Rare malignant neoplasm of the esophagus: current status and future perspectives.

Esophageal cancer is common worldwide, including in Japan, and its major histological subtype is squamous cell carcinoma. However, there are some rare esophageal cancers, including neuroendocrine neoplasm, gastrointestinal stromal tumor, carcinosarcoma and malignant melanoma. The biological and clinical features of these cancers differ from those of esophageal squamous cell carcinoma. Therefore, different treatment strategies are needed for these cancers but are based on limited evidence. Neuroendocrine neoplasm is mainly divided into neuroendocrine tumor and neuroendocrine carcinoma by differentiation and the Ki-67 proliferation index or mitotic index. Epidemiologically, the majority of esophageal neuroendocrine neoplasms are neuroendocrine carcinoma. The treatment of neuroendocrine carcinoma is similar to that of small cell lung cancer, which has similar morphological and biological features. Gastrointestinal stromal tumor is known to be associated with alterations in the c-KIT and platelet-derived growth factor receptor genes and, if resectable, is treated in accordance with the modified Fletcher classification. Carcinosarcoma is generally resistant to both chemotherapy and radiotherapy and requires multimodal treatments such as surgery plus chemotherapy to achieve cure. Primary malignant melanoma is resistant to cytotoxic chemotherapy, but immune checkpoint inhibitors have recently demonstrated efficacy for malignant melanoma of the esophagus. This review focuses on the current status and future perspectives for rare cancer of the esophagus.

A phase III randomized controlled trial comparing local field with additional prophylactic irradiation in chemoradiotherapy for clinical-T1bN0M0 esophageal cancer: ARMADILLO trial (JCOG1904).

Chemoradiotherapy has been considered as one of the standard treatment options for clinical T1bN0M0 esophageal squamous cell carcinoma with organ preservation. However, 20% of patients develop locoregional recurrence after chemoradiotherapy, which requires salvage treatment including salvage surgery and endoscopic resection. Salvage surgery can cause complications and treatment-related death. Interestingly, chemoradiotherapy with elective nodal irradiation has been reported to reduce the locoregional recurrence of advanced esophageal squamous cell carcinoma. Hence, we are conducting a clinical trial to confirm whether modified chemoradiotherapy with elective nodal irradiation was superiority to that without elective nodal irradiation for the patients with cT1bN0M0 esophageal squamous cell carcinoma. The primary endpoint is major progression-free survival, defined as the time from randomization to the date of death or disease progression, excluding successful curative resection through salvage endoscopic resection. We plan to enroll 280 patients from 54 institutions over 4 years. This trial has been registered in the Japan Registry of Clinical Trials (jRCTs031200067).

Definitive treatment for head and neck mucosal melanoma.

Head and neck mucosal melanoma is a rare clinical subtype of melanoma or head and neck cancer. Mucosal melanoma is aetiologically and molecularly distinct from cutaneous melanoma. The therapeutic efficacy of immune checkpoint inhibitors for head and neck mucosal melanoma remains unclear. Surgery is considered as the mainstay of treatment for locally advanced head and neck mucosal melanoma, and adjuvant radiotherapy has a role in local disease control. New treatment modalities, such as targeted therapy and immunotherapy, have changed the treatment of cutaneous melanoma. However, patients with mucosal melanoma have been excluded from most Phase III clinical trials. Due to its rarity, outcome data for locally advanced head and neck mucosal melanoma are scarce and are mainly based on retrospective studies with limited case numbers. The objective of this review was to provide an update and overview of clinical trials, prospective observational studies and retrospective studies and discuss future directions for multimodal treatment of locally advanced head and neck mucosal melanoma.

Association of the gut microbiome with cancer immunotherapy.

Immune checkpoint inhibitors, programmed cell death-1- and cytotoxic T-lymphocyte-associated protein 4-based immunotherapy have remarkably improved survival with durable response for patients with multiple cancer type. The accurate predictors of response and toxicity to immunotherapy are still unclear and have been focused on the gut microbiome. The gut microbiome, which refers to the microorganisms and their genes, affects the host immunity both locally and systemically. Modulation of the gut microbiota alters the immune systems and affects the efficacy of immune checkpoint inhibitor. In this review, we investigate the evidence on the role of the microbiome in cancer patients and discuss the impact of microbiome on the efficacy of immune checkpoint inhibitors in cancer.

