Cisplatin And 5-fluorouracil Research Articles

397. TREATMENT OUTCOMES OF IMMUNE CHECKPOINT INHIBITORS AS PRIMARY THERAPY FOR UNRESECTABLE OR RECURRENT ESOPHAGEAL CANCER

Abstract Background For the primary treatment of unresectable or recurrent esophageal cancer, combination therapy with immune checkpoint inhibitors (ICI) such as pembrolizumab (Pem) with CF (cisplatin and 5-fluorouracil), nivolumab (Nivo) with CF, and Nivo with ipilimumab (Ipi) has been shown the significantly improve prognosis compared to standard CF therapy in international collaborative phase III trials. As a result, these ICIs have been approved as primary treatment agents in Japan, with treatment guidelines strongly recommending therapies including ICIs. We evaluated the treatment outcomes at our institute and discussed their utility. Methods We examined the treatment outcomes of 26 esophageal cancer patients who underwent primary treatment with Pem+CF, Nivo+CF, or Nivo+Ipi from January 2018 to January 2023. The median observation period was 7.0 months. Results There were 20 male and 6 female patients, with a median age of 69 years. Histologically, there were 24 cases of squamous cell carcinoma and 2 cases of adenocarcinoma. Of the 26 patients, 9 were postoperative recurrences and 17 were unresectable diseases. They were treated with Pem+CF (12 cases), Nivo+CF (7 cases), or Nivo+Ipi (7 cases) as primary therapy. The initial response was complete response (CR) in 1 case, partial response (PR) in 14 cases, stable disease (SD) in 2 cases, and progressive disease (PD) in 9 cases, resulting in an overall response rate of 57.6%. The median progression-free survival was 5.0 months, and the median overall survival was 15.2 months. There was no significant difference in prognosis according to the regimens. Grade 3 or higher adverse events included neutropenia in 3 cases, pituitary insufficiency in 1 case, and adrenal insufficiency in 1 case. One case with lung metastasis and two cases with para-aortic lymph node metastasis showed disappearance of metastatic lesions after chemotherapy including ICIs, leading to conversion esophagectomy. One case had anastomotic failure, but no other postoperative complications were observed. All patients are currently under observation without recurrence. Conclusion ICIs for unresectable or recurrent esophageal cancer showed a prolongation of prognosis in real-world clinical practice, suggesting their significance as part of a multimodal treatment approach including conversion surgery.

Recurrence-free survival as a surrogate for overall survival in esophageal squamous cell carcinoma: Nationwide real-world data from Japan.

269 Background: One of the limitations of the established gold standard, overall survival (OS), is that it requires an extended follow-up period. Addressing this challenge involves investigating appropriate statistically and clinically relevant surrogate endpoints. However, there is a paucity of studies using real-world data (RWD) to explore surrogacy in patients with esophageal squamous cell carcinoma (ESCC). Our study aims to investigate whether recurrence-free survival (RFS) is a valid surrogate endpoint for OS in surgically resectable advanced ESCC patients, utilizing a comprehensive nationwide database in Japan. Methods: The ESCC patients who received neoadjuvant CF (cisplatin and 5-fluorouracil) or DCF (docetaxel, cisplatin and 5-fluorouracil) at 58 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. Kendall's tau between RFS and OS was used at the individual level, and the coefficient of determination was used at the institutional level to assess surrogacy. Additionally, surrogacy between each short-term postoperative endpoint (pathological complete response [pCR] or pathological grade) and OS was investigated using novel statistical methods. Results: Our study encompassed 3154 ESCC patients who underwent subtotal esophagectomy from 2010 to 2015. The cStage I/II/III/IVA/IVB (due to supraclavicular lymph node metastasis) was 224 (7.1%), 1008 (32.0%), 1664 (52.8%), 117 (3.7%), and 140 (4.4%), respectively. The 5-year OS and RFS rate for the entire cohort was 56.6% and 47.7%, respectively. In the primary analysis, a strong correlation between RFS and OS was found (Kendall's tau = 0.797, 95% confidence interval [CI]: 0.782 to 0.812) at the individual level. Subgroup analysis revealed that the better the pathological response, the higher the tau value. An adjusted R2 of 100.0% (95% CI: 40.2 to 100.0) was obtained with the meta-regression model at the institutional level. The surrogate threshold effect was 0.703. Tau between pCR or pathological grade and OS were -0.025 (95% CI: -0.335 to 0.285) and 0.062 (95% CI: -0.086 to 0.209), respectively. Conclusions: The present study was the first nationwide RWD investigation to demonstrate a strong correlation between RFS and OS in surgically resectable ESCC patients who underwent neoadjuvant chemotherapy (NAC). Notably, this correlation was more pronounced in patients who had a more effective response to NAC. These findings hold promise for expediting the development of novel neoadjuvant treatment by shortening the duration of clinical trials.

