Advanced Squamous Cell Cancer Research Articles

The flow-metabolism ratio might predict treatment response and survival in patients with locally advanced esophageal squamous cell carcinoma

BackgroundPerfusion CT can offer functional information about tumor angiogenesis, and 18F-FDG PET/CT quantifies the glucose metabolic activity of tumors. This prospective study aims to investigate the value of biologically relevant imaging biomarkers for predicting treatment response and survival outcomes in patients with locally advanced esophageal squamous cell cancer (LA ESCC).MethodsTwenty-seven patients with pathologically proven ESCC were included. All patients had undergone perfusion CT and 18F-FDG PET/CT using separate imaging systems before receiving definitive chemoradiotherapy (dCRT). The perfusion parameters included blood flow (BF), blood volume (BV), and time to peak (TTP), and the metabolic parameters included maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The flow-metabolism ratio (FMR) was defined as BF divided by SUVmax. Statistical methods used included Spearman’s rank correlation, Mann–Whitney U test or two-sample t test, receiver operating characteristic (ROC) curve analysis, the Kaplan–Meier method, and Cox proportional hazards models.ResultsThe median overall survival (OS) and progression-free survival (PFS) were 18 and 11.6 months, respectively. FMR was significantly positively correlated with BF (r = 0.886, p < 0.001) and negatively correlated with SUVmax (r = − 0.547, p = 0.003) and TTP (r = − 0.462, p = 0.015) in the tumors. However, there was no significant correlation between perfusion and PET parameters. After dCRT, 14 patients (51.9%) were identified as responders, and another 13 were nonresponders. The BF and FMR of the responders were significantly higher than those of the nonresponders (42.05 ± 16.47 vs 27.48 ± 8.55, p = 0.007; 3.18 ± 1.15 vs 1.84 ± 0.65, p = 0.001). The ROC curves indicated that the FMR [area under the curve (AUC) = 0.846] was a better biomarker for predicting treatment response than BF (AUC = 0.802). Univariable Cox analysis revealed that of all imaging parameters, only the FMR was significantly correlated with overall survival (OS) (p = 0.015) and progression-free survival (PFS) (p = 0.017). Specifically, patients with a lower FMR had poorer survival. Multivariable analysis showed that after adjusting for age, clinical staging, and treatment response, the FMR remained an independent predictor of OS (p = 0.026) and PFS (p = 0.014).ConclusionsThe flow-metabolism mismatch demonstrated by a low FMR shows good potential in predicting chemoradiotherapy sensitivity and prognosis in ESCC.

A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens.Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model.Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9–77.2 months). Median OS (21.9 months; 95% CI: 16.9–27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3–5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31–10.87; p = .01). The occurrence of grades 3–5 late toxicities was not different between treatment groups.Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC.

ASO Author Reflections: Advanced and Recurrent Pelvic Squamous Cell Cancer: Unfinished Business.

ASO Author Reflections: Advanced and Recurrent Pelvic Squamous Cell Cancer: Unfinished Business.

Multi-Institutional Randomized Double-Blind Phase II Trial of Everolimus vs. Placebo as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck (SCCHN)

Multi-Institutional Randomized Double-Blind Phase II Trial of Everolimus vs. Placebo as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck (SCCHN)

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER)

Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1-4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06-2.98; P= 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79-1.75; P= 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

Adaptive radiotherapy in locally advanced esophageal cancer with atelectasis: a case report

