bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer.
Authors: Lim Myong Cheol , Chang Suk-Joon , Yoo Heong Jong , Nam Byung-Ho , Bristow Robert , Park Sang-Yoon
Published: September 2018

5520

Background: Cytoreductive surgery followed by taxane and platinum-based chemotherapy is standard treatment for advanced ovarian cancer. We compared results of randomly allocated HIPEC in primary advanced epithelial ovarian cancer who have optimal cytoreductive surgery in this prospective randomized multicenter trial. The study endpoint is to evaluate progression free survival (PFS) and overall survival (OS). Methods: 184 patients staged III and IV were randomly allocated to trial arm (HIPEC, cisplatin 75 mg/m2, 90 min) or control arm (no HIPEC), intraoperatively based on residual tumor (size <1cm) from July 2010 to January 2016. The groups were well balanced according to the age, body mass index, performance status, stage, histology, serum CA125 level, and use of neoadjuvant chemotherapy (NAC) at study entry. Results: 184 pts (HIPEC, 92; control, 92) were included in this preplanned analysis. No mortality after surgery ± HIPEC was identified in both groups. Postoperative outcomes including extent of surgery, estimated blood loss, residual tumor, and hospitalization day were not different between both group, except operation time (487 vs. 404 min, p<0.001) due to HIPEC procedure. The most common adverse event was anemia: 67.4% in HIPEC and 50% in control group (p=0.025). The other toxicity common in HIPEC group is the elevation of creatinine (15.2% vs. 4.3%, p=0.026). There were no differences between both groups for transfusion (35.9 vs. 29.3, p=0.432), neutropenia (19.6 vs. 10.9%, p=0.151), and thrombocytopenia (9.8 vs. 3.3%, p=0.136). Two-year PFS was 43.2% and 43.5% and 5-year PFS was 20.9% and 16.0% in HIPEC and control group, respectively (p=0.569). Five-year OS was 51.0% and 49.4% in HIPEC and control group, respectively (p=0.574). In women who received NAC, the median PFS for HIPEC and control group were 20 and 19 months, respectively (log-rank test, p = 0.137) and the median OS for HIPEC and control group were 54 and 51 months, respectively (log-rank test, p = 0.407). In the subgroup with NAC, 2-year PFS was 37.2% in HIPEC group and 29.5% in control group and 5-year OS was 47.9% in HIPEC group and 27.7% in control group. After 20 months in PFS and 30 months in OS, two survival curves in women who received NAC showed the trend of gradual distinction, favoring HIPEC group. Conclusions: No mortality was identified and postoperative morbidities were not statistically different between two groups except anemia and creatinine elevation in HIPEC group. The survival analysis did not show the statistical superiority of the HIPEC arm. More follow-up is required to confirm the impact of HIPEC on long-term survival outcome in ovarian cancer, especially in NAC group. Clinical trial information: NCT01091636.
Phase II study of cabozantinib (cabo) in patients (pts) with recurrent/metastatic endometrial cancer (EC): A study of the Princess Margaret, Chicago, and California phase II consortia.
Authors: Dhani Neesha C. , Hirte Hal W. , Burnier Julia V. , Jain Angela , Butler Marcus O. , Lheureux Stephanie , Hurteau Jean , Welch Stephen , Matsuo Koji , Method Michael , Jimenez Waldo , Johnston Carolyn , Stringer Erica , Cristea Mihaela C. , Mehta Anjali , Quintos Judy , Tan Susie , Wang Lisa , Wright John Joseph , Oza Amit M.
Published: September 2018

5524

Background: Recurrent/metastatic EC has a poor prognosis with no standard 2ndline therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL & KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 & AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( > 30%) & 12-week progression-free-survival (PFS) ( > 55%). Activity was defined as > 7 partial responses (PRs) or > 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea & hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts & 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs & 24 instances of > 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs & 20 instances of > 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS > 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.
The neoantigen landscape and immune regulators in cervical cancer.
Authors: Roszik Jason , Qin Yong , Ekmekcioglu Suhendan , Forget Marie-Andree , Hwu Patrick , Grimm Elizabeth A. , Jazaeri Amir A.
Published: September 2018

5528

Background: Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. Methods: To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides using exome and RNA sequencing data of a large number of tumors in two independent data sets (n = 194 and 79), and analyzed whether mutation and neoantigen load correlate with expression of genes involved in antigen presentation, infiltrating immune cell type markers, and HPV oncoprotein-associated genes. Normal tissue expression analyses were also performed using data from the Genotype-Tissue Expression project (n = 8,555). Results: We found that potentially immunogenic and targetable neoantigens can be predicted for almost all cervix tumors, including recurrent neoantigens from mutations of known oncogenic driver genes (KRAS G12D, MAPK1 E322K, PIK3CA E545K, PIK3CA E542K, ERBB2 S310F, and ERBB3 V104M). Furthermore, we found that expression of HPV-associated “master regulator” genes is associated with mutation, neoantigen, and HPV load, and also with expression of several important markers in the immune microenvironment. Notably, the OVOL1 master regulator positively correlated with mutation and neoantigen load, and also with PD-L1 and TGFB1 expressions. Furthermore, ENO1 over-expression in cervical cancer was associated with high HPV load, and ENO1 level also positively correlated with PD-L1 and TGFB1 expressions, suggesting that it may be a potential target in cervical cancer. Conclusions: For most of the cervix tumors we report predicted neoantigens, and we also identified recurrent neopeptides derived from mutations in known oncogenes. We have also identified statistically significant associations between neoantigen availability, antigen presentation, cytotoxic T-cell function, suppressive mechanisms, and expression of HPV master regulators to help guide immunotherapies of cervical cancer.
Trends in the receipt of guideline care and survival for women with ovarian cancer.
Authors: Warren Joan , Harlan Linda C , Trimble Edward Lloyd , Stevens Jennifer , Grimes Melvin , Cronin Kathleen A
Published: September 2018

