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The Prognostic Value of a Pathologic Complete Response After Neoadjuvant Therapy for Digestive Cancer: Systematic Review and Meta-Analysis of 21 Studies

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

Abstract

Background

Neoadjuvant therapy (NAT) before radical excision has become the preferred initial option for locally advanced digestive cancers such as esophageal cancer (EC), esophagogastric junction adenocarcinoma (EGJAC), gastric adenocarcinoma (GAC), rectal cancer (RC), and pancreatic cancer (PC). Although some patients reportedly achieve a pathologic complete response (pCR) after neoadjuvant therapy, the published data are inconsistent regarding whether pCR yields a survival benefit. The current meta-analysis was performed to assess the potential prognostic value of pCR after preoperative therapy for patients with digestive cancers.

Methods

An extensive electronic search in PubMed, Web of Science, and the Cochrane Library was performed for relevant articles, from which data relative to independent correlations of pCR with overall survival (OS) and disease-free survival (DFS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs).

Results

The study identified 6780 patients who met the inclusion and exclusion criteria. The results showed that pCR was significantly correlated with better OS (HR, 0.50; 95% CI, 0.43–0.58; P < 0.001) and DFS (HR, 0.49; 95% CI, 0.40–0.60; P < 0.001) for the digestive cancer patients who achieved pCR than for those who did not achieve pCR. Subgroup analysis showed that the correlation of pCR with OS was significant in EC (HR, 0.57; 95% CI, 0.47–0.69; P < 0.001), EGJAC/GAC (HR, 0.38; 95% CI, 0.17–0.86; P = 0.02), RC (HR, 0.48; 95% CI, 0.28–0.81; P = 0.006), and PC (HR, 0.41; 95% CI, 0.17–0.97; P = 0.04). In addition, the survival benefit for pCR patients was of similar magnitude, irrespective of the type of study, type of NAT, or ethnicity.

Conclusions

A pCR is correlated with favorable survival outcomes compared with a non-pCR for digestive cancer patients after NAT.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  Google Scholar 

  2. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67:177–93.

    Article  PubMed  Google Scholar 

  3. Hsu PK, Chen HS, Liu CC, et al. Pre-versus postoperative chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2017;154:732–40;e732.

    Article  Google Scholar 

  4. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30:1926–33.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Cho H, Nakamura J, Asaumi Y, et al. Long-term survival outcomes of advanced gastric cancer patients who achieved a pathological complete response with neoadjuvant chemotherapy: a systematic review of the literature. Ann Surg Oncol. 2015;22:787–92.

    Article  PubMed  Google Scholar 

  7. de Campos-Lobato LF, Stocchi L, da Luz Moreira A, et al. Pathologic complete response after neoadjuvant treatment for rectal cancer decreases distant recurrence and could eradicate local recurrence. Ann Surg Oncol. 2011;18:1590–8.

    Article  PubMed  Google Scholar 

  8. Dossa F, Acuna SA, Rickles AS, et al. (2018) Association between adjuvant chemotherapy and overall survival in patients with rectal cancer and pathological complete response after neoadjuvant chemotherapy and resection. JAMA. 4:930–7.

    Google Scholar 

  9. Mansour JC, Tang L, Shah M, et al. Does graded histologic response after neoadjuvant chemotherapy predict survival for completely resected gastric cancer? Ann Surg Oncol. 2007;14:3412–8.

    Article  PubMed  Google Scholar 

  10. Hatogai K, Fujii S, Kojima T, et al. Prognostic significance of tumor regression grade for patients with esophageal squamous cell carcinoma after neoadjuvant chemotherapy followed by surgery. J Surg Oncol. 2016;113:390–6.

    Article  PubMed  Google Scholar 

  11. Smyth EC, Fassan M, Cunningham D, et al. Effect of pathologic tumor response and nodal status on survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial. J Clin Oncol. 2016;34:2721–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McCoy MJ, Hemmings C, Hillery S, et al. Neoadjuvant chemoradiotherapy for rectal cancer: how important is tumour regression? ANZ J Surg. 2017;87:E233–9.

    Article  PubMed  Google Scholar 

  13. Moher D, Liberati A, Tetzlaff J, Altman DG, Grp P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336–41.

    Article  Google Scholar 

  14. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Brit Med J. 2003;327:557–60.

    Article  PubMed  Google Scholar 

  16. DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials. 2015;45(Pt A):139–45.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Brit Med J. 1997;315:629–34.

    Article  CAS  PubMed  Google Scholar 

  18. Brucher BL, Becker K, Lordick F, et al. The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer. 2006;106:2119–27.

    Article  PubMed  Google Scholar 

  19. Miyata H, Yamasaki M, Takiguchi S, et al. Pre- and post-therapy nodal status equally affects survival of patients with oesophageal squamous cell carcinoma receiving preoperative chemoradiation. Oncol Rep. 2010;23:1331–7.