BackgroundTo the best of our knowledge, no study has reported mediastinal shift accompanied with obstructive atelectasis due to bulky primary esophageal tumor components treated with adaptive radiotherapy and concurrent chemotherapy.Case presentationHere we report the case of a 65-year-old male patient diagnosed with locally advanced thoracic esophageal squamous cell cancer, clinical T4bN1M0, stage IVA. Bronchoscopy and computed tomography (CT) revealed an almost complete obstruction of the lumen of the left bronchus due to compression by bulky primary esophageal tumor components. On admission, the patient presented with dyspnea and decreased arterial oxygen saturation. Chest radiography and CT on admission revealed mediastinal shift with left atelectasis, as opposed to findings from the chest radiography performed 26 days before admission. Because of the patient’s overall good condition, we recommended definitive chemoradiotherapy instead of palliative bronchial stent placement. After obtaining the patient’s consent, chemoradiotherapy was initiated on the following day and it comprised three-dimensional conformal radiotherapy with 60 Gy in 30 fractions with concurrent administration of cisplatin and 5-fluorouracil. During chemoradiotherapy, tumor location was monitored with cone-beam CT and chest radiography. Chemoradiotherapy on day 8 revealed no evidence of the mediastinal shift. CT simulation was reperformed to adjust the radiotherapy fields to account for geometrical changes induced by the absence of the mediastinal shift. Subsequently, the mediastinal shift and bronchial obstruction did not recur during the course of chemoradiotherapy. The patient completed the planned radiotherapy with concurrent and adjuvant chemotherapy, and no non-hematological grade ≥ 3 adverse events were observed. Complete response was confirmed 7 months after initiating chemoradiotherapy. Currently, no disease recurrence, dysphagia, or respiratory symptoms have been reported at 13 months after initiating chemoradiotherapy.ConclusionsIn this study, a bulky primary esophageal tumor caused mediastinal shift due to ipsilateral bronchial obstruction. The close follow-up for monitoring resolution of the mediastinal shift during the course of chemoradiotherapy enabled adequate dose delivery to targets, thus reflecting the geometrical changes induced by the absence of the mediastinal shift. Adaptive radiotherapy technique was crucial for favorable patient outcomes in this challenging clinical situation.

143P - NOTCH3 expression predicts poor survival in advanced esophageal squamous cell cancers

BackgroundOesophageal cancer is the sixth leading cause of cancer-related mortality with more than 90% of oesophageal cancer being squamous cell carcinomas (ESCC) in Asian countries. Prognosis of ESCC remains extremely poor and identification of better prognostic factors is an unmet need. MethodsWe investigated the immune- histochemical expression of Notch1, Notch2, Notch 3, HES-1 (Hairy enhancer of Split -1) (a downstream transcription factor) and p21 among ESCC and non-tumour controls. Non-tumour controls consisted of diagnostic biopsies of GERD patients in which Barrett’s and erosive esophagitis had been ruled out. We also investigated the association of these markers with clinico-pathological features and survival. We included 46 patients of ESCC and 42 controls. IHC markers were performed according to the standard guidelines and analysed with a semi-quantitative H –score (The H score was calculated as: H score= D X I with values ranging from 1-15). ResultsThe median age was 60 (37-78 years). M:F ratio was 30: 16. 65.2 % were smokers and 19.6 % were tobacco chewers. 38 cases were locally advanced (Stage III) and 8 were metastatic at baseline. Palliative intent therapy was offered to 24 % and definitive therapy to 76%. An ECOG -PS of 1,2 and 3 was observed in 26, 16 and 4 patients respectively. At a median follow up of 50.67 months, the median overall survival was10.47 mon (range= 8.23-15.1) mon. Using a cut-off score of 7.5 to define positivity, NOTCH 1,2,3 as well as p21 were found to be significantly over-expressed in ESCC as compared to normal controls, while there was no difference in Hes1 expression. Location, grade, baseline metastases, duration of symptoms showed no association with NOTCH 1,2 or 3 positivity. On univariate analysis, male sex, age >60 years, smokers, ECOG-PS>1, Notch 3 H score was found significant. On multivariate analysis, smokers (HR = 3.53, p = 0.013), ECOG-PS>1 (HR = 2.88, p = 0.006) and Notch3 H score (HR = 2.38, p = 0.047) emerged as independent adverse prognostic factors. ConclusionsNOTCH 1,2 and 3 are highly expressed in ESCC as compared to controls. Notch3 H score is an independent predictor of survival in ESCC and merits evaluation in larger studies. Legal entity responsible for the studyRaja Pramanik. FundingIntramural Research Fund, Research Section, All India Institute of Medical Sciences, New Delhi. DisclosureAll authors have declared no conflicts of interest.

Could excision repair cross-complementing group-1 mRNA expression from peripheral blood lymphocytes predict locoregional failure with cisplatin chemoradiation for locally advanced laryngeal cancer?

