|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Long-Term Risk of Second Malignancy in Survivors of Hodgkin’s Disease Treated During Adolescence or Young Adulthood
From the Departments of Epidemiology, Medical Oncology, Radiotherapy, and Pathology, the Netherlands Cancer Institute, Amsterdam, and Departments of Hematology and Radiotherapy, Dr Daniel den Hoed Cancer Center, Rotterdam, the Netherlands. Address reprint requests to Flora E. van Leeuwen, PhD, Department of Epidemiology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; email fvleeuw{at}nki.nl
PURPOSE: To quantify the long-term risk of second primary cancers (SCs) in patients diagnosed with Hodgkin’s disease (HD) during adolescence or young adulthood. PATIENTS AND METHODS: The risk of SCs was assessed in 1,253 patients diagnosed with HD before the age of 40 years and treated in two Dutch cancer centers between 1966 and 1986. The median follow-up duration was 14.1 years.
RESULTS: In all, 137 patients developed SCs, compared with 19.4 cases expected on the basis of incidence rates in the general population (relative risk [RR] = 7.0; 95% confidence interval, 5.9 to 8.3). The 25-year actuarial risk of SC overall was 27.7%. The RR of solid tumors increased greatly with younger age at the first treatment of HD, not only for breast cancer but also for all other solid tumors, with RRs of 4.9, 6.9, and 12.7 for patients first treated at ages 31 to 39 years, 21 to 30 years, and Among patients first treated at the age of 20 years or younger, the RR of developing a solid tumor before the age of 40 years was significantly greater than the RR of solid tumor development at ages 40 to 49 years (RR = 27.9 v RR = 4.2; P = .0001). Patients who received salvage chemotherapy had significantly greater risk of solid cancers other than breast cancer than did patients whose treatment was restricted to initial radiotherapy or initial combined-modality treatment (RR = 9.4 and 4.7, respectively; P = .004).
CONCLUSION: After more than 20 years of follow-up, the risk of solid tumors is still much greater in survivors of HD than in the population at large. Reassuringly, the greatly increased risk of solid tumors in patients who were young (
IN VIEW OF THE excellent cure rates that are currently achieved in the relatively young population of Hodgkin’s disease (HD) patients, it has become increasingly important to evaluate how the occurrence of late complications affects their long-term survival. The occurrence of second malignancies is generally considered to be the most serious consequence of therapy for HD.1,2 Since the first observations of increased second cancer (SC) risk in HD patients in the early 1970s,3,4 numerous studies have reported on this issue.5-20 An excess of acute nonlymphocytic leukemia in patients treated with chemotherapy (CT) and an increased risk of solid tumors in those treated with radiotherapy (RT) have been consistently reported in the literature. Although the greatly elevated risk of leukemia during early follow-up has been found to decrease beginning at 10 years after treatment, the relative risk (RR) of solid tumors seems to increase steadily with time from 5 through 20 years after treatment.11,13,15,19 The evolution of solid tumor risk for more prolonged follow-up periods has not yet been evaluated. Several other important questions remain to be answered, such as the possible contribution of CT to solid tumor risk15,17,20,21 and the issue of whether the increased risk of non-Hodgkin’s lymphoma (NHL), which has been found in several studies,11,13,15,19,22 is related to treatment for HD or to disease-associated immunosuppression. Furthermore, there are only a few studies on second malignancy risk after treatment for HD in childhood and adolescence,23-28 and median follow-up duration in those studies has rarely exceeded 10 years. We report here on the treatment-specific risk of SC development during long-term follow-up of a large series of young survivors of HD (n = 1,253) treated in two major cancer centers in the Netherlands. A previous publication described the overall risk of second malignancy in 1994.19 For the present study, the median follow-up of patients diagnosed before the age of 40 years was extended from 9.2 to 14.1 years, and analyses were focused on differences in SC risk among patients treated for HD during early adolescence, those treated during late adolescence, and those treated during early adulthood. Special attention in this study was given to the collection of complete follow-up data, pathologic confirmation of all second malignancies, and the presentation of appropriate risk measures reflecting the burden of SC occurrence in survivors of HD.
