Skip to main content

Advertisement

SpringerLink
Log in

Development and Validation of a Predictive Model of Therapeutic Effect in Patients with Esophageal Squamous Cell Carcinoma Who Received Neoadjuvant Treatment: A Nationwide Retrospective Study in Japan

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Neoadjuvant treatment has become the standard of care for patients with advanced esophageal cancer. However, few studies have elucidated the clinical factors that predict response to neoadjuvant therapy in a large multicenter cohort. We aimed to develop a predictive model of therapeutic effect in patients with esophageal squamous cell carcinoma (SCC) who received neoadjuvant treatment.

Methods

This nationwide study included 4078 patients from 85 institutions. Patients who received neoadjuvant treatment followed by surgery for esophageal SCC were eligible. We developed a logistic regression model to predict good pathological therapeutic effects, and a predictive nomogram was generated by applying the logistic regression formula.

Results

Among neoadjuvant regimens, cisplatin plus 5-fluorouracil (CF) was the most frequently used (60.2%), followed by docetaxel plus CF (DCF, 27.4%), CF with radiotherapy (CF-RT, 4.5%), adriamycin plus CF (3.6%), nedaplatin plus 5-fluorouracil (0.9%), and DCF-RT (0.5%). Multivariable analysis revealed that male sex, advanced cT category, and increased pretherapeutic SCC antigen level were independently associated with not achieving a good therapeutic effect. Moreover, intensified neoadjuvant regimens were independently associated with favorable therapeutic effects; DCF-RT elicited the best therapeutic effect, followed by CF-RT and DCF. A predictive model including nine commonly measured preoperative variables was generated, and the area under the curve was 0.679 (95% confidence interval: 0.658–0.700). This nomogram was also adequately validated internally.

Conclusions

The model developed in this study was validated and predicts the therapeutic effect in patients with esophageal SCC who received neoadjuvant treatment. This model might contribute to individualized treatment strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin. 2021;71:209–249.

  2. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002;359:1727–33.

    Article  Google Scholar 

  3. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

    Article  CAS  PubMed  Google Scholar 

  4. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19:68–74.

    Article  PubMed  Google Scholar 

  5. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84.

    Article  PubMed  Google Scholar 

  6. Shapiro J, van Lanschot JJB, Hulshof M, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015;16:1090–8.

    Article  PubMed  Google Scholar 

  7. Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018;36:2796–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–92.

    Article  PubMed  Google Scholar 

  9. Stahl M, Walz MK, Stuschke M, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009;27:851–6.

    Article  CAS  PubMed  Google Scholar 

  10. Klevebro F, Alexandersson von Dobeln G, Wang N, et al. A randomized clinical trial of neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for cancer of the oesophagus or gastro-oesophageal junction. Ann Oncol. 2016;27:660–667.

  11. Kitagawa Y, Uno T, Oyama T, et al. Esophageal Cancer Practice Guidelines 2017 edited by the Japan Esophageal Society: Part 1. Esophagus. 2019;16:1–24.

    Article  PubMed  Google Scholar 

  12. Kitagawa Y, Uno T, Oyama T, et al. Esophageal Cancer Practice Guidelines 2017 edited by the Japan esophageal society: Part 2. Esophagus. 2019;16:25–43.

    Article  PubMed  Google Scholar 

  13. Nakamura K, Kato K, Igaki H, et al. Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study). Jpn J Clin Oncol. 2013;43:752–5.

    Article  PubMed  Google Scholar 

  14. Kato K, Ito Y, Daiko H, et al. A randomized controlled phase III trial comparing two chemotherapy regimens and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study. J Clin Oncol. 2022;40:238–238.

    Article  Google Scholar 

  15. Noordman BJ, Spaander MCW, Valkema R, et al. Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study. Lancet Oncol. 2018;19:965–74.

    Article  PubMed  Google Scholar 

  16. Noordman BJ, Wijnhoven BPL, Lagarde SM, et al. Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial. BMC Cancer. 2018;18:142.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Matsuda S, Kawakubo H, Okamura A, et al. Distribution of residual disease and recurrence patterns in pathological responders after neoadjuvant chemotherapy for esophageal squamous cell carcinoma. Ann Surg. 2020.