5540

Background: Guideline care has been found to improve survival for women with ovarian cancer, yet many women do not receive appropriate care. We assessed trends in the receipt of guideline care and 2-year cause-specific survival for women diagnosed with ovarian cancer. Methods: This retrospective cohort analysis used National Cancer Institute’s Patterns of Care studies data for women diagnosed with primary ovarian cancer in 2002 and 2011 (weighted n=6867). Data included patient characteristics, type of treatment, and provider characteristics. We used logistic regression to evaluate the association of year of diagnosis with receipt of guideline surgery, multiagent chemotherapy, or both. Two-year cause-specific survival, 2002-2013, was assessed using SEER data. Results: Forty-six percent of women received stage-appropriate surgery, unchanged from 2002 to 2011. The percent of women seeing a gynecologic oncologist (GO) 2002 to 2011 increased from 43% to 77%, 53.6% of women who saw a GO received stage-appropriate surgery. The percent of women with Stages IC-IV cancer who received both stage-appropriate surgery and multiagent chemotherapy increased significantly from 31% in 2002 to 38% in 2011. From 2002 to 2011, 2-year cause-specific ovarian cancer survival did not improve for Stages I/II cancers, with slight improvement for Stages III/IV cancers. Conclusions: There has been modest improvement in the receipt of guideline care for women with ovarian cancer, 2002-2011. However, current treatment falls far short of clinical recommendations and may explain limited improvement in 2-year cause-specific survival. There has been a marked increase in the percent of women consulting a GO and seeing a GO increased the chances of receiving guideline care. However many women who consulted a GO did not receive guideline care. There needs to be a better understanding of the decision-making process about treatment during the consultation with GOs and other factors precluding receipt of guideline care.
Comparison of patient reported symptom burden in patients with ovarian cancer undergoing primary vs. interval tumor reductive surgery.
Authors: Meyer Larissa , Shi Qiuling , Iniesta Maria , Harris Melinda , Sun Charlotte C. , Lasala Javier , Wang Shelley , Nick Alpa Manchandia , Lu Karen H. , Ramirez Pedro T
Published: September 2018

5557

Background: Patient-reported outcomes (PROs) are important in comparative effectiveness research. We compared symptom burden and functional recovery in pts undergoing primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT) and interval cytoreductive surgery (ICS) within an enhanced recovery after surgery program (ERAS). Methods: Perioperative PROs were measured for women with ovarian cancer undergoing PCS or ICS using the MD Anderson Symptom Inventory- Ovarian Cancer, a 27-item validated tool which was administered preoperatively, daily in hospital, and at least weekly for 8 weeks post-op. Mixed-effect modeling was performed. Results: 108 pts (45 PCS, 63 ICS) participated. There was no difference in median age, Charlson comorbidity index, ASA status, history of chronic opioid use, length of stay or readmission rate. At pre-op baseline assessment, the mean pain score was higher in the PCS group (3.8 vs. 1.8, p = .0005). ICS pts had a lower median surgical complexity score (4.0 vs. 2.0, p = .03), and shorter median surgical time (260 min vs. 223 min, p = .05). During hospitalization, pts undergoing PCS reported significantly more bloating, urinary urgency, distress, sadness and mood disturbance. Women who received NACT had a significantly higher symptom burden of neuropathy, leg cramps and memory disturbances. There was no difference in pain, fatigue, drowsiness, nausea, or emesis within the first 5 days postoperatively. While there was no significant differences in the physical interference composite score, (walking, work, activity), those who underwent ICS had improved affective interference scores (mood, relations, enjoyment of life). Conclusions: Within an ERAS program, there were few significant differences in surgery related symptoms related to physical recovery between pts undergoing PCS or ICS. The differences in overall symptom burden suggest that disease related symptoms (pain, bloating, urinary urgency) and emotional symptoms may be related to recent diagnosis and higher tumor burden in pts undergoing PCS while the increased numbness, leg cramps and memory issues reflect chemo-related effects in the ICS cohort.
Hedgehog inhibition impaired platinum response in high-grade serous ovarian cancer harboring high hedgehog ligand expression and mTOR pathway activation.
Authors: Ho Gwo Yaw , Lieschke Elizabeth , Kyran Elizabeth , Shield-Artin Kristy , Kondrashova Olga , Barker Holly , Hollian Robert , Cazet Aurelie , Phuong Thuan , Swarbrick Alex , McNally Orla , Bowtell David , Wakefield Matthew , Scott Clare L.
Published: September 2018