Timing of the infusion of nivolumab for patients with recurrent or metastatic squamous cell carcinoma of the esophagus influences its efficacy.

BACKGROUND: The immune system is affected by the circadian rhythm. The objective of this study was to clarify whether time-of-day patterns (early or late in the daytime) of the infusion of nivolumab and whether its duration affect treatment efficacy in metastatic or recurrent esophageal squamous cell carcinoma (R/M-ESCC). METHODS: The data of 62 consecutive patients with R/M-ESCC treated with nivolumab between February 2017 and May 2022 were retrospectively reviewed. The infusion of nivolumab before 13:00 was set as 'early in the day', and that after 13:00 was set as 'late in the day'. The treatment efficacy was compared between early and late groups by 3 criteria (first infusion, during the first 3 months, and all treatment courses). RESULTS: The overall survival, progression-free survival, and response rate of patients received the first dose in the early group were significantly superior to those of patients in the late group. The progression-free survival and response rate of patients who received the majority of nivolumab infusions before 13:00 during the first 3 months were significantly superior to those who received it after 13:00, with the exception of overall survival. There were no significant differences in the overall survival, progression-free survival, and response rate between patients who received the majority of nivolumab infusions before 13:00 of all treatment courses and those who received it after 13:00. CONCLUSION: The timing of the infusion of nivolumab may affect treatment efficacy in R/M-ESCC.

A phase II study of S-1 therapy for patients with advanced and recurrent esophageal cancer resistant or intolerable to fluorouracil, platinum, and taxane therapy (OGSG 1404).

BACKGROUND: Fluorouracil (FU), platinum (PT), and taxane (TAX) therapy was the standard chemotherapy for esophageal squamous cell carcinoma (ESCC) before the era of anti-programmed death-1 antibodies. The aim of this phase II trial was to evaluate the efficacy and safety of S-1 monotherapy for patients with recurrent or metastatic (R/M) ESCC resistant or intolerable to FU, PT, and TAX therapy. METHODS: Eligible patients had R/M ESCC; no prior S-1 use; were intolerant or refractory to prior FU, PT, and TAX therapy; aged ≧ 20 years; and Eastern Cooperative Oncology Group performance status 0 or 1. S-1 was administered orally from days 1 to 28, every 6 weeks until disease progression. The primary endpoint was the disease control rate (DCR) for each patient, assessed by Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were overall survival, progression-free survival, time to treatment failure, response rate, and toxicity. RESULTS: Between October 2015 and December 2017, 17 patients were recruited, and the trial was terminated because of slow accrual. The DCR was 46.7%. The response rate was 13.3%. The median progression-free survival was 2.0 months. The median time to treatment failure was 1.9 months. The median overall survival was 8.4 months, and the 1 year overall survival rate was 30.5%. CONCLUSIONS: Although this trial closed early because of slow accrual, we observed modest clinical activity with S-1 in patients with R/M ESCC who could not tolerate or whose tumors were refractory to FU, PT, and TAX therapy.

Comprehensive genomic profiling for patients with chemotherapy-naïve advanced cancer.

Comprehensive genomic profiling (CGP) testing by next-generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first-line chemotherapy could be clinically useful is not clear. We conducted this single-center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy-naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne® companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular-based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10-329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular-based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first-line chemotherapy.

Multicenter prospective phase II trial of nivolumab in patients with unresectable or metastatic mucosal melanoma.

