Docetaxel, Cisplatin And Fluorouracil Research Articles

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.

M1 macrophage predicted efficacy of neoadjuvant camrelizumab combined with chemotherapy vs chemotherapy alone for locally advanced ESCC: A pilot study.

The efficacy and safety of immunotherapy have been widely recognized in gastrointestinal-related cancers. However, the efficacy of neoadjuvant camrelizumab for locally advanced esophageal squamous cell carcinoma (ESCC) has not been firmly established. This study compared the efficacy of camrelizumab in combination with neoadjuvant DCF (docetaxel, cisplatin and fluorouracil), with DCF alone for ESCC, and exploring biomarkers related to immune infiltration of the ESCC immunotherapy response. We enrolled and randomly assigned patients with stage II-IVa ESCC to two study treatments: camrelizumab combined with docetaxel, cisplatin and fluorouracil (DCF) regimen and DCF regimen alone. The tissue for multiplex immunofluorescence (mIF) was obtained before and after neoadjuvant therapy. The Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 (RECIST 1.1) and Tumor Regression Grade (TRG) was used to evaluate efficacy. A total of 30 patients were enrolled in the study. Following neoadjuvant camrelizumab, the objective response rate (ORR) and the disease control rate (DCR) were 46.7% (7/15) and 95.7% (14/15), respectively. No patients reported complete remission, while ORR and DCR in the chemotherapy group were 26.7% (4/15) and 86.7% (13/15), respectively. R0 resection after neoadjuvant treatment was achieved in 3 out of 15 patients in the combined group and in all patients (15/15) in the chemotherapy group. In the combined group, M1-type tumor-associated macrophages and CD56dim NK cells were more abundant in responders than in non-responders (p < 0.05). A higher M1/M2 ratio was observed in responders (p < 0.05). With respect to the NGS, among the copy number amplified genes, the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) showed the highest frequency (47%, 7/15). Neoadjuvant camrelizumab combined with chemotherapy improved ORR in locally advanced ESCC. M1-type tumor-associated macrophages and CD56dim NK cells might be utilized to predict camrelizumab efficacy.

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.

Multimodal Treatment Strategies to Improve the Prognosis of Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Narrative Review.

Esophageal cancer is the seventh most common malignancy and sixth most common cause of cancer-related death globally. Esophageal squamous cell carcinoma (ESCC) with aortic or tracheal invasion is considered unresectable, and has an extremely poor prognosis; its standard treatment is definitive chemoradiotherapy (dCRT). In recent years, induction chemotherapy (ICT) has been reported to yield high response rates for locally advanced ESCC, and the efficacy and safety of ICT followed by conversion surgery (CS) have been investigated. Multimodal treatment, combining surgery with induction chemoradiotherapy (ICRT) or ICT, is necessary to improve ESCC prognosis. CS is generally performed for locally advanced ECC after ICRT or ICT when tumor downstaging is achieved, although its prognostic benefit remains controversial. The Japan Clinical Oncology Group (JCOG) has conducted a three-arm phase III randomized controlled trial (JCOG1510) to confirm the superiority of DCF (docetaxel, cisplatin, and 5-fluorouracil) ICT, over conventional dCRT, among patients with initially unresectable ESCC. In recent years, researchers have reported favorable outcomes of induction therapy followed by CS and salvage surgery, after dCRT or systemic immunochemotherapy. In this review, we will describe the latest developments in the multimodal treatment including chemotherapy, CRT, surgery, and immunotherapy, which may improve oncological and survival outcomes for patients with cT4 ESCC.

Modified DCF (Docetaxel, Cisplatin and 5-fluorouracil) chemotherapy is effective for the treatment of advanced rectal squamous cell carcinoma.

