bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I dose escalation of stereotactic body radiation therapy and concurrent cisplatin for re-irradiation of unresectable, recurrent head and neck squamous cell carcinoma.
Authors: Echevarria Michelle , Chung Christine H. , Kirtane Kedar , Muzaffar Jameel , Arrington John , Farinhas Joaquim , Caudell Jimmy J.
Published: May 2020

6543

Background: For patients with unresectable, previously radiated, locoregionally recurrent head and neck cancer, stereotactic body radiation therapy (SBRT) has become an attractive option. The use of high daily doses of radiotherapy may overcome the inherent radioresistance of these recurrent cancers. Given the resistant and advanced nature of many of these cancers, the addition of chemotherapy to radiotherapy is typically recommended as a radiosensitizer. We therefore performed a phase I clinical trial in order to establish a maximum tolerated dose of SBRT with concurrent chemotherapy in locoregionally recurrent head and neck cancer. Methods: Major inclusion criteria were recurrence of previous squamous cell carcinoma of the head and neck in patients who had previously undergone radiotherapy to doses ≥ 45 Gy to the area of recurrence, ≥ 6 months prior to enrollment, and who were medically unfit for surgery, deemed unresectable, or refused surgery. Patients were treated with radiation therapy every other day for five fractions at three dose levels; 30 Gy, 35 Gy, and 40 Gy. Cisplatin was given prior to every SBRT fraction at a dose of 15 mg/m2. Patients were monitored for safety and tolerability for any grade 4 or greater toxicity (per CTCAE v4.0) that occurred within 3 months from the start of SBRT. Primary end point was maximum tolerated dose (MTD). Results: Twenty patients were enrolled and of those 17 patients were evaluable for the primary endpoint. Nine patients had a primary tumor in the oropharynx, four patients in the oral cavity, three in the neck, one in the larynx, and one simultaneously in the larynx and neck. Of the three patients that were not evaluable two withdrew consent, and one patient in the 30 Gy dose level died of unknown causes two weeks following completion of treatment. Due to safety concerns the 30 Gy dose level was expanded an additional three patients, and no further dose limiting toxicities (DLTs) were observed. At the 35 Gy and 40 Gy dose level there were no reported grade 4 or 5 adverse events (per CTCAE v4.0). There were 5 (27%) reported grade 3 toxicities and 12 (66%) grade 2 toxicities. Conclusions: This phase I study demonstrates that 40 Gy SBRT with concurrent cisplatin at a dose of 15mg/m2 is feasible, safe, and well tolerated. Patients continue to be followed for secondary outcomes of local control and overall survival. Clinical trial information: NCT02158234 .
Molecular biomarkers to identify patients (pts) who may benefit from durvalumab (D; anti-PD-L1) ± tremelimumab (T; anti-CTLA-4) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) from HAWK and CONDOR studies.
Authors: Li Weimin , Matakidou Athena , Ghazoui Zara , Si Han , Wildsmith Sophie , Morsli Nassim , Mann Helen , Wrona Magdalena , de Los Reyes Melissa , Raja Rajiv , Barker Craig , Whiteley Jessica , Zhang Qu , Fayette Jerome , Zandberg Dan Paul , Mesia Ricard , Siu Lillian L.
Published: May 2020

6548

Background: Baseline tumor and germline biomarkers in R/M HNSCC were analyzed for predictive potential in pts benefitting from D or D+T. Methods: In HAWK (NCT02207530), 112 pts (PD-L1 tumor cells [TC]≥25%) received D (10 mg/kg Q2W for ≤12 m); in CONDOR (NCT02319044), 67 pts (PD-L1 TC < 25%) received D (10 mg/kg Q2W for ≤12 m), 133 pts received D+T (D 20 mg/kg Q4W, T 1 mg/kg Q4W for ≤12 m), and 67 pts received T (10 mg/kg Q4W [7 doses] then Q12W [2 doses] for ≤12 m) VENTANA PD-L1 (SP263) Assay determined PD-L1 status. Paired FFPE archival tumor and PBMC samples (as germline control) in the HAWK and CONDOR trials were evaluated by whole exome sequencing (WES). Tumor mutation burden (TMB) was number of somatic mutations/megabase. HLA class I types were obtained via WES of PBMCs (CONDOR only). HPV and neutrophil-to-lymphocyte ratio (NLR) were tested locally in CONDOR. Wilcoxon, log-rank tests, and COX-PH models were used. Pooled D & D+T data were analyzed unless noted. Results: 153 pts had paired evaluable FFPE tumor and PBMC samples (HAWK, n = 48; CONDOR, n = 105). TMB distributions were similar between studies ( P= 0.43). TMB correlated with smoking ( P= 0.02) but not HPV ( P= 0.24), NLR ( P= 0.66), or PD-L1 status ( P= 0.43). Overall, high TMB (≥upper tertile) trended with longer OS vs low TMB in all evaluable pts (N = 153; 9.0 vs 5.6 m; HR = 0.70; 95% CI = 0.48-1.01); P= 0.06). In HAWK, there was no association of TMB with OS. In CONDOR, pts (D and D+T arms) with high TMB vs low had significantly longer OS (N = 76; 16.3 vs 5.3 m; HR = 0.53; 95% CI = 0.31-0.92). TMB and OS association was further assessed by increasing TMB cutoffs. Improved HRs trended with higher cutoffs; cutoffs ≥upper quartile significantly linked to OS.TMB was not associated with PFS or ORR. Pts with low PD-L1 and low TMB had worse OS compared to pts with high PD-L1 or high TMB. Pts with high NLR (≥median) and low TMB had significantly worse OS than pts with low NLR and high TMB (HR = 2.63, P< 0.001). Analysis of germline HLA alleles revealed significantly poorer survival for carriers of the HLA-B*15:01 allele (9.4%) (HLA-B variant status did not affect TMB and OS association in CONDOR). Germline HLA heterozygosity did not impact OS. Pts with mutations in ATM (5%), a DNA damage repair gene, also trended with prolonged OS. Conclusions: TMB is a possible predictive biomarker of IO HNSCC therapy. Combined analysis of NLR and TMB may provide additional PD-L1 data in assessing pts most likely to have long-term benefit. Clinical trial information: NCT002207530, NCT02319044 .
Prognostic role of pre-treatment magnetic resonance imaging (MRI) radiomic analysis in patients with squamous cell carcinoma of the head and neck (SCCHN).
Authors: Alfieri Salvatore , Romanò Rebecca , Bologna Marco , Calareso Giuseppina , Mirabile Aurora , Ferri Andrea , Marcantoni Alessandra , Grosso Enrica , Tarsitano Achille , Valerini Sara , Vecchio Stefania , Deantonio Letizia , Blengio Fulvia , Ibrahim Toni , Mancinelli Moela , Ascoli Francesco , Bossi Paolo , Locati Laura Deborah , Mainardi Luca , Licitra Lisa F.
Published: May 2020

