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Gastroenterologie
a hepatologie

Gastroenterology and Hepatology

Gastroent Hepatol 2020; 74(5): 393–403. doi:10.14735/amgh2020393.

Současné možnosti predikce léčebné odpovědi na neoadjuvantní chemoradioterapii u karcinomu konečníku

Filip Pazdírek1, Marek Minárik2,3, Lucie Benešová2, Jiří Hoch, Radka Lohynská4

+ Pracoviště

Souhrn

Standardem léčby pacientů s lokálně pokročilým karcinomem konečníku je neoadjuvantní chemoterapie v kombinaci s radiací. Hlavním cílem léčby je snížit riziko rekurence. S léčbou však mohou být spojeny také závažné nežádoucí účinky v důsledku postradiačního poškození v oblasti pánve. Mnoho skupin se snaží najít markery, které by umožňovaly předpovídat odpověď na léčbu. Tento přehledový článek přináší rešerši literatury provedenou za účelem identifikace hlavních studií zaměřených na použití klinických, radiologických, imunologických a molekulárních (proteinových, DNA a RNA) markerů. Pro každou skupinu předkládáme souhrn poznatků. Obecně lze shrnout, že interpretace v současné době získaných poznatků je spojena s určitou mírou nejednoznačnosti a nejednotnosti. Zdá se, že i v nejslibnější oblasti cirkulujících molekulárních biomarkerů je zapotřebí dalšího výzkumu, než bude možné stanovit jejich užitečnost v klinické praxi.

Klíčová slova

karcinom konečníku, neoadjuvantní chemoradioterapie, cirkulující nádorová ctDNA, prognóza, odpověď, biomarker

Článek je v angličtině, prosím přepněte do originální verze.

