bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II randomized trial for early-stage squamous cell carcinoma of the oropharynx: Radiotherapy versus trans-oral robotic surgery (ORATOR).
Authors: Nichols Anthony Charles , Theurer Julie , Prisman Eitan , Read Nancy E , Berthelet Eric , Tran Eric , Kevin Fung , de Almeida John R. , Hope Andrew , Goldstein David Paul , Hier Michael , Sultanem Khalil , Yoo John , Macneil S. Danielle , Winquist Eric , Hammond Alex , Venkatesan Varagur , Kuruvilla Sara , Eapen Libni , Palma David A.
Published: May 2019

6006

Background: The incidence of OPSCC has risen rapidly, due to an epidemic of human papillomavirus (HPV) infection. Radiation therapy (RT) has historically been the standard treatment, but transoral robotic surgery (TORS) has surpassed RT in the US as the most common approach, based on assumptions of reduced toxicity or improved quality of life (QOL). No randomized trials have previously compared these treatments. Methods: The ORATOR trial (NCT01590355) enrolled patients with T1-T2 N0-2(≤4 cm) OPSCC amenable to TORS. We randomly assigned patients, stratified by p16 status, to RT (70 Gy/35 fractions, with chemotherapy if N1-2) vs. TORS (± adjuvant [chemo]RT based on pathology). The primary endpoint was a definitive comparison of swallowing QOL at 1-year using the MD Anderson Dysphagia Inventory (MDADI), powered to detect a 10-point improvement (a clinically-meaningful change [CMC]) in the TORS arm. Secondary endpoints included adverse events (AEs), other QOL outcomes [including EORTC scales, the Voice Handicap Index-10, Neck Dissection Impairment Index, and Patient Neurotoxicity Questionnaire], overall- and progression-free survival (OS, PFS). All analyses were pre-specified and intention-to-treat. Results: Between 2012 and 2017, 68 patients were randomized (n = 34 in each arm), in Canada and Australia. Median age was 59 years; 87% were male. Primary tumor sites were palatine tonsil (74%) or base of tongue (26%). Arms were well-balanced for baseline factors, including p16 status (88% in each arm). Median follow-up was 27 months. MDADI scores at 1-year were statistically superior in the RT arm (mean ± SD: 86.9 ± 11.4 vs. 80.1 ± 13.0 in the TORS arm; p = 0.042), but not meeting the definition of a CMC. For the other QOL metrics, outcomes were similar at 1-year. Feeding tube rates at 1-year were 3% (n = 1) vs. 0% respectively. Rates of treatment-related grade ≥2 AEs were similar (91% vs. 100%, p = 0.24), with more neutropenia, constipation and tinnitus in the RT arm and more trismus in the TORS arm (all p < 0.05). There was one TORS bleeding-related death. OS and PFS were similar. Conclusions: RT had superior swallowing QOL scores at 1 year compared to TORS, but the difference was not a CMC. Toxicities differed between the arms. This study provides the first level 1 evidence to inform patients of the QOL impact of both approaches. Clinical trial information: NCT01590355.
Evolutionary action score of TP53 analysis in pathologically high-risk HPV-negative head and neck cancer from a phase II clinical trial: NRG Oncology RTOG 0234.
Authors: Michikawa Chieko , Torres-Saavedra Pedro A. , Silver Natalie L. , Harari Paul M. , Kies Merrill S. , Rosenthal David Ira , Le Quynh-Thu , Jordan Richard C. , Duose Dzifa Yawa , Mallampati Saradhi , Trivedi Sanchit , Luthra Rajyalakshmi , Wistuba Ignacio Ivan , Lichtarge Olivier , Foote Robert Leonard , Parvathaneni Upendra , Hayes David N. , Pickering Curtis R. , Myers Jeffrey
Published: May 2019

6010

Background: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations and speciation stratifies head and neck squamous cell carcinoma (HNSCC) patients bearing TP53 missense mutations as high-risk (high, EAp53≥75), associated with poor outcomes, or low-risk (low), with similar outcomes as TP53 wild-type (wt), and has been validated as a reliable prognostic marker. This study is designed to further validate prior findings that EAp53 is a prognostic marker for locally advanced HNSCC patients, and assess its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods: Eighty one resection specimens from patients treated surgically for stage III or IV human papillomavirus-negative (HPV(-)) HNSCC with high-risk pathologic features, who received either Arm 1) radiotherapy(RT)+cetuximab(CTX)+cisplatin or Arm 2) RT+CTX+docetaxel, as adjuvant treatment in a phase II randomized clinical trial (RTOG 0234) underwent TP53 targeted sequencing, and EAp53 scoring. The EAp53 scores were correlated with clinical outcomes. Due to limited sample sizes, patients were combined into 2 EAp53 groups: wt/low and high/other. Results: At median follow-up of 10 years, there was a significant interaction between treatment and EAp53 group for overall survival (OS) (p = 0.008), disease-free survival (DFS) (p = 0.05) and distant metastasis (DM) (p = 0.004). Within arm 2, high/other showed worse OS [HR 4.69 (1.52-14.50)], DFS [HR 2.69 (1.16-6.21)], and had higher DM [HR 11.71 (1.50-91.68)] than wt/low. Within arm 1, there was no significant difference by EAp53 in OS, DFS and DM. Within the wt/low group, arm 2 had better OS [HR 0.11 (0.03-0.36)], DFS [HR 0.24 (0.09-0.61)], and DM [HR 0.04 (0.01-0.31)] than arm 1 but this was not found in high/other. Conclusions: High/other EAp53 scores were associated with worse survival for patients in arm 2. Arm 2 is associated with better survival than arm 1 for patients with wt/low EAp53. This benefit appears to be largely driven by a reduction in DM. Further validation is required to determine whether EAp53 can be used for personalized post-operative treatment decisions in HPV(-) HNSCC.
EAGLE: A phase 3, randomized, open-label study of durvalumab (D) with or without tremelimumab (T) in patients (pts) with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Authors: Licitra Lisa F. , Haddad Robert I. , Even Caroline , Tahara Makoto , Dvorkin Mikhail , Ciuleanu Tudor-Eliade , Clement Paul M. , Mesia Ricard , Kutukova Svetlana I. , Zholudeva Lyubov , Daste Amaury , Caballero Javier Daroqui , Keam Bhumsuk , Vynnychenko Ihor , Lafond Cedrik , Shetty Jagdish , Morsli Nassim , Mann Helen , Fayette Jerome , Ferris Robert L.
Published: May 2019

