Second Neoplasms After Wilms' Tumor in Childhood 1

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1 Second Neoplasms After Wilms' Tumor in Childhood 1 Frederick P. Li, 2,3,4 James Cai-jie Van,5 Stephen Sallan,3 J. Robert Cassady, Jr., 3,6 Jane Danahy, 3 William Fine,3 Richard D. Gelber,3 and Daniel M. Green 7 ABSTRACT - The frequency of second neoplasms was examined among 487 Wilms' tumor patients treated at the Dana-Farber Cancer Institute and Children's Hospital of Boston, Thirty study patients (6%) developed second primary tumors: 11 cancers, benign tumors, and 3 borderline neoplasms. Cumulative probability of a second cancer was 18% (standard error, 6%) in 34 years after diagnosis of Wilms' tumor. The subgroup of 412 patients who had received radiotherapy for Wilms' tumor developed all 11 second cancers, which included 1 skin carcinoma, 1 acute leukemia, and 9 solid internal cancers (expected, 0.7 cancers other than skin carcinoma; P<.001). After exclusion of the secondary leukemia, all but 1 second cancer arose within the radiotherapy field. Concurrent therapy with dactinomycin did not reduce the risk of a radiation-associated cancer. Second cancer was the cause of death in 7 patients.-jnci1983; 71: Survival of patients with Wilms' tumor has improved markedly during recent decades (1). Among patients at this institution, Kaplan-Meier analyses showed that 5- year survival rates were 37% for those treated before 1949, 41 % for those treated during , 61 % for those treated during , and 82% for those treated during Successfully treated patients are at risk of developing late complications of therapy, including second primary neoplasms (2). The present study examines the frequency of second tumors among 487 Wilms' tumor patients treated at our center during the last 55 years. MATERIALS AND METHODS A list was made of 487 children diagnosed and treated for Wilms' tumor of the kidney at the Dana-Farber Cancer Institute and Children's Hospital of Boston, Patients were identified by review of pathology reports, medical records, and tumor registry files. The hospital record of each patient was abstracted for demographic data; age at diagnosis of Wilms' tumor; disease stage; and treatments with surgery, radiotherapy, and chemotherapy. Follow-up status was ascertained from records of repeat hospitalizations, return visits to the clinic, correspondence, and prior studies of late effects of cancer (2, 3). Table 1 shows the sex and age at diagnosis of the 487 study patients as well as the stage of their Wilms' tumor and the treatment given to them. All patients underwent a nephrectomy as part of their initial treatment. Four hundred and twelve patients received abdominal radiotherapy to the involved renal fossa, hemi-abdomen, or whole abdomen. One hundred and seventy-four of the 412 patients also received thoracic irradiation either as adjuvant treatment or as therapy for lung metastases, and patients received therapy to additional sites. Orthovoltage radiation was administered to most pa- tients and was usually in doses of 2,500-3,000 rad to the abdomen. Other sites received diverse doses, and port films and other treatment details were often not available. Among the irradiated patients, 222 received dactinomycin either concurrently or soon after completion of radiotherapy. One course of dactinomycin was given to 44 of these patients, and 178 received multiple courses (usual course, 10 Jlg/kg body wt/day iv for 7 days). Twenty-five patients in the series received dactinomycin and no radiotherapy, and the remaining 50 patients received neither treatment. In addition, 115 of the 487 patients received other drugs, including vincristine, cyclophosphamide, nitrogen mustard, triethylenemelamine, and doxorubicin, but the number in each treatment category was small. At last follow-up 241 study patients (49%) had died, and 246 were living with a median follow-up of 13 years. The date of last observation was after 1975 for 225 of the 246 survivors (93%). Second neoplasms after Wilms' tumor were diagnosed as benign or malignant tumors by histologic examination of tissue specimens. Lesions with borderline histology were handled separately in the analysis. Several patients in the study have been reported previously (2, 4-6). The observed numbers of second malignant neoplasms were compared with the expected numbers based on the incidence of new cancers in the general population. The expected numbers were obtained by use of the Third National Cancer Survey age- and sex-specific cancer incidence rates (excluding primary skin carcinomas) (7). These figures were applied to the time interval from diagnosis of Wilms' tumor to death or last observation for each patient and were summed. The relative risk of second cancer (observed/expected) was calculated for the entire series and for 3 treatment subgroups. These subgroups were as follows: 222 patients treated initially with surgery, radiotherapy, and dactinomycin; 190 patients treated with surgery and radiotherapy (no dactinomycin); and 75 patients treated with modalities other I Received May 10, 1983: accepted July 26, Clinical Epidemiology Branch, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Bethesda, Md Divisions of Biostatistics and Epidemiology, Pediatric Hematology, Oncology and Radiation Therapy, Dana-Farber Cancer Institute and Children's Hospital Medical Center, Boston, Mass Address reprint requests to Dr. Li, Dana-Farber Cancer Institute, 44 Binney St., Boston, Mass 'Southwestern Hospital, Chungking, People's Republic of China. 6 Joint Center for Radiation Therapy, Harvard Medical School, Boston, Mass Roswell Park Memorial Institute, Buffalo, N.Y

