bluuebunny/crossref_metadata_2025 huggingface dataset:
VALOR, an adaptive design, pivotal phase III trial of vosaroxin or placebo in combination with cytarabine in first relapsed or refractory acute myeloid leukemia.
Authors: Ravandi Farhad , Ritchie Ellen K. , Sayar Hamid , Strickland Stephen Anthony , Craig Michael , Selleslag Dominik L. D. , Maertens Johan , Havelange Violaine , Lancet Jeffrey E. , Ketchum Steven B , Acton Gary , Mehta Cyrus R. , Silva Eric , Craig Adam , Fox Judith Ann , Stuart Robert K. , Erba Harry Paul , Vey Norbert , Schiller Gary J. , Feldman Eric Jay
Published: March 2020

TPS6637

Background: The promising phase 2 activity/tolerability profile of vosaroxin with cytarabine in first relapsed or refractory AML (N=69) with median overall survival (OS) 7.1 mo, combined CR 28% (CR 25%), median LFS 25 mo and 30-day all‑cause mortality 3%, supported phase 3 trial. VALOR (NCT01191801), a phase 3, randomized, controlled, double-blind trial, evaluates vosaroxin and cytarabine versus placebo and cytarabine in patients with first relapsed or refractory AML and incorporates an adaptive design. Primary objective is OS; secondary/tertiary objectives include CR rates, safety, EFS, LFS, and transplantation rate. Key eligibility criteria: persistent AML or first relapsed AML after 1 or 2 induction cycles that include at least 1 regimen of cytarabine with an anthracycline/anthracenedione; adequate cardiac, hepatic, renal function; and adults with no upper age restriction. Methods: VALOR is recruiting patients at over 100 sites in 14 countries in North America, Europe, and Australia/NZ. Enrollment opened Dec 2010; 183 patients enrolled through Dec 2011. Adaptive design: Base case assumed 40% improvement in median OS (hazard ratio, HR=0.71), 90% power, 2-sided alpha of 0.05. At the interim analysis (50% events), DSMB may recommend a 50% sample size increase from 450 to 675 evaluable patients if results indicate a larger sample size is required to reduce the risk of failing to confirm a clinically meaningful OS benefit (Mehta, Pocock, Stat Med 2010). In consideration of FDA and EMA guidance on Data Monitoring Committees and adaptive design with respect to trial integrity, operational bias, firewalls, and data confidentiality and archival, VALOR uses the Access Control Execution System (ACES ) to store, share, and archive confidential DSMB reports in a secure environment with an audit trail, and to facilitate communication between the DSMB and trial sponsor. The DSMB periodically reviews a combination of blinded and unblinded analyses while the study team remains blinded as specified in the DSMB charter. The DSMB recommended VALOR continue as planned after reviewing safety data in Dec 2011.
International tailored chemotherapy adjuvant trial: Itaca trial.
Authors: Novello Silvia , Manegold Christian , Grohe Christian , Colantonio Ida , Serke Monika Heidi , Geissler Michael , Valmadre Giuseppe , Schuette Wolfgang , Stoelben Erich , Bria Emilio , Monica Valentina , Torri Valter , Scagliotti Giorgio
Published: March 2020

TPS7109

Background: This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing -1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36). Methods: In all registered patients, before randomization, expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein. It is assumed that the 5-year survival in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of patients is 700. The final statistical analysis will group together all control arms and all tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, patients in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS) 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis. Currently, 312 patients have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 13 patients/month).
ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.
Authors: Boyer Michael J. , Janne Pasi A. , Mok Tony , O'Byrne Kenneth John , Paz-Ares Luis G. , Ramalingam Suresh S. , Liang Jane Q , Taylor Ian , Campbell Alicyn , O'Connell Joseph P. , Letrent Stephen P. , Antic Vladan
Published: March 2020

TPS7615

Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.
Weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): Analysis of patient-reported neuropathy and taxane-associated symptoms.
Authors: Hirsh Vera , Okamoto Isamu , Hon Jeremy K. , Dakhil Shaker R. , Page Ray D. , Orsini James , Zhang Hui , Renschler Markus Frederic , Socinski Mark A.
Published: March 2020