The association of excision repair cross-complementing 1 mRNA (ERCC-1 mRNA) expression with the outcome has been reported with immunohistochemistry (IHC) using tumor tissue in head and neck cancer. We evaluated ERCC-1 mRNA expression by reverse transcription polymerase chain reaction (RT-PCR) from peripheral blood lymphocytes (PBLs) as bio-predictor of locoregional failure (LRF) to chemoradiation (CRT) for locally advanced laryngeal squamous cell cancer (LALSCC). A total of 107 male patients with LALSCC were enrolled in this prospective study. ERCC-1 mRNA expression by PBLs was determined by RT-PCR. Definitive CRT was delivered with 35mg/m2 weekly cisplatin. Response Evaluation Criteria in Solid Tumor 1.1 (RECIST 1.1) were used in evaluating treatment response. The primary objective was to assess LRF. The influence of patient characteristics, treatment response, weekly cisplatin cycles, ERCC mRNA expression was determined for LRF, progression-free survival (PFS) and overall survival (OS). A total of 98 patients completed definitive CRT. The median value of 2-ΔΔCT ERCC-1 mRNA expression was 3.9; based on which it was categorized as low and high. Correlation of ERCC-1 expression with treatment response was insignificant (P- .38). With a median follow-up of 33 months; 2-year LRF, PFS, and OS was 63.3%, 34.7% and 79.4%. The 2-year LRF, PFS and OS for low versus high expression were 53.1%versus 73.5% (P-value = 0.036), 44.9%versus 24.4% (P-value = 0.047) and 81.6%versus 77.2% (P-value = 0.33), respectively. In multivariate analysis, ERCC-1 expression, T-stage, N-stage and tumor subsite are predictive factors for LRF; T-stage and nodal recurrence for OS; stage and treatment response for PFS. LALSCC patient with ERCC-1 mRNA low expression was associated with lower LRF rate, and improved PFS.

839TiP - FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma

BackgroundThe standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell cancer (ESCC) is chemotherapy with CDDP + 5-FU (CF). Docetaxel (DTX) + CF (DCF) is considered a promising regimen, which has been evaluated in a phase III study, JCOG1109. Nivolumab (Nivo) has shown promising efficacy in unresectable ESCC. In a preclinical study immune-checkpoint inhibitors (ICI) have shown efficacy as NAC and may work better than when used as adjuvants. Nivo monotherapy showed a major pathologic response in 43% of lung cancer patients (pts), but it was not shown whether ICI also work with chemotherapy that can lead to myelosuppression. The operative mortality and morbidity after use of ICI as NAC in ESCC are unknown. Trial designThis multi-cohort phase I study is designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. Histologically proven ESCC pts with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), 20-75 years old, PS≤1, no prior therapy against any cancer are eligible. The primary endpoint is the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contains 4 experimental cohorts; cohort A: 2 courses of CDDP at 80mg/m2, Nivo at 360mg/body on day 1 and 5-FU at 800mg/m2 on days 1–5, q3wks; cohort B: one prior administration of Nivo at 240mg/body and otherwise the same regimen as cohort A; cohort C: 3 courses of DTX at 70mg/m2, CDDP at 70mg/m2, Nivo at 360mg/body on day 1, and 5-FU at 750mg/m2 on days 1–5, q3wks; cohort D: one prior administration of Nivo at 240mg/body and otherwise the same regimen as cohort C. DLT was defined as follows: Nivo related, grade 4 neutropenia lasting 5 days or longer, >38 degree fever or grade 4 neutropenia lasting 3 days or longer, grade 4 thrombocytopenia lasting 3 days or longer, non-hematological toxicities of grade 3 or higher, grade 4 post-operative adverse events or grade 3 post-operative adverse events excluding hematological toxicity, anastomotic leak, pleural effusion and lung infection. 6 pts are planned to enroll to each cohort and less than one DLT was determined as safety among 6 pts. After this evaluation, we will add 12 pts as an expanded cohort. Clinical trial identificationNCT03914443. Legal entity responsible for the studyThe authors. FundingOno Pharmaceutical Co.,Ltd. DisclosureK. Kato: Research grant / Funding (self), Research grant / Funding (institution): ONO Pharmaceuticals; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Eli Lilly; Research grant / Funding (institution): Beigene. T. Kojima: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Oncolys BioPharma; Research grant / Funding (institution): Astellas Amgen BioPharma; Research grant / Funding (institution): Chugaiseiyaku; Research grant / Funding (institution): Parexel; Research grant / Funding (institution): Shionogi. H. Hara: Research grant / Funding (self): Japan Agency for Medical Research and Development (AMED); Honoraria (self), Research grant / Funding (self): ONO; Honoraria (self), Research grant / Funding (self): BMS; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Dainippon Sumitomo Pharma; Honoraria (self): Lilly; Research grant / Funding (self): Merck Serono; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self), Research grant / Funding (self): Chugai; Research grant / Funding (self): Eisai; Research grant / Funding (self): LSK BioPharma; Research grant / Funding (self): Incyte; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Boehringer-ingelheim; Research grant / Funding (self): Beigene; Honoraria (self): Yakult Honsha; Honoraria (self): Sanofi; Honoraria (self): Takeda. Y. Kitagawa: Research grant / Funding (self): Taiho Pharmaceutical Co., Ltd; Research grant / Funding (self): Chugai Pharmaceutical Co., Ltd.; Research grant / Funding (self): Yakult Honsha Co. Ltd.; Research grant / Funding (self): Daiichi Sankyo Company, Limited; Research grant / Funding (self): Merck Serono Co., Ltd.; Research grant / Funding (self): AsahiKASEI Co., Ltd.; Research grant / Funding (self): EA Pharma Co., Ltd.; Research grant / Funding (self): Otsuka Pharmaceutical Co., Ltd.; Research grant / Funding (self): Takeda Pharmaceutical Co., Ltd.; Research grant / Funding (self): Otsuka Pharmaceutical Factory Inc.; Research grant / Funding (self): Shionogi & Co., Ltd.; Research grant / Funding (self): Kaken Pharmaceutical Co., Ltd.; Research grant / Funding (self): Kowa Pharmaceutical Co., Ltd.; Research grant / Funding (self): Astellas Pharma Inc.; Research grant / Funding (self): Medicon Inc.; Research grant / Funding (self): Dainippon Sumitomo Pharma Co., Ltd.; Research grant / Funding (self): Taisho Toyama Pharmaceutical Co., Ltd.; Research grant / Funding (self): Kyouwa Hakkou Kirin Co., Ltd.; Research grant / Funding (self): Pfizer Japan Inc.; Research grant / Funding (self): Ono Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.