Significance of lymphovascular invasion in esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy.

Lymphovascular invasion (LVI) was previously reported to be an independent factor associated with survival in locally advanced esophageal squamous cell carcinoma (LAESCC) patients receiving neoadjuvant chemotherapy (NAC); however, the detailed clinicopathological significance of LVI remains unclear. This study evaluated the prognostic impact of LVI in patients with LAESCC after NAC with cisplatin and 5-fluorouracil (CF) or docetaxel, cisplatin and 5-fluorouracil (DCF) followed by surgery and in LAESCC patients with recurrence after NAC and surgery. 438 patients with thoracic LAESCC who had undergone NAC followed by an esophagectomy with three-field lymphadenectomy were assessed using a propensity score matched analysis, and their long-term outcomes were retrospectively reviewed. In matched cohort, a multivariate analysis of relapse-free survival (RFS) in the NAC-CF group suggested that ypN (≥ 1, HR = 3.715, p = 0.004) and LVI (positive, HR = 3.366, p = 0.012) were independent factors associated with RFS; in the NAC-DCF group, ypN (≥ 1, HR = 4.829, p < 0.001) was the only independent factor associated with RFS. Comparisons of overall survival (OS) between the ypN + /LVI + group and other groups among patients with recurrence in each NAC regimen showed significant differences in both of NAC groups (p < 0.001, respectively). The ypN + /LVI + group had a significantly poor OS in both an oligometastatic recurrence (OMR) group (p < 0.001) and a non-OMR group (p < 0.001). The present study suggested that the independent factor associated with prognosis of patients with LAESCC after NAC and surgery may differ according to the NAC regimen, and the presence of both ypN and LVI was a prognostic factor for patients with recurrence, including those with OMR. These results might be helpful when deciding on an additional treatment strategy for LAESCC patients.

Outcomes with chemotherapy in carcinoma penis: Experience from a tertiary cancer center.

Carcinoma penis is more common in India compared to the West. The role of chemotherapy in carcinoma penis is ambiguous. We analyzed the profile and outcomes of patients with carcinoma penis treated with chemotherapy. We analyzed the details of all patients with carcinoma penis treated at our institute between 2012 and 2015. We collected particulars regarding demography, clinical presentation, treatment details, toxicities, and outcomes of these patients. Event-free and overall (OS) survival were calculated from the time of diagnosis until documentation of disease relapse/progression or death for the patients with advanced carcinoma penis who were eligible for chemotherapy. There were 171 patients with carcinoma penis treated at our institute during the study period including 54 (31.6%) patients with stage I, 49 (28.7%) patients with stage II, 24 (14.0%) patients with stage III, 25 (14.6%) patients with stage IV, and 19 (11.1%) patients with recurrent disease at presentation. The present study included 68 patients with advanced carcinoma penis (stages III and IV) who were eligible for chemotherapy, with a median age of 55 years (range: 27-79 years). Sixteen patients received paclitaxel and carboplatin (PC) and 26 patients cisplatin and 5-FluoroUracil (CF). Neoadjuvant chemotherapy (NACT) was given to four patients with stage III and nine patients with stage IV disease. Of the 13 patients given NACT, we observed a partial response in five (38.5%), stable disease in two (15.4%), and progressive disease in five (38.5%) evaluable patients. Six (46%) patients underwent surgery after NACT. Only 28/54 (52%) patients received adjuvant chemotherapy. After a median follow-up of 17.2 months, the 2-year OS rates were 95.8, 89, 62.7, 51.9, and 28.6% for stages I, II, III, IV, and recurrent disease, respectively. The 2-year OS of patients who were given chemotherapy versus those who were not given chemotherapy were 52.7 and 63.2%, respectively (P = 0.762). We report the real-world outcomes of two chemotherapeutic regimens used in consecutive patients with advanced carcinoma penis. Both PC and CF seemed effective and safe. However, approximately half of patients with advanced carcinoma penis do not receive the planned/indicated chemotherapy. We need further prospective trials regarding the sequencing, protocols and indications of chemotherapy in this malignancy.

Real-world Evaluation of the Efficacy of Neoadjuvant DCF Over CF in Esophageal Squamous Cell Carcinoma: Propensity Score-matched Analysis From 85 Authorized Institutes for Esophageal Cancer in Japan.