TPS7618

Background: Neuropathy and its associated symptoms are dose-limiting toxicities of taxane-based regimens. Measuring disease symptoms has utility for maintaining a balance between the benefits and costs of treatment. In a phase III trial nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved the primary endpoint of overall response rate (ORR) (25% vs 33%, P = 0.005), with a 1-month improvement in median overall survival (OS; P = NS), and an improved tolerability profile in pts with advanced NSCLC. Here we report on patient-assessed neuropathy and taxane-associated symptoms, important factors in a palliative patient setting. Methods: Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to C AUC 6 day 1 and either nab-P 100 mg/m2 on days 1, 8, 15 (n = 521) or sb-P 200 mg/m2 day 1 (n = 531) q 21 days. Treatment was continued until disease progression. Safety was assessed per the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. The mean change from baseline to day 1 of each cycle for the neuropathy, pain, and hearing subscales of Functional Assessment of Cancer Therapy (FACT)‑Taxane v 4.0 were assessed. Results: 1031 (98%) pts completed FACT-Taxane at baseline, and 987 (94%) during follow-up or at completion of treatment. Baseline scores for neuropathy and pain were well balanced. Significant treatment effects favoring nab-P/C were noted for patient-reported neuropathy (P < 0.001), neuropathic pain hands/feet (P < 0.001), and hearing loss (P = 0.002). Physician-assessed rates of neuropathy were significantly lower in the nab-P/C arm vs the sb-P/C arm: 47% vs 63%, P < 0.001, all grades; 3% vs 12%, P < 0.001, grade 3/4, respectively. More pts treated with nab-P/C vs sb-P/C had no neuropathy (53% vs 47%, P < 0.001). Conclusions: nab-P/C was associated with statistically and clinically significant reductions in patient-reported neuropathy, neuropathic pain in the hands and feet, and hearing loss compared with sb-P/C. Patient-reported outcomes for neuropathy were consistent with physician assessment.
A phase II randomized study of bortezomib/dexamethasone (Bort/Dex) with or without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RR MM) (CA204-009).
Authors: Jakubowiak Andrzej J. , White Darrell , Moreau Philippe , Facon Thierry , Vij Ravi , Kroog Glenn Scott , Kopit Justin , Singhal Anil , Palumbo Antonio Pierangelo
Published: March 2020

TPS8114

Background: MM is rarely curable and pts typically relapse or become refractory to current treatments. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells with little to no expression on normal tissues. The mechanism of action of Elo is primarily natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against myeloma cells. Elo + Bort significantly enhanced antimyeloma activity in a mouse xenograft model vs either agent alone. The addition of Bort enhanced the ADCC activity of Elo in preclinical studies. In a phase I study of Elo + Bort in pts with RR MM, objective response rate (ORR) was 48%, median progression-free survival (PFS) was 9.5 months, and activity was observed in 2/3 patients (67%) refractory to Bort (Jakubowiak et al. J Clin Oncol, in press). This study will assess if the addition of Elo to Bort/Dex improves PFS and, if so, whether magnitude of the improvement is linked to FcγRIIIa polymorphism. Methods: Pts (N=150) with RR MM after 1 or 2 prior therapies will be randomized in a 1:1 ratio to receive Bort 1.3 mg/m2 IV or SQ (Cycles 1-8: days 1, 4, 8, and 11; Cycles ≥9: days 1, 8, and 15) and Dex with or without Elo. Elo dose and schedule is 10 mg/kg IV (Cycles 1-2: days 1, 8, and 15 [21-day cycles]; Cycles 3-8: days 1 and 11 [21-day cycles]; Cycles ≥9: days 1 and 15 [28-day cycles]). In the arm without Elo, Dex 20 mg PO is scheduled for Cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, and 12; and Cycles ≥9: days 1, 2, 8, 9, 15, 16. In the arm with Elo, Dex 20 mg PO is scheduled for Cycles 1-2: days 2, 4, 5, 9, and 11; Cycles 3-8: days 2, 4, 5, 8, 9, 12; Cycles ≥9: days 2, 8, 9, and 16) on weeks without Elo, and on weeks with Elo, Dex 8 mg PO and 8 mg IV is scheduled on the same day as Elo. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Patients refractory or intolerant to Bort will be excluded. Efficacy will be assessed on day 1 of each cycle by IMWG criteria. The primary endpoint is PFS. Secondary endpoints include ORR and PFS/ORR in pts with ≥1 FcγRIIIa V allele. As of February 1, 2012, 1 pt was enrolled. NCT01478048.
A single-arm, open-label, multicenter phase I/II study of the combination of panobinostat (pan) and carfilzomib (cfz) in patients (pts) with relapsed/refractory multiple myeloma (RR MM).
Authors: Berdeja Jesus G. , Mace Joseph , Lamar Ruth E. , Gian Victor , Murphy Patrick Brian , Patel Manish R. , Hart Lowell L.
Published: March 2020