5583

Background: Elevated Glioma-associated Oncogene Homolog-1 (Gli1) protein expression is associated with Hedgehog (Hh) pathway activation in high-grade serous ovarian cancer (HGSOC). Inhibition of Hh signaling in Gli1-overexpressing HGSOC patient-derived xenograft (PDX) inhibited tumour growth, particularly in combination with chemotherapy. Early phase HGSOC clinical trials of vismodegib, a potent Hh inhibitor (SMO inhibitor), were disappointing. We identified a HGSOC PDX harboring both Indian Hh ligand-overexpression and bi-allelic deletion of TSC1, which latter event is reported to derepress the mTOR pathway, driving non-cannonical Gli1 expression. We explored the effect of vismodegib in combination with cisplatin or the mTOR inhibitor, everolimus, in this model. Methods: A cell-line was generated from the well-characterised PDX (identity confirmed by PDX-specific p53 mutation). In vitro response to vismodegib was assessed. qRT-PCR was performed to establish Hh-ligand and Gli1 expression with/without SMO inhibition. A PDX was generated from this cell-line and randomized to in vivo treatment with cisplatin, vismodegib, everolimus or vehicle alone, or vismodegib in combination with cisplatin or everolimus. Results: The HGSOC cell-line was sensitive to vismodegib in vitro (EC50 of 3.5µM) and qRT-PCR analysis revealed down-regulation of Hh-ligand and Gli1 expression following in vitro SMO inhibition, confirming on-target vismodegib activity. In vivo treatment with vismodegib or everolimus alone did not result in reproducible in vivo efficacy. The combination of vismodegib + everolimus caused short-lived responses in 3 of 6 mice. Strikingly, in vivo treatment with vismodegib in combination with cisplatin impaired median survival (19 days) when compared with cisplatin treatment alone (43 days; p = 0.039) due to rapid tumour progression. Conclusions: Combining chemotherapy with Hh inhibition in Hh ligand-overexpressing HGSOC PDX with mTOR pathway activation may be detrimental. These findings highlight the importance of an in-depth understanding of tumour biology in order to effectively combine therapeutic approaches.
Does treatment at a high volume center mitigate racial and ethnic disparities in ovarian cancer survival?
Authors: Cowan Renee A. , Tseng Jill , Palayekar Vinat , Gennarelli Renee L. , Abu-Rustum Nadeem , Chi Dennis , Long-Roche Kara C. , Brown Carol L.
Published: September 2018

5584

Background: Population-based studies of women with advanced ovarian cancer report racial/ethnic disparities in access to high volume centers (HVCs), surgical outcomes after primary debulking surgery (PDS), and overall survival (OS). However, there is evidence that with equal utilization of expert ovarian cancer care, differences in survival dissipate. The objective of this study is to evaluate patients (pts) with advanced ovarian cancer who had PDS at a HVC to determine whether racial/ethnic disparities persist in surgical outcome and survival. Methods: With IRB approval, all pts with stages IIIB to IV high-grade ovarian cancer who underwent PDS from 1/2001-12/2013 were identified. Pts self-identified race/ethnicity as Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Asian (A), or Hispanic (H) in the medical record. The main outcome measures were PDS <1cm residual and OS. A Cox proportional hazards model was used to compare OS by race/ethnicity. Pt and clinical factors, including age, income, BRCA status, BMI, ASA, grade, carcinomatosis, bulky abdominal disease, were adjusted for in the multivariate analysis. Results: 963 pts were identified: 851 NHW (88%); 43 A (4%), 34 H (4%), 28 NHB (3%), 7 Other (0.7%). Asian pts were younger at diagnosis (p<0.0001); there were no differences in other demographic or clinical characteristics among racial/ethnic groups. After adjusting for pt and clinical factors, the likelihood of PDS to residual <1cm was similar among NHB and H compared to NHW pts; Asian pts were more likely than NHW to have >1cm residual (OR 2.32, 95%CI 1.1-4.9, p=.03). Median OS was 55.1 mos (95%CI: 51.8-58.5) for the entire cohort. On both univariate and multivariate analysis, there was no disparity in OS among racial or ethnic groups (p=0.615). Conclusions: Racial and ethnic disparities in overall survival and surgical outcomes in women with advanced ovarian cancer can be reduced by treatment at a HVC. Additional research is needed to determine what factors are associated with receiving treatment at HVCs, and what interventions could increase the diversity of patients treated at HVCs.
Role of adjuvant chemoradiation in treatment of elderly women with advanced high-grade endometrial cancer: A SEER-Medicare analysis.
Authors: Park Hyo K. , Ruterbusch Julie J. , Cote Michele L.
Published: September 2018