6012

Background: EAGLE is a phase 3 study evaluating efficacy of D (anti-PD-L1 mAb) monotherapy and D+T (anti-CTLA-4 mAb) vs standard of care (SOC) in pts with R/M HNSCC who progressed following platinum-based therapy (NCT02369874). Methods: Pts were randomized 1:1:1 to D 10 mg/kg IV every 2 weeks (Q2W), D+T (D 20 mg/kg IV Q4W + T 1 mg/kg IV Q4W for 4 doses, then D 10 mg/kg IV Q2W), or SOC (investigator’s choice: cetuximab, taxane, methotrexate, or fluoropyrimidine-based regimen). The primary endpoint was overall survival (OS) with dual primary objectives of D+T vs SOC and D vs SOC. Additional endpoints included objective response rate (ORR), duration of response (DoR), and adverse events (AEs). Results: 240 pts were randomized to D, 247 to D+T and 249 to SOC. An imbalance for Eastern Cooperative Oncology Group performance status (ECOG PS) was seen in favor of the SOC arm (D, PS 0 = 26%, PS 1 = 74%; D+T, PS 0 = 26%, PS 1 = 74%; SOC, PS 0 = 32%, PS 1 = 68%). The risk of death was not statistically significantly different for D compared with SOC (HR: 0.88; 95% CI: 0.72–1.08; P = 0.20) or D+T vs SOC (HR: 1.04; 95% CI: 0.85–1.26; P = 0.76). Efficacy data are provided in the table. Treatment-related AEs Grade ≥3 were reported in 10.1% of pts (regardless of causality Grade ≥3 AEs were 41.4%) in the D arm, 16.3% (51.2%) for D+T, and 24.2% (44.2%) for SOC. Following treatment, 2% of pts in D, 5% in D+T and 15% in SOC received immunotherapy. Conclusions: D and D+T did not demonstrate a statistically significant improvement in OS compared to standard chemotherapy in pts with R/M HNSCC. Median OS and ORR of D arm were similar to other studies with checkpoint inhibitors. The SOC arm outperformed what has been seen for SOC arms in previous studies; subsequent immunotherapy may have confounded the OS analyses. The safety profile for D and D + T in R/M HNSCC is consistent with previous trials. Clinical trial information: NCT02369874. [Table: see text]
Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers.
Authors: Taylor Matthew H. , Gainor Justin F. , Hu Mimi I-Nan , Zhu Viola Weijia , Lopes Gilberto , Leboulleux Sophie , Brose Marcia S. , Schuler Martin H. , Bowles Daniel W. , Kim Dong-Wan , Baik Christina S , Garralda Elena , Lin Chia-Chi , Adkins Douglas , Sarker Debashis , Curigliano Giuseppe , Zhang Hui , Clifford Corinne , Turner Christopher D. , Subbiah Vivek
Published: May 2019

6018

Background: RET alterations are targetable oncogenic drivers in ~90% of advanced medullary thyroid cancer (MTC) and 20% of papillary thyroid cancer (PTC), yet no selective RET inhibitors are approved. BLU-667 is an investigational highly potent and selective RET inhibitor targeting oncogenic RET alterations including those that confer resistance to multikinase inhibitors (MKIs). We provide an update on the expanded experience of BLU-667 in RET-altered thyroid cancer from the registration-enabling ARROW study (NCT03037385). Methods: ARROW is a global DE (30-600 mg daily [QD or BID]) and dose expansion (DX; 400 mg QD) study in pts with advanced solid tumors. Primary objectives are response rate (ORR; RECIST 1.1) and safety. Results: As of 19Dec2018, 60 pts with RET-mutated MTC (M918T [37], C634R/S/W [8], V804M [4], other/pending [11]) and 5 pts with RET-fusion+ PTC (NCOA4 [3], CCDC6 [2]) received BLU-667 (37 DE, 28 DX). 58% had prior MKI therapy. Among 49 response-evaluable MTC pts, ORR is 47% (95% CI: 33, 62; 2 complete and 21 partial responses (PR); 4 PR pending confirmation; 25 stable disease; 1 progressive disease). 96% (22/23) of responding pts continue treatment; 15 with response duration ≥ 6 months. 2/4 evaluable PTC pts had PR; all 5 enrolled PTC pts continue treatment at 8-11 months. Responses in MTC occur regardless of MKI resistance (prior cabozantinib/vandetanib: ORR 46% (12/26)) or RET genotype (PR in 2/3 evaluable pts with V804M). Disease control rate in MTC pts is 98%. Rapid plasma clearance of RET variants and marked reduction in CEA and calcitonin is observed. Treatment-related toxicity in MTC/PTC pts, generally low-grade and reversible (28% had grade 3 events, no grade 4/5 events, no events requiring discontinuation), includes decreased WBC (23%), increased AST (17%), increased ALT, blood creatinine, and phosphate, hypertension, and decreased neutrophils (all 15%). Conclusions: BLU-667 demonstrates potent, durable and broad antitumor activity and is well tolerated in MTC/PTC pts regardless of MKI resistance and may significantly improve outcomes for pts with RET-altered thyroid cancers. Enrollment of the expansion is ongoing with registrational intent. Clinical trial information: NCT03037385.
Longitudinal circulating Epstein–Barr virus DNA response to induction chemotherapy and chemo-radiotherapy to identify biological phenotypes in EBV-associated nasopharynx of head and neck cancer.
Authors: Lv Jia-Wei , Sun Ying , Chen Yu-Pei , Zhou Guan-Qun , Tan Kuan Rui Lloyd , Ma Jun , Chua Melvin L.K.
Published: May 2019