TPS8115

Background: Despite novel therapies, MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM. Preclinical studies demonstrate synergistic anti-MM activity with histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) through the dual inhibition of the proteasome and aggresome pathways. Pan is an oral pan-HDACi which has shown synergy with bortezomib in clinical studies. Cfz is a 2nd generation PI which has shown marked anti-MM activity with an improved safety profile. In this trial we evaluate the safety and efficacy of the combination of pan and cfz in pts with RR MM. Methods: This multi-center US study plans to enroll up to 52 adults with RR MM. The phase I study will determine the MTD of the combination of cfz and pan and follow a standard dose escalation design. Pan will be administered orally three times weekly during weeks 1 and 3 of each 28-day cycle (Days 1, 3, 5, 15, 17, 19) at a starting dose of 20 mg. Cfz will be administered intravenously on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Cfz starting dose will be 20mg on days 1,2 of cycle 1 with escalation to the corresponding dose level beginning at 27 mg , if well tolerated. Dose modifications will not be permitted during cycle 1 unless a pt experiences a DLT. A maximum of four dose levels will be evaluated. Approximately 24 pts will be enrolled during the phase I portion to establish the MTD. In the phase II portion of this study, pts with RR MM will receive treatment with the optimal dose of pan and cfz established during phase I. Pts will be assessed for response to treatment after each cycle (4 weeks). Pts with objective response or stable disease will continue treatment until disease progression or unacceptable toxicity occurs. The primary endpoint is to establish the optimal doses of cfz and pan that can be administered to pts with RR MM (phase I) and to evaluate the overall response rate (phase II). Secondary endpoints include time-to-progression, progression-free survival, overall survival and safety. Approximately 25 pts are planned for the phase II portion. Current status: As of 1/27/12 3 patients have been enrolled.
A phase I/II trial of BKM120 combined with vemurafenib (PLX4032) in BRAFV600E/k mutant advanced melanoma.
Authors: Kantor Andrea , Daud Adil , Munster Pamela N. , Ea Roth , Algazi Alain Patrick
Published: March 2020

TPS8602

Background: Vemurafenib induces transient objective responses in half of BRAFV600E mutant melanoma patients and a median PFS of 5.3 months (NEJM. 2011;364:2507-2516). BRAF mutations are not sufficient to cause melanoma, but the combination of BRAFV600E mutation and PTEN loss is sufficient to recapitulate the malignant melanoma phenotype in vivo (Nat. Genet. 2009;41:544-552). PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause acquired resistance to BRAF inhibitors (Cancer Cell. 2010;18:683-695). This phase I/II study is the first trial to test the safety and efficacy of combining a potent BRAF inhibitor, vemurafenib, with a potent PI3K inhibitor, BKM120, in patients with metastatic BRAF mutant melanoma. Methods: Design: Phase I patients receive a single dose of oral BKM120 (d -7) then vemurafenib twice daily with BKM120 daily (starting on c1d1). PK analysis is performed for BKM120 alone and for both drugs in combination. Doses of both drugs will be escalated in 3+3 scheme. Phase II patients receive continuous dosing of vemurafenib twice daily and BKM120 daily. Serial biopsies for PD and mRNA expression analyses are required for patients with visible or palpable tumors. Reimaging will be performed every 8 weeks.Eligibility: This study is enrolling BRAFV600E/K mutant metastatic melanoma patients with no prior exposure to BRAF inhibitors or PI3K inhibitors, ECOG PS ≥ 2 and adequate organ function. Endpoints: The primary endpoint for phase 1 is the recommended phase 2 dose of the combination. The primary endpoint for phase II is the 6 month PFS rate. Secondary endpoints include median PFS and OS. Baseline PTEN expression and changes is pS6 protein levels will be examined as predictors of efficacy, and changes in gene expression profiles will be assessed. Summary: This is the first trial examining the safety and efficacy of combined BRAF/PI3K inhibition in BRAF mutant melanoma patients.
Assessing clinical appropriateness on a population basis within a regional cancer network.
Authors: Casali Paolo Giovanni , Licitra Lisa F. , Bufalino Rosaria , Pizzo Fabrizio , Tricomi Marco , Bertulli Rossella , Torresani Michele , Beretta Giordano D. , Labianca Roberto , Siena Salvatore , Bersani Maurizio , Pierotti Marco
Published: March 2020

TPS9155

Background: The Lombardia Cancer Network (ROL: “Rete Oncologica Lombarda”) connects all cancer resources of the Lombardia region, with 9,000,000-plus citizens, to improve quality of cancer care and patient data sharing. Assessment of appropriateness of cancer care on a population basis is an aim. Implementation of electronic records is partial and heterogeneous. However, clinical discharge reports for both inpatients and oupatients are released as “pdf” files onto a secure regional health care information system, accessible by physicians. Methods: ROL includes 58 oncology premises. Clinical practice guidelines are annually updated within this oncology community. For each solid cancer, guidelines enlist all main clinical presentations (“disease phases”), along with their “treatment options” (either “standard”, “individualized”, or “investigational”). ROL upgraded the existing non-structured electronic clinical discharge report into a field-based resource, with both free-text (17) and codified (25) fields. Two codified fields enlist, respectively, disease phases as per guidelines, and the corresponding treatment options. If they match, the strategic medical decision is considered tentatively “appropriate”. Even the report of a single encounter within a disease phase is enough to make this work. Results: Currently, the instrument is being incorporated stepwisely within the information systems of all oncology facilities, though a central web-based tool is also available. More than 36,000 reports were released in 2011. Appropriateness assessment proved feasible on a pilot set of patients. A research project is underway to detect causes of mistakes and mismatches, by automatically analyzing free-text fields. A training effort is ongoing to improve clinicians’ learning curve on semantics. Conclusions: To assess clinical appropriateness on a population basis in a large region, we exploited two key bottlenecks: 1) the electronic discharge report, within patient information flows, to cope with a variety of local information systems; 2) the disease phase, within the cancer-specific clinical decision-making process, to cope with a likely lack of reports from a substantial proportion of encounters.
A phase II study of dasatinib therapy in children and adolescents with newly diagnosed chronic phase chronic myelogenous leukemia (CML-CP) or Philadelphia chromosome-positive (Ph+) leukemias resistant or intolerant to imatinib.
Authors: Zwaan Michel , Stork Linda C. , Bertrand Yves , Gore Lia , Hijiya Nobuko , De Souza Carmino , de Martino Lee Maria Lucia , Bradley-Garelik M. Brigid , Kearns Pamela
Published: March 2020