We aimed to evaluate the efficacy of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy over cisplatin and 5-fluorouracil (CF) in patients with surgically resectable advanced esophageal squamous cell carcinoma (ESCC), using real-world data from 85 esophageal centers. JCOG1109 trial, which assessed the superiority of DCF over CF, and the superiority of chemoradiotherapy with CF over CF alone demonstrated the significant survival advantage of neoadjuvant DCF in overall survival (OS) over CF for ESCC. The ESCC patients who received neoadjuvant CF or DCF at 85 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. After propensity score (PS) matching, the OS and recurrence-free survival were compared between CF and DCF. We initially enrolled 4781 patients. After data cleaning and PS matching using pretreatment variables, 1074 patients for each group were selected for subsequent analysis. There was no significant difference in the incidence of postoperative pneumonia and anastomotic leakage. In the survival analysis, OS was significantly longer in DCF group than CF group (hazard ratio, 0.868; 95% confidence interval, 0.770-0.978; P =0.02), as well as recurrence-free survival (hazard ratio, 0.850; 95% confidence interval, 0.761-0.949; P =0.004). The survival advantage of DCF was not observed in patients with 76 years old or older. Neoadjuvant DCF therapy showed a remarkable survival advantage in surgically resectable ESCC patients, especially in patients who were 75 years old or younger. The current real-world evidence will encourage recommendations for DCF as a standard regimen in neoadjuvant chemotherapy-based treatment strategy for ESCC.

Neoadjuvant chemotherapy for locally advanced esophageal cancer comparing cisplatin and 5-fluorouracil versus docetaxel plus cisplatin and 5-fluorouracil: a propensity score matching analysis.

The standard treatment for locally advanced esophageal cancer is preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), followed by surgery. Although docetaxel plus cisplatin and 5-fluorouracil (DCF) has been reported to have favorable outcomes, no study has compared its therapeutic efficacy to that of standard treatment. This study aimed to compare the therapeutic effects of CF and DCF in the real world by matching patient background factors using propensity scores. We retrospectively reviewed the data of 237 patients with esophageal squamous cell carcinoma who underwent esophagectomy between January 2008 and December 2018. Patients were divided into two groups based on the preoperative chemotherapy regimens of CF (79 patients) or DCF (158 patients), and 49 matched pairs were finally analyzed using propensity score matching. Short- and long-term outcomes were compared between groups. After matching, although no significant differences in survival were observed among the groups, patients receiving DCF showed a significantly high histological response (P < 0.001). Subgroup analyses demonstrated that DCF therapy had better overall survival (P = 0.046) and relapse-free survival (P = 0.010) among pathological T3 and T4 cases. Whereas, adverse effects of chemotherapy were more frequent in the DCF group. Patients receiving DCF had higher pathological response and better survival than those receiving CF, especially in pathological T3 and T4 cases matched using propensity scores. Thus, the DCF regimen might be an effective treatment for locally advanced esophageal cancer. However, the adverse side effects of chemotherapy remain high and should be handled appropriately.

First-line treatment of patients with HER2-positive metastatic gastric and gastroesophageal carcinoma

Fluoropyrimidine+cisplatin/oxaliplatin+trastuzumab therapy is recommended for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric adenocarcinoma. However, there is no comprehensive study on which platinum-based treatment should be preferred. This study aimed to compare the treatment response and survival characteristics of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer who received fluorouracil, oxaliplatin, and leucovorin (mFOLFOX)+trastuzumab or cisplatin and fluorouracil (CF)+trastuzumab as first-line therapy. It was a multicenter, retrospective study of the Turkish Oncology Group, which included 243 patients from 21 oncology centers. There were 113 patients in the mFOLFOX+trastuzumab arm and 130 patients in the CF+trastuzumab arm. The median age was 62 years in the mFOLFOX+trastuzumab arm and 61 years in the CF+trastuzumab arm (p = 0.495). About 81.4% of patients in the mFOLFOX+trastuzumab arm and 83.1% in the CF+trastuzumab arm had gastric tumor localization (p = 0.735). The median progression-free survival (PFS) was significantly higher in the mFOLFOX+trastuzumab arm (9.4 months vs. 7.3 months, p = 0.024). The median overall survival (OS) was similar in both groups (18.4 months vs. 15.1 months, p = 0.640). Maintenance trastuzumab was continued after chemotherapy in 101 patients. In this subgroup, the median OS was 23.3 months and the median PFS was 13.3 months. In conclusion, mFOLFOX+trastuzumab is similar to CF+trastuzumab in terms of the median OS, but it is more effective in terms of the median PFS in the first-line treatment of HER2-positive metastatic gastric and GEJ cancer. The choice of treatment should be made by considering the prominent toxicity findings of the chemotherapy regimens.

Treatment Strategy for Esophageal Squamous Cell Carcinoma With Endoscopic Intramural Metastasis.

