle radiotherapy and eight were 20 years of age or younger at the time of their diagnosis of HL. Forty-five of the 98 patients are still alive at last follow-up (lung, n = 7; breast, n = 13; gastrointestinal, n = 7; genitourinary, n = 7; ear/nose/throat, n = 4; CNS, n = 1; melanoma, n = 1; thyroid, n = 3; sarcoma, n = 1; and primary unknown, n = 1). The median survival from the diagnosis of the solid tumor was 2.1 years. Compared with age- and sex-adjusted cancer rates in the general population of British Columbia, the RR of developing a solid tumor was 2.8 (95% CI, 2.3 to 3.4; P < .001).

    NHL

    Thirteen patients have developed NHL after conventional therapy alone (n = 11) or after AHSCT (n = 2) a median of 9.5 years (range, 0.66 to 22.2 years) from diagnosis of HL. The WHO classification[25] was diffuse large B-cell (n = 7), follicular grade 1 (n = 2), follicular grade 2 (n = 1), Burkitt-like (n = 1), mucosa-associated lymphoid tissue (n = 1), and not otherwise classified (n = 1). Of these 13 patients, four had received chemotherapy alone, three had received radiotherapy alone, and six had been treated with both chemotherapy and radiotherapy. The median interval from diagnosis of HL to diagnosis of NHL among the patients receiving conventional therapy alone or undergoing AHSCT was 9.1 years (range, 0.66 to 22.2 years) and 10.4 years (range, 9.5 to 11.4 years), respectively (P = .84). The time from AHSCT to the diagnosis of NHL for the two patients who had undergone AHSCT was 5.5 and 5.8 years. The 15-year cumulative incidence of developing NHL was 0.7% (95% CI, 0.3% to 1.3%) for all patients ([Fig 3]), 0.5% (95% CI, 0.2% to 1.0%) for patients receiving conventional therapy alone, and 1.6% (95% CI, 0.3% to 5.3%) for patients undergoing AHSCT (P = .13). Six of the 13 patients are still alive at last follow-up; the median survival from diagnosis of NHL was 2.5 years. Compared with age- and sex-adjusted cancer rates in the general population of British Columbia, the RR of NHL was 6.1 (95% CI, 3.3 to 10.2; P < .001).

    Risk Factors for Second Cancer

    In univariate and multivariate analysis, age at diagnosis of HL (< 35 v  35 years; P < .0001) was the only significant risk factor for the development of a second malignancy after therapy for HL. The 15-year cumulative incidence for developing a second malignancy in patients younger than 35 and  35 years of age at the time of diagnosis of HL was 5.8% (95% CI, 4.0% to 8.1%) and 16% (95% CI, 13% to 20%), respectively (P < .001; [Fig 4]). When the analysis was restricted to tAML/tMDS, age at diagnosis of HL (< 35 v  35 years; P = .03) and stage at diagnosis (I/II v III/IV; P = .03) were significant in univariate analysis. In multivariate analysis, age at diagnosis of HL (P = .03) and stage at diagnosis (P = .04) remained significantly associated with an increased risk of tAML/tMDS ([Table 4]). When the analysis was restricted to solid tumors, the only significant risk factor in univariate and multivariate analysis was age at diagnosis of HL (< 35 v  35 years; P < .0001). To examine whether patients at advancing age had an additional increase in risk of developing a second neoplasm, age at diagnosis of HL by decade (< 20 v 20 to 29 v 30 to 39 v 40 to 49 v 50 to 59 v > 60 years) was also analyzed in the univariate and multivariate model. In multivariate analysis, the risk of second malignancy increased with advancing age (< 20, RR = 1.0; 20 to 29, RR = 0.8; 30 to 39, RR = 1.3; 40 to 49, RR = 3.7; 50 to 59, RR = 4.8; more than 60 years, RR = 11.5; P < .0001). However, in multivariate analysis accounting for advancing age, the RR of second malignancy was still not significantly influenced by AHSCT. To determine the effect of age (< 35 years v  35 years at diagnosis) and risk of second malignancy compared to the general population, comparisons were made with age- and sex-specific cancer rates in British Columbia. The RR for patients younger than 35 years and  35 years at diagnosis was 6.5 (95% CI, 4.9 to 8.3; P < .001) and 2.6 (95% CI, 2.0 to 3.2; P < .001), respectively.