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Literatura

1. Maas M, Nelemans PJ, Valentini V et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11 (9): 835–844. doi: 10.1016/S1470-2045 (10) 70 172-8.
2. Habr-Gama A, Gama-Rodrigues J, São Julião GP et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys 2014; 88 (4): 822–828. doi: 10.1016/j.ijrobp.2013.12.012.
3. Appelt AL, Pløen J, Harling H et al. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol 2015; 16 (8): 919–927. doi: 10.1016/S1470-2045 (15) 00120-5.
4. van der Valk MJM, Marijnen CAM, van Etten B et al. Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer – Results of the international randomized RAPIDO-trial. Radiother Oncol 2020; 147: 75–83. doi: 10.1016/j.radonc.2020.03.011.
5. Garland ML Vather R, Bunkley N et al. Clinical tumour size and nodal status predict pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer. Int J Colorectal Dis 2014; 29 (3): 301–307. doi: 10.1007/s00384-013-1821-7.
6. Qiu HZ, Wu B, Xiao Y et al. Combination of differentiation and T stage can predict unresponsiveness to neoadjuvant therapy for rectal cancer. Colorectal Dis 2011; 13 (12): 1353–1360. doi: 10.1111/j.1463-1318.2011.02570.x.
7. Kalady MF, de Campos-Lobato LF, Stocchi L et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg 2009; 250 (4): 582–589. doi: 10.1097/SLA.0b013e3181b91e63.
8. Braendengen M, Tveit KM, Berglund A et al. Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol 2008; 26 (22): 3687–3694. doi: 10.1200/ JCO.2007.15.3858.
9. Das P, Skibber JM, Rodriguez-Bigas MA et al. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer. Cancer 2007. 109 (9): 1750–1755. doi: 10.1002/cncr. 22625.
10. Engel RM, Oliva K, Koulis Ch et al. Predictive factors of complete pathological response in patients with locally advanced rectal cancer. Int J Colorectal Dis 2020; 35 (9): 1759–1767. doi: 10.1007/s00384-020-03633-8.
11. Bustamante-Lopez LA, Rizkallah Nahas CS, Carlos Nahas S et al. Pathologic complete response implies a fewer number of lymph nodes in specimen of rectal cancer patients treated by neoadjuvant therapy and total mesorectal excision. Int J Surg 2018; 56: 283–287. doi: 10.1016/j.ijsu.2018.07.001.
12. Lorimer D, Motz BM, Kirks RC et al. Pathologic Complete Response Rates After Neoadjuvant Treatment in Rectal Cancer: An Analysis of the National Cancer Database. Annals of Surgical Oncology 2017; 24 (8): 2095–2103. doi: 10.1245/s10434-017-5873-8.
13. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001; 18 (4): 243–259. doi: 10.1385/MO: 18: 4: 243.
14. Box B, Lindsey I, Wheeler JM et al. Neoadjuvant therapy for rectal cancer: improved tumor response, local recurrence, and overall survival in nonanemic patients. Dis Colon Rectum 2005; 48 (6): 1153–1160. doi: 10.1007/s10350-004-0939-7.
15. Lee H, Park HCh, Park W et al. Negative impact of pretreatment anemia on local control after neoadjuvant chemoradiotherapy and surgery for rectal cancer. Radiat Oncol J 2012; 30 (3): 117–23. doi: 10.3857/roj.2012.30.3. 117.
16. Clarke TL, White DA, Osborne ME et al. Predicting response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer with serum bio­markers. Ann R Coll Surg Engl 2017; 99 (5): 373–377. doi: 10.1308/rcsann.2017. 0030.
17. Hötker AM, Tarlinton L, Mazaheri Y et al. Multiparametric MRI in the assessment of response of rectal cancer to neoadjuvant chemoradiotherapy: A comparison of morphological, volumetric and functional MRI parameters. Eur Radiol 2016; 26 (12): 4303–4312. doi: 10.1007/s00330-016-4283-9.
18. Kluza E, Rozeboom ED, Maas M et al. T2 weighted signal intensity evolution may predict pathological complete response after treatment for rectal cancer. Eur Radiol 2013; 23 (1): 253–261. doi: 10.1007/s00330-012- 2578-z.
