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Purpose: The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors., Methods: Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided., Results: Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR = 2.64, 95 % CI 1.88-3.70, p < 0.001). Of survivors who met the definition for infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR = 2.13, 95 % CI 1.69-2.68 for AAD ≥3 versus AAD <3), surgical excision of any organ of the genital tract (RR = 1.63, 95 % CI 1.20-2.21), testicular radiation ≥4 Gy (RR = 1.99, 95 % CI 1.52-2.61), and exposure to bleomycin (RR = 1.55, 95 % CI 1.20-2.01)., Conclusion: Many survivors who experience infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation., Implications for Cancer Survivors: Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.

Purpose: To evaluate the impact of cardiac disease and second malignant neoplasms on late mortality rate and to identify risk factors for late mortality among 15-year survivors of cancer diagnosed during childhood or adolescence., Patients and Methods: Gender-specific all-cause and cause-specific (cardiac disease, cancer) standardized mortality ratios were calculated. Kaplan-Meier survival estimates and Cox regression analyses were performed to determine the relationship of several demographic and treatment variables to survival., Results: Patients who survived for 15 years after diagnosis had excess subsequent all-cause, cancer (second malignant neoplasms only), and cardiac mortality rates. No decrease in the late mortality rate by treatment era (1960 to 1970, 1971 to 1984) was identified. Risk factors for males included disease recurrence during the first 15 years after diagnosis, treatment with doxorubicin, and the diagnosis of Hodgkin's disease. Those for females included treatment with radiation therapy, treatment with an alkylating agent, and disease recurrence during the first 15 years after diagnosis. Cox regression analysis demonstrated that only an initial duration of remission of less than 15 years (P <.01) and treatment with doxorubicin (P =.08) were significantly associated with shorter survival time for males. No variable was significantly associated with shorter survival time for females in Cox regression analysis., Conclusion: Fifteen-year survivors of childhood cancer have excess mortality. More effective treatments must be developed to reduce this excess risk. Fifteen-year relapse-free survivors did not have excess mortality. This group will require continued observation to determine whether excess mortality will become apparent as more events occur.

Background: The goal of this paper is to provide a preliminary description of the marital status for a large number of childhood cancer survivors participating in the Childhood Cancer Survivor Study (CCSS)., Procedure: This report includes children and adolescents (< 21 years of age) diagnosed with cancer between 1970 and 1986 at 25 oncology centers in the United States and Canada who survived at least 5 years from diagnosis. Self-reported data from 10,425 survivors are used in this preliminary descriptive summary. The proportion of survivors ever married and divorced/separated is compared to the U.S. population according to age-specific groups. The median age of the survivor population at diagnosis was 7 years and 26 years at the time martial status was ascertained. Excluded from this assessment are children < 15 years of age at the time of study, those whose martial status was unknown, and those married prior to diagnosis. Data for marital status of the U.S. population, as tabulated in the Bureau of Census 1995 Update, is used as a general comparison to the survivor population., Results: Overall, 32% of the survivors reported being married or living as married, 6% being divorced or separated, 0% being widowed, and 62% having never been married. In general, compared to the U.S. population, survivors were less likely to have ever married, particularly females and whites, but, once married, were less likely to divorce/separate, again particularly females and whites. Black survivors were generally found to be more likely to have married, with males and blacks more likely to divorce/separate once married. Comparison of childhood tumor types suggested that survivors of CNS tumors, particularly males, were less likely to have ever married and more likely to divorce/separate compared to those with other cancer diagnoses and the general U.S. population., Conclusions: This interim evaluation of the CCSS cohort provided preliminary data describing a suggested decreased likelihood of marriage, which may be influenced by gender and/or race. These patterns must be confirmed within the entire CCSS cohort and comparisons made with an appropriate sibling comparison group before making final conclusions.

This, the fifth official document of the SIOP Working Committee on Psychosocial Issues in Pediatric Oncology, develops another important topic: the Therapeutic Alliance between families and staff. This is addressed to the Pediatric Oncology Community as Guidelines that could be followed. Every parent, medical staff member, and psychosocial professional involved in the care of the child should be responsible for cooperating in the child's best interest. Everyone must work together toward the common goal of curing the cancer and minimizing its medical and psychosocial side-effects.