TPS9594

Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warranted. Methods: To evaluate the safety and efficacy of dasatinib monotherapy in children/adolescents with newly diagnosed CML-CP or Ph+ leukemias resistant/intolerant to imatinib, a phase II nonrandomized, global study of dasatinib in pts birth to <18 y is ongoing (NCT00777036): Cohort 1 (C1), Ph+ CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph+ ALL, accelerated or blast phase CML pts resistant/intolerant to or relapsed after imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph+ CML-CP pts. Treatments are once daily with dasatinib 60 mg/m2 (C1/C3) or 80 mg/m2 (C2) for ≥24 months. Primary endpoints are major CyR (C1), complete hematologic response (C2), and complete CyR (C3). Secondary endpoints include safety, tolerability, best response, time to/duration of response, survival, and molecular response rates. BCR-ABL mutations are evaluated. First patient first visit was March 2009; estimated trial completion is September 2016. As of January 2012, 63 pts (n=27 aged <12 y; n=36 aged ≥12 y) have been treated in C1/C2 (n=41) and C3 (n=22). Enrollment is ongoing at 79 sites.
Elevated risk of second malignant neoplasms in pediatric germ cell tumor patients.
Authors: Rodrigues Maria Clarissa de Faria Soares , Rodriguez-Galindo Carlos , Ribeiro Karina Braga , Frazier A. Lindsay
Published: March 2020

10010

Background: The probability of cure is very high for children with germ cell tumors (GCT), but late effects from cisplatinum can be quite significant. In addition to the immediate effects of oto-, neuro and nephrotoxicity, data from men treated for testicular cancer shows that the rate of second malignant neoplasm (SMN) is doubled and that a man treated before age 20 has a 50% chance of SMN by age 75. This study was designed to assess the risk of SMN among individuals treated for malignant GCT during childhood. Methods: We included all patients 0-19 years old with a primary diagnosis of malignant GCT registered in the Surveillance, Epidemiology and End Results (SEER) in the period 1973-2008. We analyzed tumors occurring at least 12 months after the first primary. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER Stat, version 8.0.1. Results: The cohort comprised 1997 patients (798 women and 1,199 men); 86.3% had primary gonadal tumors (91% in men and 79.5% in women). The median age at diagnosis of the primary malignancy was 17 years (17 for males ; 15 for females), and for second malignancies was 27 (27 for males; 30 for females). Fifty eight SMNs were observed (21 in females; 37 in males). Among women, higher risk was observed to developing breast cancer (n=5; SIR=1.29; 95% CI= 0.42-3.02), thyroid cancer (n=5; SIR= 3.40; 95% CI= 1.1-7.93) and brain cancer (n=3; SIR= 9.19; 95% CI=1.89-26.85). Twenty-seven out of 37 second primary tumors observed in men were contralateral testicular tumors, conferring a 16.2 fold higher risk of developing this neoplasm (95% CI= 10.67-23.58). When the analysis excluded testis as a second site, a higher risk was noted for the development of pancreatic cancer (SIR=19.06; 95% CI=2.31-68.83) and leukemia (SIR=3.55; 95% CI=0.43-12.81). Conclusions: Rates of SMN are elevated in both men and women treated as children for pediatric germ cell tumors. Men need to be made aware of risk in contralateral testicle. The rates of SMN may continue to rise with longer follow up. The attribution of treatment type to risk of SMNs is not possible due to the lack of this information in SEER database.
Impact of socioeconomic status on extent of disease at diagnosis and cancer and ocular outcomes in retinoblastoma: A population-based analysis.
Authors: Truong Bao , Green Adam L. , Friedrich-Medina Paola , Kamihara Junne , Frazier A. Lindsay , Ribeiro Karina Braga , Rodriguez-Galindo Carlos
Published: March 2020

