bluuebunny/crossref_metadata_2025 huggingface dataset:
PREDICTOR (UNICANCER GEP11): Randomized phase II study of preoperative afatinib in untreated head and neck squamous cell carcinoma (HNSCC) patients.
Authors: Le Tourneau Christophe , Delord Jean-Pierre , Dolivet Gilles , Malard Olivier , Fayette Jérôme , Capitain Olivier , Even Caroline , Hoffmann Caroline , Vergez Sebastien , Geoffrois Lionnel , Rolland Frederic , Zrounba Philippe , Laccourreye Laurent , Guigay Joel , Bieche Ivan , Klijanienko Jerzy , Aide Nicolas , Benavent Valerie , Gal Jocelyn , Temam Stephane
Published: September 2018

6021

Background: Afatinib, a pan-HER irreversible tyrosine kinase inhibitor, demonstrated limited antitumor activity compared to methotrexate in unselected recurrent and/or metastatic HNSCC patients (LUX-HN1, Machiels et al, Lancet Oncol 2015). The UNICANCER (GEP 11) PREDICTOR study’s objective was to identify predictive and pharmacodynamic biomarkers of biological activity and efficacy of afatinib (EUDRACT N° 2010-024046-29). Methods: This open-label, randomized, multicentric, controlled, phase II study included untreated patients with operable T2-4N0-2M0 HNSCC of the oral cavity, pharynx and larynx, with a PS < 2, adequate organ function and LVEF > 50%. Patients were randomized (2:1) to: oral afatinib (A) 40mg/day (d) for 14-28d or no treatment (NT). Patients had pre-treatment tumor biopsies, tumor imaging, and PET CT scan, with a 2nd tumor imaging before surgery and a PET scan at D15. Adverse events were classified by NCI CTCAE criteria. Based on the biological primary endpoint of tumor reduction the sample size was designed to identify biomarkers associated with a 20% difference between the study arms. Results: 61 patients were included (A: 41/NT: 20). 2 patients in the NT arm were not analyzed (consent withdrawal, no surgery). 7 patients in arm A received < 14d of treatment, including 6 patients with unacceptable toxicity. Afatinib-related toxicities were: grade (G)1 37%, G2 41%, G3 7%, G4 5%, and G5 0%. G≥3 toxicities were mainly gastrointestinal. Partial responses (RECIST1.1) were observed in 3 patients (7.3%) in arm A versus none in the NT arm (p = 0.018). Progressive disease was not observed in arm A versus 3 (16.6%) in the NT arm. Partial responses on PET CT scan by PERCIST were observed in 15/31 evaluable patients (48%) in arm A versus 1/15 (6.7%) in the NT arm (p = 0.005). Conclusions: Afatinib given to HNSCC patients in the preoperative setting is safe and is associated with improved response according to RECIST1.1 and PERCIST compared to no treatment. Clinical trial information: NCT01415674.
Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC).
Authors: Subbiah Vivek , Kreitman Robert J. , Wainberg Zev A. , Cho Jae Yong , Schellens Jan H.M. , Soria Jean-Charles , Wen Patrick Y. , Zielinski Christoph , Urbanowitz Gladys , Mookerjee Bijoyesh , Wang Dazhe , Rangwala Fatima A. , Keam Bhumsuk
Published: September 2018

6023

Background: ATC is a rare, aggressive malignancy with a dismal prognosis. Median overall survival (OS) is < 6 mo. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma and lung cancer. One-fourth of ATCs harbor activating BRAF V600E mutations; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated ATC. Methods: In this phase 2, open-label trial (NCT02034110), pts with BRAF V600E mutations in 9 rare tumor types, including ATC, received continuous D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer with no standard-of-care treatment options. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), OS, and safety. We report data from the ATC cohort. Results: 16 pts with BRAF V600E–mutated ATC had evaluable data with a median follow-up time of 47 wk (range 4-120 wk). BRAF V600E mutations were centrally confirmed in 15/16 pts. Median age was 72 y; all 16 pts had undergone prior tumor radiation and/or surgery and 6/16 pts (38%) had received ≥1 prior line of systemic therapy. Investigator-assessed confirmed ORR was 69% (11/16; 95% CI, 41%-89%), with 7/11 responses ongoing at the time of data cut. The Bayesian estimate of ORR was 69% (95% credible interval, 47%-87%) with a 100% probability that this ORR exceeded the 15% historical RR. Median DOR, PFS, and OS were not estimable due to insufficient progression and death events. Kaplan-Meier estimates of DOR, PFS, and OS at 12 mo were 90%, 79%, and 80%, respectively. The safety population comprised 100 pts enrolled in 7/9 histologies. Among all pts, 92% had an AE. Common AEs of any grade for all histologies were fatigue (38%), pyrexia (37%), and nausea (35%). In the ATC cohort, the most common grade 3/4 events were hyponatremia (19%), pneumonia (13%), and anemia (13%). Conclusions: D+T combination therapy significantly improved outcomes in ATC with a favorable safety profile. This regimen represents a clinically meaningful therapeutic advance for pts with advanced/metastatic BRAF V600–mutated ATC. Clinical trial information: NCT02034110.
A phase II multicenter trial of the multitargeted kinase inhibitor sulfatinib in advanced medullary thyroid cancer (MTC) and radioiodine (RAI)-refractory differentiated thyroid cancer (DTC).
Authors: Chen Jiaying , Ji Qinghai , Cao Junning , Ji Dongmei , Bai Chunmei , Lin Yansong , Pan Bin , Sun Guofang , Li Jing , Qi Chuan , Hua Ye
Published: September 2018