5589

Background: Use of combined adjuvant chemoradiation (CRT) in treatment of advanced stage endometrial cancer is increasing, but the survival benefit over chemotherapy (CT) or radiation therapy (RT) alone remains unclear. We examined adjuvant treatment patterns and survival associated with CRT for Stage III-IV high-grade endometrial cancer using a large population-based database. Methods: Women 66 years of age or older who underwent primary surgical treatment for Stage III-IV high-grade endometrial cancer between 2000-2011 were identified from the SEER-Medicare database. Demographic and clinical predictors for receipt of adjuvant CRT vs. CT or RT alone were examined using multinomial logistic regression. In addition, overall survival (OS) by adjuvant treatment type, histology (endometrioid vs. non-endometrioid), stage, and age group were examined using Kaplan-Meier estimates and Cox proportional hazards regression. Results: Of the 2,735 eligible women, 13.1% received CRT vs. 42.5% CT alone vs. 13.2% RT alone, and 31.1% received no adjuvant treatment. Hispanic ethnicity, carcinosarcoma, serous histology, and Stage IV disease were significant predictors of receiving CRT over CT alone. Increasing age group, non-Hispanic black race/ethnicity, endometrioid histology, having 3+ comorbidities at the time of surgery, and not being partnered were associated with receiving RT alone over CRT. For Stage III disease, those who received CT (HR 1.30; 95% CI 1.09-1.55) or RT alone (HR 1.34; 95% CI 1.09-1.64) had poorer 5-year OS compared to CRT. In a subgroup analysis, the relative survival benefit of CRT vs. CT was only significant for women < 75 years of age and was more pronounced for endometrioid (HR 1.72; 95% CI 1.22-2.41) vs. non-endometrioid histology (HR 1.22; 95% CI 0.99-1.49). For Stage IV disease, there was no survival difference among those who received CT or RT only compared to CRT regardless of histologic subtypes. Conclusions: Adjuvant CRT was associated with improved OS in elderly women with Stage III high-grade endometrial cancer. This survival benefit was more pronounced for endometrioid histology and women < 75 years of age.
Effect of neoadjuvant pertuzumab-containing regimens on pathologic complete response rates in stage II-III HER2-neu positive breast cancer: A retrospective, single institutional experience.
Authors: Murthy Rashmi Krishna , Fujii Takeo , Hess Kenneth R. , Raghavendra Akshara Singareeka , Lim Bora , Barcenas Carlos Hernando , Zhang Hong Amy , Chavez-Mac Gregor Mariana , Mittendorf Elizabeth Ann , Litton Jennifer Keating , Giordano Sharon Hermes , Thompson Alastair Mark , Valero Vicente , Tripathy Debu , Ueno Naoto T.
Published: September 2018

580

Background: Pertuzumab (P) in combination with trastuzumab (H) based chemotherapy is currently FDA- approved as a standard neoadjuvant treatment for patients with clinical stage II-III HER2-positive (HER2+) breast cancer (BC). The chemotherapy backbone of HER2-targeted therapy varies and may include taxane (T) and/or anthracycline (A), or carboplatin (C). The goal of this study was to retrospectively evaluate the pathologic complete response (pCR) rate for HP-containing regimens compared to H containing regimens for stage II-III HER2+ BC. Methods: We identified all patients (n = 1150) with stage II-III HER2+ BC who received neoadjuvant HER2-targeted therapy from 2005 to 2016 through an institutional database. All patients underwent primary breast and lymph node surgery. pCR was defined as ypT0/is, ypN0. Univariate/multivariate logistic regression and chi-squared test for comparing proportions was used for the statistical analysis. Results: pCR was significantly higher for the HP group (n = 200) compared to the H group (n = 950): 44% vs. 41%, odds ratio = 1.8 (95% CI = 1.3, 2.5; P = 0.0002). Even with adjustment for all clinically significant factors (age, stage, tumor grade, hormone receptor (HR) status, A or C exposure), the improvement was statistically significant (adjusted OR = 2.1 (95% CI = 1.5, 2.9; P < 0.0001). The pCR rate by stage and HR status for the HP group is 62% vs. 55% (stage II vs. III) and 71% vs. 51% (HR- vs. HR+). The effect of P was not modified by HR status (HR-, OR = 2.3; HR+, OR = 1.7, P = 0.39) or by A (A-yes, OR = 1.8; A-no, OR = 2.6) (P = 0.28 for interaction) or C (C-yes, OR 2.6; C-no, OR = 1.8) (P = 0.30 for interaction). P was significantly more likely to be given to patients without A (36% vs. 10%, P < 0.0001) and more likely to be given to patients with C (30% vs. 14%, P < 0.001). In both groups, significant predictors of pCR were found to be stage, HR status, and C exposure. Conclusions: Pertuzumab containing regimens yield higher pCR rates compared to non-Pertuzumab containing regimens in stage II- III HER-2 positive breast cancer. The effect of Pertuzumab is not modified by anthracycline or carboplatin use.
Developing and validating a multivariable predictive biomarker for treatment selection for oropharyngeal squamous cell carcinoma: The PREDICTR-OPC study.
Authors: Mehanna Hisham Mohamed , Haider Syed , Rapozo Davy Carlos , . von Zeidler Sandra , Harrington Kevin , Winter Stuart , Jones Terence , Pring Miranda , West Catharine , Golusinski Pawel , Sloan Philip , Thavaraj Selvam , Odell Edward William , Hunter Keith , Shah Ketan A , Thomas Gareth , Robinson Max
Published: September 2018