761P - A national comparative effectiveness study to assess definitive chemoradiation regimens in proximal oesophageal squamous cell cancer

BackgroundProximal oesophageal cancer is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone in CRT are still under debate. The objective of this study is to compare the treatment benefit of four contemporary CRT regimens. MethodsIn this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal oesophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004-2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin/paclitaxel (CP) combined with low (≤50.4Gy) or high (>50.4Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) model. Safety profiles were compared using the Chi-square test. ResultsTwo-hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI 47.9-77.2 months). Median OS (21.9 months; 95% CI 16.9-27.0 months) was comparable between treatment groups (logrank P=0.88), confirmed in the fully adjusted and PS weighted model (P>0.05). Grade 3-5 acute adverse events were less frequent in patients treated with CP-low-dose RT (P=0.01). ConclusionsOur study results suggest that carboplatin and paclitaxel combined with RT at a dose of 50.4Gy is the preferred CRT regimen in patients with locally advanced proximal oesophageal squamous cell cancer, showing comparable OS and a significantly more favourable safety profile when compared with cisplatin-based or higher RT dose regimens. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureJ. de Vos-Geelen: Travel / Accommodation / Expenses: BTG; Research grant / Funding (institution), Travel / Accommodation / Expenses: Servier; Advisory / Consultancy: Shire. B.T.A. de Greef: Research grant / Funding (institution): Prinses Beatrix Spierfonds (W.OR12-01). H.W.M. van Laarhoven: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Nordic; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Roche. V.E.P.P. Lemmens: Research grant / Funding (institution): Roche. V.C.G. Tjan-Heijnen: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Travel / Accommodation / Expenses: Accord Healthcare; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Eisai. All other authors have declared no conflicts of interest.