6553

Background: Emerging data suggest that radiomics can be used to predict outcomes in SCCHN. At present, only few data are available for pre-treatment MRI. Methods: Study population was retrieved from an ongoing multicenter, randomized, prospective trial (NCT02262221, HETeCo) evaluating health and economic outcomes of two different follow-up (FUP) strategies (intensive vs non-intensive) in effectively cured stage III-IV (VIII TNM ed.) SCCHN. We selected only patients with both pre- and post-contrast enhancement T1 and T2-weighted baseline MRI (b-MRI) and at least 2 years (2y) of FUP. A radiomic model was developed to identify high risk (HR) and low risk (LR) of disease recurrence. Radiomic features (RF) were extracted from the primary tumor in the b-MRI. The best RF combination was selected by Least Absolute Shrinkage and Selection Operator (LASSO). Ten-fold cross-validation was used to compute sensitivity, specificity and area under the curve (AUC) of the classifier. Kaplan-Meier (KM) curves were estimated for HR and LR, for both overall survival (OS) and disease-free survival (DFS) and log rank test was performed. Three years (3y)-DFS and OS were also estimated for the two groups. The radiomic risk class was used as a new variable in a multivariate Cox model including well established prognostic factors in SCCHN (TNM stage, subsite and HPV). Results: Out of 155 enrolled HETeCO patients, 98 baseline imaging were retrieved of which 57 b-MRI. Of these, 51 met the eligibility criteria (25 in intensive and 26 in non-intensive arm). Baseline patients’ characteristics were: median age 66 yr (38-86); sex (M 42; F 9); median smoking history: 30 packs/y (1-100); 25 oral cavity (49%), 18 oropharynx (35%, 14 HPV+), 6 larynx (12%), 2 hypopharynx (4%). At a median FUP of 42 months (25-64), 45 (88%) patients are still alive. The recurrence rate was 20% (10/51, of which 2 distant). In total, 1608 RF were extracted. The sensitivity, specificity and AUC of the classifier were 90%, 76%, and 80%, respectively. The radiomic risk class was found to be an independent prognostic factor for both DFS and OS (p=0.01 and p=0.046, respectively). KM curves for DFS and OS were significantly different between HR and LR groups (p=0.002 and p=0.04, respectively). In HR vs LR, 3-y DFS and OS were: 78% [61-100%] vs 97% [90-100%], and 88% [75-100%] vs 96% [88-100%], respectively. Conclusions: Radiomics of pre-treatment MRI can predict outcomes in SCCHN. External validation of this preliminary radiomics-based model is currently ongoing.
Association of radiation treatment failure in head and neck cancer with differential immune infiltrate.
Authors: Abdelhakiem Mohamed , Bao Riyue , Ferris Robert L , Pickering Curtis R. , Skinner Heath Devin
Published: May 2020

6558

Background: Previously we have shown that PD-L1 expression is associated with treatment failure in Head and Neck Cancer (HNSCC) treated with radiation. We have further evaluated the effect of pre-treatment immune infiltrate on treatment failure following radiation. Methods: A total of 75 patients with HPV negative HNSCC treated with surgery and post-operative radiation were included in this study. Pre-treatment tumors were examined via RNA-Sequencing utilizing an Illumina platform. These data were then subjected to immune profiling utilizing publicly available software (xCell) to infer relative enrichment of immune cell infiltrate per sample. Each immune cell type detected at any level in at least 15 tumors was then evaluated for effect on loco-regional recurrence using Cox-regression analysis. Clinical variables included in this analysis include tumor stage, nodal stage and treatment site. Survival analysis was performed utilizing the method of Kaplan Meier, with log rank statistics used to test for significant comparisons. Results: The majority of HNSCCs analyzed in this study were from the oral cavity (65.3%), followed by the larynx and hypopharynx (28%) and oropharynx (6.7%). The total median dose of radiation delivered was 60 Gy (range: 36-79.2) and median follow up in living patients was 80.5 months (range: 7-190). On univariate analysis, no measured clinical variable was significantly associated with loco-regional recurrence (LRR). Similar to our previous studies in other HNSCC cohorts treated with radiation, PD-L1 expression was negatively associated with LRR (p = 0.005). Additionally, multiple immune cell infiltrates were negatively associated with LRR including: Th2 helper cells (p = 0.007), CD8+ central memory T cells (p = 0.02), immature dendritic cells (p = 0.037), CD4+ memory T cells (p = 0.043). In a multivariate model including these immune cell subsets, Th2 helper cells, CD8+ central memory T cells and immature dendritic cells remained significantly negatively associated with LRR following radiation. Conclusions: This analysis demonstrates the importance of pre-treatment immune infiltrate on outcomes in HNSCC and points to potential avenues to explore to augment response to radiation.
Prognostic value of radiological extranodal extension detected by computed tomography for predicting outcomes in head and neck squamous cell cancer patients treated with radical chemoradiotherapy.
Authors: Mahajan Abhishek , Chand Ankur , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Sable Nilesh , Ahuja Ankita , Menon Nandini Sharrel , Agarwal Jaiprakash , Laskar Sarbani Ghosh , D'Cruz Anil , Chaturvedi Pankaj , Chaukar D. , Pai P. S. , Pantvaidya Gouri , Thiagarajan Shivakumar , Vaish Richa , Rane Swapnil , Prabhash Kumar
Published: May 2020