6004

Background: To date there are no validated predictive tests to inform treatment selection for patients with oropharyngeal cancer (OPC). Currently treatment is decided on disease resectability, clinician preference and patient choice. Methods: Objective To develop a predictive test to select treatment for advanced OPC. Participants Training cohort: 543 cases from 10 cancer centres. External validation cohort: 442 cases from 3 centres. Design Multivariable logistic regression of 8 clinical parameters and 10 biomarkers to develop biomarker-only and composite clinical/biomarker predictive models; subsequently validated on a separate cohort. Biomarkers scored by ≥2 ‘blinded’ pathologists. Outcomes Primary: overall survival (OS). Results: 724 males, 261 females; Median follow-up =8.8 (6.86-10.47) years. More validation cases received surgery (53.5% vs 37.9%, p=0.001) and fewer received chemo/radiotherapy (42%vs67.5%; p=0.001) compared to training cohort. The biomarker-only model performed better than the clinical/biomarker one. The final OS model - comprising p16, high risk HPV DNA ISH, survivin and tumour infiltrating lymphocyte score (TILS)- was not only prognostic for OS, but importantly was predictive for surgery+/-adjuvant RT over CRT (3yr OS 63%, vs 42.5% respectively) in the High Risk group. Treatments were equally effective in the Low Risk group. The RFS model (p16, PLK1, survivin, TILS) was prognostic, but not predictive for treatment. Validation testing confirmed good calibration and concordance (C-index =0.73; 0.68-0.79). The OS model remained prognostic and predictive for surgical treatment in High Risk group (HR=0.51; 95%CI= 0.3-0.85, p=0.01). Conclusions: To our knowledge, this is the first-ever validated model for treatment selection in HNC. Clinicians can now recommend the treatment most likely to be effective on the basis of an easily-applied, relatively inexpensive panel of 4 biomarkers. [Table: see text]
Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial.
Authors: Chen Ming-Yuan , Cao Su-Mei , Yang Qi , Guo Ling , Mai Hai-Qiang , Mo Hao-Yuan , Cao Ka-Jia , Qian Chao-Nan , Zhao Chong , Yanqun Xiang , Zhang Xiu-Ping , Lin Zhi-Xiong , Li Wei-Xiong , Guo Xiang , Hong Ming-Huang
Published: September 2018

6005

Background: The role of neoadjuvant chemotherapy (NACT) for locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. We aimed to evaluate the feasibility and efficacy of NACT followed by concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced NPC. Methods: Patients with stage III-IVB (excluding T3N0-1) NPC were randomly assigned to receive NACT followed by CCRT (investigational arm) or CCRT alone (control arm). Both arms were treated with 80 mg/m² cisplatin every three weeks concurrently with radiotherapy. The investigational arm received cisplatin (80 mg/m² d1) and fluorouracil (800 mg/m² civ d1-5) every three weeks for two cycles before CCRT. The primary endpoint was disease-free survival (DFS) and distant metastasis-free survival (DMFS). Secondary endpoint was overall survival (OS). Results: 476 patients were randomly assigned to the investigational (n = 238) and control arms (n = 238). The investigational arm achieved higher 3-year DFS rate (82.0%, 95% CI = 0.77-0.87) than the control arm (74.1%, 95% CI = 0.68-0.80, P = 0.028). The 3-year DMFS rate was 86.0% for the investigational arm versus 82.0% for the control arm, with marginal statistical significance (P = 0.056). However, there were no statistically significant differences in OS or locoregional relapse-free survival (LRRFS) rates between two arms (OS: 88.2% vs 88.5%, P = 0.815; LRRFS: 94.3% vs 90.8%, P = 0.430). The most common grade 3–4 toxicity during NACT was neutropenia (16.0%). During CCRT, the investigational arm experienced statistically significantly more grade 3–4 toxicities (P < 0.001). Conclusions: NACT improved tumor control compared with CCRT alone in locoregionally advanced NPC, particularly at distant sites. However, there was no early gain in overall survival. Longer follow-up is needed to determine the eventual therapeutic efficacy. Clinical trial information: NCT00705627.
Validation of the pathological classification of lymph node metastasis for head and neck tumors (HNSCC) according to the 8th edition of the TNM Classification of Malignant Tumors (8th TNM).
Authors: Lopez-Pousa Antonio , Garcia Jacinto , Lopez Montserrat , Bague Silvia , Granell Esther , Lopez Vilaro Laura , Farre Nuria , Majercakova Katerina , Fernández Alejandro , Gallego Rubio Oscar , Barba Andrés , Andrés Marta , Gomila Paula , Del Carpio Huerta Luis Paul , Virgili Ana , Quer Miquel , Sullivan Ivana GABRIELA , Leon Xavier
Published: September 2018