Effective Dose to Lymphocytes Predicts Lymphopenia and May Predict Survival in Patients Treated with CROSS Regimen in Patients with Squamous Cell Carcinoma of Esophagus

We hypothesized that radiation induced lymphopenia can be predicted by the effective dose to the circulating immune cells (EDIC) which can be computed by modelling the doses of the total body, lung and heart in advanced squamous cell esophageal cancer treated with trimodality therapy according to the Dutch CROSS trial regimen. To test this hypothesis, we considered circulating immune cells as an organ at risk and examined the effect of EDIC on the degree of lymphocyte drop (lymphocyte nadir) . We further explored the relationship between EDIC, lymphocyte nadir and overall survival (OS) in this group of patients. Patients with advanced non-metastatic squamous esophageal carcinoma treated in one single tertiary cancer center from 2012-2018 were eligible for this study. All patients must have RT plan available for EDIC computation and received neoadjuvant chemoRT according to Dutch CROSS trial regimen (5 weeks of weekly carboplatin AUC=2 and paclitaxel 50mg/m2, radiation dose: 41.4 Gy in 23 fractions) before a radical esophagectomy. All had weekly blood test available during and 2 months after chemoRT. We made assumptions that circulating immune cells received uniform dose for rapidly circulating ones (in heart, lung, and blood vessels) and those slow circulating ones (in lymphatic system, veins, and capillaries) inside irradiated volume. The EDIC was calculated as a function to lung, heart and total body integral doses with a verified mathematical model. Association between EDIC and lymphocyte nadir was studied, and the relationships of OS with lymphocyte nadir and EDIC were assessed using multivariant Cox regression model. This analysis included 92 eligible consecutive patients with 77 males and 15 females. The median age was 65.5 years (range 40-82). There were 1, 84, and 7 patients with stage II, III, and IV diseases, respectively. The mean PTV was 529 cc (95% CI220.5-837.5). The baseline lymphocyte was normal in 79 (86%) patients, reduced in 13 (14%) patients. The mean EDIC was 2.8 Gy (range 0.6-4.4). EDIC was found to be highly correlated with lymphocyte nadir (Spearman coefficient -0.505 p< 0.01) which was found to significantly independently associated with shorter OS (HR =0.63 p<0.001). Lymphocyte nadir was also the most significant factor in determining OS among other clinical parameters. It remained significant after adjusting for clinically significant factors Age. Exploratory analysis showed there was significant OS difference between EDIC groups (<2Gy, 2-4Gy and >4Gy). The 2-year OS rates were 66.7%, 42.7% and 16.7% for EDIC <2Gy, 2-4Gy and >4Gy respectively. Radiation dose to circulating immune cells was significantly associated with survival and lymphocyte nadir which was also a significant factor for overall survival in patients with advanced non-metastatic squamous cell cancer of esophagus. The result may advise plan optimization and further prospective study is warranted.

Treatment times in locally advanced oropharyngeal cancer: evolution from 2011 to 2016 in a Portuguese Head and Neck Oncology Centre

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Delays in cancer diagnosis and treatment are usually associated with patient anxiety, tumour progression and lower survival. This study aims to analyse the potential impact of rescheduling adjuvant treatments on survival outcome of patients with locally advanced oropharyngeal squamous cell cancer (OPSCC).&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A retrospective review of medical records comprising all patients with advanced oropharyngeal cancer who underwent primary surgery and postoperative radiotherapy (PORT) in a Tertiary Oncologic Centre from 2011 to 2016 was performed.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; 63 patients with a male/female ratio of 8:1 and mean age of 57.5±9.6 years were enrolled. Patients waited a mean of 47.2±18.2 days from diagnosis to surgery and a median of 61 days from surgery to radiotherapy. Median radiotherapy duration was 43 days and the mean package time was 104.5±21.0 days. Analysis of these parameters has shown decreasing intervals from 2011 to 2016, although this was only significant for duration of PORT (p=0.022). Longer time span from surgery to PORT and PORT duration were predictive of superior package times (p&amp;lt;0.001). Five-year overall survival and disease-free survival was 63.8% and 64.8% respectively with no statistically significant impact of waiting times on clinical outcome.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; Despite presenting favourable long-term outcomes, patients with locally advanced OPSCC have experienced longer waiting times than recommended. Waiting times were not prognostic factors in this condition, although efforts to reduce it might provide superior quality of care. Future studies assessing the factors involved in treatment delays might provide means to offer timely treatments. &lt;/p&gt;&lt;p class="abstract"&gt; &lt;/p&gt;&lt;p&gt; &lt;/p&gt;