6021

Background: Liquid biopsies have the utility for detecting minimal residual disease in several cancers, but its clinical utility for real-time treatment adaptation remains limited. We adopted Epstein-barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) as a model to investigate its potential. We characterize longitudinal response of circulating EBV DNA to induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) in locally advanced NPC (LA-NPC), and investigate the association of complete biological response (cBR, undetectable cfEBV DNA) during treatment to prognoses. Methods: The medical records of 673 LA-NPC cases with serial EBV DNA measurements (pre-treatment, after each IC cycle, post-CCRT) were extracted. Cox regression and landmark analysis were used for survival analyses. Results: Four distinct phenotypes were identified based on their longitudinal cfEBV DNA response: 1) Early responders (200/673[29.7%]) achieved cBR post-IC1; 2) Intermediate responders (332/673[49.3%]) included patients with cBR post-IC2-4, and cBR post-CCRT after two IC cycles or following a temporary bounce (detectable reading following initial cBR); 3) Late responders (75/673[11.2%]) achieved cBR only post-CCRT after 3-4 IC cycles; 4) Treatment-resistant (66/673[9.8%]) patients demonstrated non-cBR post-IC+CCRT. These phenotypes were significantly correlated with prognoses, adjusted for pre-treatment EBV DNA load, N-category and chemotherapy intensity (AHRDFS = 3.46[2.01–6.25], intermediate; 7.50[4.24–14.77], late; 17.33[10.06–33.38], treatment-resistant vs. early responders, Pall < 0.01). Interestingly, intermediate and late responders without cBR post-IC2 had inferior survival despite more IC (HRDFS = 1.83[1.17–2.84], > 2 vs. >2 IC cycles, P < 0.01). For treatment-resistant patients, adjuvant chemotherapy following IC+CCRT reduced risk of distant metastasis (HRDMFS = 0.42[0.24–0.74], P < 0.01). Conclusions: We propose investigate risk-adapted chemotherapy de-intensification and intensification strategies based on the four novel phenotypes, which could shape the individualized treatment of LA-NPC. Our study highlights the feasibility of liquid biopsy for real-time therapeutic adaptation.
Afatinib versus methotrexate as second-line treatment for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) progressing on or after platinum-based therapy: LUX-Head & Neck 3 phase III trial.
Authors: Guo Ye , Ahn Myung-Ju , Chan Anthony T. C. , Wang Cheng-Hsu , Kang Jin Hyoung , Kim Sung-Bae , Bello Maximino De Guzman , Singh Arora Rajendra , Zhang Qingyuan , He Xiaohui , Li Ping , Dechaphunkul Arunee , Kumar Vijay , Kamble Krishna , Li Wei , Kandil Alaa , Cohen Ezra E.W. , Geng Yuan , Zografos Lef , Tang Ping Zhang
Published: May 2019

6024

Background: In a previous global phase III trial (LUX-Head & Neck 1), second-line (2L) afatinib significantly improved PFS vs methotrexate (MTX) in pts with R/M HNSCC. Here, we compared efficacy/safety of 2L afatinib vs MTX in Asian pts with R/M HNSCC. Methods: Pts progressing on/after platinum therapy were randomized (2:1) to 40 mg/day afatinib (feeding tube or oral) or 40 mg/m2/week iv MTX. Primary endpoint was PFS by independent review. Secondary endpoints were OS, ORR, and patient-reported outcomes. Results: 340 pts were randomized (afatinib 228, MTX 112). Median (range) duration of treatment (Tx) was 3.0 ( < 0.1–35.9) and 1.4 ( < 0.1–8.8) mos, respectively. Afatinib significantly decreased the risk of progression or death by 37% compared with MTX (HR 0.63; 95% CI: 0.48, 0.82 p = 0.0005, median PFS, 2.9 vs 2.6 mos; landmark analysis at 12 and 24 wks, 58 vs 41%, 21 vs 9%). There was no significant difference in OS (HR 0.88; 95% CI: 0.68, 1.13; median 6.9 vs 6.4 mos). ORR was 28% with afatinib and 13% with MTX (OR 2.8; 95% CI: 1.5, 5.2, p = 0.016). More pts had clinically relevant improvements in global health status/quality of life (GHS/QoL; 40 vs 23%, p < 0.01), swallowing (34 vs 18%, p = 0.01) and pain (34 vs 25%, p = 0.22) with afatinib vs MTX. Post-baseline change in GHS/QoL score was more favorable with afatinib (p < 0.001). Treatment-related adverse events (TRAEs; all/grade ≥3) were reported in 89/16% and 67/23% pts with afatinib and MTX. The most common grade ≥3 TRAEs were rash/acne (4%), diarrhea (4%), and stomatitis (3%) with afatinib, and anemia, leukopenia, and fatigue (all 5%) with MTX. Fatal AEs were reported in 23 and 11% pts with afatinib and MTX. Two ( hypoglycemia, pneumonitis/lung infiltration) and 4 pts had fatal AEs considered related to Tx with afatinib and MTX. 11% and 17% pts discontinued Tx due to TRAEs. Conclusions: LUX-Head & Neck 3 achieved its primary endpoint. Two randomized phase III trials have now demonstrated clinical benefit with 2L afatinib vs MTX. Safety data were consistent with the known tolerability profiles of afatinib and MTX. Clinical trial information: NCT01856478.
Preclinical efficacy of copanlisib in cetuximab sensitive and resistant tumors of HNSCC.
Authors: Klinghammer Konrad Friedrich , Politz Oliver , Eder Theresa , Otto Raik , Raguse Jan D , Hoffmann Jens , Keilholz Ulrich
Published: May 2019

