bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of eltrombopag (epag) versus placebo (pbo) for the treatment (tx) of chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumors receiving gemcitabine (gem)-based chemotherapy (ctx): A phase I study.
Authors: Winer Eric S. , Safran Howard , Karaszewska Boguslawa , Richards Donald A. , Hartner Lee , Forget Frederic , Ramlau Rodryg , Kumar Kirushna , Mayer Bhabita , Johnson Brendan Mark , Messam Conrad A. , Mostafa Kamel Yasser Mostafa
Published: March 2020

9117

Background: There are limited tx options for CIT. Epag, an oral, small molecule, thrombopoietin-receptor agonist that increases platelet (plt) production, is being explored for tx of CIT. Methods: This was the Ph I portion of a Ph I/II, blinded, pbo-controlled multicenter study in adults with solid tumors and baseline plts ≤300,000µL, who received up to 6 cycles of gem (1000-1250 mg/m2 IV) as monotherapy on Days 1, 8, and 15 Q28 days or Days 1 and 8 Q21 days in combination with cisplatin (50-80 mg/m2 IV Day 1 or divided 1 and 8) or carboplatin (AUC 4-7 IV Day 1). Patients received ctx alone for Cycle 1 and ctx plus epag or matching pbo (randomized 3:1) daily on Days -5 to -1 and 2 to 6 for subsequent cycles. Epag or pbo was interrupted for plts ≥400,000/µL. Results: 33 patients were randomized; 26 received epag or pbo (Table). Data review with an external, independent physician found no safety concerns, and there were sufficient plt increases with a dose of 100 mg epag vs pbo. No dose-limiting toxicities were reported for epag but 1 for pbo. Most AEs were grade 1 or 2. The most common AE in combined epag- and combined pbo-treated groups was neutropenia. Conclusions: Epag was well-tolerated and improved plt counts. Based on these encouraging Ph I results, Ph II using 100 mg epag in thrombocytopenic patients is planned. [Table: see text]
A national survey of support and information needs of Australian women living with advanced breast cancer.
Authors: Mileshkin Linda R. , Sheeran Lisa , Robins-Browne Kate , Marven Michelle , Gough Karla , Aranda Sanchia
Published: March 2020

9124

Background: Improved treatments mean women with advanced breast cancer (ABC) are living longer, sometimes for many years. As a result, these women may experience chronic needs that are different from those with early breast cancer. We aimed to assess the support and information needs of women living with ABC. Methods: A national postal survey was sent to 2,345 women with ABC registered as members of the consumer organizations BCNA and/or BreaCan. Women were asked about their disease, treatment, experiences of care, and to complete the Supportive Care Needs Survey. Results: The response rate was 34% (792 valid responses). Mean age was 57 (range 25-99) with 21% living alone and 27% working. 18% reported living with ABC for >7 years. 656 (85%) were having current treatment: chemotherapy (43%), hormonal therapy (46%), bisphosphonates (49%), and/or trastuzumab (Herceptin) (19%) respectively. 49% of women reported having access to a Breast Care Nurse (BCN) since diagnosis of ABC but only 3% cited a BCN or cancer nurse as their main contact. The majority (76%) cited their medical oncologist as their main contact, 8% cited their family doctor. Women wanted information about: treatment options (84.2%), new treatments (79.2%), symptoms/side effects (78.9%), clinical trials (60.8%), managing pain (57.2%) and financial assistance (38%). Women ≤ 65 had significantly higher levels of unmet needs than those >65 for the 7 items below, including all items from the sexual domain. Conclusions: Women with ABC have many unmet needs with younger women particularly needing more support with sexual needs and anxiety. Women are heavily reliant on their medical oncologist, who may not be equipped or best placed to meet these needs. Models of care need to be developed to address the unmet supportive care needs of women living with ABC. [Table: see text]
YOCAS yoga, fatigue, memory difficulty, and quality of life: Results from a URCC CCOP randomized, controlled clinical trial among 358 cancer survivors.
Authors: Janelsins Michelle Christine , Peppone Luke Joseph , Heckler Charles E , Sprod Lisa , Mohile Supriya Gupta , Chandwani Kavita Dayal , Kirshner Jeffrey J. , Reddy Pavan S. , Morrow Gary R. , Mustian Karen Michelle
Published: March 2020

9142

Background: Memory difficulty is a serious problem for many cancer survivors and can negatively affect quality of life (QOL). Little evidence exists on the effects of physical activity (PA) interventions, such as yoga, on memory in cancer survivors. We previously reported in a nationwide, Phase III RCT that YOCAS Yoga, implemented over 4 weeks (2 x/wk; 75 min/session), significantly improved fatigue and QOL in cancer survivors. The purpose of this study was to assess the effects of YOCAS on memory and to identify moderating and possible mediating effects of memory in YOCAS improvements of fatigue and QOL. Methods: Cancer survivors between 2-24 months post adjuvant therapy with no participation in yoga during the previous 3 months were randomized to standard care (SC) or SC with YOCAS. YOCAS consists of breathing exercises, gentle Hatha and Restorative yoga postures and meditation. This secondary analysis included participants (N=358, mean age = 54, 96% female, 75% breast cancer) who provided pre- and post-intervention data on Difficulty Remembering Things (modified MD Anderson Symptom Inventory with 0 = “Did not Interfere” to 10 = “Interfered Completely”), fatigue and QOL (FACIT-F). ANCOVA was used to assess the effects of YOCAS on memory at post-intervention incorporating baseline memory score. Path Modeling was conducted to assess the moderating and mediating effects of memory on YOCAS changes in fatigue and QOL. Results: ANCOVA revealed a significant group effect of YOCAS on memory at post intervention (mean change: Yoga - Control = -0.44; Cohen’s D= -0.24; p <0.05). Moderation analyses revealed that baseline memory difficulty did not affect how much YOCAS would improve fatigue (p>0.05) or QOL (p>0.05). Mediation analyses identified changes in memory as a significant partial mediator for improved fatigue (p<0.05) and improved QOL (p<0.05). Conclusions: YOCAS yoga significantly reduces perceived memory difficulty in cancer survivors. Improvements in memory due to YOCAS may be a possible mediator for improving fatigue and QOL. More elaborate PA RCTs are needed to confirm these results. Funding: NCIR25CA10618, K07CA120025, and U10CA37420.
Changes in the use of eythropoetin-stimulating agents (ESAs) in cancer patients: Before and after FDA safety advisories.
Authors: Stafkey-Mailey Dana , Dickson Mike , Norris LeAnn B. , Bennett Charles L.
Published: March 2020

