Melissa M. Hudson

Long-Term Outcomes Among Adult Survivors of Childhood Central Nervous System Malignancies in the Childhood Cancer Survivor Study

BACKGROUND Adult survivors of childhood central nervous system (CNS) malignancies are at high risk for long-term morbidity and late mortality. However, patterns of late mortality, the long-term risks of subsequent neoplasms and debilitating medical conditions, and sociodemographic outcomes have not been comprehensively characterized for individual diagnostic and treatment groups. METHODS We collected information on treatment, mortality, chronic medical conditions, and neurocognitive functioning of adult 5-year survivors of CNS malignancies diagnosed between 1970 and 1986 within the Childhood Cancer Survivor Study. Using competing risk framework, we calculated cumulative mortality according to cause of death and cumulative incidence of subsequent neoplasms according to exposure and dose of cranial radiation therapy (RT). Neurocognitive impairment and socioeconomic outcomes were assessed with respect to dose of CNS radiotherapy to specific brain regions. Cumulative incidence of chronic medical conditions was compared between survivors and siblings using Cox regression models. All tests of statistical significance were two-sided. RESULTS Among all eligible 5-year survivors (n = 2821), cumulative late mortality at 30 years was 25.8% (95% confidence interval [CI] = 23.4% to 28.3%), due primarily to recurrence and/or progression of primary disease. Patients who received cranial RT of 50 Gy or more (n = 813) had a cumulative incidence of a subsequent neoplasm within the CNS of 7.1% (95% CI = 4.5% to 9.6%) at 25 years from diagnosis compared with 1.0% (95% CI = 0% to 2.3%) for patients who had no RT. Survivors had higher risk than siblings of developing new endocrine, neurological, or sensory complications 5 or more years after diagnosis. Neurocognitive impairment was high and proportional to radiation dose for specific tumor types. There was a dose-dependent association between RT to the frontal and/or temporal lobes and lower rates of employment, and marriage. CONCLUSIONS Survivors of childhood CNS malignancies are at high risk for late mortality and for developing subsequent neoplasms and chronic medical conditions. Care providers should be informed of these risks so they can provide risk-directed care and develop screening guidelines.

Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital.

PURPOSE To evaluate the incidence of and potential risk factors for second malignant neoplasms of the brain following treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS The study population consisted of 1,612 consecutively enrolled protocol patients treated on sequential institutional protocols for newly diagnosed ALL at St Jude Childrens Research Hospital (SJCRH) between 1967 and 1988. The median follow-up duration is 15.9 years (range, 5.5 to 29.9 y). RESULTS The cumulative incidence of brain tumors at 20 years is 1.39% (95% confidence interval [CI], 0.63% to 2.15%). Twenty-two brain tumors (10 high-grade gliomas, one low-grade glioma, and 11 meningiomas) were diagnosed among 21 patients after a median latency of 12.6 years (high-grade gliomas, 9.1 years; meningiomas, 19 years). Tumor type was linked to outcome, with patients who developed high-grade tumors doing poorly and those who developed low-grade tumors doing well. Risk factors for developing any secondary brain tumor included the presence of CNS leukemia at diagnosis, treatment on Total X therapy, and the use of cranial irradiation, which was dose-dependent. Age less than 6 years was associated with an increased risk of developing a high-grade glioma. CONCLUSION This single-institution study, with a high rate of long-term data capture, demonstrated that brain tumors are a rare, late complication of therapy for ALL. We report many more low-grade tumors than others probably because of exhaustive long-term follow-up evaluation. The importance of limiting cranial radiation is underscored by the dose-dependent tumorigenic effect of radiation therapy seen in this study.

Stroke As a Late Treatment Effect of Hodgkin's Disease: A Report From the Childhood Cancer Survivor Study

PURPOSE The objectives of this report are to examine the incidence of and risk factors for stroke among childhood Hodgkins disease (HD) survivors. PATIENTS AND METHODS The Childhood Cancer Survivor Study is a multi-institutional cohort study of more than 5-year cancer survivors diagnosed between 1970 and 1986 and a sibling comparison group. Incidence rates of stroke among HD survivors (n = 1,926) and siblings (n = 3,846) were calculated and compared. Cox proportional hazards models were used to estimate the hazard ratios, reported as relative risks (RR), of developing stroke between HD survivors and siblings. RESULTS Nine siblings reported a stroke, for an incidence of 8.00 per 100,000 person-years (95% CI, 3.85 to 14.43 per 100,000 person-years). Twenty-four HD survivors reported a stroke. The incidence of late-occurring stroke among HD survivors was 83.6 per 100,000 person-years (95% CI, 54.5 to 121.7 per 100,000 person-years). The RR of stroke among HD survivors was 4.32 (95% CI, 2.01 to 9.29; P = .0002). All 24 survivors received mantle radiation exposure (median dose, 40 Gy). The incidence of late-occurring stroke among HD survivors treated with mantle radiation was 109.8 per 100,000 person-years (95% CI, 70.8 to 161.1 per 100,000 person-years). The RR of late-occurring stroke among HD survivors treated with mantle radiation was 5.62 (95% CI, 2.59 to 12.25; P < .0001). CONCLUSION Survivors of childhood HD are at increased risk of stroke. Mantle radiation exposure is strongly associated with subsequent stroke. Potential mechanisms may include carotid artery disease or cardiac valvular disease.

