Purpose

Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.

Patients and Methods

We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).

Results

Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.

Conclusion

Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.

Investigations of long-term outcomes have been instrumental in designing safer and more effective contemporary therapies for pediatric hematological malignancies. Despite the significant therapeutic changes that have occurred over the last five decades, therapy modifications largely represent refinements of treatment protocols using agents and modalities that have been available for more than 30 years. This review summarizes major trends in the evolution of treatment of pediatric hematological malignancies since 1960 to support the relevance of the study of late effects of historical therapeutic approaches to the design and evaluation of contemporary treatment protocols and the follow-up of present-day survivors.

BACKGROUND

Although whole lung irradiation (WLI) is used to treat pulmonary metastases of pediatric solid malignancies, few studies have addressed its long-term pulmonary consequences.

METHODS

We conducted a retrospective study of longitudinal changes in 171 pulmonary function tests (PFTs) and their relationship with clinical features in 48 survivors of pediatric malignant solid tumors treated with WLI.

RESULTS

Although active respiratory symptoms were seen in only 9 (18.8%) patients, abnormalities in forced vital capacity (FVC; 58.3%), forced expiratory volume in 1 second (FEV1; 64.6%), total lung capacity (TLC; 72.9%), and diffusion capacity of carbon monoxide corrected for hemoglobin (DLCOcorr; 70.8%) were common. At a median follow-up of 9.7 years after WLI, FVC, FEV1, and TLC significantly declined longitudinally (P = .04, .03, and .02, respectively). Focal pulmonary boost irradiation was significantly associated with abnormal FEV1/FVC (P = .03), forced expiratory flow between 25% and 75% forced vital capacity (FEF25%–75%; P = .005), residual volume (RV; P = .005), and RV/TLC (P = .002). Ten patients had baseline PFTs, and FVC, FEV1, TLC and DLCOcorr worsened immediately after radiation, followed by transient improvement but subsequent decline. Thirteen of 32 (40.6%) patients over the age of 18 were smokers.

CONCLUSIONS

Pulmonary dysfunction, especially in lung volumes, was prevalent after WLI and worsened over time although most patients were asymptomatic. Boost irradiation impaired pulmonary function, and a significant proportion of patients were smokers. Further studies are planned to assess the predictors and clinical consequences of progressive PFT abnormalities and to evaluate educational interventions.

Introduction

Treatment regimens for childhood acute lymphoblastic leukemia (ALL) contain neurotoxic agents that may interfere with neuromuscular health. This study examined associations between neuromuscular impairments and physical function, and between neuromuscular impairments, and doses of vincristine and intrathecal methotrexate used to treat leukemia among survivors of childhood ALL.

Methods

ALL survivors 10+ years from diagnosis participated in neuromuscular performance testing. Treatment data were abstracted from medical records. Regression models were used to evaluate associations between treatment factors, neuromuscular impairments and physical performance.

Results

Among 415 survivors (median age 35 years; range 21–52), balance, mobility and six-minute walk (6MW) distances were 1.3 standard deviations below age- and sex-specific values in 15.4%, 3.6% and 46.5% of participants, respectively. Impairments included absent Achilles tendon reflexes (39.5%), active dorsiflexion range of motion (ROM) < 5 degrees (33.5%) and impaired knee extension strength (30.1%). In adjusted models (including cranial radiation), survivors treated with intrathecal methotrexate cumulative doses 215+ mg/m2 were 3.4 (95% CI 1.2–9.8) times more likely than survivors who received no intrathecal methotrexate, and those who received vincristine cumulative doses 39+ mg/m2 1.5 (95% CI 1.0–2.5) times more likely than those who received lower doses to have impaired ROM. Higher intrathecal methotrexate doses were associated with reduced knee extension strength and 6MW distances.

Conclusion

Neuromuscular impairments are prevalent in childhood ALL survivors and interfere with physical performance. Higher cumulative doses of vincristine and/or intrathecal methotrexate are associated with long-term neuromuscular impairments, which have implications on future function as these survivors age.

Purpose

Children with cancer receive mutagenic treatments, which raises concern about the potential transmissibility of germline damage to their offspring. This question has been inadequately studied to date because of a lack of detailed individual treatment exposure assessment such as gonadal radiation doses.

