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Erschienen in: Strahlentherapie und Onkologie 9/2012

01.09.2012 | Original article

Prognostic significance of changes of tumor epidermal growth factor receptor expression after neoadjuvant chemoradiation in patients with rectal adenocarcinoma

verfasst von: Assist. Prof. J. Dvorak, M.D., Ph.D., V. Sitorova, M.D., Ph.D., A. Ryska, M.D., Ph.D., I. Sirak, M.D., Ph.D., I. Richter, M.D., Ph.D., J. Hatlova, M.D., Ph.D., A. Ferko, M.D., Ph.D., B. Melichar, M.D., Ph.D., J. Petera, M.D., Ph.D.

Erschienen in: Strahlentherapie und Onkologie | Ausgabe 9/2012

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Abstract

Purpose

The aim of the present study was to examine the effect of neoadjuvant chemoradiation on tumor epidermal growth factor receptor (EGFR) expression in patients with locally advanced rectal adenocarcinoma.

Patients and methods

A total of 53 patients with rectal adenocarcinoma (clinical stages II and III) were studied. Neoadjuvant treatment consisted of 50.4 Gy/28 fractions external radiation with concomitant continuous 5-fluorouracil. Surgical resection was performed 4–6 weeks after the chemoradiation. EGFR expression in the pretreatment biopsies and in the resected specimens was assessed with immunohistochemistry.

Results

Patients with an increase of EGFR expression during chemoradiation had significantly shorter disease-free survival (DFS; p = 0.003) and overall survival (OS; p = 0.005) compared to patients with either no change or decrease in EGFR expression. The 5-year DFS in patients with increased EGFR expression was only 29% compared to 61% in patients without an increase of EGFR expression. Similarly, the 5-year OS of the patients with increased EGFR expression was 29% compared to 66% in patients without an increase of EGFR expression. All recurrences in patients who had an increase of EGFR expression occurred within the first 2 years after the treatment. The increase in EGFR expression was the only significant predictor of DFS (p = 0.007) and OS (p = 0.04) using multivariate Cox regression analysis.

