tbuckley/cabot-search huggingface dataset:
An exploration of how a countries' HTA process can affect patient access.
Authors: Ashley Jaksa, Anson Pontynen, Alexander Bastian
Journal: Journal of Clinical Oncology (2017)

e18052 Background: Drugs in the USA become available from the moment of FDA approval. Access to oncology therapies outside of the USA may be delayed by regulatory and additional payer HTA processes. This study aimed to examine differences in oncology conditions that may impact time from regulatory approval to an HTA reimbursement decision in countries with mandatory HTA. Methods: Oncology HTAs (N = 569) for medicines approved by the EMA, Health Canada, and the Therapeutic Goods Administration (Australia) were matched on indication with HTAs from France, Germany, Canada, England, Scotland, and Australia. Resubmissions were excluded. The date of the first reimbursement decision was subtracted from the date of the regulatory approval to determine the time to issue a reimbursement decision. Trends by disease were examined. Results: The time between regulatory approval and reimbursement decision was significantly longer for solid-state oncology drugs than for hematology oncology drugs (mean 344 days vs. 280 days, respectively; p = 0.03). Within hematology oncology, Non-Hodgkin’s Lymphoma had the shortest time to a decision (229 days; n = 37) while Myelofibrosis had the longest (411 days; n = 3). For solid-state diseases, Sarcoma had the shortest time (5 days; n = 2) and Small-cell Lung Cancer had the longest (752 days; n = 5) time to a decision. Conclusions: Time to patient access to oncology medications varies by disease condition, which may reflect disease-related factors that impact assessment. The time to a decision for a hematology medicine was approximately two months shorter than the time to a decision for a solid-state medicine. It is possible that unmet need, budget impact, or competitive features within hematology conditions are driving the speed of assessments in these medicines. Further research is needed to determine why there are differences in time to decisions by oncology disease conditions.
Clinical trial of traditional Chinese medicine (TCM) bionic tiger-bone powder (TB) for the prvention of AI-associatied musculoskeletal symptoms (AMISS).
Authors: Wenping Lu, FeiFei Cui, Zhenhua Zhang, Yifan Li
Journal: Journal of Clinical Oncology (2016)

e14108 Background: Aromatase inhibitors (AIs) are used for adjuvant therapy of breast cancer which has resulted in noteworthy improvements in disease-free and overall survival, however toxicities of AI including AIMSS can negatively affect quality of life and lead to discontinuation . Most patients with breast cancer in China opt for TCM to manage them. TB is mainly used for the treatment of osteoporosis and other bone disease ,whose main ingredients are calcium and collagen. The objective of this study was to evaluate whether the TB prevented AIMSS in postmenopausal women with ER/PR+and early stage breast cancer. Methods: We conducted a randomized,blind ,controlled study of comparing TB versus placebo for 12 weeks (1.2 g three times daily) in postmenopausal women with stage 0-III breast cancer who have taken AI no more than one month . patients completed the Modified Brief Pain Inventory ( M-BPI), pain Visual Analog Scale (VAS), Functional Assessment of Cancer Therapy-Breast (FACT-B) at baseline and after 3 months of AI therapy.Joint symptom incidence rate and severity of the pain including average pain,worst pain, pain interference severity, stiffness, and joint symptom interference by (M-BPI) and VAS were used as the primary outcome. FACT-B were secondary outcomes. Serum samples obtained at the baseline and 12-week time point were assayed for estradiol (E2) and FSH Results: Of 72 women enrolled, 70 were evaluable. Baseline characteristics were comparable between the two groups.eight of thirty-five patients (22.9%) develped new or worsening jonit symptoms in TB group, compared to twenty-one of thirty-five (60%) in placebo (P < 0.001), We also found differences between two groups in average pain(2 to 5.6), worst pain(3.9 to 8), pain interference severity (1.9 to 5.3), stiffness (2.4 to6.9), and joint symptom interference (1.8 to 5.7), all P < 0.001; Similar findings were seen for VAS value (3.0 to 6.6 ) at the end of intervention. HR-QOL (health-related quality of life) measured by FACT-B (P < 0.05)was improved.No change of serum estrodiol and FSH between two groups. Conclusions: TB appeared to be effective and safe in the prevention of AIMSS. Clinical trial information: ChiCTR-IPR-15007081.