  18. Brierley JDGM, (ed.) WC. TNM classification of malignant tumors. Oxford. 2017;8.

  19. Japanese Classification of Esophageal Cancer, 11th Edition: Part I. Esophagus. 2017;14:1–36.

  20. Japanese Classification of Esophageal Cancer, 11th Edition: Part II and III. Esophagus. 2017;14:37–65.

  21. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–45.

    Article  CAS  PubMed  Google Scholar 

  22. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–5.

    Article  CAS  PubMed  Google Scholar 

  23. Sato H, Tsubosa Y, Kawano T. Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg. 2012;36:617–22.

    Article  PubMed  Google Scholar 

  24. Hamai Y, Hihara J, Taomoto J, Yamakita I, Ibuki Y, Okada M. Hemoglobin level influences tumor response and survival after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma. World J Surg. 2014;38:2046–51.

    Article  PubMed  Google Scholar 

  25. Huang RW, Chao YK, Wen YW, et al. Predictors of pathological complete response to neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma. World J Surg Oncol. 2014;12:170.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chao YK, Chang CB, Chuang WY, et al. Correlation between tumor regression grade and clinicopathological parameters in patients with squamous cell carcinoma of the esophagus who received neoadjuvant chemoradiotherapy. Medicine. 2015;94:e1407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nakaya S, Ogawa R, Hayakawa S, et al. Serum IgG level is a predicting factor for the response to neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma. World J Surg Oncol. 2021;19:217.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Okamura A, Matsuda S, Mayanagi S, et al. Clinical significance of pretherapeutic serum squamous cell carcinoma antigen level in patients with neoadjuvant chemotherapy for esophageal squamous cell carcinoma. Ann Surg Oncol. 2021;28:1209–16.

    Article  PubMed  Google Scholar 

  29. Bohanes P, Yang D, Chhibar RS, et al. Influence of sex on the survival of patients with esophageal cancer. J Clin Oncol. 2012;30:2265–72.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ozdemir BC, Csajka C, Dotto GP, Wagner AD. Sex differences in efficacy and toxicity of systemic treatments: an undervalued issue in the era of precision oncology. J Clin Oncol. 2018;36:2680–3.

    Article  CAS  PubMed  Google Scholar 

  31. Davidson M, Wagner AD, Kouvelakis K, et al. Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric cancer: A pooled analysis of four randomised trials. Eur J Cancer. 2019;121:40–7.

    Article  CAS  PubMed  Google Scholar 

  32. Dijksterhuis WPM, Kalff MC, Wagner AD, et al. Gender differences in treatment allocation and survival of advanced gastroesophageal cancer: a population-based study. J Natl Cancer Inst. 2021;113:1551–60.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Okamura A, Watanabe M, Yamashita K, et al. Implication of visceral obesity in patients with esophageal squamous cell carcinoma. Langenbecks Arch Surg. 2018;403:245–53.

    PubMed  Google Scholar 

  34. Incio J, Liu H, Suboj P, et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 2016;6:852–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Willett CG, Warland G, Coen J, Shellito PC, Compton CC. Rectal cancer: the influence of tumor proliferation on response to preoperative irradiation. Int J Radiat Oncol Biol Phys. 1995;32:57–61.

    Article  CAS  PubMed  Google Scholar 

  36. Fyles AW, Milosevic M, Wong R, et al. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998;48:149–56.

    Article  CAS  PubMed  Google Scholar 

  37. Suminami Y, Nagashima S, Vujanovic NL, Hirabayashi K, Kato H, Whiteside TL. Inhibition of apoptosis in human tumour cells by the tumour-associated serpin, SCC antigen-1. Br J Cancer. 2000;82:981–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Murakami A, Suminami Y, Hirakawa H, Nawata S, Numa F, Kato H. Squamous cell carcinoma antigen suppresses radiation-induced cell death. Br J Cancer. 2001;84:851–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Suzuki T, Okamura A, Watanabe M, et al. Neoadjuvant chemoradiotherapy with cisplatin plus fluorouracil for borderline resectable esophageal squamous cell carcinoma. Ann Surg Oncol. 2020;27:1510–7.