19. DeVries AF, Kremser Ch, Hein PA et al. Tumor microcirculation and diffusion predict therapy outcome for primary rectal carcinoma. Int J Radiat Oncol Biol Phys 2003; 56 (4): 958–965. doi: 10.1016/s0360-3016 (03) 00208-6.
20. DeVries AF, Griebel J, Kremser C et al. Tumor microcirculation evaluated by dynamic magnetic resonance imaging predicts therapy outcome for primary rectal carcinoma. Cancer Res 2001; 61 (6): 2513–2516.
21. Kremser C, Trieb T, Rudisch A et al. Dynamic T (1) mapping predicts outcome of chemoradiation therapy in primary rectal carcinoma: sequence implementation and data analysis. J Magn Reson Imaging 2007; 26 (3): 662–671. doi: 10.1002/jmri.21034.
22. Lambrecht M, Vandecaveye V, De Keyzerr F et al. Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results. Int J Radiat Oncol Biol Phys 2012; 82 (2): 863–870. doi: 10.1016/j.ijrobp.2010.12. 063.
23. Barbaro B, Vitale R, Valentini V et al. Diffusion-weighted magnetic resonance imaging in monitoring rectal cancer response to neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2012; 83 (2): 594–599. doi: 10.1016/j.ijrobp.2011.07.017.
24. Elmi A, Hedgire SS, Covarrubias D et al. Apparent diffusion coefficient as a non-invasive predictor of treatment response and recurrence in locally advanced rectal cancer. Clin Radiol 2013; 68 (10): e524–e31. doi: 10.1016/j.crad.2013.05.094.
25. Maas M, Lambregts DMJ, Nelemans PJ et al. Assessment of Clinical Complete Response After Chemoradiation for Rectal Cancer with Digital Rectal Examination, Endoscopy, and MRI: Selection for Organ-Saving Treatment. Ann Surg Oncol 2015; 22 (12): 3873–3880. doi: 10.1245/s10434-015-4687-9.
26. Lambregts DM, Rao SX, Sassen S et al. MRI and Diffusion-weighted MRI Volumetry for Identification of Complete Tumor Responders After Preoperative Chemoradiotherapy in Patients With Rectal Cancer: A Bi-institutional Validation Study. Ann Surg 2015; 262 (6): 1034–1039. doi: 10.1097/SLA.0000000000000 909.
27. Yoen H, Park HE, Kim SH et al. Prognostic Value of Tumor Regression Grade on MR in Rectal Cancer: A Large-Scale, Single-Center Experience. Korean J Radiol 2020; 21 (9): 1065–1076. doi: 10.3348/kjr.2019.0797.
28. Goldberg N, Kundel Y, Purim O et al. Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using (18) F-FDG PET-CT imaging. A prospective clinical study. Radiation Oncology (London, England) 2012; 7: 124. doi: 10.1186/1748-717X-7-124.
29. Kim JW, Kim HCh, Park JW et al. Predictive value of (18) FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy. Int J Colorectal Dis 2013; 28 (9): 1217–1224. doi: 10.1007/s00384-013-1657-1.
30. Martoni AA, Fabio­ DD, Pinto C et al. Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer. Ann Oncol 2011; 22 (3): 650–656. doi: 10.1093/annonc/mdq433.
31. Cai D, Huang ZH, Yu HC et al. Prognostic value of preoperative carcinoembryonic antigen/tumor size in rectal cancer. World J Gastroenterol 2019; 25 (33): 4945–4958. doi: 10.3748/wjg.v25.i33.4945.
32. Wallin U, Rothenberger D, Lowry A et al. CEA – a predictor for pathologic complete response after neoadjuvant therapy for rectal cancer. Dis Colon Rectum 2013; 56 (7): 859–868. doi: 10.1097/DCR.0b013e31828e5a72.
33. Zeng WG, Liang JW, Wang Z et al. Clinical parameters predicting pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer. Chin J Cancer 2015; 34 (10): 468–474. doi: 10.1186/s40880-015- 0033-7.
34. Moreno García V, Cejas P, Blanco Codesido M et al. Prognostic value of carcinoembryonic antigen level in rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Colorectal Dis 2009; 24 (7): 741–748. doi: 10.1007/s00384-009-0682-6.
35. Moureau-Zabotto L, Farnault B, de Chaisemartin C et al. Predictive factors of tumor response after neoadjuvant chemoradiation for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2011; 80 (2): 483–491. doi: 10.1016/j.ijrobp.2010.02.025.
