Influence of Preoperative Chemoradiotherapy on Changes of Epidermal Growth Factor Receptor Expression in Patients Treated by Preoperative Chemoradiotherapy for Local Advanced Rectal Carcinoma
Authors:
I. Richter 1; J. Dvořák 2; A. Blüml 3; E. Čermáková 4; J. Bartoš 1; M. Urbanec 5; V. Sitorová 6; A. Ryška 6; I. Sirák 7; D. Buka 7; A. Ferko 8; B. Melichar 9; J. Petera 7
Authors‘ workplace:
Onkologické oddělení, Krajská nemocnice Liberec, a. s.
1; Onkologická klinika 1. LF UK a Thomayerova nemocnice, Praha
2; Oddělení patologie, Krajská nemocnice Liberec, a. s.
3; Ústav biofyziky a informatiky, LF UK v Hradci Králové
4; Oddělení patologie, Nemocnice s poliklinikou Česká Lípa, a. s.
5; Fingerlandův patologický ústav, LF UK v Hradci Králové
6; Klinika onkologie a radioterapie LF UK a FN Hradec Králové
7; Chirurgická klinika LF UK a FN Hradec Králové
8; Onkologická klinika LF UP a FN Olomouc
9
Published in:
Klin Onkol 2014; 27(5): 361-366
Category:
Original Articles
doi:
https://doi.org/10.14735/amko2014361
Overview
Aim:
The aim of this retrospective study was to determine the prognostic impact of expression of epidermal growth factor receptor (EGFR) changes during neoadjuvant chemoradiotherapy in patients with locally advanced rectal adenocarcinoma.
Material and Methods:
One hundred and three patients with locally advanced rectal adenocarcinoma of stage II and III were evaluated. All patients were administered the total dose of 44– 50.4 Gy. Concomitantly, the patients received capecitabine in the dose 825 mg/ m2 in two daily oral administrations or 5- fluorouracil in the dose 200 mg/ m2 in continuous infusion. Surgery was indicated at intervals of 4– 8 weeks from chemoradiotherapy completion. EGFR expression in the pretreatment biopsies and in resected specimens was assessed with immunohistochemistry.
Results:
All of 103 patients received radiotherapy without interruption up to the total planned dose. Downstaging was described in 64 patients. Six patients had complete pathologic remission. Recurrence occurred in 49 patients. Local recurrence was found in 22 patients, generalization of disease was reported in 27 patients. A total of 51 patients died. Increased EGFR expression was found in 26 patients. The statistically significantly shorter overall survival (p < 0.001) and disease-free survival (p < 0.001) was found in patients with increased expression of EGFR compared with patients where no increase in the expression of EGFR was observed during neoadjuvant chemoradiotherapy.
Conclusions:
The overexpression of EGFR during neoadjuvant chemoradiotherapy for locally advanced rectal adenocarcinoma is associated with significant shorter overall survival and disease-free survival.
Key words:
rectal cancer – neoadjuvant therapy – chemoradiotherapy – monoclonal antibodies – epidermal growth factor receptor
This study was supported by the Scientific Council of the Regional Hospital Liberec, plc VR130304 and by project PRVOUK P37/01.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Submitted:
12. 8. 2014
Accepted:
26. 8. 2014
Sources
1. Dušek L, Mužík J, Kubásek M et al (eds). Epidemiologie zhoubných nádorů v České republice [online]. Brno: Masarykova univerzita; 2005 [citováno 13. července 2009]. Dostupné z: http:/ / www.svod.cz.
2. Doleželová-Horová H, Ondrová B, Šlampa P et al. Karcinom konečníku. In: Šlampa P, Petera J et al (eds). Radiační onkologie. 1. vyd. Praha: Galén 2007: 153– 162.
3. Kocáková I, Soumarová R. Chemoradioterapie karcinomu konečníku. In: Šlampa P, Soumarová R, Kocáková Iet al (eds). Konkomitantní chemoradioterapie solidních nádorů. Praha: Galén 2005: 62– 72.
4. Šlampa P, Lovas P, Lovasová Z et al. Karcinomy konečníku. In: Šlampa P et al (eds). Radiační onkologie v praxi. 3. vyd. Brno: Masarykův onkologický ústav 2011: 70– 78.
