• efficacy analysis
• esophageal squamous cell carcinoma
• nedaplatin
• neoadjuvant chemoradiotherapy
• platinum
• safety analysis

• National Key Clinical Specialty Discipline Construction Program of China

Immunotherapy (Programmed cell death 1 blockade) has entered the ranks of advanced esophageal cancer first-line treatment; however, little is known about the efficacy of PD-1 inhibitor as neoadjuvant therapy in resectable esophageal squamous cell carcinoma (ESCC). We aim to evaluate the activity and safety of the neoadjuvant sintilimab combined with chemotherapy in the treatment of resectable thoracic ESCC.

The enrolled patients with resectable (clinical stage II to IVA) ESCC received neoadjuvant sintilimab injection (200 mg/time, day 1), paclitaxel liposomes (135 mg/m², day 1), and carboplatin (area under curve of 5 mg/mL/min, day 1) every 21 days for 2 cycles, and esophagectomy was performed within 3-6 weeks after the 2 cycles of treatment. The primary endpoint of the study was the pathological complete response (PCR) rate.

From July 2019 to March 2021, a total of 47 patients were enrolled, of which 33 patients (70.2%) had clinical stage III disease. All patients completed the full two-cycle treatment and forty-five patients received radical surgery, including 44 (97.8%) R0 resections. Ten (22.2%) of 45 patients had a PCR, and the major pathological response (MPR) rate was 44.4% (20/45). The grade 3–4 treatment-related adverse events (TRAEs) were mainly neutropenia (6 of 47,12.8%) and leucopenia (8 of 47,17.0%). One (2.1%) patient occurred postoperative immune-associated encephalitis. No delays in surgery were observed.

sintilimab combined with paclitaxel liposome and carboplatin, as demonstrated in this phase II trial to exhibit a relatively high PCR rate and acceptable safety, warrants additional investigation in resectable ESCC.

http://www.chictr.org.cn/, ChiCTR1900026593.

• Humans
• Esophageal Squamous Cell Carcinoma/drug therapy
• Esophageal Squamous Cell Carcinoma/pathology
• Neoadjuvant Therapy/adverse effects
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/surgery
• Esophageal Neoplasms/pathology
• Carboplatin/adverse effects
• Prospective Studies
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Paclitaxel

Lack of effective targeted therapy in metastatic esophageal squamous cell carcinoma (ESCC) underscores the urgent need for identifying new treatment approaches for this challenging disease. We sought to assess the addition of cetuximab to paclitaxel-cisplatin chemotherapy for first-line treatment in patients with metastatic ESCC. In this randomized, multicenter, open-label, phase II clinical trial, patients were randomized to receive paclitaxel-cisplatin (TP) (paclitaxel [175 mg/m² intravenously (i.v.) on day 1 of every 3-week cycle] and cisplatin [75 mg/m² i.v. on day 1 of every 3-week cycle]) and TP plus cetuximab (CTP) (cetuximab, 400 mg/m² i.v. on day 1 of week 1, followed by 250 mg/m² weekly), respectively. Targeted next-generation sequencing (NGS) was performed on 89 tumor samples for biomarker exploration. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. With a median follow-up of 22.6 months, median PFS was 5.7 months (95% confidence interval [CI]: 4.8–7.0) in patients administered CTP versus 4.2 months (95% CI: 3.0–5.3) in the TP group (hazard ratio [HR] = 0.61; 95% CI: 0.40–0.93; p = 0.02). Median overall survival was 11.5 months (95% CI: 7.9–13.1) in the CTP group and 10.5 months (95% CI: 9.0–13.2) in the TP arm (HR = 0.98; 95% CI: 0.67–1.44; p = 0.91). The most common reported greater than or equal to grade 3 adverse events were neutropenia (35.2% versus 22.4%) and leukopenia (25.4% versus 13.2%). In patients with epidermal growth factor receptor (EGFR) amplification tumors (15.7%), PFS was improved with CTP compared with TP treatment (HR = 0.11; 95% CI: 0.01–0.98; p = 0.018). First-line CTP significantly improves PFS, with a manageable safety profile in patients with metastatic ESCC.

•

Compare the effect of Cetuximab + chemotherapy with chemotherapy alone in ESCC

• esophageal squamous cell cancer
• liposomal paclitaxel
• neoadjuvant chemotherapy
• platinum

Effective therapeutic options are limited for patients with advanced esophageal squamous cell carcinoma (ESCC). The incorporation of an immune checkpoint inhibitor and a molecular anti‐angiogenic agent into the commonly adopted chemotherapy may produce synergistic effects. Therefore, we aimed to investigate the efficacy and safety of camrelizumab plus apatinib combined with chemotherapy as the first‐line treatment of advanced ESCC.

