1 Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo; 2 The Cancer Registry of Norway, Oslo, Norway
Received 15 January 2002; revised 2 May 2002; accepted 22 May 2002
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Abstract |
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To quantify the long-term risk of second cancers (SCs) up to 30 years after primary treatment for Hodgkins disease (HD)
Material and methods
In the period 1968 to 1985, an unselected population of 1024 patients started treatment for HD at the Norwegian Radium Hospital (NRH) and were followed for SC from 1969 through 1998 by The Norwegian Cancer Registry. The median age at diagnosis of HD was 40 years, and the median time at follow-up was 14 years.
Results:
Of 197 SCs, 14 were acute non-lymphocytic leukemia (ANLL), 31 non-Hodgkins lymphoma (NHL) and 152 solid cancers. The standardized incidence ratio (SIR) was significantly increased for SCs as a group, and for the subgroups ANLL, NHL, lung cancer, breast cancer, stomach cancer and melanoma. ANLL was related to heavy treatment with chemotherapy (CT) and combined CT and radiotherapy (RT), NHL was not treatment related, and solid tumors were related to radiotherapy only or combined RT and CT. The SIR of ANLL and NHL reached a peak between 5 and 10 years after treatment. Solid and non-solid tumors increased with young age at diagnosis of HD and solid tumors increased with follow-up time up to 28 years
Conclusion:
In a long-term follow-up study of HD patients of all ages, the SIR of solid tumors was high in patients treated at young age and decreased with increasing age. Most solid tumors had started within or at the edge of the irradiated field, and SIR of solid tumors increased even 2030 years after diagnosis.
Key words: Hodgkins disease, second malignancies
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Introduction |
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Patients and methods |
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Material
Some characteristics of the study population are listed in Table 1. The median age was 40 years, and 58% were first treated at the age of 40 years or younger. Only 3% were <15 years old, and 17% were >60 years old. Forty-five percent had advanced disease (stage III and IV). Fifty-two percent of the population were in continous complete remission, 15% had one relapse, 4% had two or more relapses, and 29% had not obtained complete remission. Forty-four per cent had received RT only, 36% had received combined RT and CT, and 20% had received CT only.The median follow-up time for the whole study population was 14 years.
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Total treatment includes first-line and relapse treatment.
Statistical analysis
The follow-up evaluation of SCs started 1 year after the date of diagnosis of HD. All patients were monitored until the end of 1998 or to the middle of the year of death or emigration, whichever came first. The study was based on comparison of the observed and expected numbers of cancers in the cohort. The 5-year, age-specific national incidence rates for each sex and for each year 1969 through 1998 were used to estimate the expected number of cancer cases. The standardized incidence ratio (SIR) was calculated for total cases of cancer and for selected cancer sites. Ninety-five percent confidence intervals (95% CIs) were determined by assuming a Poisson distribution of the observed number of cancer cases. A result was considered to be statistically significant if the 95% CI did not include 1.00.
Absolute excess risk, which estimates the excess number of SCs per 10 000 patients per year, is the most appropriate risk measure to judge which SC contributes most to the excess risk.
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Results |
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The excess risk of developing solid tumors like lung cancer, breast cancer and stomach cancer was statistically increased after RT alone or after combined RT and CT, but was not as related to CT alone. Melanoma was observed only after RT.
The relation between the localization of solid cancers and the irradiated field is shown in Table 4. Most of the solid cancers were found within or at the edge of the irradiated field.
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Risk of SC by age at diagnosis of HD
The effect of age at diagnosis on the risk of developing SCs is shown in Table 5. The observed numbers and SIR of all SCs combined, and of ANLLs, NHLs and solid tumors were highest for young patients up to 40 years old, except breast cancer, which dominated in patients <25 years old. Significantly increased SIR was not observed in stomach cancer and melanoma after age 40 years, in breast cancer after age 50 years, and in ANLL and lung cancer after age 60 years at HD diagnosis.
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Discussion |
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Only a few studies have compared long-term SC risk between age groups other than in childhood, adolescence and adults <40 years old. Recent long-term follow-up studies from two Dutch cancer centers [9] and one from a US center [7] have shown increased risks of SCs at ages <40 years at HD diagnosis, and also a British total population-based study like ours [8]. Our data have confirmed these authors observations as to the high risks in young patients. In addition, our study has shown decreased SIR of SCs after the age of 40 years, and not significantly increased SIR in older patients.