10011

Background: The strong correlation between early diagnosis and improved outcomes has been consistently reported for retinoblastoma; extent of disease and eye preservation are associated with delayed diagnosis. In this study, we aimed to analyze the impact of socioeconomic status (SES) and ethnicity on extent on disease and cancer and ocular outcomes. Methods: All retinoblastoma cases (0-9 years) recorded in 18 SEER registries between 2000-2009 were included. The county-based disparity variables analyzed included poverty level, education attainment, language isolation, crowding, and percentage of immigrants. The cut-off values were defined as the median values for the cohort of patients. We also analyzed the impact of gender, race, and ethnicity. We tested for the association between SES and ethnicity with the percentage of extraocular disease and enucleation. Relative survival was calculated using Ederer II method; estimates were compared using Z-score. Results: We identified 753 cases. Percentage of extraocular cases was consistently higher in US counties with low SES indicators: higher vs. lower poverty status (29.3% vs. 22.1%, p=0.028); lower vs. higher education attainment (30.6% vs. 22.7%, p=0.003); higher vs. lower crowding (33.2% vs. 18.1%, p<0.001); higher vs. lower language isolation (32.2% vs. 19.3%, p<0.001); higher vs. lower percentage of immigrants (30.1% vs. 21.4%, p=0.008). Hispanic patients had significantly higher percentage of extraocular disease (35.2% vs. 20.9%, p<0.001). Poor ocular outcomes, reflected by high percentage of enucleation, were associated with counties with low education attainment (p=0.025), and with Hispanic origin (p=0.019). Decreased survival was associated with language isolation (p=0.016), but not with Hispanic origin or other SES indicators. Conclusions: Our study highlights significant disparities in the care and outcome of children with retinoblastoma. A low SES negatively impacts extent of disease, presumably by limiting access to primary care and delaying diagnosis. Hispanic patients have more advanced disease and higher enucleation rates, although survival is not significantly different.
Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) to predict outcome in patients with stage 4 disease: A study from the International Neuroblastoma (NB) Risk Group (INRG) Database.
Authors: Morgenstern Daniel Alexander , London Wendy B. , Stephens Derek , Volchenboum Samuel Louis , Hero Barabara , Di Cataldo Andrea , Nakagawara Akira , Shimada Hiroyuki , Ambros Peter F , Matthay Katherine K. , Cohn Susan Lerner , Pearson Andrew DJ , Irwin Meredith
Published: March 2020

10015

Background: Patients with metastatic NB typically have a poor prognosis; however case series have suggested that those with 4N disease may have improved outcomes. Methods: Retrospective analysis of data from INRG database for patients diagnosed 1990–2002. 4N patients (INSS stage 4 disease confined to distant lymph nodes) were compared to the balance of stage 4 patients (‘non-4N’), excluding those with missing metastatic site data. 5-yr estimates of overall (OS) and event-free survival (EFS) were calculated ± standard error (Kaplan-Meier method). Patient characteristics were compared by Mann-Whitney or Fisher’s exact/Chi-square tests. Results: 2,250 INSS stage 4 patients with complete data were identified, of whom 146 (6%) had 4N disease. For 4N patients, EFS and OS (5-yr: 77% ± 4%, 85% ± 3%), were significantly better than EFS and OS (5-yr: 35% ± 1%, 42% ± 1%) for non-4N stage 4 patients (p<0.0001). 4N patients were more likely to be younger (median age at diagnosis 1.2 yr vs 2.5 yr for non-4N; p<0.0001) and have tumors with favourable International Neuroblastoma Pathologic Classification (INPC) (63% vs 26%, p<0.0001), differentiating grade (21% vs 8%, p=0.006), lower MKI (p=0.0011) and non-MYCN amplified tumors (89% vs 69%, p<0.0001). Within subgroups defined by age at diagnosis and MYCN status, 4N pattern of disease remained significantly associated with improved outcomes. For patients aged ≥547 days at diagnosis and MYCN non-amplified, 5-yr EFS for 4N patients (n=42) was 63% ± 8% vs 27% ± 2% for non-4N (n=785); OS 74% ± 7% vs 38% ± 2% (both p<0.0001). Within this subgroup, favourable INPC and differentiating grade remained more frequent in the 4N vs non-4N patients (45% vs 10%, p<0.0001; 45% vs 8%, p=0.0017, respectively). Conclusions: 4N represents a subgroup of metastatic patients with better outcome than other INSS stage 4 patients. These findings indicate that the biology and response to treatment of 4N tumors differs from other stage 4 tumors, and different therapies should be considered for this cohort. Future exploration of biological factors determining pattern of metastatic spread and response to therapy is warranted.
Chronic medical conditions in adult survivors of retinoblastoma.
Authors: Friedman Danielle Novetsky , Chou Joanne F. , Oeffinger Kevin C. , Ford Jennifer , Sklar Charles A. , Li Yuelin , McCabe Mary S. , Robison Leslie L. , Kleinerman Ruth , Marr Brian , Abramson David H. , Dunkel Ira J.
Published: March 2020