    DISCUSSION

    Few studies have compared the incidence of second neoplasms among HL patients undergoing AHSCT with those receiving conventional therapy alone.[15,20,21,26] It might be anticipated that patients undergoing AHSCT would have an even higher risk of second cancer development than patients treated conventionally because of the cumulative effects of prior therapy and the carcinogenic effects of high-dose conditioning regimens.

    In this study of 1,732 consecutive patients age younger than 66 years at diagnosis who were treated for HL, including 202 patients who underwent AHSCT, 134 second malignancies developed resulting in a cumulative incidence of 9% at 15 years. This is similar to what has been reported previously in the literature.[8-11,20,27,28] However, for the patients who underwent AHSCT, the cumulative probability of developing any second malignancy, tAML/MDS, NHL, or solid tumors was not increased in comparison with those patients receiving conventional therapy alone (8% v 10%; P = .48). In a similar study, the Société Fran?aise de Greffe de Moelle compared second cancer risk among 467 HL patients undergoing autografting with a matched population treated conventionally and also found that the risk of tAML/tMDS was not significantly increased after AHSCT, but there was an increased incidence of solid tumors in the autografted population, with a relative risk of 5.9.[20] Despite the increased incidence of solid tumors, no risk factors could be identified. At least two other studies have similarly concluded that AHSCT does not independently increase the risk of developing tAML/tMDS after therapy for HL.[21,26]

    The association of chemotherapy (particularly alkylating agents and epipodophyllotoxins) and ionizing radiation with an increased incidence of tAML/tMDS is well established.[8,15,17,19,21,26,29,30] Metayer et al[15] reported on the incidence and risk factors associated with tAML/tMDS after autotransplantation for lymphoid malignancies. The risk of tAML/tMDS was significantly increased with the intensity of pretransplantation chemotherapy with cumulative mechlorethamine doses  50 mg/m2 and a TBI dose  13.2 Gy for those patients undergoing transplantation. In our study, we did not have data regarding the cumulative doses of individual chemotherapeutic drugs administered, and we did not find an association in multivariate analysis between the use of MOPP and tAML/tMDS. Furthermore, we could not address the risks associated with TBI because all of the patients in our study except one received a non–TBI-based conditioning regimen. However, we did find that patients with advanced-stage disease at diagnosis had a higher risk of developing tAML/tMDS. This could indirectly reflect a more extensively treated patient population that may have had a greater cumulative exposure to MOPP therapy or other alkylators. This, coupled with the small number of patients with tAML/tMDS in our study, could have also reduced our ability to identify potential therapy-related risk factors for tAML/tMDS.

    In comparison with what is known about tAML/tMDS, less information is available on the risk of developing solid neoplasms after AHSCT for HL because more prolonged follow-up is required to assess the impact of the high-dose conditioning regimens and AHSCT on cancers with a known longer latency period. Several studies, however, have reported on the increased incidence of solid tumors after conventional therapy for HL.[7-14,16] A recent publication from the Netherlands evaluating the risk of second malignancy in long-term survivors of HL found that the cumulative risk of developing a solid tumor was 23% at 25 years.[9] This was confirmed in the study by Dores et al,[11] who found a high incidence of solid tumors of 11.7% at 25 years among long-term survivors of Hodgkin's disease; the most common neoplasms were lung, breast, and GI. In our study, the cumulative incidence of solid tumors was 7.2% overall and 3.2% for those patients undergoing AHSCT, which is similar to reports of patients treated with conventional therapy. The most common tumors seen in our study were breast, lung, and GI, similar to the reports from Dores et al and others.[8-11]

    Various risk factors for solid tumor development have been identified and include advanced age, prior chemotherapy and radiotherapy and, for those patients undergoing AHSCT, the use of TBI-based conditioning regimens.[4,8,10-14,16,20,27,28,31] In particular, there is a marked increase in the RR of breast cancer among young female HL patients receiving mediastinal irradiation, with an estimated actuarial incidence of 13.9% by 40 years of age.[8,31] In keeping with these reports, we also found a high incidence of breast cancer in women receiving mantle irradiation at a young age; eight of the 18 patients developing breast cancer in our study were  20 years of age at the time of radiotherapy.