FDA approves pembrolizumab for advanced esophageal squamous cell cancer

FDA approves pembrolizumab for advanced esophageal squamous cell cancer

Concurrent Chemoradiotherapy with Extended Nodal Irradiation and/or Erlotinib in Locally Advanced Esophageal Squamous Cell Cancer: Long-Term Follow-Up of a Randomized Phase 3 Trial

Background: The outcome of patients with locally advanced esophageal squamous cell cancer (ESCC) remain poor. The aim of this study was to report the long-term outcomes in a randomized controlled multicentre phase III study evaluating extended nodal irradiation (ENI) and erlotinib in locally advanced ESCC. Methods: A 2x2 factorial design was used to test two hypotheses: (1) that ENI was superior to conventional field irradiation (CFI); (2) that chemoradiotherapy plus erlotinib was superior to chemoradiotherapy in patients with locally advanced ESCC. Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to receive concurrent chemotherapy with ENI or CFI with or without erlotinib (150 mg per day during chemoradiotherapy). The primary end point was overall survival (OS). We have explored the impact of epidermal growth factor receptor (EGFR) expression on efficacy of erlotinib plus chemradiotherapy. Findings: A total of 352 patients (88 assigned to each treatment group) were enrolled. After a minimum follow-up of 5 years for surviving patients, the 5-year survival rate was 44·92%, 34·82%, 33·81% and 19·62% in group A, B, C and D (P = 0·013). The median OS was 49·97 months, 26·50 months, 23·83 months, and 20·87 months in group A, B, C and D. The radiation field-by-erlotinib interaction test was not significant for OS (HR, 0·96; P = 0·871) and progression-free-survival (PFS) (HR, 0·97; P = 0·908). The ENI significantly improved OS compared with the standard CFI (median, 38·53 v 22·60 months; HR, 0·74; P = 0·018). The addition of erlotinib significantly improved OS (median, 39·38 v 27·42 months; HR, 0·75; P = 0·025). The patients with ESCC over expressing EGFR treated by erlotinib had a better OS and PFS than patients without EGFR expression. Interpretation: Concurrent chemoradiotherapy with ENI and/or erlotinib still improved survival outcomes with long-term follow-up in locally advanced ESCC. ENI should be adopted in concurrent chemoradiotherapy for ESCC patients. The patients with ESCC over expressing EGFR could significantly benefit from the erlotinib plus chemoradiotherapy. Funding Statement: The authors state: No commercial support was provided for this study. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: All patients provided written informed consent, and the study was approved by the institutional review board or independent ethics committee of each participating center.

Safety and efficacy of nimotuzumab and concurrent intensity-modulated radiation therapy and chemotherapy for locally advanced cervical squamous cell cancer.

5532 Background: To evaluate the safety and efficacy of nimotuzumab plus concurrent intensity-modulated radiation therapy (IMRT) and chemotherapy for the treatment of locally advanced cervical squamous cell cancer (LACSCC). Methods: From December 2013 to March 2017, 31 patients with stage (FIGO 2009) IB2-IVA cervical squamous cell cancer were enrolled in this single-arm clinical trial at an academic medical center and received concurrent chemoradiotherapy plus nimotuzumab. All patients underwent at least 1 year of follow-up. The prescription radiation dose was 50.4 Gy/28 F on the pelvic field with or without extended-field radiation. An additional 30-36 Gy to Point A was delivered with high-dose-rate techniques. Cisplatin 40 mg/m2 and nimotuzumab 200 mg were infused intravenously once weekly during radiotherapy. The main and secondary outcome measures were toxicity evaluated using CTCAE 4.0., and the short-term outcome evaluated by RECIST 1.1. Results: The median follow-up duration was 29.7 months (13.3-61.2 months). All patients received external beam radiotherapy, brachytherapy, and nimotuzumab six times. Twenty-seven patients received six cycles of chemotherapy while four received only 4-5 cycles. There was no life-threatening toxicity. The incidence of acute grade 3 bone marrow depression was 51.6% (16/31) and grade 3 gastrointestinal tract reaction was 9.7% (3/31). The incidence of late toxicities was 22.6% (7/31), and these included vaginal-rectal fistula, intestinal obstruction, rectal hemorrhage, hematuria, and vaginal stenosis. Complete response was achieved in 30 cases (96.8%). The 1-year disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) rates were 87.1%, 90.3%, and 100%, respectively. The corresponding 3-year values were 74.8%, 90.3%, and 86.7%. Conclusions: Nimotuzumab plus concurrent IMRT and chemotherapy may represent a well-tolerated and effective treatment regimen in patients with LACSCC.