Data Collection Procedures A more detailed description of data collection procedures than is provided here has been published previously.19 In brief, between 1966 and 1986, 1,984 patients with HD were admitted to the Netherlands Cancer Institute or the Dr Daniel den Hoed Cancer Center for either primary diagnosis and treatment or salvage treatment. Patients were identified through the institutes’ hospital tumor registries, which contain the following treatment information: date of first treatment with RT or CT, type of first-year treatment (RT only, CT only, or RT + CT), date of first salvage treatment, type of follow-up treatment (comprising all treatments beyond the first year after start of primary treatment), and whether a splenectomy had been performed. Patients who had been treated with RT or CT for cancer or a benign condition before the diagnosis of HD (n = 35) and patients with HD who had never been treated with RT or CT (n = 10) were excluded from the study population. For the present analysis, we also excluded patients who survived less than 1 year after first treatment for HD (n = 156) and patients who were first treated for HD at the age of 40 years or older (n = 530). Thus, this study is restricted to 1,253 patients who were first treated for HD before the age of 40 years and who survived for at least 1 year after this treatment. Because the follow-up of the registries was often incomplete, the majority of follow-up data was collected directly from the medical records by three of us (M.S., U.A.O.V., and W.J.K.). Special attempts were made to establish the medical status of patients lost to follow-up at the two institutes by mailing a questionnaire to specialists in other hospitals and to general practitioners. We succeeded in obtaining medical status for up to at least January 1994 for 1,142 patients (91% of the total cohort). For the remaining patients, we obtained vital status through the municipal registries. In the case of a second NHL in a patient, the histologic slides of both HD and second NHL were reviewed by one of us (P.vH.). Ten patients with second NHLs had to be excluded from the cohort, because their original cases of HD were rediagnosed as primary NHLs. Also, for 23 of 26 cases of leukemia and of myelodysplastic syndrome (MDS), the slides were reviewed. For all other SCs, we obtained pathology reports without reviewing the slides. Patients with SCs for whom no reports could be obtained were generally excluded, except for three for whom there was strong clinical evidence and a low probability of the second tumor being a manifestation of HD (two with lung cancer and one with multiple metastases [adenocarcinoma of unknown origin]).
Treatment To evaluate the risk of developing SC and its association with the type of treatment, patients were placed into one of five treatment groups, according to the total treatment they had received to date: (1) RT alone; (2) CT alone; (3) initial combined-modality treatment without any further treatment beyond the first year after diagnosis; (4) initial combined-modality treatment with additional treatment beyond the first year after diagnosis; and (5) salvage combined-modality treatment (ie, first-year treatment with RT or CT alone and treatment with the other modality [or a combination of both modalities]) for a recurrence (Table 1).
Statistical Analysis A comparison was made between SC incidence in the population of HD patients and cancer incidence in the general population. In this person-years type of analysis, the ratio of the observed (O) and expected (E) numbers of SCs in the study population was determined. In the accumulation of person-years of observation in the study population, time at risk for SC began 1 year after the start of first treatment with RT or CT and ended at the date of diagnosis of SC, date of death, or date of the most recent medical follow-up examination, whichever occurred first. Basal cell cancers of skin (n = 26) and in situ carcinomas of the breast (n = 2) and cervix (n = 1) were not considered as second malignancies in our analysis. Patients with MDS were not included in the person-years analysis because general population rates were not available. The 16 patients in our series who developed a third primary malignancy were considered to have had only one SC in the analysis of the risk of all SCs combined; in such analyses, their time at risk ended at the date of diagnosis of the first SC. To estimate the risk of specific SCs, a third primary cancer was only retained in the analysis when it was diagnosed within one half of a year from the second malignancy or followed a second solid malignancy that was not treated by RT or CT. Other third (or fourth) malignancies (n = 9) were excluded from analysis, because they might have been related to the diagnosis or treatment of the SC. Third malignancies in the analysis (n = 7) included two cases of breast cancer after melanoma, one case of NHL synchronous with kidney cancer, one case of NHL after colon cancer, one case of osteosarcoma after NHL, one case of rectum cancer after breast cancer, and one case of tumor of the floor of the mouth after lung cancer. Taking into account the person-years of observation in the HD cohort (by age, sex, and calendar period), E numbers of SC were computed with the use of age-, sex-, and calendar-period–specific cancer incidence rates from the Eindhoven Cancer Registry32 up to 1990 and from the Netherlands Cancer Registry for the period of 1990 