6031

Background: Copanlisib is a highly selective, pan-class I PI3K inhibitor with preferential activity against the p110α and p110δ isoforms that lead to downregulation of PI3K signaling. Copanlisib has been approved for the treatment of follicular lymphoma in the US. Here, we explored the anti-tumor activity of copanlisib in head and neck squamous cell carcinoma (HNSCC), where Pi3K signaling has been defined as alternate signaling in cetuximab resistant tumors. Further, TCGA data show up to 56% of HNSCC display either amplification or mutational changes in the Pi3K pathway making Pi3K an attractive target. Methods: Using a mouse-clinical trial set-up we profiled 20 patient derived HNSCC xenograft models for their sensitivity to cetuximab or copanlisib as single agent as well as in combination. Models were selected from our HNSCC PDX platform based on Pi3K mutational status, with 6 models harboring hot spot mutations, HPV positivity (n=3) and/or cetuximab resistance based on previous drug screenings (n=12). Treatment response was defined as tumor regression, stabilization or progression expressed as relative tumor volume (RTV) after 3 weeks of treatment: RTV<0,7 responder, RTV>1,2 progressor. Results: Copanlisib single agent treatment resulted in moderate activity with 5 responders (25%). In cetuximab resistant tumors (n=12) combined treatment led to an improved tumor response in 75% (n=9) whereas 41% (n=5) resulted in tumor control. Pi3KCA mutation was not predictive for treatment response to either cetuximab or copanlisib. No PTEN mutation was detected in the selected cohort. Increased Pi3K signaling activity evaluated through gene expression profiling and computed with GSEA pathway analyses was positively correlated with response. Conclusions: The anti-tumor responses observed in monotherapy or in combination treatment support further investigation for the potential of PI3K inhibition in HNSCC with high expression of Pi3K pathway signature as a potential predictive biomarker.
Clinical implications of hyperprogression with immune checkpoint inhibitors in patients with head and neck squamous cell carcinoma (HNSCC).
Authors: Economopoulou Panagiota , Spathas Nikolaos Spiridon , Papaxoinis George , Anastasiou Maria , Gkotzamanidou Maria , Kotsantis Ioannis , Gavrielatou Niki , Oikonomopoulos Nikolaos , Kirodimos Euthymios , Vagia Elena Mihal , Kavourakis George , Psyrri Amanda
Published: May 2019

6034

Background: Hyperprogressive disease (HPD) refers to paradoxical acceleration of tumor growth kinetics (TGK) after initiation of treatment with anti- PD-1/PD- L1 agents and has been reported across tumor types in 4-29% of patients using different definitions. Preliminary data suggest that HPD might affect response to subsequent therapies. Methods: We compared TGK prior and TGK upon immunotherapy (IO) in 62 patients (pts) with recurrent/metastatic (R/M) HNSCC treated with PD-1/PD-L1 inhibitors. The TGK ratio (TGKR, ratio of tumor growth velocity before and upon treatment) was calculated. The first imaging assessment was performed 3 months (mo) after IO initiation. HPD was defined as 1. Radiological HPD (TGKR≥2) or 2. Clinical HPD (Disease-related rapid clinical deterioration post IO). Results: After median follow-up of 12.3 mo (range, 0.4-28.1), 43 pts progressed and 38 died. Median PFS was 2.8 mo (95%CI, 2.2-3.4) and median OS 8.6 mo (95%CI, 4.2-12.9). HPD was observed in 16 pts (25.8%), while 15 pts had early PD (Time to Treatment failure, TTF < 3 mo) and 31 late PD (TTF > 3mo). Among 16 pts with HPD, 11 had radiological HPD and 10 had clinical HPD. 4 pts had both clinical and radiological HPD. Pts with late PD had median OS 11.3 mo (95%CI, 9.3-13.3), those with early PD 5.2 mo (95%CI, 3.1-7.3 months) and those with HPD 5.1 mo (95%CI, 4.4-5.9) (p < 0.005). Regarding post-progression OS, pts with late PD had median 11.3 mo (95%CI 0-22.8), those with early PD 2.5 mo (95%CI 0.6-4.4) and those with HPD 4.2 mo (95%CI 1.7-6.7) (p = 0.001). Pts with HPD had a trend for longer median post-progression OS compared to pts with early PD (p = 0.121). Median PFS with chemotherapy after immunotherapy failure was 3.0 mo (95%CI 2.4-3.6) for pts with late PD, 2.1 mo (95%CI 0.9-3.4) for pts with early PD and 6.1 mo (95%CI 3.0-9.3) for those with HPD (p = 0.040). HPD was associated with longer median PFS with chemotherapy compared to pts with early PD (p = 0.016), while the difference in median PFS with chemotherapy between pts with HPD and late progressors was non-statistically significant (p = 0.260). Conclusions: Radiological or clinical HPD was observed in 25.8% of patients with R/M HNSCC treated with IO. Early progression to immunotherapy is an important predictor of short survival, while HPD was associated with improved PFS to subsequent chemotherapy.
Personalized TPF induction chemotherapy on the basis of stathmin expression in patients with locally advanced oral squamous cell carcinoma.
Authors: Zhong Lai-Ping , Ju Wu-tong , Ma Hai-long , Zhao Tong-chao , Zhang Zhi-yuan
Published: May 2019