Conclusion

An increase of EGFR expression during chemoradiation may be associated with significantly shorter DFS and OS. The increase of EGFR could identify a population of patients in whom the effect of the treatment with anti-EGFR therapy should be studied.
Literatur
1.
Zurück zum Zitat Akimoto T, Hunter NR, Buchmiller L et al (1999) Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 5:2884–2890PubMed Akimoto T, Hunter NR, Buchmiller L et al (1999) Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 5:2884–2890PubMed
2.
Zurück zum Zitat Azria D, Bibeau F, Barbier N et al (2005) Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer. BMC Cancer 5:62PubMedCrossRef Azria D, Bibeau F, Barbier N et al (2005) Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer. BMC Cancer 5:62PubMedCrossRef
3.
Zurück zum Zitat Baumann M, Krause M, Dikomey E et al (2007) EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 83:238–248PubMedCrossRef Baumann M, Krause M, Dikomey E et al (2007) EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother Oncol 83:238–248PubMedCrossRef
4.
Zurück zum Zitat Bertolini F, Chiara S, Bengala C et al (2009) Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 73:466–472PubMedCrossRef Bertolini F, Chiara S, Bengala C et al (2009) Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 73:466–472PubMedCrossRef
5.
Zurück zum Zitat Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578PubMedCrossRef Bonner JA, Harari PM, Giralt J et al (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578PubMedCrossRef
6.
Zurück zum Zitat Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase three randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28PubMedCrossRef Bonner JA, Harari PM, Giralt J et al (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase three randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11:21–28PubMedCrossRef
7.
Zurück zum Zitat Bonner JA, Maihle NJ, Folven BR et al (1994) The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivities. Int J Radiat Oncol Biol Phys 29:243–247PubMedCrossRef Bonner JA, Maihle NJ, Folven BR et al (1994) The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivities. Int J Radiat Oncol Biol Phys 29:243–247PubMedCrossRef
8.
Zurück zum Zitat Ceelen WP, Van Nieuwenhove Y, Fierens K (2009) Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev (1):CD006041 Ceelen WP, Van Nieuwenhove Y, Fierens K (2009) Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer. Cochrane Database Syst Rev (1):CD006041
9.
Zurück zum Zitat Chung KY, Minsky B, Schrag D et al (2006) Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer. J Clin Oncol 24(18 suppl):Abstract 3560 Chung KY, Minsky B, Schrag D et al (2006) Phase I trial of preoperative cetuximab with concurrent continuous infusion 5-fluorouracil and pelvic radiation in patients with local-regionally advanced rectal cancer. J Clin Oncol 24(18 suppl):Abstract 3560
10.
Zurück zum Zitat Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedCrossRef Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedCrossRef
11.
Zurück zum Zitat Dent P, Reardon DB, Park JS et al (1999) Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 10:2493–2506PubMed Dent P, Reardon DB, Park JS et al (1999) Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 10:2493–2506PubMed
12.
Zurück zum Zitat Douillard JY, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705PubMedCrossRef Douillard JY, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705PubMedCrossRef
13.
Zurück zum Zitat Giralt J, las Heras M de, Cerezo L et al (2005) Grupo Espanol de Investigacion Clinica en Oncologia Radioterapica (GICOR): The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol 74:101–108PubMedCrossRef Giralt J, las Heras M de, Cerezo L et al (2005) Grupo Espanol de Investigacion Clinica en Oncologia Radioterapica (GICOR): The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol 74:101–108PubMedCrossRef
14.
Zurück zum Zitat Glynne-Jones R, Mawdsley S, Harrison M (2011) Antiepidermal growth factor receptor radiosensitizers in rectal cancer. Anticancer Drugs 22:330–340PubMedCrossRef Glynne-Jones R, Mawdsley S, Harrison M (2011) Antiepidermal growth factor receptor radiosensitizers in rectal cancer. Anticancer Drugs 22:330–340PubMedCrossRef
15.
Zurück zum Zitat Hofheinz RD, Horisberger K, Woernle C et al (2006) Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys 66:1384–1390PubMedCrossRef Hofheinz RD, Horisberger K, Woernle C et al (2006) Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer. Int J Radiat Oncol Biol Phys 66:1384–1390PubMedCrossRef
16.
Zurück zum Zitat Horisberger K, Treschl A, Mai S et al (2009) Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a Phase II MARGIT trial. Int J Radiat Oncol Biol Phys 74:1487–1493PubMedCrossRef Horisberger K, Treschl A, Mai S et al (2009) Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a Phase II MARGIT trial. Int J Radiat Oncol Biol Phys 74:1487–1493PubMedCrossRef
17.
Zurück zum Zitat Kaufman M, Mehrotra B, Limaye S et al (2008) EGFR expression in gallbladder carcinoma in North America. Int J Med Sci 5:285–291PubMedCrossRef Kaufman M, Mehrotra B, Limaye S et al (2008) EGFR expression in gallbladder carcinoma in North America. Int J Med Sci 5:285–291PubMedCrossRef
18.
Zurück zum Zitat Kavanagh BD, Dent P, Schmidt-Ullrich RK et al (1998) Calcium-dependent stimulation of mitogen-activated protein kinase activity in A431 cells by low doses of ionizing radiation. Radiat Res 149:579–587PubMedCrossRef Kavanagh BD, Dent P, Schmidt-Ullrich RK et al (1998) Calcium-dependent stimulation of mitogen-activated protein kinase activity in A431 cells by low doses of ionizing radiation. Radiat Res 149:579–587PubMedCrossRef
19.