6560

Background: As per the AJCC 8th edition ENE/ECS is the most important predictor for N staging of HNSCC and is one of the key predictor of outcomes. Because ENE/ECS is based on pathological findings after surgery and it is difficult to predict outcomes for locally advanced squamous head and neck cancer (LASHNC) treated radically with CCRT. We hypothesized that ENE assessed by CT imaging (rENE) may directly correlate with outcomes in LASHNC treated radically with CCRT. Methods: This open-label, investigator-initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with LASHNC who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66-70 grays) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT). 536 patients were accrued,182 were excluded due to non-availability DICOM CT scan, 354 patients were analysed for rENE (based on 6 criterion for metastasis and 3 for rENE). Near equal distribution of patients was achieved in CRT arm (170 patients) and NCRT arm (184 patients). There were 181 (51.1%) oropharynx and 173(48.9%) larynx and hypopharynx patients. We evaluated association of radiological ENE and clinical outcomes.The endpoints were disease-free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). Results: There were 244(68.9%) patients with radiologically metastatic nodes, out of which 140(57.3%) had rENE. There was no significant association between rENE and CRT (p value 0.3) or NCRT (p value 0.412). The median follow-up was 33.0 months (95%CI 30.7-35.2 months). Complete response was achieved in 204 (57.6%) cases, PR/SD in 126(35.6%) cases and PD in 24(6.8%) cases. rENE positive patients had poor overall 3-year survival (46.7%), poor DFS (48.8%) and LRC (39.9%) than rENE negative cases (63.6%, 87%, 60.4%). rENE positive cases had 1.71 times increase chances of incomplete response than rENE negative cases. Overall stage, clinical positive node, response, rENE and site were the only significant factors for predicting OS, DFS and LRC. Conclusions: In conclusion, pre-treatment rENE can be regarded as an independent prognostic factor for survival (OS, DFS, LRC) in patients with LASHNC treated radically with CCRT. Pre-treatment rENE is not only associated with CCRT response but is also associated with poor prognosis and hence rENE, as an imaging biomarker, can stratify responder’s vs non-responders. Clinical trial information: CTRI/2014/09/004980 .
Detection of somatic mutations in saliva of patients with oral cavity squamous cell carcinoma.
Authors: Izumchenko Evgeny , Hasina Rifat , Hariharan Arun K , Shanmugam Ashwini , Irusappan Sivaraj , Maji Shiuli , Bahadur Urvashi , Veeramachaneni Vamsi , Bettadapura Radhakrishna , Ravichandran Aarthi , Hariharan Ramesh , Gupta Vaijayanti , Rao Vishal Uchila Shishir , Bagadia Ritvi K , N.M.L Manjunath , Lingen Mark W. , Agrawal Nishant
Published: May 2020

6562

Background: Oral cavity squamous cell carcinoma (OCSCC) frequently presents as clinically advanced disease with poor prognosis. When diagnosed at early stages, survival rates approach 80%, underscoring the need for validated, cost-effective detection methods. OCSCC is driven by the serial acquisition of genetic alterations. Tumor-defining somatic mutations are attractive biomarkers and hence their presence in saliva may be associated with malignancy as shown in a few proof-of-concept studies, including our previous work. Based on this premise, we present a low-cost, accurate, next generation sequencing (NGS) test with high clinical utility aimed at detecting mutations in the saliva for early diagnosis and potential screening of OCSCC. Methods: We have designed a custom NGS panel that covers exons of 7 most frequently mutated genes in OSCC. This minimal gene set derived from the analysis from 3 public datasets, predicted incidence of at least one somatic aberration in 89% of patients. We recruited 91 treatment-naïve OCSCC patients and profiled DNA from tissue and matched pre-operative saliva using this test. We also tested DNA from 12 subjects with premalignant lesions with high-grade oral dysplasia and matched saliva. Results: Using stringent variant calling criteria, at least one somatic variant was detected in 88 (96%) of the 91 primary tumors. 90.9% of the matched saliva were concordant, with only a minor decrease in early stage disease. Tumor-specific mutations (≥5% AF) in driver genes were detected in 10 (83.3%) dysplastic lesions, suggesting that driving clonal events may occur early in disease development. Interestingly, in 3 matched saliva of the dysplastic samples, the same mutations were detected. To ensure a variant is not a false positive call, we performed a vigorous multistep analytical validation of this saliva-based test: (i) independent re-sequencing of 24 saliva confirmed 94% reproducibility; (ii) no functionally relevant variants were detected in saliva from 12 of 13 healthy subjects without history of tobacco and alcohol usage; (iii) reproducibility, sensitivity, and specificity were confirmed using a positive control with 7 loci at 0.25% AF across 8 independent saliva sequencing runs and a certified negative control and was found to be on par with droplet digital PCR. Conclusions: These data highlight the feasibility of saliva-based testing for early diagnosis of OCSCC and premalignant lesions.
SNOW: Sitravatinib and nivolumab in oral cavity cancer (OCC) window of opportunity study.
Authors: Oliva Bernal Marc , Araujo Daniel Vilarim , Chepeha Douglas Brian , Prawira Amy , Spreafico Anna , Bratman Scott Victor , Shek Tina , de Almeida John R , Hansen Aaron Richard , Hope Andrew J. , Goldstein David Paul , Weinreb Ilan , Perez-Ordonez Bayardo , Pugh Trevor John , Ohashi Pamela S , Wang Ben X , Irish Jonathan Crawford , Der-Torossian Hirak , Chen Isan , Siu Lillian L.
Published: May 2020