Phase I study of oncolytic virus (OV) MG1 maraba/MAGE-A3 (MG1MA3), with and without transgenic MAGE-A3 adenovirus vaccine (AdMA3) in incurable advanced/metastatic MAGE-A3-expressing solid tumours: CCTG IND.214.
Authors: Derek J. Jonker, Sebastien J. Hotte, Albiruni Ryan Abdul Razak, Daniel John Renouf, Brian Lichty, John C. Bell, Jean Powers, Caroline J Breitbach, David F Stojdl, Kyle B Stephenson, Jonathan L Bramson, Jeff Hummel, Chantal G Lemay, Jean-Claude Cutz, Julie Wells, Robin Eady, Xiaoqun Sun, Dongsheng Tu, Janet Dancey
Journal: Journal of Clinical Oncology (2017)

e14637 Background: OVs display oncolytic activity and boost adaptive cell immunity. MG1MA3 is a Maraba virus modified to express tumour antigen MAGE-A3. MG1MA3, both alone and after immune priming with a MAGE-A3 modified adenovirus (AdMA3) may trigger anti-tumour T-cell responses. Methods: N = 41 patients (pts) with MAGE-A3 expressing solid tumours were evaluated in 3 groups (A) Dose escalation of MG1MA3 iv d1+4, q8w (n = 9); (B) Single fixed dose AdMA3 1e10 pfu IM d1 (n = 6); (C) AdMA3 priming d(-14) followed by dose escalated MG1MA3 (d1+4, q8w) (n = 25). Arm A and C had a 3+3 design. Pre + post treatment blood and tissue biopsies were evaluated for viral and immune markers. Endpoints included MTD/MFD, RP2DL, safety, tolerability, pharmacokinetics, viral delivery and replication. Results: Dose limiting toxicities (hypoxia/dyspnea, vomiting, headache) occurred in 4 pts (2 each Arm A +C). RP2DL for arm C was AdMA3 1e10 pfu IM d(-14) then MG1MA3 1e11 pfu iv d1+4. Common treatment related toxicities on Arm C occurring hours to a few days after MG1MA3 included diarrhea, nausea, vomiting, anorexia, chills, fatigue, fever, flu-like symptoms, hypophosphatemia, headache, and hypotension. Preliminary tumour gene expression results reveal induction of pro-inflammatory genes, including chemokines (CCL2, CCL5, CX3CL1, CXCL10), acute phase response proteins (IL-6, TNF), antigen presenting cell (APC) activation markers (CD80, HLA-A, HLA-B), markers of APC and Natural Killer cell infiltration (CD56, CD68, TLR3), as well as a co-incident decrease in the suppressive cytokine TGF-β. MG1MA3 replication was observed in some pts, inferred by detection of circulating genomes on days 4, 8 and 15 after clearance of the input dose. Induction of anti-tumour immune responses (CD8 T cells and antibodies vs MAGE-A3) was demonstrated in 3 of 6 Arm C pts evaluated to date. In one patient, over 1% of circulating CD8 T cells were directed against MAGE-A3. Conclusions: AdMA3 prime followed by MG1MA3 OV boost is feasible with a defined RP2DL, and capable of inducing potent anti-tumour immune response. Alternate schedules will be evaluated. Clinical trial information: NCT02285816.
<i>ALK</i>-amplified circulating tumor cells as a surrogate marker for crizotinib benefit in <i>ALK</i>-rearranged non-small cell lung cancer patients.