Methods

Within the Childhood Cancer Survivor Study, we performed a retrospective cohort analysis of validated cases of congenital anomalies among 4,699 children of 1,128 male and 1,627 female childhood cancer survivors. We quantified chemotherapy with alkylating agents and radiotherapy doses to the testes and ovaries and related these exposures to risk of congenital anomalies using logistic regression.

Results

One hundred twenty-nine children had at least one anomaly (prevalence = 2.7%). For children whose mothers were exposed to radiation or alkylating agents versus neither, the prevalence of anomalies was 3.0% versus 3.5% (P = .51); corresponding figures were 1.9% versus 1.7% (P = .79) for the children of male survivors. Neither ovarian radiation dose (mean, 1.19 Gy; odds ratio [OR] = 0.59; 95% CI, 0.20 to 1.75 for 2.50+ Gy) nor testicular radiation dose (mean, 0.48 Gy; OR = 1.01; 95% CI, 0.36 to 2.83 for 0.50+ Gy) was related to risk of congenital anomalies. Treatment with alkylating agents also was not significantly associated with anomalies in the children of male or female survivors.

Conclusion

Our findings offer strong evidence that the children of cancer survivors are not at significantly increased risk for congenital anomalies stemming from their parent's exposure to mutagenic cancer treatments. This information is important for counseling cancer survivors planning to have children.

Purpose

This study was undertaken to evaluate the effect of prior treatment with radiation therapy or chemotherapy for unilateral Wilms tumor (WT) diagnosed during childhood on pregnancy complications, birth weight, and the frequency of congenital malformations in live-born offspring.

Patients and Methods

We reviewed pregnancy outcomes among female survivors and partners of male survivors of WT treated on National Wilms Tumor Studies 1, 2, 3, and 4 by using a maternal questionnaire and a review of both maternal and offspring medical records.

Results

We received reports of 1,021 pregnancies with duration of 20 weeks or longer, including 955 live-born singletons, for whom 700 sets of maternal and offspring medical records were reviewed. Rates of hypertension complicating pregnancy (International Classification of Diseases [ICD] code 642), early or threatened labor (ICD-644) and malposition of the fetus (ICD-652) increased with increasing radiation dose in female patients. The percentages of offspring weighing less than 2,500 g at birth and of those having less than 37 weeks of gestation also increased with dose. There was no significant trend with radiation dose in the number of congenital anomalies recorded in offspring of female patients.

Conclusion

Women who receive flank radiation therapy as part of the treatment for unilateral WT are at increased risk of hypertension complicating pregnancy, fetal malposition, and premature labor. The offspring of these women are at risk for low birth weight and premature (ie, < 37 weeks gestation) birth. These risks must be considered in the obstetrical management of female survivors of WT.

Purpose

We assessed risk factors for end stage renal disease (ESRD) in Wilms Tumor (WT) patients without known WT1-related syndromes. We hypothesized that patients with characteristics suggestive of a WT1 etiology (early onset, stromal predominant histology, intralobar nephrogenic rests) would have a higher risk of ESRD due to chronic renal failure (CRF). We predicted a high risk of ESRD due to progressive bilateral WT (PBWT) in patients with metachronous bilateral disease.

Methods

ESRD was ascertained in 100 of 7,950 non-syndromic patients enrolled on a National Wilms Tumor Study during 1969-2002. Risk factors were evaluated with cumulative incidence curves and proportional hazard regressions.

Results

The cumulative incidence of ESRD due to CRF 20 years after WT diagnosis was 0.7%. For ESRD due to PBWT, it was 4.0% at 3 years post-WT diagnosis in patients with synchronous BWT and 19.3% in patients with metachronous BWT. For ESRD due to CRF, stromal predominant histology had a hazard ratio (HR) of 6.4 relative to mixed (95% CI [3.4 11.9], p <.001); intralobar rests had a HR of 5.9 relative to no rests (95% CI[2.0, 17.3], p = .001); and WT diagnosis <24 months had a HR of 1.7 relative to 24-48 months and 2.8 relative to >48 months (p=.003 for trend).