The SIR of ANLL reached a peak during 510 years after treatment, as stated in other studies [811]. All these patients had received combination chemotherapy including an alkylating agent and procarbazine. The extensive treatment received by these patients and the increased SIR in relapsed patients point to the importance of intense treatment for developing ANLL.
The increased risk of developing NHL reached a peak during the first 10 years of follow-up, as shown in two previous studies [8, 19]. In general, however, a consistent pattern has not been reported [10, 11]. The SIR of NHL was not related to age or treatment modality. It is suggested that these patients have a propensity for lymphoproliferative disorders, possibly associated with some immune deficiency [3].
Most studies have generally attributed the excess risk of solid cancers to RT [811, 17]. In our study, the SIR of lung cancer increased with follow-up time. Eighty-eight percent of patients with lung cancer had received RT, most of them mantle field. Twenty-two of 23 irradiated patients (96%) had a tumor within or at the edge of the radiation field. These data support RT to be the dominant risk factor for lung cancer after HD.
An unresolved issue in the literature is whether CT for HD can also induce solid cancers and, if so, at which sites [9]. A few recent studies have raised concern about a possible long-term effect of CT on lung cancer risk [9, 15, 2022]. We could not show increased risk of solid tumors after CT alone, but the expected percentage in our study was only 3%.
Breast cancer dominated in women aged <25 years, and was not observed in women >50 years old, at HD diagnosis. The SIR of breast cancer was not increased during the first 10 years after diagnosis, but increased with long-term follow-up. Most of the patients had received RT alone or combined RT and CT, and only one of 23 patients had received CT only. Most of the patients had received mantle field irradiation, and 19 of 23 patients (83%) had the tumor localized within or at the edge of the radiation field. The increased risk of breast cancer in long-term follow-up of young HD patients is in agreement with the findings of previous studies [8, 9, 11, 17].
We observed a significantly increased SIR of stomach cancer and a borderline risk of rectum cancer. Stomach cancer was not significantly increased during the first 10 years after diagnosis, but the SIR increased with long-term follow-up. Increased risk of stomach cancer was only observed in patients <40 years old at HD diagnosis. The increasing risk of gastrointestinal cancers with longer follow-up of HD has been observed previously [8, 9, 11]. There are, however, limited data available on treatment-related risks of gastrointestinal cancer after HD. In our study, the SIR of stomach cancer was related to previous RT and combined RT and CT, but not to CT alone. A British study [8] observed a borderline significant risk after RT, but a larger and highly significant risk after combined RT and CT. The risk after CT alone was not significantly increased, which is in agreement with our results. Nine of 12 patients with stomach cancer (75%) had the tumor localized within or at the edge of the irradiated field.
We observed an increased SIR of melanoma in patients <40 years old at treatment, and only during the first 5 years of follow-up. In contrast to other solid tumors, the risk of melanoma was not increased in long-term survivors. Seven of eight patients had received RT only, and none had received CT only. The increased risk of melanoma in this cohort is in accordance with previous findings [8, 10, 11]. The timing of this risk in the first years after treatment accords with two previous studies [8, 23]. There was previously limited evidence of an association of risk of melanoma with RT. The previous dominant treatment in our melanoma patients was RT alone (91%), and in another study [8] all melanoma patients had received RT alone. In general the development of melanoma has not been associated with RT. It has been suggested that the early risk of melanoma after RT might reflect immunological dysfunction from HD and immunosuppressive effects of the treatment [24].
In conclusion, treatment-related SCs remain a major problem in long-term survivors of HD. The risk is greatly increased in childhood, adolescent or young adult patients at first treatment. The increased risk of ANLL and NHL levelled off at 10 years after treatment. Solid cancers increased with follow-up time up to 28 years after first treatment. ANLL was related to CT with procarbazine and an alkylating agent, and may be substantially decreased after introduction of ABOD-based regimens [9, 11]. NHL seemed not to be related to treatment modality. The solid cancers were related to RT or combined RT and CT, and most of them occurred within or at the edge of the irradiated field. Reduced radiation doses and fields may reduce the development of some solid cancers [24].
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Footnotes |
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References |
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