Abstract
Background/Aim
Definitive chemoradiotherapy with cisplatin (CDDP) plus 5-fluorouracil is the standard treatment for locally advanced esophageal squamous cell carcinoma (LA-ESCC); however, CDDP is unsuitable for patients with cardiac and/or renal dysfunction. Based on the results of the PRODIGE5/ACCORD17 trial, 5-fluorouracil and leucovorin with oxaliplatin plus radiotherapy (FOLFOX-RT) has been recognized as a treatment option. However, the efficacy and safety of FOLFOX-RT is still unclear in Japan.
Patients and Methods
Medical records were reviewed for patients with LA-ESCC who received FOLFOX-RT between April 2019 and July 2021 at our institution. We evaluated complete response rate, progression-free survival (PFS), overall survival (OS), and adverse events.
Results
Fifteen patients were analyzed and median age was 72.5 years (range=51-83 years). All patients completed three courses of FOLFOX and the planned radiotherapy. The complete response rate was 40.0%. With a median follow-up of 10.6 months, the 6-month PFS rate was 63.0% (95%CI=32.3-82.8%), and the 6-month OS rate was 85.7% (95%CI=53.9-96.2%). Common adverse events were esophagitis (80.0%), leukopenia (53.3%), fatigue (53.3%), and neutropenia (46.7%). Only one patient had grade 4 esophageal perforation.
Conclusion
FOLFOX-RT for LA-ESCC was well tolerated and could be a treatment option for CDDP-intolerant patients.
Keywords: Locally advanced esophageal squamous cell carcinoma, chemoradiotherapy, 5-fluorouracil, leucovorin oxaliplatin, FOLFOX plus radiation
Esophageal cancer is the eighth most common type of cancer and the sixth most common cause of cancer-related deaths worldwide (1). In Japan, it is the seventh most common type of cancer and accounts for 3% of cancer-related deaths (2). Esophageal cancer has two major subtypes, namely, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma. ESCC accounts for about 90% of cases of esophageal cancer. The major risk factors are alcohol and smoking for squamous cell carcinoma and Barrett’s epithelium for adenocarcinoma (1).
For patients with local ESCC, the standard treatment option is neoadjuvant chemoradiation plus surgery, or definitive chemoradiation with the option of salvage. Chemoradiotherapy has been shown to be non-inferior to surgery in terms of survival in patients with early ESCC and is the standard of care for patients who are unsuitable for surgery. The standard definitive chemoradiotherapy regimen consists of 5-fluorouracil and cisplatin (CDDP). However, based on evidence from clinical trials, the standard dosage of these cytotoxic agents is set differently depending on the clinical stage of ESCC (3). The standard regimen is 5-fluorouracil 700 mg/m2 and CDDP 70 mg/m2 plus radiotherapy (60 Gy) for stage I (primary tumor has invaded the submucosa or deeper), 5-fluorouracil 1,000 mg/m2 and CDDP 75 mg/m2 plus radiotherapy (50.4 Gy) for stage II and III disease without clinical T4, and 5-fluorouracil 700 mg/m2 and CDDP 70 mg/m2 plus radiotherapy (60 Gy) for unresectable locally advanced ESCC (clinical T4 or M1 lymph node metastasis). Patients who receive the standard treatments with CDDP are prone to develop grade ≥3 hematologic adverse events, with at least 10% developing neutropenia, and gastrointestinal toxicity, 10%-20% developing nausea and at least 20% developing anorexia. Although we should pay attention to renal and cardiac function when giving CDDP, adverse events have been reported, including elevation of creatinine and cardiac overload (4-6). Therefore, patients with ESCC who have poor performance status and those with renal or cardiac dysfunction are unsuitable for the standard treatments.