6014

Background: Changes in 8th TNM edition are a specific staging for p16+oropharyngeal carcinoma and the inclusion of extracapsular spread (ECS) in N extension. We evaluate the improvement in prognostic capacity from the inclusion of the ECS in HNSCC patients treated with a neck dissection (ND). Methods: Retrospective study based on prospectively collected information of 1188 HNSCC patients (oral cavity, HPV-oropharynx, hypopharynx, or larynx) diagnosed from 1990 to 2013, treated with unilateral or bilateral ND and a minimum fw-up of 2 years. We performed 1820 ND: 410 radical, 1410 selective ND; 683 patients (60.1%) had bilateral ND. Mean lymph nodes/patient: 32.6 (SD 19.9, 7-118). In 157 cases (13.8%) ND was performed after radiotherapy (RT, n =71) or chemoradiotherapy (CHRT, n = 86) with a median interval of 8.5 weeks (6-10). 596 patients (52.4%) had postoperative RT (n=525) or CHRT (n=71). Mean fw-up: 5.6 years (SD 4.9): 213 patients (18.7%) had local failure, 158 (13.9%) regional failure, 172 (15.14%) metastases. Results: 570 patients (50.1%) had lymph node metastases, 288 (50.5%) with ECS. The 8th TNM produced upstaging of 20.9% of pN1 patients to pN2a (n=33), and of 58.4% of the patients classified as pN2 to pN3b (n=220). The 7th TNM Classification (7thTNM), 5-year cause-specific survival for pN2 (35.5%) was similar to pN3 (21.6%). In the 8th TNM, 5-year cause-specific survival for pN2 (53.3%) sits in an more intermediate position between pN1 (70.5%) and pN3 (24.0%). Five-year cause-specific survival for pN2 patients with ECS (n=217) was 22.4%, and for patients without ECS (n=157) was 51.4%. There were statistically significant differences in survival between the two reclassified groups (P=0.0001). pN1 patients in the 7thTNM did not show survival differences when stratified by the presence of ECS: 5-y SV: 63.5% for ECS (n=33), 70.5% for non-ECS (n=125) (p=0.838). Conclusions: Inclusion of ECS in the pathological classification of the 8th TNM Classification edition improved the prognostic capacity, as compared with the previous version, basically produced by the migration of 58.4% of pN2 in the 7th TNM to the new pN3b category
Nivolumab (Nivo) vs investigator’s choice (IC) for platinum-refractory (PR) recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN; Checkmate 141): Outcomes in first-line (1L) R/m patients and updated safety and efficacy.
Authors: Gillison Maura L. , Blumenschein George R. , Fayette Jérôme , Guigay Joel , Colevas A. Dimitrios , Licitra Lisa , Harrington Kevin , Kasper Stefan , Vokes Everett E. , Even Caroline , Worden Francis P. , Saba Nabil F. , Iglesias Docampo Lara Carmen , Haddad Robert I. , Rordorf Tamara , Kiyota Naomi , Tahara Makoto , Lynch Mark John , Kopit Justin , Ferris Robert L.
Published: September 2018

6019

Background: In CheckMate 141, a randomized, phase 3 trial, nivo demonstrated superior overall survival (OS) and better tolerability in patients (pts) with PR R/M SCCHN compared with IC. Pts with SCCHN progressing within 6 mos of platinum in the primary treatment setting have dismal prognosis. We report outcomes in pts who were PR in the primary or adjuvant setting, and updated results in the overall population. Methods: Pts (N = 361) with PR R/M SCCHN were randomized 2:1 to nivo 3 mg/kg every 2 weeks or weekly IC (methotrexate, docetaxel, or cetuximab). Primary endpoint was OS estimated by Kaplan-Meier method. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs). Additional endpoints include objective response rate (ORR) and safety. Outcomes were analyzed overall and post hoc in pts who were PR in the primary/adjuvant setting and received nivo/IC as 1L R/M therapy. Results: Characteristics of the 78 (21.6%) pts who received nivo (n = 52) or IC (n = 26) in the 1L R/M setting were similar to the overall population.Nivo significantly improved OS vs IC among 1L R/M pts (median [95% CI]: 7.7 mo [3.1, 13.8] vs 3.3 mo [2.1, 6.4]; HR [95% CI] = 0.56 [0.33, 0.95]); 12-mo OS rate: 39.2% vs 15.4%. ORR was 19.2% for nivo vs 11.5% for IC in this subgroup. At 11.4-mo minimum follow-up, updated efficacy and safety in the overall population were similar to the primary analysis. Median OS (95% CI) was 7.7 mo (5.7, 8.8) for nivo vs 5.1 mo (4.0, 6.2) for IC; HR (95% CI) = 0.71 (0.55, 0.90); P = 0.0048. For nivo vs IC, the 18-mo OS rate was 21.5% vs 8.3% and ORR was 13.3% vs 5.8%. Nivo doubled the median duration of response vs IC (9.7 vs 4.0 mo). Grade 3–4 treatment-related adverse event rates for nivo vs IC were 15.3% vs 36.0% overall and 27.5% vs 32.0% for 1L R/M pts; there were no new deaths due to study drug toxicity. Conclusions: Nivo significantly improved OS and increased ORR vs IC in a 1L R/M subgroup, supporting its use as 1L therapy for pts with PR R/M SCCHN. Nivo continued to show a significant survival benefit and better tolerability vs IC in pts with PR R/M SCCHN. Clinical trial information: NCT02105636.
Nivolumab (Nivo) vs investigator’s choice (IC) in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Efficacy and safety in CheckMate 141 by prior cetuximab use.
Authors: Ferris Robert L. , Licitra Lisa , Fayette Jérôme , Even Caroline , Blumenschein George R. , Harrington Kevin , Guigay Joel , Vokes Everett E. , Saba Nabil F. , Haddad Robert I. , Ramkumar Shanmugasundaram , Russell Jeffrey , Brossart Peter , Tahara Makoto , Monga Manish , Zhu Jin , Colevas A. Dimitrios , Gillison Maura L.
Published: September 2018