6037

Background: Sulfatinib is an oral tyrosine kinase inhibitor targeting Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor 1 (FGFR 1), and Colony Stimulating Factor 1 Receptor (CSF1R). In a proof of concept (PoC) phase II study, sulfatinib showed promising efficacy in patients (pts) with neuroendocrine tumors (NETs). Methods: This is an open label, two cohorts phase II study using Simon's two-stage design. In stage I, 15 pts will be enrolled in each cohort (advanced MTC or iodine-refractory DTC), and 10 more pts will be enrolled in a cohort in stage II if at least 2 PR observed in that cohort in stage I. Pts are required to have progressive disease in the past 12 months, but could not have received > 1 prior anti-angiogenesis therapy. Pts are treated with oral sulfatinib 300 mg once daily until disease progression, death, or intolerable toxicity. Primary endpoint is Objective Response Rate (ORR) by investigator per RECIST 1.1. Results: As of Dec 31 2016,the studyenrolled 18 pts (MTC: 6, DTC: 12), amongst whom 17 pts were efficacy evaluable. There were a total of 4 confirmed PRs, 1 in the MTC cohort and 3 in the DTC cohort, respectively. The others best response was stable disease (SD). 11 pts (61.1%) had dose interruption due to adverse events (AEs) and 5 pts (27.8%) had dose reduction. Two pts discontinued therapy (1 patient due to disease progression, another due to subject's decision). The most commonly reported AEs were proteinuria 72.2% (Grade 3-4: 22.2%), hypertriglyceridemia 50.0% (Grade 3-4: 0%), hypertension 44.4% (Grade 3-4: 16.7%), blood bilirubin increased 44.4% (Grade 3-4: 5.6%), and diarrhea 33.3% (Grade 3-4: 0%). No Grade 5 AE was reported by the time of data cut-off. Conclusions: Sulfatinib appears to be well tolerated in the pts with advanced MTC and RAI refractory DTC. Safety profile seems to be consistent to previous report, with mostly manageable AEs. Efficacy is encouraging in both indications. Further investigation is warranted. Clinical trial information: NCT02614495.
Population assessment of head and neck cancer outcomes by race and HPV status in chance.
Authors: Sheth Siddharth , Farquhar Doug , Mazul Angela , Hayes David N. , Zevallos Jose , Olshan Andrew F
Published: September 2018

6045

Background: Growing literature suggests that racial disparities exist in patients with head and neck squamous cell carcinoma (HNSCC). Currently, there are many hospital-based cohorts assessing racial disparities, however only a limited number of population-based cohorts exist. This study aims to explore the association between clinical characteristics and patient demographics with overall survival by race and HPV status. Methods: Patients were identified from the Carolina Head and Neck Cancer Study (CHANCE), a population based case-control study with enrollment from 2001-2006 in North Carolina. Vital status was determined by linkage with the National Death Index. Survival was considered at 5 years after diagnosis or study enrollment. We used Kaplan-Meyer analyses and Cox proportional hazards regression modeling to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: A total of 1361 HNSCC patients with no baseline metastasis and adequate survival time were identified. Of these, 1010 patients were white while 351 patients were black. Black patients were statistically more likely to be younger at age of diagnosis, have a history of tobacco or alcohol use, be uninsured, and not have completed high school (p-value < 0.001). In an unadjusted cox regression analysis, blacks had 1.50 times (95% CI 1.01-1.57) decreased overall survival than whites. Adjusting for gender, stage of disease, age, treatment, and smoking status, this relationship remained (HR 1.30, CI 1.1-1.6). In a subset analysis of male patients by disease site, there was decreased overall survival in black patients in oral cavity cases (p < 0.01). This relationship trended towards significant in pharynx cancer (p = 0.054) and was not found in laryngeal cancer. In pharyngeal cases only, there was decreased overall survival in black patients with HPV+ disease (p = 0.03) but not in HPV- cases (p = 0.33). Conclusions: This is the first population-based study that confirms racial disparities in HPV+ HNSCC. We also found worse overall survival prognosis for black patients with oral cavity cancer and a similar trend in pharynx cancer. Further studies are needed to evaluate if this difference is driven by either biological or socioeconomic factors.
Impact of p16 expression on induction taxotere-cisplatin-5 FU (TPF) followed by cetuximab-radiotherapy in N2b-N3 head and neck squamous cell carcinoma (HNSCC): Results of GORTEC 2007-02 phase III randomized trial.
Authors: Tao Yungan , Geoffrois Lionnel , Martin Laurent , De Raucourt Dominique , Miny Joelle , Maingon Philippe , Lafond Cedrik , Tuchais Claude , Sire Christian , Babin Emmanuel , Coutte Alexandre , Rolland Frederic , Girard-Calais Marie-Helene , Casiraghi Odile , Garaud Pascal , Bourhis Jean
Published: September 2018

