DCF Therapy Research Articles

261. CONVERSION ESOPHAGECTOMY FOR CT4B ESOPHAGEAL CANCER - MIE VS OPEN -

Abstract Background and Aims The standard treatment for locally advanced unresectable esophageal cancer is definitive chemoradiotherapy (dCRT), however, after induction chemotherapy with a triplet chemotherapy regimen (docetaxel, cisplatin, and 5-FU: DCF) or dCRT, conversion surgery could be performed if esophageal cancer is considered resectable. Furthermore, minimally invasive surgery such as robot-assisted or thoracoscopic procedures are expected to improve the outcome of patients with advanced esophageal cancer. We investigated the feasibility of minimally invasive esophagectomy (MIE) in conversion surgery. Materials and Methods Sixty-six patients who underwent conversion thoracic esophagectomy for cT4b esophageal cancer from 2007 to 2023 were included. The short-term outcomes of 25 open esophagectomy group and 41 MIE group (8 robot-assisted and 33 thoracoscopic) were compared. Results No differences in age, gender, PS, tumor location, histology, cN, or cM were observed between the two groups. cT4b organs tended to be in the airway in the MIE group (airway 70.7% vs 44%, major vessels 19.5% vs 24%, both 9.7% vs 32%, p=0.04) and DCF therapy was significantly performed in the MIE group for induction therapy (DCF 87.8% vs 56%, dCRT 12.2% vs 44%, p<0.001). On the other hand, salvage surgery was significantly associated with open esophagectomy (24.3% vs. 52%, p=0.003). There was no difference in surgical outcomes regarding thoracic operation time (157 min vs. 180 min, p=0.09), whereas the total operation time was significantly shorter in the MIE group (392 min vs. 439 min, p=0.02). Blood loss was significantly lower in the MIE group (79 ml vs. 470 ml, p<0.001), and R0 resection rate did not differ (82.9% vs. 72%, p=0.357). There were no significant differences in postoperative complications including pneumonia (26.8% vs. 44%, p=0.183) and recurrent nerve palsy (21.9% vs. 36%, p=0.260), but anastomotic leakage was significantly lower in the MIE group (4.8% vs. 24%, p=0.04). There was no difference in median postoperative hospital stay (16 [11-20] vs. 16 [14-29] days), however, median ICU stay (3 [3-4] vs. 4 [3-4] days, p=0.03) and readmission within 1 month after discharge (2.4% vs. 16%, p=0.04) were significantly lower in the MIE group. In-hospital mortality was observed in 1 case in the MIE group and 3 in the open esophagectomy group. Conclusion Despite the bias associated with the transition of treatment modalities and surgical techniques, MIE may contribute to improved short-term outcomes in conversion surgery.

Optimizing Organ-Preservation Strategies Through Chemotherapy-Based Selection in Esophageal Squamous Cell Carcinoma: Results From the CROC Multi-Institutional Phase 2 Clinical Trial

PurposeThis study aimed to assess the viability of definitive chemoradiotherapy (dCRT) as an organ-preservation strategy for remarkable responders who were downstaged to stage IA after receiving induction chemotherapy for resectable esophageal squamous cell carcinoma (ESCC). Methods and MaterialsChemotherapy-naïve patients with resectable ESCC (stage IB–III, UICC, International Cancer Control 7th edition) were eligible for the study. All patients received three cycles of DCF therapy (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and 5-fluorouracil [5-FU] 750 mg/m2 on days 1–5, repeated every three weeks). A remarkable response was defined as a reduction of the tumor to T1, metastatic lymph nodes smaller than 1 cm on the short axis, and downstaging to stage IA after three cycles of DCF therapy. Remarkable responders then underwent dCRT, which included two courses of cisplatin 75 mg/m2 and 5-FU 1000 mg/m2 on days 1–4, repeated every four weeks, along with 50.4 Gy of concurrent radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) in remarkable responders following DCF therapy and subsequent dCRT. Secondary endpoints included 3-year overall survival (OS) and esophagectomy-free survival (EFS). ResultsOf the 92 patients registered, 90 were analyzed. A remarkable response to three courses of DCF therapy was observed in 58.4% of patients. Among these responders, 89.8% achieved a complete response after dCRT. During the median follow-up period of 33 months (range: 1–85 months), the 1-year PFS was 89.8% (95% confidence interval = 77.2%–95.6%, primary endpoint), and the 3-year OS was 83.7%. The 3-year OS and EFS rates in the analysis group were 74.1% and 45.3%, respectively. An 18F-fluorodeoxyglucose-positron emission tomography response after two courses of DCF therapy was significantly associated with OS (p = 0.0049). ConclusionsIn patients with resectable ESCC, dCRT for remarkable responders downstaging to stage IA after induction chemotherapy with three courses of DCF therapy is a feasible treatment option and provides an optimizing organ-preservation strategy of chemotherapy-based selection.