6020

Background: In CheckMate 141, nivo resulted in significantly prolonged overall survival (OS), favorable safety, and stable quality of life vs IC in patients (pts) with platinum-refractory (PR) R/M SCCHN. Cetuximab, a formal trial stratification factor, permits exploratory subgroup assessment. Outcomes by prior cetuximab use are described. Methods: CheckMate 141 was a randomized, open-label, phase 3 trial (NCT02105636) in which pts (N = 361) with PR R/M SCCHN were randomized 2:1 and stratified by prior cetuximab use to nivo 3 mg/kg every 2 weeks or IC of methotrexate, docetaxel, or cetuximab. The primary endpoint was OS; additional endpoints were progression-free survival (PFS), objective response rate (ORR), and safety. A multivariate analysis will explore influence of additional factors. Results: Nivo improved OS vs IC regardless of prior cetuximab, and improvement was greater in pts without prior cetuximab (Table). Median OS was longer for nivo vs IC in pts with PD-L1 expression ≥ 1% regardless of prior cetuximab, and in pts with PD-L1 expression < 1% without prior cetuximab. Among pts with PD-L1 expression ≥ 1%, ORR was higher with nivo vs IC with/without prior cetuximab. PFS was similar regardless of prior cetuximab. Grade 3–4 treatment-related adverse event rates for nivo vs IC were 11.7% vs 40.9% with prior cetuximab and 15.4% vs 26.7% without prior cetuximab. Conclusions: OS and ORR improved with nivo vs IC regardless of prior cetuximab use, and the magnitude of benefit was greater in pts without prior cetuximab exposure. These results support the use of nivo for R/M SCCHN regardless of prior cetuximab use. Clinical trial information: NCT02105636. [Table: see text]
Cost-effectiveness of nivolumab for treatment of platinum-resistant recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Carroll Kate , Tringale Kathryn Ries , Zakeri Kaveh , Sacco Assuntina Gesualda , Barnachea Linda , Murphy James Don
Published: September 2018

6026

Background: The Checkmate 141 randomized trial found that patients with platinum-refractory, recurrent or metastatic (R/M) squamous-cell carcinoma of the head and neck (SCCHN) treated with nivolumab had significantly longer overall survival than those treated with standard, single-agent therapy. However, nivolumab is more expensive than standard treatment. We conducted a cost-effectiveness analysis of nivolumab for the treatment of R/M SCCHN. Methods: We constructed a Markov model to simulate treatment with nivolumab or other single-agent therapy (docetaxel, cetuximab, or methotrexate) for patients with R/M SCCHN. Transition probabilities including disease progression, survival, and toxicity were derived from clinical trial data, while costs (in 2016 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated with values less than $100,000/QALY considered cost-effective from a healthcare payer perspective. We conducted one-way and probabilistic sensitivity analyses to examine model uncertainty. Results: Our base-case model found that treatment with nivolumab increased overall cost by $59,000 and improved effectiveness by 0.2443 QALYs compared to single-agent therapy, leading to an ICER of $241,100/QALY. In sensitivity analyses, the model was most sensitive to the cost of nivolumab and assumptions about survival. Nivolumab would become cost-effective if the cost per cycle decreased from $13,432 to $5,716. If we assumed that all patients alive at the end of the Checkmate 141 trial were cured of their disease then nivolumab was still not considered cost-effective (ICER $160,000/QALY). Probabilistic sensitivity analysis also demonstrated relative stability of the cost-effectiveness model and found that treatment with nivolumab was cost-effective 0% of the time at a willingness-to-pay threshold of $100,000/QALY. Conclusions: While nivolumab significantly improves overall survival, at the current cost it would not be considered a cost-effective treatment option for patients with R/M SCCHN.
Nimotuzumab combined with cisplatin plus fluorouracil chemotherapy in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: A multicentre, open-label, phase II clinical trial.
Authors: Zhao Chong , Miao Jingjing , Shen Guanzhu , Li Jin-Gao , Zhang Ning , Shi Mei , Wang Lin , Hu Guoqing , Chen Xiaozhong , Hu Xuefeng , Wu Shi Xiu , Chen Jiaxin , Shao Xunfan , Xie Conghua
Published: September 2018