Oxaliplatin, a third-generation platinum-based drug, is less nephrotoxic than CDDP and does not require hydration. Therefore, patients with cancer who have renal or cardiac dysfunction can receive oxaliplatin (7). However, oxaliplatin has adverse effects, including bone marrow suppression, dysphagia, nausea, vomiting, paresthesia, and a characteristic form of peripheral neuropathy. The PRODIGE5/ACCORD17 study compared progression-free survival (PFS) between a group that received chemoradiotherapy consisting of 5-fluorouracil and leucovorin with oxaliplatin (FOLFOX) with that in a group that received chemoradiotherapy with a combination of 5-fluorouracil and CDDP (CF) for clinical stage I-IVA esophageal cancer (squamous cell carcinoma, 86%; adenocarcinoma, 14%). Median PFS was similar between the two groups: 9.4 months [95% confidence interval (CI)=8.1-10.6] in the CF group and 9.7 months (95%CI=8.1-14.5) in the FOLFOX group [hazard ratio (HR)=0.93, 95%CI=0.70-1.24, p=0.64], and superiority of FOLFOX was not demonstrated. Median OS and complete response (CR) rates were also similar between the two groups. In terms of adverse events, all-grade sensory neuropathy was more frequent in the FOLFOX group than in the CF group (18.3% vs. 0.8%), while all-grade mucositis (26.7% vs. 32.0%), alopecia (1.5% vs. 9.4%), and renal dysfunction (3.0% vs. 11.7%) were more frequent in the CF group. However, there was no significant between-group difference in grade 3 or 4 hematologic toxicity or in all grades of non-hematologic toxicity, and treatment-related deaths and sudden deaths were less frequent in the FOLFOX group (8). Therefore, chemoradiotherapy with FOLFOX (FOLFOX-RT) is expected to show similar efficacy and safety to chemoradiotherapy with CF, and has been added as a treatment option for patients who are intolerant to CDDP in the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines (9,10).
Based on the results of the PRODIGE5/ACCORD17 trial, FOLFOX became available for patients with esophageal cancer under the Japanese health insurance system in April 2019. However, information on the efficacy and safety of FOLFOX-RT for patients with ESCC in Japan is limited and unclear (11,12).
Therefore, in this study, we retrospectively examined the efficacy and safety of definitive FOLFOX-RT in patients with ESCC who are intolerant to CDDP.
Patients and Methods
Patients. The main selection criteria for this retrospective, single-institution study was a histological diagnosis of ESCC, clinical stage I-IVA based on the UICC-TNM 8th classification, and definitive treatment with FOLFOX-RT between April 2019 and July 2021. Patients with poor performance status and renal and/or cardiac dysfunction (renal dysfunction was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 over three months, and cardiac dysfunction as being treated for chronic heart failure), and those who were elderly were deemed to be intolerant to the standard of care, including CDDP. Also, patients were included up to Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2.
The study was approved by an appropriate ethics committee (approval number: 2017-229) in accordance with the Declaration of Helsinki. The consent from patients was taken in an opt-out manner and the informed consent was obtained from all subjects and/or their legal guardians.
Treatments. FOLFOX consisted of three cycles of oxaliplatin 85 mg/m2, bolus 5-fluorouracil 400 mg/m2, and leucovorin 200 mg/m2 on day 1 followed by a continuous infusion of 5-fluorouracil 1,600 mg/m2 for 46 h, administered at 2-week intervals. The radiation dose was set at 50 or 60 Gy. Patients could receive three additional cycles of chemotherapy after radiation if they did not experience tumor progression, develop intolerable toxicity, or declined treatment.
Evaluations and statistical analysis. We evaluated the objective response rate in patients with at least one measurable lesion according to the 11th edition of the Japanese Classification of Esophageal Cancer published by the Japanese Society for Esophageal Diseases (13). Treatment was deemed complete if three courses of chemotherapy and all planned doses of radiation were administered.
PFS was defined as the interval between initiation of treatment and occurrence of an event (disease progression, death from any cause, or the last visit without disease progression). OS was defined as the interval between initiation of therapy and patient death from any cause or the date of last follow-up in survivors. The distribution of time to events was estimated using the Kaplan-Meier method.
Adverse events were evaluated using Common Terminology Criteria for Adverse Events version 5.0. All statistical analyses were performed using EZR (version 1.50) which was developed by Yoshinobu Kanda of the Department of Hematology, Saitama Medical Center, Jichi Medical University, Japan. A p-value of less than 0.05 was considered statistically significant.
Results
Patient characteristics and treatment. Fifteen patients (ten male, five female) met the study eligibility criteria and were enrolled. Their median age was 72.5 years (range=51-83). Performance status was 0 in four patients, PS 1 in eight, and PS 2 in three at the start of chemoradiotherapy. Eight patients had stage IVA disease. Ten patients had not received any therapy previously. The most frequent reasons for selecting FOLFOX were renal dysfunction (9/15) and older age (4/15) (Table I).