9143

Background: Benefits of ESAs in the treatment of cancer-induced anemia have been well documented, most importantly reducing the likelihood of patients needing red blood cell transfusions. However, in early 2007, the FDA issued a series of cautions and Black Box Warning (BBW), that ESAs may enhance tumor progression, increase likelihood of a VTE and decrease patient survival. The objective of this study is to elucidate population patterns and trends in ESA use for cancer patients pre- and post- the BBW and examine their associated outcomes. Methods: Data for this analysis was derived from South Carolina Medicaid claims. Patients with a diagnosis of Lung Cancer (162.x), Breast Cancer (174.x) or Non-Hodgkin's Lymphoma (200.x or 202.x) receiving chemotherapy between January 1, 1994 and December 31, 2010 were eligible for inclusion. The main outcome measures were ESA utilization, blood transfusion, and venous thromboembolism. The percentage of patients experiencing these outcomes were plotted over time to allow for visual examination of changes due to the BBW. In addition, we used multivariable logistic regression models to analyze each of the associated outcomes with clinical and demographic variables. Results: Among the 9,280 patients with one of the study cancers, an average of 25.4% received an ESA. The proportion of patients receiving an ESA increased from 6.2% in 1994 to a high of 47.1% in 2005 at which time utilization began to decline. In 2010, only 7.8% of these patients received an ESA. Use was associated with older age, female sex, and receipt of radiation therapy. The rate of blood transfusion varied sporadically throughout the study period from 5.2% (2008) to 11.7% (1994) (p<0.0001). Venous thromboembolisms developed in 12.3% and 8.5% of patients receiving and not receiving an ESA, respectively (OR= 1.31;p<0.001). Conclusions: As the FDA advisory cautioned, we find an increased risk of venous thromboembolisms associated with ESA use. In contrast to our a priori beliefs initial decline in utilization of ESAs began, in 2005, prior to the BBW and was likely due to changes in reimbursement rates. However, the BBW resulted in the largest decline in ESA use, 19.1 percentage points, between 2007 and 2008.
Efficacy of rituximab plus FAB group C chemotherapy without CNS radiation in CNS-positive pediatric Burkitt lymphoma/leukemia: A report from the Children’s Oncology Group.
Authors: Frazer J. Kimble , Goldman Stanton , Smith Lynette , Harrison Lauren , Perkins Sherrie L , Cairo Mitchell S.
Published: March 2020

9501

Background: Historically, CNS-positive (CNS+) mature B-NHL in children and adolescents has been associated with a dismal outcome (Miles/Cairo, Br J Haematol, 2012). Adding CNS radiation and high-dose MTX and cytarabine to group C therapy for children with CNS+ B-NHL yielded a 77% 5-yr EFS in LMB89 (Patte et al., Blood, 2001). An ensuing FAB/LMB96 trial replaced cranial radiation with further HD-MTX and intrathecal therapy with similar results (75% 4-yr EFS) (Cairo et al., Blood, 2007). Here, patients with marrow and CNS+ disease fared worse than isolated CNS+ (61% vs. 83% 4-yr EFS, p<0.001), with >50% of CNS+ patients who progressed or recurred having systemic, but not CNS, relapse. Rituximab, a chimeric anti-CD20 antibody, improved EFS, PFS, and OS when added to chemotherapy for adults with DLBCL (Coiffier et al., N Engl J Med, 2002; Pfreundschuh et al., Lancet Oncol, 2006). We tested whether adding rituximab to FAB group C chemotherapy in pediatric patients with CNS+ B-NHL was safe and efficacious. Methods: Children and adolescents (<21 yrs.) with CNS+ B-NHL received FAB group C1 therapy (Cairo et al., Blood, 2007). Rituximab (375 mg/m2/dose) was given twice in COPADM courses 1 & 2 and once in CYVE courses (Cairo et al., ASCO, 2010). CSF blasts (>1), cranial nerve palsy (CNP), intra-cerebral mass (ICM), and/or parameningeal extension (PME) defined cases as CNS+. Results: Of 40 eligible Group C patients,15 (38%) were CNS+; all 15 had Burkitt morphology. Eight CNS+ patients were CSF+ [WBC median 35 (range 1-1104)] with 6 cases CNP+, 4 PME+, and 1 ICM+. No adverse events were attributed to rituximab. Fourteen of 15 CNS+ patients (93%) are alive and disease-free. Of 7 BM-/CNS+ patients, 100% are NED. In BM+/CNS+ cases, 7/8 (88%) are NED, with one patient progressing with systemic and CNS disease. Conclusions: Addition of rituximab to group C FAB therapy was well tolerated. Outcomes in this small cohort of 15 children and adolescents with CNS+ BL (93%) suggest that adding rituximab to FAB group C therapy without CNS radiation may reduce systemic relapse. Large randomized studies are warranted to test this hypothesis in this previously high-risk clinical subgroup.
Stanford V chemotherapy and involved field radiotherapy for children and adolescents with unfavorable risk Hodgkin lymphoma: Results of a multi-institutional prospective clinical trial.
Authors: Metzger Monika , Billett Amy , Friedmann Alison M. , Krasin Matthew J. , Howard Scott C. , Weinstein Howard J. , Larsen Eric , Marcus Karen Chayt , Billups Catherine , Wu Jianrong , Donaldson Sarah S. , Link Michael Paul , Hudson Melissa M.
Published: March 2020