Pegfilgrastim for the management of neutropenia during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer patients.

Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy is a new standard for locally advanced esophageal squamous cell carcinoma. The optimal timing of pegfilgrastim with the DCF regimen to prevent febrile neutropenia (FN) remains controversial. The effectiveness of concomitant pegfilgrastim administration with continuous 5-fluorouracil (5-FU) infusion in the DCF regimen was therefore assessed. All patients who received neoadjuvant DCF for esophageal cancer were retrospectively assessed. Patients who had been scheduled to receive pegfilgrastim on days 3-5 (early group) or days 7-9 (regular group) of the DCF regimen were included. Uni- and multivariate analyses were used to assess risk factors for FN. Eighty-eight patients were included in the analysis. The 26 patients in the early group received pegfilgrastim as scheduled. In the 62 patients of the regular group, 51 received pegfilgrastim at a median of 7days after starting DCF chemotherapy. However, 11 patients in the regular group could not receive pegfilgrastim. Twenty-two patients of the regular group and 2 patients of the early group developed FN after the first session of DCF. Early administration of pegfilgrastim and grade 4 neutropenia were significantly associated with onset of FN, with multivariate analysis identifying early administration of pegfilgrastim as an independent preventive factor and grade 4 neutropenia as a risk factor, after adjusting for sex and age. Early pegfilgrastim administration is a safe approach that reduces the incidence of FN in DCF therapy. Using pegfilgrastim with continuous 5-FU infusion in the DCF regimen represents a reasonable option to prevent FN.

Tumor-infiltrating lymphocytes in patients undergoing esophagectomy following neoadjuvant DCF therapy.

Accumulating evidence suggests that expression levels of tumor-infiltrating (TI) cells may play a prognostic role in patients with esophageal cancer who have undergone esophagectomy. However, its effect on patients undergoing neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy followed by esophagectomy for esophageal squamous cell carcinoma (ESCC) remains unclear. Therefore, this study aimed to elucidate the prognostic impact of TI cells in patients who underwent esophagectomy following neoadjuvant DCF therapy. Overall, 81 patients with ESCC who underwent curative esophagectomy following neoadjuvant DCF therapy were included. The number of TI CD8+ cells was determined using light microscopy at ×400 in tumor invasive margins. Receiver operative characteristic curve was used to determine the cutoff values for mortality for continuous variables; the patients were separated into high and low TI CD8+ cell groups and their backgrounds and clinical outcomes were compared. Overall and relapse-free survival were significantly worse in the TI CD8+-low group than that in the TI CD8+-high group (p < 0.01). Multivariate analysis revealed that positive ypN (hazard ratio [HR], 3.12; 95% confidence interval [CI], 1.08-9.02) and low TI CD8+ cell levels (HR, 2.77; 95% CI, 1.31-5.85) were independent prognostic factors for overall survival. Furthermore, positive venous invasion (HR, 2.63; 95% CI, 1.29-5.35) and low TI CD8+ cell levels (HR, 2.77; 95% CI, 1.70-5.46) were significant prognostic factors for relapse-free survival. Low TI CD8+ cell level was a prominent prognostic factor for patients with ESCC undergoing neoadjuvant DCF therapy followed by esophagectomy.