36. Wang L, Zhong XG, Peng YF et al. Prognostic value of pretreatment level of carcinoembryonic antigen on tumour downstaging and early occurring metastasis in locally advanced rectal cancer following neoadjuvant radiotherapy (30 Gy in 10 fractions). Colorectal Dis 2014; 16 (1): 33–39. doi: 10.1111/codi.12 354.
37. Kleiman A, Al-Khamis A, Farsi A et al. Normalization of CEA Levels Post-Neoadjuvant Therapy is a Strong Predictor of Pathologic Complete Response in Rectal Cancer. J Gastrointest Surg 2015; 19 (6): 1106–1112. doi: 10.1007/s11605-015-2814-3.
38. Jakob C, Liersch T, Meyer W et al. Predictive value of Ki67 and p53 in locally advanced rectal cancer: correlation with thymidylate synthase and histopathological tumor regression after neoadjuvant 5-FU-based chemoradiotherapy. World J Gastroenterol 2008; 14 (7): 1060–1066. doi: 10.3748/wjg.14.1060.
39. Negri FV, Campanini N, Camisa R et al. Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy. Br J Cancer 2008; 98 (1): 143–147. doi: 10.1038/sj.bjc.6604131.
40. Spolverato G, Pucciarelli S, Bertorelle R et al. Predictive factors of the response of rectal cancer to neoadjuvant radiochemotherapy. Cancers (Basel) 2011; 3 (2): 2176–2194. doi: 10.3390/cancers3022176.
41. Kudrimoti M, Lee EY, Kang Y et al. Genetic markers predictive of response to induction chemoradiotherapy for locally advanced rectal cancers. J Ky Med Assoc 2007; 105 (1):  18–22.
42. Bengala C, Bettelli S, Bertolini F et al. Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. Br J Cancer 2010; 103 (7):  1019–1024. doi: 10.1038/sj.bjc.6605853.
43. Grimminger PP, Danenberg P, Dellas K  et al. Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer. Clin Cancer Res 2011; 17 (10): 3469–3477. doi: 10.1158/1078-0432.CCR-10- 2273.
44. Garcia-Aguilar J, Chen Z, Smith DD et al. Identification of a bio­marker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg 2011; 254 (3): 486–493. doi: 10.1097/SLA.0b013e31822b8cfa.
45. Garg H, Suri P, Gupta JC, Talwar GP et al. Survivin: a unique target for tumor therapy. Cancer Cell Int 2016; 16: 49. doi: 10.1186/ s12935-016-0326-1.
46. Terzi C, Canda AE, Sagol O et al. Survivin, p53, and Ki-67 as predictors of histopathologic response in locally advanced rectal cancer treated with preoperative chemoradiotherapy. Int J Colorectal Dis 2008; 23 (1): 37–45. doi: 10.1007/s00384-007-0376-x.
47. Kim K, Chie EK, Wu HG et al. High survivin expression as a predictor of poor response to preoperative chemoradiotherapy in locally advanced rectal cancer. Int J Colorectal Dis 2011; 26 (8): 1019–1023. doi: 10.1007/s00384-011- 1180-1.
48. Bettegowda C, Sausen M, Leary RJ et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6 (224): 224ra24. doi: 10.1126/scitran slmed.3007094.
49. Shinto E, Hashiguchi Y, Ueno H et al. Pre­treatment CD133 and cyclooxygenase-2 expression as the predictive markers of the pathological effect of chemoradiotherapy in rectal cancer patients. Dis Colon Rectum 2011; 54 (9): 1098–1106. doi: 10.1097/DCR.0b013e3182218 155.
50. Giralt J, Navalpotro B, Hermosilla E et al. Prognostic significance of vascular endothelial growth factor and cyclooxygenase-2 in patients with rectal cancer treated with preoperative radiotherapy. Oncology 2006; 71 (5–6): 312–319. doi: 10.1159/000107105.
51. Folkvord S, Flatmark K, Dueland S et al. Prediction of response to preoperative chemoradiotherapy in rectal cancer by multiplex kinase activity profiling. Int J Radiat Oncol Biol Phys 2010; 78 (2): 555–562. doi: 10.1016/j.ijrobp.2010.04.036.
52. Huh JW, Lee JH, Kim HR. Pretreatment expression of 13 molecular markers as a predictor of tumor responses after neoadjuvant chemoradiation in rectal cancer. Ann Surg 2014; 259 (3): 508–515. doi: 10.1097/SLA.0b013e31829b 3916.