Advanced rectal squamous cell carcinoma (rSCC) is a very rare and aggressive entity, and the best initial management is crucial for long survival as well as organ preservation and quality of life. Whereas local diseases are treated with chemo-radiotherapy and salvage surgery, data are scarce on how to treat more advanced diseases, and the role of induction chemotherapy is unknown. We retrospectively analyzed all consecutive patients with advanced rSCC and treated with modified DCF (docetaxel, cisplatin, 5-fluorouracil; mDCF) regimen, from January 2014 and December 2021 in two French centers. Exploratory endpoints were efficacy (overall survival, recurrence-free survival, response rate, organ preservation rate) and safety. Nine patients with locally advanced or metastatic diseases received a mDCF regimen and were included for analysis. The median age was 62.0 years, 7 patients (77.8%) were women, and all eight available tumors were positive for HPV, mostly (85.7%) to genotype 16. With a median follow-up of 33.1 months, 77.8% of patients were still alive and disease-free, and the median overall survival was not reached at six years. The objective response rate was 87.5% after mDCF, and the complete response rate was 25.0% after mDCF and was increased to 75.0% after chemoradiotherapy. Only one patient underwent surgery on the primary tumor, with a complete pathological response. The median mDCF cycle was eight over eight scheduled, and all patients received the complete dose of radiotherapy without interruptions. Induction mDCF chemotherapy followed by chemoradiotherapy is safe and highly effective in patients with advanced rSCC, and should be considered as an option in metastatic stage or locally advanced disease with an organ-preservation strategy.

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial.

Squamous Cell Carcinoma of the Anal canal (SCCA) is a rare disease associated with a Human Papillomavirus (HPV) infection in most cases, predominantly the HPV16 genotype. About 15% of SCCA are diagnosed in metastatic stage and some will relapse after initial chemoradiotherapy (CRT). Treatment of patients by Docetaxel, Cisplatin and 5-fluorouracil (DCF) has been recently shown to improve their complete remission and progression-free survival. The aim of this retrospective study was to explore the impact of HPV infection, HPV DNA integration, TERT promoter mutational status and somatic mutations of oncogenes on both progression-free (PFS) and overall survivals (OS) of patients treated by DCF. Samples obtained from 49 patients included in the Epitopes-HPV02 clinical trial, diagnosed with metastatic or non-resectable local recurrent SCCA treated by DCF, were used for analyses. Median PFS and OS were not associated with HPV status. Patients with episomal HPV had an improved PFS compared with SCCA patients with integrated HPV genome (p=0.07). TERT promoter mutations were rarely observed and did not specifically distribute in a subset of SCCA and did not impact DCF efficacy. Among the 42 genes investigated, few gene alterations were observed, and were in majority amplifications (68.4%), but none were significantly correlated to PFS. As no biomarker is significantly associated with patients’ survival, it prompts us to include every patient failing CRT or with metastatic disease in DCF strategy.

The Role of Immunotherapy in the Treatment of Anal Cancer and Future Strategies.

Despite being markedly sensitive to chemoradiotherapy, patients with locally advanced (T3-4 and/or node-positive) squamous cell carcinoma of the anal canal (SCCA) still present high rates of disease recurrence, which is characterized by meaningful morbidity and mortality. Abdominoperineal resection as salvage surgery may be considered for patients with local recurrence, but with an important negative impact in the quality of life. Systemic therapy of advanced SCCA is an unmet clinical need. Palliative chemotherapy for the management of unresectable or metastatic disease yields approximately 60% of objective response rate; however, it still portends a grim prognosis. Based on the recently published InterAACT trial, carboplatin plus paclitaxel has become the standard of care of advanced disease; modified DCF (docetaxel, cisplatin, and 5-fluorouracil) may also be considered for fit patients amenable to intensive therapy. There are no FDA-approved therapies for the treatment of chemorefractory patients. Nevertheless, both nivolumab and pembrolizumab may be considered for these patients with promising results, regardless of PD-L1 expression or other predictive biomarkers. It is estimated that approximately 1 out of 5 patients with SCCA will derive large benefit from PD-1 inhibitors, which may produce considerable durations of response. Ongoing clinical trials exploring the combination of chemotherapy plus immune checkpoint inhibitors in the first-line therapy, combination of anti-PD-1/PD-L1 plus anti-CTLA-4, and emerging immunotherapeutic approaches, such as adoptive T cell therapies, are eagerly awaited and may bring practice-changing results in the next few years for the treatment of this challenging disease.