6028

Background: Cisplatin plus fluorouracil (PF) is main therapy for metastatic nasopharyngeal carcinoma (NPC). However, the efficacy is not satisfactory, especially in patients with metastasis after radical radiotherapy. The purpose of this study was to investigate the efficacy and toxicity of Nimotuzumab combined with PF in patients with metastatic NPC after radical radiotherapy. Methods: Patients with untreated metastatic NPC after radical radiotherapy were recruited from 9 hospitals in China with Simon’s two-stage design. All patients received Nimotuzumab (200mg/w) and cisplatin (100mg/m2, day 1) plus fluorouracil (4g/m², day 1-4) every 3 weeks until progressive disease (PD) or unacceptable toxicity or a maximum of 6 cycles. If patients had still not progressed at this stage, Nimotuzumab (200mg/w) as monotherapy would be delivered until PD. This study was registered in ClinicalTrials.gov, Number NCT01616849. Results: Between Jun, 2012 and April, 2015, 35 patients were enrolled (Table). The objective response rate (ORR) and disease control rate (DCR) were 71.4% and 85.7%, and the median time of progression free survival (PFS) and overall survival (OS) were 6.97 and 11.01 months. The most common toxicities were leukopenia (94.1%), vomiting (97.1%) and nausea (97.1%); the grade 3/4 toxicities were leukopenia (62.9%) and mucositis (20.0%). There was only 1 patient have mild hypotension which related to Nimotuzumab. The ORR, DCR, median time of PFS and OS were 88.9%, 100.0%, 7.29 and 11.47 months in patients who received a total dose of Nimotuzumab ≥ 2400mg, respectively. Conclusions: Nimotuzumab combined with PF has achieved encouraging efficacy with an acceptable safety profile in metastatic NPC after radical radiotherapy. A phase III randomised study is needed. Clinical trial information: NCT01616849. [Table: see text]
Impact of early trials in molecularly-characterized patients (pts) with head and neck cancer (HNC).
Authors: Baste Neus , Dienstmann Rodrigo , Brana Irene , Viaplana Cristina , Jimenez Jose , Ruiz-Pace Fiorella , Bescos Coro , Lorente Juan , Giralt Jordi , Alberola Margarita , Nuciforo Paolo , Vivancos Ana , Del Campo Jose Maria , Tabernero Josep , Felip Enriqueta , Rodon Jordi
Published: September 2018

6031

Background: Multiple genomic alterations were described in HNC, including squamous cell carcinomas (SCC), salivary gland (SG) and nasopharyngeal (NF) tumors. Tumor molecular profiling (TMP) may increase therapeutic alternatives in early trials for pts with refractory metastatic (met) HNC. We evaluate the impact of matched/unmatched therapy (mT/uT) in HNC with potentially targetable alterations. Methods: From 2010-16, 47 met HNC pts were treated in 57 early trials after TMP. Clinical benefit was measured by: time to progression (TTP); clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] > 4months [m]); progression-free survival [PFS] ratio≥1.3 (PFS under molecular therapeutics/PFS upon last prior chemotherapy [pT]). Results: Median age was 51 years; median number of pT lines was 1 (0-5). In total, 26 SCC, 11 SG, 8 NF and 2 nasosinusal pts (mostly with lymph nodes and lung met) were treated with small kinases (SK) inhibitors (inh) (50%; main targets PI3K/HER/FGFR), immune-oncology (IO) drugs (40%, PD-1/PD-L1), angiogenesis inh (5%) or chaperone, cytidine analog, RNA polymerase (5%). 14/57 trials were mT including CDKinh (1 CDKN2A mutation [mut]), PI3Kinh (5 PIK3CA mut, 2 PTEN mut), PI3K/MEKinh (1 NRAS mut), HERinh (1 ERBB3mut), FGFRinh (2 FGFR1mRNA high, 1 FGF3/4/19 ligand amplified) and porcupine inh (1 ZNFR3mut). Distribution by tumor: IO (16 SCC/5 NF), SKmT (8SG/4SCC/2NF) and SKuT (9SCC/4SG). Responses: 1CR in SCC (IO), 5 PR in SCC (4 IO, 1 FGFRinh), 3 PR in NF (1 cytidin analog, 1 IO, 1 PI3K/MEKinh). Benefit: median TTP 9.33m (CI95% 7-20) with upward trend in NF and SG vs SCC (HR 0.6;p = 0.28), without differences according to target therapies (HR 0.8; p = 0.9); CBR of 58%, without differences by tumor type (p = 0.42) or therapy (SKmT, SKuT, IO; p = 0.5); 60% with PFS ratio≥1.3, significantly higher in SCC and SG (p = 0.016), particularly with IO drug and SKmT, respectively. Conclusions: Considering our preselected fit population as bias selection, individualized treatment selection with novel therapeutics based on TMP, especially in NF and SG irrespective of targets (SKmT, SKuT, IO), and in SCC with IO drugs, seems to confer substantial clinical benefit.
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck.
Authors: Tinhofer Inge , Eder Theresa , Konschak Robert , Niehr Franziska , Jöhrens Korinna , Keilholz Ulrich , Budach Volker
Published: September 2018

6059

Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN.
Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients.
Authors: Rainey Hope , Roy Elizabeth , Selkridge Isaiah , Misiukiewicz Krzysztof , Gupta Vishal , Bakst Richard Lorne , Zhang David Y. , Kotz Tamar , Som Peter , Anderson Karen S. , Miles Brett A. , Genden Eric , Teng Marita , Bonomi Marcelo , Sikora Andrew Gregory , Demicco Elizabeth , Jia Rachel , Posner Marshall R.
Published: September 2018

6069

Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and < 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were < 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939.