Authors: Emma Pailler, Jordi Remon, Marianne Oulhen, Isabelle Borget, Kirsty Ross, Nathalie Auger, Fanny Billiot, Maud Ngocamus, David Planchard, Jean-Charles Soria, Francoise Farace, Benjamin Besse
Journal: Journal of Clinical Oncology (2016)

11515 Background: Duration of response in ALK-rearranged NSCLC patients treated by crizotinib is in the range of 10 months but all patients invariably acquire resistance. Using filter-adapted fluorescence in situ hybridization (FA-FISH) we previously reported ALK-rearrangement detection in circulating tumor cells (CTCs) from ALK-rearranged patients (Pailler et al., J Clin Oncol., 2013). Here we report the monitoring of ALK-rearranged and ALK-amplified CTCs under crizotinib therapy in an extended cohort of ALK-rearranged patients. The correlation between CTC subsets harboring distinct FISH patterns and clinical parameters including progression-free survival (PFS) and overall survival (OS) is presented. Methods: Forty ALK-rearranged patients were recruited of whom one was not evaluable. Blood samples were collected at baseline and at an early time point (1-3 months). Abnormal ALK-FISH patterns were examined in CTCs using immunofluorescence staining (DAPI/CD45) combined with FA-FISH after isolation by size of epithelial tumor cells (ISET) filtration. CTCs were defined into distinct subsets according to the number of FISH ‘break-apart’ signals (3’ and 5’) or isolated red signals (3’) and/or native copies (3’/5’). All ALK-abnormal cells were validated by a cytogeneticist. Clinical data was collected retrospectively. Results: ALK rearrangement was detected in CTCs: 32/39 patients (82%) had ≥4 ALK-rearranged CTCs per 1 ml of blood. Age ≥60 years (36%) and smoking status ≥15 pack years (33%) were associated with a higher mean number of ALK-amplified CTCs (p=0.0361 and p=0.0023 respectively). Using log-rank test, we observed a significant correlation (p=0.0255) between the evolution under crizotinib of the numbers of ALK-amplified CTCs and PFS. An increase in the numbers of ALK-amplified CTCs during treatment is associated with a PFS of 6 months, while a decrease in this subset is associated with a PFS of 13.9 months. There was no corresponding correlation with OS. Conclusions: Our data suggest that variation of ALK-amplified CTCs may be a surrogate biomarker for crizotinib benefit in ALK-rearranged NSCLC patients.
A phase I study of sequential ipilimumab in the definitive treatment of node positive cervical cancer: GOG 9929.
Authors: Jyoti Mayadev, William E. Brady, Yvonne Gail Lin, Diane M Da Silva, Heather A. Lankes, Paula M. Fracasso, Sharad A. Ghamande, Kathleen N. Moore, Huyen Q. Pham, Kelly Jeanes Wilkinson, Vanessa Amy Kennedy, Carol Aghajanian, Wui-Jin Koh, Bradley J. Monk, Russell J. Schilder
Journal: Journal of Clinical Oncology (2017)

5526 Background: The outcome of lymph node positive (LN) cervical cancer (CC) with chemoradiation (CRT) is dismal, especially with involved para-aortic nodes (PAN). The anti-CTLA-4 immune checkpoint inhibitor ipilimumab (ipi) holds promise. We report the safety, tolerability, and efficacy in this GOG phase I study examining sequential ipi after CRT for CC. Methods: Patients (pts) with LN CC were treated with 6 weekly doses of cisplatin (40 mg/m2) and extended field radiation (RT). 2-6 weeks after RT, if there was no progression of disease, sequential ipi was given at the following dose levels: dose level 1: 3mg/kg, level 2: 10mg/kg, and an expansion cohort of 10mg/kg. The primary endpoints (endpts) were the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of adjuvant ipi. Secondary endpt included the 1-yr disease free survival (DFS). Translational endpts included the effect of CRT on enumeration and subsets of T-cells, and CTLA4, PD-1 and ICOS expression. Results: 34 pts were enrolled, and 19 pts are evaluable for the endpts: 14 pts went off study to reasons unrelated to the study drug, 1 pt continues in her DLT evaluable period. Of the evaluable pts, all had pelvic LN, with 25% PAN. All pts completed CRT, 90% had 4 cycles of ipi, and the other 10% had 2 cycles of ipi. The ipi MTD was 10 mg/kg. There were 3 pts (16%) with acute grade 3 toxicity (lipase, ↓ANC, rash) which self-resolved. Most of the acute toxicities were grade 1-2 GI distress, rash, endocrinopathies. There were no minor or major RT quality deviations. With a median follow up of 12 months, there were no major late toxicities reported, with a 1-year DFS of 74%. There was no difference in CD4 + - and CD8 + - T cell levels nor CTLA-4 expression with sequential ipi. CRT itself increased ICOS and PD-1 expression. Conclusions: This study is the first to describe the safety of immunotherapy sequencing with definitive CRT in CC. Our data suggests that immunotherapy is tolerable and shows possible activity in this population with a historical dismal prognosis with standard therapy. CRT increased ICOS and PD-1 expression which was sustained with ipi, illustrative of immune modulation targets for future clinical trials and radioimmunotherapy combinations. Clinical trial information: NCT01711515.