6070

Background: TPF is a reference induction chemotherapy regimen in non-operated locally advanced (LA) HNSCC. GORTEC 2007-02 phase III randomized trial was restricted to HNSCC patients with large nodal spread (N2b-N3). Results showed no benefit of 3 cycles of induction TPF followed by cetuximab-radiotherapy (RT), as compared to concurrent chemoradiotherapy (CRT) (Geoffrois et al ASCO 2016). Methods: Patients were randomized to receive concurrent CRT (arm A) or induction TPF followed by cetuximab-RT (arm B). RT was 70 Gy/35F/7 weeks. Concurrent chemotherapy was 3 cycles of carboplatin-5FU as previously described (Calais JNCI 1999). About 2/3 of patients had oropharyngeal cancers (OPC) and HPV status was determined in these patients using p16 expression as a surrogate (immunohistochemistry). Smoking status was also collected. Primary endpoint was progression free survival (PFS). Results: Between May 2009 and Aug 2013, 360 eligible patients were randomized including 231 (64%) OPC. Overall, p16 expression could be assessed in 172 / 231 OPC patients (74%) with 84 in arm A and 88 in arm B. 26 patients were found p16+ in arm A (31%) and 19 in arm B (22%). Only 8 out 45 (18%) p16+ patients were non-smokers showing that the large majority of OPC patients randomized were p16- (127/172) and smokers (117/129). A significant improvement in PFS was found in p16+ compared to p16- OPC (p < 0.0001). The absence of benefit in PFS associated with TPF + cetux-RT compared with CRT was suggested both in p16+ (HR: 0.78, 95% CI: 0.28 – 2.20) and in p16- OPC (HR: 1.28, 95% CI: 0.84 – 1.93), and the interaction between p16 and treatment modality was not significant (p = 0.35). A significant benefit was observed in favor of arm B regarding distant metastasis, but this effect was not different between the p16+ and p16- OPC, while there was no benefit of TPF + cetux-RT compared with CRT for loco-regional control, regardless of p16 status. Conclusions: The OPC p16 subpopulations were small. No benefit of induction TPF chemotherapy followed by cetuximab-RT compared with CRT in OPC patients regardless of p16 status. Clinical trial information: NCT01233843.
A multicenter phase II trial of docetaxel, cisplatin and cetuximab (TPE) followed by cetuximab concurrent with radiotherapy in patients with local advanced squamous cell carcinoma of the head and neck (ECRIPS study).
Authors: Zenda Sadamoto , Ota Yosuke , Kiyota Naomi , Okano Susumu , Fujii Masato , Kitamura Morimasa , Takahashi Shunji , Ueda Tsutomu , Monden Nobuya , Yamanaka Takeharu , Tahara Makoto
Published: September 2018

6071

Background: Induction chemotherapy is a treatment option for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, Docetaxel, Cisplatin, and 5-FU (TPF) followed by Cisplatin with radiotherapy is currently not recommended due to toxicity concerns. The aim of this phase II study was to assess the feasibility of Docetaxel, Cisplatin, and Cetuximab (TPE) followed by Cetuximab with concurrent radiotherapy for LA-SCCHN. Methods: Patients were eligible if they had histologically proven SCC of oropharynx, hypopharynx or larynx, a PS of 0-1, adequate organ function, and no distant metastasis. Induction chemotherapy consisted of Cisplatin 75mg/m2 and Docetaxel 75mg/m2 on day1 and the induction regimen was repeated every 3 weeks up to a total of 3 courses. Cetuximab was administered at an initial dose of 400mg/m2 followed by 250mg/m2 weekly until the end of radiotherapy. Radiotherapy (70Gy/35fr/7w) was started after last administration of Docetaxel. Primary endpoint was the rate of treatment completion. The planned sample size was 55 with one-sided alpha of 0.025 and the power of more than 90% based on the expected and threshold treatment completion rates of 65% and 40%. Results: Between August 2013 and October 2015, 54 patients with a median age of 58 years were eligible and had the study treatment. There were 50 males, hypopharynx/oropharynx/larynx cancer of 28/19/7 cases, and 48 Stage IV disease. Response rate at induction chemotherapy was 72% while that after radiotherapy was 76% . Of 54 patients, 50 (93%) received > 2 courses of induction chemotherapy, and 41 (76%) had the full dose of radiotherapy. The rate of treatment completion was thus 76% (95%CI, 62–87%). The frequency of grade 3-4 neutropenia, febrile neutropenia, and allergy/infusion reaction was 93%, 39%, and 11%, respectively. One treatment-related death was observed. Conclusions: Induction TPE followed by Cetuximab with concurrent radiotherapy was feasible with a promising efficacy. A phase III study to evaluate this treatment strategy is warranted. Clinical trial information: UMIN000009928.
Cost-effectiveness of prophylactic antibiotics to prevent pneumonia in patients treated with chemoradiotherapy (CRT) for locally advanced head and neck carcinoma (LAHNC).
Authors: Ham Janneke , Driessen Chantal , Hendriks Mathijs P , Fiets W. Edward , Kreike Bas , Hoeben Ann , Slingerland Marije , Opstal Claudia van , Kullberg Bart-Jan , Adang Eddy MM , Kaanders Johannes , Van Der Graaf Winette T.A. , Van Herpen Carla M.L.-
Published: September 2018

6075

Background: Recently, we reported about a prospective randomized study (PANTAP-study) investigating the effect of prophylactic antibiotics in LAHNC pts treated with CRT. We did not show a reduction in pneumonias, but did find a significant decrease in the number of hospitalizations. Detailed quality of life (QoL) results have been reported elsewhere. Now we present the results of the cost-effectiveness analysis. Methods: A multicenter study was performed in LAHNC pts treated with CRT, i.e.cisplatin weekly or 3-weekly combined with radiotherapy for 42 or 49 days. The standard treatment group (STG) received no prophylactic antibiotics; the intervention group (IG) received prophylactic antibiotics, i.e. amoxicillin/clavulanic acid, from day 29 until 14 days after completion of CRT. QoL questionnaires, including EQ-5D, QLQ-C30, EORTC Head&Neck35 and PSSHN, were taken before start of CRT, before start of antibiotics, at the end of CRT and at the end of follow up. Costs of hospitalization, prophylactic antibiotics, pain medication and anti-emetics were taken into account for the cost-effectiveness analysis. Results: A total of 94 pts were randomized; 48 pts to the STG and 47 pts to the IG. Between the STG and IG we found a difference per patient in costs of hospitalization of €2076 and €682 (p = 0.03), respectively, but not in the costs for pain medication per patient €78 and €46, respectively, (p = 0.382). The total costs of hospitalization in combination with prophylactic antibiotics, pain medication and anti-emetics were €2462 and €1037 (p = 0.046) in the STG and IG respectively, leading to a difference in total costs per patient of €1425 in favor of the IG. There were no significant differences in QoL between the groups. Conclusions: Prophylactic antibiotics during CRT for LAHNC did not reduce the rate of pneumonias, but reduced the number of hospitalizations in the IG, which led to a significant reduction in costs. Given the lack of adverse clinical effects, the same QoL, the cost savings and the impact of costs of hospitalization on health care globally, we recommend the use of prophylactic antibiotics in LAHNC pts receiving CRT. Clinical trial information: NCT01598402.
Institutional treatment volume and outcomes in salivary gland cancer.
Authors: Steuer Conor Ernst , Switchenko Jeffrey M. , Griffith Christopher C , Patel Mihir , Cassidy Richard John , Gillespie Theresa Wicklin , McDonald Mark William , Higgins Kristin Ann , Beitler Jonathan Jay , Owonikoko Taofeek Kunle , Chen Zhuo Georgia , Shin Dong Moon , Saba Nabil F.
Published: September 2018