6569

Background: Sitravatinib (receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) is predicted to increase M1-type tumor-associated macrophages (TAMs) and decrease MDSCs in the tumor microenvironment. SNOW is a window-of-opportunity study evaluating the immunogenic and antitumor effects of preoperative sitravatinib and nivolumab in patients (pts) with OCC. Early results demonstrated the combination was safe and active (Oliva et al, SITC 2019). Biomarker analyses and updated results are presented. Methods: Pts with untreated T2-4a, N0-2 or T1>1cm-N2 OCC are eligible. All pts receive oral sitravatinib 120mg daily from day (D) 1 up to 48h pre-surgery and 1 dose of Nivolumab 240mg on D15. Surgery planned between D23-D30. Standard of care adjuvant radiotherapy given based on clinical stage. Tumor pictures, fresh tumor biopsies, blood samples taken at baseline, D15 and pre-surgery. Tumor flow cytometry and multiplex immunofluorescence staining performed on all biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing (WES) performed on baseline biopsies. Results: As of Jan 31st 2020, 10 out of 12 planned pts were enrolled. Study treatment was well-tolerated: only 1 pt had grade (G) >3 toxicity (hypertension) and 1 pt required surgery delay due to G2 thrombocytopenia. None had intraoperative complications. 1 pt had wound infection and tracheostomy bleeding 11 days post-surgery, possibly-related to study drugs. All pts had tumor reduction, 9/10 had pathological downstaging, including 1 complete response (Table). All had clear margins with no extranodal extension; none required adjuvant chemotherapy. All pts are alive with no recurrence (median follow-up= 69 weeks). Lower % of MDSCs and increased % of M1-TAMs and M1:M2 ratio trend was seen at D15 and pre-surgery, with stronger effect in major responders. Best responders (Pts S1-S2) had higher % of PD-L1+ TAMs at baseline. Tumor WES revealed an HRAS G12D mutation in pt S2 and a BLM mutation (DNA repair) in pt S6 (no downstaging). Conclusions: Pharmacodynamic analyses support the antitumor and immune effects of sitravatinib and nivolumab in OCC. Immune pathological response assessment and transcriptomics are on-going. Clinical trial information: NCT03575598 . [Table: see text]
Dose and volume de-escalation for HPV-associated oropharyngeal cancer: Long-term follow-up of the OPTIMA trial.
Authors: Rosenberg Ari , Agrawal Nishant , Pearson Alexander T. , Seiwert Tanguy Y. , Gooi Zhen , Blair Elizabeth A. , Cursio John , Howard Adam , Chin Jeffrey , Foster Corey Christian , Kochanny Sara , Lingen Mark W. , Haraf Daniel J. , Vokes Everett E.
Published: May 2020

6575

Background: Human papilloma virus (HPV) associated oropharyngeal cancer is associated with a favorable prognosis, but standard multimodality treatment is associated with substantial treatment related toxicity. A de-escalation treatment paradigm that optimizes oncologic outcomes while reducing toxicity is needed. We sought to further expound on our published OPTIMA data with long-term follow-up and additional pts subsequently treated using the OPTIMA treatment paradigm. Methods: Long-term follow-up of our institutional de-escalation OPTIMA trial (NCT02258659) and retrospective review of additional patients treated subsequently per OPTIMA outline was performed. Pts were classified as low-risk (LR) (≤T3, ≤N2B, ≤10PYH) or high-risk (HR) (T4, ≥N2c, > 10PYH). Pts received induction chemotherapy (IC) of 3 cycles of dose dense carboplatin and nab-paclitaxel (OPTIMA) or paclitaxel (subsequently treated). LR with ≥50% response received low-dose radiotherapy (RT) to 50 Gy. LR with 30-50% response or HR with ≥50% response received intermediate-dose chemoradiotherapy (CRT) to 45Gy. All others received full-dose CRT to 75Gy. Results: 108 pts consented and 107 were treated (61 on study; 46 subsequently) from October 2014 through November 2019. 1 pt transferred care post-enrollment. Median follow-up was 36 months (interquartile range 17-45). Median age was 63 years (range 33-84) and 95% were male. 47% were LR and 53% were HR. ≥50% tumor shrinkage occurred in 78/107 (73%) of pts overall, and 37/51 (73%) among LR; 41/56 (73%) among HR. 82% of pts received de-escalated (C)RT. Overall, 94% of pts were alive at last follow-up (98% LR; 89% HR). 3 pts (2 HR and 1 LR) developed disease recurrence (2.7%), with 2 local recurrences and 1 distant recurrence. Likelihood of G-tube placement was 3% in low-dose RT, 35% in intermediate-dose CRT, and 84% in full-dose CRT. Conclusions: IC followed by risk-adapted dose and volume de-escalated treatment for HPV+ oropharyngeal cancer demonstrates excellent oncologic and functional outcomes with long-term follow-up. Supported by Celgene, Alinea benefit supported by Grant Achatz/Nick Kokonas, and National Cancer Institute of the National Institutes of Health (NIH) through Grant Number P30 CA14599. Clinical trial information: NCT02258659 .
Recurrent or metastatic salivary gland tumor (MSGT) patients treated with selinexor, a first in class selective exportin-1 (XPO1) inhibitor.
Authors: Malone Eoghan Ruadh , Spreafico Anna , Weinreb Ilan , Jennings Sarah , Carlsson Lindsay , Noori Ahmad , Wang Lisa , Siu Lillian L. , Hansen Aaron Richard
Published: May 2020