The mutational profile analysis of different response to neoadjuvant chemoradiation therapy in local advanced esophageal squamous cell cancer patients.

e15560 Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant diseases in the world and especially in China. The combined modality therapy neoadjuvant chemoradiation therapy (nCRT) has become the new standard of care. This study was aimed to investigate the molecular features in cell-free DNA (cfDNA) that is related with the response to nCRT in the local advanced ESCC. Methods: 24 eligible ESCC patients with received nCRT were included and baseline blood were collected from Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. 14 patients had response and the other 10 patients had no response to nCRT, respectively. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment of a 0.96M size panel covering exon regions of 1,408 genes. Gene alterations were analyzed to explore the relationship between genetic characterizations of cfDNA and response to nCRT. Results: The most common mutated genes were NOTCH1, IRS1, TP53. The somatic alternation of NOTCH1, IRS1, ZFHX4 occurred more frequently in response group than in non-response group. On the contrary, patients with response to nCRT had significantly less mutations of PDE11A, STK11. Moreover, the tumor mutation burden (TMB) of cfDNA in response group was significantly higher than non-response group(p = 0.024). Conclusions: The molecular features in cfDNA of patients with response to nCRT were different from those without response. Five genes’ mutational profile could identify the response and non-response patients with local advanced ESCC. However, prospective studies are needed to validate our findings.

A multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for 2nd line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA)

BackgroundAdvanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients. The impact of 2nd line chemotherapy is poorly defined. Recent data demonstrated effectiveness of checkpoint inhibitors in different squamous cell carcinomas. Therefore, we assess combined nivolumab/ipilimumab as 2nd line therapy in elderly ESCC patients.MethodsRAMONA is a multicenter open-label phase II trial. The primary objective is to demonstrate a significant survival benefit of nivolumab/ipilimumab in advanced ESCC compared to historical data of standard chemotherapy. Primary endpoint is therefore overall survival (OS). Major secondary objective is the evaluation of tolerability. Time to QoL deterioration will thus be determined as key secondary endpoint. Further secondary endpoints are tumor response, PFS and safety. We aim to recruit a total of n = 75 subjects that have to be > 65 years old. Eligibility is determined by the geriatric status (G8 screening and Deficit Accumulation Frailty Index (DAFI)). A safety assessment will be performed after a 3 cycle run-in phase of nivolumab (240 mg Q2W) to justify escalation for eligible patients to combined nivolumab (240 mg Q2W) and ipilimumab (1 mg/kg Q6W), while the other patients will remain on nivolumab only. RAMONA also includes translational research sub-studies to identify predictive biomarkers, including PD-1 and PD-L1 evaluation at different time points, establishment of organoid cultures and microbiome analyses for response prediction.DiscussionThe RAMONA trial aims to implement checkpoint inhibitors for elderly patients with advanced ESCC as second line therapy. Novel biomarkers for checkpoint-inhibitor response are analyzed in extensive translational sub-studies.Trial registrationEudraCT Number: 2017–002056-86; NCT03416244, registered: 31.1.2018.

Multicenter open-label phase II trial to evaluate nivolumab and ipilimumab for second line therapy in elderly patients with advanced esophageal squamous cell cancer (RAMONA).