Atezolizumab plus modified DCF (docetaxel, cisplatin, and 5-fluorouracil) as first-line treatment for metastatic or locally advanced squamous cell anal carcinoma: A SCARCE-PRODIGE 60 randomized phase II study.

3508 Background: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen is one of the first-line standard regimens for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating an improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 have been shown to be effective as monotherapy in advanced SCCA, refractory to chemotherapy. The aim of this study was to evaluate the combination of atezolizumab and mDCF as first-line treatment. Methods: This is a 2:1 randomized, non-comparative, multicenter, phase II study (NCT03519295) with an experimental arm (Arm A, mDCF plus atezolizumab) and standard arm (Arm B, mDCF). Patients with chemo-naive SCCA, metastatic or unresectable locally advanced recurrence were eligible. In Arm A, survival probabilities for null and alternative hypotheses for the primary endpoint 12-months PFS rate were 35 and 50%, respectively. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 81%, 64 patients in 2 years with 1 year of follow-up need to be randomized in Arm A. The lowest expected critical value would be a PFS rate of 46% to reject H0. In both arms, 8 cycles of mDCF were administered. In Arm A, patients received a fixed dose of atezolizumab (800 mg every 2 weeks) before each mDCF cycle and were followed up to 1 year. Results: Ninety-sevenevaluable patients were enrolled, 64 in Arm A and 33 in Arm B. The median age was 64.1 years, 73.2% were women, and 78,3% had a metastatic disease. More patients in Arm A had an ECOG-PS 1 (42.2% vs 27.3%), liver involvement (56.9% vs 48%), and an extensive local recurrence (23.5% vs 8%). The median follow-up was 22.3 months (95% CI 20.8-24.8).The 12-month PFS rate was 44.2% (90% CI 33.7-54.2) and 43.2% (90% CI 28.5-57.0) in Arm A and Arm B, respectively, and the 12-month OS rate was 77.7% (95% CI 68.1-88.7) and 80.8% (95% CI 68.1-95.9).The objective response rate was 74.6% and 78.1% in Arm A and Arm B, respectively. A high dose-intensity and a good safety profile were observed in both arms. Grade ≥3 toxicities were observed in 59.0% and 36.4% of patients in Arm A and Arm B, respectively, with no toxic death. Conclusions: The results of SCARCE trial are consistent with previous results of mDCF, with high efficacy and safety at first-line in patients with advanced SCCA. However, the concomitant addition of CKI did not make a significant clinical impact at 12 months. Updated results will be presented. Clinical trial information: NCT03519295.

Adoptive γδT-cell transfer alone or combined with chemotherapy for the treatment of advanced esophageal cancer

Background aimsAfter therapy with platinum, 5-fluorouracil and taxane, no further recommended therapy is available for recurrent or metastatic esophageal cancer (r/mEC). Here the authors report two phase 1 trials of adoptive γδT-cell therapy, one for treatment-refractory r/mEC (γδT-monotherapy-P1, UMIN000001419) and the other for r/mEC with no prior systemic therapy (DCF-γδT-P1, UMIN000008097). MethodsFor γδT-monotherapy-P1, patients received four weekly and four biweekly injections of autologous γδT cells. For DCF-γδT-P1, patients received docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy consisting of docetaxel (60 mg/m2) and cisplatin (60 mg/m2) on day 1 and continuous injection of 5-fluorouracil (600 mg/m2/day) on days 1–5 of each 28-day cycle; additionally, they received autologous γδT-cell injections on day 15 and day 22 of each cycle. ResultsTwenty-six patients were enrolled for γδT-monotherapy-P1. No severe adverse events were associated with γδT-cell therapy. Median overall survival was 5.7 months (95% confidence interval [CI], 4.3–10.0), and median progression-free survival was 2.4 months (95% CI, 1.7–2.8). Eighteen patients received DCF-γδT-P1. All treatment-related adverse events were associated with DCF chemotherapy, not γδT injection. Median overall survival was 13.4 months (95% CI, 6.7–not reached), and median progression-free survival was 4.0 months (95% CI, 2.5–5.7). The response rate and disease control rate were 39% and 78%, respectively. ConclusionsThe use of γδT-cell immunotherapy with or without chemotherapy was safe and feasible for r/mEC patients. Although the authors failed to demonstrate any clinical benefit of γδT-monotherapy-P1, survival benefits were observed in the DCF-γδT-P1 trial.

