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Narita K, Higaki E, Abe T, Fujieda H, Hashimoto S, Kadowaki S, Tajika M, Kodaira T, Muro K, Shimizu Y. Conversion from Radical Esophagectomy to Definitive Chemoradiotherapy After Neoadjuvant Chemotherapy for Advanced Esophageal Squamous Cell Carcinoma: Treatment Options Based on Chemotherapy Response. Ann Surg Oncol 2025; 32:3157-3166. [PMID: 39953348 DOI: 10.1245/s10434-025-16955-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 01/16/2025] [Indexed: 02/17/2025]
Abstract
BACKGROUND Radical esophagectomy after neoadjuvant chemotherapy (NAC) is the established strategy for resectable advanced esophageal cancer. However, some patients are converted to definitive chemoradiotherapy (dCRT) after NAC due to reasons such as their wishes or disease progression, and their prognosis remains uncertain. This study aimed to investigate the prognosis of patients who converted to dCRT. METHODS Patients who underwent NAC for resectable advanced esophageal squamous cell carcinoma between 2006 and 2020 were enrolled in this study retrospectively. The prognostic impact of subsequent treatment after NAC, planned surgery, or conversion to dCRT, was compared. RESULTS The study analyzed 686 patients, 70 who were converted to dCRT (dCRT group) and 616 who underwent surgery (Surg group). The dCRT group had a poorer prognosis than the Surg group, with more advanced tumors and poorer response to NAC. Therefore, further analysis was performed by categorizing patients as Responders (complete or partial response) and Non-responders (stable or progressive disease) to NAC. Among the Responders in the dCRT group, 76.7 % achieved a complete response, and the 5-year esophageal preservation survival rate was 66.9 %. The 5-year survival rates for Responders were 77.5 % in the dCRT group and 71.3 % in the Surg group. Multivariable analysis showed that dCRT did not worsen prognosis (P = 0.706; hazard ratio, 1.13; 95 % confidence interval, 0.59-2.16). Conversely, among the Non-responders, dCRT had a significantly poorer prognosis, with 5-year survival rates of 22.3 % in the dCRT group and 45.1 % in the Surg group (P < 0.001). CONCLUSIONS For patients responding to NAC, conversion to dCRT is considered a potential treatment option.
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Affiliation(s)
- Kiyoshi Narita
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Eiji Higaki
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.
| | - Tetsuya Abe
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Hironori Fujieda
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Shingo Hashimoto
- Department of Radiation Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Masahiro Tajika
- Department of Endoscopy, Aichi Cancer Center Hospital, Aichi, Japan
| | - Takeshi Kodaira
- Department of Radiation Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
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Matsuda S, Takeuchi H, Kato K, Machida R, Ito Y, Tsubosa Y, Daiko H, Koyanagi K, Ogata T, Fukuda T, Fujita T, Abe T, Bamba T, Watanabe M, Kawakubo H, Shibuya Y, Otsubo D, Kakisita T, Hashimoto T, Sasaki K, Kitagawa Y. Prognostic Impact of Thoracic Duct Resection in Patients Who Underwent Transthoracic Esophagectomy Following Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma: Exploratory Analysis of JCOG1109. Ann Surg Oncol 2025; 32:293-301. [PMID: 39373925 DOI: 10.1245/s10434-024-16303-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 09/20/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Although several studies have investigated whether thoracic duct (TD) resection improves prognosis, the conclusion remains controversial. JCOG1109 is a three-arm randomized phase III trial to confirm the survival advantage of docetaxel, cisplatin, 5-fluorouracil (DCF), and cisplatin plus 5-fluorouracil (CF) combined with radiotherapy (CF-RT) over CF as neoadjuvant treatment. The study aimed to evaluate the survival impact of TD resection and its association with neoadjuvant treatment and pathological response in patients enrolled in JCOG1109. PATIENTS AND METHODS Clinicopathological factors, surgical results, and prognosis were compared between TD preserved and resected groups. The survival impact of TD resection was also evaluated in the subgroups on the basis of combinations of preoperative therapy and pathological response. RESULTS Between December 2012 and July 2018, 601 patients were randomized (CF/DCF/CF-RT; 199/202/200) in JCOG1109. Of them, 541 patients underwent esophagectomy (183/181/177), and TD was resected in 265 patients (93/91/81). For the entire cohort, TD resection was not a significant prognostic factor for overall survival in the multivariable analysis (HR 1.20, 95% CI 0.91-1.57). In the subgroup analyses by combinations of neoadjuvant treatment and pathological response, TD resected group had a significantly better overall survival compared with TD preserved group in patients who received DCF and achieved pathological response (HR 0.20, 95% CI 0.07-0.61). CONCLUSIONS The survival benefit of TD resection was not demonstrated in patients with surgically resectable esophageal squamous cell carcinoma enrolled in JCOG1109. The residual tumor burden after neoadjuvant treatment might be linked to the survival impact of TD resection.
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Affiliation(s)
- Satoru Matsuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
| | - Ken Kato
- Department of Head and Neck and Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ryunosuke Machida
- Japan Clinical Oncology Group Data Center, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshinori Ito
- Department of Radiation Oncology, Showa University School of Medicine, Tokyo, Japan
| | - Yasuhiro Tsubosa
- Division of Esophageal Surgery, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Hiroyuki Daiko
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuo Koyanagi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Takashi Ogata
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Takashi Fukuda
- Department of Gastrointestinal Surgery, Saitama Cancer Center, Saitama, Japan
| | - Takeo Fujita
- Division of Esophageal Surgery, National Cancer Center Hospital East, Kashiwa, Japan
| | - Tetsuya Abe
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | - Takeo Bamba
- Department of Gastroenterological Surgery, Niigata Cancer Center, Niigata, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuichi Shibuya
- Department of Gastroenterological Surgery, Kochi Health Science Center, Kochi, Japan
| | - Dai Otsubo
- Department of Gastroenterological Surgery, Hyogo Cancer Center, Akashi, Japan
| | | | - Tadayoshi Hashimoto
- Japan Clinical Oncology Group Data Center, National Cancer Center Hospital, Tokyo, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Keita Sasaki
- Japan Clinical Oncology Group Data Center, National Cancer Center Hospital, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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Lan K, Yan X, Lei J, Guo X, Zhou Y, Wang X, Liu H, Tian F, Lu Q, Gu Z, Sun J, Yang E, Zhong D, Wang T, Huang L, Wang J, Liu X, Ni Y, Jiang T, Zhao J. Clinical outcomes and short-term survival of neoadjuvant immunochemotherapy for resectable esophageal cancer: a multicenter retrospective cohort study. Int J Surg 2025; 111:1547-1551. [PMID: 40053810 PMCID: PMC11745577 DOI: 10.1097/js9.0000000000002011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 07/25/2024] [Indexed: 03/09/2025]
Abstract
OBJECTIVE The present retrospective cohort study aims to evaluate the efficacy and safety of neoadjuvant immunochemotherapy for resectable esophageal cancer and report the preliminary short-term survival. METHODS A multicenter, retrospective study was conducted concerning patients who received neoadjuvant PD-1 agents plus platinum-based chemotherapy between January 2019 and January 2022. The primary endpoint was the tumor pathologic complete response (pCR) rate. RESULTS Two hundred and thirteen patients with initial stage cI-IVA esophageal cancer who received neoadjuvant immunochemotherapy were identified. The complete tumor resection(R0) rate was 99.1%. The pCR rate was 31.9%, and the overall major pathological response rate was 49.8%. The 2-year DFS rate was 78.9% (95% CI: 72.9-85.4%) and the 2-years OS rate was 80.9% (95% CI: 75.3-86.9%). The incidence of TRAEs and surgical complications rate were 68.5 and 35.2%, respectively. CONCLUSION The PD-1 agents combined with chemotherapy in the neoadjuvant treatment for resectable stage I-IVA esophageal cancer had a high pCR rate as well as good short-term survival benefits and tolerable toxicity.
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Affiliation(s)
- Ke Lan
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Jie Lei
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Xufeng Guo
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
| | - Yongan Zhou
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Xiaoping Wang
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Honggang Liu
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Feng Tian
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Qiang Lu
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Zhongping Gu
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Jianyong Sun
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Ende Yang
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Daixing Zhong
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Tao Wang
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Lijun Huang
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Jian Wang
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Xu Liu
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Yunfeng Ni
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Tao Jiang
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tang Du Hospital, Air Force Military Medical University, Xian
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Varshney VK, Jain V, Selvakumar B, Soni S, Varshney P, Agarwal L, Suman S, Varshney B, Hussain S, Goel AD, Pareek P, Elhence P. Neoadjuvant Chemotherapy vs Chemoradiotherapy for Malignancy of Esophagus: A Prospective Comparative Study. Cureus 2024; 16:e73525. [PMID: 39669860 PMCID: PMC11636392 DOI: 10.7759/cureus.73525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2024] [Indexed: 12/14/2024] Open
Abstract
INTRODUCTION Neoadjuvant chemoradiation (NACRT) followed by surgery has become the standard of care for esophageal squamous cell carcinoma (ESCC). This study compared the tolerability and oncological benefit of neoadjuvant chemotherapy (NACT) with those of NACRT for the treatment of ESCC. METHODS A prospective quasi-experimental comparative study was conducted from July 2019 to August 2023 to assess the efficacy of the NACT regimen of two cycles of paclitaxel and carboplatin as an alternative to standard NACRT. Either NACT or NACRT was given to patients with resectable ESCC (clinical stage IB-IIIC), after which they underwent minimally invasive esophagectomy with two-field lymphadenectomy. Radiological and pathological responses to neoadjuvant therapy, perioperative morbidity, mortality, and recurrence-free and overall survival rates were compared. RESULTS Out of the 74 patients enrolled, 63 were included in the study after exclusion. Of these, 30 received NACT, and 33 received NACRT. The baseline demographics, tumor characteristics, incidence of neoadjuvant therapy-related adverse events, and perioperative morbidity were comparable between the two groups. The median number of lymph nodes retrieved (21 vs 19, p=0.19) and R0 resection rate (100% vs 94%) were similar. Although the pathological response was significantly better in the NACRT arm, at a median follow-up of 32.5 (20.75-48) months, there was a non-significant trend toward better recurrence-free survival in the NACRT group (57 vs 36 months, p-value - 0.831), with median overall survival yet to be achieved in both groups. CONCLUSION Compared with NACRT, NACT for ESCC is well tolerated and has non-inferior oncological outcomes. NACT could be a feasible alternative to NACRT in such patients, especially if the radiotherapy option is not feasible or available.