This is the fourth official document of the SIOP Working Committee on psychosocial issues in pediatric oncology constituted in 1991. This document develops another topic discussed and approved by the SIOP Committee: "communication of the diagnosis" is addressed to the pediatric oncology community as guidelines that could be followed. The highly stressful nature of the diagnostic period must be acknowledged, and communication involving the staff and all family members should cover both medical and psychosocial issues. A well-planned and extensive initial session should be followed by continuing discussions. The goal is a knowledgeable family that can talk openly with its members and with the staff.

Objective: To determine the effect of chemotherapy for cancer during childhood and adolescence on subsequent pregnancy outcome and the occurrence of cancer in the offspring., Design: We reviewed the history of 405 former patients with pediatric cancer. A self-administered questionnaire was completed by members of a cohort of consecutively treated patients who were aged 18 years or older at the most recent follow-up visit and who were at least 5 years beyond the initial diagnosis of their cancer., Setting: Department of Pediatrics of a National Cancer Institute-designated comprehensive cancer center., Results: One hundred forty-eight patients reported 280 pregnancies. Ninety-one of the patients who reported 1 or more liveborn or stillborn infants following the completion of treatment had received 1 or more chemotherapeutic agents as part of their treatment of cancer. The frequency of congenital anomalies was 3.3% among the liveborn offspring of the treated women and 3.3% among the liveborn offspring of the spouses or female companions of the treated men. No cases of childhood cancer have been diagnosed among the offspring., Conclusions: The present data suggest that prior treatment with mutagenic chemotherapeutic agents, in the dosage ranges examined, does not increase the frequency of congenital anomalies in the offspring of former pediatric and adolescent patients with cancer. Although no cases of childhood cancer have been observed thus far among the offspring, additional follow-up is necessary to adequately assess their risk of childhood cancer.

Background: Etoposide, ifosfamide, and cisplatin (VIP) are each active in treating pediatric solid tumors, and this combination has been shown to be effective in treating adult germ cell tumors. Etoposide, ifosfamide, and cisplatin therapy was used to treat 11 patients, with ages ranging from 14 months to 22 years, with relapsed sarcoma, Wilm's tumor, and hepatoblastoma., Methods: Etoposide, ifosfamide, and cisplatin therapy was administered daily for 3 days in doses of cisplatin 20 mg/m2 with mannitol 10 g/m2 for 1 hour, etoposide 100 mg/m2, and ifosfamide 1.5 g/m2 with MESNA 360 mg/m2 x 3 doses. A total of 65 courses (range, 3-10/patient) were administered, with 86% of the courses administered at full dose. Hematopoietic growth factors were not used., Results: All 10 evaluable patients responded. Six patients had a complete response (CR) by computed tomographic or magnetic resonance imaging scan after one to three courses. The remaining four patients had a partial response (PR) (> 50% decrease in disease). One PR was converted to a CR by resection of the residual lesions. The major toxicity was myelosuppression. The median nadirs after full doses were as follows: leukocyte count of 900/mm3, absolute neutrophil count (ANC) of 156/mm3, platelet count of 61,000/mm3, and hemoglobin count of 8.6 g/dl; 75% of full dose courses led to an ANC of less than 500. Fever and neutropenia were observed after 8/55 (15%) full dose courses. Two episodes of bacteremia were noted, one with Staphylococcus epidermidis after full recovery of counts. The median time to hematologic recovery was 21 days (range, 14-29 days). No patient developed a decreased creatinine clearance level during therapy. Significant renal solute losses were observed in two patients, both of whom had been pretreated heavily with ifosfamide and had losses before VIP therapy., Conclusions: Etoposide, ifosfamide, and cisplatin appear to be active in treating childhood solid tumors. This therapy has predictable and tolerable myelotoxicity, and nephrotoxicity does not appear to be more severe than that observed after treatment with ifosfamide alone.

Many pediatric and adolescent cancer patients are treated with carcinogenic chemotherapeutic agents and radiation therapy to achieve permanent control of their malignancy. These modalities may induce a new cancer in the successfully treated patient. To identify disease and treatment factors which increased the risk of occurrence of a second malignant tumor following modern treatment for cancer during childhood or adolescence, we reviewed the courses of 1,406 previously untreated patients who were less than 20 years of age at diagnosis and were treated at Roswell Park Cancer Institute between January 1, 1960 and December 31, 1989. Eighteen patients developed a second malignant tumor, including two meningiomas, 2.65-25.65 years after diagnosis of the first cancer. The actuarial risk of a second malignant tumor was 5.6% at 25 years after diagnosis. Using Cox proportional hazards modelling, we identified prior therapy with BCNU (P = 0.0055) and doxorubicin (P = 0.0254) as the only factors that were significantly associated with the risk of a second malignant tumor. Three second malignant tumors of the central nervous system occurred following treatment with a nitrosourea. Successfully treated patients must be carefully followed to identify treatment related malignant tumors at an early stage.