Conclusions

Metachronous BWT is associated with high rates of ESRD due to surgery for progressive WT. Characteristics associated with a WT1 etiology markedly increased the risk of ESRD due to CRF, despite a low risk in non-WT1 syndromic patients overall.

Wilms tumors (WT) have provided broad insights into the interface between development and tumorigenesis. Further understanding is confounded by their genetic, histologic, and clinical heterogeneity, the basis of which remains largely unknown. We evaluated 224 WT for global gene expression patterns; WT1, CTNNB1, and WTX mutation; and 11p15 copy number and methylation patterns. Five subsets were identified showing distinct differences in their pathologic and clinical features: these findings were validated in 100 additional WT. The gene expression pattern of each subset was compared with published gene expression profiles during normal renal development. A novel subset of epithelial WT in infants lacked WT1, CTNNB1, and WTX mutations and nephrogenic rests and displayed a gene expression pattern of the postinduction nephron, and none recurred. Three subsets were characterized by a low expression of WT1 and intralobar nephrogenic rests. These differed in their frequency of WT1 and CTNNB1 mutations, in their age, in their relapse rate, and in their expression similarities with the intermediate mesoderm versus the metanephric mesenchyme. The largest subset was characterized by biallelic methylation of the imprint control region 1, a gene expression profile of the metanephric mesenchyme, and both interlunar and perilobar nephrogenic rests. These data provide a biologic explanation for the clinical and pathologic heterogeneity seen within WT and enable the future development of subset-specific therapeutic strategies. Further, these data support a revision of the current model of WT ontogeny, which allows for an interplay between the type of initiating event and the developmental stage in which it occurs.

Objective

To evaluate the effect of hypothalamic/pituitary radiation dose on the occurrence of first pregnancy

Design

Retrospective cohort study of childhood cancer five-year survivors (CCS) diagnosed between 1970 and 1986 prior to 21 years of age at one of 26 North American pediatric cancer treatment centers

Setting

Self-administered questionnaire

Patient(s)

3619 female CCS who participated in the Childhood Cancer Survivor Study and received no/scatter (≤ 0.1 Gy) radiation to the ovaries and 2081 female siblings (Sibs) of the participants

Intervention(s)

None

Main Outcome Measure(s)

Self-reported pregnancy events

Result(s)

As a group CCS were as likely to report being pregnant as Sibs (Hazard Ratio (HR), 1.07; 95% Confidence Interval (95%CI), 0.97 to 1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses ≥ 22 Gy compared with those CCS receiving no HPT RT.

Conclusion(s)

These results support the hypothesis that exposures of 22 to 27 Gy HPT RT may be a contributing factor to infertility among female CCS.

Background

To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long-term childhood cancer survivor health, St. Jude Children’s Research Hospital (SJCRH) is establishing a lifetime cohort of survivors.

Methods

Eligibility criteria for inclusion in the St. Jude Lifetime Cohort (SJLIFE) study include: 1) diagnosis of childhood malignancy treated at SJCRH; 2) survival ≥ 10 years from diagnosis; and 3) current age ≥ 18 years. Three levels of participation are offered: 1) comprehensive evaluation on SJCRH campus; 2) limited home evaluation; or 3) completion of health surveys only. A systematic recruitment structure based upon blocks of 50 patients initially focused on leukemia and lymphoma survivors and patients eligible for pilot studies.

Results

As of 01/01/2010, 1625 (42%) of 3900 eligible ≥ 10 year survivors have been contacted. Among the first 1000 potentially eligible survivors selected for recruitment, 971 were subsequently confirmed to fulfill eligibility criteria. To date, 898/971 (92.5%) have been successfully contacted of whom 825 (91.8%) have agreed to participate. Among participants, 88.6% agreed to comprehensive medical evaluation, 0.4% limited local evaluation, and 11.0% survey only. Anticipated minimum overall participation rate for medical evaluation is 75.3% (731/971). Comparison of those contacted who agreed versus declined to participate revealed a greater proportion of males who declined participation (p = 0.001).

Conclusions

Early results of the SJLIFE study support its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments.