Effects of Different Chemoradiotherapy Regimens on Early Survival Outcomes in Patients with Locally Advanced Nasopharyngeal Carcinoma

To compare the early survival outcomes of patients with locally advanced nasopharyngeal carcinoma received EPF (epirubicin, cisplatin and fluorouracil) induced chemotherapy combined with concurrent nimotuzumab with radiotherapy (CNRT) or DPF (docetaxel, cisplatin and fluorouracil) induced chemotherapy combined with concurrent chemoradiotherapy (CCRT). Patients with locally advanced nasopharyngeal carcinoma (stage Ⅲ to Ⅳb) from March 2010 to September 2017 were included. The primary endpoint was disease-free survival (DFS). The secondary endpoints were distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), and overall survival (OS). Propensity score matching was used to balance the differences in clinical characteristics between the two groups. Kaplan-Meier method and log-rank test were used to compare the survival differences between the two groups. Multivariate Cox proportional hazards model was used to identify potential prognostic factors. After matching, a total of 153 patients were enrolled, including 51 patients in the EPF combined with CNRT group and 102 patients in the DPF combined with CCRT group. There was no difference in 2-year DFS (82.4% vs. 85.3%, P=0.880), OS (88.2% vs. 96.0%, P=0.410), LRFS (100.0% vs. 92.1%, P=0.278), and DMFS (82.3% vs. 88.2%, P=0.120) between EPF combined with CNRT group and DPF combined with CCRT group. Treatment regimen (EPF combined with CNRT vs. DPF combined with CCRT) was not an independent prognostic factor of DFS (hazard ratio (HR)=0.530, P=0.075). In the subgroup analyses, EPF combined with CNRT could reduce the risk of disease progression in T3 (HR=0.174, P=0.045), N1/N2 (HR=0.432, P=0.036), and male patients (HR=0.437, P=0.044). During concurrent radiotherapy, the incidence of grade 3-4 neutropenia in EPF combined with CNRT was significantly lower than that of DPF combined with CCRT (P=0.007). EPF combined with CNRT regimen is similar to DPF combined with CCRT regimen in survival outcomes, but the patients with T3, N1/N2, and male nasopharyngeal carcinoma may benefit from EPF combined with CNRT regimen.

Anti-Telomerase CD4+ Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials

Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients’ clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients’ survival.

ABCB1 and ABCC2 genetic polymorphism as risk factors for neutropenia in esophageal cancer patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy.

The combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is a newly developed chemotherapy regimen for esophageal cancer. Severe neutropenia is dose-limiting toxicity of docetaxel and it is well known to be frequently occurred during DCF chemotherapy. This study aimed to investigate the relationship between severe neutropenia and genetic polymorphisms in patients treated with preoperative DCF chemotherapy. A total of 158 patients were investigated for their absolute neutrophil count (ANC) within the first cycle of DCF chemotherapy at the National Cancer Center (NCC) Hospital East. DNA samples obtained from the NCC Biobank Registry were used for the analysis of nine genetic polymorphisms related to docetaxel pharmacokinetics. These genotypes were evaluated for their association with severe neutropenia, and further their risk factors were examined using a multivariate logistic regression. A total 81 (51.3%) patients developed severe neutropenia. Multivariate analysis revealed that age (OR 1.054; CI 1.008-1.102, P = 0.022), baseline ANC (OR 1.019; CI 1.002-1.037, P = 0.030), ABCB1 3435C>T (OR 2.191; CI 1.087-4.417, P = 0.028) and ABCC2 *+9383C>G (OR 2.342; CI 1.108-4.948, P = 0.026) were significant risk factors for severe neutropenia development. The results from this study showed that age, ANC, ABCB1 3435C>T, and ABCC2 *+9383 G>C increased the incidence of severe neutropenia with the number of identified risk factors. In addition to age and baseline ANC, ABCB1 3435C>T and ABCC2 *+9383C>G were identified as independent predictors for severe neutropenia in esophageal cancer patients treated with DCF chemotherapy.

Total Lesion Glycolysis Ratio in Positron Emission Tomography/Computed Tomography Images During Neoadjuvant Chemotherapy Can Predict Pathological Tumor Regression Grade and Prognosis in Patients with Locally Advanced Squamous Cell Carcinoma of the Esophagus.

The usefulness of quantitating tumor lesion glycolysis (TLG) from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings as a tool for determining the effect of neoadjuvant chemotherapy (NAC) in esophageal squamous cell carcinoma (ESCC) has not yet been established. The cohort of this retrospective study comprised 46 patients who had undergone NAC and subsequent esophagectomy for locally advanced ESCC between January 2008 and December 2017. PET/CT was conducted before and after NAC to assess its therapeutic effect. Associations between changes in TLG values during NAC and clinicopathological findings, pathological tumor regression grade (TRG), and prognosis were assessed. Most patients received two courses of DCF (Docetaxel, Cisplatin, and Fluorouracil) as NAC. The mean TLG value of the primary tumor decreased significantly after NAC. The median follow-up period was 41months. The Kaplan-Meier method, analyzed by log-rank test, showed that low TLG ratio (≤ 0.4) and low SUVmax ratio (≤ 0.6) were associated with favorable survival outcomes (P = 0.0073 and P = 0.032, respectively). Univariate and multivariate analysis revealed that TLG ratio and achievement of pathological cure were independent prognostic factors for overall survival. TLG ratio was also associated with pathological TRG (TRG 0-1a vs 1b-3) (P = 0.0016). TLG ratio before and after NAC is clinically useful in predicting both histological response and survival outcome after NAC and subsequent esophagectomy in patients with ESCC.

Efficacy and safety of early administration of pegfilgrastim for esophageal cancer treated with DCF: A phase 2 study

Abstract Background It has been reported that docetaxel, cisplatin and 5-fluorouracil (DCF) regimen was effective for advanced esophageal cancer. However, the DCF regimen is associated with a high risk of severe neutropenia or febrile neutropenia (FN). In our retrospective study evaluating the efficacy of pegfilgrastim administration on day 7 (D7) in DCF regimen, the neutrophil count nadir was observed from D7. Thus, the timing of its administration could be too late. In this study, we assess the efficacy and safety of early administration (D3) of pegfilgrastim in DCF therapy for advanced esophageal cancer. Methods In this single-arm phase 2 study, patients with advanced esophageal cancer were recruited. They were treated with DCF therapy (DTX: 70mg/m2 on D1, CDDP: 70mg/m2 on D1, and 5-FU: 750mg/m2 on D1-5), and were administrated pegfilgrastim on D3. The primary endpoint was grade4 neutropenia. The secondary endpoints were the rate of FN and the incidence of other adverse events. This study was registered in UMIN system (UMI23393). Results Between July 2016 and Dec. 2018, we enrolled 23 patients (median age 62y ). The incidence of grade4 neutropenia was 8.7% (95%CI:4.7 - 22.1). The rate of FN was 0%. The rate of grade3 neutropenia was 17.4% (95%CI: 1.7 - 33.1), but no other serious adverse events related to pegfilgrastim were observed. Conclusion Primary prophylaxis with pegfilgrastim is recommended for the prevention of FN in patients receiving high-risk chemotherapy regimens such as DCF. According to the guidelines, G-CSF should be administered 24 h after the completion of chemotherapy. The optimal administration schedule remains unclear in regimens including IV continuous 5-FU administration like DCF. These results have shown that early administration (D3) of pegfilgrastim was safe and seemed to be more effective than D7 in DCF therapy. Further clinical studies with a larger sample size should be conducted to confirm our results.