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Affiliation(s)
- Vaibhav K Varshney
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Vishu Jain
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - B Selvakumar
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Subhash Soni
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Peeyush Varshney
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Lokesh Agarwal
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Sunita Suman
- Surgical Gastroenterology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Bharti Varshney
- Pathology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Sabir Hussain
- Gastroenterology, Dr. Sampurnanand Medical College, Jodhpur, IND
| | - Akhil Dhanesh Goel
- Community Medicine & Family Medicine, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Puneet Pareek
- Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
| | - Poonam Elhence
- Pathology, All India Institute of Medical Sciences, Jodhpur, Jodhpur, IND
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Sugawara K, Fukuda T, Murakami C, Oka D, Yoshii T, Amori G, Ishibashi K, Kobayashi Y, Hara H, Kanda H, Motoi N. Impacts of tumor microenvironment during neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma. Cancer Sci 2024; 115:2819-2830. [PMID: 38693726 PMCID: PMC11309932 DOI: 10.1111/cas.16203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/26/2024] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4+, CD8+, CD20+, Foxp3+, HLA class-1+, CD204+, and programmed death ligand-1 [PD-L1+]) on 264 pre-NAC and 204 paired post-NAC specimens. Patients were classified by their pre- and post-NAC immune cell status and their changes following NAC. Our findings showed that pre-NAC TME status was not significantly associated with survival outcomes. In contrast, post-NAC TME status, such as low level of T cells, CD4+ T cells, and high PD-L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4+ T cells, or high levels of PD-L1 (CPS) had very poor OS (3-year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4+ T cells, and high PD-L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post-NAC status (T cells, CD4+, and PD-L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD-L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized.
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Affiliation(s)
- Kotaro Sugawara
- Department of Gastroenterological SurgerySaitama Cancer CenterSaitamaJapan
| | - Takashi Fukuda
- Department of Gastroenterological SurgerySaitama Cancer CenterSaitamaJapan
| | - Chiaki Murakami
- Department of PathologySaitama Cancer CenterSaitamaJapan
- Department of PathologySaitama Medical Center, Saitama Medical UniversitySaitamaJapan
| | - Daiji Oka
- Department of Gastroenterological SurgerySaitama Cancer CenterSaitamaJapan
| | - Takako Yoshii
- Department of GastroenterologySaitama Cancer CenterSaitamaJapan
| | - Gulanbar Amori
- Department of PathologySaitama Cancer CenterSaitamaJapan
- Division of PathologyCancer Institute, Japanese Foundation for Cancer ResearchTokyoJapan
- Department of PathologyCancer Institute Hospital of JFCR, Japanese Foundation for Cancer ResearchTokyoJapan
| | | | | | - Hiroki Hara
- Department of GastroenterologySaitama Cancer CenterSaitamaJapan
| | - Hiroaki Kanda
- Department of PathologySaitama Cancer CenterSaitamaJapan
| | - Noriko Motoi
- Department of PathologySaitama Cancer CenterSaitamaJapan
- Center for Cancer Genomic MedicineSaitama Cancer CenterSaitamaJapan
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Kubo Y, Nozaki R, Igaue S, Utsunomiya D, Kubo K, Yamamoto S, Kurita D, Kashihara T, Ishiyama K, Honma Y, Oguma J, Kato K, Daiko H. Neoadjuvant Chemotherapy Improves Feasibility of Larynx Preservation and Prognosis in Resectable Locally Advanced Cervical Esophageal Cancer. Ann Surg Oncol 2024; 31:5083-5091. [PMID: 38755340 DOI: 10.1245/s10434-024-15432-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/24/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND The optimal strategy for cervical advanced esophageal cancer remains controversial in terms of oncologic outcome as well as vocal and swallowing function. Recently, in East Asian countries, neoadjuvant chemotherapy (NAC) has been a standard strategy for advanced esophageal cancer. METHODS This study included 37 patients who underwent NAC, and 33 patients who underwent definitive chemoradiation therapy (dCRT) as larynx-preserving treatment for locally advanced cervical esophageal cancer from 2016 to 2021. This study retrospectively investigated outcomes, with comparison between NAC and dCRT for locally advanced cervical esophageal cancer. RESULTS Larynx preservation was successful for all the patients with NAC and dCRT. After NAC, the rate of complete or partial response was 78.4%, and 30 patients underwent larynx-preserving surgery. On the other hand, after dCRT, the complete response rate was 71.9%, and 4 patients underwent larynx-preserving salvage surgery. Overall survival (OS) and progression free survival were similar between the two groups. However, for the patients with resectable cervical esophageal cancer (cT1/2/3), the 2-year OS rate was significantly higher with NAC (79.9%) than with dCRT (56.8%) (P = 0.022), and the multivariate analyses identified only NAC and cN0, one of the two as a significantly independent factor associated with a better OS (NAC: P = 0.041; cN0, 1: P = 0.036). CONCLUSION The study showed that NAC as larynx-preserving surgery for resectable cervical esophageal cancer preserved function and had a better prognosis than dCRT. The authors suggest that NAC may be standard strategy for larynx preservation in patients with resectable cervical esophageal cancer.
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Affiliation(s)
- Yuto Kubo
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Ryoko Nozaki
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Shota Igaue
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Daichi Utsunomiya
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kentaro Kubo
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Shun Yamamoto
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Daisuke Kurita
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Tairo Kashihara
- Department of Radiation Oncology, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Koshiro Ishiyama
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshitaka Honma
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Junya Oguma
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroyuki Daiko
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan.
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Kubo Y, Igaue S, Utsunomiya D, Kubo K, Kurita D, Ishiyama K, Oguma J, Daiko H. Association between preoperative serum zinc level and prognosis in patients with advanced esophageal cancer in the neoadjuvant treatment era. Ann Gastroenterol Surg 2024; 8:595-603. [PMID: 38957556 PMCID: PMC11216781 DOI: 10.1002/ags3.12781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 07/04/2024] Open
Abstract
Background Zinc (Zn), an essential trace element, has an adverse influence on the prognosis of several cancers. However, the association between the preoperative serum Zn level and outcomes in patients with advanced esophageal cancer in the current neoadjuvant treatment era remains unclear. Methods This study involved 185 patients with esophageal cancer who underwent R0 surgery after neoadjuvant chemotherapy from August 2017 to February 2021. We retrospectively investigated the relationship between the preoperative serum Zn level and the patients' outcomes. Results The patients were divided into a low Zn group (<64 μg/dL) and a high Zn group (≤64 μg/dL) according to the mean preoperative serum Zn level. Low Zn had significantly worse overall survival (OS) (2-year OS rate: 76.2% vs. 83.3% in low vs. high Zn; p = 0.044). A low Zn in pathological non-responders (Grade ≤ 1a) was significantly associated with a shorter 2-year recurrence-free survival (RFS) rate (39.6% vs. 64.1% in low vs. high Zn; p = 0.032). The multivariate analysis identified low BMI and Zn level among preoperative nutritional status indices as an independent risk factor for worse RFS in non-responders. Compared with responders, pathological non-responders comprised significantly more males and a performance status of ≥1, and there was no difference in Zn level according to pathological response. Conclusion A preoperative low Zn level had a negative impact on early recurrence in esophageal cancer patients who underwent neoadjuvant chemotherapy. This suggests the need to administer Zn supplementation to patients with esophageal cancer who have preoperative Zn deficiency.
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Affiliation(s)
- Yuto Kubo
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Shota Igaue
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Daichi Utsunomiya
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Kentaro Kubo
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Daisuke Kurita
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Koshiro Ishiyama
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Junya Oguma
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
| | - Hiroyuki Daiko
- Department of Esophageal SurgeryNational Cancer Center HospitalTokyoJapan
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Sato Y, Tanaka Y, Yokoi R, Tsuchiya H, Sengoku Y, Fukada M, Yasufuku I, Asai R, Tajima JY, Kiyama S, Kato T, Murase K, Matsuhashi N. Oligometastases of Esophageal Squamous Cell Carcinoma: A Review. Cancers (Basel) 2024; 16:704. [PMID: 38398095 PMCID: PMC10886923 DOI: 10.3390/cancers16040704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Patients with oligometastases show distant relapse in only a limited number of regions. Local therapy such as surgical resection, radiotherapy, chemoradiotherapy, and radiofrequency ablation for the relapsed sites may thus improve patient survival. Oligometastases are divided into oligo-recurrence and sync-oligometastases. Oligo-recurrence indicates a primary lesion that is controlled, and sync-oligometastases indicate a primary lesion that is not controlled. The management of oligo-recurrence and sync-oligometastases in esophageal squamous cell carcinoma has not been clearly established, and treatment outcomes remain equivocal. We reviewed 14 articles, including three phase II trials, that were limited to squamous cell carcinoma. Multimodal treatment combining surgical resection and chemoradiotherapy for oligo-recurrence of esophageal squamous cell carcinoma appears to be a promising treatment. With the development of more effective chemotherapy and regimens that combine immune checkpoint inhibitors, it will become more likely that sync-oligometastases that were unresectable at the initial diagnosis can be brought to conversion surgery. Currently, a randomized, controlled phase III trial is being conducted in Japan to compare a strategy for performing definitive chemoradiotherapy and, if necessary, salvage surgery with a strategy for conversion surgery in patients who can be resected by induction chemotherapy.