Purpose: Intramural metastasis (IM) in esophageal squamous cell carcinoma (ESCC) is sometimes found, and the prognosis of ESCC patients with pathologically diagnosed IM is known to be dismal. However, there are few reports on ESCC patients with clinically diagnosed IM.Methods: This study assessed 2,772 ESCC patients who underwent endoscopy for initial evaluation. Among them, 85 patients (3.1%) were diagnosed with endoscopic IM. In this study, we investigated these patients’ characteristics, survival among the groups stratified by the treatment modalities, and survival predictors.Results: Of 85 patients, 76 (89.4%) had T3 or T4 tumors, 73 (85.9%) had nodal metastases, and 36 (42.4%) had M1 diseases. Curative-intent treatment could be given to 63 patients (74.1%) with a median survival time (MST) of 15.6 months (95% CI: 10.7-20.4). As initial treatment, upfront surgery (US), neoadjuvant chemotherapy (NAC) using cisplatin and 5-fluorouracil (CF), neoadjuvant chemoradiotherapy, and definitive chemoradiotherapy (dCRT) were given to 17 (27.0%), 27 (42.9%), 2 (3.2%), and 17 patients (27.0%), respectively. dCRT was preferred for T4 tumors compared with US or NAC (P = 0.02). The MST of US and NAC patients was 19.3 (95% CI: 12.9-25.6) and 23.4 months (95% CI: 9.4-37.4), respectively. No significant difference was noted between US and NAC patients (P= 0.89).Conclusion: The prognosis of ESCC patients with endoscopic IM is poor even if curative-intent treatment is done. Moreover, no significant survival benefit of NAC with CF for these patients was observed when compared with US.

Identification of gene signatures and potential therapeutic targets for acquired chemotherapy resistance in gastric cancer patients.

Gastric cancer (GC) is the most common type of gastrointestinal cancer, and has been studied extensively. However, resistance to chemotherapeutic agents has become a major problem, leading to treatment failure. This study aimed to investigate the molecular mechanisms mediating acquired resistance to cisplatin and fluorouracil (CF) combination-based chemotherapy in GC patients. The microarray datasets (GSE14209, GSE30070) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) using the limma package in R/Bioconductor. Possible targets of the DEMs were predicted using miRWalk, and the putative miRNA-mRNA regulatory network was constructed using Cytoscape software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were then conducted and visualized using the Search Tool for Retrieval of Interacting Genes (STRING) and Cytoscape. The prognostic value of hub genes was revealed by Kaplan-Meier Plotter. The causal relationships and interactions between proteins were displayed using DisNor. Finally, similarity analysis was conducted using the Connectivity Map (CMap) profiles to predict a group of small molecules in GC treatment. A total of 394 DEGs and 31 DEMs were identified after analysis of pre- and post-treatment samples of clinical responders to CF therapy. TM9SF4, hsa-miR-185-5p, and hsa-miR-145-5p were found to be critical in the miRNA-mRNA regulatory network. The DEGs were found to be mainly enriched in the processes of ribonucleoprotein complex assembly, catalytic activity acting on RNA, mitochondrial matrix, and thermogenesis. The DEMs were predominantly found to be involved in single-stranded RNA binding and endoplasmic reticulum lumen. HDAC5, DDX17, ILF3, and SDHC were identified as hub genes in the PPI network. Of these, HDAC5, DDX17, and ILF3 were found to be closely related to the overall survival of GC patients. DisNor identified the first neighbors of the key genes. Furthermore, CMap profiles predicted a group of small molecules, including several histone deacetylase inhibitors (HDACIs), menadione, and mibefradil, which could serve as promising therapeutic agents to reverse acquired resistance to CF therapy. Our findings reveal new targets and alternative therapies to overcome the acquired resistance of GC patients to CF treatment.

Preoperative cisplatin, fluorouracil, and docetaxel with or without radiotherapy after poor early response to cisplatin and fluorouracil for resectable oesophageal adenocarcinoma (AGITG DOCTOR): results from a multicentre, randomised controlled phase II trial

Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) ≥35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1 : 1 to two cycles of CF and docetaxel (DCF, n= 31) or DCF+ 45 Gy radiotherapy (DCFRT, n= 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. ACTRN12609000665235.

767P - Comparison of chemoradiotherapy (CRT) followed by consolidation with cisplatin and 5-fluorouracil (CF) versus definitive CRT with carboplatin and paclitaxel (CP) in esophageal cancer