BACKGROUND: Mucosal melanoma is a rare and aggressive malignancy with poorer response compared with cutaneous melanoma. Prospective trials of immune checkpoint inhibitors in unresectable or metastatic mucosal melanoma have not been reported. PURPOSE: This phase II trial assessed the efficacy and safety of nivolumab monotherapy for unresectable or metastatic mucosal melanoma. PATIENTS AND METHODS: Eligibility criteria were as follows: histological diagnosis of unresectable or metastatic mucosal melanoma; age ≥ 20 years; ECOG performance status 0 or 1; and with measurable lesions. Patients received nivolumab 2 mg/kg every 3 weeks. The primary endpoint was the response rate (RR) according to Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were overall survival, progression-free survival, disease control rate, and toxicity. RESULTS: Twenty patients were enrolled between December 2014 and July 2017. Two patients without measurable lesions and one patient with uveal melanoma were excluded from analysis of efficacy. The best overall RR was 23.5%. One patient achieved a complete response, three partial response, and five stable disease as their best response. The median progression-free survival was 1.4 months (95% CI 1.2-2.8). The median overall survival was 12.0 months (95% CI 3.5 to not reached). The 1-year overall survival was 50.0% (95% CI 25.9-70.0%). Treatment-related adverse events of grades 3 or 4 occurred in 15% (3/20) of the patients. Grade 3 adverse events were resolved by corticosteroid treatment. CONCLUSION: Although this trial met the primary endpoint, the RR was still unsatisfactory. Therefore, further treatment development is required.

Predicting marker for early progression in unresectable melanoma treated with nivolumab.

BACKGROUND: The objective of this study was to identify predictive markers, including inflammatory and nutritional status measures, of early progressive disease (EPD) in unresectable melanoma patients treated with nivolumab. METHODS: A retrospective review was performed on 39 consecutive patients with unresectable melanoma treated with nivolumab. EPD was defined as progressive disease within 60 days after starting nivolumab according to Response Evaluation Criteria in Solid Tumors version 1.1. The predictive index model [melanoma inflammation index (MII)] was determined by the number of predictive factors. RESULTS: Seventeen patients had cutaneous melanoma and 22 patients had mucosal melanoma. The overall response rate was 18.4%, and the response rates for cutaneous and mucosal melanoma were 29.4% and 9.5%, respectively. EPD was observed in 13 patients (34.2%). By multivariate analysis, body mass index (BMI) and C-reactive protein to albumin ratio (CAR) were independently and significantly associated with EPD, disease control rate, progression-free survival, and overall survival. Low BMI (cutoff 20) and high CAR (cutoff 0.0055) were predictive factors of EPD and were determined to be prognostic factors. MII, from 0 to 2, was determined by the number of these factors. The incidence of EPD was 0% in the low-risk group (MII = 0), 50% in the intermediate-risk group (MII = 1), and 83% in the high-risk group (MII = 2). CONCLUSIONS: An MII status of low BMI and high CAR may be used to predict EPD in unresectable melanoma patients treated with nivolumab.

Comparison between neoadjuvant chemotherapy followed by surgery and definitive chemoradiotherapy for overall survival in patients with clinical Stage II/III esophageal squamous cell carcinoma (JCOG1406-A).

BACKGROUND: Neoadjuvant chemotherapy followed by surgery (NAC-S) represents the standard treatment for patients with Stage II/III esophageal squamous cell carcinoma (ESCC) in Japan. Chemoradiotherapy (CRT) is performed in patients who refuse or have contraindications to surgery. However, randomized clinical trials that compare NAC-S with CRT have not been conducted. The aim of this study was to explore subgroups of patients undergoing CRT to identify those with survival outcomes potentially equivalent to NAC-S. METHODS: Pooled data from two clinical trials in patients with Stage II/III ESCC, the JCOG9907 trial and the JCOG9906 trial were used. JCOG9907 demonstrated that NAC-S resulted in superior overall survival (OS) compared with surgery followed by adjuvant chemotherapy. JCOG9906 was a single-arm trial that explored the efficacy and safety of CRT. The eligibility criteria in the two trials were almost identical. Subgroup analyses of clinical data (serum albumin, cT, cN, cstage and tumor location) were conducted with Cox proportional hazards regression models for patients assigned to receive NAC-S in JCOG9907 and patients in JCOG9906. RESULTS: The analysis comprised 163 patients from JCOG9907 in NAC-S arm (NAC-S group) and 73 patients from JCOG9906 who received CRT (CRT group). Baseline characteristics were similar between the two groups. OS was better in the NAC-S group than the CRT group (adjusted hazard ratio 1.72; 95% confidence interval 1.19-2.50). All subgroups in the NAC-S group had longer OS compared with those in the CRT group. CONCLUSIONS: OS was superior after NAC-S rather than CRT. None of the CRT subgroups had similar OS to the NAC-S groups.