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Affiliation(s)
- Yuta Sato
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Yoshihiro Tanaka
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Ryoma Yokoi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Hiroshi Tsuchiya
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Yuki Sengoku
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Masahiro Fukada
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Itaru Yasufuku
- Department of Clinical Anatomy Development Studies, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Ryuichi Asai
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Jesse Yu Tajima
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Shigeru Kiyama
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Takazumi Kato
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Katsutoshi Murase
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu City 501-1194, Gifu Prefecture, Japan
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9
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Wang J, Tong T, Zhang G, Jin C, Guo H, Liu X, Zhang Z, Li J, Zhao Y. Evaluation of neoadjuvant immunotherapy in resectable gastric/gastroesophageal junction tumors: a meta-analysis and systematic review. Front Immunol 2024; 15:1339757. [PMID: 38352873 PMCID: PMC10861722 DOI: 10.3389/fimmu.2024.1339757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 01/16/2024] [Indexed: 02/16/2024] Open
Abstract
Background Neoadjuvant therapy for resectable gastric cancer/gastroesophageal junction tumors is progressing slowly. Although immunotherapy for advanced gastric cancer/gastroesophageal junction tumors has made great progress, the efficacy and safety of neoadjuvant immunotherapy for locally resectable gastric cancer/gastroesophageal junction tumors have not been clearly demonstrated. Here, we conducted a systematic review and meta-analysis to assess the efficacy and safety of neoadjuvant immunotherapy and advance the current research. Methods Original articles describing the safety and efficacy of neoadjuvant immunotherapy for resectable gastric cancer/gastroesophageal junction tumors published up until October 15, 2023 were retrieved from PubMed, Embase, the Cochrane Library, and other major databases. The odds ratios (OR) and 95% confidence intervals (CIs) were calculated for heterogeneity and subgroup analysis. Results A total of 1074 patients from 33 studies were included. The effectiveness of neoadjuvant immunotherapy was mainly evaluated using pathological complete remission (PCR), major pathological remission (MPR), and tumor regression grade (TRG). Among the included patients, 1015 underwent surgical treatment and 847 achieved R0 resection. Of the patients treated with neoadjuvant immunotherapy, 24% (95% CI: 19%-28%) achieved PCR and 49% (95% CI: 38%-61%) achieved MPR. Safety was assessed by a surgical resection rate of 0.89 (95% CI: 85%-93%), incidence of ≥ 3 treatment-related adverse events (TRAEs) of 28% (95% CI: 17%-40%), and incidence of ≥ 3 immune-related adverse events (irAEs) of 19% (95% CI: 11%-27%). Conclusion Neoadjuvant immunotherapy, especially neoadjuvant dual-immunotherapy combinations, is effective and safe for resectable gastric/gastroesophageal junction tumors in the short term. Nevertheless, further multicenter randomized trials are required to demonstrate which combination model is more beneficial. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=358752, identifier CRD42022358752.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yinghao Zhao
- Department of Thoracic Surgery, Second Hospital of Jilin University, Changchun, China
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10
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Li C, Yu P, Li H, Yang X, Wang J, Jiang B. Study on the efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy regimen for III-IVA esophageal squamous cell carcinoma post-surgery. J Cardiothorac Surg 2024; 19:26. [PMID: 38273405 PMCID: PMC10811942 DOI: 10.1186/s13019-024-02500-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 01/14/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND AND AIMS The treatment of esophageal squamous cell carcinoma is still controversial, and neoadjuvant chemotherapy combined with immunotherapy is a hot topic of current research. We investigated the recent efficacy and surgical safety of patients with III-IVA esophageal squamous cell carcinoma after neoadjuvant regimen of paclitaxel + cisplatin/nedaplatin/carboplatin + sindilizumab, to provide a theoretical basis for evaluating the feasibility of surgery after neoadjuvant therapy. METHODS The clinical data of patients with stage III-IVA esophageal squamous cell carcinoma admitted from January 2022 to April 2023 at our hospital were collected for retrospective analysis. The patients were divided into the neoadjuvant combination surgery group (34 patients with the regimen of paclitaxel + cisplatin/nedaplatin/carboplatin + sintilimab two/three cycles of preoperative neoadjuvant therapy) and surgery-only group (36 patients). Statistical analysis was performed to compare the differences between both groups particularly for intraoperative bleeding, operative time, incidence of postoperative pulmonary complications, laryngeal recurrent nerve injury, thoracic duct injury, anastomotic fistula, and postoperative hospital days. Additionally, the pCR/MPR rates of the neoadjuvant group were analysed. RESULTS Significant differences were present in the clinical and pathological staging before and after neoadjuvant treatment (P ≤ 0.001). The neoadjuvant group had a pCR rate of 26.47% and an ORR rate of 88.23%. No significant differences were discovered in R0 resection rate between both groups, as well as intraoperative bleeding, operative time, intraoperative laryngeal recurrent nerve injury rate, thoracic duct injury rate, postoperative anastomosis incidence, postoperative hospital days, and postoperative lung infection incidence (P > 0.05). CONCLUSIONS The neoadjuvant immune combination chemotherapy regimen had considerable tumor regression and pathological remission benefits, without reducing the safety of surgery, possibly presenting as a new treatment plan.
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Affiliation(s)
- Chunyang Li
- Department of Thoracic Surgery, The First People's Hospital of Chang-Zhou City, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Jiangsu, 213003, China
| | - Pengyi Yu
- Department of Thoracic Surgery, The First People's Hospital of Chang-Zhou City, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Jiangsu, 213003, China
| | - Hong Li
- Department of Thoracic Surgery, The First People's Hospital of Chang-Zhou City, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Jiangsu, 213003, China
| | - Xin Yang
- Department of Oncology, The First People's Hospital of Chang-Zhou City, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Jiangsu, 213003, China
| | - Jun Wang
- Department of Thoracic Surgery, The First People's Hospital of Chang-Zhou City, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Jiangsu, 213003, China
| | - Bo Jiang
- Department of Thoracic Surgery, The First People's Hospital of Chang-Zhou City, The Third Affiliated Hospital of Soochow University, 185 Juqian Road, Jiangsu, 213003, China.
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11
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Wang FM, Mo P, Yan X, Lin XY, Fu ZC. Present situation and prospect of immunotherapy for unresectable locally advanced esophageal cancer during peri-radiotherapy. World J Gastrointest Oncol 2024; 16:1-7. [PMID: 38292836 PMCID: PMC10824118 DOI: 10.4251/wjgo.v16.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/14/2023] [Accepted: 12/06/2023] [Indexed: 01/11/2024] Open
Abstract
Four major studies (Checkmate577, Keynote-590, Checkmate649 and Attraction-4) of locally advanced esophageal cancer published in 2020 have established the importance of immunotherapy, represented by anti-programmed death protein (PD)-1 in postoperative adjuvant treatment and advanced first-line treatment of locally advanced or advanced esophageal cancer and esophagogastric junction cancer, from the aspects of proof of concept, long-term survival, overall survival rate and progression-free survival. For unresectable or inoperable nonmetastatic esophageal cancer, concurrent radiotherapy and chemotherapy is the standard treatment recommended by various guidelines. Because its curative effect is still not ideal, it is necessary to explore radical radiotherapy and chemotherapy in the future, and it is considered to be promising to combine them with immunotherapeutic drugs such as anti-PD-1. This paper mainly discusses how to combine radical concurrent radiotherapy and chemotherapy with immunotherapy for unresectable local advanced esophageal cancer.
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Affiliation(s)
- Feng-Mei Wang
- Department of Obstetrics and Gynecology, Fuzong Clinical Medical College (900th Hospital), Fujian Medical University, Fuzhou 350025, Fujian Province, China
- Department of Obstetrics and Gynecology, Dongfang Hospital, Xiamen University, Fuzhou 350025, Fujian Province, China
| | - Peng Mo
- Department of Radiotherapy, Fuzong Clinical Medical College (900th Hospital), Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Xue Yan
- Department of Radiotherapy, Fuzong Clinical Medical College (900th Hospital), Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Xin-Yue Lin
- Department of Radiotherapy, Fuzong Clinical Medical College (900th Hospital), Fujian Medical University, Fuzhou 350025, Fujian Province, China
| | - Zhi-Chao Fu
- Department of Radiotherapy, Fuzong Clinical Medical College (900th Hospital), Fujian Medical University, Fuzhou 350025, Fujian Province, China
- Department of Radiotherapy, Dongfang Hospital, Xiamen University, Fuzhou 350025, Fujian Province, China
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12
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Wang HC, Huang X, Chen J, Li Y, Cong Y, Qu BL, Feng SQ, Liu F. Long-term efficacy and predictors of pembrolizumab-based regimens in patients with advanced esophageal cancer in the real world. World J Gastroenterol 2023; 29:5641-5656. [PMID: 38077159 PMCID: PMC10701330 DOI: 10.3748/wjg.v29.i41.5641] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/07/2023] [Accepted: 10/23/2023] [Indexed: 11/07/2023] Open
Abstract
BACKGROUND Pembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease. AIM To analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the real world. METHODS Patients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study. Clinical staging of the patients was based on the 8th edition of the American Joint Committee on Cancer TNM staging system. The patients received different treatments based on clinical stage. In brief, patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery. For those who were not candidates for resection, radical concurrent chemoradiotherapy plus pembrolizumab was more preferable. Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab. Long-term survival outcomes such as overall survival (OS), progression-free survival, disease-free survival, long-term adverse effects (AEs), immune maintenance therapy and predictors of immune checkpoint inhibitors (ICIs) efficacy were evaluated. RESULTS A total of 55 patients with advanced ESCC were enrolled in this retrospective, observational study. The median age was 61 years (range 44-74), with 47.3% (26/55) of the patients in stage IV and 45.5% of the patients had the tumor (25/55) located in the middle third of the esophagus. The median OS in all patients was not reached. The 12-mo OS rate among all patients was 78.8% and the 18-mo OS rate was 72.7%. 9 patients died due to tumor progression and 7 patients died due to treatment-related complications. The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome. Patients with complete response or partial response in all patients (P = 0.005) and in the chemoradiotherapy plus pembrolizumab group (P = 0.007) obtained a better prognosis than non-responders. A total of 20 patients (20/55, 36%) received immune maintenance therapy. Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-to-(leukocyte-neutrophil) ratio did not predict the efficacy of ICIs. CONCLUSION Pembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC, with safe and manageable long-term AEs.
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Affiliation(s)
- Hong-Chi Wang
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Xiang Huang
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Jing Chen
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Ye Li
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Yang Cong
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Bao-Lin Qu
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
| | - Sheng-Qiang Feng
- Health Service, The Guard Bureau of Joint Staff Department of Chinese PLA, Beijing 100017, China
| | - Fang Liu
- Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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13
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Liu Y. Perioperative immunotherapy for esophageal squamous cell carcinoma: Now and future. World J Gastroenterol 2023; 29:5020-5037. [PMID: 37753366 PMCID: PMC10518742 DOI: 10.3748/wjg.v29.i34.5020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 07/19/2023] [Accepted: 08/15/2023] [Indexed: 09/08/2023] Open
Abstract
Esophageal cancer (EC) ranks among the most prevalent malignant tumors affecting the digestive tract. Esophageal squamous cell carcinoma (ESCC) stands as the prevailing pathological subtype, encompassing approximately 90% of all EC patients. In clinical stage II-IVA locally advanced ESCC cases, the primary approach to treatment involves a combination of neoadjuvant therapy and surgical resection. Despite concerted efforts, the long-term outcomes for ESCC patients remain unsatisfactory, with dismal prognoses. However, recent years have witnessed remarkable strides in immunotherapy, particularly in the second- and first-line treatment of advanced or metastatic ESCC, with the development of monoclonal antibodies that inhibit programmed death 1 or programmed death ligand 1 demonstrating encouraging responses and perioperative clinical benefits for various malignancies, including ESCC. This comprehensive review aims to present the current landscape of perioperative immunotherapy for resectable ESCC, focusing specifically on the role of immune checkpoint inhibitors during the perioperative period. Additionally, the review will explore promising biomarkers and offer insights into future prospects.
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Affiliation(s)
- Yong Liu
- Department of Thoracic Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430011, Hubei Province, China
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14
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Yang W, Niu Y, Sun Y. Current neoadjuvant therapy for operable locally advanced esophageal cancer. Med Oncol 2023; 40:252. [PMID: 37498350 DOI: 10.1007/s12032-023-02097-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/19/2023] [Indexed: 07/28/2023]
Abstract
Locally advanced esophageal cancer has a poor prognosis, while an increasing number of patients are diagnosed with that. Neoadjuvant therapy has become a hot topic in treating locally advanced esophageal cancer to improve its survival benefit. The efficacy of neoadjuvant therapy followed by surgery has been confirmed by many studies, and neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy are included in the guidelines. In recent years, targeted therapy and immunotherapy have emerged, and more studies are evaluating the efficacy of combining them with neoadjuvant therapy for operable esophageal cancer patients. Even though the preliminary data is disappointing, many trials are still under investigation without improving survival benefits. New indexes used as surrogate endpoints (e.g., major pathologic response and pathological complete response) are emerging to accelerate the development and approval of neoadjuvant drugs. This review summarized the research progress in neoadjuvant therapy for locally advanced esophageal cancer and discussed which primary endpoint should be used in neoadjuvant therapy trials.