MO40-5 Early administration of pegfilgrastim contributes to the safety of DCF therapy as neoadjuvant chemotherapy for esophageal cancer

MO40-5 Early administration of pegfilgrastim contributes to the safety of DCF therapy as neoadjuvant chemotherapy for esophageal cancer

Skeletal Muscle Quality and Quantity Affect Prognosis after Neoadjuvant Chemotherapy with a Triple Regimen of Docetaxel/Cisplatin/5-FU in Patients with Esophageal Cancer.

The purpose of this study was to identify factors associated with the prognosis after docetaxel, cisplatin, and 5-fluorouracil (DCF) neoadjuvant chemotherapy (NAC) in patients with advanced esophageal squamous cell carcinoma (ESCC) undergoing surgical resection. We retrospectively examined a total of 100 patients who received neoadjuvant DCF therapy for ESCC at our institution between 2011 and 2020. The psoas muscle index (PMI) was calculated from the psoas muscle area at the L3 vertebral level, and the intramuscular adipose tissue content (IMAC) was calculated from the mean CT value of the multifidus muscle and from four points of subcutaneous fat. The median PMI value was 6.11 cm2/m2 (range, 3.12-11.07 cm2/m2) in men and 3.65 cm2/m2 (range, 2.70-6.82 cm2/m2) in women. The median IMAC was -0.426 (range, -0.079--0.968) in men and -0.359 (range, -0.079--0.671) in women. Based on the PMI, IMAC, and other patient factors, factors associated with NAC-DCF postoperative survival were identified using multivariate Cox regression analysis. A high IMAC was significantly related to overall survival after surgery (p = 0.005, hazard ratio 2.699). A comparison of Kaplan-Meier curves showed that the 5-year survival rate was 76.5% in the low IMAC group and 42.7% in the high IMAC group (log-rank test; p = 0.001). A low IMAC was associated with good survival outcomes and was an independent prognostic factor in patients with cStage II/III ESCC who were treated with the NAC-DCF regimen and underwent surgical resection.

Efficacy and Cost-effectiveness of Pegfilgrastim for Preventing Febrile Neutropenia During Docetaxel, Cisplatin, and 5-Fluorouracil Therapy for Esophageal Cancer.

The docetaxel, 5-fluorouracil, and cisplatin (DCF) regimen is an effective form of chemotherapy for advanced esophageal cancer. However, the incidence of adverse events, such as febrile neutropenia (FN), is high. This study retrospectively examined whether pegfilgrastim treatment reduces FN development during DCF therapy. This study evaluated 52 patients who were diagnosed with esophageal cancer and underwent DCF therapy at Jikei Daisan Hospital, Tokyo, Japan, between 2016 and 2020. They were divided into non-pegfilgrastim and pegfilgrastim-treated groups, and side-effects of chemotherapy and cost-effectiveness of pegfilgrastim were examined. Eighty-six cycles of DCF therapy were conducted (33 and 53 cycles, respectively). FN was observed in 20 (60.6%) and seven (13.2%) cases, respectively (p<0.001). The lowest absolute neutrophil count during chemotherapy was significantly lower in the non-pegfilgrastim group (p<0.001), and the number of days until improvement from nadir was significantly shorter in the pegfilgrastim group (9 vs. 11 days; p<0.001). No significant difference was found in the onset of grade 2 or more adverse events by Common Terminology Criteria for Adverse Events. However, renal dysfunction was significantly lower in the pegfilgrastim group (30.7% vs. 60.6%, p=0.038). Hospitalization costs were also significantly lower in this group (692,839 vs. 879,431 Japanese yen, p=0.028). This study revealed the usefulness and cost-effectiveness of pegfilgrastim in prevention of FN in patients treated with DCF.

