Samet RAHATLI, Nadire KUCUKOZTAS, SELİM YALÇIN, Merih TEPEOĞLU, Dalokay KILIÇ, Özden ALTUNDAĞ

Neoadjuvan Kemoterapi ile Tedavi Edilen Lokal İleri Evre Küçük Hücreli Dışı Akciğer Kanseri Hastalarının Sağkalımında Histopatolojik Yanıt ve Prognostik Belirteçlerin Korelasyonu

Amaç: Neoadjuvan kemoterapi almış olan evre III küçük hücreli dışı akciğer kanserli (KHDAK) hastalarda neoadjuvan tedavi yanıtlarının belirlenmesi ile, prognoza katkısı ile eksizyon onarım çapraz-tamamlayıcı grup 1 (ERCC1) ve Ribonükleotid Redüktaz alt ünitesi Ml (RRM1) ekspresyonunun tedavi yanıtı ve prognozla ilişkisinin belirlenmesini hedeflendi.Gereç ve Yöntemler: Bu çalışmaya 2003-2013 yılları arasında Evre III KHDAK tanısıyla neoadjuvan kemoterapi alıp 27 hasta dahil edildi. Neoadjuvan cisplatin alan hastaların akciğer biyopsi dokularında ERCC1 ve gemsitabin alan hastaların biyopsi materyallerinde RRM1 protein ekpresyonu immünohistokimyasal yöntemle değerlendirildi.Bulgular: Medyan yaş 59 (45-75)’du. Hastaların 19 (%70.4)’u evre IIIA, 8 (%29.6)’i evre IIIB idi. Hastaların hepsi cisplatin bazlı neoadjuvan kemoterapi aldı. Hastaların 15 (%55.6)’inin takiplerinde nüks tespit edildi. Ortanca takip süresi 36 aydı. Tüm olgulara ilişkin ortalama hastalıksız sağ kalım (HSK) 26.6 aydı. Genel sağkalım (GSK) ise 48 ay olarak bulundu. Evre IIIA ve IIIB açısından bakıldığında HSK (p=0.379) ve GSK (p=0.69) açısından anlamlı fark bulunmadı. Hastaların 16 (%59.3)’sında neoadjuvan KT sonrası cerrahi patoloji materyallerinde viabl tümör oranı %10 ve altında, 11 (%40) hastada ise viabl tümör oranı %10’nun üstünde bulundu. Bu açıdan da değerlendirildiğinde HSK (p=0.16) ve GSK (p=0.097) farkı saptanmadı. Düşük ERCC1 ekspresyonu olan hastalarla yüksek ERCC1 ekspresyonu olan hastalar arasında sağkalım farkı saptanmadı. Gemsitabin direncini gösteren RRM1 yüksek ekpresyonu olan hastalar da düşük ekspresyon olan hastalar ile benzer sağ kalım oranlarına sahipti.Sonuç: Çalışmamızda neoadjuvan kemoterapi alan evre III KHDAK’li hastalarda HSK ve GSK süreleri genel verilere göre daha uzun bulundu. Sisplatin ve gemsitabin tedavisi açısından prediktif markerlar olan ERCC1 ve RRM1 ile tedavi yanıtı ve sağkalım arasında anlamlı ilişki bulunmadı.

Anahtar Kelimeler:

ERCC1, RRM1, akciğer Kanseri, Evre III, Neoadjuvan Kemoterapi

CORRELATION OF HISTOPATHOLOGIC RESPONSE AND PROGNOSTIC MARKERS WITH THE SURVIVAL IN LOCALLY ADVANCED NON-SMALL CELL LUNG CANCER PATIENTS TREATED WITH NEOADJUVANT CHEMOTHERAPY