6082

Background: Salivary gland cancer (SGC) is a rare malignancy and has been understudied in the literature. Given the rarity of SGC, we sought to compare outcomes of SGC within high volume (HV) and low volume (LV) centers, utilizing the National Cancer Database (NCDB). Methods: The NCDB was queried from 2004 to 2014 for SGC using ICD-O-3 codes for the 4 most common histologies: (mucoepidermoid carcinoma (ME), adenoid cystic carcinoma (AdCC), acinic cell carcinoma(ACC), and adenocarcinoma NOS(A)) for consistency. The number of cases treated at each facility was calculated, and the threshold for distinguishing high volume vs. low volume was determined using the 80th percentile of the number of cases treated per facility. Patient characteristics were compared using chi-squared tests and ANOVA. Overall survival was estimated using the Kaplan-Meier method, and was compared using log-rank tests. Statistical analyses were performed using SAS 9.4. Results: There were 31,189 SG patients overall; 16,373 were either ME, AdCC, ACC, or A and were included in the analysis. There were 6534 patients treated in LV (41%) and 9839 in HV (59%). HV centers were more likely to be academic and integrated network cancer programs (p < .001). The median age for LV vs. HV was 61y vs. 58y (p < .001), 49% vs. 47% male (p = .007), and 84% vs. 80% White (p < .001), respectively. Patients presented with slightly more advanced disease at HV, with 24.4% having stage 3-4 disease, vs 23% in LV (p = .004). The majority of patients underwent surgical resection (57% LV vs. 64% HV). HV had more negative margins (59% vs 55%, p < .001), more neck dissections (72% vs. 64%, p < .001), and longer hospital stays (mean 2.21d vs 1.55d, p < .001). More patients in LV received radiation than HV (55% vs. 52%, p < .001), but there was no difference in chemotherapy use (p = 0.650). Patients had better survival (m1 disease excluded) in HV as compared to LV (5-year OS HV 77.4% vs LV 75.5%, HR 0.89, p = 0.002). Conclusions: Our results indicate that survival of SGC is affected by institutional treatment volume and the significant differences in treatment at LV vs. HV institutions urges for the need of better standardization of care.
Analysis of reimbursement (R) for next generation sequencing (NGS) on patients' tumors in the context of a personalized medicine program.
Authors: Brown Thomas D. , Tameishi Mariko , Liu Xiaoyu , Scanlan James , Beatty J. David , Drescher Charles , Pagel John M. , Gold Philip Jordan , Alexander Shlece , Summers Lauren K. , Brindle Madeleine , Varghis Nina , Yates James , Fondren Kathleen N. , Birchfield George Richard , Dong David Edwin , Benkers Tara L. , Wahl Tanya A. , Ramsey Scott David , Berry Anna Belinda
Published: September 2018

6506

Background: R policies for NGS testing vary widely among private and public insurers. While drug costs are the greatest challenge in personalized or precision medicine, cost and R are substantial barriers to genomic profiling with NGS. We examined variation in coverage and R for a cohort of cancer patients (pts) treated at a tertiary oncology center. Methods: An Institutional Review Board approved prospective registration protocol was activated with the objective of establishing a centralized longitudinal clinical, molecular phenotypic, and research data repository for pts diagnosed with cancer. Based on provider assessment of medical necessity, mutations in 68 cancer associated genes were analyzed. Evaluation of R for NGS was performed from Sept, 2014 through Jan, 2017, with use of CPT code 81455. R was analyzed based on: payer type; pt age; localized vs. metastatic disease; and actionability of data. Results: 588 pts with evaluable analytic cases, and NGS testing, with R results shown in the table below. For groups with >= 10 pts: R frequency was highest in managed care programs, either private or Medicare, and least frequent in non-HMO Medicare (p<.001). In pts receiving R, payments by private HMOs were highest (p<.02). NGS results with labelled drug indications were associated with less frequent R (26% vs. 35%; p<.05), and lower payments (mean of $358 vs. $567; p<.02) compared to other NGS results. Younger age was associated with more frequent R (38% in pts <60 years, 24% in pts >= 60 years; p<.005). Neither cancer diagnosis nor stage were significantly associated with R. Conclusions: One third of pts received some R for NGS testing. R was more frequent and higher in managed care programs, both private and Medicare. R was more likely for younger age pts, while actionable NGS results were associated with lower R. These data demonstrate the need for rational, transparent, and consistent R policies, along with a value-based R model for NGS across all payer groups. [Table: see text]
The impact of positive SWOG treatment trials on population survival.
Authors: Unger Joseph M. , LeBlanc Michael Leo , Blanke Charles David
Published: September 2018