2 1206 Li, Van, Sallan, et al. TABLE I.-Characteristics of the 487 Wilms' tumor patients Characteristic" No.ofpatients Percent Sex Male Female Age at diagnosis of Wilms' tumor, yr Wilms' tumor stage b I II III IV V 18 4 Initial radiotherapy and Act D for Wilms' tumor' Radiotherapy given With ActD No Act D No radiotherapy ActD 25 5 No ActD " Act D=dactinomycin. b Staging system reported in (1). 'Numbers of patients treated with drugs other than Act D were too small for analysis. than radiotherapy. Further division of the study series by treatment category was not done because of the small numbers of patients with second cancers in each subset. In this series, dactinomycin was first used to treat Wilms' tumor in 1954, and radiotherapy was first used in Duration of follow-up observation was up to 26 years among dactinomycin-treated patients, 41 years among irradiated patients, and 48 years among patients treated with neither modality. Statistical significance and confidence intervals of the relative risk estimates were determined with the use of exact methods based on the Poisson distribution (8). A Patient No. two-sided test for comparison of two Poisson distributions accounting for expected numbers was used to determine the statistical significance of differences between groups (9). The Kaplan-Meier method and Greenwood's formula were used to estimate the cumulative probability of a second cancer and the standard error, respectively (10). The records of the patients in the study were also examined for the development of benign second neoplasms; however, relative risk could not be determined because incidence rates of benign tumors in the general population are not available. RESULTS TABLE 2.-Patients with second cancer after treatment for Wilms' tumor Of the 487 patients, 30 (6%) developed second neoplasms after Wilms' tumor. Eleven (patients #1-11) had second cancers (table 2). Two other patients had second tumors with borderline malignant histology, and a third patient had either a second cancer or an atypical recurrent Wilms' tumor. The remaining patients had benign second tumors. Patients with second neoplasms did not significantly differ from others in the study with regard to sex, age at diagnosis, and stage of Wilms' tumor. Patients # I-II had diverse forms of second cancers: thyroid carcinoma (2 patients) and chondrosarcoma, neurofibrosarcoma, mesenchymoma, mesothelioma, acute myelocytic leukemia, and carcinomas of breast, rectum, liver, and skin (1 each) (table 2). The interval between diagnosis of the multiple primary cancers ranged from 7 to 34 years (median, 17 yr). Kaplan Meier analysis showed that the cumulative probability of a second cancer was 6% (standard error, 2%) in 20 years after diagnosis of a Wilms' tumor and 18% (standard error, 6%) in 34 years (text-fig. I). Orthovoltage radiotherapy for Wilms' tumor had been given to the patient with acute leukemia and all 10 patients with solid malignant tumors. Of these 10 solid tumors, 9 were within the field of prior radiotherapy that received 600-4,000 rad. Multiple courses of dacti- Age, yr, at diag- Initial radiotherapy, Initial chemotherapy Sex nosis (stage) of rad" Second neoplasm, site (No. of courses)b Wilms' tumor Abdominal Thoracic 1 a 2 (IV) Act D (9) Adenocarcinoma, thyroid gland' 2 a 1 (II) 3,500 1,200 Act D (7) Mesenchymoma, mediastinum" d 3 <j' 3 (II) 4,000 1,200 Act D (8); other Chondrosarcoma, iliac crest, d 4 <j' 4 (III) 5,000 1,200 Act D (2); other Adenocarcinoma, thyroid gland' 5 a 5 (V) 1,200 Denopterin Carcinoma, liver, d 6 <j' 9 (II) 2, Adenocarcinoma, breast' 7 a <1 (II) 1,900 Adenocarcinoma, rectum, d 8 <j' <1 (II) 1,500 Acute myelocytic leukemia d 9 <j' 3 (II) 2,900 N eurofibrosarcoma, pelvis" d. e 10 a <1 (I) 2,800 Basal cell carcinoma, skin' 11 a 5 (II) 3,300 TEM Mesothelioma, pleura d Interval between neoplasms, yr "Radiation dose estimate made in some patients without port films and other treatment details. -=no radiotherapy. bact D=dactinomycin; TEM=triethylenemelamine; -=no chemotherapy. 'Second solid malignant tumor within field of prior radiotherapy for Wilms' tumor. ddied of the second primary cancer. epatient also had familial neurofibromatosis.