796P - Randomised phase II trial of first-line docetaxel, carboplatin, capecitabine (CTX) and epirubicin, oxaliplatin, capecitabine (EOX) in advanced esophagogastric adenocarcinoma (SEED)

BackgroundChemotherapy is associated with a survival benefit in advanced gastric cancer. Several options exist, including EOX. The regimen docetaxel, cisplatin and 5-fluorouracil (DCF) is toxic and modifications have been developed. In our institution CTX was a standard treatment from 2004 to 2012 when it was replaced by EOX. Afterwards, a randomised trial with CTX was conducted. MethodsSEED was a prospective, single-center, phase 2 trial in unresectable HER2-negative esophagogastric adenocarcinoma. Patients were randomised to either docetaxel 60mg/m2, carboplatin AUC5 and capecitabine 1000mg/m2 bd for 14 days q4w (CTX) or epirubicin 50mg/m2, oxaliplatin 130mg/m2 and capecitabine 625mg/m2 bd for 21 days q3w (EOX). Treatment continued until progression, intolerance or a maximum of 9 cycles. The primary endpoint was 1-year-survival for patients treated with CTX. The trial sought to accept (lower boundary 55%) or reject (higher boundary 40%) CTX for further study without making direct comparisons to EOX. Secondary endpoints included OS, PFS and grade 3/4 toxicities. ResultsFrom 2014 to 2019 a total of 98 patients were randomised (49 in each arm). The median age was 63 (36 - 79). Male/female: 79/19; ECOG PS (0/1): 46/52; oesophageal/GEJ/gastric: 29/44/25; metastatic/non-metastatic: 96/2. As of 26 April 2019, 85 patients had died. The estimated 1-year survival was 32% (95% CI 19 - 46) for CTX and 39% (95% CI 25 - 52) for EOX. The median PFS and OS was 6.2 months (95% CI 5.2 - 7.2) and 9.2 months (95% CI 7.2 - 11.2), respectively, for CTX, and 5.2 months (95% CI 3.5 - 7.0) and 10.2 months (95% CI 7.9 - 12.4), respectively, for EOX. Grade 3/4 related toxicities in>5% were neutropenia (78%), febrile neutropenia (25%), diarrhoea (8%) and fatigue (6%) for CTX, and neutropenia (49%), febrile neutropenia (10%), peripheral neuropathy (8%) and nausea (8%) for EOX. There were no treatment-related deaths. ConclusionsCTX resulted in a 1-year-survival rate of 32% and so is rejected for further study. Also, CTX had a high rate of febrile neutropenia. CTX is not recommended for patients with esophagogastric cancer, except selected patients intolerant of other standard therapies, and then only with G-CSF support. Clinical trial identificationNCT02177552. Legal entity responsible for the studyLene Baeksgaard. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Effects of gene polymorphisms on the risk of severe hyponatremia during DCF chemotherapy for patients with esophageal squamous cell carcinoma.