to 1994.33,34 Cancer incidence data for the whole country were not available for the total study period. The registration area of the Eindhoven Cancer Registry covers 6% of the Dutch population. The confidence limits of O/E were obtained with the use of the Poisson distribution of O numbers.35 O/E ratios were calculated for all HD patients together and separately by follow-up interval, type of treatment, age at first treatment, attained age, and sex. Results from the person-years analysis were also used to calculate the absolute excess risks of SCs by site. This was done by subtracting the E number of cases from the O number and dividing by person-years at risk. Cumulative (actuarial) probabilities of SC were estimated as a function of time since initial treatment using life-table analysis.36 We also used the Kaplan-Meier method to calculate actuarial overall survival of the cohort and to estimate survival after the diagnosis of selected second malignancies. The impact of SCs on overall survival was estimated in an analysis in which all deaths from SC were treated as censored. The Cox proportional hazards model was used to quantify the effects of different treatments on SC risk (adjusting for different follow-up periods) and to explore the effect of concomitant variables (age at treatment and sex) on SC risk.37 In a time-dependent covariate analysis, a patient was included in his or her initial treatment category until a change in treatment occurred, at which time risk of SC was assigned to the new treatment category. Thus, the study subjects could contribute time at risk to one or several treatment groups, depending on the types of treatments received and the dates of administration of the different therapies. Cox’s models were fitted with the use of BMDP statistical software (SPSS, Inc, Chicago, IL).
Table 1 lists the distribution of the patient population with respect to age, sex, and a number of patient and treatment characteristics. Twenty-six percent of patients were first treated at the age of 20 years or younger. Of those, 41% were  16 years of age at first treatment (median age, 14.1 years) and 59% were treated during late adolescence (aged 17 to 20 years). Relatively few patients (6%) received only CT, which was administered mainly for advanced disease. The median follow-up time for the whole study population was 14.1 years; for patients alive at the most recent follow-up examination (61% of the cohort), median follow-up was 16.9 years. In all, 153 second (or subsequent) invasive primary malignancies in 137 patients were observed after the start of first treatment for HD. We excluded nine third cancers from subsequent analyses because they might have been related to the diagnosis or treatment of the SC (see Patients and Methods). Thus, 144 invasive SCs in 137 patients were retained in the analysis. In addition, eight cases of MDS were diagnosed.
Risks of Second Primary Cancers
Absolute excess risk, which estimates the excess number of second malignancies per 10,000 patients per year, is the most appropriate risk measure to judge which second malignancies contribute most to the excess risk. As is shown in Table 2, compared with the general population, our cohort experienced an excess of 72 cancer cases per 10,000 person-years. Seventy-five percent of the absolute excess risk of cancer was a result of solid tumors.
Risk by Age at First Treatment and Time Since First Treatment: General Population Comparisons
Table 4 lists the relative and absolute excess risks of selected second malignancies by interval after first treatment. The risk of all solid tumors combined was already increased in the 1- to 9-year observation period and rose steadily with longer follow-up time (P < .001), up to a 9.1-fold excess risk in the 15- to 19-year interval and an 8.5-fold excess in the 20- to 24-year interval. The RR was somewhat lower in patients who survived more than 25 years (RR = 5.3; 95% CI, 1.9 to 11.4). Similar patterns were observed for individual solid tumor sites, such as lung cancer and cancers of the gastrointestinal tract. Breast cancer followed a slightly different pattern, in that the excess risk did not become apparent until after 15 years of observation.
For all sites except leukemia, the absolute excess risks greatly increased with longer follow-up time. Patients who survived 20 or more years after first treatment experienced 221 excess SCs per 10,000 patients per year. Ninety-one percent of this excess risk was a result of solid tumors. The manifestation of increased risk of second malignancy only after a certain follow-up interval is generally assumed to be a result of the length of the induction period but may also be an effect of the patients attaining a specific age (the age range in which the cancer involved normally occurs). Table 5 lists the results of an analysis in which we evaluated the risks of breast cancer and nonbreast solid malignancies by attained age in all patients and in subgroups according to age at first treatment for HD. We observed strong, highly significant trends of decreasing RRs with advancing attained age, a pattern similar to that seen with age at first treatment (Table 3). Among patients first treated at the age of 20 years or younger, the RR of developing breast cancer at ages 40 to 49 years was significantly lower than the RR of a breast cancer diagnosis before the age of 40 years (RR = 5.4 v RR = 61.5; P = .0006). A similar result was observed for nonbreast solid tumors.