6586

Background: MSGT are rare with limited systemic treatments. This single institution, prospective study in recurrent or metastatic (RM) MSGT involved 2 phases: genomic profiling followed by treatment with either genomically-matched or unmatched therapy. Here we present the results of the unmatched arm for patients (pts) treated with S an oral selective inhibitor of XPO1 that leads to activation of tumor suppressor proteins and retention of oncoprotein mRNAs in the cell nucleus, inducing cancer cell apoptosis. Methods: Patients (pts) with RM-MSGT had archived paraffin embedded tumor samples profiled with targeted next generation sequencing, immunohistochemistry for androgen receptor (AR) and fluorescent in-situ hybridization for HER-2 and ALK. If no actionable mutations were identified or if no matched agents were available, pts with progressive disease could receive S (60mg given twice weekly Q28 days). The study had a simon-2 stage design; 1 partial response in the first 18 pts treated with S, would trigger an additional 7pts to receive S in stage 2. Results: Between July 2014 and April 2019 85 pts were enrolled on study: 73 had sequencing which identified 41 with no actionable mutations and 32 with actionable mutations. 18 pts (10F/8M, median age 61 years [40-79]) were treated with S and included adenoid cystic (n = 8), salivary duct (n = 4), acinic cell (n = 2) and other subtypes (n = 4). Of these 18, 4 pts had actionable aberrations: AR amplification (n = 2), mutations in SMARCB1 (n = 1) and CDKN2A (n = 1). 13pts were treatment naïve, 3pts and 2pts received 1 and 2 or more lines of treatment respectively prior to enrollment: androgen deprivation therapy (n = 2), chemotherapy (n = 3), early phase clinical trials (n = 3). The median number of cycles of S received were 3 (range: 1-19). The best response by RECIST was SD in 13pts (72%) (SD > 6 months (range: 6-18 months) in 5pts (28%); tumor reduction measured in 7pts (39%)), no PRs, PD in 3pts (17%), and 2pts (11%) were not evaluable for response due to insufficient duration of treatment coming off early due to toxicity. The median PFS (95% CI) was 7.6 (3.5-NA) months and the median OS (95% CI) was 15.4 (7.3-NA) months. The most common drug-related toxicities were grade 1-2 fatigue 14pts (78%), nausea 13pts (72%) and dysguesia 10pts (56%). 5 (28%) pts had a dose reduction and 6 (33%) in total had a dose interruption due to toxicity. Conclusions: Single agent antitumor activity was limited and the side effect profile was tolerable. No specific genomic aberration was associated with response to S. Clinical trial information: NCT02069730 .
A multicenter study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of taxotere/cyclophosphamide-induced febrile neutropenia in patients with early-stage breast cancer.
Authors: Clemons Mark J. , Fergusson Dean , Joy Anil A. , Meza-Junco Judith , Price Hiller Julie A. , Mackey John Robert , Zhu Xiaofu , Ibrahim Mohammed FK , Basulaiman Bassam Mohammed , Awan Arif Ali , Sienkiewicz Marta , Vandermeer Lisa , Pitre Lacey D. , Nixon Nancy Alice , Hutton Brian , Pond Gregory Russell , Hilton John Frederick
Published: May 2020

7001

Background: Docetaxel-cyclophosphamide (TC) adjuvant chemotherapy is commonly used in patients with early stage breast cancer (EBC). Due to the risk of febrile neutropenia (FN) with TC, primary prophylaxis with either ciprofloxacin (cipro) or granulocyte-colony stimulating factors (G-CSF) is recommended. Despite significant differences in costs (7-120 $US/course [cipro] vs. 2100-7000 $US/dose [G-CSF]) and toxicity profiles, optimal primary FN prophylaxis is unknown. We performed a pragmatic randomised trial comparing the superiority of G-CSF to cipro. Methods: EBC patients receiving TC chemo were randomized to receive cipro or G-CSF as primary FN prophylaxis. The primary outcome is a composite of either treatment-related hospitalisations or FN. Secondary outcomes included: chemo dose reductions, delays, discontinuations and incidence of C. difficile infections. Primary analysis was performed with the intention to treat (ITT) population. Results: 455 eligible patients were randomized to cipro (227) or G-CSF (228). 37/227 (16.3%) patients on cipro had a hospitalization, compared with 25/228 (11.0%) on G-CSF (Fisher’s exact test p-value=0.10). Relative risk (RR) of hospitalization for patients on G-CSF:0.68, 95%CI=0.42 to 1.09. Patients on cipro were statistically significantly more likely to be hospitalized for FN (30/227, 13.2%) vs 9/228 (4.0%) patients on G-CSF(p<0.001). RR of developing FN and being hospitalized for patients on G-CSF: 0.44, 95%CI=0.26 to 0.76. There was no significant difference between groups for chemo dose reductions, delays, and C. difficile rates. Twenty patients on cipro (8.8%) and 9 on G-CSF (3.9%) discontinued chemo early (p=0.036). RR of discontinuing chemo: 0.43, 95%CI=0.19 to 0.96. Conclusion: G-CSF was superior to cipro at reducing FN. While a trend towards reduced hospitalizations was also observed with G-CSF, it did not attain statistical significance. However, as 18 patients would need to be treated with G-CSF to prevent one hospitalization compared to cipro, this would suggest a cost of over $100000 $US to prevent a hospitalization. A formal cost-effectiveness analysis will be performed. Clinical trial information: NCT02173262, NCT02816112 .
Phase III randomized controlled trial of eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and advice)—An eHealth intervention during chemotherapy.
Authors: Velikova Galina , Absolom Kate , Warrington Lorraine , Morris Carolyn , Hudson Eleanor , Carter Robert , Gibson Andrea , Holmes Marie , Holch Patricia , Hulme Claire , Brown Julia
Published: May 2020