9502

Background: To evaluate the efficacy of 12 weeks of Stanford V chemotherapy (prednisone, vinblastine, doxorubicine, nitrogen mustard, etoposide, vincristine, and bleomycin) without routine growth factor support plus response-adapted low-dose, involved-field radiotherapy (IFRT) in children and adolescents with unfavorable risk Hodgkin lymphoma (HL). Methods: Multi-institutional (St. Jude Children’s Research Hospital, Stanford University, Children’s Hospital Boston, Massachusetts General Hospital and Maine Children’s Hospital) clinical trial. One hundred forty-one patients with clinical stages IIB (n=43), IIIB (n=19), IVA (n=27), and IVB (n=52) HL were treated with 12 weeks of Stanford V chemotherapy and low dose IFRT between June 2002 and May 2011. Involved nodal sites in complete remission (CR, defined as > 75% shrinkage of the original tumor and PET negative) after 8 weeks of Stanford V received 15 Gy IFRT; those sites that achieved only partial response received 25.5 Gy IFRT after completion of all 12 weeks of chemotherapy. Results: With a median follow-up of 4.6 years, the 3-year overall and event-free survival (EFS) are 97% (SE=2%) and 79% (SE=4%) respectively. There was no significant difference in EFS by stage (IIB vs. IIIB vs. IV; P=0.84). Ten patients developed progessive disease and 18 relapsed, while 5 have died (1 after relapse in an accident and 4 of refractory disease). Most common toxicities were grade 3 hematologic with 234 episodes of neutropenia in 101 patients (72%) and 85 episodes of anemia in 52 patients (37%); Fever and neutropenia occurred 13 times in 12 patients (9%). Conclusions: Risk-adapted, combined-modality therapy using 12 weeks of Stanford V chemotherapy plus IFRT is well tolerated in this population with manageable acute toxicities. Overall survival is comparable to other more intense chemotherapy regimens. Future high-risk front line therapies may consider a Stanford V backbone with targeted intensification and further tailoring of radiation therapy.
The effects of dexrazoxane on cardiac status and second malignant neoplasms (SMN) in doxorubicin-treated patients with osteosarcoma (OS).
Authors: Kopp Lisa M. , Bernstein Mark L. , Schwartz Cindy L. , Ebb David , Krailo Mark D. , Grier Holcombe E. , Meyers Paul A. , Wexler Leonard H. , Marina Neyssa , Womer Richard , Janeway Katherine A. , Gorlick Richard Greg , Lipshultz Steven E. ,   Children's Oncology Group
Published: March 2020

9503

Background: Anthracyclines are highly efficacious in OS but associated with risk of cardiotoxicity. We conducted two studies using dexrazoxane as a cardioprotectant: i) AOST0121, a phase II study for metastatic OS and ii) P9754, a series of pilot studies including doxorubicin dose intensification in patients with localized OS. Methods: Patients on AOST0121 received methotrexate, doxorubicin (375 mg/m2), cisplatin, ifosfamide and etoposide (MAPIE). Those with HER2-positive tumors also received trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). On P9754, patients received MAP in Pilot 1, MAPI or MAPIE in Pilots 2 and 3. Total doxorubicin was 450 mg/m2 or 600 mg/m2 with each dose preceded by dexrazoxane (10:1 ratio). Etoposide was never given simultaneously with dexrazoxane. Measurements of left ventricular systolic function by echocardiography, serum troponin-T (cTnT, a myocardial injury marker) and N-terminal pro-brain natriuretic peptide (NT-proBNP, a cardiomyopathy marker) were obtained at baseline and repeated during therapy. Secondary malignancies were reported to the NCI. Results: None of the 47 patients (17 receiving trastuzumab) evaluated for cardiac toxicity on AOST0121 had significant changes in left ventricular fractional shortening, measurable cTnT, elevation of NT-proBNP or clinical evidence of cardiotoxicity (CTCv2.0). In P9754, 242 patients were evaluated for cardiotoxicity. Only 1 patient had CTCv2.0 grade 3 toxicity and 1 patient had a measurable cTnT. Three of 96 patients treated on AOST0121 and two of 272 patients on P9754 developed AML. Combining both studies: 5/398 or 1.4%. Conclusions: This large group of OS patients demonstrates that dexrazoxane is an effective cardioprotectant for doxorubicin alone (375-600 mg/m2), and in combination with trastuzumab. Dexrazoxane did not lead to an increase in secondary malignancies in OS patients treated with these regimens as compared to historical rates of 1-2%. Our results do not support the findings of a recent European Medicines Agency safety review that concluded dexrazoxane was unsafe for use in children and adolescents due to risk of SMN.
Cardioprotection and safety of dexrazoxane (DRZ) in children treated for newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or advanced stage lymphoblastic leukemia (T-LL).
Authors: Asselin Barbara , Devidas Meenakshi , Zhou Tianni , Camitta Bruce M. , Lipshultz Steven E. ,   Children's Oncology Group ALL Committee
Published: March 2020

