1 First Department of Internal Medicine, University Hospital Cologne and the German Hodgkin Lymphoma Study Group (GHSG); 2 Department of Radiation Oncology, University of Cologne, Germany
*Correspondence to: Dr K. Behringer, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany. Tel: +49-221-473558; Fax: +49-221-476311; Email: karolin.behringer{at}biometrie.uni-koeln.de
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Abstract |
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Patients and methods: From 1983 to 1998, the GHSG conducted three generations of clinical trials for early, intermediate and advanced stage HD (HD1HD9) involving a total of 5367 patients. Data on incidence, risk factors and relative risk were updated in March 2003.
Results: A total of 127 patients with secondary solid tumors were identified. Among these, lung cancer (23.6%), colorectal cancer (20.5%) and breast cancer (10.2%) were the most frequent. After a median follow-up of 72 months the cumulative risk of developing a solid tumor was 2%, with an overall relative risk (RR) of 2.4 (lung cancer, 3.8; colorectal cancer, 3.2; breast cancer, 1.9). For most patients (n=67; 52.8%) developing a secondary solid tumor, treatment modality consisted of chemotherapy combined with radiotherapy in extended field technique (RR = 3.3).
Conclusions: With a median follow-up of 72 months, there were 127 patients developing solid tumors out of a total of 5367 HD patients treated in the GHSG studies HD1HD9. The cumulative risk of 2% is expected to increase over time due to the rather short median observation time and slow progression of solid malignancies.
Key words: Hodgkin's lymphoma, risk factors, secondary solid tumors
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Introduction |
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So far, the German Hodgkin Lymphoma Study Group (GHSG) has analyzed their database for secondary non-Hodgkin's lymphoma (sNHL) [8] and for secondary AML/MDS (sAML/MDS) [7
]. The sAML/MDS update in the GHSG database involved 5411 patients treated in the studies HD1HD9 from 1978 to 1998. There was an incidence of 1% sAML/MDS after a median observation time of 55 months. Treatment protocols included a variety of treatment options ranging from palliation to allogeneic stem cell transplantation. No difference was observed in overall survival (OS) between patients receiving allogeneic stem cell transplantation and those receiving conventional treatment or palliation. Outcome was very poor: 39 of 46 (85%) patients developing sAML/MDS did not survive >1 year after diagnosis. After 24 months, OS was 8%. The complex karyotype aberration observed in six of 15 patients analyzed does not allow one to link secondary AML/MDS in these patients to one particular cytostatic drug or group of drugs. In addition, 36 of 46 patients had combined modality treatment suggesting that the risk is higher in those patients receiving both chemotherapy and radiotherapy [7
].
Analysis of sNHL within the GHSG database showed a 5-year actuarial risk of 0.9% with a median follow up of 46 months. For all patients, the actuarial OS at 2 years was 30%. The outcome was significantly influenced by the time of occurrence after HD. For patients developing sNHL within 3 months of the end of first-line therapy, OS was 20% compared with 42% for patients developing their sNHL within 12 months of first treatment [8].
Since solid tumors are the secondary malignancy most often observed after successful treatment for HD, we retrospectively analyzed 5367 patients registered in the database of the German Hodgkin's Lymphoma Study Group (GHSG) for secondary solid tumors. The aim of the present analysis was to determine incidence, relative risk and risk factors associated with the development of solid tumors in HD.
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Patients and methods |
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Statistics
The cumulative risk of developing secondary solid tumors was assessed according to the KaplanMeier method [10]. The time to occurrence of solid tumor was calculated from the date of diagnosis of HD to the date of diagnosis of secondary solid tumor. The incidence of a given solid tumor in HD-treated patients and the incidence in the general population were compared. The relative risks were determined as the ratio of observed (O) and expected (E) number of solid tumors in the study population and 95% confidence limits were calculated. The expected number of solid tumors was calculated based on the listings of the Cancer Registry of Saarland (Germany), 2nd edition. Overall survival (OS) was measured from diagnosis of solid tumor until death from any cause. OS rates were estimated according to the KaplanMeier method [10
]. Demographics and disease characteristics were summarized using descriptive statistics, and all statistical analyses were performed using SPSS 10.0 for Windows (SPSS, Chicago, IL).
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Results |
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Chemotherapy regimens included a variety of different agents (Table 1) making it difficult to dissect their individual roles in the carcinogenesis of the secondary solid tumor.
Treatment consisting of radiotherapy or chemotherapy alone was rare in the group of patients with solid tumors (RT only, 11.0%; CT only, 11.8%) as well as in the group of all other patients included in the analysis (RT only, 12.9%; CT only, 11.8%) (Table 6).
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The RR of developing a solid tumor was 3.3 (95% CI 2.44.4) for patients with combined-modality treatment with irradiation in EF technique, 2.4 (95% CI 1.73.3) for those treated with chemotherapy alone, 2.1 (95% CI 1.52.8) for radiotherapy alone and 1.6 (95% CI 1.12.3) for combined treatment with local radiotherapy.