423. POSTOPERATIVE SKELETAL MUSCLE MASS IN ESOPHAGEAL CANCER SURGERY PATIENTS AFTER NEOADJUVANT CHEMOTHERAPY

Abstract Recently, the significant decrease in skeletal muscle mass after esophagectomy in patients who underwent neoadjuvant chemotherapy, which in turn has been reported to affect long-term survival. The results of JCOG1109 have been published, and while DCF has become the standard of care as neoadjuvant chemotherapy, its toxicity has also been pointed out. In this study, we analyzed the relationship between changes in body composition before and after neoadjuvant chemotherapy and postoperative complications after esophagectomy. Among esophageal cancer patients who underwent esophagectomy after preoperative chemotherapy from September 2018 to May 2020, 74 patients were included, excluding patients with recurrence within 1 year after surgery and patients with gastrointestinal fistula. The relationship between body composition and postoperative complications, and changes in body weight and skeletal muscle mass were analyzed. The male-to-female ratio was 60:14, and the median age was 65.0 years. When the subjects were divided into DCF and Others, there was a significant difference in skeletal muscle loss in the Others group. There was no significant difference in the incidence of postoperative complications by chemotherapy, nor an incidence of postoperative complications between the DCF and Others. There was no significant difference in weight loss between the DCF group and the Others group, but a significant decrease in skeletal muscle mass in the DCF group at one year. The decrease up to 4 months after surgery was particularly large. In the present analysis, DCF therapy as preoperative treatment had no effect on the occurrence of postoperative complications, but was associated with a long-term decrease in skeletal muscle mass, suggesting that the toxicity of DCF therapy may have a long-term effect. Although the tumor suppression effect of preoperative treatment was proven, long-term nutritional and rehabilitative interventions were considered necessary to establish a truly favorable long-term prognosis for the patients.

388. PREOPERATIVE TREATMENT AND THORACOSCOPIC ESOPHAGECTOMY FOR BORDERLINE RESECTABLE ESOPHAGEAL CANCER

Abstract Preoperative DCF therapy is recommended for cStage II/III esophageal cancer based on the results of JCOG1109. However, there is no established treatment strategy for Borderline Resectable (BR) esophageal cancer that is suspected of invading vital organs. And the pros and cons of thoracoscopic surgery have not been clarified. We have been performing preoperative chemoradiotherapy (NACRT) followed by thoracoscopic subtotal esophagectomy for BR esophageal cancer. Details and short-term results are presented. After 2 courses of FP therapy and 40 Gy total dose (2 Gy x 20 times) of fractionated conventional irradiation, patients underwent thoracoscopic subtotal esophagectomy with D2 dissection if T4 factor was considered to have been removed by CT evaluation. From April 2017 to present, NACRT was performed in 25 BR esophageal cancer patients. Two of them were unresectable, and thoracoscopic subtotal esophagectomy was performed in 23 cases. All patients had squamous cell carcinoma. 4 patients had complications of Clavien-Dindo Grade III or higher. The median postoperative hospital stay was 23 days. Of the 23 cases that were resectable, R0 resection could be performed in 21 cases (91.3%). The pathological response of the primary tumor was Grade3 in 11 patients (47.8%), Grade2 in 5 (21.7%), and Grade1 in 7 (30.4%). Pathological-CR including regional lymph nodes was 7 cases (30.4%). NACRT is effective for BR esophageal cancer, and thoracoscopic subtotal esophagectomy can be performed safely. We would like to continue to study the long-term results of NACRT with more cases in the future.

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.

Strategy Treatment of cT4b Esophageal Squamous Cell Carcinoma Using Docetaxel, Cisplatin, and 5-Fluorouracil.