Risk by Type of Treatment: General Population Comparisons Table 6 lists RRs by type of treatment. Breast cancer and nonbreast solid malignancies were considered separately because breast cancer risk is known to be related to ovarian function, which in turn may be affected by CT. Significantly elevated risks of breast cancer and other solid tumors were noted in all treatment categories except among patients who received CT alone. However, the number of patients in this treatment group was small. Patients treated with RT only and patients who received initial combined-modality treatment without any further treatment beyond the first year after diagnosis had similar RRs of breast cancer and of nonbreast solid malignancies. However, patients in the two salvage treatment categories, the majority of whom received multiple courses of CT in addition to RT, had significantly greater risk of solid cancers other than breast cancer than did patients whose treatment was restricted to initial RT or combined-modality treatment (RR = 9.4 [95% CI, 6.9 to 12.4]; and RR = 4.7 [95% CI, 3.2 to 6.7]; P = .004). Strikingly, a very different pattern was observed for breast cancer. Patients with salvage CT experienced significantly lower risk of breast cancer than did patients whose only treatment consisted of RT or initial treatment with both modalities (RR = 2.8 [95% CI, 1.0 to 6.0] v RR = 7.6 [95% CI, 4.7 to 11.7]; P = .035).
Prognostic Factors for SC Development: Cox Model Analysis In the Cox model analysis (Table 7), prognostic factors for SC development are examined within the patient group, as opposed to the person-years analysis (Tables 2 through 6) in which risk is compared with that in the general population. Because 94% of our HD patients received radiation treatment, the effect of RT could not be evaluated by the Cox analysis. For breast cancer, the only factors found to influence risk were follow-up treatment with CT or with a combination of CT and RT. When combining these two treatment categories, we found that any CT for relapse was associated with a 67% decrease of the risk of breast cancer (hazard ratio, 0.33; P = .02). By contrast, follow-up treatment with CT or with a combination of CT and RT significantly increased the risk of nonbreast solid malignancies (hazard ratio, 2.2 and P = .007 for both factors). Similar results were obtained when gastrointestinal cancers were considered separately. Neither for breast cancer nor for other solid tumors did the combination of CT with RT during initial (first year) treatment alter the risk associated with RT alone.
Of the 145 patients who developed a second malignancy or MDS, 74 died of their disease. SC deaths represented 16% of all deaths in our cohort. Figure 3 illustrates the impact of second malignancies on overall survival. After correction for increased mortality from SC, the proportion of surviving patients at 25 years increased by 8%, from 55% to 63%.
This long-term follow-up study in young survivors of HD shows that, even more than 20 years after first treatment, the risk of second malignancies continues to be significantly increased compared with general population expectations. In 20-year survivors, the excess number of cancer cases was 221 per 10,000 patients per year. Solid tumors contributed most to this excess risk (91%). Another important finding of our study is that the RR of solid malignancies greatly increases with younger age at first treatment. This was observed not only for breast cancer but also for nonbreast solid malignancies. Reassuringly, our data suggest that the high RR of solid tumors in patients treated at a young age does not persist throughout life. Furthermore, our data indicate that intensive combined-modality treatment, compared with RT alone, decreases the risk of breast cancer, whereas it seems to increase the risk of other solid tumors. Complete follow-up and valid ascertainment of second malignancies through pathology reports are critical aspects in the methodology of SC research. Overestimation of SC risk occurs when follow-up in the original treatment center is more complete for survivors who develop a second malignancy than for those who remain healthy. This is likely to happen, because patients who remain healthy tend to lose contact with clinical follow-up, whereas those with SCs return to clinical follow-up because of their new cancer.38 In view of this serious potential for bias, it is of great concern that completeness of follow-up is rarely reported in SC studies. In the present study, we succeeded in obtaining information on recent medical status for 91% of the cohort. For all other patients, we obtained recent information on vital status. Because we considered the latter small group of patients as free of SC in the interval between the dates of last known medical status and most recent vital status, our RRs are slightly conservative estimates of the true risk. Although several studies have examined SC risk in children or young adolescents treated for HD23-28 and have reported greatly increased risks, few