BackgroundFor patients (pts) with esophageal (ES) cancer and fragility or limiting comorbidities resulting in contraindications for surgery, CRT is the only treatment option with curative potential. In this scenario, the best evidence is CRT followed by consolidation chemotherapy based on fluoropyrimidine/platin combination (RTOG 98-01/PRODIGE 5). However, definitive CRT with CP is frequently used due to better tolerance and convenience, despite the lack of phase III trials. MethodsConsecutive frail/comorbid pts with ES cancer were retrospectively selected. Primary objective was to compare response rate (RR) by RECIST 1.1, disease-free survival (DFS) and overall survival (OS) between CRT followed by consolidation with 2 cycles of CF and definitive CRT with weekly CP (carboplatin AUC 2 and paclitaxel 50mg/m2). Radiotherapy dose: 50,4Gy. Secondary objectives: prognostic factors and safety. Descriptive statistics were used for population characteristics analysis and Kaplan-Meier curves, Log-Rank Test and Cox Regression for survival analysis. ResultsFrom May, 2010 to May, 2018, 99 pts were treated, 18 (18.2%) with CF and 81 (81.8%) with CP. Median follow-up was 38.7 months (m). 48 (48.5%) were alive at the cut-off date. Median age at diagnosis was 65 (32-86). 72.7% were men. 86.9% had squamous cell carcinoma; 42.4% stage II and 49.5% III. Localization: thoracic (53.3%), abdominal (20.1%), cervical (15.2%) and EGJ (10.1%). General characteristics were well balanced between groups. RR after the CRT phase were similar (CP: 53.1%; CF: 55.5%; p=0.198). Median DFS was 23.2m (95%CI 5.9-not reached) and 7.2m (95%CI 4.9-9.4) for CF and CP, respectively (HR 0.55; 95%CI 0.29-1.56; p=0.08). In the multivariate analysis CF was an independent prognostic factor for improved OS (HR 0.36; 95%CI 0.15-0.91; p=0.03), as were higher body mass index (p=0.03) and staging (p=0.04). Rates of major toxicities were similar between the groups. ConclusionsCRT followed by consolidation with CF seems to offer better outcomes than definitive CRT with CP for ES cancer pts not eligible for surgery. Consolidation therapy or type of chemotherapy may have contributed for this difference in outcomes. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Cisplatin and 5-Fluorouracil with or Without Epidermal Growth Factor Receptor Inhibition Panitumumab for Patients with Non-Resectable, Advanced or Metastatic Esophageal Squamous Cell Cancer: A Prospective, Open-Label, Randomised Phase 3 AIO/EORTC Trial (Power)

Background: Advanced unresectable esophageal squamous cell cancer (ESCC) is treated with palliative chemotherapy of cisplatin and 5-fluorouracil (CF). Targeting epidermal growth factor receptor (EGFR) with antibodies panitumumab (P) or cetuximab with chemotherapy enhanced overall survival (OS) in metastatic colorectal cancer or squamous cell cancer of head and neck. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in confirmed advanced ESCC. Methods: 146 patients, not curatively resectable and not qualified for definitive radio-chemotherapy were randomised 1:1 to CF (cisplatin [100 mg/m² i.v., day 1] and 5-fluorouracil [1000 mg/m²/day i.v., days 1-4]), versus CF plus P [9 mg/kg, i.v., day 1], each q3-week cycle) until progressive disease or inacceptable toxicity. Safety was reviewed by a pre-planned Monitoring Board after 40, 70 and 100 patients completing at least one cycle. After 53 patients enrolled, cisplatin was amended from 100 to 80 mg/m². Findings: The academic phase 3 trial was terminated early for futility on an interim efficacy analysis: median OS favoured CF over CFP, regardless of cisplatin dose (HR 1·77, 95%CI 1·06-2·98; p=0·028). In the final analysis, median OS was 10·2 vs 9·4 months for CF vs CFP, respectively (HR 1·17, 95%CI 0·79-1·75; p=0·43). Most deaths were related to disease progression, 44 (56·4%) in CF and 34 (43·6%) in CFP. Objective responses (27/73 [37·0%]) were identical in both arms. Most common severe adverse events were kidney injury (3 [4·3%] vs 7 [9·7%]), general deterioration (5 [7·1%] vs 5 [6·9%]), and dysphagia (4 [5·7%] vs 4 [5·6%]) in CF vs CFP, respectively. High levels of soluble (s)EGFR were associated with worse PFS. sEGFR was induced under CFP. Interpretation: Cisplatin/5-fluorouracil is an established palliative regimen in unselected advanced or metastatic ESCC patients. EGFR inhibition added to CF did not improve survival. Biomarker results support further liquid biomarker studies. Trial Registration Number: The study is registered with ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15). Funding: The trial was funded by AIO-Studien-gGmbH. Partial financial support and panitumumab were provided by Amgen Inc. Declaration of Interest: MM has travel support and advisory role for Amgen. FL reports personal fees from Amgen. All other authors declare that they have no conflicts of interest during the conduct of the study. Ethical Approval: The clinical study protocol was reviewed and approved by the responsible ethics committees of all participating sites. The trial was conducted in accordance with the principles of the International Conference on Harmonisation on Good Clinical Practice. All patients gave written informed consent before enrolment and any trial-specific procedures.