    Article  PubMed  Google Scholar 

  40. Kanie Y, Okamura A, Maruyama S, et al. Clinical significance of serum squamous cell carcinoma antigen for patients with recurrent esophageal squamous cell carcinoma. Ann Surg Oncol. 2021;28:7990–6.

    Article  PubMed  Google Scholar 

  41. Suzuki T, Okamura A, Watanabe M, et al. Serum squamous cell carcinoma antigen is a predictive factor of outcomes in patients with locally advanced unresectable esophageal squamous cell carcinoma treated by definitive chemoradiotherapy. J Cancer Metastasis Treat. 2022.

  42. Sugimura K, Yamasaki M, Yasuda T, et al. Long-term results of a randomized controlled trial comparing neoadjuvant adriamycin, cisplatin, and 5-fluorouracil vs docetaxel, cisplatin, and 5-fluorouracil followed by surgery for esophageal cancer (OGSG1003). Ann Gastroenterol Surg. 2021;5:75–82.

    Article  PubMed  Google Scholar 

  43. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393:1948–57.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

The authors sincerely appreciate all participating investigators for their valuable assistance with data collection: Sohei Matsumoto (Nara Medical University); Katsushi Takebayashi (Shiga University); Tomokazu Kakishita (Shikoku Cancer Center); Youichi Kumagai (Saitama Medical University); Takahisa Suzuki (Kure Medical Center and Chugoku Cancer Center); Yasuyuki Kawachi (Nagaoka Chuo General Hospital); Yasuhiro Tsubosa (Shizuoka Cancer Center Hospital); Naoya Yoshida (Kumamoto University); Yusuke Sato (Akita University); Noriaki Sadanaga (Saiseikai Fukuoka General Hospital); Tomoyuki Matsunaga (Tottori University); Masahiko Koike (Nagoya University); Kentaro Kishi (Osaka Police Hospital); Fumihiko Kato (International University of Health and Welfare); Hiroaki Nagano (Yamaguchi University); Shirou Kuwabara (Niigata City General Hospital); Takahiro Yoshida (Tokushima University); Katsunori Nishikawa (The Jikei University); Koichi Okamoto (Kanazawa University); Yoshihiko Kawaguchi (University of Yamanashi); Shinsuke Sato (Shizuoka General Hospital); Hironori Ohdaira (International University of Health and Welfare Hospital); Koji Kono (Fukushima Medical University); Akihiro Hoshino (Tokyo Medical and Dental University); Yousuke Kubota (Hiraka General Hospital); Sanshiro Kawata (Hamamatsu University); Takayoshi Kishino (Kagawa University); Yoshihiro Tanaka (Gifu University); Shuji Takiguchi (Nagoya City University Hospital); Fumihiro Yoshimura (Fukuoka University); Takeo Bamba (Niigata Cancer Center Hospital); Akio Kaito (Tsuchiura Kyodo General Hospital); Shinichi Kadoya (Ishikawa Prefectural Central Hospital); Yoshinori Hosoya (Jichi Medical University); Takuji Sato (Kochi Health Sciences Center); Makoto Kobayashi (Hakodate Goryoukaku Hospital); Kentaro Iwaki (Oita Red Cross Hospital); Gousuke Takiguchi (Kobe University); Motohisa Hagiwara (Nihonkai General Hospital); Koichi Ono (Obihiro Kosei Hospital); Ryuichiro Ohashi (Kagawa Prefectural Central Hospital); Shunichi Okushiba (Tonan Hospital); Takashi Nomura (Yamagata Prefectural Central Hospital); Yoichi Hamai (Hiroshima University); Eigo Otsuji (Kyoto Prefectural University); Koichi Demura (JCHO Osaka Hospital); Koichi Ogawa (University of Tsukuba); Yusuke Umeki (Fujita Health University); Dai Otsubo (Hyogo Cancer Center); Naoki Mori (Kurume University); Takashi Fukuda (Saitama Cancer Center); Tomohisa Egawa (Saiseikai Yokohamashi Tobu Hospital); Ken Sasaki (Kagoshima University); Shota Maruyama (Hachinohe City Hospital); Hisayuki Matsushita (Tochigi Cancer Center); Syoji Takagi (Okayama Red Cross Hospital); Takuo Takehana (Saku Central Hospital Advanced Care Center); Kotaro Yamashita (Osaka University); Tatsusi Suwa (Kashiwa Kousei General Hospital); Takushi Yasuda (Kindai University); Sang-Woong Lee (Osaka Medical and Pharmaceutical University); Nobutoshi Hagiwara (Nippon Medical School); Hirokazu Noshiro (Saga University); Shigeru Tsunoda (Kyoto University Hospital); Yukinori Kamio (Yamagata University); Hiroshi Ichikawa (Niigata University); Tomotaka Shibata (Oita University); Masaru Morita (Kyushu Cancer Center); Masanobu Nakajima (Dokkyo Medical University); Kazuhiro Noma (Okayama University); Shinya Mikami (St. Marianna University); Yusuke Taniyama (Tohoku University); Kiminari Naoshima (Iwate Prefectural Chubu Hospital); Ryo Maeyama (JCHO Kyushu Hospital); Yoshiro Aoki (Hiroshima City Asa Citizens Hospital); Hiroshi Miyata (Osaka International Cancer institute); Tomoki Yamatsuji (Kawasaki Medical School); Yoshihiro Ota (Tokyo Medical Unversity Hospital); Yuji Akiyama (Iwate Medical University); Kazuo Koyanagi (Tokai University); Yuji Kikuchi (Tokyo Dental College Ichikawa General Hospital); Kazuhiko Yamada (National Center for Global Health and Medicine); and Takeo Fujita (National Cancer Center Hospital East). The authors wish to acknowledge Kumiko Motooka and Sanae Oikawa, staff of the study team, for their help in collecting patient data.