6040

Background: A randomized phase 3 trial failed to demonstrate a survival advantage for TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in the overall study population of patients with locally advanced and resectable oral squamous cell carcinoma (OSCC). It is possible that personalized TPF-based induction chemotherapy might improve outcomes in biomarker-defined subsets of patients. Methods: Immunohistochemical staining against stathmin was performed in pre-treatment biopsy specimens in 170 OSCC patients from our randomized trial. Chemoresistance to TPF chemotherapy drugs regulated by stathmin expression was investigated. The anti-cancer activity of TPF chemotherapy drugs alone, a combination of TPF drugs and PI3K-AKT-mTOR pathway inhibitors, and vincristine were investigated using in vitro and in vivo OSCC models. Results: OSCC patients with low stathmin expression benefited from TPF induction chemotherapy in terms of overall survival (HR = 0.102, 95% CI:0.013-0.781, P = 0.028), disease-free survival (HR = 0.070, 95% CI:0.009-0.525, P = 0.010), locoregional recurrence-free survival (HR = 0.070, 95% CI:0.009-0.524, P = 0.010), and distant metastasis-free survival (HR = 0.101, 95% CI:0.013-0.767, P = 0.027). Stathmin overexpression promoted cellular proliferation and chemoresistance to TPF drugs in OSCC (P < 0.05). PI3K pathway inhibitors decreased stathmin expression and phosphorylation, and improved the chemosensitivity to TPF drugs in vitro and in vivo (P < 0.05). Vincristine decreased stathmin expression and phosphorylation, and OSCC lines were significantly sensitive to vincristine in vitro and in vivo (P < 0.01). Conclusions: Our results suggest a potential personalized TPF induction chemotherapy on the basis of stathmin expression in OSCC patients: patients with low stathmin expression in the biopsy samples are suggested to receive TPF induction chemotherapy followed by surgical resection and post-operative radiotherapy. For patients with stathmin overexpression PI3K inhibitor is a good choice to improve the inductive effect of TPF chemotherapy drugs; vincristine is a potential alternative for a chemotherapy drug when a patient is chemoresistant to or unsuitable to receive TPF chemotherapy drugs; however, more clinical trials are warranted to verify this optimization protocol.
A phase II randomized control trial of erlotinib in combination with celecoxib in patients with operable oral squamous cell carcinoma (OSCC): Erlo-Xib Study.
Authors: Nair Sudhir Vasudevan , Joshi Amit , Patil Vijay Maruti , Noronha Vanita , Sable Nilesh , Mahajan Abhishek , Dharavath Bhasker , Gardi Nilesh , Bal Munita , Nair Deepa , Gupta Tejpal , Laskar Sarbani , Agarwal Jaiprakash , Chaturvedi Pankaj , Dutt Amit , D'Cruz Anil , Gupta Sudeep , Prabhash Kumar
Published: May 2019

6054

Background: When combined with COX-2 inhibitors, the EGFR tyrosine kinase inhibitor Erlotinib has shown a better antitumor response in preclinical studies. Since high volume hospitals in many countries usually have a longer waiting period for surgery, neoadjuvant targeted therapy may be helpful in reducing disease progression and downstaging oral squamous cell cancers. Methods: Sixty-four treatment-naïve operable oral cancer patients were randomized into a four-arm window of opportunity study consisting of treatment with erlotinib 150mg daily, celecoxib 200mg twice daily, the combination of both or observation alone (NCT02748707). Since the regular wait period for surgery at our hospital was four to five weeks, we planned a 21-day drug treatment versus observation followed by definitive surgery in the fourth week. MRI scans and biopsies were done before and after drug treatment. Post-operative adjuvant treatments were given as per the standard guidelines used for regular patients. Results: There were 10 females and 54 males with a mean and median age of 44 and 45 years respectively. Taking a 20% reduction in the maximum tumor dimension after drug treatment (assessed clinically and radiologically) as partial response, the combination arm had a 60% partial response and a 25% stable disease. Whereas, 60% in the control arm had disease progression. The ratio of the longest tumor dimension at day 21 versus day 0 (Clinical & MRI assessment) also showed a significant difference between the observation vs erlotinib arms (p < 0.001) using Mann-Whitney Test. Grade II/III rashes was the commonly observed toxicity predominantly in the combination arm. Though not powered for survival analysis, a significant difference (p = 0.048) was observed for two-year overall survival for celecoxib + control (60%) versus erlotinib + combination groups (86%) using Kaplan Meier estimator. Biomarker analysis (transcriptome sequencing and IHC) is being done on pre and post-treatment tumor specimens and the final results will be presented. Conclusion: Preoperative targeted therapy with erlotinib and celecoxib combination can arrest disease progression and downstage tumors with possible impact on survival. The identified biomarkers can further refine a future cohort for effective neoadjuvant targeted therapy in oral cancers. Clinical trial information: CTRI/2012/07/002828.
Prophylactic gabapentin decreases fatigue and swallowing difficulty in patients undergoing concurrent chemo-radiation (CCR) for head and neck cancer (HNC): Interim results from a randomized controlled trial.
Authors: Murphy Barbara A. , Ghiam Michael , Niermann Kenneth J. , Cmelak Anthony , Gibson Michael K. , Gilbert Jill , Smith Derek
Published: May 2019

6059

Background: Preliminary data suggest that gabapentin (G) administered during HNC radiation may decrease treatment associated pain. To confirm this, we undertook a prospective, randomized trial in HNC patients undergoing CCR. Primary outcomes: pain severity (scale of 0-10) and opioid use. Exploratory outcomes: local and systemic symptoms measured by the Vanderbilt Head and Neck Symptom Survey version 2 plus the general symptom survey (VHNSSv2/GSS). We report results of the exploratory endpoints from the interim analysis. Methods: Measures: VHNSSv2 - 50 items, demonstrated reliability/validated, captures acute/chronic local HNC specific symptoms; GSS – 11 item checklist, demonstrated content validity, captures acute/chronic systemic symptoms. Population: HNC patients (≥ stage 2) undergoing primary or adjuvant CCR. Procedures: Randomized to standard pain management (SPM) or SPM + G dose escalated to 900mg tid. VHNSSv2/GSS completed weekly during treatment beginning week 1 and ending the last week of radiation therapy. Results were analyzed using a mixed-effects regression analysis adjusting for baseline levels of each symptom. Results: 71 patients completed a mean of 5.5 surveys. Patients on G experienced a reduction in overall systemic symptoms as measured by the GSS (11-items, p = 0.0073), fatigue (two-items, p = 0.013 ) sleep disturbance (five items, p < 0.0001) , neurosensory eating (3 items, p = 0.026), phlegm-related symptoms (4 items, p = 0.004), and trend to better smell (2 items, p = 0.055). No impact on swallow, xerostomia, voice, dental or musculoskeletal symptoms was noted. Conclusions: This exploratory analysis suggests that G may moderate neurological and neuropsychiatric toxicities in HNC patients undergoing CCR. Further studies are warranted.
Prognostic impact of baseline circulating tumor cells (CTCs) detected by the isolation by size of epithelial tumor cells (ISET) in locally advanced head and neck squamous cell carcinoma (LAHNSCC): Results of a prospective study.
Authors: Oliveira Thiago Bueno , Braun Alexcia Camila , Nicolau Ulisses Ribaldo , Abdallah Emne Ali , Alves Vanessa Silva , Jesus Victor Hugo Fonseca , Calsavara Vinicius Fernando , Kowalski Luiz Paulo , Chinen Ludmilla T.D.
Published: May 2019