Purpose

Children's Oncology Group defines very low-risk Wilms tumors (VLRWT) as stage I favorable histology Wilms tumors weighing less than 550 g in children younger than 24 months of age. VLRWTs may be treated with nephrectomy alone. However, 10% to 15% of VLRWTs relapse without chemotherapy. Previous studies suggest that VLRWTs with low WT1 expression and/or 11p15 loss of heterozygosity (LOH) may have increased risk of relapse. The current study validates these findings within prospectively identified children with VLRWT who did not receive adjuvant chemotherapy.

Patients and Methods

Fifty-six VLRWTs (10 relapses) were analyzed for mutation of WT1, CTNNB1, and WTX; for 11p15 LOH using microsatellite analysis; and for H19DMR and KvDMR1 methylation.

Results

11p15 LOH was identified in 19 (41%) of 46 evaluable VLRWTs and was significantly associated with relapse (P < .001); 16 of 19 were isodisomic for 11p15. WT1 mutation was identified in nine (20%) of 45 evaluable VLRWTs and was significantly associated with relapse (P = .004); all nine cases also had 11p15 LOH. All evaluable tumors showing LOH by microsatellite analysis also showed LOH by methylation analysis. Retention of the normal imprinting pattern was identified in 24 of 42 evaluable tumors, and none relapsed. Loss of imprinting at 11p15 was identified in one of 42 tumors.

Conclusion

WT1 mutation and 11p15 LOH are associated with relapse in patients with VLRWTs who do not receive chemotherapy. These may provide meaningful biomarkers to stratify patients for reduced chemotherapy in the future. VLRWTs show a different incidence of WT1 mutation and 11p15 imprinting patterns than has been reported in Wilms tumors of all ages.

Objectives To assess the incidence of and risks for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities among adult survivors of childhood and adolescent cancers.

Design Retrospective cohort study.

Setting 26 institutions that participated in the Childhood Cancer Survivor Study.

Participants 14 358 five year survivors of cancer diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. Comparison group included 3899 siblings of cancer survivors.

Main outcome measures Participants or their parents (in participants aged less than 18 years) completed a questionnaire collecting information on demographic characteristics, height, weight, health habits, medical conditions, and surgical procedures occurring since diagnosis. The main outcome measures were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings.

Results Survivors of cancer were significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001), myocardial infarction (HR 5.0, 95% CI 2.3 to 10.4; P<0.001), pericardial disease (HR 6.3, 95% CI 3.3 to 11.9; P<0.001), or valvular abnormalities (HR 4.8, 95% CI 3.0 to 7.6; P<0.001). Exposure to 250 mg/m2 or more of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1500 centigray or more increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold compared to non-irradiated survivors. The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis.

Conclusion Survivors of childhood and adolescent cancer are at substantial risk for cardiovascular disease. Healthcare professionals must be aware of these risks when caring for this growing population.

A combined cohort of 8,884 North American, 2,893 British and 1,574 Nordic subjects with Wilms tumor (WT) diagnosed before 15 years of age during 1960–2004 was established to determine the risk of secondary malignant neoplasms (SMN). After 169,641 person-years (PY) of observation through 2005, 174 solid tumors (exclusive of basal cell carcinomas) and 28 leukemias were ascertained in 195 subjects. Median survival time following a solid SMN diagnosis 5 years or more from WT was 11 years; it was 10 months for all leukemia. Age-specific incidence of secondary solid tumors increased from approximately 1 case per 1,000 PY at age 15 to 5 cases per 1,000 PY at age 40. The cumulative incidence of solid tumors at age 40 for subjects who survived free of SMNs to age 15 was 6.7%. Leukemia risk, by contrast, was highest during the first 5 years following WT diagnosis. Standardized incidence ratios (SIRs) for solid tumors and leukemias were 5.1 and 5.0, respectively. Results for solid tumors for the 3 geographic areas were remarkably consistent; statistical tests for differences in incidence rates and SIRs were all negative. Age-specific incidence rates and SIRs for solid tumors were lower for patients whose WT was diagnosed after 1980, though the trends with decade of diagnosis were not statistically significant. Incidence rates and SIRs for leukemia were highest among those diagnosed after 1990 (p-trend =0.003). These trends may reflect the decreasing use of radiation therapy and increasing intensity of chemotherapy in modern protocols for treatment of WT.