10019

Background: Increased risk of second malignant neoplasms (SMN) in retinoblastoma survivors (RBS) is well documented, but little is known about their long-term burden of chronic non-visual morbidity. Methods: RBS treated in NYC were asked to complete a comprehensive questionnaire, adapted from the Childhood Cancer Survivor Study (CCSS) surveys; frequencies of chronic conditions, excluding SMN, in 470 RBS and 2,377 CCSS siblings were calculated. A severity score, based on the NCI CTCAE v4 (ranging from grade 1 [mild] to grade 4 [disabling/life-threatening]) was assigned to each condition. Logistic regression was used to estimateodds ratios of chronic condition risk in RBS vs CCSS siblings, adjusted for age, sex, and race/ethnicity, reported as relative risks (RR) and 95% confidence intervals (CIs). Results: RBS and CCSS siblings were mean ages of 43 years (SD 11) and 38 years (SD 9), respectively, at the time of questionnaire completion. 53.6% of RBS had bilateral disease. After excluding SMN, 70.2% of RBS had at least one non-visual chronic condition while 14% had a grade 3-4 condition. The adjusted RR of a non-visual chronic condition in a survivor compared to siblings was 1.5 (95% CI, 1.2-1.8); for a grade 3-4 condition, the risk was 1.5 (95% CI, 1.1-2.1). The most common grade 3-4 non-visual conditions in RBS were hearing loss (3.6%; bilateral 5.6%, unilateral 1.3%, p=0.023) and thyroid nodules requiring partial or full thyroidectomy (3.4%; bilateral 5.6%, unilateral 0.9%, p=0.008). Rates of grade 3-4 thyroid nodules and hearing loss did not differ significantly when stratified by treatment received. Rates of all conditions in RBS are reported in the Table. Conclusions: RBS have a modestly increased risk of non-visual chronic conditions when compared to individuals of comparable age, sex and race/ethnicity. [Table: see text]
Role of IGF-1R inhibition on an Src-family kinase bypass resistance pathway: A rational basis for cotargeting IGF-1R and Src kinase in pediatric sarcomas?
Authors: Wan Xiaolin , Yeung Choh L , Heske Christine , Mendoza Arnulfo , Helman Lee J.
Published: March 2020

10025

Background: Dysregulation of IGF signaling plays a fundamental role in oncogenesis in pediatric sarcomas. We recently completed a Phase II study targeting the IGFI receptor signaling pathway in refractory Ewing’s and other sarcomas. We demonstrated an objective response rate of 16 percent, but most responses were transient lasting less than 18 weeks. The majority of patients, even those with initial responses, do not have long term benefit from IGFIR blockade, indicating the presence of an innately resistant tumor mass or the recruitment of compensatory pathways allowing for continued growth. To improve on these responses, we have been probing these tumors to identify other critical pathways that might allow combined targeting approaches. Methods: Multiple RMS and ES cell lines were treated with IGF1R kinase inhibitors and assayed for up-regulation of various signaling pathways. Combination treatment with IGF1R inhibitors and inhibitors of additional signaling pathways were then tested in vitro and in vivo using standard techniques. For in vivo xenograft studies, treatments began 11 days following orthotopic injection of tumor cells. Results: We have identified repid up-regulation of Src family kinase (SFK) signaling within 4 hours of IGF1R blockade in both RMS and ES cell lines. Of note, combined treatment with IGF1R Ab plus IGF1R kinase inhibitors most potently upregulated SFK signaling. Based on these findings, we tested combined IGF1R blockade with SFK inhibition using the commercially available drug, dasatinib. We show that dual blockade of IGF1R and SFK pathways were synergistic in vitro. Furthermore, in xenograft models of RMS, the combination IGF1R and SFK inhibition led to long-term disease free status for at least 90 days in some mice, never seen in our hands previously using these models. Conclusions: This work identified that IGF-1R inhibition induced activation of Src kinase that may act as a by-pass pathway. Synergistic activity of IGF-1R and SFK kinase inhibitors was observed in vitro and in vivo. Dual IGFI and SFK kinase inhibition may lead to improved therapeutic outcomes.
Socioeconomic status and incidence of pediatric embryonal tumors in the United States.
Authors: Silva Raquel Ataide Peres , Pace-Emerson Tamara P. , Rodriguez-Galindo Carlos , Frazier A. Lindsay , Ribeiro Karina Braga
Published: March 2020