Challenges in implementing a guideline for the early diagnosis of suspected ovarian cancer in Ireland.
Authors: Marie Laffoy, Regina Codd, Lois OConnor, Barbara McGrogan, Catherine Duffy, Triona McCarthy, Jerome Coffey
Journal: Journal of Clinical Oncology (2016)

e17062 Background: Ovarian cancer is the main cause of gynaeocological death in Ireland (incidence 14.8/100,000). Most patients present with advanced disease. Ireland’s five-year survival, under 40%, compares poorly internationally. Ovarian cancer screening is not national policy but early diagnosis of symptomatic women is a priority. Methods: A guideline was developed for the investigations appropriate in primary care and referral criteria to gynae-oncology. This followed NICE guidance1. Multiple challenges emerged in implementing the guideline, including concern among family physicians regarding their access to CA125 and pelvic ultrasound testing, fears among radiologists about over-referral for ultrasound testing, concern among gynae-oncologists regarding referral of large numbers benign ovarian lesions and desire by ovarian charities for speedy implementation of the guideline. Results: Research was undertaken to identify and overcome implementation barriers. A national survey of CA125 access for family doctors showed that two geographic regions provided no CA125 access to them. A national survey of ultrasound access for family doctors showed the median wait time for urgent pelvic ultrasound was 2.5 days (range 1-90 days) but one large geographic area provided no access to family physicians. There was a large variation in ultrasound activity in hospitals with similar facilities. There was no national standardized approach for the surveillance of benign ovarian lesions. Collaboration with Acute Hospital and Primary Care Directorates was undertaken to rectify each deficit. A pilot study of the guideline was undertaken among 180 family doctors and one major hospital (catchment population 500,000). After three months there were only ten referrals to ultrasound and no increase in CA125 testing. It is now intended to implement the guideline nationally. Conclusions: Initiatives such as this are complex. They involve multiple specialties that may already be working with scarce resources. It is essential that all organisational problems are rectified prior to changing the structure of services. This guideline should lead to the earlier diagnosis of ovarian cancer and streamline the diagnostic pathway.
Neoadjuvant chemotherapy (NAC) with dose-dense gemcitabine/cisplatin (DDGC) in localized muscle-invasive bladder cancer (MIBC).