6513

Background: Recently, tremendous prominence has been given to the investigation of the impact of different research processes as part of the Cancer Moonshot. More than half a century ago, the National Cancer Institute (NCI) established a network of publicly-funded cancer cooperative research groups to systematically advance the science of clinical trial research and the evaluation of new treatments for efficacy and safety. Our objective was to examine the extent to which positive NCI-sponsored cancer treatment trials have benefited cancer patients in the U.S. population. Methods: We used study data from SWOG, an NCI-sponsored Network cooperative research group. We identified all treatment trials over SWOG’s 60-year history (1956-2016) for which the new experimental therapy provided a statistically significant improvement in overall survival. We assumed the new, proven treatments from these trials established new standards for care in the treatment community. Twenty-three treatment trials were identified from a variety of difference cancer types. We estimated population life-years gained from the trials through 2015 by mapping the impact of the new treatments onto the U.S. cancer population, using an area-under-the-survival-curve approach that combined trial-specific hazard function and hazard ratio results with SEER and life-table data. Calculations were age-adjusted. Dollar return on investment was estimated as the ratio of total investment by the National Cancer Institute in the SWOG treatment trial program divided by the estimate of life-years gained. Results: In total, 12,361 patients were enrolled to the 23 positive trials from 1965-2012. We estimated that 3.34 million years of life were gained through 2015. Estimates were greater than 2 million life years gained under 95% of model simulations. The dollar return on investment was $125 per life year gained. Conclusions: SWOG treatment trials have had a substantial impact on population survival for cancer patients over 60 years. The National Cancer Institute’s investment in its cancer cooperative group research program has provided exceptional value and benefit to the American public.
Cancer drug assessment: What is driving high clinical added value in France?
Authors: Fernandez Judith , Grande Mathilde , Dahmani Bachir , Stanel Sorin , Galbraith Margaret , Albin Nicolas , Belorgey Chantal , Guillevin Loic , d'Andon Anne
Published: September 2018

6526

Background: Concerns about the increase of cancer drug prices emphasized the need to base pricing decisions on clinical added value (CAV). In France, the CAV assessment is done by the National Authority for Health (HAS) on a 5-point scale based on clinical data. The magnitude of the CAV is partly used by the economic committee for healthcare products to determine drugs prices: a major to moderate CAV leads to the highest prices. Recognizing the importance of presenting clear statements, we analyzed which criteria are taking into account for CAV appraisal. Methods: A retrospective and descriptive study analysis of all new hematology/oncology cancer indications assessed by HAS between 2010 and 2015 has been conducted. For each appraisal, information regarding the level of evidence and clinical effect has been collected. Results: 78 new cancer indications (58 drugs) have been assessed: 20 had a major to moderate CAV (25%), 32 a minor CAV (41%) and 26 no CAV (33%). The percentage of major to moderate CAV was higher when a comparative pivotal trial was conducted (25%, 16/62 vs. 20%, 4/16). Among the 62 comparative trials, 58 had a superiority design (94%) supporting a major to moderate CAV in 27% (16/58) of the cases. Overall survival (OS) was measured in 91% of the pivotal trials (n = 71) and in 24% (n = 19) as a primary outcome. A higher proportion of major to moderate CAV were observed in trials using OS as a primary endpoint (31%, 6/19) than progression free survival (PFS) (23%, 9/39) or response rate (25%, 5/20).When a major to moderate CAV was obtained, a median absolute gain of 4 and 8 months for OS and PFS respectively were observed. All non-inferiority or non-conclusive designs led to no or minor CAV whatever the quantity of clinical effect. Conclusions: CAV is assessed in a two-step process where clinical effect is taken into account when level of evidence is appropriate. Consequently, there is not a unique profile of outcomes supporting a major to moderate CAV but a combination of several key elements such as study design, primary endpoint, and statistical significance. HAS appraisals remain multi-factorial, and medical need add a nuance to HAS expectations in terms of level of evidence.
Communication about immunotherapy: Barriers and information to discuss.
Authors: Gillespy Kristen , Dixon Margie D , Pentz Rebecca D.
Published: September 2018

6543

Background: Since immunotherapy is a promising new therapeutic approach to cancer treatment, improving physician/patient communication about this approach is important. No communication guidelines exist. To begin to fill this gap, we identified provider and patient preferences for information, and identified barriers to communication about immunotherapy. Methods: We qualitatively interviewed 15 oncology professionals who offer immunotherapy treatment about the information they deemed important to communicate to patients and the communication barriers. After a discussion about immunotherapy options with a provider, we interviewed 18 oncology patients about the information that was most useful to them and their impressions of immunotherapy. We captured impressions on two 1-5 scales with 5 being ‘very positive impression’ and ‘very likely to be cured’ and by picking words from a list of positive and negative terms like ‘effective’ and ‘risky.’ All open-ended questions were qualitatively coded. We reached saturation of themes with 18 patients. Results: Patients identified 4 useful topics to discuss: treatment options, benefits, treatment logistics, and side effects. Providers identified 3 topics important topics to convey: side effects, realistic view of benefit and treatment logistics. The most frequently provider-identified barrier to communication was patients’ baseline misconceptions about immunotherapy’s effectiveness. Supporting this, patients’ impressions were very positive (average of 4 on impressions scale and 3.9 on potential to be cured scale.) The most frequently chosen word patients chose to describe immunotherapy treatment was ‘hopeful’ (10/18 55%). Conclusions: There is largely agreement on the important topics to discuss about immunotherapy, though half of the patients thought a discussion of treatment options would be useful and only one physicians mentioned options. Of note, communication is hampered by patients’ preconceptions about immunotherapy’s effectiveness. Communication guidelines should identify techniques to effectively overcome this barrier.
Temporal trends in the intensity and duration of oncologic care among colorectal cancer (CRC) patients (pts).
Authors: Chen Leo , Spinelli John Joseph , Cheung Winson Y. , Kennecke Hagen F.
Published: September 2018