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Affiliation(s)
- Wenwei Yang
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yaru Niu
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yongkun Sun
- National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
- National Cancer Center, National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, 065001, China.
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15
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Matsuda S, Kitagawa Y, Takemura R, Okui J, Okamura A, Kawakubo H, Muto M, Kakeji Y, Takeuchi H, Watanabe M, Doki Y. 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. Ann Surg 2023; 278:e35-e42. [PMID: 35837977 DOI: 10.1097/sla.0000000000005533] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE 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. BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Satoru Matsuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Ryo Takemura
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Jun Okui
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Akihiko Okamura
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Manabu Muto
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto Prefecture, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo Prefecture, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka Prefecture, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka Prefecture, Japan
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Liu J, Chen H, Qiao G, Zhang JT, Zhang S, Zhu C, Chen Y, Tang J, Li W, Wang S, Tian H, Chen Z, Ma D, Tian J, Wu YL. PLEK2 and IFI6, representing mesenchymal and immune-suppressive microenvironment, predicts resistance to neoadjuvant immunotherapy in esophageal squamous cell carcinoma. Cancer Immunol Immunother 2023; 72:881-893. [PMID: 36121452 PMCID: PMC10992089 DOI: 10.1007/s00262-022-03288-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/29/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Immunotherapy has largely improved clinical outcome of patients with esophageal squamous cell carcinoma (ESCC). However, a proportion of patients still fail to benefit. Thus, biomarkers predicting therapeutic resistance and underlying mechanism needs to be investigated. METHODS Transcriptomic profiling was applied in FFPE tissues from 103 ESCC patients, including surgical samples from 66 treatment-naïve patients with long-term follow-up, and endoscopic biopsies from 37 local advanced ESCC cases receiving neoadjuvant immunotherapy plus chemotherapy. Unsupervised clustering indicated an aggressive phenotype with mesenchymal character in 66 treatment-naïve samples. Univariant logistic regression was applied to identify candidate biomarkers potentially predicted resistance to neoadjuvant immunotherapy within the range of mesenchymal phenotype enriched genes. These biomarkers were further validated by immunohistochemistry. Putative mechanisms mediating immunotherapy resistance, as indicated by microenvironment and immune cell infiltration, were evaluated by transcriptomic data, and validated by multiplex immunofluorescence. RESULTS PLEK2 and IFI6, highly expressed in mesenchymal phenotype, were identified as novel biomarkers relating to non-MPR in neoadjuvant immunotherapy cohort [PLEK2high, OR (95% CI): 2.15 (1.07-4.33), P = 0.032; IFI6high, OR (95% CI): 2.21 (1.16-4.23), P = 0.016). PLEK2high and IFI6 high ESCC patients (versus low expressed patients) further exhibit higher chance of non-major pathological remissions (90%, P = 0.004) in neoadjuvant immunotherapy cohort and high mortality (78.9%, P = 0.05), poor prognosis in retrospective cohort. PLEK2high/IFI6high ESCC recapitulated mesenchymal phenotype, characterized by extracellular matrix composition and matrix remodeling. In addition, PLEK2high or IFI6high ESCC displayed an immune-unfavored microenvironment, represented by positive correlating with regulatory T cells, Helper 2 T cell as well as less infiltration of B cells, effector T cells and mast cells. CONCLUSIONS PLEK2 and IFI6 was discovered of first time to identify a distinct ESCC subpopulation cannot be benefited from neoadjuvant immunotherapy and present a poor survival, which putatively associated with mesenchymal and immune-suppressive microenvironment.
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Affiliation(s)
- Jianhua Liu
- The Second School of Clinical Medicine, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, China
- Department of Oncology, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.123 Huifu Road West, Guangzhou, 510180, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Guibin Qiao
- Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Jia-Tao Zhang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Shuaitong Zhang
- School of Engineering Medicine, Beihang University, No.37 Xueyuan Road, Haidian District, Beijing, 100191, China
- CAS Key Laboratory of Molecular Imaging, Institute of Automation,, Chinese Academy of Sciences, Beijing, 100190, China
| | - Changbin Zhu
- Department of Translational Medicine, Amoy Diagnostics Co., Ltd, Xiamen, 361027, China
| | - Yu Chen
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Jiming Tang
- Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Weiwei Li
- Department of Translational Medicine, Amoy Diagnostics Co., Ltd, Xiamen, 361027, China
| | - Siyun Wang
- Department of PET Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Hongxia Tian
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Zhihong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Dong Ma
- Department of Oncology, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, No.123 Huifu Road West, Guangzhou, 510180, China.
| | - Jie Tian
- School of Engineering Medicine, Beihang University, No.37 Xueyuan Road, Haidian District, Beijing, 100191, China.
- CAS Key Laboratory of Molecular Imaging, Institute of Automation,, Chinese Academy of Sciences, Beijing, 100190, China.
| | - Yi-Long Wu
- The Second School of Clinical Medicine, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, China.
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
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17
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Li Y, Zhou A, Liu S, He M, Chen K, Tian Z, Li Y, Qin J, Wang Z, Chen H, Tian H, Yu Y, Qu W, Xue L, He S, Wang S, Bie F, Bai G, Zhou B, Yang Z, Huang H, Fang Y, Li B, Dai X, Gao S, He J. Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial : A randomized clinical trial of neoadjuvant therapy for ESCC. BMC Med 2023; 21:86. [PMID: 36882775 PMCID: PMC9993718 DOI: 10.1186/s12916-023-02804-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/22/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND A Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS Sixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety. RESULTS A total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1-84.0% vs. 42.4-78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1-60.9% vs. 13.5-47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature. CONCLUSIONS The neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates. TRIAL REGISTRATION Registration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. REGISTRATION NUMBER NCT04460066.
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Affiliation(s)
- Yong Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shuoyan Liu
- Fujian Provincial Cancer Hospital, Fujian, China
| | - Ming He
- The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Keneng Chen
- Peking University Cancer Hospital, Beijing, China
| | - Ziqiang Tian
- The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Yin Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Jianjun Qin
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Zhen Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Haiquan Chen
- Fudan University Cancer Hospital, Shanghai, China
| | - Hui Tian
- Qilu Hospital of Shandong University, Shandong, China
| | - Yue Yu
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wang Qu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shun He
- Department of Endoscopy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shuhang Wang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fenglong Bie
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Guangyu Bai
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Bolun Zhou
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
| | - Zhaoyang Yang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Huiyao Huang
- Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yan Fang
- PET-CT Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Benjamin Li
- Lee's Pharmaceutical Limited, Shenzhen, China
| | | | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, NO. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, China
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Impact of Perineural Invasion and Preexisting Type 2 Diabetes on Patients with Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Chemoradiotherapy. Cancers (Basel) 2023; 15:cancers15041122. [PMID: 36831461 PMCID: PMC9954405 DOI: 10.3390/cancers15041122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/04/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the cornerstone treatment strategy in locally advanced esophageal squamous cell carcinoma (ESCC). Despite this high- intensity multimodality therapy, most patients still experience recurrences and metastases, especially those who do not achieve a pathological complete response (pCR) after neoCRT. Here, we focused on identifying poor prognostic factors. In this retrospective cohort study; we enrolled 140 patients who completed neoCRT plus surgery treatment sequence with no interval metastasis. Overall, 45 of 140 patients (32.1%) achieved a pCR. The overall survival, disease-free survival (DFS), and metastasis-free survival was significantly better in patients with a pCR than in patients with a non-pCR. In the non-pCR subgroup, the presence of perineural invasion (PNI) and preexisting type 2 diabetes (T2DM) were two factors adversely affecting DFS. After adjusting for other factors, multivariate analysis showed that the hazard ratio (HR) was 2.354 (95% confidence interval [CI] 1.240-4.467, p = 0.009) for the presence of PNI and 2.368 (95% CI 1.351-4.150, p = 0.003) for preexisting T2DM. Patients with a combination of both factors had the worst survival. In conclusion, PNI and preexisting T2DM may adversely affect the prognosis of patients with ESCC receiving neoadjuvant chemoradiotherapy.
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Umeki Y, Matsuoka H, Fujita M, Goto A, Serizawa A, Nakamura K, Akimoto S, Nakauchi M, Tanaka T, Shibasaki S, Inaba K, Uyama I, Suda K. Docetaxel+Cisplatin+5-FU (DCF) Therapy as a Preoperative Chemotherapy to Advanced Esophageal Squamous Cell Carcinoma: A Single-center Retrospective Cohort Study. Intern Med 2023; 62:319-325. [PMID: 36725064 PMCID: PMC9970804 DOI: 10.2169/internalmedicine.9751-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/22/2022] [Indexed: 02/03/2023] Open
Abstract
Objective The aim of this study was to determine the safety and clinical efficacy of docetaxel+cisplatin+5-fluorouracil (DCF) as neoadjuvant chemotherapy (NAC). Methods In this single-center study, patient background and treatment outcomes (NAC efficacy assessment, NAC adverse events, short-term postoperative outcomes, and one-year postoperative outcomes) in patients treated with preoperative DCF and preoperative cisplatin+5-FU (CF) were compared retrospectively. Patients Seventeen patients diagnosed with esophageal squamous cell carcinoma (ESCC) and treated with preoperative DCF therapy and 50 patients treated with preoperative CF therapy between January 2013 and July 2019 were included in this study. Results There were significant differences in clinical T factor and clinical stage between the CF and DCF groups (p<0.05). All patients in the DCF therapy group were above clinical T3 and clinical stage III. The clinical response after NAC was partial response (PR) for 23 patients (46.0%) in the CF group and 13 patients (76.5%) in the DCF group (p=0.030). Regarding adverse events in NAC, neutropenia, febrile neutropenia (FN), diarrhea, and stomatitis were observed more frequently in the DCF group than in the CF group (p<0.05). The postoperative results [overall survival (OS), recurrence-free survival (RFS), one-year OS, one-year RFS] of the DCF group were comparable to those of the CF group. Conclusion DCF therapy has been recognized as an effective treatment option for advanced ESCC. However, the indication for DCF therapy should be chosen carefully because of the high incidence of adverse events.