have directly compared SC risk between adolescents and adults treated for HD.16,17,39,40 Long-term follow-up is needed to validly compare SC risk between age groups, because the induction period might be longer in patients treated at a young age. The median follow-up time in our study was more than 14 years, which is considerably longer than the median 6- to 11-year follow-up durations reported in other large series.13,16,19,23,26,39-41 Our data further add to the evidence that the RR of breast cancer strongly increases with decreasing age at first HD treatment.16,40 The overall RR of breast cancer after HD treatment at ages less than 16 years has ranged from 17 to 458,16,26 with other studies showing RRs near 100.23,40 We found a RR of 40 for females treated at the age of 16 years or younger. This huge variation in calculated risk is not surprising in view of the large differences between studies in important variables such as proportion of patients irradiated, duration of follow-up, and completeness of follow-up. For solid tumors other than breast cancer, the RRs according to age at first treatment have hardly been evaluated. Surprisingly, we also found that for nonbreast solid tumors, the RR increased dramatically with younger age at first treatment. For gastrointestinal cancers, this trend was even stronger than for breast cancer. A recent study of HD patients treated at Stanford University also found that the highest risk for gastrointestinal cancer was among patients treated before the age of 25 years (RR = 7.2), with no excess risk for those treated who were older than 45 years.41 Among patients who received radiation treatment for peptic ulcer disease, Griem et al42 also reported a significant trend of decreasing risk of gastric cancer with increasing age at exposure. Several studies have already shown that, unlike the pattern for leukemia, the RR of solid tumors increases steadily with increasing follow-up time from 5 to at least 20 years after first treatment.13,16,19,40,41 There are almost no data on the time course of risk 20 or more years after treatment, and those that were published were based on small numbers.23,28,40,41 Our study indicates that solid cancer risk continues to be significantly elevated even in patients who were treated 20 or more years ago. However, the RR of solid tumor development in 25-year survivors was somewhat lower than in patients in the 15- to 24-year follow-up period (RR = 5.3 v RR = 8.8; P = .29), which may point to decreasing RRs in long-term survivors.
The greatly increased RRs of solid tumors among 15-year survivors of HD might be a result of the (relatively young) patient population attaining an age in the range of which solid tumors become common in the general population. So far, only three studies have evaluated RR of solid malignancies according to attained age.17,40,41 Our study is the first in which the separate contributions of age at first treatment and attained age are distinguished. The general pattern is clear, showing in each category according to age at first treatment a decline of RRs as patients grow older. Clearly, solid tumor risk was greatest among patients treated at a young ( Studies that report increased risk of solid cancers after HD have generally attributed the excess to radiation treatment.11,13,15,19,23,40,44 An unresolved issue in the literature is whether CT for HD can also induce solid cancers and, if so, at which sites. A few recent studies have raised concern about a possible long-term effect of CT on lung cancer risk.15,17,21,45 The British National Lymphoma Investigation cohort study among 2,846 patients15 found significantly increased lung cancer risk after CT alone, with the RR (4.2) being of similar magnitude as that seen in patients treated with extensive RT or with combined-modality treatment. A similar excess risk of lung cancer in patients with CT, but no RT, was observed in another study from the United Kingdom.17 No increased risk of solid tumors after CT alone was observed in several other studies.11,13,18,19,23 However, the E numbers of solid tumors 10 years or more after treatment with CT alone were less than one in all negative studies, rendering it impossible to exclude a moderate risk increase. If CT affects solid tumor risk, one would expect that patients receiving combined-modality treatment would have a greater RR than would patients treated solely with RT. So far, significantly greater risk with CT and RT as opposed to RT alone has been reported in only three studies,16,20,45 whereas no such difference was found in the majority of studies.11,13,15,17-19,23,28 A trend of higher risk after combined-modality treatment than after RT alone was reported for selected solid cancer sites (ie, gastrointestinal tract41 and breast40 ). For lung cancer risk in irradiated patients, two case-control studies found no association with CT overall, the number of CT cycles, or the cumulative doses of mechlorethamine and procarbazine,21,46 which suggests that the contribution of CT to lung cancer risk is not