There were seven patients with relapse and salvage therapy before the occurrence of secondary neoplasia.
Relation to first-line treatment modality by type of solid tumor
For patients who developed lung, colorectal and breast cancers, the combination of chemotherapy and radiotherapy was also the most commonly used treatment modality (Table 7). Within these groups, most of the patients developing secondary breast (n=7; 53.8%) or colorectal cancer (n=11; 57.9%) had received radiotherapy in EF technique. There was no difference for patients with secondary lung cancer concerning treatment with EF irradiation or local radiotherapy (40.0% in each group). Interestingly, all those patients developing secondary breast cancer had been treated with radiotherapy involving EF technique (n=7), IF (n=4) or radiotherapy alone (n=2).
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Discussion |
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Lung cancer (RR 3.8), colorectal cancer (RR 3.2) and breast cancer (RR 1.9) were most frequently observed.
A considerable number of patients (52.8%) in the solid tumor group were treated with irradiation in EF technique (RR 3.3). For patients treated with a combination of chemotherapy and irradiation restricted to local fields (24.4%), RR was 1.6. These data need to be interpreted carefully due to the fact that extended field irradiation represents the older standard treatment. Consequently, observation time for patients treated with this modality is longer than for patients treated with involved field irradiation.
Several reports document the incidence of secondary solid tumors after primary HD. The cumulative risk varies between 7.8% and 23.3% at 15 to 25 years, respectively, after first-line treatment [4, 5
, 11
14
]. An increased overall RR ranges from 2.0 to 6.1 [11
13
]. The comparatively low cumulative risk found in our analysis may be due in part to the fact that the median follow-up was only 72 months.
The comprehensive list of risk factors for the development of solid tumors after HD is difficult to determine. Disease-related immunosuppression, genetic factors, first-line treatment, age at first treatment, vulnerability of breast tissue, hormonal factors, chemotherapy-induced premature menopause, and smoking have been shown to play a role. In the literature, solid tumors are frequently related to radiotherapy as well as to combined modality treatment [11, 15
, 16
], and they often appear in or adjacent to the initial irradiation field [16
20
]. This is particularly true for the development of breast cancer, where chemotherapy seems to have a protective effect [12
, 19
]. Most patients receiving radiotherapy as part of their treatment for HD are at higher risk of developing secondary breast cancer [11
13
, 19
]. Van Leeuwen et al. [19
] found a chemotherapy-associated risk reduction on the development of secondary breast cancer. This observation might be related to chemotherapy-induced ovarian failure preventing ovarian hormones promoting tumorigenesis.
The role of specific chemotherapeutics in the etiology of solid tumors is unclear. The data found in previous studies concerning treatment modality do not allow for unanimous conclusions. Some studies report on an increased risk after chemotherapy alone [21, 22
] whereas others found no relation to chemotherapeutic treatment [4
, 5
, 12
, 16
, 18
, 23
]. These discrepancies are probably related to the variety of different tumor entities. Some authors report an increased risk for the development of lung cancer after chemotherapy alone [12
, 20
]. In other studies, the highest RRs for development of solid tumors were observed after combined-modality treatment [13
, 18
, 24
]. Swerdlow et al. found a significantly increased risk for the development of secondary gastrointestinal tumors only in patients who had received combined-modality treatment [12
]. Several authors report on an increased RR of developing secondary solid tumors with younger age at first treatment [11
14
, 16
]. This is most obvious in female patients who develop breast cancer [11
, 17
, 24
26
]. Early onset of menopause seems to reduce the risk of breast cancer [19
]. Thus, mammography is recommended for female HD patients between 8 [27
, 28
] and 10 years [29
] after first-line treatment.
In many studies, treatment-related solid tumors appear several years after first-line treatment and the risk remains elevated over a 15- and 20-year follow-up period [2, 11
14
, 16
18
, 24
, 25
, 27
]. The increased risk remains higher than expected for up to 30 years [2
, 3
].
This led to speculation that solid tumors in particular are at least in part irradiation-induced late toxicities. In contrast, Travis et al. reported an increased risk of secondary lung cancer as early as 14 years after first-line treatment when patients received alkylating agents [30].
In general, the outcome of secondary solid tumors depends on tumor entity and is not different from that of primary solid tumors [27]. The outcome in secondary lung cancer is as poor as it is in primary lung cancer [17
, 24
, 30
]. Very similar findings were observed in the present study.
In conclusion, the cumulative risk of secondary solid tumors in the GHSG trials HD1HD9, involving 5367 patients and a median observation time of 72 months, is low (2%). Longer follow-up is needed to assess the final risk.
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Acknowledgements |
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Received for publication November 23, 2003. Revision received February 29, 2004. Accepted for publication March 5, 2004.
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References |
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