This study analyzed the outcomes of docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy and DCF plus concurrent radiotherapy (DCF-RT), both followed by conversion surgery, if possible, in patients with cT4b esophageal cancer. Forty-six patients with cT4b esophageal cancer, including borderline cT4b lesions, were eligible. Borderline cT4b lesions were treated with induction DCF therapy. For definitive cT4b lesions, definitive DCF-RT was administered. Patients unsuitable for induction DCF therapy or DCF-RT were treated with other therapies. After treatment, conversion surgery (CS) was performed for the residual tumor in resectable cases. Induction DCF therapy was administered to 12 patients (group A), and DCF-RT was provided to 18 patients (group B). Meanwhile, other therapies were provided to 16 patients (group C). The 1-, 3-, and 5-year overall survival (OS) rates were 66.7, 30.0, and 15.0%, respectively, in group A; 66.7, 37.5, and 37.5%, respectively, in group B; and 62.5, 0, and 0%, respectively, in group C. DCF-RT tended to prolong survival, albeit without significance (p=0.1040). The group A + B had significantly better overall survival than group C (p=0.0437). Fourteen patients underwent CS (30.4%), and patients who underwent CS had significantly better overall survival than those who did not undergo surgery (p=0.0291). Induction DCF or DCF-RT is promising for the treatment of cT4b esophageal cancer. Effective CS including combined resection of the invaded organ can contribute to improved therapeutic outcomes.

Analysis of Factors Influencing Acute Kidney Injury with Docetaxel, Cisplatin, and 5-fluorouracil in Patients with Esophageal Cancer

The docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen is considered to be one of the treatment choices for esophageal cancer. Acute kidney injury (AKI) is one of the side effects of cisplatin, and the onset of AKI limits the use of cisplatin. However, the factors influencing the onset of AKI remain unknown. Therefore, we examined retrospectively the new factors influencing the onset of AKI in patients with DCF therapy. This study included forty-four cases, and nine cases (20.5％) had the onset of AKI. We examined clinical laboratory values before treatment as the factors influencing the onset of AKI. The incidence of AKI in patients whose serum β2-microglobulin values were above the upper limit of normal values (2.0 mg/L) was 42.9％ (6/14) and significantly high (P = 0.019). As a result of this study, it was revealed that serum β2-microglobulin is a new useful marker predicting the onset of CDDP-induced AKI.

Relevance of pharmacogenetic polymorphisms with response to docetaxel, cisplatin, and 5-fluorouracil chemotherapy in esophageal cancer.

Docetaxel, cisplatin, and 5-fluorouracil (DCF) have high response rates, but severe neutropenia is frequently observed. The occurrence of neutropenia is associated with high histological response in solid tumors, and it might be associated with tumor shrinkage after DCF therapy. This study aimed to determine the genetic polymorphisms involved in the clinical response to preoperative DCF therapy in esophageal cancer patients. We included 56 patients with measurable lesions who received preoperative DCF therapy for esophageal cancer. Twenty-one genetic polymorphisms were analyzed, and univariate logistic regression analysis was used to evaluate the association between genetic polymorphisms and tumor shrinkage. A multivariate logistic regression analysis adjusted for T category and tumor location and a univariate analysis for potential genetic factors with P values < 0.05 were performed to explore the predictive factors and to estimate odds ratios and their 95% confidence intervals. No patient achieved a complete response, whereas 20 patients achieved a partial response, 31 patients had stable disease, and 5 patients had progressive disease. Although no association was found between pharmacokinetic-related gene polymorphisms, XRCC3 rs17997944 was extracted as the only genetic factor that affected tumor shrinkage (P = 0.033) by univariate analysis. The multivariate analysis adjusted for T category and tumor site also showed that XRCC3 rs1799794: AA was a predictive factor that affected tumor shrinkage (odds ratio, 0.243; 95% confidence interval, 0.065-0.914; P = 0.036). XRCC3 rs1799794, which is involved in homologous recombination, is a genetic factor that affects clinical responses to DCF therapy.

Cost-effectiveness of primary prophylaxis of febrile neutropenia with pegfilgrastim in docetaxel, cisplatin and 5-fluorouracil therapy for esophageal cancer.