Combination chemotherapy using docetaxel, cisplatin and 5-fluorouracil (DCF) is a promising treatment option for patients with advanced esophageal squamous cell carcinoma (ESCC), although its clinical application is limited by severe systemic toxicities. There are no validated markers for predicting the adverse effects caused by this regimen. This pharmacogenetic study enrolled 57 patients with chemotherapy-naive advanced ESCC between July 2012 and March 2016 (UMIN000008462). All patients received at least one course of DCF chemotherapy (docetaxel, 60 mg/m2 on day 1; cisplatin, 70 mg/m2 on day 1; 5-fluorouracil, 600 mg/m2 on days 1-5). The associations between four gene polymorphisms (ERCC1 rs11615, GSTP1 rs1695, TYMS rs151264360 and XPD rs13181) and the development of grade 3/4 adverse events during the first course of chemotherapy were prospectively investigated. The patients had a median age of 66 years (range, 45-77 years) and the majority were male (51 males vs. 6 females). The treatment settings were neoadjuvant (47 patients), adjuvant (1 patient) and salvage (9 patients), with dose intensities of 100% (51 patients) or 80% (6 patients). The severe adverse events were leukopenia (70.2%), neutropenia (86.0%), febrile neutropenia (36.8%), acute kidney injury (29.1%) and hyponatremia (43.9%). Two polymorphisms were independently associated with the development of severe hyponatremia among patients carrying the minor allele (vs. patients with major homozygote genotype): TYMS 3'-UTR rs151264360 (odds ratio, 3.64; 95% confidence interval, 1.11-11.9) and XPD Lys751Gln rs13181 (odds ratio, 10.1; 95% confidence interval, 1.10-93.3). Therefore, the presence of the TYMS and XPD polymorphisms may aid in identifying patients with a high risk of developing severe hyponatremia during DCF chemotherapy.

Definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced cervical esophageal cancer.

Recently, definitive chemoradiotherapy (dCRT) has become one of the essential treatment strategies for esophageal squamous cell carcinoma (ESCC) and has been especially gaining prevalence for cervical ESCC to preserve the larynx. Our department recently introduced dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for treating advanced cervical ESCC. This study aims to assess the safety and outcomes of DCF-R in patients with advanced cervical ESCC. We retrospectively assessed 11 patients with advanced cervical ESCC (clinical stage: II-IV, including T4b and/or M1 lymph node) who received DCF-R as the first-line treatment between December 2010 and February 2015. Our patient cohort comprised 8 males and 3 females (median age 68years; range 54-76years). The pretreatment clinical stage included stage II (1), stage III (7), and stage IV (3) cases [including 3 patients with T4b (2 trachea and 1 thyroid) and 3 patients with M1 lymph node]. We attained complete response (CR) in 10 patients and stable disease in 1 patient. Of 10 patients with CR, 5 experienced recurrence and 5 continued exhibiting CR. Furthermore, grade 3 or more adverse events included leucopenia (91%), neutropenia (91%), febrile neutropenia (45%), and pharyngeal pain (55%). While the 2-year overall survival rate was 72%, the 2-year recurrent-free survival rate was 64%, respectively. DCF-R treatment for advanced cervical esophageal cancer could be completed by the careful administration; although a strong blood toxicity might occur, this treatment may provide the chance to obtain favorable prognosis with larynx preservation.

Adverse Prognostic Factors of Advanced Esophageal Cancer in Patients Undergoing Induction Therapy with Docetaxel, Cisplatin and 5-Fluorouracil

The purpose of this study was to identify adverse prognostic factors for patients with advanced esophageal cancer undergoing chemotherapy with docetaxel, cisplatin and 5-fluorouracil (DCF). The study cohort comprised of 45 patients with advanced esophageal cancer who underwent induction DCF therapy followed by esophagectomy or chemoradiotherapy. Treatment outcomes and factors affecting early recurrence and death were analyzed. Overall 3-year survival was 61.4%, and 3-year disease-free survival was 44.7%. Clinically evident lymph node metastasis and clinical stage were associated with recurrence within 1 year and death within 2 years. Low maximum standardized uptake value (SUVmax) after induction DCF therapy and small decreases in SUVmax from pre- to post-DCF therapy were also predictors of recurrence and poor prognosis. Induction DCF therapy may be ineffective for advanced-stage esophageal cancer and clinical lymph node metastasis (≥N2, ≥stage IIIB). Moreover, small decreases in SUVmax DCF therapy are associated with early disease relapse and death.