3 Second Neoplasms After Wilms' Tumor 1207 ~ Q) " c j ~0.20. o :~ :s ~ lo..io. 1 Uo I Years After Diagnosis of Wilms' Tumor l TEXT-FIGURE I.-Cumulative probability of second cancer after diagnosis of Wilms' tumor and standard error. nomycin were administered to 4 of these 9 patients (patients # 1-4) with radiation-associated solid tumors_ Table 3 shows the effect of radiotherapy and dactinomycin on the risk of developing a second cancer. Among all 487 patients, 10 new cancers other than skin carcinoma were observed during 4,255 person-years of follow-up observation, whereas only 1.0 internal cancer was expected. The observed-to-expected ratio was 10, and the 95% confidence interval of this ratio (4.8; 18.2) differed from unity by P<.OO1. All these 10 cancers developed in the subgroup of 412 patients who had received radiotherapy: 8 solid tumors within irradiated tissues, 1 solid tumor outside the treatment field, and 1 acute myelocytic leukemia. The relative risk of a second cancer was fourteenfold among both the 222 patients treated with combined modalities and the 190 patients treated with radiotherapy only. In addition, second cancer risk was the same among Wilms' tumor patients treated prior to the introduction of dactinomycin at our TABLE 3.-Risk of second cancer after radiotherapy for Wilms' tumor No. of patients No. of new cancersb Relative risk (95% confi- (person-yr of Observed Expected' dence follow-up) interval) Wilms' tumor therapy" Radiotherapy 412 (3,696) 10 (8) (6.8; 25.9) given With Act D 222 (1,987) 4 (4) No Act D 190 (1,709) 6 (4) No radiotherapy 75 (559) (0; 12.3) All treatment 487 (4,255) 10 (8) (4.8; 18.2) categories a All patients had nephrectomy as part of initial treatment. Diverse chemotherapy drugs other than dactinomycin (Act D) were administered to 115 patients in the series. bexcludes primary carcinomas of the skin. Numbers in parentheses are No. of second solid tumors (other than skin cancer) arising within irradiated tissues. 'Expected number based on age- and sex-specific U.S. cancer incidence rates as reported in the Third National Cancer Survey (7). hospital and those treated thereafter. The 75 patients who did not initially receive radiotherapy have been free of second cancer. This finding differs significantly from the observation of 10 internal cancers among the 412 irradiated patients (P<.05 by testing for equality of two Poisson distributions) (8). All patients with radiation-associated second cancers had received orthovoltage radiotherapy. Among patients who received megavoltage radiotherapy, only 0.1 new cancer was expected. This number is too small to reveal the relative carcinogenic hazard of orthovoltage and megavoltage treatments. One patient (#9) with a second cancer (neurofibrosarcoma) had von Recklinghausen's neurofibromatosis, a predisposing genetic disease (6). The neurofibrosarcoma arose within the field of prior irradiation and may have been due to a genetic-radiation interaction. No other study patient with multiple primary cancers was known to have a cancer susceptibility syndrome (11). Of the 30 patients with multiple primary neoplasms, 19 had second tumors that were either benign ( patients) or not readily classified (3 patients). Of the benign tumors, 9 were within the radiotherapy field: 4 osteomas, 2 thyroid adenomas, 2 uterine leiomyomas, and 1 desmoid. Six of these lesions were also associated with prior dactinomycin therapy. The other 7 benign tumors were not associated with radiation exposure and included 2 uterine leiomyomas and neurofibroma, osteoma, parotid tumor, breast adenoma, and ovarian cyst (1 each). One of the not readily classified lesions was a radiation-associated bone tumor that was considered as cancer by some observers; the second was a microscopic adenocarcinoma in an irradiated thyroid gland; the third was a round cell tumor occurring in the lung nearly 15 years after a Wilms' tumor and was either a second cancer or an atypical recurrent Wilms' tumor. DISCUSSION This study examined the frequency of second tumors among 487 Wilms' tumor patients treated during the 55-year period Ten new cancers (excluding 1 skin carcinoma) developed during 4,255 person-years of follow-up, as compared with 1 cancer expected on the basis of cancer incidence rates in the general population. The diagnosis of a second cancer was considered in 3 additional patients, but expert opinions differed and these cases were excluded from the analysis. Histologically benign second neoplasms were diagnosed in other patients. The corresponding expected number cannot be determined because children who have Wilms' tumor tend to have closer medical supervision and biopsy of benign growths. One irradiated patient developed acute myelocytic leukemia, and 9 irradiated patients developed solid malignant tumors within the field of prior radiotherapy for Wilms' tumor. The histologic types of the second cancers, their anatomic location within the radiation port, and time interval from treatment suggest a carcinogenic effect of the radiotherapy (12). Other case reports have