9504

Background: POG 9404 evaluated the efficacy of DRZ as a cardioprotectant and its side effects in children receiving doxorubicin (DOX) as part of chemotherapy for T-ALL/T-LL. Methods: Between 6/1996 and 9/2001, 537 T-ALL/T-LL patients were treated with multi-agent chemotherapy that included 12 DOX doses of 30 mg/m2. Patients were randomized at diagnosis to treatment with or without DRZ (300 mg/m2 IV immediately prior to each DOX dose). Cardiac effects were assessed by serial echocardiograph measurements of left ventricular (LV) function (fractional shortening) and structure (end-diastolic dimension, wall thickness, and mass). Adverse events, grades 3-5 were recorded using CTCAE version 2.0. Results: Five-year EFS was similar for the DRZ (0.77±0.03%) and no-DRZ (0.76±0.03%) groups (p=0.9). Acute cardiac toxicity occurred in 1 patient (arrhythmia) on DRZ and 4 patients treated without DRZ (1-arrhythmia, 3-decreased LV fractional shortening). At each of the three time-points post-baseline (end-induction, after the last DOX dose and two years post study entry) LV dimensions were larger from baseline for patients who did not receive DRZ. In univariate analyses, change in LV end-diastolic dimension from baseline was the only variable that was significantly different between DRZ and no-DRZ arms. This was true at each of the three time points (p=0.005-0.02). The frequencies of grade 3 or 4 toxicity (hematologic, infection, CNS events, mucositis) or death were similar in groups with or without DRZ (p<0.24). There were 13 second malignancies, 10 patients had received DRZ and 3 had not (p=0.07). Conclusions: Our LV dimension measurements suggest that DRZ may protect against the early LV remodeling and enlargement that is seen with DOX cardiotoxicity. Addition of DRZ did not interfere with the anti-tumor efficacy of this DOX-containing, multi-agent regimen, and there was no significant increase in toxicities. An increased rate of second malignancies with DRZ did not reach conventional levels of statistical significance. The study was not powered to assess second malignancy rates and this trend is of unknown clinical significance.
Increasing risk of chronic health conditions in aging survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Armstrong Gregory T. , Kawashima Toana , Leisenring Wendy M. , Stovall Marilyn , Sklar Charles A , Robison Leslie L. , Oeffinger Kevin C.
Published: March 2020

9514

Background: Survivors of childhood cancer are at an increased risk for treatment-related chronic health conditions during early adulthood. However, the incidence, severity, and spectrum of chronic health conditions in the fourth and fifth decades of life have not been well studied. Methods: Analyses included 14,358 > 5 yr survivors of childhood cancer (median age at last follow-up 32.3 yrs, range 8.0-58.0; 21.4% > 40 years) and a sibling comparison group (n = 4,031). Self-reported health conditions were classified using NCI CTCAE 4.0 grading system. Analyses focused on two primary outcomes: severe/life-threatening/fatal conditions (grades 3-5), and multiple (≥ 2) conditions. Cumulative incidence of a new chronic health condition was calculated from age 26 yrs. Cox proportional hazards models adjusted for gender and race, were evaluated using age as the time scale. Results: Among survivors with no previous health conditions through age 25, the cumulative incidence for a new grade 3-5 condition by age 50 compared to siblings was 45.9% (95% CI 45.9-45.9) vs. 13.9%, (95% CI 13.9-14.0) and for new onset of ≥ 2 conditions 33.0% (95% CI 33.0-33.1) vs. 24.9% (95% CI 24.8-24.9) . Survivors ≥ 40 yrs of age had a 5.8-fold (95% CI 5.3 – 6.5) increased risk of a grade 3-5 condition compared to same age siblings, in contrast to those < 40 years of age (HR 2.7, 95% CI 2.5-3.0). A similar magnitude of difference was present for risk of >2 conditions (HR 2.7 vs. 1.2). In comparison to siblings, survivors > 40 years of age had a significantly increased risk for: congestive heart failure (HR 15.7, 95% CI 9.2-26.7), myocardial infarction (HR 8.8, 95% CI 6.0-12.9), stroke (HR 8.6, 95% CI 5.6-13.2),joint replacement (HR 6.8, 95% CI 4.1-11.4), renal failure (HR 5.1, 95% CI 2.2-11.9) among other serious conditions. Conclusions: As they age, adult survivors of childhood cancer continue to develop new and serious health conditions at substantially higher rates than siblings. These data emphasize the importance of placing a greater focus on investigations of premature aging and organ senescence in this high risk population.
Family history of cancer and clinical outcome in pediatric oncology.
Authors: Schiffman Joshua David , Smith Ken R , Burningham Zachary , Kohlmann Wendy , Curtin Karen
Published: March 2020

9525

Background: We previously reported in a small study (n=363) that children diagnosed with cancer who have a family history of cancer (FHC) may have worse prognosis than those without FHC, specifically children diagnosed with Hodgkin Disease (HD) and acute lymphoblastic leukemia (ALL) (Eichstadt et al., ASCO 2009). The Utah Population Database (UPDB), a unique resource, includes a Surveillance Epidemiology and End Results (SEER) registry (the Utah Cancer Registry) record-linked to extensive genealogies for 6.5 million people in which most Utah families are represented. A majority of pedigrees include ≥3 generations and several span 7+ generations. The UPDB provides an accurate, objective assessment of FHC. We expanded our original study by examining cancer mortality of 4,482 pediatric cases (age ≤18) diagnosed from 1966-2009 with adequate follow-up (median 9.5 years) and family information. Methods: We compared survival from cancer-caused mortality for pediatric cases diagnosed from 1966-2009 with FHC of any cancer diagnosed <80 yo in 1st-degree, 2nd-degree, or 3rd-degree relatives to pediatric cases without FHC. Nonparametric estimates of survivor function were determined by the life-table method and a log-rank test of homogeneity was used to test for differences between pediatric probands with FHC compared to no FHC. Results: Overall survival was significantly lower in children with positive FHC (n=1,128) than in children with no FHC (n=3,354) independent of stage (p<0.0001; 10yr survival, 69% with FHC vs.78% with no FHC). We observed lower survival in children with any leukemia and FHC (n=279) compared to children with leukemia and no FHC (n=871; p<0.0001). In particular, cases with ALL and FHC had lower survival (p<0.0001; 10yr survival, 61% vs. 75%). Pediatric lymphoma cases had lower survival when positive for FHC (n=150) vs. no FHC (n=428; p<0.0001), specifically for an HD diagnosis (p=0.0004; 10yr survival, 83% vs. 94%). Conclusions: Pediatric cancer cases with FHC of any cancer (children or adults) have decreased survival compared to cases with no FHC, specifically in children diagnosed with ALL or HD, thus validating our earlier findings. Familial factors likely contribute to increased pediatric cancer mortality.
Renal carcinoma following therapy for cancer in childhood: A report from the Childhood Cancer Survivor Study.
Authors: Wilson Carmen Louise , Ness Kirsten K. , Neglia Joseph Philip , Hammond Sue , Leisenring Wendy M. , Stovall Marilyn , Robison Leslie L. , Armstrong Gregory T.
Published: March 2020