7002

Background: Routine monitoring of patients’ symptoms can improve symptom management, quality of life (QOL) and survival. eRAPID is an online system for patients to report symptoms, uniquely providing automated severity-dependent advice (self-management or alerts for hospital contact). We evaluated eRAPID impact on patient experiences & clinical care. Methods: A prospective randomized two-arm parallel group trial (1:1 allocation Usual Care (UC): UC+eRAPID). Eligible patients started chemotherapy for colorectal, breast & gynecological cancers at Leeds Cancer Centre. In eRAPID arm, patients completed weekly online symptoms for 18 weeks. Primary outcome: QOL/symptom control (FACT-PWB Physical Wellbeing Scale) at 18 weeks. Secondary outcomes: process of care (admissions/ chemotherapy delivery), patient self-efficacy (Lorig Self-Efficacy Scale) & global QOL (EQ5D).Mixed effects repeated measures models were employed. Results: During Jan 2015-June 2018, we screened 1484 patients; 508/690 eligible patients (73.6%) consented & were randomized (256 eRAPID:252 UC). No statistically significant effect of eRAPID on FACT-PWB score was found at 18 weeks (difference in means 0.20 95% CI -0.81, 1.20; p = 0.699). There was a positive impactat 6 & 12 weeks (1.08, 95% CI 0.12, 2.05; p = 0.028 & 1.01, 95% CI 0.05, 1.98; p = 0.039).In responder analysis lower proportion of eRAPID patients had clinically meaningful deterioration 47.5% at 12 weeks vs 56.3% UC. Pre-planned subgroup analysis found no effect in metastatic disease, but better FACT-PWB in non-metastatic/adjuvant group at 6 & 12 weeks (1.45, 95% CI 0.32, 2.58; p = 0.011 & 1.13; 95% CI 0.07, 2.19; p = 0.036). eRAPID patients reported better self-efficacy (p = 0.007) & QOL EQ5D-VAS at 12 (p = 0.030) & 18 weeks (p = 0.010). There were no differences for admissions/chemotherapy delivery. 3314 online reports were completed, median per patient 14.0 (range 0-117). Emergency alerts were activated in 29/3314 cases (0.9%), self-management advice 2714/3314 (81.9%). Post-hoc analysesshowed high patient adherence was associated with clinicians’ use of the data, high baseline FACT-PWB & older age. High adherence patients had better FACT-PWB scores at 12 weeks. Conclusions: Online symptom monitoring with immediate advice improved symptom control early during adjuvant chemotherapy (6 &12 weeks), helping patient education & self-efficacy. The results support its utility as an improved model for patient care during adjuvant chemotherapy. Clinical trial information: ISRCTN88520246 .
Associations between psoas muscle area (PMA) and density (PMD) with phase I oncology clinical trial outcomes.
Authors: Iyer Pritish , Whooley Peter , Handorf Elizabeth A. , Blau Matthew , Chertock Yana , Levin Laura , Hall Michael J. , Jain Rishi
Published: May 2020

7007

Background: Malnutrition and cancer cachexia can lead to loss of muscle mass (sarcopenia) and are associated with poor outcomes. Muscle status can be evaluated by computed tomography (CT)-based radiographic measures, specifically at the L3 vertebrae where the psoas and other core muscles reside. We previously found that baseline malnutrition was associated with worse phase 1 clinical trial outcomes including increased toxicity and reduced survival (Jain et al. Oncologist, 2019). We sought to evaluate the relationship between muscle status and phase 1 trial outcomes. Methods: CT-based psoas muscle area (PMA) and psoas muscle density (PMD) were evaluated in 83 patients who enrolled in a phase 1 trial. We localized the L3 vertebral body on axial imaging and manually outlined the psoas muscle to calculate PMA (standardized to height) and PMD. Two reviewers independently conducted the analyses. We stratified patients by having a PMA or PMD above or below the group’s median. We evaluated for associations between PMA/PMD and the following clinical trial outcomes: rates of grade ≥ 3 toxicity, frequency of dose reductions/interruptions, hospitalizations, tumor response, duration on study (DOS), and overall survival (OS). We also evaluated for correlations between PMA/PMD and a validated measure of nutritional status, the PG-SGA. Chi-square analysis was used to determine statistical significance between groups. Kaplan-Meier curves were used to compare DOS and OS. Results: 83 patients were included (38 male, 45 female), with a median age of 60 (range 28-85). The most common cancer type was gastrointestinal (33%). Mean PMA was 2.89 cm2/m2 (range 1.41-5.72) and mean PMD 37.77 Hounsfield units (range 13.27-56.18). PMA above the median was associated with a reduced risk of grade ≥ 3 toxicity (32.5% vs 67.4%, p = 0.001). There was no association between PMD and grade ≥ 3 toxicity, or between PMA/PMD and other phase 1 trial outcomes. There was a significant correlation between nutritional status and PMA (r = -0.278, p = 0.01) but not PMD. Conclusions: PMA and PMD are readily available CT-based measures of muscle status. In oncology phase 1 clinical trial participants, lower baseline PMA was associated with a two-fold increased risk of grade ≥ 3 toxicity. Baseline PMA was moderately correlated with nutritional status which was previously shown to be associated with poor trial outcomes. More research is necessary to further understand the specific mechanisms by which nutritional status and muscle mass may influence toxicity risk in this population.
Association between Medicaid expansion status and metastatic disease at diagnosis in patients with melanoma.
Authors: Fabregas Jesus C. , Brant Jeannine M.
Published: May 2020