Comparison between chemoselection and definitive radiotherapy in patients with cervical esophageal squamous cell carcinoma.

BACKGROUD: Laryngeal preservation is an important consideration when treating cervical esophageal cancers (CECs) such as laryngeal cancer. The standard treatment for CEC allowing laryngeal preservation is chemoradiotherapy. However, in cases of laryngeal cancer, chemoselection has also been applied as a treatment strategy that promotes larynx preservation. This strategy involves assigning the appropriate radical treatment according to the primary tumor's response to induction chemotherapy. Since there have been no studies of the application of chemoselection in CEC cases, the present study compared the results, including laryngeal preservation rates, obtained upon applying chemoselection and chemoradiotherapy to CEC. STUDY DESIGN: This was a retrospective cohort study of cervical esophageal squamous cell carcinoma patients treated using chemoselection or chemoradiotherapy at Aichi Cancer Center Hospital between January 2000 and March 2013. A total of 42 patients were enrolled. RESULTS: The 2-year overall survival and laryngeal preservation rates for the chemoselection group versus the primary radiotherapy group were 65.1 and 57.3 versus 40 and 83.3%, respectively (P = 0.017 and P = 0.122, respectively). The 2-year locoregional control rates for the chemoselection and primary radiotherapy groups were 68 and 25%, respectively (P = 0.045). CONCLUSION: The chemoselection group achieved favorable results. Therefore, chemoselection can be applied as a treatment strategy for CEC.

Factors affecting dilation force in balloon dilation of severe esophageal strictures: an experiment using an artificial stricture model.

BACKGROUND: The multidiameter balloon catheter is used widely for severe esophageal stricture dilation. However, the relationships between inflation pressure, balloon size, and radial dilation force at the stricture site have not been examined fully. METHODS: We performed an experiment using phantom models to investigate the relationships between inflation pressure, balloon size, and radial dilation force. The balloon dilation procedure was performed for each stricture model using three sizes of balloon: 10-11-12, 12-13.5-15, and 15-16.5-18 mm. RESULTS: A positive association between inflation pressure and dilation force was observed for each balloon size. In balloons inflated by targeting the same diameter, the dilation force was higher for smaller balloons than for larger balloons. An inverse association between stricture size and dilation force was observed in the 12-13.5-15 mm balloon (3 vs 5 mm, P = .002; 5 vs 7 mm, P < .001). CONCLUSIONS: We found relationships between inflation pressure, balloon size, severity of strictures, and dilation force. To perform safe and effective esophageal balloon dilation, the inflation pressure and balloon size should be selected after considering the stricture size and target diameter.

Comparison between surgery and definitive chemoradiotherapy for patients with resectable esophageal squamous cell carcinoma: a propensity score analysis.

PURPOSE: Our intent was to compare survival following neoadjuvant chemotherapy followed by surgery versus chemoradiotherapy (CRT) among patients with potentially resectable esophageal squamous cell carcinoma. METHODS: Information about 406 consecutive esophageal cancer patients with resectable disease who underwent surgery with neoadjuvant chemotherapy consisting of cisplatin plus 5-fluorouracil or who underwent definitive CRT was reviewed. The survival outcomes were analyzed using the Kaplan-Meier method and propensity score-adjusted Cox proportional hazards models. Relevant variables were included in the propensity score model. RESULTS: Overall, 206 patients planned to undergo surgery (S group) and 200 patients planned to undergo CRT (CRT group). In the unadjusted situation, progression-free survival and overall survival did not differ statistically between the groups. After matching, both survival outcomes were better in the S group compared to the CRT group. Subanalysis showed both survival outcomes were better in the S group for patients with only stage III disease. However, survival outcomes for stages I, II, and IV were not significantly different between treatment groups. CONCLUSIONS: Among patients with resectable disease, survival outcomes in the S group were favored over those of the CRT group. These results indicate that different therapeutic strategies should be used for stage III esophageal cancer than for other stages.