Authors: George Tsironis, Roubini Zakopoulou, Konstantinos Koutsoukos, Kimon Tzanis, John Varkarakis, Athanasios Papatsoris, Kostas Stravodimos, Efthymios Kostouros, Charalampos Fragkoulis, Theodosia Choreftaki, Dimitrios Filippiadis, Sofia Fontara, Athanasios Dellis, Sparti Ntai, Anna Zygogianni, Konstantinos Ntoumas, Constantinos A Constantinides, Penelope Korkolopoulou, Meletios A. Dimopoulos, Aristotelis Bamias
Journal: Journal of Clinical Oncology (2018)

e16527 Background: NAC prior to radical cystectomy (RC) with MVAC or GC represents a standard for non-metastatic MIBC. DDGC has shown similar efficacy and favorable toxicity to DDMVAC in metastatic disease. Neoadjuvant DDGC has shown encouraging efficacy but concerns due to increased incidence of serious vascular events have been raised. For this reason, we analyzed our experience of DDGC as NAC in MIBC. Methods: Patients (pts) with non-metastatic MIBC (cT2-T4a) received NAC with 4 Cycles of DDGC (2500mg/m2, 70mg/m2) and G-CSF support every 2 weeks. Efficacy and safety were the primary end-points of the analysis. Clinical lymph-node involvement (cN+) was assessed radiologically. In pts eventually not undergoing RC, response to NAC was assessed with TURB-T, urine cytology and CT scan of chest, abdomen and pelvis. Results: 44 pts received NAC from 19/01/2012 to 2/10/2017: median age 68 (37-82); cT1: 1 (2.3%), cT2 39 (88.6%), cT3 2 (4.5%), cT4a 1 (2.3%), no muscle included 2 (4.5%); hydronephrosis 10 (23%); pure TCC 42 (96%); cN+ 8 (18%). 41 pts (93%) received all 4 cycles of NAC. Post-chemotherapy management included: RC in 29 (66 %) pts, Radiotherapy in 7 (16%) and non-surgery/non-RT in 8 (18%). Median time from NAC completion to cystectomy was 5.8 weeks. Following RC, pT0 was found in 5/28 (18%) and ≤pT1 in 11/28 (39%) pts. Complete response (CR) rate for pts not undergoing RC was 39%. Among 5 pts with cN+ who underwent RC, 2 achieved pN0. Median follow-up was 18 months (95% CI: 10-41). 1, 2 and 3 year disease-free survival rates were 81% (95% CI: 56-92), 67% (95% CI: 39-84) and 67% (95% CI: 39-84), respectively. Grade ≥3 toxicities were reported in 5 (11%) pts: thrombocytopenia (2 pts), non-neutropenic sepsis, GI hemorrhage, electrolyte abnormalities. No vascular events were reported during follow-up. Conclusions: Our analysis did not confirm excessive vascular toxicity by NAC DDGC. NAC achieved pN0 in 2 among 5 pts with cN+ disease. pCR rate was modest, probably due to the inclusion of cN+ disease and the selection of patients with best response to NAC for bladder preservation. Shortening the time to cystectomy from the end of NAC represents an important target.
Uptake of pediatric-inspired acute lymphoblastic leukemia (ALL) regimens by adult oncologists treating adolescent and young adults (AYA): A population based analysis across Northern California.