In this single‐arm prospective phase II trial, patients with unresectable locally advanced or recurrent/metastatic ESCC received camrelizumab 200 mg, liposomal paclitaxel 150 mg/m², and nedaplatin 50 mg/m² on day 1, and apatinib 250 mg on days 1‐14. The treatments were repeated every 14 days for up to 9 cycles, followed by maintenance therapy with camrelizumab and apatinib. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Secondary endpoints included disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety.

We enrolled 30 patients between August 7, 2018 and February 23, 2019. The median follow‐up was 24.98 months (95% confidence interval [CI]: 23.05‐26.16 months). The centrally assessed ORR was 80.0% (95% CI: 61.4%‐92.3%), with a median duration of response of 9.77 months (range: 1.54 to 24.82+ months). The DCR reached 96.7% (95% CI: 82.8%‐99.9%). The median PFS was 6.85 months (95% CI: 4.46‐14.20 months), and the median OS was 19.43 months (95% CI: 9.93 months – not reached). The most common grade 3‐4 treatment‐related adverse events (AEs) were leukopenia (83.3%), neutropenia (60.0%), and increased aspartate aminotransferase level (26.7%). Treatment‐related serious AEs included febrile neutropenia, leukopenia, and anorexia in one patient (3.3%), and single cases of increased blood bilirubin level (3.3%) and toxic epidermal necrolysis (3.3%). No treatment‐related deaths occurred.

Camrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first‐line treatment demonstrated feasible anti‐tumor activity and manageable safety in patients with advanced ESCC. Randomized trials to evaluate this new combination strategy are warranted.

This trial was registered on July 27, 2018, at ClinicalTrials.gov (identifier: NCT03603756).

• anti-angiogenesis
• apatinib
• camrelizumab
• chemotherapy
• esophageal squamous cell carcinoma
• first-line
• immunotherapy
• liposomal paclitaxel
• nedaplatin
• objective response rate

• Aged
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols
• Esophageal Neoplasms/drug therapy
• Esophageal Squamous Cell Carcinoma/drug therapy
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Recurrence, Local
• Prospective Studies
• Pyridines/therapeutic use

• Chemotherapy
• Esophageal cancer
• Metastatic
• Squamous cell cancer, SCC

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Cisplatin/administration & dosage
• Cisplatin/adverse effects
• Drug Administration Schedule
• Drug Combinations
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/mortality
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma/drug therapy
• Esophageal Squamous Cell Carcinoma/mortality
• Esophageal Squamous Cell Carcinoma/secondary
• Female
• Humans
• Male
• Middle Aged
• Oxonic Acid/administration & dosage
• Oxonic Acid/adverse effects
• Progression-Free Survival
• Survival Analysis
• Tegafur/administration & dosage
• Tegafur/adverse effects
• Tumor Burden/drug effects

The purpose of this study is to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) versus chemotherapy alone for patients with stage IV esophageal squamous cell carcinoma (ESCC).

Eligible patients were retrospectively enrolled at the authors’s institution from January 2010 to October 2015. Of the 141 patients enrolled, 55 (39.0%) received CCRT and 86 (61.0%) received chemotherapy alone. The outcomes and adverse events (AEs) were compared between the two groups.

The baseline clinical characteristics of the two groups were similar. However, the CCRT group showed a significantly better primary tumor objective response rate (ORR) than that of the chemotherapy group (74.5% versus 45.3%, p = 0.001). The 1-year, 2-year, 3-year overall survival (OS) rates and median OS were 58.0% versus 43.0%, 25.5% versus 14.0%, 10.7% versus 4.7%, and 14 months versus 11 months for patients treated with CCRT or chemotherapy, respectively (p = 0.007). The 1-year and median progression-free survival (PFS) were 29.8% versus 14.9% and 8 months versus 6 months (p = 0.005). Multivariate analysis identified CCRT (p = 0.013) and solitary metastasis (p = 0.037) as independent factors for greater OS. The frequency of leucocytopenia (grade 3 or higher) was significantly higher in the CCRT group than in the chemotherapy-alone group (p = 0.040), whereas the rates of other AEs did not differ.