6061

Background: The prognostic impact of CTCs in LAHNSCC is yet to be determined, with conflicting results in previous trials, the majority utilizing cytokeratin dependent techniques for identification and counting of CTCs. The primary objective of this study is to determine the detection rates using the ISET method, and the prognostic role of CTCs in LAHNSCC patients (pts) treated with a curative intent. Methods: In this prospective study, peripheral blood samples of pts with non-metastatic LAHNSCC, stages III/IV, were analyzed for CTCs using the ISET method, in two scenarios: curative surgical resection and adjuvant radiotherapy (CTCs before RT) and candidates for a non-surgical strategy (unresectable or organ preservation) either with upfront RT concurrent with chemotherapy (CT) or cetuximab (CTCs before RT), or preceded by induction CT (CTCs before ICT). Results: Eighty-three pts were included, the majority males (83%), with oropharynx primary (50%) and submitted to ICT (40%). The detection rate of baseline CTCs was 94% (78/83), and CTCs counts were significantly correlated with survival. For each increase of 1 CTC at baseline there was a relative increase of 18% in the risk of death (HR = 1.18; 95%CI: 1.06-1.31; p < 0.001), 16% in the risk of progression (HR = 1.16; 95%CI: 1.04-1.28; p = 0.004) and a reduction of 26% in the odds of complete response to treatment (non-surgical group only - OR = 0.74; 95%CI: 0.58-0.95; p = 0.022). Using the maximum of the standardized log-rank statistic proposed by Lausen and Schumacher we establish cut off points for overall survival (OS) and progression-free survival (PFS). Pts with CTCs < 6.5/ml had an estimated 2y OS of 85.6% versus 22.9% for CTCs ≥ 6.5/ml (HR = 0.18; 95%CI: 0.06-0.49; P < 0.0001) and pts with CTCs ≤ 3.8/ml had an estimated 2y PFS of 71.8% versus 37% for CTCs > 3.8/ml (HR = 0.32; 95%CI:0.15-0.67; p = 0.001). Conclusions: The detection rate of baseline CTCs using the ISET method was very high in LAHNSCC and the counts of CTCs were strongly correlated with survival and response to treatment.
Impact of antiviral prophylaxis in HSV positive patients treated with concurrent chemoradiotherapy for head and neck cancer.
Authors: Letarte Nathalie , Taillefer Vincent-T. , Marty Céline , Lambert Louise , Aubin Francine , Soulieres Denis , Jamal Rahima , Adam Jean-Philippe
Published: May 2019

6078

Background: Chemoradiotherapy used for the treatment of locally advanced head and neck cancer (HNC) causes a high incidence of mucositis that may be accentuated by a reactivation of herpes simplex virus (HSV). To date, no study has evaluated the impact of antivirals used as prophylaxis to prevent mucositis or their severity. Methods: This is a retrospective observational study including patients who received at least one cycle of concurrent chemoradiotherapy for the treatment of head and neck cancer between January 2014 and June 2017 at the Centre hospitalier de l’Université de Montréal (CHUM). HSV negative patients were excluded. After approval by the IRB, we compared the incidence and severity of mucositis in HSV positive patients who started an antiviral prophylaxis before cycle 1 or 2 (prophylaxis group) to HSV+/unknown HSV patients who did not receive antiviral prophylaxis (control group). Emergency visits and hospitalizations related to mucositis were collected. Mucositis were assessed regularly by radiation oncologists during the treatment. Results: Of 482 patients who received concurrent chemoradiotherapy for HNC, 75 were HSV negative and 407 were included in this study. In the group with (n = 94) and without prophylaxis (n = 313), patients received carboplatin and 5-FU (77% vs 62%) and cisplatin (23% vs 38%) with concurrent radiation respectively. The rate of all grade mucositis in patients with and without prophylaxis (99% vs 96%; p = 0.19) was not statistically significant. The rate of grade 3 and 4 mucositis (42% vs 49%; p = 0.29), the rate of emergency visit (29% vs 28%; p = 0.91) and hospitalization (9% vs 8%; p = 0.80) were not statistically significant between each group. However, in a subgroup of patient receiving carboplatin and 5-FU, antiviral prophylaxis seems to decrease significantly the rate of grade 3 (49% vs 63%; p = 0.04). Conclusions: The addition of antiviral prophylaxis in HSV positive in patients undergoing concurrent chemoradiotherapy for locally advanced HNC didn’t decrease the rate of all grade mucositis. In the subgroup of patients receiving carboplatin and 5-FU mainly of oropharynx origin, HSV prophylaxis decreased the severity of mucositis.
Outcomes of postoperative treatment with concurrent chemoradiotherapy (CRT) in high risk resected oral cavity squamous cell carcinoma (OCSCC): A multi-institutional collaboration.
Authors: Geiger Jessica Lyn , Woody Neil McIver , Tsai C. Jillian , Ghanem Ahmed I. , Dunlap Neal , Liu Howard , Burkey Brian B. , Lamarre Eric , Ku Jamie , Scharpf Joseph , Joshi Nikhil Purushottam , Caudell Jimmy J. , Siddiqui Farzan , Porceddu Sandro , Lee Nancy Y. , Koyfman Shlomo A. , Adelstein David J.
Published: May 2019