Table I. Patient demographics and clinical characteristics (n=15).
ECOG: Eastern Cooperative Oncology Group; TNM 8th: Tumor-Node-Metastasis Classification of Malignant Tumors, 8th edition; FOLFOX: 5-fluorouracil and leucovorin with oxaliplatin.
Response and survival. Six (40.0%) of the 15 patients achieved a CR (Table II). All patients completed the concurrent chemoradiotherapy; however, six could not receive additional chemotherapy. The reasons for discontinuation were poor performance status in five patients, adverse events in one, and progressive disease in three, with some overlap. Five patients received further treatment after termination of FOLFOX-RT, which consisted of chemotherapy in four patients (nivolumab and paclitaxel, n=2; nivolumab, n=2) and radiotherapy in one. Four patients did not receive further treatment because of poor performance status or adverse events.
Table II. Tumor response*.
*Evaluated by the Japanese Classification of Esophageal Cancer, the 11th edition. CR: Complete response; PD: progressive disease.
Eight patients (53.3%) received reduced doses of FOLFOX. Five (33.3%) had reduced doses since the first dose, four of whom reduced both 5-FU and oxaliplatin (both at 80% dose in two, both at 80% dose without 5-FU bolus in one, 80% dose of 5-FU and 60% dose of oxaliplatin in one), and only without 5-FU bolus in one patient. The five patients did not require dose reduction during FOLFOX-RT. Of the remaining three patients (20.0%), two discontinued the 5-FU bolus from the second course, one of whom reduced oxaliplatin dose to 80% from the fifth course. One discontinued the 5-FU bolus from the fifth course and further reduced 5-FU continuous dose to 60% and oxaliplatin dose to 80%.
Over a median follow-up of 10.6 months, median PFS was 6.9 months and the 6-month PFS rate was 63.0% (95%CI=32.3-82.8) (Figure 1); median OS was 25.4 months and the 6-month OS rate was 85.7% (95%CI=53.9-96.2) (Figure 2). At the time of this analysis, four patients had died, none of whom received further treatment after FOLFOX-RT.
Figure 1. Progression-free survival (PFS) time. Tick marks indicate censored cases in the Kaplan-Meier survival curve. Median PFS: 6.9 months; 6-month PFS rate: 63.0% (95%CI=32.3-82.8).
Figure 2. Overall survival (OS) time. Tick marks indicate censored cases in the Kaplan-Meier survival curve. Median OS was 25.4 months and the 6-month OS rate was 85.7% (95%CI=53.9-96.2).
Adverse events. Grade 3 leukopenia was seen in five patients (33.3%), neutropenia in one (6.7%), esophagitis in two (13.3%), and esophageal perforation in one (6.7%). One patient who had bronchial invasion at the start of FOLFOX-RT died of septic shock because of esophageal perforation. However, most adverse events were grade 1 or 2; there were three cases of peripheral neuropathy (20.0%), all of which were grade 1. Despite the fragility of patients who are intolerant to CDDP, there were no cases of febrile neutropenia (Table III).
Table III. Adverse events.
Discussion
Median PFS was shorter in this study than in PRODIGE5/ACCORD17 (6.9 months vs. 9.7 months) (8), which might be explained by differences in patient background characteristics between the two studies, including median age (72.5 years vs. 61 years) and the proportions with Eastern Cooperative Oncology Group performance status 2 (20% vs. 0%) and clinical stage IV (53.3% vs. 10%). However, median OS in our study was similar to that in PRODIGE5/ACCORD17 (25.4 months vs. 20.2 months) despite the difference in patient characteristics. These data could reflect the fact that the proportion of patients who had more advanced disease and/or were elderly was higher in our study than in PRODIGE5/ACCORD17.
The CR rate in our present study, which included vulnerable patients who would not have been accepted in clinical trials, was comparable with that in the FOLFOX group in PRODIGE5/ACCORD17 (40% vs. 44%). Moreover, our present findings are not significantly different from those of another retrospective study of CF plus radiation (60 Gy) in elderly patients aged over 71 years in terms of the CR rate (40.0% vs. 63.6%) and median OS (25.4 months vs. 14.7 months) (14). CF combined with radiotherapy for stage II-III disease achieved a CR rate of 70% in a phase II study (5) and 74.2% in the JCOG0909 trial (15). In PRODIGE5/ACCORD17, the group that received CF had a CR rate of 41.3%, median PFS of 9.4 months, and median OS of 17.5 months (8). In another study of CF plus radiation for patients with local advanced ESCC which had unresectable T4 and/or M1 lymph node metastasis without distant metastasis, median OS was 13.0 months (6). Although these findings from clinical trials are not directly comparable with those from our retrospective study that included elderly and vulnerable patients who could not receive CDDP, the efficacy in this study is considered non-inferior. Furthermore, in another study of definitive CF plus radiation for ESCC median OS was 13.3 months and median PFS was 8.1 months (16). With similar patients’ background, PFS was comparable and OS was longer in this study.