10036

Background: Of the 13,000 children diagnosed with cancer each year in the United States (US), the embryonal solid tumors, neuroblastoma (NB), retinoblastoma (RB), Wilms tumors (WT), hepatoblastoma (HB), rhabdomyosarcomas (RMS) and germ cell tumors (GCT), account for over 30% of the cases. Social disparities in cancer are well studied for adults, but few studies have focused on children, mostly for leukemia. The aim of this study is to evaluate the differences in incidence of rare cancers according to socioeconomic status (SES). Methods: Cases aged 0-19 were identified from the Surveillance Epidemiology and End Results (SEER) cancer registries from 1992-2009. Using data from the US 2000 Census, the county of residence of the cases was categorized above or below the national average for SES measures including: % persons with< high school education, % persons below poverty, % persons unemployed and % households with > 1 person/room. Age standardized rates per million (ASR), rate ratios (RR) and 95% confidence intervals (CI) were obtained. The findings were validated using cases from the National Program of Cancer Registries (NPCR) from 1999-2009, analyzed with the same SES variables. Results: Among cases identified in SEER, rates of NB and WT are higher in counties with upper SES measures whereas RB and GCT occurred more frequently in counties with lower SES measures. No association was found between SES and rates of HB and RMS. The results were reproducible with NPCR cases. For instance, ASR of NB is lower (SEER: 5.86; NPCR: 7.48) in counties where >19.6% of the population had not completed high school and higher (SEER: 8.41; NPCR: 8.47) in counties where ≤19.6% had not achieved a high school degree. (SEER: RR=0.69; 95%CI=0.62-0.77; NPCR: RR=0.88; 95%CI=0.84-0.93). Analysis of NB rates according to poverty, unemployment and crowding showed consistent results, with higher rates in counties with higher SES. Conclusions: The findings are suggestive of a relation between SES and cancer susceptibility that may be connected to environment and lifestyle. Understanding the role of contributing causes demands further studies to evaluate why cancer rates vary across cultural and ethnic groups as well as the magnitude of specific SE aspects.
Outcome in congenital hepatoblastoma compared with previously reported data.
Authors: Trobaugh-Lotrario Angela D , Chaiyachati Barbara H , Meyers Rebecka , Haberle Beate , Tomlinson Gail Elizabeth , Katzenstein Howard M. , Malogolowkin Marcio H. , von Schweinitz Dietrich , Krailo Mark D. , Feusner James Henry
Published: March 2020

10037

Background: Congenital hepatoblastoma, defined as diagnosis in the first month of life (Ammann RA, Plaschkes JLeibundgut K. Congenital hepatoblastoma: A distinct entity? Med Pediatr Oncol 1999:32:466-468.), has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking. Methods: We performed a retrospective review including three patients from the senior authors’ personal series and 23 cases identified in the databases of several multicenter group studies (INT-0098, P9645, 881, P9346, HB 89, HB94 and HB 99). We then compared this series with the data of all cases of congenital hepatoblastoma previously published in the literature. Results: The overall 2-year survival in our case series was 86% (18/21) with a median followup of 85.5 months (range 44 to 230 months). Presentation and treatment were not substantially different from hepatoblastoma cohorts unselected for age. The infants in our study exhibited a comparable survival rate to the reported disease free survival for a similar cohort of hepatoblastoma patients unselected for age between 1986 and 2002 (82.5%) [Tiao GM, Bobey N, Allen S, et al. The current management of hepatoblastoma: A combination of chemotherapy, conventional resection, and liver transplantation. J Pediatr 2005:146:204-211.]. The overall 2-year survival rate of cases previously reported in the literature was 0% (0/11) for patients reported before 1992, and 47% (8/17) for those reported after 1992. The improved survival of our current series of patients, collected from the past 20 years of German and American multicenter trials and personal series, suggests that the outcome of HB at this young age is much better than has been historically reported. Conclusions: Congenital hepatoblastoma does not appear to confer a worse prognosis. The overall survival in our series does not appear to be worse than in older children; more rigorous analysis should be conducted in future multicenter trials. It is possible that congenital HB should be treated like all other patients with hepatoblastoma provided that the child is stable enough to proceed with surgery and chemotherapy and complete staging is performed.
Time trends in the use of adjuvant chemotherapy (CTX) and outcomes in women with T1N0 breast cancer (BC) in the National Comprehensive Cancer Network (NCCN).
Authors: Luis Ines Maria Vaz Duarte , Ottesen Rebecca A , Hughes Melissa E , Mamet Rizvan , Burstein Harold J. , Edge Stephen B. , Gonzalez-Angulo Ana M. , Javid Sara H. , Moy Beverly , Rugo Hope S. , Theriault Richard L. , Weeks Jane C. , Lin Nancy U.
Published: March 2020

1006

Background: The role of adjuvant CTX in women with small BC is controversial. Here we analyze time trends of CTX use and outcomes in women with T1N0 BC treated at NCCN cancer centers. Methods: 8917 women were identified who received surgery or systemic therapy at an NCCN center with T1a, T1b or T1c N0 M0 BC between 2000-09. Tumors were grouped by biologic subgroups by hormone receptor (HR) and HER2 status and T subgroups (T1a, T1b, T1c). Primary endpoints were receipt of adjuvant CTX (± trastuzumab) and BC specific survival (BCSS). Chi-square, Cochran Armitage trend, Kaplan Meier estimates, log-rank test and Cox hazard proportional regression were used for analysis. In this report we focus on T1a/b results (N=4113). Results: Median follow up time was 5.5 years (range, 0.7-12.7). CTX use differed according to biologic and T subgroups, with significant changes over time (Table). In 2009, more than 50% of patients (pts) with HER2+ and HR-2- T1a/b breast cancers received CTX (± trastuzumab). The table lists use of CTX by year and subset and the 5 year BCSS for pts treated and not treated with CTX. Conclusions: A high proportion of pts with HER2+ and HR-HER2- T1N0 breast cancers received adjuvant CTX, with a sharp increase in use of CTX among HER2+ over the past decade. Use of CTX is higher in T1b compared to T1a tumors. In this study, women with T1a and T1b tumors have an excellent prognosis without CTX at 5 Yr. Careful examination of cutoffs for absolute benefit sufficient to recommend CTX is warranted. [Table: see text]
Surveillance and follow up of pediatric cancer from a developing country.
Authors: Nandy Argha , Mukhopadhyay Soma , Maity Debdatta , Bhattacharyya Gouri Shankar , Mukhopadhyay Ashis
Published: March 2020