53. Chang HJ, Jung KH, Kim DY et al. Bax, a predictive marker for therapeutic response to preoperative chemoradiotherapy in patients with rectal carcinoma. Hum Pathol 2005; 36 (4): 364–371. doi: 10.1016/j.humpath.2005.01. 018.
54. Moral M, Fdez-Aceñero MJ, Cuberes R et al. Factors influencing prognosis after neo-adjuvant chemoradiation therapy for rectal carcinoma. Acta Chir Belg 2009; 109 (3): 345–351. doi: 10.1080/00015458.2009.11680 437.
55. Lin LC, Lee HH, Hwang WS et al. p53 and p27 as predictors of clinical outcome for rectal-cancer patients receiving neoadjuvant therapy. Surg Oncol 2006; 15 (4): 211–216. doi: 10.1016/j.suronc.2007.01.001.
56. Sturm I, Rau B, Schlag PM et al. Genetic dissection of apoptosis and cell cycle control in response of colorectal cancer treated with preoperative radiochemotherapy. BMC Cancer 2006; 6: 124. doi: 10.1186/1471-2407-6- 124.
57. Troncarelli Flores BC, Souza E Silva V, Abdallah EA et al. Molecular and Kinetic Analyses of Circulating Tumor Cells as Predictive Markers of Treatment Response in Locally Advanced Rectal Cancer Patients. Cells 2019; 8 (7): 641. doi: 10.3390/cells8070641.
58. Spitz FR, Giacco GG, Hess K et al. p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer. Clin Cancer Res 1997; 3 (10): 1685–1690.
59. Rebischung C, Gérard JP, Gayet J et al. Prognostic value of P53 mutations in rectal carcinoma. Int J Cancer 2002; 100 (2): 131–135. doi: 10.1002/ijc.10480.
60. Chen MB, Wu XY, Yu R et al. P53 status as a predictive bio­marker for patients receiving neoadjuvant radiation-based treatment: a meta-analysis in rectal cancer. PLoS One 2012; 7 (9): e45388. doi: 10.1371/journal.pone.0045 388.
61. Chen Z, Liu Z, Li W et al. Chromosomal copy number alterations are associated with tumor response to chemoradiation in locally advanced rectal cancer. Genes Chromosomes Cancer 2011; 50 (9): 689–699. doi: 10.1002/gcc.20 891.
62. Sun W, Sun Y, Zhu M et al. The role of plasma cell-free DNA detection in predicting preoperative chemoradiotherapy response in rectal cancer patients. Oncol Rep 2014; 31 (3): 1466–1472. doi: 10.3892/or.2013.2949.
63. Spindler KLG, Nielsen JN, Lindebjerg J et al. Germline polymorphisms may act as predictors of response to preoperative chemoradiation in locally advanced T3 rectal tumors. Dis Colon Rectum 2007; 50 (9): 1363–1369. doi: 10.1007/s10350-007-0264-z.
64. Hur H, Kang J, Kim NK et al. Thymidylate synthase gene polymorphism affects the response to preoperative 5-fluorouracil chemoradiation therapy in patients with rectal cancer. Int J Radiat Oncol Biol Phys 2011; 81 (3): 669–676. doi: 10.1016/j.ijrobp.2010.06.049.
65. Ghadimi BM, Grade M, Difilippantonio MJ et al. Effectiveness of Gene Expression Profiling for Response Prediction of Rectal Adenocarcinomas to Preoperative Chemoradiotherapy. J Clin Oncol 2005; 23 (9): 1826–1838. doi: 10.1200/JCO.2005.00.406.
66. Rimkus C, Friederichs J, Boulesteix AL et al. Microarray-based prediction of tumor response to neoadjuvant radiochemotherapy of patients with locally advanced rectal cancer. Clin Gastroenterol Hepatol 2008; 6 (1): 53–61. doi: 10.1016/j.cgh.2007.10.022.
67. Brettingham-Moore KH, Duong CP, Greenawalt DM et al. Pretreatment transcriptional profiling for predicting response to neoadjuvant chemoradiotherapy in rectal adenocarcinoma. Clin Cancer Res 2011; 17 (9): 3039–3047. doi: 10.1158/1078-0432.CCR-10- 2915.
68. Della Vittoria Scarpati G, Falcetta F, Carlomagno Ch et al. A specific miRNA signature correlates with complete pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2012; 83 (4): 1113–1119. doi: 10.1016/ j.ijrobp.2011.09.030.
69. Kheirelseid EA, Miller N, Chang KH et al. miRNA expressions in rectal cancer as predictors of response to neoadjuvant chemoradiation therapy. Int J Colorectal Dis 2013; 28 (2): 247–260. doi: 10.1007/s00384-012- 1549-9.