9528

Background: Limited data exists describing the incidence of and risk factors for subsequent renal carcinoma among long-term survivors of childhood cancer. Methods: The study included 14,351 five-year survivors of childhood cancer diagnosed between 1970 and 1986 who participated in the Childhood Cancer Survivor Study. Chemotherapy and radiotherapy exposures were abstracted from medical records; total dose of radiation to the renal beds was estimated by a radiation physicist. Standardized incidence ratios (SIRs) were calculated using age-, sex-, and calendar-specific incidence data from the Surveillance, Epidemiology and End Results (SEER) program. Cumulative incidence was calculated treating death as a competing risk. Poisson regression analyses were used to assess associations between diagnosis and treatment characteristics and the risk of subsequent renal carcinoma while adjusting for changes in risk due to age. Results: Twenty-six survivors were diagnosed with a renal carcinoma at a median follow-up of 19.3 years (range: 1 month to 34.3 years) from study entry at 5 years post diagnosis. Eight patients received ≥5Gy radiotherapy to a renal bed, 16 received chemotherapy, seven of whom seven received both radiotherapy ≥5Gy and chemotherapy. Cumulative incidence of renal carcinoma at 20 years was 0.16% (95% CI 0.12-0.20). The SIR was 8.1 (95% CI 5.3-11.8) comparing survivors to the general population. Highest risk for renal carcinoma was observed among survivors of neuroblastoma (SIR 87.1, 95% CI 38.4-175.2), non-Hodgkin lymphoma (SIR 9.3, 95% CI 1.9-27.4), and bone tumors (SIR 7.0, 95% CI 1.4-20.4). In multivariable analyses, the risk of subsequent renal carcinoma was elevated among survivors exposed to platinum-based chemotherapy (Rate Ratio 3.1, 95% CI 0.9-10.6) or renal bed radiotherapy ≥5Gy (RR 3.6, 95% CI 1.5-8.4). Conclusions: While cumulative incidence is low, survivors of childhood cancer are at an eight-fold increased risk for subsequent renal carcinoma compared to the general population. In addition to a primary diagnosis of neuroblastoma, radiotherapy directed to the renal bed increased the risk for renal carcinoma.
Tumor location and neurocognitive impairment in adult survivors of pediatric brain tumors: A report from the St. Jude Lifetime Cohort (SJLIFE).
Authors: Brinkman Tara M. , Liu Wei , Armstrong Gregory T. , Gajjar Amar J. , Merchant Thomas E. , Kimberg Cara I. , Kun Larry E. , Srivastava Deo Kumar , Gurney James G. , Robison Leslie L. , Hudson Melissa M. , Krull Kevin R.
Published: March 2020

9531

Background: Follow-up guidelines identify supratentorial tumor location as a risk factor for poor neurocognitive outcomes during childhood; yet few studies have systematically compared long-term cognitive outcomes between adult survivors of childhood infratentorial and supratentorial brain tumors. Methods: Neurocognitive functions were evaluated in 130 adult survivors of pediatric brain tumors (58 supratentorial and 72 infratentorial, mean [SD] current age = 27.4 years [5.2], age at diagnosis = 8.6 years [4.6], and time since diagnosis = 18.8 years [4.8]) participating in the SJLIFE long-term follow-up protocol. Age-adjusted standard scores for measures of intelligence, attention, memory, processing speed, and executive functioning were calculated, with clinical impairment defined as scores <10th percentile. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models to examine associations between neurocognitive functions and tumor location. Results: As a group, survivors performed below average across multiple neurocognitive domains, including full scale IQ (mean=88.1; SD=18.2), with 34% demonstrating impaired IQ. Survivors of infratentorial tumors were more likely to be impaired on measures of focused attention (OR=2.19, 95% CI=1.03-4.65) and fine motor dexterity (OR=2.62, 95% CI=1.21-5.66) compared to survivors of supratentorial tumors. After adjusting for sex, age at diagnosis, shunt placement and cranial radiation (yes/no), infratentorial tumor location was only associated with reduced performance on a task of visual abstract reasoning (OR=3.76, 95% CI=1.40-10.1). Cranial radiation therapy was independently associated with impaired short-term memory (OR=15.6, 95% CI=1.64-147.8) and processing speed (OR=3.86, 95% CI=1.15-13.0). Conclusions: Tumor location was not associated with neurocognitive impairment after adjusting for treatment exposures. To further delineate potential differences associated with tumor location, future studies will examine factors including radiation dose/volume, extent of surgical resection, and medical complications.
Relationship of fusion protein status and outcome for children with intermediate-risk rhabdomyosarcoma: A Children's Oncology Group report.
Authors: Skapek Stephen , Anderson James Robert , Barr Frederick G. , Bridge Julia Ann , Gastier-Foster Julie M , Parham David , Rudzinski Erin R. , Triche Timothy J. , Hawkins Douglas S. ,   Children's Oncology Group
Published: March 2020