To evaluate the further survival, and to identify disease and treatment factors which influence the further survival, of five-year survivors of cancer diagnosed during childhood or adolescence, we reviewed the courses of 591 previously untreated patients who were less than 20 years of age at diagnosis and survived for five years after diagnosis. Fifty-three of 143 patients who experienced disease recurrence during the first five years after diagnosis died during the period of observation, compared to 18 of 448 patients who did not experience disease recurrence during the first five years after diagnosis. The sex-specific standardized mortality ratios for the group of patients who never relapsed or relapsed more than five years after diagnosis were not significantly different from those of the New York State population. Cox proportional hazards modelling of the subgroup of patients who relapsed during the first five years after diagnosis demonstrated that disease which was treated surgically, a diagnosis of Hodgkin's disease or acute lymphoblastic leukemia, and older age at diagnosis were significantly associated with further survival in this group, whereas similar modelling of the patients who did not experience disease recurrence during the first five years after diagnosis failed to identify any variables which were associated with continued survival. The results of this study suggest that childhood and adolescent cancer patients who survive for five years without disease recurrence have a survival rate similar to that of the general population. Continued follow-up of this cohort is required to determine if the present findings can still be demonstrated as the majority of the cohort ages beyond 35 years of age.

Recognizing the importance of psychosocial issues in the care and cure of the child with cancer, the board of the International Society of Pediatric Oncology (SIOP) in 1991 constituted a Working Committee on Psychosocial Issues in Pediatric Oncology, with Giuseppe Masera as chair and John Spinetta as co-chair. This committee met for the first time in Rhodes, Greece, in October 1991. The committee discussed various psychosocial issues and developed a document on Aims and Recommendations, summarizing the experiences of major centers. This document was approved by the SIOP board, which recommended diffusion of the document to the pediatric oncology community.

Background: Many patients who have been treated successfully for childhood cancer with regimens that contain one or more mutagenic chemotherapeutic agents are concerned that their own treatment during childhood or adolescence may adversely affect their children., Methods: To determine the effect of chemotherapy for cancer during childhood and adolescence on the outcome of subsequent pregnancies, we reviewed the records of 306 men and women who had been treated for pediatric cancer and who responded to our questionnaire. One hundred of the 306 patients reported 202 pregnancies. Among the patients who had received chemotherapy as part of their treatment for cancer, 60 patients or wives of patients had had one or more pregnancies of 20 or more weeks' gestation. The 60 former patients had a total of 100 live-born and 2 stillborn children., Results: The frequency of congenital anomalies was 8.1 percent (5 of 62) among the live-born children of the women and 7.9 percent (3 of 38) among the live-born children of the men. Structural congenital cardiac defects were identified in 10.0 percent (2 of 20) of the children of women who had been treated with dactinomycin, as compared with 0.6 percent (144 of 24,153) among the children in a multicenter survey of fetal anomalies (P = 0.0126). We found no relation between the number of mutagens received or the cumulative dose of any agent received and the frequency of congenital anomalies in the children., Conclusions: These data suggest that treatment of children and adolescents with mutagenic chemotherapeutic agents, in the dose ranges we examined, does not increase the frequency of congenital anomalies in the children subsequently born to the former patients. However, the possible adverse effect of dactinomycin on the children of such patients requires further study.