In this study, it is suggested that CCRT is more effective than chemotherapy alone for stage IV ESCC, yielding better primary responses and survival outcomes with tolerable side effects.

• Chemoradiotherapy
• Chemotherapy
• Esophageal squamous cell carcinoma
• Overall survival
• Primary tumor response rate
• Progression-free survival

• lung adenocarcinoma
• maintenance therapy
• nedaplatin
• pemetrexed

Introduction and Objectives. Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a simple marker of the systemic inflammatory response in critical care patients. We previously assessed the utility of NLR as a biomarker to predict tumor recurrence and cancer death in bladder cancer patients who underwent radical cystectomy. In this study, we evaluated the prognostic impact of NLR in bladder cancer patients who received gemcitabine and nedaplatin (GN) chemotherapy. Methods. A total of 23 patients who received GN chemotherapy for advanced bladder cancer were enrolled in this study. The cut-off point of NLR according to the sensitivity and specificity levels was derived from the area under receiver operator characteristics (AUROC) curve plotted for disease progression or overall mortality. Results. The NLR cut-off point was determined as 4.14 for both tumor progression and overall mortality. Median progression-free survival (PFS)/overall survival (OS) in the higher NLR group (NLR ≥ 4.14) and lower NLR group (NLR < 4.14) were 194/468 days versus 73/237 days, respectively. Kaplan-Meier analysis showed that higher NLR significantly correlated with poorer PFS (p = 0.011) and OS (p = 0.045). Conclusions. NLR may serve as a new biomarker to predict responses to GN-based chemotherapy in advanced bladder cancer patients and/or their prognosis.

Purpose: To retrospectively compare taxane-based with fluorouracil-based chemoradiotherapy in terms of toxicity profiles, efficacy and survival in patients with inoperable esophageal cancer.

Methods and Materials: We analyzed retrospectively 179 consecutive patients who were unresectable or medically unfit for surgery between March 2009 and November 2014. Eight-three patients were included in the taxane group and 96 cases were in the fluorouracil group.

Results: The overall response rate (ORR) in the taxane group was higher than fluorouracil group, but was not significantly different (71.6% vs. 63.5%, respectively, P=0.255). In total, 53.0% (44/83) of the patients in the taxane group had progressive disease versus 54.2% (52/96) in the fluorouracil group (not significantly different (P=0.758)). There was no significant difference in overall response rate, progression free survival and overall survival, as well as treatment-related death. In terms of non-hematological toxicity, patients in the taxane group experienced a lower incidence of ≥ grade 3 esophageal perforation or fistula (4.8% vs. 13.5%, P=0.047) and pneumonia (4.8% vs. 9.7%, P=0.242). Regarding hematological toxicity, thrombocytopenia in the taxane group was significantly lower (4.8% vs. 13.5%, P=0.047), but there was a trend towards a higher rate of ≥ grade 3 leukopenia (34.9% vs.26.0%, P=0.196).

Conclusions: Chemoradiation with taxane-based regimens is well tolerated, with potentially promising efficacy, and could become a good alternative treatment in a first line setting for patients with inoperable esophageal squamous cell carcinoma.

• chemoradiotherapy
• esophageal cancer
• esophageal squamous cell carcinoma
• taxane

Although standard chemotherapy for esophageal cancer patients is fluorouracil and cisplatin, the prognosis is still unsatisfactory. A new therapeutic regimen combining docetaxel, cisplatin, and 5‐fluorouracil was recently developed to improve both local and distant tumor control. We developed a new regimen of docetaxel, nedaplatin, and S1 (DGS) and previously reported the recommended dose in a phase I dose‐escalation study. We then undertook a phase II study of DGS for advanced esophageal squamous cell carcinoma. Patients with clinical stage IB/II/III disease were eligible. Patients received two courses of chemotherapy: docetaxel 35 mg/m² with nedaplatin 40 mg/m² on day 8, 80 mg/m² S1 on days 1–14, and 2 weeks off. After completion of chemotherapy, patients underwent esophagectomy. The primary endpoint was the completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery [no residual tumor]). We enrolled 32 patients. The completion rate of protocol treatment was 96.9%. During chemotherapy, the most common grade 3 or 4 toxicity was neutropenia (25.0%). No treatment‐related deaths were observed, and the incidence of operative morbidity was tolerable. The overall response rate after chemotherapy was 83.3%. This DGS regimen was well tolerated and highly active. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014626).