FA06.06: CLINICAL UTILITY OF YPTNM STAGE GROUPING IN AJCC 8TH EDITION FOR JAPANESE PATIENTS WITH ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background The 8th edition of the American Joint Committee on Cancer staging (AJCC-8th) of esophageal cancer presents independent stage grouping for patients who underwent neoadjuvant therapy followed by esophagectomy (ypTNM). The aim of this study is to elucidate the clinical utility of ypTNM stage grouping in Japanese patients with esophageal squamous cell carcinoma (ESCC). Methods A total of 146 patients (121 men and 25 women, with a median age of 65 years) who underwent curative esophagectomy following neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (CF) for ESCC between 2005 and 2011 were enrolled in this retrospective study. We compared the distribution of patients and disease-specific survival after esophagectomy (DSS) stratified by ypStage between AJCC-7th and 8th. Additionally, we evaluated the association between clinicopathological features including ypStage in AJCC-8th and DSS. Results The number of patients classified into ypStage 0/IA/IB/IIA/IIB/IIIA/IIIB/IIIC/IV was 5/1/14/11/35/40/18/18/4 in AJCC-7th, and that classified into ypStage I/II/IIIA/IIIB/IVA/IVB was 27/18/21/58/18/4 in AJCC-8th. According to the revision from AJCC-7th to 8th, ypStage of 85 and 7 patients was up- and down-graded, respectively. Up-grading of ypStage was observed in 83% of patients with ypT4 tumor and in 78% of patients with ypN1–3. The 5-year DSS of ypStage 0/IA/IB/IIA/IIB/IIIA/IIIB/IIIC/IV was 100/100/93/91/75/62/50/28/50% in AJCC-7th, and that of ypStage I/II/IIIA/IIIB/IVA/IVB was 96/83/68/58/28/50% in AJCC-8th. The 5-year DSS of ypStage III was 61% in AJCC-8th comparing to 51% in AJCC-7th, and that of ypStage IV was 31% in AJCC-8th comparing to 50% in AJCC-7th. Univariate analyses identified ypT-8th (P = 0.028), ypN-8th (P &lt; 0.001), cStage-8th (P = 0.006) and ypStage-8th (P &lt; 0.001) in addition to surgical procedure (P = 0.027) and histological response (P = 0.019) as significant prognostic factors for DSS. Among these, multivariate analysis showed that ypStage-8th was a significant independent prognostic factor for DSS (P &lt; 0.001). Conclusion ypTNM stage grouping in AJCC-8th can more accurately stratify the prognosis of patients who underwent neoadjuvant CF therapy for ESCC, by classifying patients with residual tumor invasion to adjacent structures and regional lymph node metastasis into more unfavorable prognostic group than that in AJCC-7th. ypStage according to AJCC-8th is the most reliable prognosticator for this disease. Disclosure All authors have declared no conflicts of interest.

Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD groups (Epitopes-HPV02 study)

BackgroundThe squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months.We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses.Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients.MethodsThis multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) <2, and being eligible for DCF. Patients receive either 6 cycles of standard DCF or 8 cycles of modified DCF depending on age (> vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon’s optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy.DiscussionSince the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA.Trial registrationNCT02402842, EudraCT: 2014–001789-81.

Failure of neoadjuvant chemotherapy for resectable esophageal squamous cell carcinoma.

Neoadjuvant treatment has become standard care for patients with resectable esophageal cancer. However, some patients cannot undergo surgery or curative resection because of disease progression during neoadjuvant treatment. The aim of this study is to identify the pretreatment characteristics of patients in whom neoadjuvant treatment failed. The study enrolled 231 patients who underwent chemotherapy with cisplatin and 5-fluorouracil (CF) as neoadjuvant therapy for T1N1-3 or T2-3 any-N esophageal squamous cell carcinoma (ESCC). Of these patients, 201 (87.0%) underwent curative resection (R0) and 30 (13.0%) could not undergo curative resection; 19patients (8.2%) underwent incomplete resection (R1 or R2), and 11 patients (4.8%) could not undergo surgery because of disease progression. We compared clinical characteristics and survival between patients who underwent curative resection (curative group) and those who could not undergo curative resection (noncurative group) to determine the factors predicting noncurative treatment. The noncurative group had significantly worse disease-specific survival than the curative group (P<0.001). All patients in the noncurative group had cT3 tumors. In 141 patients with cT3 tumors, those in the noncurative group were more likely to have higher serum SCC antigen concentration (P=0.021), location of the main tumor in the upper to the middle third of the esophagus (P=0.071), intramural metastases (P<0.001), advanced N category (P=0.016), and bulky lymph node metastases (P=0.060). Multivariate logistic regression analysis identified location of the main tumor in the upper to the middle third of the esophagus (P=0.047), intramural metastases (P=0.002), and nodal metastases (N1, P=0.014; N2, P=0.015, respectively) as independent predictors of treatment failure in patients with cT3 tumors. Neoadjuvant CF therapy alone may not be effective for patients with cT3 tumors accompanied by these risk factors, and the efficacy of alternative strategies, such as triplet chemotherapy or chemoradiotherapy, should be evaluated.

Investigation of operative outcomes of thoracoscopic esophagectomy after triplet chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for advanced esophageal squamous cell carcinoma.