9535

Background: Rhabdomyosarcoma (RMS) includes both alveolar (ARMS) and embryonal (ERMS) subtypes, with ARMS generally having a worse prognosis. Most ARMS express one of two fusion genes generated by balanced translocations fusing DNA binding domains of PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The prognostic value of fusion gene versus histological subtype is not clear. We carried out a multi-institutional clinical trial through the Children’s Oncology Group (COG) to evaluate this molecular feature. Methods: All participants were enrolled on COG D9803 from 1999-2005 for children and young adults with intermediate risk ARMS or ERMS, and were treated with vincristine, dactinomycin, and cyclophosphamide (+/- topotecan), radiotherapy, and surgery. Diagnostic specimens were reviewed centrally and fusion gene was assessed by fluorescence in situ hybridization (FISH), RT-PCR, or both. Event-free (EFS) and overall survival (OAS) at 5 years (yr) was correlated with histology and fusion gene status. Results: Of 327 cases included in a re-review of the pathology, 295 could be classified biologically. Cases with ARMS but unknown trans status (N=23) and those with mixed or RMS-NOS histology without trans (N=17) and 12 with inadequate clinical data were excluded. ARMS cases with detectable fusion gene were defined as ARMS P3F+, ARMS P7F+, while ARMSn was reserved for those without detectable fusion. P3F and P7F were not observed in ERMS. An additional 189 pts with ERMS tumors not re-reviewed were also included in the survival analysis. There was a trend toward better EFS for those with ARMSn than for ERMS (p=0.15); EFS for ARMS P3F+ and P7F+ were worse than that for ERMS (p<0.001). Only ALV P3F+ cases had poorer OAS (p=0.004). Conclusions: ARMSn has an outcome similar to ERMS and a superior EFS compared to ARMS with P3F or P7F, when given therapy designed for intermediate risk RMS. This analysis, from a single, prospective trial restricted to those with non-metastatic disease and with near universal molecular evaluation, supports incorporating fusion status into treatment allocation. [Table: see text]
Carboplatin (CBP) versus cisplatin (CP) within prognostic groups in pediatric extracranial malignant germ cell tumors (MGCTs).
Authors: Hale Juliet , Olson Thomas Arthur , Nicholson James , Dang Ha , Krailo Mark D. , Billmire Deborah , Donachie Paul , Thornton Claire , Rodriguez-Galindo Carlos , Frazier A. Lindsay
Published: March 2020

9539

Background: It is established that CBP is inferior to CP in adult MGCTs when used at AUC 5 or 400mg/m2. There are no randomised data for paediatric MGCTs, so conclusions from adult MGCTs have been generalised despite differences in site, histology and biology. A database, pooling patients from US and UK paediatric MGCT studies, was established to determine prognostic factors in paediatric MGCTs. We examined the effect of CBP and CP in identified prognostic groups. Methods: A dataset of 1110 paediatric MGCTs was created, treated 1983 to 2009. Treatment was CBP (JEB, AUC 7.9) in the UK and CP (PEB) in the US. After excluding patients with surgery only, pure germinoma or immature teratoma , 697 patients remained. The cure model was used to assess the prognostic significance of chemotherapy regimen after adjustment for patient characteristics. Results: Analysis stratified prognosis according to age (0-10 v 11+yrs) and stage (1-3 v 4) at diagnosis by site (testis: ovary: extragonadal). Outcome for CBP and CP in these prognostic groups is shown in the table. Conclusions: Interpretation of the results of this nonrandomised comparison requires caution. However, after adjustment for other prognostic factors, the risks of failure for JEB and PEB were not statistically different . This is particularly true for 0-10yrs. At AUC7.9 CBP is tolerable in paediatric patients, with potentially fewer late toxicities than CP. [Table: see text]
A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours.
Authors: Hargrave Darren R , Pearson Andrew DJ , Moreno Lucas , Morland Bruce , Elliott Martin , Makin Guy , Campbell-Hewson Quentin , Wyld Peter J. , Halford Sarah E. R. , Lock Victoria , Lyons John F. , Boddy Alan V. , Yule Murray
Published: March 2020

9542

Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK & ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged >2 to <19 years with relapsed/ refractory solid tumours. Results: Eighteen patients treated with a median age of 10 (range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2/day. The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 neuroblastomas, 3 sarcomas & 3 others. There has been only one dose limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2/day. The majority of adverse events (AEs) have been grade 1/2 & considered unrelated/ unlikely related to study drug. Two patients have experienced Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m2/day & Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count and aspartate transaminase in a patient treated at 11.5 mg/m2/day. Pharmacokinetics of AT9283 in this population are largely in keeping with those seen in adult patients at similar doses (Arkenau et al., 2011) although there may be greater variability. Pharmacodynamic evidence of aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation in normal skin biopsies pre & post infusion, has been documented at all dose levels tested. Stable disease (up to 6 cycles) has been observed in 3 patients. Conclusions: This paediatric phase I study has demonstrated AT9283 administered as a 72 hour continuous infusion can be given at a dose level of 11.5 mg/m2/day which is higher than the maximum tolerated dose observed in adult patients (9 mg/m2/day) with advanced solid tumours. Myelosuppresion is the main toxicity but the regimen is well tolerated with preliminary anticancer activity seen in heavily pre-treated paediatric patients. [Table: see text]
Safety and biological activity of the FLT3 inhibitor lestaurtinib in infant MLL-rearranged (MLL-r) ALL: Children's Oncology Group protocol AALL0631.
Authors: Sun Di , Kaeding Allison , Magoon Daniel , Jones Tamekia , Devidas Meenakshi , Carroll Andrew J , Heerema Nyla A. , Loh Mignon L. , Raetz Elizabeth A. , Winick Naomi Joan , Carroll William L. , Dreyer ZoAnn Eckert , Hunger Stephen , Hilden Joanne M. , Brown Patrick Andrew
Published: March 2020