Another standard treatment option for LA-ESCC is nedaplatin and 5-fluorouracil plus radiation (60 Gy), for which the reported CR rate (12.0%) and median OS (12 months) (17) do not appear to be very different from those in our present study. Moreover, our data are similar to those of a study of docetaxel plus radiation therapy (60 Gy) in patients over 70 years of age with stage II/III disease, in whom the CR rate was 43.8% and median OS was 27.7 months (18). FOLFOX-RT has some advantages over these regimens. Nedaplatin can be used in patients with poor renal function but needs dose reduction. Moreover, patients who receive nedaplatin are prone to hematologic adverse events, particularly thrombocytopenia. Furthermore, patients who receive FOLFOX-RT can receive a taxane after failure of chemoradiotherapy.
The safety profile of definitive FOLFOX-RT in this study provided no new signals for patients with LA-ESCC. Overall, grade 1-2 hematological and non-hematological adverse events were common. There were more adverse events in our study than in either the FOLFOX group or the CF group in PRODIGE5/ACCORD17, including neutropenia (46.7% vs. 29.0% and 28.9%, respectively) and esophagitis (80.0% vs. 26.7% and 32.0%). These differences can be attributed to the differences in patient characteristics between the two studies. However, the rates of grade ≥3 adverse events were comparable between our study and the FOLFOX and CF groups in PRODIGE5/ACCORD17, including for febrile neutropenia (0% vs. 6% and 7%, respectively), leukopenia (33.3% vs. 21% and 25%), and esophagitis (13.3% vs. 7% and 9%) (8). There was no significant difference in the incidence of grade ≥3 esophagitis between our study and the JCOG0909 trial [13.3% (n=2) vs. 3.2% (n=3)] (5). One patient (6.7%) died from pneumonia caused by esophageal perforation. Although this finding from clinical trial is not directly comparable with those from our retrospective study of fewer patients that included elderly and vulnerable patients, the late toxicity was not worst compared to JCOG0909 trial (1.1%) (11). Although all patients received treatment, six (40.0%) received three courses, three received four courses, and six (40.0%) received six courses. None of these patients could receive more than six courses in view of their older age, poor performance status, and renal or cardiac dysfunction. However, even though the patient characteristics were unfavorable, adverse events occurred at the same rate as found with standard treatment.
Compared with CDDP, oxaliplatin is more likely to cause peripheral neuropathy but less likely to cause nephrotoxicity or adverse cardiac events. Moreover, CDDP requires high-volume hydration for renal protection, as does nedaplatin, and infusions of 5-fluorouracil take 120 h to administer, and all require hospitalization. However, oxaliplatin can be administered on an outpatient basis, except for insertion of the port. FOLFOX-RT can be recommended as an easy-to-use treatment option but requires careful monitoring for adverse events, including peripheral neuropathy.
Study limitations. It had a single-center retrospective design and a short observation period, which meant that only a small number of patients could be included. Furthermore, there were no indicators of whether the treatment should be CDDP or oxaliplatin, and the choice of chemotherapy was left to the physician’s discretion.
Conclusion
This study showed that FOLFOX-RT is well tolerated by vulnerable patients who are intolerant to CDDP. However, the tumor response and survival rates were lower than those in previous studies. Given that the observation period was short, further follow-up is necessary. FOLFOX-RT is a treatment option for patients with LA-ESCC intolerant for CDDP in Japan.
Funding
No funding was received to assist with the preparation of this manuscript.