TPS174 Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients (pts) and impact of 2nd line chemotherapy is poorly defined. In line with recent data demonstrating effectiveness of checkpoint inhibitors Nivolumab (Nivo) and Ipilimumab (Ipi) in squamous cell carcinoma pts, combined Nivo/Ipi therapy will be assessed as 2nd line therapy of advanced ESCC in elderly pts. Methods: RAMONA is a multicenter open-label phase II trial (NCT03416244). Eligibility and geriatric status of the pts will be assessed by the G8 screening tool and the Deficit Accumulation Frailty Index (DAFI). Upon safety assessment after a three cycle run-in phase of Nivo (240 mg Q2W), eligible pts will be escalated to Nivo (240 mg Q2W)/Ipi (1 mg/kg Q6W) combination therapy. The other pts will remain on Nivo only. The primary objective of this trial is to demonstrate a significant survival benefit of the Nivo/Ipi combination therapy in advanced ESCC compared to historical data of standard chemotherapy regimens. Primary endpoint is overall survival (OS); secondary endpoints are tumor response, PFS, safety and quality of life (QoL). The trial has a 90% Power to detect a hazard ratio of 0.68 at a one-side significance level of alpha = 0.05 under the assumption of exponential survival. This corresponds to an increase of the 1-year OS rate by a margin of 13% compared to historical controls for standard chemotherapy (i.e. 30% vs 17%). Subjects are accrued for a period of 12 month. Follow-up continues for 24 month after the last subject is added. Including a sample size increase to compensate for uninformative drop-outs a total of n = 75 subjects will be recruited. The primary endpoint will be assessed using a one-sample log-rank test. A particular study objective is the evaluation of the tolerability of Nivo as single agent and in combination with Ipi in terms of QoL. Therefore time to QoL deterioration will be determined. 18 pts have been enrolled by mid of September 2018. RAMONA also includes translational research to identify predictive biomarkers, establish organoid cultures from tumor tissues and assess the utility of microbiome analyses for response prediction. Clinical trial information: NCT03416244.

Squamous cell carcinoma of the rectum: Practice trends and patient survival.

625 Background: Leverage the National Cancer Database (NCDB) to evaluate trends in management of squamous cell cancer (SCC) of the rectum and their effect on survival for this uncommon tumor. Methods: Data was obtained from the NCDB for patients diagnosed with SCC of the rectum between 2004 and 2014, including cT1-4, cN0-2, cM0 (cohort A, n = 2,296) tumors. A subgroup analysis was performed on locally advanced tumors (cT1-T2, N+ or cT3, N any, subcohort B, n = 883), treated with chemoradiation (n = 706) or trimodality therapy (n = 177) including chemotherapy, radiation, and surgery. Pathological complete response rate following neoadjuvant therapy was obtained. Univariate and multivariate logistic regression analyses were performed to generate hazard ratios (HR) investigating factors associated with overall survival. Kaplan-Meier (K-M) method was used to estimate overall surviving proportion at 5 and 10 years. Results: The median age was 60 years with a strong female predilection (71% female). Among patients treated with neoadjuvant therapy, 36% achieved a complete pathological response at a median interval of 67 days from completion of radiation therapy to surgery. The K-M estimated 5 and 10 year overall survival for stage I disease was 71.3% and 57.8%, respectively; stage II disease was 57.0% and 38.9%, respectively; stage III disease was 57.8% and 41.5%, respectively. On multivariate analysis, increased age, male gender, more co-morbidities, and higher cT category ( P &lt; 0.001 for each) resulted in worse survival. For locally advanced tumors (subcohort B), there was no difference in survival between chemoradiation alone compared to trimodality therapy ( P = 0.909 on multivariate analysis). Conclusions: Most providers manage locally advanced SCC of the rectum similar to anal cancer, which results in equivalent overall survival and spares patients from the additional morbidity associated with surgical resection. [Table: see text]

GST (Gefitinib as Salvage Treatment) in Pretreated Head and Neck Squamous Cell Cancer

Purpose: To determine the efficacy and safety profiles of GST (gefitinib as salavage therapy) in patients with advanced recurrent, residual and/or metastatic squamous cell cancer of the head and neck (HNSCC). Subjects and Methods: Patients with recurrent, residual, or metastatic (R/R/M) HNSCC, were treated with gefitinib 250mg orally daily for 3 weeks. Results and Conclusion: Partial response (PR) was noted in 10% of patients, median progression free survival (PFS) was 3.3 months. Anemia was observed in 16.7% of patients, toxicity related to total leucocyte count grade I,II &III toxicities were observed in 20%, 3.3% and 0%. Only grade I hepatic toxicity was observed in 20%. No case of renal toxicity was seen. Grade I-II upper gastrointestinal toxicity (nausea/ vomiting) was noted in 13.3% patients. Lower gastrointestinal toxicity (diarrhea) was observed in 46.7% of patients. Skin rash was graded and 8 (26.7%) patients demonstrated skin reactions. Overall survival (OS) was 4 months. Gefitinib was well tolerated in this heavily pretreated HNSCC population and produced prolonged disease stabilization.