important. The inconsistent results reported on the influence of CT on solid tumor risk may be partly related to the fact that most studies considered all solid tumors combined, whereas CT may affect the risk of tumors at different sites differently. Furthermore, few studies examined the intensity of CT.21,46 The present study demonstrates that the addition of salvage CT to initial RT significantly increases the risk of solid tumors other than breast cancer. Patients who received initial combined-modality treatment without any further treatment, however, did not experience greater risk than did patients treated with RT alone. An explanation may be that patients managed with initial combined-modality treatment alone generally receive less intensive CT regimens than do patients who are further treated with CT for relapse. Because our data show that the greater risk of solid malignancy after CT for relapse was most pronounced for gastrointestinal cancers, the roles of specific cytostatic drugs in the pathogenesis of these tumors should be further examined. Our results with regard to breast cancer demonstrate the importance of distinguishing different solid tumors when examining the effects of CT. Female HD patients managed with intensive CT often experience temporary or permanent ovarian failure.47-49 Because loss of ovarian function is known to reduce the risk of breast cancer considerably,50 it is certainly possible that CT may be protective against the carcinogenic effects of radiation on the breast. Theoretically, the prescription of hormone replacement therapy (HRT) for premature CT-induced menopause might counteract this protective effect of CT. Unfortunately, information on age at menopause and the use of HRT was not collected in our study. However, according to treating physicians, HRT for CT-induced menopause was not prescribed for women with HD treated before the 1980s. In an ongoing case-control study, we will investigate the separate and joint effects of radiation dose and a number of hormonal factors on breast cancer risk. In conclusion, the occurrence of treatment-related SCs remains a major problem in long-term survivors of HD. The substantial increase of solid tumor risk with time since diagnosis necessitates careful, lifelong medical surveillance of all patients. Women treated with mantle-field irradiation before the age of 30 years are at greatly increased risk of breast cancer. The importance of regular breast examinations should be explained to them, and they should be taught breast self-examination. From 7 to 10 years after irradiation, the follow-up program of these women should include yearly breast palpation and mammography.51 Physicians should also be alert to the increased risk of cancers of the digestive tract. Because smokers experience a significantly greater risk of lung cancer attributable to RT than do nonsmokers,46 physicians should make a special effort to dissuade HD patients even from smoking before treatment starts. The most devastating second malignancy to occur after cured HD is CT-related leukemia. Because the poor prognosis of this complication cannot be countered by early diagnosis, it is promising that our earlier data have shown that leukemia risk has substantially decreased with the introduction of doxorubicin/bleomycin/vinblastine–based regimens in the 1980s.19 It is hoped that current treatment protocols that limit the dose and fields of irradiation will similarly reduce the late risks of solid cancers. An important issue to address in future research concerns the precise role of CT in the pathogenesis of various solid malignancies.
Supported by grants no. NKI 88-11 and NKI 98-1833 from the Dutch Cancer Society, Amsterdam, the Netherlands. We thank the hospital cancer registries of the Netherlands Cancer Institute and the Dr Daniel den Hoed Cancer Center for assistance in obtaining follow-up data.
1. Urba WJ, Longo DL: Hodgkin’s disease. N Engl J Med 326:678-687, 1992[Medline] 2. Henry-Amar M, Joly F: Late complications after Hodgkin’s disease. Ann Oncol 4:115-126, 1996 3. Arsenau JC, Sponzo RW, Levin DL, et al: Nonlymphomat-ous malignant tumors complicating Hodgkin’s disease: Possible association with intensive therapy. J Med 287:1119-1122, 1972 4. Canellos GP, DeVita VT Jr, Arsenau JC: Second malignancies complicating Hodgkin’s disease in remission. Lancet 1:947-949, 1975[Medline] 5. Glicksman AS, Pajak TF, Gottlieb A, et al: Second malignant neoplasms in patients successfully treated for Hodgkin’s disease: A Cancer and Leukemia Group B study. Treat Rep 66:1035-1044, 1982 6. Henry-Amar M: Second cancers after radiotherapy and chemotherapy for early stages of Hodgkin’s disease. J Natl Cancer Inst 71:911-916, 1983 7. Boivin JF, Hutchinson GB, Lyden M, et al: Second primary cancers following treatment of Hodgkin’s disease. J Natl Cancer Inst 72:233-241, 1984 8. Tester WJ, Kinsella TJ, Waller B, et al: Second malignant neoplasms complicating Hodgkin’s disease: The National Cancer Institute’s experience. J Clin Oncol 2:762-769, 1984[Abstract]
9.