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Affiliation(s)
- Yusuke Umeki
- Department of Surgery, Fujita Health University, Japan
| | | | | | - Ai Goto
- Department of Surgery, Fujita Health University, Japan
| | | | | | | | - Masaya Nakauchi
- Department of Advanced Robotic and Endoscopic Surgery, Fujita Health University, Japan
| | - Tsuyoshi Tanaka
- Collaborative Laboratory for Research and Development in Advanced Surgical Technology, Fujita Health University, Japan
| | | | - Kazuki Inaba
- Department of Advanced Robotic and Endoscopic Surgery, Fujita Health University, Japan
| | - Ichiro Uyama
- Department of Advanced Robotic and Endoscopic Surgery, Fujita Health University, Japan
- Collaborative Laboratory for Research and Development in Advanced Surgical Technology, Fujita Health University, Japan
| | - Koichi Suda
- Department of Surgery, Fujita Health University, Japan
- Collaborative Laboratory for Research and Development in Advanced Surgical Intelligence, Fujita Health University, Japan
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20
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Testa U, Castelli G, Pelosi E. The Molecular Characterization of Genetic Abnormalities in Esophageal Squamous Cell Carcinoma May Foster the Development of Targeted Therapies. Curr Oncol 2023; 30:610-640. [PMID: 36661697 PMCID: PMC9858483 DOI: 10.3390/curroncol30010048] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/24/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Esophageal cancer is among the most common tumors in the world and is associated with poor outcomes, with a 5-year survival rate of about 10-20%. Two main histological subtypes are observed: esophageal squamous cell carcinoma (ESCC), more frequent among Asian populations, and esophageal adenocarcinoma (EAC), the predominant type in Western populations. The development of molecular analysis techniques has led to the definition of the molecular alterations observed in ESCC, consistently differing from those observed in EAC. The genetic alterations observed are complex and heterogeneous and involve gene mutations, gene deletions and gene amplifications. However, despite the consistent progress in the definition of the molecular basis of ESCC, precision oncology for these patients is still virtually absent. The recent identification of molecular subtypes of ESCC with clinical relevance may foster the development of new therapeutic strategies. It is estimated that about 40% of the genetic alterations observed in ESCC are actionable. Furthermore, the recent introduction of solid tumor immunotherapy with immune checkpoint inhibitors (ICIs) showed that a minority of ESCC patients are responsive, and the administration of ICIs, in combination with standard chemotherapy, significantly improves overall survival over chemotherapy in ESCC patients with advanced disease.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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21
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Kim Y, Yamamoto S, Kato K. Profile of Nivolumab in the Treatment of Resected Esophageal Squamous Cell Carcinoma: A Review of the Clinical Data. Cancer Manag Res 2023; 15:399-406. [PMID: 37197006 PMCID: PMC10183349 DOI: 10.2147/cmar.s390499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/04/2023] [Indexed: 05/19/2023] Open
Abstract
Esophageal cancer (EC) is the seventh most common malignancy globally. There are two main histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC is the predominant histological type of esophageal cancer worldwide and has worse prognosis than esophageal adenocarcinoma. However, effective treatment for patients with ESCC remains limited. Moreover, the risk of recurrence remains high in patients with resectable ESCC even with perioperative multidisciplinary treatment, such as chemoradiotherapy or chemotherapy. Nivolumab, a human monoclonal immunoglobulin G4 antibody that inhibits programmed cell death protein 1, has recently been identified as a potential treatment for patients with metastatic esophageal cancer based on the results of the ATTRACTION-3 and CheckMate 648 trials. The CheckMate 577 trial showed survival benefits of postoperative nivolumab monotherapy compared with placebo in patients with resectable locally advanced esophageal cancer who did not achieve a pathological complete response after preoperative chemoradiotherapy. In this review, we discuss the data on the efficacy and safety of postoperative nivolumab and share future perspectives on immune checkpoint inhibitors as perioperative therapy for patients with locally advanced ESCC.
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Affiliation(s)
- Yuntae Kim
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
- Department of Gastroenterology, St. Luke International Hospital, Tokyo, Japan
| | - Shun Yamamoto
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
- Correspondence: Ken Kato, Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan, Tel +81-3-3542-2511, Fax +81-3-3542-3815, Email
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22
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Nagata Y, Yamamoto S, Kato K. Immune checkpoint inhibitors in esophageal cancer: Clinical development and perspectives. Hum Vaccin Immunother 2022; 18:2143177. [PMID: 36375821 PMCID: PMC9746438 DOI: 10.1080/21645515.2022.2143177] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/11/2022] [Accepted: 10/31/2022] [Indexed: 11/16/2022] Open
Abstract
Esophageal cancer is the sixth most common cause of cancer-related mortality worldwide. The standard treatment for unresectable esophageal cancer is systemic chemotherapy. However, the survival benefit is limited, with a median overall survival of less than 10 months. The advent of immune checkpoint inhibitors (ICIs), including programmed cell death-1 antibodies, has revolutionized the treatment paradigm for esophageal cancer. Since demonstrating promising efficacy with manageable safety in several clinical trials, ICIs has finally reached the point where they can be used in various tumor stages in the clinical setting. ICIs are most promising treatments that can be expected to improve the prognosis in patients with esophageal cancer now and in the future. This review outlines the mechanisms, results of clinical trials, and prospects for future studies of ICIs in esophageal cancer. It also discusses clinical questions and challenges in the therapeutic development of ICIs.
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Affiliation(s)
- Yusuke Nagata
- Department of Gastroenterology, Nagano Municipal Hospital, Nagano, Japan
| | - Shun Yamamoto
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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Liu M, Yan W, Chen D, Luo J, Dai L, Chen H, Chen KN. IGFBP1 hiWNT3A lo Subtype in Esophageal Cancer Predicts Response and Prolonged Survival with PD-(L)1 Inhibitor. BIOLOGY 2022; 11:biology11111575. [PMID: 36358276 PMCID: PMC9687176 DOI: 10.3390/biology11111575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/19/2022] [Accepted: 10/21/2022] [Indexed: 01/25/2023]
Abstract
PD-(L)1 inhibitor could improve the survival of locally advanced esophageal cancer (ESCA) patients, but we cannot tailor the treatment to common biomarkers. WNT signaling activation was associated with primary resistance to immunotherapy. In this study, we used our two clinical cohorts (BJCH n = 95, BJIM n = 21) and three public cohorts to evaluate and verify a new immunotherapeutic biomarker based on WNT signaling in ESCA patients. Our findings showed that WNT signaling-related genes stratified TCGA patients into Cluster 1, 2, and 3, among which, Cluster 3 had the worst prognosis. The most up- and down-regulated genes in Cluster 3 were IGFBP1 and WNT3A. Further analysis validated that IGFBP1hiWNT3Alo ESCA patients had significantly poor RFS and OS in the TCGA and BJCH cohorts. Interestingly, IGFBP1hiWNT3Alo patients had a good response and prognosis with immunotherapy in three independent cohorts, exhibiting better predictive value than PD-L1 expression (signature AUC = 0.750; PD-L1 AUC = 0.571). Moreover, IGFBP1hiWNT3Alo patients may benefit more from immunotherapy than standard treatment (p = 0.026). Immune cell infiltration analysis revealed a significant increase in DC infiltration in IGFBP1hiWNT3Alo patients post-immunotherapy (p = 0.022), which may enhance immune response. The IGFBP1hiWNT3Alo signature could predict patients who benefited from PD-(L)1 inhibitor treatment and may serve as a biomarker in ESCA.
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Affiliation(s)
- Meichen Liu
- Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
| | - Wanpu Yan
- Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
| | - Dongbo Chen
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China
| | - Jiancheng Luo
- Aiyi Technology Co., Ltd., Room 1004, Building 3, Greenland Qihang, Biomedical Industry Base, Daxing District, Beijing 102629, China
| | - Liang Dai
- Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
| | - Hongsong Chen
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China
- Correspondence: (H.C.); (K.-N.C.)
| | - Ke-Neng Chen
- Department of Thoracic Surgery I, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China
- Correspondence: (H.C.); (K.-N.C.)
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Recent Advances in Combination of Immunotherapy and Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14205168. [PMID: 36291954 PMCID: PMC9599968 DOI: 10.3390/cancers14205168] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 12/02/2022] Open
Abstract
Simple Summary Neoadjuvant chemoradiotherapy (CRT), followed by surgery or definitive CRT, is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC); however, the clinical outcomes remain unsatisfactory. Immunotherapy combined with CRT is currently being investigated as a novel treatment option for locally advanced ESCC. In this review, we discuss the theoretical background and status of immunotherapy for locally advanced ESCC and potential biomarkers for predicting tumor response and prognosis. Abstract Esophageal cancer has a high mortality rate and a poor prognosis, with more than one-third of patients receiving a diagnosis of locally advanced cancer. Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophageal cancer in Asia and Eastern Europe. Although neoadjuvant or definitive chemoradiotherapy (CRT) has been the standard treatment for locally advanced ESCC, patient outcomes remain unsatisfactory, with recurrence rates as high as 30–50%. The combination of immune checkpoint inhibitors (ICIs) and CRT has emerged as a novel strategy to treat esophageal cancer, and it may have a synergistic action and provide greater efficacy. In the phase III CheckMate-577 trial, one year of adjuvant nivolumab after neoadjuvant CRT improved disease-free survival in patients with residual disease on pathology. Moreover, several phase I and II studies have shown that ICIs combined with concurrent CRT may increase the rate of pathologic complete response for resectable ESCC, but they lack long-term follow-up results. In unresectable cases, the combination of camrelizumab and definitive CRT showed promising results against ESCC in a phase Ib trial. Phase III randomized trials are currently ongoing to investigate the survival benefits of ICIs combined with neoadjuvant or definitive CRT, and they will clarify the role of immunotherapy in locally advanced ESCC. Additionally, valid biomarkers to predict tumor response and survival outcomes need to be further explored.
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25
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Wang J, Zhang K, Liu T, Song Y, Hua P, Chen S, Li J, Liu Y, Zhao Y. Efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy in locally advanced esophageal cancer: A meta-analysis. Front Oncol 2022; 12:974684. [PMID: 36158679 PMCID: PMC9495441 DOI: 10.3389/fonc.2022.974684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/11/2022] [Indexed: 12/24/2022] Open
Abstract
ObjectiveThe progress of neoadjuvant therapy for resectable locally advanced esophageal cancer has been stagnant. There has been much progress in immunotherapy for advanced esophageal cancer, but the efficacy and safety of neoadjuvant immunotherapy for resectable locally advanced esophageal cancer have not yet been definitively demonstrated.MethodsOriginal articles describing the safety and efficacy of neoadjuvant immunotherapy in resectable locally advanced esophagus published until July 2022 were retrieved from PubMed, Embase, and the Cochrane Library. The ratio (OR) and 95% confidence interval (CI) were calculated to conduct heterogeneity and subgroup analysis.ResultsIn total, 759 patients from 21 studies were enrolled. The effectiveness of neoadjuvant immunotherapy in combination with chemotherapy was evaluated using the major pathologic response (MPR) and pathologic complete response (PCR). In the enrolled patients, 677 were treated surgically and 664 achieved R0 resection. Major pathological remission was achieved in 52.0% (95% CI: 0.44–0.57) of patients on neoadjuvant immunotherapy combined with chemotherapy and complete pathological remission in 29.5% (95% CI: 0.25–0.32) of patients. The safety was primarily assessed by the incidence of treatment-related adverse events (TRAEs) and surgical resection rates. The incidence of TRAEs and the surgical resection rate combined ORs were 0.15 (95% CI: 0.09–0.22) and 0.86 (95% CI: 0.83–0.89), respectively.ConclusionNeoadjuvant immunotherapy combined with chemotherapy in locally advanced resectable esophageal cancer is effective and safe.