5. Dvořák J, Richter I, Buka D et al. Chemoradioterapie lokálně pokročilých karcinomů rekta. Farmakoterapie 2013; Suppl: 42– 46.
6. Richter I, Dvořák J, Bartoš J. Neoadjuvantní léčba karcinomu rekta. Onkologie 2013; 7: 287– 290.
7. Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351(17): 1731– 1740.
8. Bosset JF, Calais G, Mineur L et al. Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results – EORTC 22921. J Clin Oncol 2005; 23(24): 5620– 5627.
9. Gerard JP, Conroy T, Bonnetain F et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorine in T3– 4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24(28): 4620– 4625.
10. Ceelen WP, Van Nieuwenhove Y, Fierens K et al. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev 2009; 1: CD006041. doi: 10.1002/ 14651858.CD006041.pub2.
11. Hofheinz RD, Wenz F, Post S et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012; 13(6): 579– 588. doi: 10.1016/ S1470-2045(12)70116-X.
12. De Caluwé L, van Nieuwenhove Y, Ceelen WP et al. Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev 2013; 2: CD006041. doi: 10.1002/ 14651858.CD006041.pub3.
13. Sirák I, Hatlová J, Petera J et al. Receptor pro epidermální růstový faktor a jeho úloha v radioterapii. Klin Okol 2008; 21(6): 338– 347.
14. Steele RJ, Kelly P, Ellul B et al. Epidermal growth factor receptor expression in colorectal cancer. Br J Surg 1990; 77(12): 1352– 1354.
15. Mayer A, Takimoto M, Fritz E et al. The prognostic signifikance of proliferating cell nuclear antigen, epidermal growth factor receptor, and MDR gene expression in colorectal cancer. Cancer 1993; 71(8): 2454– 2460.
16. Khorana AA, Ryan CK, Cox et al. Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with stage II and stage III colon carcinoma: a role for the host response in prognosis. Cancer 2003; 97(4): 960– 968.
17. Withers HR, Taylor JM, Maciejewski B et al. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27(2): 131– 146.
18. M, Petersen C, Eichler W et al. Mechanism of repopulation in experimental squamous cell carcinoma. In: Kogelnik HD, Lukas P, Sedlmayer F (eds). Progress in radiation-oncology. 7th ed. Bologna: Monduzzi: 2002: 417– 422.
19. Begg AC. Prediction of repopulation rates and radiosensitivity in human tumours. Int J Radiat Biol 1994; 65(1): 103– 108.
20. Fowler JF. Rapid repopulation in radiotherapy: a debate on mechanism. The phantom of tumor treatment-continually rapid proliferation inmasked. Radiother Oncol 1991; 22(3): 156– 158.
21. Schmitdt-Ullrich RK, Contessa JN, Dent P et al. Molecular mechanism of radiation-induced accelerated repopulation. Radiat Oncol Investig 1999; 7(6): 321– 330.
22. Richter I, Dvořák J, Bartoš J. Neoadjuvantní chemoradioterapie karcinomu rekta v kombinaci s inhibitory receptoru pro růstový epidermální faktor. Klin Onkol 2014; 27(3): 166– 172.
23. Dvořák J, Sitorová V, Ryška A et al. The prognostic signifikance of changes of tumor epidermal growth factor receptor expression after neoadjuvant chemoradiation in patiens with rectal adenocarcinoma. Strahlenter Onkol 2012; 10: 145– 147.
24. Richter I, Dvořák J, Urbanec M et al. The prognostic significance of change tumor epidermal growth factor receptor expression after neoadjuvant chemoradiation in patients with rectal adenocarcinoma. Contemporary Oncology, accepted 16. 7. 2014.
25. Azria D, Bibeau F, Barbier N et al. Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer. BMC Cancer 2005; 5: 62.
26. Li S, Kim JS, Cho MJ et al. Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patiens treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 2006; 65(3): 705– 712.
27. Giralt J, de las Heras M, Cerezo L et al. The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy. Radiother Oncol 2005; 74(2): 101– 108.
28. Kopp R, Rothbauer E, Ruge M et al. Clinical implications of the EGF receptor ligand systém for tumour progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options. Recent Results Cancer Res 2003; 162: 115– 132.
29. Li S, Kim JS, Kim JM et al. Epidermal growth factor receptor as a prognostic factor in locally advanced rectal cancer patiens treated with preoperative chemoradiotion. Int J Radiat Oncol Biol Phys 2006; 65(3): 1019– 1028.