Efficacy and toxicity of multiagent chemotherapy and low-dose involved-field radiotherapy in children and adolescents with Hodgkin's disease.

PURPOSE Between May 1980 and September 1990, 85 patients with Hodgkins disease were treated with a regimen designed to increase cure rates while reducing late toxicity. PATIENTS AND METHODS Therapy consisted of five cycles of cyclophosphamide, Oncovin (vincristine; Eli Lilly and Co, Indianapolis, IN), and procarbazine (COP), alternated with four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and low-dose (20 Gy) regional radiotherapy. Vincristine and cyclophosphamide were administered as tolerated during irradiation and during the 2- to 4-week rest period between radiation volumes. The need for staging laparotomy was defined by clinical presentation. RESULTS The median age at diagnosis was 14 years (range, 4 to 20), and 56% of patients were male. The majority (67%) had stage III or IV disease and 68% (19 of 28) of stage II patients had bulky mediastinal disease. Nodular sclerosing histology predominated (67%). Ninety-three percent of patients were alive without disease with a median follow-up of 4.1 years. Abnormalities were detected on chest roentgenograms and/or pulmonary function tests in 58% and 25% of clinically asymptomatic patients who were tested at least 1 year after completion of therapy. The only symptomatic patient had pulmonary fibrosis after treatment with bleomycin (20 U/m2) and mantle (20 Gy)/lung (13 Gy) irradiation, and developed multiple spontaneous pneumothoraces that required cortical stripping. One patient had congestive heart failure 19 months post-treatment, and two had abnormalities on echocardiograms. Thyroid abnormalities occurred in 21 (27%) patients who were assessable for late toxicity. The majority of female patients have had regular menstrual cycles. Six developed ovarian failure, and 10 have had a total of 17 pregnancies. Other than one documented case of oligospermia, information was not available on male fertility. CONCLUSION The results demonstrate excellent disease control for the COP/ABVD regimen, with acceptable toxicity.

Noninvasive evaluation of late anthracycline cardiac toxicity in childhood cancer survivors.

UNLABELLED PURPOSEl: Childhood cancer survivors treated with anthracyclines and cardiac radiation are at risk for late-onset cardiotoxicity. The purpose of this study was to delineate the relationship between clinical factors and abnormalities of noninvasive cardiac testing (NICT). PATIENTS AND METHODS Participants were recruited from a long-term follow-up clinic. Study measures comprised physical examination, laboratory evaluation, echocardiogram, and ECG. Mean fractional shortening (FS) and afterload were compared for survivors who did (at risk [AR]) and did not (no risk [NR]) receive potentially cardiotoxic modalities, and with values expected for comparable age- and sex-matched controls. RESULTS The 278 study participants (mean age, 18.1 years; median age, 16.8 years; range, 7.5 to 39.7 years) included 223 survivors AR for cardiotoxicity after treatment with anthracyclines (median dose +/- standard deviation [SD], 202 +/- 109 mg/m(2)) and/or cardiac radiation. Mean FS (+/- SD) was lower for AR (0.33 +/- 0.06) compared with NR survivors (0.36 +/- 0.05; P = .004) and normative controls (0.36 +/- 0.04; P < .001). Mean afterload (+/- SD) was higher for AR (58 +/- 21 g/cm(2)) compared with NR survivors (46 +/- 15 g/cm(2); P < .001) and normative controls (48 +/- 13 g/cm(2); P < .001). The distribution of FS and afterload among NR survivors did not differ from that of controls. After adjustment for age group at diagnosis and time since completion of therapy, anthracycline dose predicted decline in distribution of FS (P < .001) and increase in distribution of afterload (P < .001). Treatment with anthracycline doses >or= 100 mg/m(2) increased the risk of abnormal NICT; survivors who received >or= 270 mg/m(2) had a 4.5-fold excess risk of abnormal NICT (95% CI, 2.1 to 9.6) compared with controls. CONCLUSION Childhood cancer survivors treated with anthracycline doses >or= 270 mg/m(2) are at greatest risk for abnormalities of FS and afterload.