Valagussa P, Santoro A, Fossati-Bellani F, et al: Second acute leukemia and other malignancies following treatment for Hodgkin’s disease. J Clin Oncol 4:830-837, 1986 10. Pedersen-Bjergaard J, Larsen SO, Struck J, et al: Risk of therapy-related leukaemia and preleukaemia after Hodgkin’s disease: Relation to age, cumulative dose of alkylating agents and time from chemotherapy. Lancet 2:83-88, 1987[Medline] 11. Tucker MA, Coleman CN, Cox RS, et al: Risk of second cancers after treatment for Hodgkin’s disease. N Engl J Med 318:76-81, 1988[Abstract] 12. Van Leeuwen FE, Somers R, Taal BG, et al: Increased risk of lung cancer, non-Hodgkin’s lymphoma, and leukemia following Hodgkin’s disease. J Clin Oncol 7:1046-1058, 1989[Abstract] 13. Henry-Amar M: Second cancer after the treatment for Hodgkin’s disease: A report from the International Database on Hodgkin’s Disease. Ann Oncol 3:S117–S128, 1992 (suppl 4) 14. Cimino G, Papa G, Tura S, et al: Second primary cancer following Hodgkin’s disease: Updated results of an Italian multicentric study. J Clin Oncol 9:432-437, 1991[Abstract] 15. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, et al: Risk of second primary cancers after Hodgkin’s disease by type of treatment: Analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304:1137-1143, 1992
16.
Mauch PM, Kalish LA, Marcus KC, et al: Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin’s disease: Long-term analysis of risk factors and outcome. Blood 87:3625-3632, 1996 17. Swerdlow AJ, Barber JA, Horwich A, et al: Second malignancy in patients with Hodgkin’s disease treated at the Royal Marsden Hospital. Br J Cancer 75:116-123, 1997[Medline] 18. Abrahamsen JF, Andersen A, Hannisdal E, et al: Second malignancies after treatment of Hodgkin’s disease: The influence of treatment, follow-up time, and age. Oncol 11:255-261, 1993 19. Van Leeuwen FE, Klokman WJ, Hagenbeek A, et al: Second cancer risk following Hodgkin’s disease: A 20-year follow-up study. J Clin Oncol 12:312-325, 1994[Abstract]
20.
Boivin JF, Hutchison GB, Zauber AG, et al: Incidence of second cancers in patients treated for Hodgkin’s disease. Cancer Inst 87:732-741, 1995 21. Kaldor JM, Day NE, Bell J, et al: Lung cancer following Hodgkin’s disease: A case-control study. Int J Cancer 52:677-681, 1992[Medline] 22. Krikorian JG, Burke JS, Rosenberg SA, et al: Occurrence of non-Hodgkin’s lymphoma after therapy for Hodgkin’s disease. Engl J Med 300:452-458, 1979[Abstract]
23.
Bhatia S, Robison LL, Oberlin O, et al: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. J Med 334:745-751, 1996 24. Tarbell NJ, Gelber RD, Weinstein HJ, et al: Sex differences in risk of second malignant tumours after Hodgkin’s disease in childhood. Lancet 341:1428-1432, 1993[Medline]
25.
Beaty O, Hudson MM, Greenwald C, et al: Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease. J Clin Oncol 13:603-609, 1995
26.
Sankila R, Garwicz S, Olsen JH, et al: Risk of subsequent malignant neoplasms among 1,641 Hodgkin’s disease patients diagnosed in childhood and adolescence: A population-based cohort study in the five Nordic countries—Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14:1442-1446, 1996 27. Jenkin D, Greenberg M, Fitzgerald A: Second malignant tumours in childhood Hodgkin’s disease. Pediatr Oncol 26:373-379, 1996 28. Wolden SL, Lamborn KR, Cleary SF, et al: Second cancers following pediatric Hodgkin’s disease. J Clin Oncol 16:536-544, 1998[Abstract] 29. 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—The 1977-1982 H5 controlled trials program. J Clin Oncol 6:239-252, 1988[Abstract]
30.