Conflicts of Interest
SY received honoraria from MSD, Ono Pharmaceutical and Bristol-Myers Squibb, Taiho. YH received honoraria from Novartis, Chugai pharma, MSD, Ono pharmaceutical, Bristol-Myers Squibb, Merck biopharma, Eisai, Eli Lilly, Nutri, Teijin pharma and participates on advisory boards of Janssen, Eisai and Rakuten medical. HS received funding from Ono Pharmaceutical, MSD, AstraZeneca, Amgen, Eisai, Bristol-Myers Squibb, Taiho, Daiichi-Sankyo and expenses from Ono Pharmaceutical as representative of clinical study. SI received funding from Chugai Pharma, Aglient, BMS, Daiichi-Sankyo, Eisai, Ono Pharmaceutical, Taiho, Lilly, Amgen, Seagen and Zymeworks. KK received funding from Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Taiho, Janssen, Merck Bio, Chugai, Astrazeneca and Oncolys Biopharma. The other Authors declare that they have no conflicts of interest.
Authors’ Contributions
MY, SY and KK designed the study, the main conceptual ideas. MY and SY collected the data. MY, SY and KK worked on the manuscript with the other author’s support. All Authors discussed the results and commented on the manuscript.
Acknowledgements
The Authors would like to thank the doctors in the National Cancer Center Hospital not listed as Authors. The Authors would also like to thank the patients and families.
References
- 1.WHO. GLOBOCAN 2020. Available at: http://globocan.iarc.fr/ [Last accessed on November 6, 2023]
- 2.Cancer Control Information Center, National Cancer Center, Cancer Information Service. Available at: http://ganjoho.jp/reg_stat/index.html. [Last accessed on November 6, 2023]
- 3.Kitagawa Y, Ishihara R, Ishikawa H, Ito Y, Oyama T, Oyama T, Kato K, Kato H, Kawakubo H, Kawachi H, Kuribayashi S, Kono K, Kojima T, Takeuchi H, Tsushima T, Toh Y, Nemoto K, Booka E, Makino T, Matsuda S, Matsubara H, Mano M, Minashi K, Miyazaki T, Muto M, Yamaji T, Yamatsuji T, Yoshida M. Esophageal cancer practice guidelines 2022 edited by the Japan esophageal society: part 1. Esophagus. 2023;20(3):343–372. doi: 10.1007/s10388-023-00993-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kato K, Ito Y, Nozaki I, Daiko H, Kojima T, Yano M, Ueno M, Nakagawa S, Takagi M, Tsunoda S, Abe T, Nakamura T, Okada M, Toh Y, Shibuya Y, Yamamoto S, Katayama H, Nakamura K, Kitagawa Y. Parallel-group controlled trial of surgery versus chemoradiotherapy in patients with stage I esophageal squamous cell carcinoma. Gastroenterology. 2021;161(6):1878–1886.e2. doi: 10.1053/j.gastro.2021.08.007. [DOI] [PubMed] [Google Scholar]
- 5.Kato K, Eguchi Nakajima T, Ito Y, Katada C, Ishiyama H, Tokunaga S, Tanaka M, Hironaka S, Hashimoto T, Ura T, Kodaira T, Yoshimura K. Phase II study of concurrent chemoradiotherapy at the dose of 50.4 Gy with elective nodal irradiation for stage II-III esophageal carcinoma. Jpn J Clin Oncol. 2013;43(6):608–615. doi: 10.1093/jjco/hyt048. [DOI] [PubMed] [Google Scholar]
- 6.Shinoda M, Ando N, Kato K, Ishikura S, Kato H, Tsubosa Y, Minashi K, Okabe H, Kimura Y, Kawano T, Kosugi S, Toh Y, Nakamura K, Fukuda H, Japan Clinical Oncology Group Randomized study of low-dose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303) Cancer Sci. 2015;106(4):407–412. doi: 10.1111/cas.12622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Takimoto CH, Graham MA, Lockwood G, Ng CM, Goetz A, Greenslade D, Remick SC, Sharma S, Mani S, Ramanathan RK, Synold TW, Doroshow JH, Hamilton A, Mulkerin DL, Ivy P, Egorin MJ, Grem JL. Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function. Clin Cancer Res. 2007;13(16):4832–4839. doi: 10.1158/1078-0432.CCR-07-0475. [DOI] [PubMed] [Google Scholar]