    Article  PubMed  Google Scholar 

  20. Tong DK, Law S, Kwong DL, Chan KW, Lam AK, Wong KH. Histological regression of squamous esophageal carcinoma assessed by percentage of residual viable cells after neoadjuvant chemoradiation is an important prognostic factor. Ann Surg Oncol. 2010;17:2184–92.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Orditura M, Galizia G, Morgillo F, et al. Complete response to preoperative chemoradiation and survival in esophageal cancer: a pooled analysis of three single-institution phase II trials. Dis Esophagus. 2012;25:130–6.

    Article  CAS  PubMed  Google Scholar 

  22. Donohoe CL, O’Farrell NJ, Grant T, et al. Classification of pathologic response to neoadjuvant therapy in esophageal and junctional cancer: assessment of existing measures and proposal of a novel 3-point standard. Ann Surg. 2013;258:784–92; discussion 792.

    Article  PubMed  Google Scholar 

  23. Wang CC, Cheng JC, Tsai CL, et al. Pathological stage after neoadjuvant chemoradiation and esophagectomy superiorly predicts survival in patients with esophageal squamous cell carcinoma. Radiother Oncol. 2015;115:9–15.

    Article  PubMed  Google Scholar 

  24. Alnaji RM, Du W, Gabriel E, et al. Pathologic complete response is an independent predictor of improved survival following neoadjuvant chemoradiation for esophageal adenocarcinoma. J Gastrointest Surg. 2016;20:1541–46.

    Article  PubMed  Google Scholar 

  25. Blum Murphy M, Xiao L, Patel VR, et al. Pathological complete response in patients with esophageal cancer after the trimodality approach: the association with baseline variables and survival: the University of Texas MD Anderson Cancer Center experience. Cancer. 2017;123:4106–13.

    Article  PubMed  Google Scholar 

  26. Hamai Y, Hihara J, Emi M, et al. Preoperative prediction of a pathologic complete response of esophageal squamous cell carcinoma to neoadjuvant chemoradiotherapy. Surgery. 2018;164:40–48.

    Article  Google Scholar 

  27. Xi M, Yang Y, Zhang L, et al. Multi-institutional analysis of recurrence and survival after neoadjuvant chemoradiotherapy of esophageal cancer: impact of histology on recurrence patterns and outcomes. Ann Surg. 2018. https://doi.org/10.1097/SLA.0000000000002670.

    Article  PubMed  Google Scholar 

  28. Ott K, Rachakonda PS, Panzram B, et al. DNA repair gene and MTHFR gene polymorphisms as prognostic markers in locally advanced adenocarcinoma of the esophagus or stomach treated with cisplatin and 5-fluorouracil-based neoadjuvant chemotherapy. Ann Surg Oncol. 2011;18:2688–98.

    Article  PubMed  Google Scholar 

  29. Koh YW, Park YS, Ryu MH, et al. Postoperative nodal status and diffuse-type histology are independent prognostic factors in resectable advanced gastric carcinomas after preoperative chemotherapy. Am J Surg Pathol. 2013;37:1022–9.

    Article  PubMed  Google Scholar 

  30. Lorenzen S, Thuss-Patience P, Al-Batran SE, et al. Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy. Ann Oncol. 2013;24:2068–73.

    Article  CAS  PubMed  Google Scholar 

  31. Chan AK, Wong A, Jenken D, Heine J, Buie D, Johnson D. Posttreatment TNM staging is a prognostic indicator of survival and recurrence in tethered or fixed rectal carcinoma after preoperative chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61:665–77.

    Article  PubMed  Google Scholar 

  32. Topova L, Hellmich G, Puffer E, et al. Prognostic value of tumor response to neoadjuvant therapy in rectal carcinoma. Dis Colon Rectum. 2011;54:401–11.

    Article  PubMed  Google Scholar 

  33. Mace AG, Pai RK, Stocchi L, Kalady MF. American Joint Committee on Cancer and College of American Pathologists regression grade: a new prognostic factor in rectal cancer. Dis Colon Rectum. 2015;58:32–44.

    Article  PubMed  Google Scholar 

  34. De Felice F, Musio D, Magnante AL, et al. disease control, survival, and toxicity outcome after intensified neoadjuvant chemoradiotherapy for locally advanced rectal cancer: a single-institution experience. Clin Colorect Cancer. 2016;15:e17–22.

    Article  Google Scholar 

  35. Wasmuth HH, Rekstad LC, Trano G. The outcome and the frequency of pathological complete response after neoadjuvant radiotherapy in curative resections for advanced rectal cancer: a population-based study. Colorect Dis. 2016;18:67–72.

    Article  CAS  Google Scholar 

  36. Wilkins S, Haydon A, Porter I, et al. Complete pathological response after neoadjuvant long-course chemoradiotherapy for rectal cancer and its relationship to the degree of t3 mesorectal invasion. Dis Colon Rectum. 2016;59:361–8.

    Article  PubMed  Google Scholar 

  37. Suzuki T, Sadahiro S, Tanaka A, et al. A modified classification of prognostic factors based on pathological stage and tumor regression grade in patients with rectal cancer who receive preoperative chemoradiotherapy. Oncology. 2017;93:287–94.