• Docetaxel
• S1
• esophageal cancer
• nedaplatin
• phase II

• Breast cancer
• Chemotherapy
• Efficacy
• Nedaplatin
• Toxicity

• Esophageal squamous cell cancer
• Front-line chemotherapy
• Nedaplatin
• Paclitaxel

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/mortality
• Carcinoma, Squamous Cell/secondary
• China
• Disease Progression
• Disease-Free Survival
• Drug Administration Schedule
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/mortality
• Esophageal Neoplasms/pathology
• Esophageal Squamous Cell Carcinoma
• Female
• Humans
• Intention to Treat Analysis
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Organoplatinum Compounds/administration & dosage
• Paclitaxel/administration & dosage
• Time Factors
• Treatment Outcome

Esophageal cancer is a major health hazard in many parts of the world and is often diagnosed late. The objective of this study was to explore the efficacy and safety of nanoparticle albumin-bound paclitaxel (Nab-PTX) combined with cisplatin (DDP) in patients with metastatic esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC were treated with Nab-PTX 250 mg/m² and DDP 75 mg/m² intravenously on day 1, every 21 days. Evaluation was performed after every two cycles of therapy and the therapy was continued until disease progression or unacceptable toxicity. From April 2010 to December 2012, 33 patients were enrolled. Ten patients had recurrent and metastatic tumors after surgery and 23 patients were diagnosed with unresectable metastatic disease. Patients received a median of four cycles of therapy (ranging from two to six cycles). Twenty patients achieved partial response and nine patients achieved stable disease; no complete response was observed. The objective response rate was 60.6% and the disease control rate was 87.9%. The median progression-free survival was 6.2 months (95% confidence interval: 4.0 to 8.4 months) and the median overall survival was 15.5 months (95% CI: 7.6 to 23.4 months). Only four patients experienced grade 3 adverse events, including vomiting, neutropenia, and sensory neuropathy. The most common adverse events were nausea/vomiting (81.8%), neutropenia (63.6%), leucopenia (48.5%), anemia (24.2%) and sensory neuropathy (24.2%). In conclusion, the combination of Nab-PTX and DDP is a highly effective and well-tolerated first-line treatment in metastatic ESCC.

• chemotherapy
• esophageal squamous cell carcinoma
• metastasis
• nanoparticle albumin-bound paclitaxel

Nedaplatin, a cisplatin analog, has been developed to decrease the toxicities induced by cisplatin, such as nephrotoxicity and gastrointestinal toxicity. The dose of nedaplatin is determined by body surface area, not by the area under the curve (AUC). The recommended therapeutic dose is 80–100 mg/m², although the pharmacokinetic profile of nedaplatin is similar to that of carboplatin. In our preliminary study, there was a favorable correlation between AUC and creatinine clearance (CL), suggesting that renal function should be considered when nedaplatin is administered. Ishibashi’s formula, ie, Dose_NDP = AUC × CL_NDP, where CL_NDP = 0.0738 × creatinine clearance + 4.47, would be predictable and useful for estimating the individual dose of nedaplatin. Several Phase II studies have suggested that nedaplatin might be a useful second analog, especially for patients with non-small cell lung cancer, esophageal cancer, uterine cervical cancer, head and neck cancer, or urothelial cancer. Further, nedaplatin was reported to be a useful chemotherapeutic agent with radiosensitizing properties; however, there is no Phase III study of nedaplatin, neither with chemotherapy nor with concurrent chemoradiotherapy, because nedaplatin is not commonly used throughout the world. Further evaluation in a randomized controlled trial is warranted to demonstrate definitively the activity of nedaplatin.

• area under the curve
• chemotherapy
• concurrent chemoradiotherapy
• nedaplatin

• cancer of unknown primary
• chemotherapy
• esophageal cancer
• squamous cell carcinoma

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Transitional Cell/drug therapy
• Carcinoma, Transitional Cell/pathology
• Disease-Free Survival
• Drug Administration Schedule
• Female
• Humans
• Ifosfamide/administration & dosage
• Ifosfamide/adverse effects
• Kidney Neoplasms/drug therapy
• Kidney Neoplasms/pathology
• Kidney Pelvis
• Male
• Middle Aged
• Organoplatinum Compounds/administration & dosage
• Organoplatinum Compounds/adverse effects
• Paclitaxel/administration & dosage
• Paclitaxel/adverse effects
• Treatment Outcome
• Ureteral Neoplasms/drug therapy
• Ureteral Neoplasms/pathology
• Urinary Bladder Neoplasms/drug therapy
• Urinary Bladder Neoplasms/pathology