6552

Background: Substantial advances in therapy of CRC pts occurred between 2000 and 2012 contributing to a significant increase in overall survival. The objective of this study is to quantify the change in treatment (tx) intensity as measured by clinic and tx visits at a network of medical and radiation oncology clinics. Methods: Electronic scheduling records of stage I-IV CRC patients referred between 2000-2012 to the six oncology centers comprising the British Columbia Cancer Agency were reviewed and stratified by tx phases: I and II (adjuvant first 6 months, continued), III and IV (palliative first 6 months, continued), and V (last 6 months of life). Clinic Visit Intensity (CVI), Chemo Tx Intensity (CTI), number of chemo agents and number of cycles (CC), Radiotherapy (Rx) courses (RC) and fractions (RF) were measured, and trends by referral year were modelled using zero inflated negative binomial regression. Mean duration of visit for chemo tx (CHD) and clinic visits (CVD) were modelled using linear regression. Sex, age at diagnosis, stage, income, and community size were included in models if terms were significant. Results: 15,157 pts were included across 10 cohorts. CTI and CC increased significantly in tx phases II-V with later year of referral, while phase I results were stable or decreased, likely due to the substitution of oral for intravenous regimens. Rx increased only in advanced phases. Mean duration of scheduled time showed significant increases. Conclusions: CRC pts referred in 2012 vs 2000 receive significantly greater intensity and duration of care in tx phases II-V. Results have significant implications for resource allocation and the patient experience. [Table: see text]
Global Cancer Institute multidisciplinary tumor boards as a tool to improve patterns of clinical practice for breast and gynecologic cancer in resource-limited settings.
Authors: St. Louis Jessica , Bukowski Alexandra , Rodrigues Angelica Noguelra , Moreno Joel , Ferreyra Mayra , Lopes Andre , De La Serna Frances , Tindwa Chakou Halfani , Mollah Obayedullah Baki , Villarreal-Garza Cynthia , Duarte Carlos , Hambardzumyan Vahagn , Salman Pamela , Soria Tannia , Goss Paul E.
Published: September 2018

6556

Background: Multidisciplinary tumor boards (MTBs) are commonly practiced in high-income countries (HICs) to ensure adherence to guidelines through a team approach to patient care. The Global Cancer Institute (GCI) established online MTBs in 2012 to facilitate live telemedicine discussions of breast and gynecologic case scenarios between specialists in low- and middle-income countries (LMICs) and expert specialists in HICs. GCI MTBs aim to improve clinical knowledge and patterns of practice for specialists in LMICs through an interactive online forum. Methods: In each monthly MTB, three patient case scenarios are presented by specialists in LMICs for live discussion with an expert panel of specialists based in HICs. Guideline or clinical trial-based discussions are held for each case scenario. Best practices for clinical care in limited resource settings are also discussed. Links to clinical practice guidelines, clinical trials, and resources are provided to all MTB attendees. For educational purposes, each MTB is live streamed and uploaded to a private YouTube channel for viewing by community oncologists and trainees worldwide. Results: The GCI MTBs program has recruited over 500 LMIC participants from 48 hospitals in 24 countries across Latin America, Eastern Europe, Africa, and Asia. 17 expert breast cancer specialists and 13 expert gynecologic cancer specialists provide multidisciplinary guidance. To date, 130 breast cancer case scenarios and 80 gynecologic cancer case scenarios have been presented. For breast MTBs, 73% of case scenarios were invasive ductal carcinomas. Common subtypes presented were ER/PR+ (63%), HER2+ (30%), and triple negative disease (28%). 56 cases involved advanced disease management (43%). For gynecologic MTBs, common gynecologic cancer case scenarios were cervical (74%) and ovarian (15%). 37 cases involved advanced disease management (46%). Conclusions: GCI MTBs are a useful educational tool for specialists in LMICs to improve patterns of clinical practice and engage in multidisciplinary discussions. GCI continues to expand its MTBs to cancer facilities in LMICs.
Difference in cardiovascular disease incidence by sociodemographic factors in adolescent and young adult (AYA) cancer survivors.
Authors: Keegan Theresa , Kushi Lawrence H. , Li Qian , Brunson Ann , Malogolowkin Marcio H. , Wun Theodore
Published: September 2018

6565

Background: AYA cancer survivors are at increased risk of developing cardiovascular disease (CVD) compared to AYAs without a history of cancer. In AYA cancer survivors, few population-based studies have focused on CVD risk and none have considered whether the occurrence of CVD differs by sociodemographic factors. Methods: Analyses focused on 64,918 patients aged 15-39 y at diagnosis for one of 14 first primary cancers during 1996-2010 and surviving > 2 years after diagnosis, with follow-up through 2013. Data were obtained from the California Cancer Registry and State hospital discharge data. CVD included coronary artery disease, heart failure, and stroke. We estimated the cumulative incidence of developing CVD, accounting for death as a competing risk, stratified by race/ethnicity, neighborhood socioeconomic status (SES) at diagnosis, health insurance status at diagnosis/initial treatment and cancer type. We examined the impact of CVD on mortality using multivariable Cox proportional hazards regression with CVD as a time-dependent covariate. Results: Overall, 2374 (3.7%) patients developed CVD, and 7690 (11.9%) died over the follow-up period. Survivors of acute myeloid leukemia (12.6%), acute lymphoid leukemia (11.1%), central nervous system cancer (9.0%) and non-Hodgkin lymphoma (6.0%) had the highest incidence of CVD at 10-years. Incidence was significantly higher among Blacks (6.7%) at 10-years than non-Hispanic Whites (3.0%), Hispanics (3.7%) and Asian/Pacific Islanders (3.7%) (p < 0.001). AYA survivors with public or no insurance (vs private) had a higher 10-year incidence of CVD (5.8% vs 2.9%; p < 0.001), as did survivors residing in low (vs high) SES neighborhoods (4.1% vs 2.7%; p < 0.001). These sociodemographic differences in CVD incidence were apparent across most cancer sites. The risk of death was increased by five-fold or higher among AYAs who developed CVD. Conclusions: AYA cancer survivors who were uninsured or publicly insured, of Black race/ethnicity, or who resided in lower SES neighborhoods are at increased risk for developing CVD and experiencing higher mortality. The proactive management of CVD risk factors in these subgroups may improve patient outcomes.
Differences in mortality among patients with acute leukemia admitted on weekends as compared to weekdays.
Authors: Parikh Kaushal , Shah Mahek , Mehta Dhruv , Liu Delong
Published: September 2018