Preoperative chemotherapy with cisplatin and 5-fluorouracil (CF) has become the standard treatment for resectable stage II/III thoracic esophageal carcinoma in Japan. Recently, preoperative triplet chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) has been reported to be effective for locally advanced esophageal cancer. Thoracoscopic esophagectomy (TE) has been increasingly accepted worldwide for the treatment of esophageal cancer. We conducted a retrospective study to evaluate the safety and outcomes of TE after DCF therapy for patients with advanced esophageal cancer. The medical records of 63 consecutive patients with esophageal squamous cell carcinoma who underwent thoracoscopic surgery after chemotherapy were reviewed. Thirty-four patients received neoadjuvant chemotherapy with CF, and 29 received DCF as first-line chemotherapy. The clinical T stage was significantly higher in the DCF group than in the CF group (p<0.0001), including 17 patients with T4. Lymph node metastasis was more frequent in the DCF group (p=0.0005), and the clinical stage of the tumor was significantly higher in the DCF group than in the CF group (p=0.0001). No significant difference existed between the two groups in operation time for the thoracic procedure (DCF 277.2min vs. CF 302min). Blood loss during the thoracic procedure was less in the DCF group than in the CF group (DCF 46.9mL vs. CF 88.8mL; p=0.0056). No significant differences existed between the two groups in postoperative morbidity (DCF 34.5% vs. CF 47%) or mortality (DCF 0% vs. CF 2.9%) rates. Our study suggests that TE after DCF therapy for advanced esophageal cancer is as safe as TE after CF therapy.

Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus Adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003)

This phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment of patients with ESCC. Patients with resectable advanced ESCC were randomly assigned to either ACF (Adriamycin 35 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 7 days) every 4 weeks or DCF (docetaxel 70 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 5 days) every 3 weeks. Surgery was scheduled after completion of two cycles of chemotherapy. The primary end point was RFS, analyzed by the intention-to-treat. Between October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, all of whom were eligible and randomly assigned to the two groups (81 to the ACF group and 81 to the DCF group). The R0 resection rates for the ACF and DCF groups were equivalent (95.9% versus 96.2%, P = 0.93). The 2-year RFS and overall survival rates for DCF versus ACF were 64.1% versus 42.9% (hazard ratio 0.53, 95% confidence interval 0.33-0.83, P = 0.0057) and 78.6% versus 65.4% (P = 0.08), respectively. Compared with ACF, DCF chemotherapy was associated with prolonged RFS for patients with resectable advanced ESCC. Thus, DCF chemotherapy has potential as a standard neoadjuvant therapy for resectable ESCC. University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN000004555/000004616).

P2.04-031 Predictors of Pathological Complete Response (TRG=1) among Esophageal Cancer Cases; NCI Pooled Data: Topic: Esophageal Cancer and Other Malignancies

Commonly used chemotherapy regimens for esophageal cancer (EC) are EOX(Epirubicin/Oxaloplatin/Capecitabine) for adenocarcinoma and CF(Cisplatin and 5-Fluorouracil) for squamous carcinoma. In this study we aim to assess prevalence of pathological complete response (pCR) after current chemotherapeutic regimens among our EC cases and compare pCR cases to the remaining cohort. We retrospectively reviewed Pathology Department database to retrieve EC patients treated in our National Cancer Institute (NCI), Cairo University during the past 5-years. Available variables were age, gender, operation, diagnosis, tumor size and grade, LN-size, presence of Barrett’s esophagus or in-situ/micro-invasive carcinoma, gross and microscopic pictures. MANDARD’s pathological response using tumor regression grade (TRG) was quantitated into five grades (1-5) with TRG=1 showing absence of residual cancer (Mandard et al.,1994. Esophageal carcinoma regression after chemoradiotherapy, Cancer,73(11),2680-86). Logistic regression was used to identify pCR(TRG-1)predictors. Kaplan-Meier survival curves were used. 334 patients were encountered with males predominance; 202 (60.5%), Median age was 64(Inter-quartile range;IQR;58-68), Pathology was SqCC in 227 (68%), adenocarcinoma in 94 (28.1%), undifferentiated ca in 9 (2.7%)and others in 4 (1.2%). pCR (TRG-1) was evident in 15 cases (4.5%). Among mentioned variables, only advanced age, non SqCC and high grade tumors adversely affect pathological response to induction treatment. On MVA, Advanced age (Odd Ratio (OR)=0.923, 95%Confidence interval (CI)=0.86-0.99) p=0.025), moderate/high grade tumors(OR=0.03, p<0.001)adversely affect response while SqCC pathology has better response trend(OR4.39, p=0.086). 3-years overall survival (OS) was 100% in pCR (TRG-1) vs 82.3% in the remaining cohort (Figure). Among esophagectomy cases, surgery was done in 71.7% males vs28.3% females (p=0.093). Gastric pull up was performed in all surgical cases. R1 was present in 2.2%. Median tumor size was 4.3cm (IQR;3-5.6cm), least surgical margin was 3 (2-4) and max (LN) size was 1(1-2cm).Median +veLN, total LNnumber&LN-ratio was 0 (0-1), 10 (7-17) and 0 (0-5%) respectively. 30-days-perioperative mortality was 6.5%. 3 years OS among esophagectomy patients was 79.6%. Young EC patients and low grade tumor show better response to chemotherapy so aggressive treatment is warranted among this cohort. SqCC carries a good prediction to pathological response and hence better survival mandating aggressive chemo-radiation in this cohort aiming to cure.