Increased mortality after successful treatment for Hodgkin's disease.

PURPOSE To determine the impact of treatment toxicity on long-term survival in pediatric Hodgkins disease. PATIENTS AND METHODS We studied late events in 387 patients treated for pediatric Hodgkins disease on four consecutive clinical trials at St Jude Childrens Research Hospital from 1968 to 1990. Relative risks, actuarial risks, and absolute excess risks for cause-specific deaths were calculated. RESULTS As of April 1997, 316 (82%) of patients were alive, with a median follow-up of 15.1 (range, 2.9 to 28.6) years. In this cohort, which represented 5,623 person-years of follow-up, 71 fatal events resulted from Hodgkins disease (n=36), second malignancies (n=14), infections (n=7), accidents (n=7), cardiac disease (n=6), and asphyxiation (n=1). The 5-year estimated event-free survival (EFS) for the entire cohort was 79.6%+/-2.1 %, which declined to 63.1%+/-4.4% by 20 years. Cumulative incidences of cause-specific deaths at 25 years were 9.8%+/-1.6% for Hodgkins disease, 8.1%+/-2.6% for second malignancy, 4.0%+/-1.8% for cardiac disease, 3.9%+/-1.5% for infection, and 2.1%+/-0.8% for accidents. Standardized incidence ratios showed excess risk for all second malignancies (12; 95% confidence interval [CI], 8 to 17), acute myeloid leukemia (81; 95% CI, 16 to 237), solid tumors (11; 95% CI, 7 to 16), and breast cancer (33; 95% CI, 12 to 72). Standardized mortality ratios also showed excess mortality from cardiac disease (22; 95% CI, 8 to 48) and infection (18; 95% CI, 7 to 38). CONCLUSION Compared with age- and sex-matched control populations, survivors of pediatric Hodgkins disease who were treated before 1990 face an increased risk of early mortality related to second cancers, cardiac disease, and infection.

The Cancer Screening Practices of Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study

The current study characterized the self‐reported cancer screening practices of adult survivors of childhood cancer.

Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group.

Pediatric oncologists are curing increasing numbers of patients with childhood cancer, and most children diagnosed with a malignancy may now be expected to become long-term survivors. As the number of childhood cancer survivors grows, so too does the need for evidence-based surveillance of the long-term effects of cancer therapy. Long-term effects involving the endocrine system represent a frequent complication of therapy. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers(COG LTFUG), most recently updated in 2006, provide a summary of the known endocrine late effects of surgery, radiation, chemotherapy, and stem cell transplant. This paper summarizes the scope and nature of the endocrine late effects of childhood cancer therapy based upon a review of the pertinent medical literature, and demonstrates how pediatric oncologists can use these guidelines in clinical practice.

The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study

Estimation of the risk of adverse long‐term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.

Phase I study of escalating targeted doses of carboplatin combined with ifosfamide and etoposide in children with relapsed solid tumors.

PURPOSE The tolerance of escalating targeted doses of carboplatin combined with ifosfamide (IFOS)/etoposide (VP-16) (ICE) was assessed in children with recurrent solid tumors. PATIENTS AND METHODS To reduce interpatient variability in carboplatin systemic exposure, 45 children were treated with doses individualized to a target area under the serum concentration versus time curve (AUC) based on renal function, using technetium 99-diethyl-enetriamine pentaacetic acid (99mTc-DTPA) clearance to estimate glomerular filtration rate (GFR). Cohorts of at least three patients received carboplatin at an initial target AUC of 2 mg/mL x min, with escalations of 1 mg/mL x min in subsequent cohorts. Courses consisted of carboplatin on day 1 followed by IFOS 2 g/m2 plus VP-16 100 mg/m2 on days 2 and 3. Patients received at least two courses, with a maximum of eight courses possible in the absence of progressive disease. When only moderate toxicity occurred after escalation to 5 mg/mL x min, a third dose of IFOS plus VP-16 was added. After three patients were treated at this level, carboplatin escalation proceeded. RESULTS Neutropenia and thrombocytopenia were the dominant toxicities in the 43 assessable patients. At the target AUC of 8 mg/mL x min, 13 of 20 cycles were associated with febrile neutropenia. For phase II trials, we recommend a carboplatin target AUC of 6 mg/mL x min with three doses of IFOS and VP-16 for patients with prior craniospinal irradiation or high-dose cisplatin (CDDP)/VP-16, or 7 mg/mL x min for patients without such histories. There were two complete responses (CRs), 13 partial responses (PRs), and 17 objective responses (ORs). CONCLUSION The ICE regimen shows promising activity in pediatric solid tumors. The clear relationship between hematologic toxicity and carboplatin systemic exposure supports the use of targeted dosing in further trials of ICE chemotherapy.