    A number of reports have highlighted the increased incidence of lung cancer with both increasing radiation dose and cycles of alkylating chemotherapeutic agents.[12,14,16] In our study, when we examined risk factors for developing any solid neoplasm, we did not find an association between radiotherapy or chemotherapy. A possible explanation for this may be the long latency period of solid tumors. The increased incidence of solid tumors in many studies including our own, is just beginning to be appreciated 15 to 20 years from the diagnosis of HL.[9-13,28] It is therefore likely that even longer follow-up than that seen in our study will be needed to fully assess the impact of radiotherapy and other factors on solid tumor development.

    Analysis of various patient and treatment characteristics in our study cohort revealed that age at diagnosis of HL  35 years was associated with an increased likelihood of developing second malignancies, including solid tumors and tAML/tMDS, compared with younger patients with HL. The increased risk of second cancers in association with advanced patient age has been shown previously,[4,17,19,20,27,28] and should be interpreted with caution, given that the incidence of cancer in the general population increases with patient age. Therefore, measurements such as RR tend to decrease with advancing age, whereas absolute risk and cumulative incidence tend to increase. However, in our study, the increase in age-adjusted risk indicates that the risk of a new malignancy is higher even after accounting for advanced age. This is consistent with the multistep hypothesis of carcinogenesis. The impairment of DNA repair that occurs with aging may result in an increased susceptibility to the effects of DNA-damaging agents among older patients.[32] Furthermore, we also found that younger patients with HL (age < 35 years at diagnosis) were also at increased risk of second malignancy compared with the general population (RR = 6.5), reflecting either the carcinogenic effects of prior therapy or an enhanced susceptibility to cancer development.

    It is apparent in our study that a number of significant differences in the baseline and treatment characteristics between the patients receiving conventional therapy alone compared with the patients undergoing AHSCT could have influenced our results. However, a majority of patients undergoing AHSCT compared with the patients receiving conventional therapy were at an advanced stage at diagnosis, had a more advanced disease status at AHSCT, and had received chemotherapy (including exposure to MOPP) with or without radiotherapy as opposed to radiotherapy alone. Considering these factors, one might have anticipated that the risk of second malignancy would have been even higher for those patients undergoing AHSCT relative to those patients receiving conventional therapy alone, given that prior chemotherapy is known to be an important factor influencing the risk of second neoplasm.[15,21,26] This was not the case, and in fact the risk of second neoplasm was lower for those patients undergoing AHSCT when compared with the patients treated conventionally. The median age at diagnosis of HL for the patients undergoing AHSCT was lower compared with the conventional-therapy group (27 v 29 years) and this might have led us to underestimate the risk of second cancer in the AHSCT group. However, in multivariate analysis, after accounting for advancing age by decade, the risk of second malignancy for patients receiving therapy for HL was still not significantly influenced by AHSCT.

    This study evaluated a large group of patients treated for HL undergoing a variety of treatments with chemotherapy, radiotherapy, and/or AHSCT. From our data it is evident that these patients are at increased risk of developing a second neoplasm compared with the general population. It is reassuring, however, that those patients undergoing AHSCT do not seem to be at greater risk of developing second cancer compared with those patients receiving conventional therapy alone, at least during the first decade from diagnosis. Thus, concern about a possible higher risk of second neoplasm after AHSCT should not affect the formulation of an overall strategy for the management of patients with HL. Longer follow-up in large patient cohorts such as ours will enable investigators to address more fully the risk of second tumors after AHSCT, particularly with respect to solid tumors where the latency is prolonged.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Acknowledgment

    We thank the medical and nursing staff of T15 Ward and BMT Daycare at the Vancouver General Hospital; the staff of 6W Ward at the British Columbia Cancer Agency; the staff of 3B Ward at the British Columbia's Children's Hospital; and Jane Donaldson for maintenance of the Hodgkin's lymphoma database.

    NOTES

    Presented in part at the American Society of Hematology Annual Meeting, San Diego, CA, December 6-9, 2003.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

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    Submitted March 7, 2005; accepted June 13, 2005.

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《临床肿瘤学医学期刊》2005年11月第23卷第11期