- 8.Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A, Fédération Francophone de Cancérologie Digestive, UNICANCER-GI Group Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014;15(3):305–314. doi: 10.1016/S1470-2045(14)70028-2. [DOI] [PubMed] [Google Scholar]
- 9.Obermannová R, Alsina M, Cervantes A, Leong T, Lordick F, Nilsson M, Van Grieken N, Vogel A, Smyth E, ESMO Guidelines Committee Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(10):992–1004. doi: 10.1016/j.annonc.2022.07.003. [DOI] [PubMed] [Google Scholar]
- 10.Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Corvera C, Das P, Denlinger CS, Enzinger PC, Fanta P, Farjah F, Gerdes H, Gibson M, Glasgow RE, Hayman JA, Hochwald S, Hofstetter WL, Ilson DH, Jaroszewski D, Johung KL, Keswani RN, Kleinberg LR, Leong S, Ly QP, Matkowskyj KA, McNamara M, Mulcahy MF, Paluri RK, Park H, Perry KA, Pimiento J, Poultsides GA, Roses R, Strong VE, Wiesner G, Willett CG, Wright CD, McMillian NR, Pluchino LA. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Canc Netw. 2019;17(7):855–883. doi: 10.6004/jnccn.2019.0033. [DOI] [PubMed] [Google Scholar]
- 11.Yoshii T, Hara H, Asayama M, Kumekawa Y, Miyazawa S, Takahashi N, Matsushima T, Shimizu S, Saito Y. Chemoradiotherapy with FOLFOX for esophageal squamous cell cancer with synchronous rectal cancer: Four case reports and a literature review. Mol Clin Oncol. 2020;12(1):23–30. doi: 10.3892/mco.2019.1945. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mitani S, Kadowaki S, Kato K, Masuishi T, Muro K. Combination of oxaliplatin and 5-fluorouracil/leucovorin for advanced esophageal squamous cell carcinoma refractory or intolerant to standard therapies. Case Rep Oncol. 2019;12(1):304–310. doi: 10.1159/000499705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Japan Esophageal Society Japanese Classification of Esophageal Cancer, 11th Edition: part I. Esophagus. 2017;14(1):1–36. doi: 10.1007/s10388-016-0551-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Takeuchi S, Ohtsu A, Doi T, Kojima T, Minashi K, Mera K, Yano T, Tahara M, Muto M, Nihei K. A retrospective study of definitive chemoradiotherapy for elderly patients with esophageal cancer. Am J Clin Oncol. 2007;30(6):607–611. doi: 10.1097/COC.0b013e3180ca7c84. [DOI] [PubMed] [Google Scholar]
- 15.Takeuchi H, Ito Y, Machida R, Kato K, Onozawa M, Minashi K, Yano T, Nakamura K, Tsushima T, Hara H, Okuno T, Hironaka S, Nozaki I, Ura T, Chin K, Kojima T, Seki S, Sakanaka K, Fukuda H, Kitagawa Y, Japan Esophageal Oncology Group of the Japan Clinical Oncology Group A single-arm confirmatory study of definitive chemoradiation therapy including salvage treatment for clinical stage II/III esophageal squamous cell carcinoma (JCOG0909 study) Int J Radiat Oncol Biol Phys. 2022;114(3):454–462. doi: 10.1016/j.ijrobp.2022.07.007. [DOI] [PubMed] [Google Scholar]
- 16.Koh HK, Park Y, Koo T, Park HJ, Lee MY, Chang AR, Hong S, Bae H. Adjuvant chemotherapy and dose escalation in definitive concurrent chemoradiotherapy for esophageal squamous cell carcinoma. Anticancer Res. 2020;40(3):1771–1778. doi: 10.21873/anticanres.14131. [DOI] [PubMed] [Google Scholar]
- 17.Ishikura S, Ohtsu A, Shirao K, Muro K, Kagami Y, Nihei K, Mera K, Ito Y, Boku N, Yoshida S. A phase I/II study of nedaplatin and 5-fluorouracil with concurrent radiotherapy in patients with T4 esophageal cancer: Japan Clinical Oncology Group trial (JCOG 9908) Esophagus. 2005;2(3):133–137. doi: 10.1007/s10388-005-0055-3. [DOI] [Google Scholar]
- 18.Ohba A, Kato K, Ito Y, Katada C, Ishiyama H, Yamamoto S, Ura T, Kodaira T, Kudo S, Tamaki Y. Chemoradiation therapy with docetaxel in elderly patients with stage II/III esophageal cancer: A phase 2 trial. Adv Radiat Oncol. 2016;1(4):230–236. doi: 10.1016/j.adro.2016.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]