9548

Background: MLL-r infant ALL overexpresses activated FLT3. Lestaurtinib potentiates chemotherapy(chemo)-induced cytotoxicity in MLL-r ALL. AALL0631 therapy is stratified based on age and MLL status: high risk (HR) <90 days, MLL-r; intermediate risk (IR) ≥ 90 days, MLL-r; standard risk any age, not MLL-r. IR and HR patients (pts) get intensive chemo and are eligible for lestaurtinib. A safety/activity (S/A) phase to determine a safe and biologically active dose of lestaurtinib is followed by an efficacy phase randomizing MLL-r patients to chemo +/- lestaurtinib. The S/A phase proceeds independently for IR & HR pts, as optimal lestaurtinib dosing may differ between neonates and older infants. We previously reported successful completion of the S/A phase for IR pts; here, we report results of the S/A phase for HR pts. Methods: Lestaurtinib-related dose limiting toxicities (DLTs) were defined as grade ≥ 3 non-heme toxicities excluding those expected with chemo alone (e.g., F&N/infection); a dose of lestaurtinib was “safe” if 0 or 1 DLTs were seen in 5 evaluable pts. FLT3 inhibition was assessed using a plasma inhibitory activity (PIA) assay that measures % inhibition of phospho-FLT3 at 5 trough time points relative to pre-treatment baseline. A dose of lestaurtinib was “biologically active” if PIA was > 90% for the majority (≥3 of 5) of troughs in at least 3 of 5 pts. Results: 11 eligible HR pts received lestaurtinib, 6 at dose level 1 (DL1, 3.5 mg/kg/day) and 5 at DL2 (4.25 mg/kg/day). There were no DLTs in 5 evaluable pts at DL1. The inevaluable pt discontinued lestaurtinib due to parental refusal, not toxicity. There was 1 DLT in 5 evaluable pts at DL2. The DLT was grade 4 intestinal perforation secondary to severe typhlitis during neutropenia following reinduction, possibly related to lestaurtinib. The pt was taken off protocol and chemo and died of progressive disease. By PIA assay, 2 of 5 pts treated at DL1, and 4 of 5 at DL2 demonstrated FLT3 inhibitory biologic activity. Conclusions: DL2 is safe and biologically active in HR pts. The efficacy phase of AALL0631 is expanding such that HR pts will join IR pts in being randomized (1:1) post-induction to chemo +/- lestaurtinib at DL2.
Preclinical study of a Bcl-2 inhibitor in neuroblastoma.
Authors: Belounis Assila , Addioui Anissa , Conan Anne-Hélène , Thanvilay Dominic- Vidaroun , Cournoyer Sonia , Nyalendo Carine , Teira Pierre , Beaunoyer Mona , Brito Rose- Marie , Sartelet Hervé
Published: March 2020

9563

Background: Neurblastoma (NB) is the most common and deadly extracranial solid tumor of childhood. This malignant tumor exhibits a broad spectrum of clinical features, including spontaneous regression or maturation without any treatment or progression to metastisis leading to death. However, in spite of many therapeutic improvements, only 60% survive long term. In fact, 40% of patients with high-risk NB still relapse and eventually die of the disease despite aggressive combinations of multi-agent chemotherapy. In those cases, new therapeutic strategies must be developed. Studies have shown that BCl-2, a central anti-apoptotic protein, is over-expressed in NB. Although Bcl-2 is not a significant prognostic factor in NB, its increased expression would contribute to chemotherapy resistance. BCl-2 is also shown to be involved in the modulation of autophagy by inhibiting Beclin-1. Therefore, BCl-2 protein represents an attractive target for new therapeutic strategies in NB.The objective of this study is to determine the efficacy in vitro of Obatoclax (OB), a BCl-2 inhibitor, used in monotherapy or in combination to cisplatine (CP), a classical chemotherapeutic agent used in NB treatment, on NB cell survival. Methods: Six NB cell lines (SK-N-DZ, SK-N-FI, SK-N-SH, N91, NB8 and NB10) were treated with OB alone or in association to CP. Cell survival was measured by MTT test. Autophagy was measured by MDC test. Western Blots (WB) were done to evaluate the modulation of apoptotic and autophagic pathways in treated cells. Results: OB used in monotherapy shows promising results on NB cell lines with an average IC50 of 0.12µM. Also, OB demonstrates synergistic effects when associated to CP. The IC50 of CP treated cells varied from 3.183µM to 6.837µM but dropped from 0.003µM to 0.008µM when combined with 0.5µM of OB. Moreover, our WB show an increase in cleaved Caspase-3 and PARP-1 expression, suggesting an upregulation of apoptosis in treated cells. Autophagy is also upregulated confirmed by an increase in autophagic vacuoles and cleaved LC3 II protein. Conclusions: OB used in monotherapy or in combination at potentially therapeutic doses shows promising results in NB. These results will allow for the improvement of NB treatments by introducing a new therapeutic strategy.
Circulating myeloid-derived suppressor cells in pediatric solid tumor patients.
Authors: Goldberg John M. , Zidan Abdel-Aziz , Siddiqi Rabia , Zayas Myriam , Brown Camille D. , Forster Lourdes , Ludwig David A. , Montero Alberto J. , Diaz-Montero C Marcela
Published: March 2020