4 1208 Li, Van, Sallan, et al. also noted the development of acute leukemia and diverse solid malignant tumors after Wilms' tumor (13-17). In a recent abstract, Sotelo et al. (18) reported 7 second cancers and 1 second benign tumor among a series of 260 Wilms' tumor patients. The proportion of patients with second cancers (7/260,2.7%) is comparable to that in our study (11/487, 2.3%). However, benign second tumors were much more common in our series (/487 as compared with 1/260), perhaps because of more complete registration of these tumors. All 8 patients with second tumors in Sotelo's series had received radiotherapy. Most of these tumors developed within the radiation port, as was noted in our series of second tumors. Studies have analyzed the carcinogenic risk of radiotherapy for childhood cancers other than Wilms' tumor. Patients irradiated for diverse childhood cancers are prone to second cancers, although the risk estimates differ. Studies from our institution and a 13-center study showed a 12% cumulative probability of developing a new cancer in 25 years, more than fifteenfold above the general population rate (19, 20). Most of these second cancers arose within the field of prior radiotherapy and included secondary leukemia that developed in patient #8 in our series at 17 years after radiotherapy. Other studies of childhood cancer survivors have reported a much smaller increase in risk of second tumors (21, 22). However, these reports differ with regard to criteria for patient eligibility and exclusion, duration of observation, completeness of follow-up, and analytic methods (21, 22). Treatment factors, including radiation dose, volume, and energy and use of chemotherapy, also differed. Data suggest that adults are less susceptible than children to the carcinogenic effect of radiotherapy for cancer. Age has been reported as a modifying influence in the development of certain radiation-induced cancers, such as breast cancer, thyroid cancer, and acute leukemia in the first decade following exposure (23-26). Adults irradiated for carcinoma of the cervix show only a small excess of cancers of heavily irradiated pelvic organs and no secondary leukemias (27). Acute non lymphocytic leukemia that develops after therapy for Hodgkin's disease, ovarian cancer, and multiple myeloma is attributed mainly to alkylating agent chemotherapy, though an interaction with radiotherapy remains a possibility (28-30). The 1 study patient who developed a second cancer outside the radiotherapy field (patient #11 who developed a mesothelioma) had received an alkylating agent (triethylenemelamine), but this drug is not known to induce any solid tumor in humans (28). Genetic susceptibility may be an important factor in the development of multiple primary cancers in young patients (11). Wilms' tumor has been diagnosed simultaneously with sarcoma, hepatoma, and acute leukemia, suggesting host susceptibility to these combinations of tumors (12). In addition, the rhabdoid variant of Wilms' tumor is associated with development of posterior fossa neuroectodermal tumors (31). Patients who have hereditary retinoblastoma are prone to develop new cancers, including osteosarcoma, pinealoma, and perhaps other cancers (32, 33). In addition, von Recklinghausen's neurofibromatosis predisposes to diverse childhood cancers, including Wilms' tumor and peripheral nerve tumors (11). These 2 cancers developed in 1 patient with neurofibromatosis in our series, and her neurofibrosarcoma may have been a complication of the underlying genetic disease, the radiotherapy, or both influences (6). Dactinomycin was found in a case-control study to reduce the risk of radiation-associated second cancers by more than 80% among treated children (34). However, laboratory studies have shown that dactinomycin alone can induce transformation, mutation, and chromosome aberration in vitro and cancer in experimental animals (35-38). One study (39) of dactinomycin-radiation interaction found that the drug suppressed cellular transformation by radiation, but another study (40) found no protective effect of the drug on radiogenic rat mammary cancers. In our cohort study, risk of second cancer was essentially the same for individuals treated with radiotherapy alone and those treated with combined modalities. Moreover, multiple courses of dactinomycin had no protective effect, and radiation-associated benign tumors also developed after combined modality treatment. The divergent findings in our series and the other report of children with cancer may be due to inadequate matching in the selection of controls in the prior study (34). However, each treatment subgroup in this report included only a small number of patients with second cancers; the maximum follow-up duration was much longer in our irradiated group than in the group treated with combined modalities (41 and 26 yr, respectively), and more of the former patients were adults with a higher expected incidence of cancer. In our study and in the prior study, treatment subgroups may have differed with regard to radiation field size, number of treatment ports, and other radiation characteristics. Wilms' tumor caused the death of 241 patients in this study. In contrast, a second primary cancer developed in only 11 patients and was the cause of death in 7. Risk of death is clearly greater from inadequate treatment of Wilms' tumor than from treatment-associated second cancers. Nevertheless, studies are needed to identify patients prone to develop second primary cancers and to eliminate unnecessary treatments (1, 31). REFERENCES (J) GREEN DM,jAFFE N. 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