Authors: Parveen Shiraz, Daphne Lichtensztajn, Scarlett Lin Gomez, Theresa H.M. Keegan, Lori S. Muffly
Journal: Journal of Clinical Oncology (2016)

7031 Background: Studies show superior outcomes for AYA ALL patients treated following pediatric, as opposed to adult, ALL regimens. Whether adult oncologists have adopted this treatment approach to AYA ALL is not currently known. We sought to provide a population based description of the landscape of AYA ALL treatment over the past decade. Methods: Data on AYAs aged 15-39 years and diagnosed with ALL between 2004-2014 in Northern California was obtained from the Greater Bay Area Cancer Registry. Treating hospital and provider were designated as pediatric or adult. Induction treatment regimen was abstracted from a text data field. Results: Of 304 eligible AYAs with ALL, complete treatment regimen data could be abstracted for 229 (75%). Location of care could be identified for 296 (97%), of whom 70% were treated at adult centers. AYAs aged 19-24 were increasingly treated in pediatric centers over time (P = 0.003). Location of care did not change over time in younger or older AYAs. All AYAs treated at pediatric centers received pediatric regimens. Prior to 2008, none of the AYAs treated by adult oncologists received pediatric regimens. In 2008-2012, while C10403 was open to accrual, 31% of AYAs treated by adult oncologists received pediatric regimens, but this fell to 21% in 2013-2014. Those treated at high volume adult centers ( ≥ 4 AYA ALL patients/year) were more likely to receive pediatric regimens than those treated at low volume centers (P < 0.0001). Conclusions: As of 2014, < 25% of AYAs with ALL treated at adult centers in Northern California received pediatric regimens. Investigation into the barriers that preclude the use of pediatric ALL regimens by adult oncologists is warranted. Treatment regimens administered in adult setting to AYA ALL patients 2004-2014. Regimen Total N = 149 2004-2007 N = 36 2008-2012 N = 84 2013-2014 N = 29 Adult ALL Regimen 117 (79%) 36 (100%) 58 (69%) 23 (79%) Hypercvad 45 11 23 11 Adult CALGB Regimen 41 16 20 5 Linker Regimen 26 5 15 6 Other Adult Regimen 5 < 5 0 < 5 Pediatric Inspired Regimen 32 (21%) 0 (0%) 26 (31%) 6 (21%) C10403 (on or off study) 27 0 24 < 5 COG/POG Regimen 5 0 < 5 < 5
The prognostic role of gender, race and human papillomavirus (HPV) in oropharyngeal squamous cell cancer (OPC) and non-oropharyngeal head and neck squamous cell cancer (non-OP HNC).
Authors: Carole Fakhry, William H. Westra, Steven Wang, Annemieke VanZante, Yuehan Zhang, Eleni Marie Rettig, Alicia Wentz, Young Jun Kim, Justin A. Bishop, Wayne Koch, Christine Gail Gourin, Jeremy Richmon, David Eisele, Gypsyamber D'Souza
Journal: Journal of Clinical Oncology (2016)

6068 Background: HPV tumor status is a well-established prognostic marker in OPC. Gender and racial/ethnic differences in prognosis have not been well explored in OPC due to limited numbers of women and non-whites in studies. Additionally, the prognostic role for HPV in non-OP HNC remains controversial. Therefore, survival differences were explored among OPCs by gender and race in the context of HPV tumor status and non-OP HNCs by HPV tumor status. Methods: Retrospective multi-institution study including OPCs and non-OP HNCs of oral cavity, larynx and nasopharynx diagnosed 1995-2012. Women and non-whites were oversampled. Race/ethnicity categories used included White non-Hispanic, Black non-Hispanic and Asian/Hispanic of any race. HPV tumor detection consisted of p16 immunohistochemistry and HPV in situ hybridization (ISH; for HPV16 and any high-risk HPV). Tumors that were HPV16 and/or high-risk positive were considered HPV ISH-positive. Kaplan Meier and Cox proportional hazards models were used to evaluate overall survival (OS). Results: Study population included 239 OPCs and 625 non-OP HNCs with median follow-up time of 42.5 and 42.3 months, respectively. Univariate factors associated with better OS for OPC included younger age, lower stage, female gender, Asian/Hispanic race/ethnicity, not currently smoking, and HPV-positive tumor status (ISH: HR 0.34, p < 0.001; p16: HR 0.46, p = 0.01). After controlling for HPV ISH, age, current smoking, and stage, risk of death was significantly lower for women relative to men (HR 0.54, p = 0.04) and Asian/ Hispanics compared to Whites (HR 0.35, p = 0.06). Among non-OP HNCs, univariate factors associated with OS included age, stage, race, current smoking and alcohol use, and anatomic site. Tumor HPV ISH and p16 were not associated with OS. In multivariate analysis, significant risk factors for better OS included younger age, lower stage and not currently smoking (each p < 0.01). Conclusions: In OPC, there are marked differences in survival by gender and race, even after accounting for HPV tumor status. In non-OP HNCs, HPV tumor status whether measured by ISH or p16 has no prognostic significance.