Objective: We aimed to determine the response and prognosis to neoadjuvant chemotherapy in patients with stage III non-small-cell lung cancer (NSCLC) who had received neoadjuvant therapy and to determine the relationship with prognosis and treatment response of the expression of excision repair cross-complementation group 1 protein (ERCC1) and Ribonucleotide reductase regulatory subunit M1 (RRM1) protein.Material and Methods: Twenty-seven patients with stage III NSCLC who received neoadjuvant chemotherapy and had been operated between 2003 and 2013 were included in this study. Lung tissue biopsies were evaluated by immunohistochemical methods for ERCC1 protein expression in patients who received cisplatin and RRM1 protein expression who received gemcitabine.Results: Median age was 59 (45-75). Nineteen patients (70.4%) were at stage IIIA and eight patients (29.6 %) were at stage IIIB. All patients received neoadjuvant cisplatin-based chemotherapy. Fifteen patients (55.6%) relapsed during follow-up. The median follow-up time was 36 months. The median disease-free survival (DFS) was 26.6 months, overall survival (OS) was 48 months. From the perspective of stage IIIA and IIIB DFS (p=0.379) and OS (p=0.69) did not differ significantly. Sixteen patients’ (59.3%) viable tumor ratio was ≤10%, 11 patients’ (40%) viable tumor ratio was >10%. When considered from this point of view DFS (p=0.16) and OS (p=0.097) showed no difference. More patients survived in the low ERCC1 expression group. Patients with low ERCC1 expression and patients with high ERCC1 expression showed no difference in terms of survival.Conclusion: Patients with high RRM1 expression showing resistance to gemcitabine and with low RRM1 expression had similar survival rates. In patients with stage III NSCLC who received neoadjuvant chemotherapy, OS and DFS durations longer than literature were found.

Keywords:

ERCC1, RRM1, Lung Cancer, Stage III, Neoadjuvant Chemotherapy,

PDF

___

1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
2. Jiang J, Liang X, Zhou X, Huang R, Chu Z, Zhan Q. ERCC1 expression as a prognostic and predictive factor in patients with non-small cell lung cancer: a meta-analysis. Mol Biol Rep. 2012;39(6):6933-42.
3. Gadgeel SM, Ramalingam SS, Kalemkerian GP. Treatment of lung cancer. Radiol Clin North Am Sep. 2012;50(5):961-74.
4. Fakhrejahani F, Sadraei NH, Mekhail T. The Role of consolidation treatment in locally advanced unresectable NSCLC. Curr Oncol Rep. 2013;15(4):424-32.
5. Pataer A, Kalhor N, Correa AM, Raso MG, Erasmus JJ, Kim ES et al. University of Texas M. D. Anderson Lung Cancer Collaborative Research Group. Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J Thorac Oncol. 2012;7(5):825-32.
6. Kelsey CR, Marks LB, Hollis D, Hubbs JL, Ready NE, D'Amico TA et al. Local recurrence after surgery for early stage lung cancer: An 11-year experience with 975 patients. Cancer. 2009;115(22):5218-27.
7. Park BB, Park JO, Kim H, Ahn YC, Choi YS, Kim K et al. Is trimodality approach better then bimodality in stage IIIA, N2 positive non-small cell lung cancer? Lung Cancer. 2006;53(3):323-30.
8. Saynak M, Higginson DS, Morris DE, Marks LB. Current status of postoperative radiation for non-small-cell lung cancer. Semin Radiat Oncol. 2010;20(3):192-200.
9. Anderson CS, Curran WJ. Combined modality therapy for stage III non-small-cell lung cancer. Semin Radiat Oncol. 2010;20(3):186-91.
10. Carretta A, Ciriaco P, Melloni G, Sayed I, Bandiera A, Ferla L et al. Results of surgical treatment after neoadjuvant chemotherapy for stage III non-small cell lung cancer. World J Surg. 2008;32(12):2636-42.
11. Lv C, Ma Y, Wu N, Shi Yan, Qingfeng Zheng, Yu Sun et al. A retrospective study: platinum-based induction chemotherapy combined with gemcitabine or paclitaxel for stage IIB-IIIA central non-small-cell lung cancer. World J Surg Oncol. 2013;11(76):1-11.
12. Besse B, Olaussen KA, Soria JC. ERCC1 and RRM1: ready for prime time? J Clin Oncol. 2013;31(8):1050-60.
13. Bepler G, Williams C, Schell MJ, Chen W, Zheng Z, Simon G et al. Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versusgemcitabine/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2013;31(19):2404-12.
14. Burdett S, Stewart LA, Rydzewska L. A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol. 2006;1(7):611-21.
15. Gilligan D, Nicolson M, Smith I, Dalesio O, Goldstraw P, Hatton M et al. Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRCLU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007;369(9577):1929-37.
16. Song WA, Zhou NK, Wang W, Chu XY, Liang CY, Tian XD et al. Survival benefit of neoadjuvant chemotherapy in non-small cell lung cancer: an updated meta-analysis of 13 randomized control trials. J Thorac Oncol. 2010;5(4):510-6.
17. Horita N, Miyazawa N, Morita S, Kojima R, Kimura N, Kaneko T et al. Preoperative chemotherapy is effective for stage III resectable non-small cell lung cancer: metaanalysis of 16 trials. Clin Lung Cancer. 2013;14(5):488-94.
18. Burdett S, Rydzewska LH, Tierney JF, Auperin A, Le Pechoux C, Le Chevalier T et al. Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data. NSCLC Meta-analysis Collaborative Group. Lancet. 2014;383(9928):1561-71.
19. Liao WY, Chen JH, Wu M, Shih JY, Chen KY, Ho CC et al. Neoadjuvant chemotherapy with docetaxel-cisplatin in patients with stage III N2 non-small-cell lung cancer. Clin Lung Cancer. 2013;14(4):418-24.
20. Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B et al. French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20(1):247-53.
21. Scagliotti G. Preliminary results of Ch.E.S.T.: A phase III study of surgery alone or surgery plus preoperative gemcitabine-cisplatin in clinical early stages non-small cell lung cancer. Journal of Clinical Oncology. 2005; abst23, no.16_suppl. DOI: 10.1200/jco.2005.23.16_suppl.lba7023. PubMed PMID: 27943944. (Epub 2011 Nov 28).
22. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350(4):351-60.
23. Bepler G, Sommers KE, Cantor A, Li X, Sharma A, Williams C et al. Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer. J Thorac Oncol. 2008;3(10):1112-8.
24. Britten RA, Liu D, Tessier A, Hutchison MJ, Murray D. ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer. 2000;89(5):453-7.
25. Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V et al. DNA repair by ERCC1 in non-small cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006; 355(10):983-91.
26. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M et al. Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: a phase III trial in non-small-cell lung cancer. J Clin Oncol. 2007;25(19):2747-54.
27. Li J, Li ZN, Yu LC, Bao QL, Wu JR, Shi SB et al. Association of expression of MRP1, BCRP, LRP and ERCC1 with outcome of patients with locally advanced non-small cell lung cancer who received neoadjuvant chemotherapy. Lung Cancer. 2010;69(1):116-22.
28. Cappi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 2006;17(12):1818-25.
29. Lord RVN, Brabender J, Gandara D, Alberola V, Camps C, Domine M et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res. 2002;8(7):2286-91.
30. Simon GR, Begum M, Bepler G. Setting the stage for tailored chemotherapy in the management of non-small cell lung cancer. Future Oncol. 2008;4(1):51-9.
31. Gong W, Zhang X, Wu J, Chen L, Li L, Sun J et al. RRM1 expression and clinical outcome of gemcitabine-containing chemotherapy for advanced non-small-cell lung cancer: a meta-analysis. Lung Cancer. 2012;75(3):374-80.
32. Lee JJ, Maeng CH, Baek SK, Kim GY, Yoo JH, Choi CW et al. The immunohistochemical overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1) protein is a predictor of shorter survival to gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Lung Cancer. 2010;70(2):205-10.
33. Rosell R, Felip E, Taron M, Majo J, Mendez P, Sanchez-Ronco M et al. Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Clin Cancer Res. 2004;10(12):4215-9.