30. Kim JS, Kim JM, Li S et al. Epidermal growth factor receptor as a predictor of tumour downstaging in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiation Oncol Biol Phys 2006; 66(1): 195– 200.
31. Bertolini F, Bengala C, Losi L et al. Prognostic and predictive value of baseline and post-treatment molecular marker expression in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007; 68: 1455– 1468.
32. Zlobec I, Vuong T, Compton CC et al. Combined analysis of VEGF and EGFR predicts komplete tumour response in rectal cancer treated with preoperative radiotherapy. Br J Cancer 2008; 98(2): 450– 456. doi: 10.1038/ sj.bjc.6604172.
33. Bengala C, Bettelli S, Bertolini F et al. Prognostic role of EGFR gene copy number and KRAS station in patiens with locally advanced rectal cancer treated with preoperative chemoradiotherapy. Br J Cancer 2010; 103(7): 1019– 1024. doi: 10.1038/ sj.bjc.6605853.
34. Spindler KL, Nielsen JN, Lindebjerg J et al. Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promotera region. Int J Radiat Oncol Biol Phys 2006; 66(2): 500– 504.
35. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotekan in irinotekan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351(4): 337– 345.
36. Finocchiaro G, Capuzzo F, Janne PA et al. EGFR HER2, and K-ras as predictive factors for cetuximab sensitivity in colorectal cancer. Proc Am Soc Clin Oncol 2007; 25: 168.
37. Van Cutsem E, Kohne CH, Láng I et al. Cetuximab plus irinotecan, fluorouracil, and leucovorine as first-line treatment for metastatic colorectal cancer: update analysis of overall survival according to tumor KRAS and BRAF station status. J Clin Oncol 2011; 29(15): 2011– 2019. doi: 10.1200/ JCO.2010.33.5091.
38. Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009; 27(5): 663– 671. doi: 10.1200/ JCO.2008.20.8397.
39. Maugham TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatine-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 2011; 377(9783): 2013– 2114. doi: 10.1016/ S0140-6736(11)60613-2.
40. Tveit KM, Guren T, Glimelius B et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, luecovorine, and oxaliplatine (Nordic FLOX) versus FLOX alone in first-line treatment of metstatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 2012; 30(15): 1755– 1762. doi: 10.1200/ JCO.2011.38.0915.
41. Van Cutsem E, Peeters M, Siena S et al. Open-label phase III trial of panitumumab plus bets supportive care compared with best supportive care alone in patiens with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25(1): 1658– 1664.
42. Oliner KS, Douillard JY, Siena S et al. Analysis of KRAS/ NRAS and BRAF station in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol 2013; 31 (Suppl): abstr. 3511.
43. Nyati MK, Morgan MA, Feng FY et al. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 2006; 6: 876– 885.
44. Chinnaiyan P, Huang S, Vallabhaneni G et al. Mechanism of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 2005; 65(8): 3328– 3335.
45. Rau B, Sturm I, Lage H et al. Dynamic expression profile of p21WAF1/ CIP1 and Ki-67 predicts survival in rectal carcinoma treated with preoperative radiochemotherapy. J Clin Oncol 2003; 21(18): 3391– 3401.
46. Alberts SR, Sargent DJ, Nair S et al. Effect of oxaliplatine, fluorouracil, and leucovorine with or without cetuximab on survival among patiens with resected stage IIIcolon cancer: a randomised trial. JAMA 2012; 307(13): 1383– 1393. doi: 10.1001/ jama.2012.385.
47. Mishani E, Abourbeh G. Cancer molecular imaging: radionuclide-based biomarkers of the epidermal growth factor receptor (EGFR). Curr Top Med Chem 2007; 7(18): 1755– 1772.
Labels
Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
2014 Issue 5
Most read in this issue
- Prognostic Markers of Advanced Non-small Cell Lung Carcinoma – Assessing the Significance of Oncomarkers Using Data-mining Techiques RPA
- Breast Cancer Patient Satisfaction with Immediate Two-stage Implant-based Breast Reconstruction
- Cereblon – a New Target of Therapy in the Treatment of Multiple Myeloma
- Function of CDK12 in Tumor Initiation and Progression and Its Clinical Consequences