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Affiliation(s)
- Jincheng Wang
- Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Kun Zhang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, China
| | - Tianzhou Liu
- Department of the Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Ying Song
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Peiyan Hua
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Shu Chen
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Jindong Li
- Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yang Liu
- Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yinghao Zhao
- Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Yinghao Zhao,
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26
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Kadono T, Yamamoto S, Kato K. Current perspectives of the Japanese Esophageal Oncology Group on the development of immunotherapy for esophageal cancer. Jpn J Clin Oncol 2022; 52:1089-1096. [PMID: 36047845 PMCID: PMC9538995 DOI: 10.1093/jjco/hyac138] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 08/03/2022] [Indexed: 12/24/2022] Open
Abstract
Esophageal cancer is the seventh most common cancer worldwide and continues to have a poor prognosis. Starting with the development of immune checkpoint inhibitors for patients with metastatic melanoma, many clinical trials have been conducted to evaluate the efficacy and safety of immune checkpoint inhibitors against various malignancies. Although few effective drugs are available for patients with advanced esophageal cancer, two immune checkpoint inhibitors, nivolumab and pembrolizumab, have been approved as second-line treatments for advanced esophageal squamous cell carcinoma. Recently, immune checkpoint inhibitors have shown promising results as post-operative therapies and first-line treatments for advanced esophageal cancer. Nivolumab has been approved as a post-operative therapy based on the CheckMate-577 trial, and nivolumab, ipilimumab and pembrolizumab have been approved as first-line treatments based on the CheckMate-648 trial and the KEYNOTE-590 trial. In addition, many trials of immune checkpoint inhibitors plus pre-operative treatment or definitive chemoradiotherapy are ongoing. The Japan Esophageal Oncology Group was established in 1978 and has conducted numerous clinical trials, most of which have examined multimodality treatments. In the era of immunotherapy, Japan Esophageal Oncology Group is conducting a clinical trial studying multimodality treatment with an immune checkpoint inhibitor. JCOG1804E (FRONTiER) is a phase I trial to evaluate the safety and efficacy of nivolumab plus pre-operative chemotherapy followed by surgery. These results might improve the clinical outcomes of esophageal cancer patients.
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Affiliation(s)
- Toru Kadono
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shun Yamamoto
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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27
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Tustumi F, Agareno GA, Galletti RP, da Silva RBR, Quintas JG, Sesconetto LDA, Szor DJ, Wolosker N. The Role of the Heat-Shock Proteins in Esophagogastric Cancer. Cells 2022; 11:2664. [PMID: 36078072 PMCID: PMC9454628 DOI: 10.3390/cells11172664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 01/05/2023] Open
Abstract
Heat-shock proteins (HSPs) are a family of proteins that have received considerable attention over the last several years. They have been classified into six prominent families: high-molecular-mass HSP, 90, 70, 60, 40, and small heat shock proteins. HSPs participate in protein folding, stability, and maturation of several proteins during stress, such as in heat, oxidative stress, fever, and inflammation. Due to the immunogenic host's role in the combat against cancer cells and the role of the inflammation in the cancer control or progression, abnormal expression of these proteins has been associated with many types of cancer, including esophagogastric cancer. This study aims to review all the evidence concerning the role of HSPs in the pathogenesis and prognosis of esophagogastric cancer and their potential role in future treatment options. This narrative review gathers scientific evidence concerning HSPs in relation to esophagus and gastric cancer. All esophagogastric cancer subtypes are included. The role of HSPs in carcinogenesis, prognostication, and therapy for esophagogastric cancer are discussed. The main topics covered are premalignant conditions for gastric cancer atrophic gastritis, Barrett esophagus, and some viral infections such as human papillomavirus (HPV) and Epstein-Barr virus (EBV). HSPs represent new perspectives on the development, prognostication, and treatment of esophagogastric cancer.
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Affiliation(s)
- Francisco Tustumi
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 255, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Gabriel Andrade Agareno
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Ricardo Purchio Galletti
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Rafael Benjamim Rosa da Silva
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Julia Grams Quintas
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Lucas de Abreu Sesconetto
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Daniel José Szor
- Department of Gastroenterology, Universidade de São Paulo, Av. Dr. Enéas Carvalho de Aguiar, 255, São Paulo 05403-000, SP, Brazil
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
| | - Nelson Wolosker
- Department of Surgery, Hospital Israelita Albert Einstein, Av. Albert Einstein, 627, São Paulo 05652-900, SP, Brazil
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Matsuda S, Kawakubo H, Okamura A, Takahashi K, Toihata T, Takemura R, Mayanagi S, Hirata K, Irino T, Hamamoto Y, Takeuchi H, Facs, Watanabe M, Kitagawa Y. Distribution of Residual Disease and Recurrence Patterns in Pathological Responders After Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma. Ann Surg 2022; 276:298-304. [PMID: 33074909 DOI: 10.1097/sla.0000000000004436] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE This study aimed to elucidate the residual disease distribution and recurrence patterns in patients with ESCC responding to NAC. SUMMARY BACKGROUND DATA To appropriately plan a prospective trial for the organ preservation approach which includes additional chemoradiotherapy in patients who responded to NAC, the distribution of residual disease needs to be elucidated. Given that the residual tumor is located in the regional field, chemoradiotherapy can be safely added to eliminate the residual disease. METHODS Overall, 483 patients with resectable ESCC who received NAC followed by transthoracic esophagectomy at 2 high-volume centers were reviewed. The recurrence-free survival, overall survival (OS), and residual and recurrent tumor patterns were compared among the pathological responses. RESULTS Compared with nonpathological responders, pathological responders exhibited significantly longer recurrence-free survival [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.25 ( P < 0.001)/0.17 ( P < 0.001)/0.16 ( P = 0.003)] and OS [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.26 ( P < 0.001)/0.12 ( P < 0.001)/0.11 ( P = 0.003)]. In terms of the distribution of recurrence, the percentages of solitary recurrence in the regional field out of all recurrence was significantly higher in patients with Grade 1b (60%)/2 (67%)/3 (67%) whereas less than 25% in Grade 0 or 1a. CONCLUSIONS It was found that postoperative recurrence in responders occurred in the regional field mostly as a solitary lesion without the distant failure, indicating that the residual tumor cells can be eliminated by additional chemoradiotherapy.
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Affiliation(s)
- Satoru Matsuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Akihiko Okamura
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Keita Takahashi
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tasuku Toihata
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ryo Takemura
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan
| | - Shuhei Mayanagi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Kenro Hirata
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tomoyuki Irino
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yasuo Hamamoto
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Facs
- Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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Kovács SA, Győrffy B. Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review. J Transl Med 2022; 20:249. [PMID: 35641998 PMCID: PMC9153191 DOI: 10.1186/s12967-022-03409-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/24/2022] [Indexed: 12/12/2022] Open
Abstract
The availability of immune-checkpoint inhibitors (ICI) in the last decade has resulted in a paradigm shift in certain areas of oncology. Patients can be treated either by a monotherapy of anti-CTLA-4 (tremelimumab or ipilimumab), anti-PD-1 (nivolumab or pembrolizumab), or anti-PD-L1 (avelumab or atezolizumab or durvalumab) or as combination therapy of anti-CTLA-4 and anti-PD-1. To maximize the clinical treatment benefit of cancer immunotherapy, the prediction of the actual immune response by the identification and application of clinically useful biomarkers will be required. Whole transcriptomic datasets of patients with ICI treatment could provide the basis for large-scale discovery and ranking of such potential biomarker candidates. In this review, we summarize currently available transcriptomic data from different biological sources (whole blood, fresh-frozen tissue, FFPE) obtained by different methods (microarray, RNA-Seq, RT-qPCR). We directly include only results from clinical trials and other investigations where an ICI treatment was administered. The available datasets are grouped based on the administered treatment and we also summarize the most important results in the individual cohorts. We discuss the limitations and shortcomings of the available datasets. Finally, a subset of animal studies is reviewed to provide an overview of potential in vivo ICI investigations. Our review can provide a swift reference for researchers aiming to find the most suitable study for their investigation, thus saving a significant amount of time.
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Affiliation(s)
- Szonja Anna Kovács
- grid.11804.3c0000 0001 0942 9821Department of Bioinformatics, Semmelweis University, Tűzoltó utca 7-9, 1094 Budapest, Hungary ,grid.429187.10000 0004 0635 9129Research Centre for Natural Sciences, Oncology Biomarker Research Group, Institute of Enzymology, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, 1117 Budapest, Hungary
| | - Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, Tűzoltó utca 7-9, 1094, Budapest, Hungary. .,Research Centre for Natural Sciences, Oncology Biomarker Research Group, Institute of Enzymology, Eötvös Loránd Research Network, Magyar Tudósok körútja 2, 1117, Budapest, Hungary.
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Murakami K, Yoshida N, Taniyama Y, Takahashi K, Toyozumi T, Uno T, Kamei T, Baba H, Matsubara H. Maximum standardized uptake value change rate before and after neoadjuvant chemotherapy can predict early recurrence in patients with locally advanced esophageal cancer: a multi-institutional cohort study of 220 patients in Japan. Esophagus 2022; 19:205-213. [PMID: 34993673 DOI: 10.1007/s10388-021-00896-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 11/16/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND Neoadjuvant chemotherapy (NAC) followed by esophagectomy can improve the prognosis of locally advanced esophageal cancer (LAEC). However, LAEC reportedly recurred in 17-21% of patients within 6 months post surgery. Thus, current treatment strategies may be inadequate for LAECs with poor prognosis. Preoperative identification of patients with poor prognosis might aid in modification of treatment strategies. This study aimed to evaluate the usefulness of the maximum standardized uptake value change rate (ΔSUVmax) in predicting treatment effects on the primary lesion, prognosis, and LAEC recurrence. METHODS This study involved 220 esophageal cancer patients who underwent esophagectomy after NAC at three facilities in Japan. The optimal cut-off point for ΔSUVmax in predicting tumor regression grade (TRG) was calculated and used to assess the correlation between ΔSUVmax and postoperative survival. RESULTS The optimal cut-off point for ΔSUVmax was 0.5. The 5-year overall survival rate in patients with ΔSUVmax ≥ 0.5 was significantly higher than that in patients with ΔSUVmax < 0.5 (71.5% vs. 50.5%, P = 0.001). Multivariate analysis identified ΔSUVmax (hazards ratio, 0.496; P = 0.004) as an independent prognostic factor. Among 199 patients evaluated for recurrence, 24 (12.1%) showed recurrence within 6 months post surgery. Univariate analysis revealed ΔSUVmax as the only predictor for early recurrence (odds ratio, 0.222; P = 0.004). CONCLUSION ΔSUVmax before and after NAC is clinically useful as it could help predict TRG, survival outcome, and early recurrence within 6 months post esophagectomy and is easily obtainable in general clinical practice. We believe that it may also help determine suitable treatment strategies for LAEC.