Objective: The efficacy of docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy in treating esophageal cancer has been reported. However, febrile neutropenia (FN) is a potentially serious adverse event of DCF therapy with an incidence of 10 to 40%. Pegfilgrastim, a granulocyte colony-stimulating factor (G-CSF), has been shown to have a primary prophylactic role in FN. However, it has been suggested that excessive use of expensive G-CSF should be avoided. Therefore, we performed a cost-utility analysis of primary prophylaxis with pegfilgrastim. Design: Cost-effectiveness analysis using decision tree modelling. Methods: We used a decision tree analysis model based on the report of primary prophylaxis with pegfilgrastim. Based on a previous study, the FN incidence rate was set at 40.0% (95% confidence interval (CI): 11.9-68.1) for the pegfilgrastim group and 43.5% (95%CI: 21.6-65.4) for the no pegfilgrastim group. The FN treatment cost was US$726.63, and the duration of FN was 3.65±1.20 days. The utility value of patients who received DCF therapy was 0.643, and the change in utility value at FN onset was -0.15. Expected cost, quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER) were calculated, and cost-utility analysis was performed. Results: The ICER of pegfilgrastim was 184,976.75 USD/QALY. As a result of sensitivity analysis, the utility of FN had the greatest impact on the cost-effectiveness analysis, followed by the drug cost of pegfilgrastim. Conclusion: Primary prophylaxis of FN with pegfilgrastim might not be cost-effectiveness. In determining whether to administer pegfilgrastim it is necessary to consider patient factors, not just the incidence of FN.

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma (JCOG1804E)—The short-term results of cohort A and B.

202 Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell cancer (ESCC) is CDDP + 5-FU (CF). Immune checkpoint inhibitors (ICI) such as nivolumab provide a survival benefit in ESCC, and have potential as NAC agents in lung, skin, and breast cancers, amongst others. However, whether ICI are efficacious in combination with cytotoxic agents, and whether ICI impact the safety of subsequent surgery after they are used as NAC for ESCC patients (pts) is currently unclear. Methods: FRONTiER is a multi-cohort phase I study 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 therapies against any cancer were eligible. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 4 experimental cohorts, the NAC regimen of cohort A consisted of 2 courses of CDDP at 80 mg/m2, nivolumab at 360 mg/body on day 1 and 5-FU at 800 mg/m2 on days 1–5, q3wks. The regimen of cohort B consisted of one administration of nivolumab at 240 mg/body 2 weeks before chemotherapy, followed by the same treatments as cohort A. Results: Thirteen pts were enrolled to cohort A (n = 6) and B (n = 7). Characteristics were follows; median age: 62 (range: 34–75), PS 0/1: 9/4 pts, clinical stage I/II/III: 2/1/10 pts. One pt in cohort B was excluded from safety evaluation due to R2 resection, no DLTs were observed in 12 pts. The most frequent adverse events (≥ grade 3) were neutropenia in 6 pts during NAC, lung infection in 1, hyperglycemia in 1, pleural effusion in 1, infection (right neck) in 1, anemia in 1, abdominal pain in 1, and anatomic leakage in 1 during the postoperative period. Within 30 days post-operation, grade 2 adrenal insufficiency was observed in 1 pt of cohort B. No grade 4 adverse events or treatment-related deaths were seen. All pts received two courses of NAC + nivolumab and R0 resection was achieved in 12 pts (92.3%) without interruption of treatment. A pathological complete response was achieved in 2 pts (33.3%) in cohort A. Conclusions: Neoadjuvant CF + nivolumab with/without prior administration of nivolumab followed by surgery for locally advanced ESCC was well tolerated and showed promising efficacy. Clinical trial information: NCT03914443.

Long-term outcomes and safety of radical transmediastinal esophagectomy with preoperative docetaxel, cisplatin, and 5-fluorouracil combination chemotherapy for locally advanced squamous cell carcinoma of the thoracic esophagus