9565

Background: Cure rates have reached a plateau for many pediatric solid tumors. Identifying new therapeutic targets, biomarkers of response and prognostic indicators should improve clinical outcomes. Accumulation of myeloid derived suppressor cells (MDSCs) is an important mechanism of tumor mediated immune evasion. Increased levels of MDSCs in adult cancer patients correlate with a worse prognosis, and decrease in levels with treatment is associated with benefit. Little is known about MDSCs in childhood, or in children with cancer. This pilot measured levels of MDSCs in pediatric patients with cancer and healthy children. Methods: We enrolled subjects using an Institutional Review Board approved protocol after obtaining informed consent. Blood was obtained from 14 children with newly diagnosed or recurrent solid tumors at start of therapy. In 10 of these patients, levels were also drawn after therapy. Blood was obtained once from 6 healthy children in a primary care office. Samples were obtained concurrently with complete blood counts. MDSCs were measured on fresh whole blood and were defined as Lin-1+/HLADR-/CD 33+/CD11b+/ by flow. Total MDSC numbers were then calculated. Results: The mean total number of MDSCs was 596 cells/ul at diagnosis for the 14 children with cancer and 170 cells/ul for the 6 healthy children (t(18) = 3.02, p = .0073). For the 10 children with cancer who had repeat values measured after treatment, MDSCs decreased in 4 and increased in 6. The mean initial MDSC count for these children was 494 cells/ul, and the mean post treatment count was 1716 cells/ul (t(9) = 1.81, p = .1036). Larger change scores tended to be associated with children treated with alkylator therapy followed by G-CSF. The results for percent MDSC in white cells mirrored those of total number. Conclusions: Circulating MDSCs were higher in pediatric cancer patients than healthy controls. Cancer treatment did not reliably reduce MDSC levels. After some treatments, the levels increased, potentially increasing immune tolerance. Further research is needed to determine if circulating MDSCs are a reliable predictive or prognostic marker in pediatric cancer, and whether they represent a potential target for therapeutic intervention.
Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.
Authors: Desai Ami Vijay , Fox Elizabeth , DiSipio Theresa C. , Smith L. Mary , Lim Allison , Maris John M. , Balis Frank M.
Published: March 2020

9576

Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb) that significantly improves survival in high-risk neuroblastoma, was previously reported to be highly variable in children, and its clearance (CL, 130 mL/h · m2) and volume of distribution (Vdss, 32 L/m2) were >10-fold higher than the CL and Vdss of other cMoAbs. Characterizing the PK of ch14.18 and the factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. Methods: Detailed PK sampling was performed prior to, during and for 25 d after 4 daily 10 h infusions of 25 mg/m2 of ch14.18 administered with sargramostim (ANBL0032) in children enrolled on an IRB-approved institutional correlative protocol supported by United Therapeutics Corp. Ch14.18 concentrations were measured with a validated ELISA with a lower limit of detection of 0.44 mcg/mL. PK parameters were derived using non-compartmental methods and reported as median (range). Results: 5 males and 4 females, median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were re-studied on C3. Data from 3 patients are not included because pre-treatment plasma samples contained a substance that interfered with the ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220 (120-390) h, and the CL was 11 (3.8-16) mL/h · m2, which is similar to the average CL of 4 other cMoAbs (11 mL/h · m2). The Vdss of 2.8 (1.2-3.9) L/m2 approximated blood volume and was similar to the Vdss of other cMoAbs (1.7 L/m2) and humanized MoAbs (2.8 L/m2). AUC0-∞ in 2 patients studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690 mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children are similar to those in adults receiving ch14.18 at the same dose and similar to other cMoAbs. Ch14.18 PK in children was less variable than previously reported. The identity of the interfering substance in the plasma of some patients requires further investigation. A limited sampling strategy will be developed from these data for use in larger multi-institutional PK studies of ch14.18.
A phase I trial of MK 2206 in children with refractory solid tumors: A Children’s Oncology Group study.
Authors: Phillips Christine L. , Fouladi Maryam , Perentesis John Peter , Leary Sarah , McGovern Renee M. , Reid Joel M. , Ingle Ashish M , Ahern Charlotte H , Ames Matthew M. , Houghton Peter , Doyle L. Austin , Weigel Brenda , Blaney Susan
Published: March 2020

9581

Background: AKT, a serine threonine protein kinase, is activated downstream of phosphatidylinositol 3-kinase (PI3K) which transmits signals from cytokines, growth factors and oncoproteins to multiple targets. Activated AKT regulates survival, proliferation, and growth. The PI3K/AKT pathway is downstream of most of the common growth factor tyrosine kinase receptors in cancer, e.g., EGFR, HER2, IGFR, etc., and is a driver of tumor progression in many cancers. AKT protein kinase is activated in many pediatric solid tumors, including glioblastoma, malignant rhabdoid tumors, neuroblastoma, synovial sarcoma, rhabdomyosarcoma and medulloblastoma. MK2206, an oral allosteric AKT1, 2,3 inhibitor, has demonstrated antitumor activity in in vitro and in vivo cancer models.A phase I trial evaluating MK2206 was conducted in children with refractory solid tumors. Methods: Using a rolling-6 design, MK2206 was administered either once every 7 days (schedule 1), or once every other day (schedule 2) in a 28-day cycle. Serial PK studies were obtained on day 1, cycle 1 and trough samples were obtained on days 7, 14, 21 and 28. Biological studies included analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Results: Forty-five patients [23 males, median age 13.6 years (range 3.1-21.9)] with malignant glioma (14), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2) or other tumors (22) were enrolled; 34 were fully evaluable for toxicity (schedule 1 n=17; schedule 2 n=17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m2; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m2. There were no DLTs at 35 mg/m2 and dose level 4 (58 mg/m2) is currently open for patient accrual with one enrollment. Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m2; grade 3 rash in 1/6 patients at 120 mg/m2), and grade 3 rash in 2/6 patients at 155 mg/m2. Conclusions: The recommended pediatric phase II dose of weekly MK2206 is 120 mg/m2 and the last cohort of patients to the every other day dosing schedule of MMK206 is enrolling. PK and PD data are currently being analyzed and will be presented.