Objective

GH and IGFs have mitogenic properties, causing speculation that GH treatment could increase risk of malignancy. While studies in GH-treated childhood cancer survivors have suggested a slight increase in second neoplasms, studies in GH-treated adults have been equivocal.

Design

Incidence of de novo and second cancers was evaluated in 6840 GH-treated and 940 non GH-treated adult patients in the Hypopituitary Control and Complications Study pharmacoepidemiological database.

Methods

Evident cancer cases were evaluated in the main analysis, with sensitivity analyses including probable and possible cancers. Standardized incidence ratios (SIRs) for cancers were calculated using Surveillance, Epidemiology and End Results for the USA and GLOBOCAN for all other countries.

Results

During the mean follow-up of 3.7 years/GH-treated patient, 142 evident cancer cases were identified, giving an overall SIR of 0.88 (95% confidence interval (CI) 0.74–1.04); 95% CIs included the value of 1.0 for each country examined. The SIR for GH-treated patients from the USA (71 cases) was 0.94 (95% CI 0.73–1.18), and for non GH-treated patients from the USA (27 cases) was 1.16 (95% CI 0.76–1.69). For GH-treated patients from the USA aged <35 years, the SIR (six cases) was 3.79 (1.39–8.26), with SIR not elevated for all other age categories; SIR for patients from the USA with childhood onset (CO) GH deficiency (GHD) was 2.74 (95% CI 1.18–5.41). The SIR for colorectal cancer in GH-treated patients (11 cases) was 0.60 (95% CI 0.30–1.08).

Conclusions

With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs were found for subgroups in the USA cohort defined by age <35 years or CO GHD.

Purpose

There are no published reports on the optimal management and survival rates of children with Wilms tumor (WT) and peritoneal implants (PI).

Methods and Materials

Among FH WT patients enrolled in the NWTS-4 and 5, 57 children had PI at the time of nephrectomy. The median age was 3 years and 5 months (range, 3 months – 14 years). The majority of children (42/57, 74%) had stage III tumors; 15 had stage IV disease. All patients received multimodality therapy. Forty-eight of 56 of children (84%) who underwent primary surgery had gross total resection of all tumors. All patients received 3-drug chemotherapy with vincristine, actinomycin-D and doxorubicin. Forty-seven patients (82%) received WART and in 50 patients (88%) the RT dose was 10.5 Gy.

Results

After a median follow-up of 7.5 years, the overall abdominal and systemic tumor control rates were 97% and 93% respectively. A comparative analysis between children with and without PI revealed no significant differences in the clinical characteristics between the two groups. The 5-year EFS with and without PI were 90% (95% CI 78%, 96%) and 83% (95% CI 81%, 85%) respectively (p = 0.20).

Conclusions

Multimodality therapy with surgery, WA RT and 3-drug chemotherapy delivered according to the NWTS-4 and -5 protocols resulted in excellent abdominal and systemic tumor control rates. All children should be monitored in long-term surveillance programs for the early detection and management of therapy-related toxicities.

Purpose

This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with WT.

Methods

Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated on NWTS 1-4. A nested case-control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors.

Results

Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors (p=0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17, 94%) received right flank RT either alone or as part of whole abdomen RT and received > 15Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would in modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin (p=0.32) and 2.8 for females (p=0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose >15 Gy vs. ≤15 Gy was 2.5 (p=0.001); it was 2.4 for a maximum liver dose >15 Gy vs. ≤15 Gy (p=0.001).

Conclusions

There was a strong association between higher doses of liver RT (>15 Gy) and the development of PHTN among WT patients.

Purpose

This study was undertaken to determine the effect of treatment for childhood cancer on male fertility.

Patients and Methods

We reviewed the fertility of male Childhood Cancer Survivor Study survivor and sibling cohorts who completed a questionnaire. We abstracted the chemotherapeutic agents administered, the cumulative dose of drug administered for selected drugs, and the doses and volumes of all radiation therapy from medical records. Risk factors for siring a pregnancy were evaluated using Cox proportional hazards models.