10069

Background: Childhood cancers, a leading cause of childhood deaths, affect more than 200,000 children worldwide, of which >80% are from developing nations. This demands for proper measurement of the incidence of various childhood cancers which led to a novel study in assessing the burden of childhood cancers in eastern India through analysis of hospital-based cancer registry data from our institute in between January 2001- December 2011. Methods: 3,200pediatriccancer patients between 0-15 yearsdiagnosed by means of histological and cytological examinations were included in this study. Based on histopathological classification, cancer cases were distributed into 3 different age groups. Their respective family functioning, mental health, self-esteem and social competence were examined. Details of disease, tobacco usage along with socio demographic data were collected through standard questionnaires. Comparative measures of disease incidence were also calculated. For measuring the tolerance, different drugs were administered to patients. Results: The incidence of different malignancies was recorded which were Leukemia (34.9%), Lymphoma (24.1%), Hodgkin’s disease (18.1%), NHL (6.0%), Ewing’s sarcoma (4.9%), Rhabdomyosarcoma (3.6%), Neuroblastoma (2.0%), Brain tumour (9.9%), Wilm’s tumour (6.0%), Lymphoid Leukemia (26.9%), Myeloid Leukemia (7.9%), Germ cell tumour (4.2%), Osteosarcoma (4.0%), Retinoblastoma (2.0%) and Soft tissue sarcoma (2.3%). The disease free survival (DFS) for ALL was 76%, NHL (84%), Soft tissue sarcoma (78%), CML (98%), AML (48%) and germ cell tumour (95%). Finally, 53.33% patients were subjected to post-therapy assessment, of which 98% showed no after effect of therapy on growth chart, heart and endocrine function. The toxicity of grade III and IV chemotherapy ranges from 10-20%. Conclusions: Based on our study, the most happening cancer was Leukemia (34.9%) followed by Lymphoma (24.1%) and soft tissue sarcoma (18%). The overall disease free survival for pediatric patients was 72% with acceptable toxicity. Our results are comparable with the studies of other developed countries.
Use of the FoundationOne next-generation sequencing (NGS) assay to detect actionable alterations leading to clinical benefit of targeted therapies for relapsed and refractory breast cancer.
Authors: Ross Jeffrey S. , Cristofanilli Massimo , Downing Sean , Yelensky Roman , Lipson Doron , Otto Geoff , Palmer Gary A. , Ali Siraj M. , Miller Vincent A. , Stephens Phil
Published: March 2020

1009

Background: Genomically-informed cancer therapy linking therapeutics targeting the molecular alterations driving the malignancy has the potential to transform the care of patients with metastatic breast cancer (MBC). Methods: DNA was isolated from 4 FFPE sections cut at 10 microns from 177 consecutive MBC that had relapsed after surgery, conventional hormonal/chemo and anti-HER2 targeted therapies received by our CLIA lab (Foundation Medicine). DNA sequencing was performed for 3,320 exons of 182 cancer-related genes to average depth of 1017X. Actionable Genomic alterations (GA) were defined as those linked to targeted anti-cancer therapies approved or being evaluated in active registered clinical trials. Results: Genomic profiles were generated from 169/177 (95%) BCs identifying 565 GA, averaging 3.34 GAs per tumor (range 0 to 10). 152 (90%) tumors harbored an actionable alteration mean 1.88 per tumor (range 0 to 6). In 124 (73%) tumors, ≥1.0 actionable GA was detected that would be missed by current “hotspot assays”. Notable GA involved PIK3CA (37%), ERBB2 (14%), FGFR1/2 (14%), PTEN (10%), MDM2 (7%), CCND1/CCNE1/CDK4 (7%), BRCA1 and BRCA2 (6% each) and ESR1 and EGFR (3% each). Of 23 ERBB2 GA, 74% were amplifications and 26% were mutation/gene fusion. The frequency of ERBB2 mutation/fusion was significantly enriched in CDH1 mutated ILC (~9% of total BC) with a frequency of 19.0% (4/21) compared to other histological types of BCs 1.4% (2/148) [p=0.002]. Significant clinical efficacy included patients with HER2 IHC/FISH negative tumors featuring HER2 and EGFR activating mutations benefitting from lapatinib/trastuzumab and erlotinib respectively. Conclusions: Comprehensive genomic profiling with a NGS assay identified actionable GAs in the majority of MBC patients including ERBB2 and EGFR mutations that initiated use of targeted therapies resulting in significant clinical benefit. These data provide a framework for the GAs expected in advanced BC and should facilitate the implementation of molecularly targeted trials supporting the efforts for a modern approach to precision medicine for the disease.