6080

Background: Adjuvant CRT with high-dose cisplatin remains standard treatment for OCSCC with high risk pathologic features of positive surgical margins (SM+) and/or extranodal extension (ENE). High-dose cisplatin is associated with significant toxicities, and alternative dosing schedules or treatments are used. We evaluated outcomes associated with different systemic therapies concurrent with RT and the effect of cumulative dosing of cisplatin. Methods: An IRB-approved collaborative database of patients (pts) with primary OCSCC (Stage I-IVB AJCC 7th edition) treated with primary surgical resection between 1/1/2005 and 1/1/2015 with or without adjuvant therapy was established from 6 academic institutions. Pts were categorized by systemic therapy received, and resultant groups compared for demographic data, pathologic features, and outcomes by t-test and Chi-squared tests. Kaplan-Meier curves, log-rank p-values, and multivariate analysis (MVA) for disease free survival (DFS) and freedom from metastatic disease (DM). Results: From a total sample size of 1282 pts, 196 pts were identified with high risk features (SM+, ENE) who were treated with adjuvant CRT. Median age was 56 years, 63.3% of pts were men, 81.1% were Caucasian, 70.9% had significant tobacco history. 35.7% of pts had SM+, 82.7% ENE, 65.3% with perineural invasion (PNI), 49% had lymphovascular space invasion (LVSI). There was a trend associating higher cisplatin dose delivered with improved locoregional control, DM, and overall survival (OS) (p-values 0.131, 0.084, and 0.187, respectively). DFS was significantly better with higher cisplatin dose (HR = 0.95 per 100 mg/m2 increase in cisplatin). Administration schedule of cisplatin (weekly versus high-dose) was not significantly associated with DFS. On MVA, PNI and higher cisplatin dose remained statistically significant for DFS (p < 0.001 and 0.007). Median OS by cisplatin dose was 10.5 ( < 200 mg/m2) vs. 20.8 months ( > / = 200 mg/m2). Conclusions: This multi-institutional analysis demonstrated cumulative cisplatin dose > / = 200 mg/m2 was associated with improved DFS in high risk resected OCSCC pts. It remains unclear by this analysis if cisplatin administration schedule has any prognostic implication. Further study is warranted to elucidate the optimal cisplatin schedule for this population.
PROSPERO: A study to determine the utility of focused genomic profiling to guide selection of drug therapy in salivary gland cancer.
Authors: Rack Samuel , Li Yonghan , McKay Craig , Wallace Andrew , Metcalf Robert
Published: May 2019

6086

Background: For most patients with recurrent or metastatic salivary gland cancer (RM-SGC), there are no standard therapies. Many patients undergo genomic profiling to guide selection of targeted therapy. The MSK-IMPACT study applied a 468 gene next generation sequencing (NGS) panel, identifying actionable mutations in 34/114 patients (30%) with RM-SGC. Minimising cost will facilitate application within publically funded healthcare systems. We therefore sought to determine the utility of genomic profiling using a focused 24 gene targeted NGS panel to identify actionable mutations in RM-SGC with a sub-group analysis in adenoid cystic carcinoma (ACC) and non-ACC sub-types. Methods: From January 2017 to 2018, 125 patients with RM-SGC provided informed consent to an ethically approved study. Clinical and demographic characteristics were collected. DNA was extracted from FFPE samples and analysed using Qiagen GeneRead DNAseq Targeted Panel V2 in the Manchester Centre for Genomic Medicine Diagnostic Laboratory, an NHS clinically accredited lab. A custom bioinformatic pipeline was validated to detect single nucleotide variants and indels ( < 40bp) to 5% mutant allele frequency. Alterations were categorised following American College of Medical Genetics guidelines and Association for Molecular Pathology tiering. Results: DNA from 101 tumours (69 major, 32 minor salivary gland) was sequenced with 95% coverage at > 350x read depth over the target enrichment. 65 patients had adenoid cystic carcinoma (ACC) and 36 had non-ACC SGC. Median age was 55 years (range 18-80). 43 actionable alterations were identified in 33 patients within the following genes: TP53 (21%), PIK3CA (8%), ERBB2 (6%), PTEN (3%), BRAF (2%), EGFR (T790M) (1%), and AKT1 (1%). Targeted therapy was selected based on genomic findings in 12% of these patients. In ACC patients, actionable alterations were seen in 25% compared with 55% of non-ACC patients (9 adenocarcinoma, 5 salivary duct carcinoma, 3 carcinoma ex pleomorphic adenoma, 2 mucoepidermoid carcinoma and 1 myoepithelial carcinoma). Conclusions: This study identified actionable alterations in 33% of SGC patients using focused genomic profiling, demonstrating comparable utility to larger research panels. This focussed panel is being expanded to include emerging biomarkers such as NOTCH gene mutations, with NOTCH inhibitors currently in trials in ACC. Greater access to basket studies incorporating therapies matched to genomic alterations will maximise the clinical utility of this approach.
Preventing excess narcotic prescriptions in MIS urologic oncology discharges (PENN): A prospective cohort quality improvement initiative.
Authors: Talwar Ruchika , Xia Leilei , Serna Juan , Lee Daniel , Ziemba Justin , Guzzo Thomas J.
Published: May 2019