    Article  PubMed  PubMed Central  Google Scholar 

  38. He J, Blair AB, Groot VP, et al. (2018) Is a pathological complete response following neoadjuvant chemoradiation associated with prolonged survival in patients with pancreatic cancer? Ann Surg. 268:1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sung JJ, Ng EK, Lin JT, et al. Digestive cancer management in Asia: position statements: a report on GI Oncology Summit in 2011. J Gastroenterol Hepatol. 2012;27:1417–22.

    Article  PubMed  Google Scholar 

  40. Sherman KL, Merkow RP, Shah AM, Wang CE, Bilimoria KY, Bentrem DJ. Assessment of advanced gastric cancer management in the United States. Ann Surg Oncol. 2013;20:2124–31.

    Article  PubMed  Google Scholar 

  41. Pasini F, de Manzoni G, Zanoni A, et al. Neoadjuvant therapy with weekly docetaxel and cisplatin, 5-fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long-lasting pathological complete response: a phase 2 study. Cancer. 2013;119:939–45.

    Article  CAS  PubMed  Google Scholar 

  42. Al-Batran SE, Homann N, Pauligk C, et al. Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: the AIO-FLOT3 Trial. JAMA Oncol. 2017;3:1237–44.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Jang JY, Han Y, Lee H, et al. (2018) Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg. 268:215–22.

    Article  PubMed  Google Scholar 

  44. Onaitis MW, Noone RB, Hartwig M, et al. Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience. Ann Surg. 2001;233:778–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Foxtrot Collaborative G. Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial. Lancet Oncol. 2012;13:1152–60.

    Article  CAS  Google Scholar 

  46. Garces CA, McAuliffe PF, Hochwald SN, Cance WG. Neoadjuvant therapy in the treatment of solid tumors. Curr Probl Surg. 2006;43:457–551.

    Article  Google Scholar 

  47. Trimble EL, Ungerleider RS, Abrams JA, et al. Neoadjuvant therapy in cancer treatment. Cancer. 1993;72(11 Suppl):3515–24.

    Article  CAS  PubMed  Google Scholar 

  48. Pucciarelli S, Toppan P, Friso ML, et al. Complete pathologic response following preoperative chemoradiation therapy for middle to lower rectal cancer is not a prognostic factor for a better outcome. Dis Colon Rectum. 2004;47:1798–807.

    Article  PubMed  Google Scholar 

  49. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72.

    Article  PubMed  Google Scholar 

  50. Houssami N, Macaskill P, von Minckwitz G, Marinovich ML, Mamounas E. Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy. Eur J Cancer. 2012;48:3342–54.

    Article  CAS  PubMed  Google Scholar 

  51. Kong X, Moran MS, Zhang N, Haffty B, Yang Q. Meta-analysis confirms achieving pathological complete response after neoadjuvant chemotherapy predicts favourable prognosis for breast cancer patients. Eur J Cancer. 2011;47:2084–90.

    Article  PubMed  Google Scholar 

  52. Petrelli F, Coinu A, Cabiddu M, Ghilardi M, Vavassori I, Barni S. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol. 2014;65:350–7.

    Article  PubMed  Google Scholar 

  53. Garcia M, Martinez-Villacampa M, Santos C, et al. Phase II study of preoperative bevacizumab, capecitabine and radiotherapy for resectable locally advanced rectal cancer. BMC Cancer. 2015;15:59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xiao J, Chen Z, Li W, et al. Sandwich-like neoadjuvant therapy with bevacizumab for locally advanced rectal cancer: a phase II trial. Cancer Chemother Pharmacol. 2015;76:21–7.

    Article  CAS  PubMed  Google Scholar 

  55. Badakhshi H, Ismail M, Boskos C, Zhao K, Kaul D. The role of concomitant radiation boost in neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Anticancer Res. 2017;37:3201–5.

    CAS  PubMed  Google Scholar 

  56. Tulchinsky H, Shmueli E, Figer A, Klausner JM, Rabau M. An interval > 7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer. Ann Surg Oncol. 2008;15:2661–7.

    Article  PubMed  Google Scholar 

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Acknowledgment

We thank Doctor Yanfang Zhao from the Department of Health Statistics of the Second Military Medical University (Shanghai, China) for her critical revision of the meta-analysis section.

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Author notes

  1. Xiao-Feng Zhang and Chao Liang have contributed equally to this study.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Jiangxi Provincial People’s Hospital, Nanchang, China

    Tao Wan MS, Chao Liang MS & Chuan-Wen Liao MD

  2. Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China

    Xiao-Feng Zhang MD

  3. Department of Hepatobiliary and Pancreatovascular Surgery, First Affiliated Hospital of Xiamen University, Xiamen, China

    Jia-Yi Li MD & Yan-Ming Zhou MD

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  1. Tao Wan MS
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Wan, T., Zhang, XF., Liang, C. et al. The Prognostic Value of a Pathologic Complete Response After Neoadjuvant Therapy for Digestive Cancer: Systematic Review and Meta-Analysis of 21 Studies. Ann Surg Oncol 26, 1412–1420 (2019). https://doi.org/10.1245/s10434-018-07147-0

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