To assess the impact of the diagnosis and modern treatment of childhood cancer on achievement of adult goals, the authors evaluated employment, health and life insurance coverage, marriage, divorce, and reproduction in 227 former pediatric cancer patients. Each area was evaluated in relation to a common set of disease and demographic factors that included age at follow-up, age at diagnosis, gender, marital status, history of disease recurrence, and diagnosis. Patients were younger than 20 years of age at diagnosis, and their diagnoses were made between January 1, 1960, and December 31, 1984. The median age at diagnosis was 11.4 years, and the median age at follow-up was 26.6 years. The percentage of unemployed male respondents did not differ from population norms. The percentage of unemployed female respondents, however, was slightly higher than that of the United States population. Approximately 11% of the survivors reported some form of employment-related discrimination, a level significantly lower than that of prior reports. Company-offered health insurance was provided to 92.4% of full-time and 90.0% of part-time employed respondents. Life insurance was purchased by 60% of full-time employed men and 55% of women. These percentages were lower than those reported for the United States population. Twenty-four percent of those with life insurance had difficulty obtaining it. Fifty-eight percent of the subjects were married or lived as married. The percentages of married men and women were significantly lower than United States norms. Twenty percent of those who were married or lived as married have divorced or separated or no longer live as married. Women aged 20 to 24 years were less likely to marry, and women aged 35 to 44 years had a significantly higher frequency of divorce than similarly aged United States women. In general, the history of childhood cancer did not influence the decision to marry or live as married but was occasionally (20%) important in the decision to dissolve a marital relationship. Many former patients indicated that their diagnosis and treatment for childhood cancer influenced their decision to have children. The current study suggests that most former pediatric cancer patients achieve adult life goals. Additional research is necessary to define those populations at greatest risk of failure to achieve these goals.

To determine the maximum tolerated dose of 5-fluorouracil administered as a 120-hour continuous intravenous infusion to pediatric patients, we performed a phase I study using a starting dosage of 900 mg/m2/day. The maximum tolerated dosage (MTD) was 1,100 mg/m2/day. At this dosage level 40% of courses were complicated by grade 3 mucositis. Three additional patients were treated at the dosage level of 1,000 mg/m2/day after the MTD was determined. We recommend the dosage level of 1,000 mg/m2/day for phase II studies of 5-fluorouracil administered as a 120-hour continuous intravenous infusion to pediatric patients.

Bolus chemotherapy with vincristine, actinomycin D, and cyclophosphamide was administered to 31 patients with solid tumors. Among 12 patients with measurable disease who had not received prior treatment, a complete response was achieved in one with Ewing's sarcoma and a partial response was achieved in another with rhabdomyosarcoma. The dose-limiting toxicity was granulocytopenia.

The medical records of 973 previously untreated patients diagnosed between January 1960 and December 31, 1978 with childhood cancer were reviewed. Siblings in 13 families were diagnosed with cancer 9/12 to 15 years after the diagnosis of cancer in the index sibling. Previously unreported association of acute lymphoblastic leukemia with Hodgkin's disease, neuroblastoma with malignant hemangiopericytoma, non-Hodgkin's lymphoma with malignant melanoma, Wilms' tumor with non-Hodgkin's lymphoma, Hodgkin's disease with malignant teratoma of the testis and craniopharyngioma with acute myeloblastic leukemia were identified. Two families appeared to transmit a predisposition to childhood tumors. The data from these families extend previous observations regarding multiple cases of cancer in sibships.

Research in animal and human cell cultures has shown that some chemotherapeutic agents, cisplatin in particular, have cytotoxicity that is significantly potentiated at elevated temperatures. Concurrent administration of systemic cisplatin and local hyperthermia in human patients has not been previously reported. A phase I/II study was undertaken to assess the systemic and local toxicities and activity of concurrently administered local hyperthermia and systemic cisplatin in human tumours. Nine patients with histologically proven malignant tumours have been treated from March 1985 to July 1987. Their histologies were: breast, four; SCC of head and neck, two; SCC of skin, one; malignant melanoma, one; synovial cell sarcoma, one. Once-weekly hyperthermia was administered for 60 min by external microwave devices in an attempt to achieve minimum intratumoral temperatures of 42 degrees C. Plastic catheters were placed intratumorally under CT guidance for thermometry purposes. Cisplatin 40-60 mg/m2 was given over 60 min when steady-state heating was achieved. A total of 44 treatments are available for analysis. All nine patients had minimum intratumoral temperatures below the desired goal of 42 degrees C, and only two patients achieved average intratumoral temperatures of 42 degrees C or greater. Two of the responding patients sustained significant thermal injury consisting of blistering and necrosis. Three patients required transfusion and delay of weekly treatment because of anaemia and leukopenia. Four patients had partial response (PR) and one patient had minor response (MR) within the heated treatment volume. Three of these five patients experienced significant subjective palliation. This combination of treatment modalities can be delivered safely.(ABSTRACT TRUNCATED AT 250 WORDS)