BackgroundIt is unknown whether transmediastinal esophagectomy (TME) is an acceptable surgical procedure for locally advanced esophageal squamous cell carcinoma (ESCC). Therefore, we investigated the feasibility of long-term survival after TME with neoadjuvant docetaxel, cisplatin, and 5-fluorouracil combination chemotherapy (DCF therapy).MethodsThis retrospective, observational study included locally advanced resectable ESCC. All patients received two cycles of preoperative DCF therapy (60 mg/m2 of docetaxel and cisplatin on day 1 and 700 mg/m2/day of 5-FU on days 1–5 in each cycle) followed by radical TME. The main outcomes were survival and the rate of adverse events of chemotherapy and surgery.ResultsSixteen patients were included in this study. All patients received two cycles of DCF therapy, followed by surgery. The median follow-up duration of the 16 patients was 35.4 months. The 2-year overall survival (OS) was 93.3% (95% confidence interval [CI], 61.3–99.0), and the 3-year OS was 78.8% (95% CI, 47.3–92.7). The 2-year and 3-year relapse-free survivals were both 73.3% (95% CI, 43.6–89.1). Leukopenia and neutropenia occurred in most patients; however, they were controllable. Fifteen patients completed TME, and one was converted to open transthoracic esophagectomy because of tracheal injury. Three-field dissection was performed for 12 of 16 patients (75%), and R0 resection was achieved in 15 of 16 patients (93.8%). Three cases of grade IIIb chylothorax were observed. There was no mortality in this study.ConclusionCombined neoadjuvant DCF and TME for locally advanced ESCC was safe and less invasive than traditional therapies and had a satisfactory long-term prognosis.

Ring box protein-1 is associated with a poor prognosis and tumor progression in esophageal cancer.

Ring box protein-1 (RBX1) is an essential component of the S-phase kinase-associated protein, Cullin and F-box containing ubiquitin ligases. Overexpression of RBX1 has been reported in several cancer types; however, little is known regarding the prognostic value and role of RBX1 in esophageal cancer. The present study examined 120 patients with esophageal cancer (EC) who underwent curative esophagectomy and 61 patients with EC who underwent neoadjuvant combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil (5-FU; DCF) using immunohistochemistry. All specimens were classified into two groups according to the percentage of RBX1-positive tumor cells. In addition, the impact of RBX1 expression on cancer cell proliferation was analyzed in vitro using a small interfering RNA silencing technique. RBX1 expression levels showed significant differences according to tumor size (P<0.001), tumor depth (P=0.002), lymph node metastasis (P=0.004), pathological stage (P=0.001), lymphatic invasion (P=0.001) and venous invasion (P=0.001). The overall survival (OS) rate in the RBX1 high expression group was significantly lower compared with that in the low group (P=0.004). Multivariate analysis demonstrated that RBX1 status was an independent prognostic factor. RBX1 gene silencing inhibited the proliferation of human EC cells and enhanced the antitumor effect of 5-FU. Among patients who underwent neoadjuvant DCF therapy, the RBX1 high expression group had a significantly lower OS rate compared with that of the RBX1-low group (P<0.001). In conclusion, RBX1 has notable prognostic value, and RBX1 may serve an important function in the tumor progression of EC.

Down-staging and histological effects might be predictive factors for DOC+CDDP+5-FU for esophageal cancer

Abstract Background In Japan, two courses of CDDP+5-FU (CF) therapy followed by surgery is accepted as a standard treatment for stage II/III esophageal cancer (EC) based on the results of the JCOG9907 trial. However, in some cases, especially stage III disease, the anti-tumor effect of CF is insufficient. Therefore, a three-arm phase III trial (neoadjuvant [NAC] setting: CF vs. CF+radiation vs. DOC+CF [DCF]) is on-going. We have aggressively performed DCF therapy mainly in NAC settings since October 2014. We herein review the outcomes of DCF therapy. Methods Twenty-three patients (20 men, 3 women; median age: 70.0 years) with stage III or IV EC who received DCF therapy (October 2014 to February 2018) were retrospectively reviewed. Results The response rate was 43.5%. Down-staging was achieved in 11 patients (47.8%) over the course of treatment. Twenty-one patients transited to surgery, and 20 of them underwent R0 resection. One patient with disease progression was converted to chemoradiation therapy. Histological efficacy was observed in 21 patients, including 7 cases of grade 2. Those treated with DCF therapy who achieved down-staging had a significantly longer relapse-free survival (RFS) than those without down-staging (median RFS: not reached vs. 167 days, p = 0.0011) and also tended to have a longer overall survival (OS) than those without down-staging (MST: not reached vs. 824 days, p = 0.0637). Patients receiving CF therapy with down-staging tended to show a better RFS and OS than those without down-staging, although not to a significant degree. Patients receiving DCF therapy with grade ≥1b histological efficacy tended to have a longer RFS than those with grade Conclusions These findings suggest that down-staging and the histological efficacy might be predictive factors for DCF therapy for EC.