Treatment Outcome of Pharmacokinetics-Based Dosing of Docetaxel and Fluorouracil in Advanced Head and Neck Cancer Patients

Introduction: Docetaxel, Cisplatin and 5-Fluorouracil (DPF) became the standard induction chemotherapy in advanced Head and Neck Cancer (HNC) but associated with high toxicity rate. Several studies reported higher response rates with better tolerability when chemotherapy dose is calculated based on Pharmacokinetics (PK) versus conventional Body Surface Area (BSA). Patients and Methods: Thirty nine patients with stage III and IV HNC who received induction DPF were included in the study. Dose of cycle 1 was BSA-based then Docetaxel and 5-FU doses were PK-adjusted starting from cycle 2 whereas Cisplatin dose was BSA-based throughout the study. Results: After median follow up period of 14 months the median overall survival (OS) and progression free survival (PFS) were 15.1 and 10.6 months respectively. Twenty nine patients were available for response assessment. Seven patients (24.1%) achieved complete response while partial response encountered in 19 patients (65.5%) with and Overall response rate of 89.6%. Both treatment related side effects and mortality significantly decreased after the application of PK dose adjustments (p-value 0.007 and 0.01 respectively). Conclusion: PK-guided dose adjustments of 5-FU and Docetaxel in DPF regimen can significantly decrease the treatment related side effects and mortality without compromising the tumor response rate. A randomized clinical trial is needed to compare the PK-guided dose adjustment with the standard BSA based protocol.

Docetaxel, cisplatin and S-1 as first and second-line regimen in patients with unresectable esophageal cancer

Introduction: The combination of fluorouracil and cisplatin is considered as the standard first-line regimen for unresectable esophageal cancer. However, the prognosis is still dismal. Moreover, there is no established regimen after failure of the first-line therapy. Recently, some study showed the efficacy of induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF). Considering the results of this regimen, we have been treated the patients with advanced esophageal cancer with docetaxel, cisplatin and S-1(DCS) chemotherapy since 2010. Here, we retrospectively assess the safety and efficacy of DCS for unresectable esophageal cancer as first and second-line therapy. Methods: We enrolled the patients who received DCS as first-line or second-line (or later) for unresectable esophageal cancer. Patients received docetaxel (35mg/m2) plus cisplatin (35mg/m2) intravenously on day1 and 15, and S-1 (80mg/m2) on days 1-14, of a 28 day cycle. If the adverse event was tolerable, patients continued receiving cycles until the progression of the disease was observed or the tumor turned to be resectable. Results: Between May2011 to March 2017, 44 patients were treated with the systemic regimen. Thirty two patients received DCS as first-line therapy (1st-line group), and twelve as second-line or later (2nd-line group). Median age was 62 years (range 47-85) in all. The reason for unresectable were locally advanced (75.0%) and distant metastasis (25.0%). The median number of therapy cycles applied for 1st-line group and 2nd-line group were 3.5 and 3, respectively. In the 1st-line group, complete response (CR), partial response (PR) and stable disease rates ware 12.5%, 62.5% and 18.8%, respectively. Those in the 2nd-line group were 8.3%, 41.7% and 33.3%. In nine patients(20.5%) of all, tumors were turned to be resectable after DCS, they were converted to surgery. The progression free survival (PFS) in all was 6.7±0.2 months [95% confidence interval (CI), 6.3-7.4], and the median overall survival(OS) was 22.7±0.2 months(95%CI, 22.3-23.4). Grade3-4 toxicity were observed in 77.3% with 1st-line and 91.7% with 2nd-line, there was no statistical significance between two groups(p = 0.16). Neutropenia was found as the most common grade3-4 toxicity (65.9%). All the adverse events occurred were manageable. Conclusion: DCS for unresectable esophageal cancer was effective as first-line therapy, and still effective even after failure of the other treatment. Grade3-4 toxity was experienced at a high rate but manageable.