6576

Background: The association between weekend admissions and patient outcomes has been widely reported for several acute illnesses. However, this is the first study using a nationwide database to focus on outcomes of weekend admissions for acute leukemia. Methods: We used the 2002-2012 Nationwide Inpatient Sample Databases to identify patients admitted with a diagnosis of acute leukemia. Admissions were identified as weekend or weekday admissions and rates of mortality, in-hospital complications, existing comorbidities, and demographic differences were assessed. Adjusted logistic regression models were used to analyze mortality and complication outcomes. Results: Out of a total of 71,392 patients included in the analysis, 12,234 (17.1%) patients were admitted over the weekend. While there has been a general decline in admissions and mortality in acute leukemia from 2002-2012, mortality was 18.8% for weekend admissions and 16.3% for weekday admissions (p < 0.001). Weekend admissions independently predicted higher mortality (adjusted odds ratio 1.128, 95% confidence interval, 1.06 to 1.20; p < 0.001). These patients were also less likely to receive an early bone marrow biopsy than their weekday counterparts (45% vs 26.5%; p < 0.001). Bone marrow biopsy was independently associated with a reduced in-hospital mortality (aOR 0.395, 95% CI 0.373 to 0.417; p < 0.001). Admissions to teaching hospital were also associated with a lower mortality (aOR 0.890, 95% CI 0.845 to 0.936; p < 0.001). Weekend admissions were also more likely to have in-hospital complications than weekday admissions (52.4% vs 50.5%; p < 0.001). Conclusions: There was a significantly increased mortality among acute leukemia patients admitted on a weekend. Our study suggests that patients admitted over the weekend may be clinically sicker or receive inferior care than weekday admissions. We also conclude that patients admitted to teaching hospitals have a better outcome and emphasize the importance of availability of resources and early presentation to tertiary care centers.
Financial impact of flat dosed (FD) monoclonal antibodies (MABs) at a single institution in 2016.
Authors: Kane Michael P. , Silk Ann W. , Lee Fuwing , Auriemma Paul , Mehnert Janice M.
Published: September 2018

6617

Background: Immuno-oncology (I/0) agents represent an important, accelerated breakthrough in cancer therapy. Like other MABs, these agents have been adjusted after FDA approval to have a flat-dose. Purportedly, flat dosing simplifies prescribing, dispensing, inventory and billing. Nivolumab (N) and Pembrolizumab (P) achieved FDA approval in several malignancies. Original studies determined the dosing of N @ 3 mg/kg q2-weeks and P @ 2 mg/kg q3-weeks. Based on simulations from population pharmacokinetics models, the FDA approved a FD of N 240 mg in melanoma, RCC and NSCLC. The financial impact of this FD methodology in our patient population was compared with weight based dosing (3mg/kg) of N with a cap of 240 mg versus flat dosing. The potential impact of this change was also evaluated for P, including if a 50 mg vial of P was still available. Methods: Applicable dispensed doses (N & P) and patients’ weights for 2016 were mined from the electronic health record. Wholesale Acquisition Costs at end of year were used for financial comparison. Results: see table. Conclusions: Weight based dosing with a cap (N 240mg; P 200mg) versus flat dosing would have saved $198,567 and $80,037, respectively. Additionally, $760,351 would have been saved if 50 mg vials of P were available. With the current drug pricing structure, wide-scale adoption of flat dosing for I/O mABs may result in higher drug costs. Labeling I/O mABs with both weight-based and FD options and ensuring the availability of proper vial sizes, particularly multi-dose vials, to fit the population and dosing schema would restrain the costs of care. [Table: see text]
Price trajectories assessment for Medicare Part B generic anti-cancer drugs.
Authors: Gordon Noa , Ben-Aharon Omer , Stemmer Salomon M. , Greenberg Dan , Goldstein Daniel A.
Published: September 2018