A single-arm phase II trial of combined chemotherapy with S-1, oral leucovorin, and bevacizumab in heavily pre-treated patients with metastatic colorectal cancer.

BACKGROUND: The mean 5-6-month survival after failed standard chemotherapy for metastatic colorectal cancer (mCRC) necessitates more effective treatments for refractory mCRC. For untreated mCRC, S-1 + oral leucovorin (SL) therapy offers promising results without severe toxicity. The ML18147 trial demonstrated that bevacizumab (Bev) prolongs overall survival after mCRC progression. We conducted a single-centre phase-II trial to evaluate the safety and efficacy of SL/Bev combination chemotherapy as mCRC salvage therapy. METHODS: Major eligibility criteria were confirmed adenocarcinoma diagnosis; age >20 years; Eastern Cooperative Oncology Group performance status, 0-2; and progression after administration/intolerance of/to approved drugs for mCRC. (5-FU, oxaliplatin, irinotecan, Bev, and anti-EGFR antibody, if KRAS wild-type). S-1 (80-120 mg/body) and leucovorin (25 mg) were orally administered in a 1-week-on/1-week-off schedule. Bev (5 mg/kg) was administered on day 1 of every 2-week cycle. The primary endpoint was disease control rate (DCR). RESULTS: A total of 31 patients were enrolled. DCR was 65% [95% confidence interval (CI), 48-100%] and the response rate was 7% (95% CI, 0.7-22%). One patient showing partial response to SL/Bev had a BRAF-mutant tumor. Median progression-free survival and overall survivals were 5.3 [95% CI, 2.1-9.3] and 9.9 [95% CI, 7.4-NA] months, respectively. The most-frequent grade-3/4 adverse events were mucositis (26%) and diarrhea (11%), which were manageable by dose reduction/interruption. CONCLUSIONS: SL/Bev showed impressive activity in refractory mCRC and was tolerable, suggesting its potential as an alternative chemotherapy for refractory mCRC. TRIAL REGISTRATION: This study has been registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry ( ID UMIN000009083 ) on 11 October 2012.

Differences in attitude toward adjuvant chemotherapy between colorectal cancer survivors and the medical staff of Japanese hospitals.

BACKGROUND: Adding oxaliplatin to fluorouracil-based chemotherapy can improve the survival of patients with stage III colorectal cancer by approximately 20 %. Reportedly, cancer patients are much more likely to prefer chemotherapy than medical professionals, although there is only a very small chance of achieving benefits from treatment. However, chronic neurotoxicity may be long lasting after the administration of oxaliplatin-based chemotherapy. This study aimed to evaluate potential side effects and differences in attitude between colorectal cancer patients and medical staff regarding the risk-benefit trade-offs of chemotherapy. METHODS: Relapse-free colorectal cancer patients who received adjuvant chemotherapy, doctors, and nurses were surveyed using a questionnaire regarding the side effects of chemotherapy and hypothetical clinical scenarios to quantify gains in the risk of relapse that were deemed necessary to make chemotherapy worthwhile. RESULTS: Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Of these, 39 % of patients and 85 % of doctors replied that moderate side effects of adjuvant chemotherapy were worthwhile to achieve an absolute gain in the risk of relapse of 10 % from a baseline of 40 %. More severe side effects, as reported by colorectal cancer patients, were not associated with the larger gains necessary to make treatment worthwhile. Seven percent of patients treated with oxaliplatin, 40 % of doctors, and 43 % of nurses replied that side effects associated with oxaliplatin-based chemotherapy were severe. CONCLUSIONS: Doctors should consider potential heterogeneity in side effects and attitudes regarding the risk-benefit balance of adjuvant chemotherapy, and that patient perspectives should enhance shared decision-making.

Efficacy of palliative radiotherapy for gastric bleeding in patients with unresectable advanced gastric cancer: a retrospective cohort study.