70. Lopes-Ramos CM, Habr-Gama A, de Souza Quevedo B et al. Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients. BMC Med Genomics 2014; 7: 68. doi: 10.1186/s12920-014- 0068-7.
71. McDowell DT, Smith FM, Reynolds JV et al. Increased spontaneous apoptosis, but not survivin expression, is associated with histomorphologic response to neoadjuvant chemoradiation in rectal cancer. Int J Colorectal Dis 2009; 24 (11): 1261–1269. doi: 10.1007/s00384-009- 0755-6.
72. Tannapfel A, Nüsslein S, Fietkau R et al. Apoptosis, proliferation, bax, bcl-2 and p53 status prior to and after preoperative radiochemotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 1998; 41 (3): 585–591. doi: 10.1016/s0360-3016 (98) 00 076-5.
73. Stone HB, Peters LJ, Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst 1979; 63 (5):  1229–1235.
74. Yasuda K, Nirei T, Sunami E et al. Density of CD4 (+) and CD8 (+) T lymphocytes in bio­psy samples can be a predictor of pathological response to chemoradiotherapy (CRT) for rectal cancer. Radiat Oncol 2011; 6: 49. doi: 10.1186/1748-717X-6-49.
75. Kitayama J, Yasuda K, Kawai K et al. Circulating lymphocyte is an important determinant of the effectiveness of preoperative radiotherapy in advanced rectal cancer. BMC Cancer 2011; 11: 64. doi: 10.1186/1471-2407-11-64.
76. Tada N, Kawai K, Tsuno NH et al. Prediction of the preoperative chemoradiotherapy response for rectal cancer by peripheral blood lymphocyte subsets. World J Surg Oncol 2015; 13: 30. doi: 10.1186/s12957-014-0 418-0.
77. Milne K, Alexander Ch, Webb JR et al. Absolute lymphocyte count is associated with survival in ovarian cancer independent of tumor-infiltrating lymphocytes. J Transl Med 2012; 10: 33. 10.1186/1479-5876-10-33.
78. Bidard FC, Peeters DJ, Fehm T et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol 2014; 15 (4): 406–414. doi: 10.1016/S1470-2045 (14)  70069-5.
79. Ignatiadis M, Rack B, Rothé F et al. Liquid bio­psy-based clinical research in early breast cancer: The EORTC 90091-10093 Treat CTC trial. Eur J Cancer 2016; 63: 97–104. doi: 10.1016/j.ejca.2016.04.024.
80. Rahbari NN, Aigner M, Thorlund K et al. Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology 2010; 138 (5): 1714–1726. doi: 10.1053/j.gastro.2010.01.008.
81. Magni E, Botteri E, Ravenda PS et al. Detection of circulating tumor cells in patients with locally advanced rectal cancer undergoing neoadjuvant therapy followed by curative surgery. Int J Colorectal Dis 2014; 29 (9): 1053–1059. doi: 10.1007/s00384-014-1958-z.
82. Sun W, Guichao Li, Wan J et al. Circulating tumor cells: A promising marker of predicting tumor response in rectal cancer patients receiving neoadjuvant chemo-radiation therapy. Oncotarget 2016; 7 (43): 69507–69517. doi: 10.18632/oncotarget.10875.
83. Kustanovich A, Schwartz R, Peretz T et al. Life and death of circulating cell-free DNA. Cancer Biol Ther 2019; 20 (8): 1057–1067. doi: 10.1080/15384047.2019.1598759.
84. Zitt M, Müller HM, Rochel M et al. Circulating cell-free DNA in plasma of locally advanced rectal cancer patients undergoing preoperative chemoradiation: a potential dia­gnostic tool for therapy monitoring. Dis Markers 2008; 25 (3): 159–165. doi: 10.1155/2008/598071.
85. Agostini M, Pucciarelli S, Enzo MV et al. Circulating cell-free DNA: a promising marker of pathologic tumor response in rectal cancer patients receiving preoperative chemoradiotherapy. Ann Surg Oncol 2011; 18 (9): 2461–2468. doi: 10.1245/s10434-011-1638-y.
86. Carpinetti P, Donnard E, Bettoni F et al. The use of personalized bio­markers and liquid bio­psies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation. Oncotarget 2015; 6 (35): 38360–38371. doi: 10.18632/oncotarget.5256.

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