7030

Background: The Affordable Care Act (ACA) expanded Medicaid coverage in 2010. It is unknown what impact the ACA expansion has had on a timely diagnosis for patients with melanoma. We hypothesize Medicaid ACA expansion has decreased the odds of being diagnosed with Stage IV melanoma. Methods: The National Cancer Database was queried. Analysis was restricted to patients diagnosed (dx’d) in or after 2010. Stage IV dx was the outcome variable. Predictors were dx’d at an already expanded ACA state (ES) or not (NES). Covariates were age, race, sex, education status, income, rural setting, and Charlson co-morbidity index. Univariate and Multivariate analyses were performed using logistic regression (table). The outcome model was adjusted using a generated Propensity Score as a continuous variable. An interaction term was used to evaluate for effect modification of ES on the association between race and Stage IV. Results: 219,475 patients diagnosed in 2010 or later were included. Median age was 62 years. By Univariate analysis, NES, age > = 65, black race, male sex, lower educational and income level, rural area, and a higher Charlson score were significantly associated with increased odds of being dx’d with Stage IV melanoma (all p < 0.001). By Multivariate Analysis, these associations persisted except for rural area and age. After adjusting for propensity score, ES patients were 9% less likely to be diagnosed with Stage IV melanoma as compared with NES patients (OR = 0.91 p < 0.001; 95% CI 0.867 – 0.959). ACA expansion status was an effect modifier on the association between race and late diagnosis (p = 0.004 for interaction term). For NES patients, black race had 3.26 odds (p < 0.001 95% CI 2.56 – 4.18) of being diagnosed with Stage IV as compared with white patients. The odds dropped to 1.76 (p 0.004; 95% CI 1.20 – 2.57) for ES patients. Conclusions: ES patients were less likely to be diagnosed with Stage IV melanoma as compared to NES patients. Medicaid expansion decreased the likelihood for black patients to be diagnosed with Stage IV as compared with whites. This suggests Medicaid expansion improves access to care and earlier diagnosis of melanoma and decreases racial gaps. [Table: see text]
Association of medical comorbidities and cardiovascular disease with toxicity and survival in patients receiving checkpoint inhibitor immunotherapy.
Authors: Johns Andrew , Wei Lai , Grogan Madison , Patel Sandipkumar , Li Mingjia , Husain Marium , Kendra Kari Lynn , Otterson Gregory Alan , Burkart Jarred Thomas , Owen Dwight Hall , Presley Carolyn J
Published: May 2020

7039

Background: Checkpoint inhibitor immunotherapy (IO) is widely used to treat advanced cancer in pts. with medical comorbidities (MC), but the effect of MC on outcomes is poorly understood. Methods: We performed a single institution retrospective cohort study of pts. who received IO from 2011-2018. Immune-related adverse events (irAEs) were graded by Common Terminology for Adverse Events criteria, v4.0. MC were abstracted by query of ICD-10 codes corresponding to diagnoses in the Charlson Comorbidity Index (CCI) at any time prior to IO start. Modified CCI scores excluding points for cancer were calculated for each pt. Bivariate analysis with chi-squared statistics was used to describe characteristics and MC of pts. with vs. without irAEs. Overall survival (OS) was estimated by the Kaplan-Meier method (from start of first-line IO) and compared using the log-rank test. The association of CCI score and individual MC with irAEs and OS was tested with regression models adjusted for pt. characteristics. Results: Among 671 pts. with advanced cancer (39.6% melanoma; 21.8% non-small cell lung) treated with IO, median age 65 (IQR 55-74) years, the most common MC were COPD (24%) and diabetes (20%). 33.8% of pts. had CCI score ≥2. Neither CCI score nor any specific MC were associated with any grade or ≥G3 irAEs (P > 0.05). Increasing CCI score was significantly associated with decreased OS (P = 0.002). CHF (13.9 vs. 8.1 months, P = 0.008) and previous MI (14.2 vs. 10.1 months, P = 0.009) were associated with decreased median OS but did not remain significant in the regression model. Among pts. without cardiovascular disease (CVD), pts. with ≥G3 irAEs had longer OS than pts. with no ≥G3 irAEs (P < 0.001). This OS benefit for ≥G3 irAEs was not seen in pts. with CVD (P = 0.94). See table for adjusted HR. Conclusions: Risk for irAEs does not appear to be impacted by MC. Pts. with MC have shorter OS, but no specific MC are associated with OS after adjustment for pt. characteristics. OS is significantly increased among pts. without CVD who experience ≥G3 irAEs. CVD may be an important predictor of OS in pts. with irAEs and should be evaluated in patients receiving IO. [Table: see text]
Nurse, oncologist, and patient impressions of electronic symptom monitoring via patient-reported outcomes in community oncology practices: Qualitative results from the U.S. national PRO-TECT trial (AFT-39, NCT03249090).
Authors: Basch Ethan M. , Teal Randall , Dueck Amylou C. , Jansen Jennifer , Henson Sydney , Vu Maihan , Carda-Auten Jessica , Carr Philip M , Wang Mian , Bennett Antonia Vickery , Stover Angela M.
Published: May 2020

7044

Background: There is growing interest to implement electronic patient-reported outcomes in oncology practices for symptom monitoring. It is not well known what nurse, physician, and patient impressions of benefits, acceptability, and challenges are in routine care use. Methods: PRO-TECT is an ongoing U.S. national trial including 26 community oncology practices across 15 states that implemented PRO symptom monitoring [NCT03249090]. Patients complete weekly PROs between visits, nurses receive alerts for severe/worsening symptoms, and oncologists review PROs at office visits. Interviews were conducted with 147 stakeholders including nurses (N = 46), oncologists (N = 27), data managers (N = 15), and patients (N = 59). Each stakeholder group had different interview guides with overlapping topics to explore experiences with the PRO system. Interviews lasted 15-60 minutes, were digitally recorded, transcribed, and entered into a qualitative analysis software program. A codebook was developed from the research questions, interview guides, and discussions with the project team. Standardized coding methods were applied, with transcripts double coded for thematic analysis. Feedback surveys were also completed by nurses (N = 57), oncologists (N = 38), and patients (N = 435). Results: Key benefits perceived across stakeholder groups included increased patient self-awareness of symptoms; improved direct communication of patients with care teams; more open and honest conveying of symptom experiences; ability to track symptoms over time; and increased involvement of patients in their own care. Most stakeholders felt PRO symptom monitoring had a positive impact on quality of care delivery, and believed benefits of PROs outweighed necessary staff efforts. Challenges included additional work by nurses to review and respond to alerts, staff turnover requiring retraining, and limited time of oncologists. In the survey, 39/56 (70%) nurses felt the PRO system improved quality of care; 27/33 (82%) oncologists noted PROs were useful for team discussions and care delivery; and 320/434 (74%) patients agreed that weekly PRO reporting improved discussions with their care team. Conclusions: Clinicians and patients perceived weekly PRO symptom monitoring between visits to be valuable despite added staff effort. Results of additional analyses are forthcoming. Clinical trial information: NCT03249090 .
Inclusion of economic outcomes in NCI grants: A portfolio analysis.
Authors: Halpern Michael T. , McCarthy Sharon , Tuovinen Priyanga
Published: May 2020