Tubiana M, Henry-Amar M, Carde P, et al: Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin’s disease: The EORTC Lymphoma Group controlled clinical trials—1964-1987. Blood 73:47-56, 1989 31. Somers R, Tubiana M, Henry-Amar M: EORTC lymphoma cooperative studies in clinical stage I-II Hodgkin’s disease 1963-1987, in Diehl V, Pfreundschuh M, Loeffler M (eds): New Aspects in the Diagnosis and Treatment of Hodgkin’s Disease. Berlin, Germany,Springer-Verlag, 1989, pp 175-181 32. Muir C, Waterhouse J, Mack T, et al (eds): Cancer Incidence in Five Continents (vol 5). IARC Scientific Publications no. 88. Lyon, France, International Agency for Research on Cancer, 1987 33. van der Sanden GAC, Coebergh JWW, Schouten LJ, et al: Cancer incidence in the Netherlands in 1989 and 1990: First results of the nationwide Netherlands cancer registry—Coordinating Committee for Regional Cancer Registries. Eur J Cancer 31A:1822-1829, 1995 34. Parkin DM, Whelan SL, Ferlay J, et al (eds): Cancer Incidence in Five Continents (vol 7). IARC Scientific Publications no. 143. Lyon, France, International Agency for Research on Cancer, 1997 35. Pearson ES, Hartley HO (eds): Biometrika Tables for Statisticians (ed 3). London, United Kingdom, Biometrika Trust, 1976 36. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 37. Cox DR: Regression models and life-tables. J R Stat Soc Ser B 334:187-202, 1972
38.
Donaldson SS, Hancock SL: Second cancers after Hodgkin’s disease in childhood. Med 334:792-794, 1996 (editorial) 39. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, et al: Risk of second primary cancer after Hodgkin’s disease in patients in the British National Lymphoma Investigation: Relationships to host factors, histology and stage of Hodgkin’s disease, and splenectomy. Br J Cancer 68:1006-1011, 1993[Medline]
40.
Hancock SL, Tucker MA, Hoppe RT: Breast cancer after treatment of Hodgkin’s disease. Cancer Inst 85:25-31, 1993 41. Birdwell SH, Hancock SL, Varghese A, et al: Gastrointestinal cancer after treatment of Hodgkin’s disease. Biol Phys 37:67-73, 1997
42.
Griem ML, Kleinerman RA, Boice JD Jr, et al: Cancer following radiotherapy for peptic ulcer. J Natl Cancer Inst 86:842-849, 1994
43.
Land CE: Studies of cancer and radiation dose among atomic bomb survivors: The example of breast cancer. JAMA 274:402-407, 1995 44. Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin’s disease. Med 325:599-605, 1991 [Abstract] 45. Biti G, Cellai E, Magrini SM, et al: Second solid tumors and leukemia after treatment for Hodgkin’s disease: An analysis of 1121patients from a single institution. Int J Radiat Oncol Biol Phys 29:25-31, 1994[Medline]
46.
Van Leeuwen FE, Klokman WJ, Stovall M, et al: Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. Natl Cancer Inst 87:1530-1537, 1995 47. Schilsky RL, Sherins RJ, Hubbard SM, et al: Long-term follow up of ovarian function in women treated with MOPP chemotherapy for Hodgkin’s disease. Am J Med 71:552-556, 1981 [Medline] 48. Andrieu JM, Ochoa-Molina ME: Menstrual cycle, pregnancies and offspring before and after MOPP therapy for Hodgkin’s disease. Cancer 52:435-438, 1983[Medline] 49. Horning SJ, Hoppe RT, Kaplan HS, et al: Female reproductive potential after treatment for Hodgkin’s disease. Med 304:1377-1382, 1981[Abstract] 50. Trichopoulos D, MacMahon B, Cole P: The menopause and breast cancer risk. J Natl Cancer Inst 48:605-613, 1972
51.
Goss PE, Sierra S: Current perspectives on radiation-induced breast cancer. J Clin Oncol 16:338-347, 1998 Submitted February 2, 1999; accepted September 23, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