6624

Background: Patented anti-cancer drugs launch prices have increased in recent years with subsequent increases after launch. Recently, large price increases of generic drugs were at the center of public attention in the United States. Our aim was to assess price changes with time for Medicare part B anti-cancer generic drugs and to understand how drug characteristics and market structure influence price trajectories. Methods: We included all Medicare part B anti-cancer drugs with price reported in both 2006 and 2016. Patent expiration dates were attached using the Medicare Drug Patent Expiration engine and drugs with a patent expiration date later than 2006 were excluded. Generic manufacturers' FDA approvals for each drug were extracted from the FDA Orange Book. For each drug we extracted the Average Sales Price (ASP) history from October 2006 to October 2016, published by the Center for Medicare and Medicaid services (CMS). Prices were adjusted for inflation, using information obtained from the United States Department of Labor. For each drug we calculated the cumulative ASP change during the follow-up period. Data were analyzed using IBM SPSS Statistics software. Results: We identified 31 anti-cancer generic drugs that met the inclusion and exclusion criteria. During the follow-up period, 15 (48%) drugs had increases in price (median 139%, range 18-2632%). Seven (23%) drugs increased by more than 200% (Table 1). Both gradual price and acute price increases were observed. Some of the drugs which had substantial price increases had no market competition market. Conclusions: Generic drug prices may change substantially with time. Gradual or rapid price increases may be due to lack of generic drug competition, substitution shortages or marketing reasons. New regulations may be needed to prevent further increases in generic drug costs, while balancing the need to maintain financial incentives for drug production and competition. [Table: see text]
Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX).
Authors: Harrison Claire N. , Vannucchi Alessandro M. , Platzbecker Uwe , Cervantes Francisco , Gupta Vikas , Lavie David , Passamonti Francesco , Winton Elliott F. , Dong Hua , Kawashima Jun , Maltzman Julia D. , Kiladjian Jean-Jacques , Verstovsek Srdan
Published: September 2018

7001

Background: MMB, an oral JAK inhibitor, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion requirements in patients (pts) with MF. This study of previously RUX treated pts with MF tested the superiority of MMB vs BAT in splenic volume reduction, Sx amelioration, and transfusion requirement at 24 weeks. Methods: Eligibility included primary or post-ET/PV MF; DIPSS high risk, Int-2, or symptomatic Int-1; prior RUX ≥4 weeks who either required transfusions or dose reduction to <20 mg BID with at least one of Gr ≥3 thrombocytopenia, anemia, or bleed; palpable spleen ≥5cm; and no Gr ≥2 peripheral neuropathy. Stratification was by transfusion dependency and baseline TSS (modified MPN-SAF Total Sx Score) <18 or ≥18. Pts were randomized 2:1 to 24 weeks of open-label MMB 200 mg QD or BAT. Assessments included spleen volume by MRI, and patient-reported Sx using a daily eDiary for TSS. 1° endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline). 2°endpoints, evaluated sequentially, were rates of TSS response (TSS RR; ≥50% reduction from baseline), RBC transfusion, RBC transfusion independence (TI) and RBC transfusion dependence (TD). Results: 73 of 104 (70%) and 40 of 52 (77%) pts receiving MMB or BAT, respectively, completed the 24 week randomized treatment phase. BAT for 88% of pts included RUX, and 27% of pts were on RUX in combination with other drugs. Efficacy results are in Table. The most common Gr ≥3 adverse events in MMB pts were anemia (13%) and thrombocytopenia (7%), and in BAT pts, anemia (13%), thrombocytopenia (6%) and abdominal pain (6%); treatment emergent peripheral neuropathy occurred in 11 (11%) of MMB (1 Gr3) and in no BAT pts. Conclusions: In previously RUX-treated patients with MF, 24 weeks of MMB was not superior to BAT for SRR, but significantly better in improving disease related symptoms and transfusion independence. Clinical trial information: NCT02101268. [Table: see text]
Factors associated with allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO) versus (v) conventional chemotherapy (C).
Authors: Kebriaei Partow , DeAngelo Daniel J. , Stelljes Matthias , Gökbuget Nicola , Kantarjian Hagop M. , Advani Anjali S. , Merchant Akil , Wang Tao , Loberiza Fausto Rodriguez , Sleight Barbara , Vandendries Erik , Marks David I.
Published: September 2018

7007

Background: InO therapy in R/R ALL resulted in superior complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates v C in the Phase 3 INO-VATE trial (NCT01564784; Kantarjian NEJM 2016). More InO v C pts proceeded to HSCT (41% [45/109] v 11% [12/109]; P<0.001). Factors associated with outcomes after HSCT are described. Methods: Full details have been published. Multivariate analyses (MVA) using Cox regression modeling were conducted to determine predictors of non-relapse mortality (NRM) and overall survival (OS). Results: As of 3/8/16, 108/326 pts underwent allogeneic HSCT (InO n=77; C n=31). Baseline characteristics were generally similar, except baseline platelet values were lower in InO v C pts. More InO v C pts achieved minimal residual disease negativity (MRDneg [best status]; 71% v 26%; P<0.0001). Less InO v C pts received additional therapy before HSCT (14% v 55%, P<0.0001). NRM rates were higher in InO v C pts at 1 year (yr; 36% [95% CI 26–47] v 20% [8–36]) and 2 yrs (39% [27–51] v 31% [13–51]), but relapse rates were lower (1 yr, 23% [15–33] v 29% [13–48]; 2 yrs, 33% [22–44] v 46% [24–65]). No significant difference in post-HSCT survival was detected in InO v C pts; however, visual inspection of the curve suggested the survival probability varied before and after 15 months post-HSCT (1 yr, 44% [95% CI 33–55] v 65% [44–79]; 2 yr, 39% [28–50] v 34% [15–54]). Fatal veno-occlusive disease (VOD) was observed in 5 InO pts (all during the first 100 days from the date of HSCT) and no C pts. MVA showed that conditioning regimens without dual alkylators and thiotepa were associated (2-sided; P<0.05) with lower risk of NRM and post-HSCT survival, respectively. Conclusions: Compared with C, InO permitted more pts with R/R ALL to proceed to HSCT in CR/CRi with MRDneg (best status). Despite increased NRM and fatal VOD, long-term survival was attainable in InO pts. In pts previously treated with InO, interventions to reduce NRM and improve OS after HSCT include avoiding dual alkylator conditioning regimens, especially those containing thiotepa. Funding: Pfizer Clinical trial information: NCT01564784.