Zurück zum Zitat Kim JS, Kim JM, Li S et al (2006) Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 66:195–200PubMedCrossRef Kim JS, Kim JM, Li S et al (2006) Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 66:195–200PubMedCrossRef
20.
Zurück zum Zitat Li S, Kim JS, Kim JM et al (2006) Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patients treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 65:705–712PubMedCrossRef Li S, Kim JS, Kim JM et al (2006) Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patients treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 65:705–712PubMedCrossRef
21.
Zurück zum Zitat Liang K, Ang KK, Milas L et al (2003) The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 57:246–254PubMedCrossRef Liang K, Ang KK, Milas L et al (2003) The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys 57:246–254PubMedCrossRef
22.
Zurück zum Zitat Machiels JP, Sempoux C, Scalliet P et al (2007) Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18:738–744PubMedCrossRef Machiels JP, Sempoux C, Scalliet P et al (2007) Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18:738–744PubMedCrossRef
23.
Zurück zum Zitat Marquardt F, Rödel F, Capalbo G et al (2009) Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol 185:371–378PubMedCrossRef Marquardt F, Rödel F, Capalbo G et al (2009) Molecular targeted treatment and radiation therapy for rectal cancer. Strahlenther Onkol 185:371–378PubMedCrossRef
24.
Zurück zum Zitat Milas L, Akimoto T, Hunter NR et al (2002) Relationship between cyclin D1 expression and poor radioresponse of murine carcinomas. Int J Radiat Oncol Biol Phys 52:514–521PubMedCrossRef Milas L, Akimoto T, Hunter NR et al (2002) Relationship between cyclin D1 expression and poor radioresponse of murine carcinomas. Int J Radiat Oncol Biol Phys 52:514–521PubMedCrossRef
25.
Zurück zum Zitat Mishani E, Abourbeh G (2007) Cancer molecular imaging: radionuclide-based biomarkers of the Epidermal Growth Factor Receptor (EGFR). Curr Top Med Chem 7:1755–1772PubMedCrossRef Mishani E, Abourbeh G (2007) Cancer molecular imaging: radionuclide-based biomarkers of the Epidermal Growth Factor Receptor (EGFR). Curr Top Med Chem 7:1755–1772PubMedCrossRef
26.
Zurück zum Zitat Nasu S, Ang KK, Fan Z et al (2001) C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys 51:474–477PubMedCrossRef Nasu S, Ang KK, Fan Z et al (2001) C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability. Int J Radiat Oncol Biol Phys 51:474–477PubMedCrossRef
27.
Zurück zum Zitat Pantaleo MA, Fanti S, Nannini M et al (2008) What oncologists need and require from nuclear medicine. Eur J Nucl Med Mol Imaging 35:1761–1765PubMedCrossRef Pantaleo MA, Fanti S, Nannini M et al (2008) What oncologists need and require from nuclear medicine. Eur J Nucl Med Mol Imaging 35:1761–1765PubMedCrossRef
28.
Zurück zum Zitat Peeters M, Price TJ, Cervantes A et al (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:4706–4713PubMedCrossRef Peeters M, Price TJ, Cervantes A et al (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:4706–4713PubMedCrossRef
29.
Zurück zum Zitat Pinto C, Di Fabio F, Maiello E et al (2011) Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study). Ann Oncol 22:2424–2430PubMedCrossRef Pinto C, Di Fabio F, Maiello E et al (2011) Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study). Ann Oncol 22:2424–2430PubMedCrossRef
30.
Zurück zum Zitat Rödel C, Arnold D, Hipp M et al (2008) Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 70:1081–1086PubMedCrossRef Rödel C, Arnold D, Hipp M et al (2008) Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 70:1081–1086PubMedCrossRef
31.
Zurück zum Zitat Rödel C, Sauer R (2007) Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 183:227–235PubMedCrossRef Rödel C, Sauer R (2007) Integration of novel agents into combined-modality treatment for rectal cancer patients. Strahlenther Onkol 183:227–235PubMedCrossRef
32.
Zurück zum Zitat Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740PubMedCrossRef Sauer R, Becker H, Hohenberger W et al (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740PubMedCrossRef
33.
Zurück zum Zitat Schmidt-Ullrich RK, Mikkelsen RB, Dent P et al (1997) Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15:1191–1197PubMedCrossRef Schmidt-Ullrich RK, Mikkelsen RB, Dent P et al (1997) Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15:1191–1197PubMedCrossRef
34.
Zurück zum Zitat Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417CrossRef Van Cutsem E, Köhne CH, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417CrossRef
35.
Zurück zum Zitat Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664CrossRef Van Cutsem E, Peeters M, Siena S et al (2007) Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658–1664CrossRef
36.
Zurück zum Zitat Wadlow RC, Ryan DP (2010) The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer 116:3537–3548PubMedCrossRef Wadlow RC, Ryan DP (2010) The role of targeted agents in preoperative chemoradiation for rectal cancer. Cancer 116:3537–3548PubMedCrossRef
Metadaten
Titel
Prognostic significance of changes of tumor epidermal growth factor receptor expression after neoadjuvant chemoradiation in patients with rectal adenocarcinoma
verfasst von
Assist. Prof. J. Dvorak, M.D., Ph.D.
V. Sitorova, M.D., Ph.D.
A. Ryska, M.D., Ph.D.
I. Sirak, M.D., Ph.D.
I. Richter, M.D., Ph.D.
J. Hatlova, M.D., Ph.D.
A. Ferko, M.D., Ph.D.
B. Melichar, M.D., Ph.D.
J. Petera, M.D., Ph.D.
Publikationsdatum
01.09.2012
Verlag
Springer-Verlag
Erschienen in
Strahlentherapie und Onkologie / Ausgabe 9/2012
Print ISSN: 0179-7158
Elektronische ISSN: 1439-099X
DOI
https://doi.org/10.1007/s00066-012-0160-x

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