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Affiliation(s)
- Kentaro Murakami
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan.
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yusuke Taniyama
- Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Kozue Takahashi
- Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Takeshi Toyozumi
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan
| | - Takashi Uno
- Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takashi Kamei
- Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba, 260-8670, Japan
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Combining serum inflammation indexes at baseline and post treatment could predict pathological efficacy to anti‑PD‑1 combined with neoadjuvant chemotherapy in esophageal squamous cell carcinoma. J Transl Med 2022; 20:61. [PMID: 35109887 PMCID: PMC8809030 DOI: 10.1186/s12967-022-03252-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/13/2022] [Indexed: 01/03/2023] Open
Abstract
Background The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been used to predict therapeutic response in different tumors. However, no assessments of their usefulness have been performed in esophageal squamous cell carcinoma (ESCC) patients receiving anti‑PD‑1 combined with neoadjuvant chemotherapy. Methods The respective data of 64 ESCC patients receiving anti‑PD‑1 combined with neoadjuvant chemotherapy were analyzed. Whether NLR, LMR, PLR, and SII at baseline and post-treatment might predict pathological response to anti‑PD‑1 plus neoadjuvant chemotherapy, and cutoff values of these parameters were all determined by ROC curve analysis. Results NLR (cutoff = 3.173, AUC = 0.644, 95% CI 0.500–0.788, P = 0.124, sensitivity = 1.000, specificity = 0.373), LMR (cutoff = 1.622, AUC = 0.631, 95% CI 0.477–0.784, P = 0.161, sensitivity = 0.917, specificity = 0.137), PLR (cutoff = 71.108, AUC = 0.712, 95% CI 0.575–0.849, P = 0.023, sensitivity = 1.000, specificity = 0.059), and SII at baseline (cutoff = 559.266, AUC = 0.681, 95% CI 0.533–0.830, P = 0.052, sensitivity = 0.373, specificity = 1.000) seemed to be a useful predictor for distinguishing responders from non-responders. Combining NLR with SII at baseline (AUC = 0.729, 95% CI 0.600–0.858, P = 0.014, sensitivity = 0.917, specificity = 0.510), LMR and SII at baseline (AUC = 0.735, 95% CI 0.609–0.861, P = 0.012, sensitivity = 1.000 specificity = 0.471), PLR and SII at baseline (AUC = 0.716, 95% CI 0.584–0.847, P = 0.021, sensitivity = 1.000 specificity = 0.431), and LMR and PLR at post-treatment in the third period (AUC = 0.761, 95% CI 0.605–0.917, P = 0.010, sensitivity = 0.800, specificity = 0.696) might slightly increase the prediction ability to determine patients who have response or no response. Finally, combining LMR at baseline, SII at post-treatment in the second period with PLR at post-treatment in the third period could be considered a better predictor for discriminating responders and non-responders than single or dual biomarkers (AUC = 0.879, 95% CI 0.788–0.969, P = 0.0001, sensitivity = 0.909, specificity = 0.800). Conclusions The models we constructed allowed for the accurate and efficient stratification of ESCC patients receiving anti-PD-1 plus chemotherapy and are easily applicable for clinical practice at no additional cost.
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Matsuda S, Kawakubo H, Irino T, Kitagawa Y. Role sharing between minimally invasive oesophagectomy and organ preservation approach for surgically resectable advanced oesophageal cancer. Jpn J Clin Oncol 2021; 52:108-113. [PMID: 34891170 DOI: 10.1093/jjco/hyab192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/22/2021] [Indexed: 11/14/2022] Open
Abstract
Oesophageal cancer is a dismal disease since it metastasizes widely even from an early stage. In order to improve treatment outcomes, multidisciplinary treatments including surgery, chemotherapy and radiotherapy have been developed. While oesophagectomy is the mainstay in the treatment strategy, it is highly invasive since it requires two to three field approaches. To reduce surgical stress and morbidity, minimally invasive oesophagectomy including thoracoscopy, robotic assisted surgery and mediastinoscopy were introduced. Various clinical trials proved that these techniques decrease the post-operative morbidity rate. Furthermore, with the advancement of multidisciplinary treatment with a higher response rate, the possibility arose for omission of surgical resection in remarkable responders to neoadjuvant therapy. However, in order to safely provide organ preservation without increasing the risk of post-treatment recurrence, an accurate tumour monitoring system is required. Although endoscopy and computed tomography imaging have been a standard, the detection rate of residual tumours after treatment is still unsatisfactory. Utilizing liquid biopsy which could evaluate tumour derivative and host response, an appropriate monitoring system of tumour burden during multidisciplinary treatment can be developed. With the advancement of minimally invasive surgery and multidisciplinary treatment, the treatment strategy needs to be highly individualized based on the tumour biology, patients' condition and their preferences. Along with the improvement of the tumour monitoring system, appropriate role sharing can be achieved between a minimally invasive surgery and the organ preservation approach.
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Affiliation(s)
- Satoru Matsuda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Tomoyuki Irino
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
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Yang P, Zhou X, Yang X, Wang Y, Sun T, Feng S, Ma X. Neoadjuvant camrelizumab plus chemotherapy in treating locally advanced esophageal squamous cell carcinoma patients: a pilot study. World J Surg Oncol 2021; 19:333. [PMID: 34809658 PMCID: PMC8609728 DOI: 10.1186/s12957-021-02446-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/08/2021] [Indexed: 02/07/2023] Open
Abstract
Background Camrelizumab (a PD-1 inhibitor) has been used as a potential therapy in unresectable advanced esophageal squamous cell carcinoma (ESCC) along with adjuvant treatment in locally advanced ESCC, exhibiting an acceptable efficacy and safety profile. This pilot study was designed to further investigate the clinical value and tolerance of neoadjuvant camrelizumab plus chemotherapy in locally advanced ESCC. Methods A total of 16 patients with locally advanced ESCC were recruited. Patients received 2 cycles of neoadjuvant therapy including 2 doses of camrelizumab concurrent with 2 cycles of paclitaxel plus carboplatin followed by surgery 4 weeks afterward. Then, the treatment response after neoadjuvant therapy, R0 resection rate, tumor regression grade (TRG), and pathological complete remission (pCR) rate were measured. Besides, adverse events were documented. At last, progression-free survival (PFS) and overall survival (OS) were assessed. Results Generally, objective remission rate (ORR) was 81.3% whereas disease control rate (DCR) was 100% after neoadjuvant therapy. Concerning TRG grade, 31.3, 37.5, 18.8, and 12.5% patients reached TRG0, TRG1, TRG2, and TRG3, respectively. Then, pCR rate and R0 resection rate were 31.3 and 93.8%, respectively. Besides, mean PFS and OS were 18.3 months (95%CI: (16.2–20.5) months) and 19.2 months (95%CI: (17.7–20.7) months), respectively, with a 1-year PFS of 83% and OS of 90.9%. Adverse events included white blood cell decrease (37.5%), neutrophil decrease (31.3%), reactive cutaneous capillary endothelial proliferation (37.5%), and nausea or vomiting (25.0%), which were relatively mild and manageable. Conclusion Neoadjuvant camrelizumab plus chemotherapy exhibits good efficacy and acceptable tolerance in patients with locally advanced ESCC.
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Affiliation(s)
- Peng Yang
- Department of Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, 163000, Heilongjiang, China
| | - Xiao Zhou
- Department of Oncology, Daqing Oilfield General Hospital, No. 9 Zhongkang Street, Saertu District, Daqing, 163000, Heilongjiang, China.
| | - Xuefeng Yang
- Department of Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, 163000, Heilongjiang, China
| | - Yuefeng Wang
- Department of Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, 163000, Heilongjiang, China
| | - Tao Sun
- Department of Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, 163000, Heilongjiang, China
| | - Shiying Feng
- Department of Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, 163000, Heilongjiang, China
| | - Xianyou Ma
- Department of Cardiothoracic Surgery, Daqing Oilfield General Hospital, Daqing, 163000, Heilongjiang, China
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Huang B, Shi H, Gong X, Yu J, Xiao C, Zhou B, Liang Z, Li X. Comparison of efficacy and safety between pembrolizumab combined with chemotherapy and simple chemotherapy in neoadjuvant therapy for esophageal squamous cell carcinoma. J Gastrointest Oncol 2021; 12:2013-2021. [PMID: 34790369 PMCID: PMC8576253 DOI: 10.21037/jgo-21-610] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/19/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Immunotherapy can activate the recognition of tumor antigen, build immune memory, and more and more clinical trials have taken the scheme of immunochemotherapy or immunoradiotherapy as a treatment strategy for esophageal squamous cell carcinoma (ESCC). Our objective was to compare the efficacy and safety between pembrolizumab combined with the chemotherapy group and simple chemotherapy in neoadjuvant therapy of ESCC. METHODS Fifty-four ESCC patients with stage II-IVa were enrolled at the Fifth Affiliated Hospital of Sun Yat-sen University between January 2018 and December 2020, including 23 in the pembrolizumab combined with chemotherapy group (combined group), and 31 in the simple chemotherapy group. All patients received radical surgical treatment after two cycles of neoadjuvant therapy. RESULTS The pathological complete response (pCR) and objective response rate (ORR) in the combined group were significantly higher than that of the simple chemotherapy group (30.4% vs. 9.7%, P=0.048; 86.9% vs. 95.7%, P=0.017) as well as the score of tumor regression ≥2 (80.7% vs. 50.0%, P=0.013). And the complete rate of esophagectomy and R0 /R1 resection rate in the two groups were not statistically significant. Otherwise, the incidence of adverse events in the combined group was similar compared with the simple chemotherapy group. CONCLUSIONS Pembrolizumab combined with chemotherapy showed promising activity with a manageable safety profile. And it could offer a potential new neoadjuvant treatment approach for patients with ESCC.