Results

The 6,224 survivors age 15 to 44 years who were not surgically sterile were less likely to sire a pregnancy than siblings (hazard ratio [HR], 0.56; 95% CI, −0.49 to 0.63). Among survivors, the HR of siring a pregnancy was decreased by radiation therapy of more than 7.5 Gy to the testes (HR, 0.12; 95% CI, −0.02 to 0.64), higher cumulative alkylating agent dose (AAD) score or treatment with cyclophosphamide (third tertile HR, 0.42; 95% CI, −0.31 to 0.57) or procarbazine (second tertile HR, 0.48; 95% CI, −0.26 to 0.87; third tertile HR, 0.17; 95% CI, −0.07 to 0.41). Compared with siblings, the HR for ever siring a pregnancy for survivors who had an AAD score = 0, a hypothalamic/pituitary radiation dose = 0 Gy, and a testes radiation dose = 0 Gy was 0.91 (95% CI, 0.73 to 1.14; P = .41).

Conclusion

This large study identified risk factors for decreased fertility that may be used for counseling male cancer patients.

Purpose

We undertook this study to determine 1) the frequency with which spilled tumor cells of favorable histology produced intra-abdominal disease in patients treated with differing chemotherapy regimens and abdominal radiation therapy (RT) and 2) the patterns of relapse and outcomes in such patients.

Materials and Methods

The influence of RT dose (0, 10 and 20 Gy), RT fields (flank, Whole abdomen) and chemotherapy with dactinomycin and vincristine (2 drugs) vs. added DOX (3 drugs) on intra-abdominal tumor recurrence rates was analyzed by logistic regression in 450 patients. Each patient was considered at risk for two types of failure: flank and sub-diaphragmatic beyond-flank recurrence, with the correlation between the two outcomes accounted for in the analyses.

Results

The crude odds ratio for the risk of recurrence relative to no RT was 0.35 (0.15–0.78) for 10Gy and 0.08 (0.01–0.58) for 20Gy. The odds ratio for the risk of recurrence for DOX relative to 2 drugs after adjusting for RT was not significant. For stage II patients (NWTS-4), the 8 yr. event rates with and without spillage respectively were 79% and 87% for relapse-free survival (p=0.07), and 90% and 95% for overall survival (p=0.04).

Conclusions

Irradiation (10 Gy or 20 Gy) reduced abdominal tumor recurrence rates following tumor spillage. Tumor spillage in stage II patients reduced relapse-free survival and overall survival, but only the latter was of statistical significance. These data provide a basis for assessing the risks versus benefits when considering treatment for children with favorable histology Wilms tumor and surgical spillage.

Summary

Background

The reproductive implications of mutagenic treatments given to children with cancer are not clear. By studying the risk of untoward pregnancy outcomes, we indirectly assessed the risk of transmission of germline damage to the offspring of survivors of childhood cancer who were given radiotherapy and chemotherapy.

Methods

We did a retrospective cohort analysis, within the Childhood Cancer Survivor Study (CCSS), of the risk of stillbirth and neonatal death among the offspring of men and women who had survived childhood cancer. Patients in CCSS were younger than 21 years at initial diagnosis of an eligible cancer, were treated at 25 US institutions and one Canadian institution, and had survived for at least 5 years after diagnosis. We quantified the chemotherapy given to patients, and the preconception radiation doses to the testes, ovaries, uterus, and pituitary gland, and related these to the risk of stillbirth or neonatal death using Poisson regression analysis.

Findings

Among 1148 men and 1657 women who had survived childhood cancer, there were 4946 pregnancies. Irradiation of the testes (16 [1%] of 1270; adjusted relative risk 0·8 [95% CI 0·4–1·6]; mean dose 0·53 Gy [SD 1·40]) and pituitary gland (17 [3%] of 510, 1·1 [0·5–2·4] for more than 20·00 Gy; mean dose 10·20 Gy [13·0] for women), and chemotherapy with alkylating drugs (26 [2%] of 1195 women, 0·9 [0·5–1·5]; ten [1%] of 732 men, 1·2 [0·5–2·5]) were not associated with an increased risk of stillbirth or neonatal death. Uterine and ovarian irradiation significantly increased risk of stillbirth and neonatal death at doses greater than 10·00 Gy (five [18%] of 28, 9·1 [3·4–24·6]). For girls treated before menarche, irradiation of the uterus and ovaries at doses as low as 1·00–2·49 Gy significantly increased the risk of stillbirth or neonatal death (three [4%] of 69, 4·7 [1·2–19·0]).