Funding

Yuko Kitagawa, Relevant Financial Activities Outside the Submitted Work: Chugai Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd, Yakult Honsha Co. Ltd., Asahi Kasei Pharma Corporation, Otsuka Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Tsumura & Co., Kyouwa Hakkou Kirin Co. Ltd., EA Pharma Co. Ltd., Medicon Inc., Kaken Pharmaceutical Co. Ltd., Eisai Co. Ltd., Otsuka Pharmaceutical Factory Inc., Teijin Pharma Ltd., Nihon Pharmaceutical Co. Ltd., Nippon Covidien Inc., Shionogi & Co. Ltd., Ethicon Inc., Olympus Corporation, Bristol-Myers Squibb K.K., AstraZeneca K.K., MSD K.K., Smith & Nephew K.K., Aska Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd.

Author information

Author notes

  1. Akihiko Okamura, Jun Okui, and Satoru Matsuda have contributed equally to this article.

Authors and Affiliations

  1. Department of Esophageal Surgery, Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    Akihiko Okamura MD, PhD & Masayuki Watanabe MD, PhD

  2. Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan

    Jun Okui MD, MPH

  3. Department of Surgery, School of Medicine, Keio University, Tokyo, Japan

    Jun Okui MD, MPH, Satoru Matsuda MD, PhD, Hirofumi Kawakubo MD, PhD & Yuko Kitagawa MD, PhD

  4. Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, Tokyo, Japan

    Ryo Takemura PhD

  5. Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan

    Hiroya Takeuchi MD, PhD

  6. Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Manabu Muto MD, PhD

  7. Division of Gastrointestinal Surgery, Department of Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan

    Yoshihiro Kakeji MD, PhD

  8. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Yuichiro Doki MD, PhD

Authors
  1. Akihiko Okamura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masayuki Watanabe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Okui MD, MPH
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoru Matsuda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryo Takemura PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hirofumi Kawakubo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroya Takeuchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manabu Muto MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshihiro Kakeji MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuko Kitagawa MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuichiro Doki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masayuki Watanabe MD, PhD.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okamura, A., Watanabe, M., Okui, J. et al. Development and Validation of a Predictive Model of Therapeutic Effect in Patients with Esophageal Squamous Cell Carcinoma Who Received Neoadjuvant Treatment: A Nationwide Retrospective Study in Japan. Ann Surg Oncol 30, 2176–2185 (2023). https://doi.org/10.1245/s10434-022-12960-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-022-12960-9

Search

Navigation