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Affiliation(s)
- Bingjiang Huang
- Department of Thoracic Oncology, The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Haiyan Shi
- Department of Cardiothoracic Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Xiaohua Gong
- Department of Cardiothoracic Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Jing Yu
- Department of Minimally Invasive Surgery, The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Caixia Xiao
- Department of Minimally Invasive Surgery, The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Bin Zhou
- Department of Minimally Invasive Surgery, The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Zibin Liang
- Department of Thoracic Oncology, The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Xiaojian Li
- Department of Thoracic Oncology, The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
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Hirose T, Yamamoto S, Kato K. Emerging data on nivolumab for esophageal squamous cell carcinoma. Expert Rev Gastroenterol Hepatol 2021; 15:845-854. [PMID: 34251958 DOI: 10.1080/17474124.2021.1948836] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Esophageal cancer (EC) is the seventh most common malignancy in the world. The standard treatment for advanced EC patients is systemic chemotherapy, but few effective cytotoxic agents are available. Recently, nivolumab, a human monoclonal immunoglobulin G4 antibody that inhibits programmed cell death protein 1, has been tested for the treatment of advanced squamous cell carcinoma (ESCC) patients. The ATTRACTION-1 trial showed a promising efficacy of nivolumab monotherapy for advanced ESCC patients after prior chemotherapy. The ATTRACTION-3 phase III trial showed the superiority of nivolumab monotherapy over taxane monotherapy for advanced ESCC patients as a second-line treatment. The CheckMate-577 trial also showed survival benefits of postoperative nivolumab monotherapy in patients with resectable EC. AREAS COVERED This review mainly outlines emerging data on nivolumab for patients with advanced ESCC after prior chemotherapy. Additionally, this review includes data from the CheckMate-577 trial for patients with resectable EC. EXPERT OPINION Nivolumab has been approved by the US Food and Drug Administration for treatment after prior chemotherapy in patients with advanced ESCC. Several trials evaluating nivolumab-containing treatments are ongoing in patients with not only advanced EC, but also locally advanced EC, and these investigational treatments might improve the clinical outcomes of EC patients.
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Affiliation(s)
- Toshiharu Hirose
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Shun Yamamoto
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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Yu R, Wang W, Li T, Li J, Zhao K, Wang W, Liang L, Wu H, Ai T, Huang W, Li L, Yu W, Wei C, Wang Y, Shen W, Xiao Z. RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma. Future Oncol 2021; 17:4081-4089. [PMID: 34269067 DOI: 10.2217/fon-2021-0632] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Definitive chemoradiotherapy is the standard of care for inoperable locoregionally advanced esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have led to a paradigm shift in advanced, metastatic ESCC treatment; however, the effect of incorporating checkpoint inhibitors in the definitive management of ESCC is unclear. Tislelizumab is an anti-PD-1 antibody specifically engineered to minimize FcɣR binding on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. The RATIONALE 311 study described here (BGB-A317-311; NCT03957590) is a registrational multicenter, double-blind, placebo-controlled, randomized, Phase III clinical trial designed to evaluate the efficacy and safety of tislelizumab combined with concurrent chemoradiotherapy in patients with inoperable localized ESCC.
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Affiliation(s)
- Rong Yu
- Department of Radiation Oncology, Peking University Cancer Hospital, Beijing, China
| | - Wenqing Wang
- Cancer Hospital & Institute, Chinese Academy of Medical Sciences, Beijing, China
| | - Tao Li
- Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, China
| | - Jiancheng Li
- Department of Radiation Oncology, Fujian Cancer Hospital, Fuzhou, China
| | - Kuaile Zhao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Weihu Wang
- Department of Radiation Oncology, Peking University Cancer Hospital, Beijing, China
| | - Long Liang
- Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu, China
| | - Haishan Wu
- Department of Radiation Oncology, Fujian Cancer Hospital, Fuzhou, China
| | - Tashan Ai
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Wei Huang
- BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Liyun Li
- BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Wentao Yu
- BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Chenlu Wei
- BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Yidi Wang
- BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Wei Shen
- BeiGene (Beijing) Co., Ltd., Beijing, China
| | - Zefen Xiao
- Cancer Hospital & Institute, Chinese Academy of Medical Sciences, Beijing, China
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Abstract
Introduction: Esophageal cancer (EC) is the seventh most common cancer and the sixth leading cause of cancer death worldwide. The prognosis for advanced EC patients remains poor and there are few effective therapeutic agents available. Nivolumab is a fully human IgG4 monoclonal antibody that exerts antitumor activity by inhibiting the interaction of programmed cell death protein 1 on activated lymphocytes with its ligands. Nivolumab monotherapy showed significant benefit for overall survival of patients with advanced esophageal squamous cell carcinoma (ESCC) relative to taxane as a second-line treatment. Additionally, adjuvant nivolumab monotherapy showed significant disease-free survival benefit relative to placebo for resectable EC patients with residual pathologic disease who had received neoadjuvant chemoradiotherapy followed by surgery.Areas covered: Here, we provide an overview of checkpoint blockade with nivolumab and present the available clinical data related to its use in EC.Expert opinion: Nivolumab should be the standard second-line treatment for advanced ESCC patients and possibly adjuvant treatment of choice after neoadjuvant chemoradiotherapy followed by surgery. Trials assessing efficacy of a combination of cytotoxic agents and nivolumab as first-line treatment, nivolumab-containing chemoradiotherapy, and neoadjuvant chemotherapy are ongoing. These trials should result in improved protocols for better clinical outcomes in EC.
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Affiliation(s)
- Hayato Mikuni
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Shun Yamamoto
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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Koyanagi K, Kanamori K, Ninomiya Y, Yatabe K, Higuchi T, Yamamoto M, Tajima K, Ozawa S. Progress in Multimodal Treatment for Advanced Esophageal Squamous Cell Carcinoma: Results of Multi-Institutional Trials Conducted in Japan. Cancers (Basel) 2020; 13:51. [PMID: 33375499 PMCID: PMC7795106 DOI: 10.3390/cancers13010051] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
In Japan, the therapeutic strategies adopted for esophageal carcinoma are based on the results of multi-institutional trials conducted by the Japan Esophageal Oncology Group (JEOG), a subgroup of the Japan Clinical Oncology Group (JCOG). Owing to the differences in the proportion of patients with squamous cell carcinoma among all patients with esophageal carcinoma, chemotherapeutic drugs available, and surgical procedures employed, the therapeutic strategies adopted in Asian countries, especially Japan, are often different from those in Western countries. The emphasis in respect of postoperative adjuvant therapy for patients with advanced esophageal squamous cell carcinoma (ESCC) shifted from postoperative radiotherapy in the 1980s to postoperative chemotherapy in the 1990s. In the 2000s, the optimal timing of administration of perioperative adjuvant chemotherapy returned from the postoperative adjuvant setting to the preoperative neoadjuvant setting. Recently, the JEOG commenced a three-arm randomized controlled trial of neoadjuvant therapies (cisplatin + 5-fluorouracil (CF) vs. CF + docetaxel (DCF) vs. CF + radiation therapy (41.4 Gy) (CRT)) for localized advanced ESCC, and patient recruitment has been completed. Salvage and conversion surgeries for ESCC have been developed in Japan, and the JEOG has conducted phase I/II trials to confirm the feasibility and safety of such aggressive surgeries. At present, the JEOG is conducting several trials for patients with resectable and unresectable ESCC, according to the tumor stage. Herein, we present a review of the JEOG trials conducted for advanced ESCC.
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Affiliation(s)
- Kazuo Koyanagi
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara 259-1193, Japan; (K.K.); (Y.N.); (K.Y.); (T.H.); (M.Y.); (K.T.); (S.O.)
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Leng XF, Daiko H, Han YT, Mao YS. Optimal preoperative neoadjuvant therapy for resectable locally advanced esophageal squamous cell carcinoma. Ann N Y Acad Sci 2020; 1482:213-224. [PMID: 33067818 DOI: 10.1111/nyas.14508] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/02/2020] [Accepted: 09/14/2020] [Indexed: 12/18/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide, especially in East Asia. ESCC accounts for more than 90% of esophageal cancer. Currently, neoadjuvant therapy in combination with surgical resection is the mainstay of treatment. However, the overall survival rate of patients with locally advanced ESCC is not satisfactory even when treated following the standard treatment guidelines. With neoadjuvant chemoradiotherapy, chemotherapy, or emerging immunotherapy, continuous exploration of efficacy in relation to ESCC is expected to improve overall survival further. Here, we review and summarize current evidence for efficacy of preoperative therapy for locally advanced ESCC.
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Affiliation(s)
- Xue-Feng Leng
- Division of Thoracic Surgery, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China (UESTC), Chengdu, China
| | - Hiroyuki Daiko
- Department of Esophageal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yong-Tao Han
- Division of Thoracic Surgery, Sichuan Cancer Hospital & Research Institute, School of Medicine, University of Electronic Science and Technology of China (UESTC), Chengdu, China
| | - You-Sheng Mao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Abstract
Esophageal cancer (EC) is the seventh most common cancer, with a poor prognosis for metastatic EC patients and limited effective drugs for treatment. Nivolumab and pembrolizumab, monoclonal antibodies that inhibit interactions of PD-1 and its ligand (PD-L1), which induce lymphocyte activation, have antitumor activity. The ATTRACTION-3 trial compared nivolumab with taxane after first-line chemotherapy and demonstrated superior overall survival (OS) for esophageal squamous cell carcinoma. The KEYNOTE-181 trial that compared pembrolizumab with chemotherapy demonstrated superior OS for EC with a PD-L1 combined positive score ≥10. Trials to evaluate efficacy of combined cytotoxic agents and immune checkpoint inhibitors (ICI) as first-line chemotherapies, ICI-containing chemoradiotherapy, and pre/postoperative chemotherapy are ongoing and might provide important data to improve clinical outcomes.
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Affiliation(s)
- Shun Yamamoto
- Department of Head & Neck Medical Oncology/Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ken Kato
- Department of Head & Neck Medical Oncology/Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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Abstract
INTRODUCTION Esophageal cancer (EC) is the seventh most common cancer and the sixth leading cause of cancer death. However, the prognosis of unresectable advanced or recurrent EC patients remains poor and there are few effective therapeutic agents for EC. Pembrolizumab is a monoclonal antibody that exerts anti-tumor activity by inhibiting the interaction of programmed cell death protein 1 with its ligand (PD-L1) on activated lymphocytes. Pembrolizumab monotherapy shows a significant survival benefit in metastatic or recurrent EC patients with PD-L1 CPS ≥10 as second-line treatment. AREA COVERED In this review, we provide an overview of pembrolizumab as a compound and present the available clinical data related to EC treatment. EXPERT OPINION In our opinion, pembrolizumab is one of the standard treatment agents for second-line metastatic or recurrent esophageal squamous cell carcinoma patients with PD-L1 CPS ≥10. Trials assessing the efficacy of a combination of cytotoxic agents and pembrolizumab as first-line treatment and pembrolizumab-containing chemoradiation are ongoing. Their results may provide important data to improve clinical outcomes.
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Affiliation(s)
- Shun Yamamoto
- Department of Head and Neck Medical Oncology/Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital , Tokyo, Japan
| | - Ken Kato
- Department of Head and Neck Medical Oncology/Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital , Tokyo, Japan
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