Interpretation

Our findings do not support concern about heritable genetic changes affecting the risk of stillbirth and neonatal death in the offspring of men exposed to gonadal irradiation. However, uterine and ovarian irradiation had serious adverse effects on the offspring that were probably related to uterine damage. Careful management is warranted of pregnancies in women given high doses of pelvic irradiation before puberty.

Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and the cause of cervical cancer, the second most common cancer among women worldwide. HPV vaccine uptake is particularly important for females surviving cancer, some of whom are at high risk for HPV complications due to the direct and indirect effects of cancer treatment. Thus, Version 3.0 of the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancer recommends HPV vaccination for all eligible females surviving childhood cancer. Because this vaccine was only FDA approved in 2006, little is known about the complexity of vaccination uptake among those surviving cancer. The purpose of this article is to describe the HPV vaccine and its usefulness in the survivorship population, provide a rationale for describing cancer survivors as being at increased risk for HPV complications, identify factors which associate with HPV vaccination, and discuss the utilization of these predictors in designing strategies to promote adherence to HPV vaccination recommendations within the survivorship context.

Purpose

Recent studies suggest that children <24 months with stage 1 favorable histology Wilms tumors <550g (Very Low Risk Wilms Tumors, VLRWT) have an excellent prognosis when treated with nephrectomy only, without adjuvant chemotherapy. The identification of risk categories within VLRWT may enable refinement of their definition and optimization of their therapy.

Experimental Design

To define biologically distinct subsets, global gene expression analysis was performed on 39 VLRWT that passed all quality control parameters and the clusters identified were validated on in independent set of 11 VLRWT. Validation of select differentially expressed genes was performed with immunohistochemistry on a tissue microarray from 20/39 tumors. Loss of heterozygosity for 11p15, 1p, and 16q was analyzed in 52 tumors using polymerase chain reaction.

Results

Two distinctive clusters were identified. One cluster included nine tumors with epithelial tubular differentiated histology, paucity of nephrogenic rests, lack of LOH for 1p, 16q and 11p, absence of relapse, and a unique gene expression profile consistent with arrest following mesenchymal-to-epithelial transition. The second cluster included 13 tumors with mixed histology, intralobar nephrogenic rests, and decreased expression of WT1. Three of six relapses occurred in this cluster. Of 43 informative tumors, 11p LOH was present in 5/5 relapses and in 11/38 non-relapses.

Conclusions

Two subsets comprising a total of 56% of VLRWT are identified that have pathogenetic and molecular differences and apparent differences in risk for relapse. If these predictors can be prospectively validated, this would enable the refinement of clinical stratification and less arbitrary definition of VLRWT.

Purpose

This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility.

Patients and Methods

We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy.

Results

There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P < .001) compared with female siblings. In multivariate models among survivors only, those who received a hypothalamic/pituitary radiation dose ≥ 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant.

Conclusion

This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.

Survival for childhood cancer has increased dramatically over the last 40 years with 5-year survival rates now approaching 80%. For many diagnostic groups, rapid increases in survival began in the 1970s with the broader introduction of multimodality approaches, often including combination chemotherapy with or without radiation therapy. With this increase in rates of survivorship has come the recognition that survivors are at risk for adverse health and quality-of-life outcomes, with risk being influenced by host-, disease-, and treatment-related factors. In 1994, the US National Cancer Institute funded the Childhood Cancer Survivor Study, a multi-institutional research initiative designed to establish a large and extensively characterized cohort of more than 14,000 5-year survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. This ongoing study, which reflects the single most comprehensive body of information ever assembled on childhood and adolescent cancer survivors, provides a dynamic framework and resource to investigate current and future questions about childhood cancer survivors.

These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.