7047

Background: While new interventions have improved cancer screening, treatment, and survivorship, the costs and other economic impacts of interventions may affect their uptake and availability. It is unknown what proportion of recently-funded National Cancer Institute (NCI) grants include economic outcomes. Methods: We used the NIH Query/View/Report (QVR) System to determine the number of competitive grants funded by NCI 2015-2020 that included economic outcomes. Grants were identified using the NIH Research, Condition, and Disease Categorization (RCDC) category “Cost Effectiveness Research”; 19 RCDC terms/concepts related to economic analyses; and 18 economic phrases searched for in grant titles, abstracts, and specific aims. The specific aims and abstracts of all grants meeting any of these search criteria were reviewed by an NCI scientist to ensure the presence of economic study outcomes. Results: Among over 13,700 competitive grants awarded by NCI 2015-2020, the search identified 149 grants; following abstract/specific aims review, 102 of these grants (0.74% of all grants) included an economic outcome. Most (69 of 102, 67.6%) included cost-effectiveness analysis; 24 included other cost analyses, 7 assessed financial hardship or similar outcomes, and 2 focused on developing economic methods. Among RCDC terms, more than half (53) listed modeling (9 listing Cancer Intervention and Surveillance Modeling Network), 24 randomized controlled trials, 15 QALYs, 11 implementation science, 3 willingness to pay. The most common cancer sites listed were breast (28), lung (23), cervical (19), and colorectal (17) cancer. Almost half (48) mentioned screening and 24 cancer prevention. Risk factors listed included 28 for smoking, 18 HPV, 8 HIV, 8 physical activity, 6 obesity, 4 nutrition. Ten listed treatment efficacy, 6 chemotherapy, 4 radiation therapy, 3 hormone therapy, and 1 chemoradiation. “Treatment as usual” was listed by 16, symptom management 4, and telehealth 4. Survivors were listed for 15, caregivers 3, health disparity 18, rural 15, young adult 4. The majority of grant mechanisms were R01 (76, 74.5%); 3 were R21/R03, 4 other R mechanisms, 7 K awards, 6 U grants, 6 P, F, or L grants. Conclusions: While this search may not have identified all funded NCI grants over the past 5 years involving economic analyses, we found that less than 1% included economic outcomes. Recommendations to assist NCI in supporting health economics research focused on cancer across the entire care spectrum should be considered.
Comparative effectiveness of proton versus photon chemoradiotherapy for patients with private insurance.
Authors: Baumann Brian Christopher , Mitra Nandita , Harton Joanna , Xiao Ying , Wojcieszynski Andrzej , Gabriel Peter Edward , Zhong Haoyu , Geng Huaizhi , Doucette Abigail , Wei Jenny J. , O'Dwyer Peter J. , Bekelman Justin E. , Metz James M.
Published: May 2020

7049

Background: Proton therapy may increase the tolerability/efficacy of concurrent chemoradiotherapy (CRT) but is controversial & generally not covered by private insurers. There is little data on the comparative effectiveness (CE) of proton vs photon CRT among private insurance pts to guide payers on proton coverage policies. Methods: We conducted a CE study of adult non-metastatic cancer pts with private insurance treated with curative-intent proton vs photon CRT from 2011-2016 at Penn. The choice of radiation modality was heavily influenced by the insurer’s proton coverage policy. Data on adverse events (AEs) & survival were gathered prospectively using standardized templates. Primary endpoint was 90-day AEs associated with unplanned hospitalizations (CTCAEv4 grade ≥3 AEs). Secondary endpoints included 90-day grade ≥2 AEs, decline in ECOG performance status (PS) during treatment, disease-free survival (DFS) & overall survival (OS). Modified Poisson regression models with inverse propensity score weighting were used for adverse event outcomes. Weighted Cox proportional hazards models were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. P<0.01 was significant. Results: 920 pts were included (178 proton/742 photon), with H&N(25 proton/296 photon); CNS(44/128); lung(41/120); upper GI(34/78) & lower GI/GYN(34/120). Median age was 57. Race, comorbidity score, BMI, baseline AEs & baseline PS were similar (p>0.05 for all). 11.2% of proton pts had grade ≥3 AE’s vs 26.8% of photon pts. On propensity score weighted-analyses, proton CRT was associated with significantly lower relative risk (RR) of 90-day grade ≥3 AEs (RR 0.51, 95%CI 0.32-0.81, p<0.01). 90-day grade ≥2 AE’s (RR 0.91, 95%CI 0.83-0.99, p=0.03); decline in PS (RR 0.85, 95%CI 0.70-1.04, p=0.11); DFS (HR 0.64, 95%CI 0.27-1.52, p=0.31) & OS (HR 0.53, 95%CI 0.18-1.52, p=0.24) favored protons. Sensitivity analysis showed that a substantial imbalance in an unmeasured confounder would be needed to alter the significance of the primary outcome. Proton accepting insurance status was not associated with a difference in 90-day grade ≥3 AE’s (RR 1.02, 95%CI 0.95-1.10, p=0.54) for pts treated with photon CRT (608 with non-proton accepting insurance & 134 with proton-accepting insurance). Conclusions: In adults with private insurance, proton CRT was associated with significantly reduced acute grade ≥3 AE’s with similar DFS & OS. Proton-accepting insurance status was not associated with better health outcomes when adjusting for RT modality.