A role of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer plus hydronephrosis with or without pelvic nodal involvement.

To retrospectively evaluate the failure patterns of multimodality bladder-preserving therapy in patients with muscle-invasive bladder cancer. Patients with muscle-invasive bladder cancer underwent maximal transurethral resection of bladder tumor and induction chemotherapy, followed by concurrent chemoradiotherapy (CCRT). Radiotherapy was given with 45Gy to the pelvis, 50.4Gy to the bladder, and 64.8Gy to the tumor bed. Three protocols of trimodality treatment were used: Protocol A, three cycles of cisplatin and fluorouracil (CF), followed by CCRT with 6 weekly cisplatin; Protocol B, three cycles of weekly paclitaxel plus CF, followed by CCRT with 6 weekly paclitaxel and cisplatin; Protocol C, three cycles of gemcitabine and cisplatin, followed by CCRT with 6 weekly cisplatin. Interval cystoscopy confirmed complete response (CR) after induction chemotherapy and 40-50Gy of radiotherapy. Patients without CR were referred for salvage cystectomy. A total of 60 patients were enrolled, including 11 patients with unfavorable factors defined as hydronephrosis and/or pelvic nodal involvement. After a median follow-up of 86.7 months, the 5-year overall, progression-free, and bladder preservation-specific survival rates were 76.3%, 62.9%, and 71.5%, respectively. Three patients underwent salvage cystectomy for invasive bladder recurrence. Of 45 surviving patients, 42 patients (93.3%) retained functioning bladders. Patients with unfavorable factors had significantly lower metastasis-free survival (p=0.002), but not bladder preservation-specific survival (p=0.25). With trimodality treatment involving visually complete transurethral resection of bladder tumor, cisplatin-based induction chemotherapy, and CCRT, patients with unfavorable factors maintained satisfactory bladder preservation but not systemic control.

610O - An AGITG trial –A randomised phase II study of pre-operative cisplatin, fluorouracil and DOCetaxel +/-radioTherapy based on poOR early response to cisplatin and fluorouracil for resectable esophageal adenocarcinoma

Patients (pts) with esophageal/ gastro-esophageal junction (GOJ) adenocarcinoma (EAC) who do not show early metabolic response (as defined by 18-FDG PET) to chemotherapy have poorer survival and histological response rates <5%. We investigate if, by tailoring the neoadjuvant therapy, histological response can be improved in pts not showing early metabolic response after the first cycle of treatment. Pts with resectable EAC were enrolled to a multicentre randomised phase II trial. PET scans were performed at baseline and after receiving one cycle of cisplatin and fluorouracil (CF) (day 15). If SUVmax decreased by ≥ 35%, pts were classified as early metabolic responders (EMR), otherwise as non-metabolic responders (NMR). EMR pts continued with a 2nd cycle of CF follow by surgery while the NMR pts were randomised 1:1 to receive either CF and docetaxel (DCF) for two cycles, or DCF concurrent with 45Gy radiotherapy (DCFRT). The primary endpoint was histological response (<10% residual tumor) in each randomised arm. 124 pts were enrolled (62% esophagus and 38% GOJ) and received one cycle of CF. At day 15, 45/122 (37%) pts were EMR and 77/122 (63%) were NMR and 2 did not have a day 15 PET. Of the NMR group, 31 were randomised to DCF; 35 to DCFRT; 11 were not randomised (2 pts progressed, 4 had toxicities and 5 refused). Grade 3 or 4 toxicities (AE) were seen in 19/58 (33%) pts on CF, 14/31 (45%) DCF pts and 25/35 (71%) DCFRT pts. No treatment related deaths were seen. Esophagectomy was performed in 45 (100%) EMR, 28/31 (90%) DCF (1 refused DCF, 1 refused surgery and 1 AE) and 33/35 (94%) DCFRT (2 progressed). R0 (>1mm margin) resection was achieved in 31/45(69%) of EMR, 18/28 (64%) of DCF, 31/33 (94%) of DCFRT pts. A major histological response was achieved in 3/45 (7%) EMR pts, 6/30 (20%) DCF pts, and 22/35 (63%) DCFRT pts. Docetaxel added to CF, particularly DCFRT, can induce high rates of histological responses in NMR pts. Therefore tailoring multimodality therapy based on individual PET response is safe and feasible in EAC, although the impact on survival requires longer follow up.