Risk factors for febrile neutropenia and effectiveness of primary prophylaxis with pegfilgrastim in patients with esophageal cancer treated with docetaxel, cisplatin, and 5-fluorouracil

BackgroundThe docetaxel, 5-fluorouracil, and cisplatin (DCF) regimen is an effective form of chemotherapy for advanced esophageal cancer. However, the incidence of adverse events such as febrile neutropenia and hematological toxicity is high.MethodsAmong 937 patients with esophageal cancer at Toranomon Hospital between January 2011 and December 2018, 92 who underwent the DCF regimen as initial treatment were selected. We investigated the risk factors for febrile neutropenia in patients with esophageal cancer treated with DCF regimen and the effectiveness of pegfilgrastim as primary prophylaxis.ResultsAdverse events (CTCAE grade ≥ 3) were observed in 45 of the 92(48.9%) patients with esophageal cancer treated with an initial DCF regimen. Febrile neutropenia was observed in 20 (21.7%) patients. Non-use of pegfilgrastim (odds ratio = 16.393; 95% confidence interval 2.049–125.0) as primary prophylaxis was identified as an independent factor predictive of febrile neutropenia. The pegfilgrastim group had a significantly lower incidence of neutropenia than the control group (9.1% vs 61.0%; p < 0.001). The incidence of febrile neutropenia was 3.0% in the pegfilgrastim group and 32.2% in the control group (p = 0.001). In addition, the incidence of any adverse effect ≥ CTCAE grade3 was also significantly lower in the pegfilgrastim group (12.1% vs 69.5%; p < 0.001). The reduced/interruption rate of next DCF therapy was 6.1% in the pegfilgrastim group and 30.5% in the control group (p = 0.006).ConclusionThis study revealed that the non-use of pegfilgrastim was an independent factor predictive of febrile neutropenia in multivariate analysis. Pegfilgrastim as primary prophylaxis prevents severe neutropenia and febrile neutropenia in patients with esophageal cancer treated with the DCF regimen.

Efficacy of pegfilgrastim administration in patients with esophageal cancer treated with docetaxel, cisplatin, and 5-fluorouracil.

Chemotherapy is among the standard treatments for esophageal cancer. The docetaxel, 5-fluorouracil, and cisplatin (DCF) protocol yields a better response rate than 5-fluorouracil plus cisplatin. However, the incidence of side effects, such as febrile neutropenia and hematologic toxicity, is also significantly high with the DCF protocol. The granulocyte colony-stimulating factor and pegfilgrastim are prophylactically administered to prevent febrile neutropenia. This retrospective study evaluated the efficacy and safety of pegfilgrastim in patients receiving DCF therapy. Of the 65 patients who were administered DCF therapy in our hospital from 2011 through 2016, 21 received pegfilgrastim 24 hours or more after the end of chemotherapy. The protocol comprised 70 mg/m2 each of docetaxel and cisplatin on day 1 and 700 mg/m2 5-fluorouracil on days 1 to 5 via intravenous injection in a 3-week cycle. The primary endpoint was the rate of grade 3-4 neutropenia and febrile neutropenia. The mean patient age was 66.4 years. The incidence of grade 3 and 4 neutropenia was 14.2 % and 11.4 %, respectively, in the pegfilgrastim group and 31.9 % and 37.8 %, respectively, in the non-pegfilgrastim group. The incidence of febrile neutropenia in the pegfilgrastim group and non-pegfilgrastim group was 11.4 % and 40.3 %, respectively. Statistical analysis showed that the incidence of neutropenia and febrile neutropenia was significantly different (p<0.05) between the two groups. Pegfilgrastim prevents severe neutropenia and febrile neutropenia in patients with esophageal cancer who are treated according to the DCF protocol.