6502

Background: In the setting of the national opioid crisis, there is increasing interest in non-narcotic pain strategies, particularly for oncology patients. Robotic urologic surgeries for cancer have been shown to result in less pain than open approaches. We hypothesized that the majority of these patients could be safely discharged with adequate analgesia without opioids. Methods: This prospective cohort study aimed to reduce narcotics prescribed at discharge after robotic radical prostatectomy (RARP), robotic radical nephrectomy (RARN) and robotic partial nephrectomy (RAPN). Prior to 9/2018, 100% of patients were discharged on varying amounts of oxycodone (range: 75-337.5 oral morphine milligram equivalents [MME]). We implemented a standard non-opioid analgesia pathway with escalation options across the continuum of care. Patients received gabapentin 300 mg and acetaminophen 975 mg once PO pre-operatively, as well as gabapentin 300 mg every 8 hours, acetaminophen 975 mg every 8 hours PO, and ketorolac 15 mg every 6 hours IV post-operatively. If complaining of persistent pain despite the standing regimen, patients were given 50 mg or 100 mg of tramadol every 6 hours as needed for pain level 5-7 or 8-10 on the visual analog scale, respectively. If requiring further escalation, patients were given 5 or 10 mg of oxycodone every 6 hours as needed on the aforementioned scale. Regardless of escalation status, all patients were discharged on the standing non-narcotic protocol. If escalated, ten pills of tramadol 50 mg or oxycodone 5 mg were prescribed accordingly. Results: Our cohort (n = 170) consisted of patients undergoing RARP (n = 87), RARN (n = 25), RAPN (n = 58) between 9/1/2018-1/9/2019. Overall, 67.7% were discharged without opioids, 24.4% with ten pills of tramadol 50 mg (50 MME) and 8.2% with ten pills of oxycodone 5 mg (75 MME). On multivariate analysis, older age (OR: 0.961, 95% CI: 0.923-0.995, p = 0.026) was associated with lower odds of needing opioids at discharge. There was no difference in postoperative telephone encounters between those discharged with or without opioids. Conclusions: The majority of robotic surgery patients do not require opioids upon discharge. An escalation protocol allows for a patient centered approach to reduce narcotic prescribing while still addressing cancer and surgical pain.
Clinical benefit of breakthrough cancer drugs approved by the United States Food and Drug Administration.
Authors: Molto Consolacion , Hwang Thomas J. , Andres Marta , Borrell Maria , Gich Saladich Ignasi J. , Barnadas Agust , Amir Eitan , Kesselheim Aaron S. , Tibau Martorell Ariadna
Published: May 2019

6513

Background: The Breakthrough Therapy program was established in July 2012 to expedite drug development and approval by the FDA. We compared the characteristics of clinical trials leading to FDA approval as well as the magnitude of clinical benefit and value framework scores of breakthrough-designated and non-breakthrough-designated cancer drugs. Methods: We searched the Drugs@FDA website for cancer drug approvals from July 2012 and December 2017. For each indication, we applied the value frameworks and used thresholds of high clinical benefit developed by American Society of Clinical Oncology Value Framework version 2 (ASCO VF v2; scores ≥45), the ASCO Cancer Research Committee (OS gains ≥2.5 months PFS gains ≥3 months), the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1; grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks (scores of 4 and 5). Trial characteristics and value framework scores were compared using Chi squared or Mann Whitney U tests. Results: We identified 106 pivotal trials supporting the approval of 52 individual drugs for 96 indications. Of these indications, 38 (40%) received breakthrough designation. Compared with trials for non-breakthrough drugs (n = 62), trials for breakthrough drugs (n = 44) had smaller sample size (median 373 vs 612, P= .03), were less often randomized (57% vs 86%; P= .001) and more likely to be open-label (84% vs 53%, P= .001). Trials for breakthrough drugs were more likely to demonstrate high clinical benefit using ASCO VF (68% vs 31%, P= .002) and NCCN Evidence Blocks (86% vs 56%, P= .002). A similar proportion of trials supporting breakthrough and non-breakthrough drugs demonstrated high clinical benefit using the ASCO Cancer Research Committee (82% vs 68%, P= .25) and ESMO-MCBS (35% vs 33%; P= .87) frameworks. Conclusions: In patients with advanced solid tumors, cancer drugs approved under breakthrough therapy designation were more likely to demonstrate high clinical benefit as defined by the ASCO VF and NCCN value frameworks. A similar proportion of approved breakthrough and non-breakthrough therapy drugs met the high benefit thresholds using the ASCO Cancer Research Committee and ESMO-MCBS frameworks.
Quantification of the financial burden of antineoplastic agent price increases.
Authors: Alevizakos Michail , Gaitanidis Apostolos , Appleman Leonard Joseph
Published: May 2019

6519

Background: Antineoplastic medication prices are overall increasing yet this phenomenon is not limited to new medications but can also be observed in already established medications. Methods: We accessed the yearly payment files from Medicare Part B for injectable antineoplastic agents (codes J8501-J9999) for the years 2010-2017 and all costs were adjusted to 2017 USD to adjust for inflation. We then calculated the price-per-dose for every medication and compared that price with the price-per-dose that the medication would have if its initial price was only affected by inflation. We subsequently multiplied the difference with the total doses of the medication administered in order to calculate the additional cost accrued by Medicare from medications whose price had increased more than the inflation rates. Only medications with total annual payments >10 million USD/yr were included in the analysis. Notably, Medicare provides reimbursement based on average U.S. market prices. Results: Price increases were noted on average in 64.5% of already established medications (median 69.6%, range 45.4-74.1%), leading to an average additional extra cost of 243 million USD per year (range 140-330 million USD), for a total of 1.7 billion USD over the 7 years of observation. Rituximab (539 million USD), trastuzumab (221 million USD), and bevacizumab (178 million USD) accrued the highest extra costs. This extra cost represented 4.6-8.9% of the annual total Medicare Part B spending for antineoplastic medications (Table). Conclusions: The majority of already established injectable chemotherapeutics demonstrate price increases that lead to substantial additional financial cost to Medicare and likely other U.S. markets as well. Price increases of Medicare Part B antineoplastic medications with cost >10 million USD/yr. [Table: see text]