BACKGROUND: Bleeding negatively impacts quality of life in patients with unresectable advanced gastric cancer and has the potential to be lethal. When blood transfusion and endoscopic hemostasis are unsuccessful to stop bleeding, radiation to stomach is selected in patients with unsuitable condition for surgery. We performed a retrospective cohort study to clarify the utility of radiotherapy in treating gastric bleeding, particularly for patients with limited life expectancy. METHODS: We evaluated the efficacy and safety of palliative radiotherapy in patients with advanced gastric cancer between January 2007 and December 2012 in Aichi Cancer Center Hospital. All patients had gastric bleeding requiring blood transfusion. We defined hemostasis as an increase in hemoglobin level to more than 7.0 g/dL together with the cessation of melena or hematemesis for at least 1 week. RESULTS: During the study period, 313 advanced gastric cancer patients treated in our institution. Of these 17 patients received gastric radiotherapy to stop bleeding. Two patients were excluded from analysis due to combined treatment of intravascular embolization. Eleven out of 15 patients (73 %) had undergone two or more previous chemotherapy regimens. Ten patients (67 %) had an Eastern Cooperative Oncology Group performance status of 3 and 14 patients (93 %) were in palliative prognostic index group B or C. The median total planned radiation dose was 30 Gy in 10 fractions. At a median interval of 2 days after initiation of radiotherapy, 11 patients (73 %) achieved hemostasis; rebleeding was observed in four patients (36 %). The median hemoglobin level before radiotherapy was significantly increased from 6.0 to 9.0 g/dL (p < 0.0001). The median volume of red blood cell transfusion was significantly decreased from 1120 to 280 mL (p = 0.007). The median rebleeding-free survival interval was 27 days, with a median overall survival of 63 days. The cause of death was bleeding in 1 patient (7 %) and cancer progression without bleeding in 12 patients (80 %). There were no severe adverse events attributable to radiotherapy. CONCLUSIONS: Palliative radiotherapy for gastric bleeding achieves hemostasis within a short time frame. This appears to be a useful treatment option, especially for patients with end-stage, unresectable advanced gastric cancer.

[A questionnaire survey on QOL and toxicity in colorectal cancer survivors who received adjuvant chemotherapy].

The relative risk of cancer recurrence with postoperative adjuvant FOLFOX/CapeOX therapy(Ox)for stage III colorectal cancer is reduced by approximately 20%when compared to that with fluorouracil plus Leucovorin. We performed a questionnaire survey to evaluate the quality of life(QOL)and extent of side effects in patients who received adjuvant chemotherapy. In order to evaluate the risks and benefits of oxaliplatin administration, we also examined the differences in awareness of oxaliplatin side effects between patients and medical staff. Responses were obtained from 147 patients, 54 doctors, and 84 nurses. Analysis of the patient responses showed higher current QOL scores regardless of the chemotherapy regimen, although patients in the Ox group had a high rate of residual sensory peripheral neuropathy. In the Ox group, 81% of patients responded that the side effects were moderate. In contrast, 40% of medical staff identified the side effects of oxaliplatin as severe, which differed from that reported by the patients. Considering that Ox adjuvant chemotherapy may reduce the risk of recurrence by approximately 20%, the risk/benefit balance is acceptable.

Successful Management of Malignant Pericarditis Using Nivolumab for Metastatic Esophageal Squamous Cell Carcinoma.

Esophageal cancer is a malignant disease with a poor prognosis and is one of the most common causes of cardiac metastasis. Malignant pericarditis may cause the repetitive accumulation of pericardial effusion, which can occasionally pose a clinical challenge. We herein report a case of malignant pericarditis in a patient with metastatic esophageal squamous cell carcinoma with cardiac tamponade, which was successfully managed with single pericardial drainage and systemic nivolumab monotherapy. This is the first case report to suggest that systemic therapy with nivolumab is a promising option for the management of malignant pericarditis.

Optimizing Organ Preservation Strategies through Chemotherapy-Based Selection in Esophageal Squamous Cell Carcinoma: Results from the CROC Multi-Institutional Phase II Clinical Trial.

PURPOSE: This 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 MATERIALS: Chemotherapy-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). RESULTS: Of 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). CONCLUSIONS: In 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.