Is FOLFIRINOX Better In Primary Resected Metastatic Pancreatic Cancer ?

Öz

Objective: Pancreatic cancer is a very fatal disease and is estimated to be the second leading cause of cancer deaths in the USA in 2030. Chemotherapy is usually the most important treatment option in metastatic pancreatic ductal adenocarcinoma and is applied for palliative purposes. FOLFIRINOX, which is a multi-drug regimen, is an important treatment option in patients with good performance in order to overcome chemoresistance in this desmoplastic cancer. Surgery is the most important way to eliminate chemoresistance in pancreatic cancer. FOLFIRINOX is preferred in adjuvant therapy because the disease reoccurs even in patients who can undergo surgery and it gives better survival results than gemcitabine. There is data suggesting that patients with pancreatic ductal adenocarcinoma who underwent surgery for the primary lesion and subsequently metastasized may have a better response with the FOLFIRINOX regimen than patients with metastatic presentation (de novo metastatic). This retrospective study was planned to investigate the response of previously operated patients who developed metastases (surgical group) and those with metastatic disease at the time of diagnosis (de novo metastatic group) to the FOLFIRINOX regimen. Materials and Methods: 35 patients followed between 2013 and 2017 were included in the study and their medical records were examined. Results: Progression free survival of surgery group was median 10 months. De novo metastatic group progression free survival was median 6 months (table 2). Surgery group progression free survival was statistically significant longer than de novo metastatic group (p:0.033). Surgery group overall survival was 20 months. De novo metastatic group overall survival was 7 months. Surgery group overall survival was statistically significant longer than de novo metastatic group (p:0.020). Conclusion: According to the results of our study, FOLFIRINOX treatment is more effective in patients with pancreatic ductal adenocarcinoma who underwent surgery for a primary pancreatic tumor and then developed metastasis. Therefore, regardless of performance, administration of FOLFIRINOX may be appropriate in patients who have undergone surgery. In addition, surgical treatments can be applied to metastatic patients to reduce the disease burden, since better results are obtained in patients who have been operated for palliative purposes. Randomized studies with larger patient populations are needed to validate our results.

Anahtar Kelimeler

• Pancreatic Cancer
• FOLFIRINOX
• Surgery.

Is FOLFIRINOX Better In Primary Resected Metastatic Pancreatic Cancer ?

Öz

Giriş ve Amaç: Pankreas kanseri çok ölümcül bir hastalık olup 2030 yılında ABD'de kanser ölümlerinde ikinci sırada olacağı tahmin edilmektedir. Kemoterapi genellikle metastatik pankreas duktal adenokarsinomunda en önemli tedavi seçeneğidir ve palyatif amaçlı uygulanmaktadır. Çok ilaçlı bir rejim olan FOLFIRINOX, desmoplastik özellikteki bu kanserde kemorezistansın üstesinden gelmek için iyi performans gösteren hastalarda önemli bir tedavi seçeneğidir. Pankreas kanserinde kemorezistansı ortadan kaldırmanın en önemli yolu cerrahidir. FOLFIRINOX, cerrahi uygulanabilen hastalarda dahi hastalık yeniden ortaya çıktığı ve gemsitabinden daha iyi sağkalım sonuçları verdiği için adjuvan tedavide kullanılmıştır. FOLFIRINOX rejimi ile, primer lezyona yönelik cerrahi olan ve sonrasında metastaz yapmış pankreas duktal adenokarsinomlu hastalarda, metastatik olarak prezente olmuş (de novo metastatik) hastalara gore daha iyi yanıt elde edilebildiğine dair veriler mevcuttur. Bu retrospektif çalışma, daha önce opere edilmiş ve metastaz geliştirmiş (cerrahi grubu) ve tanı anında metastatik hastalığı olanların (de novo metastatik grup) FOLFIRINOX rejimine verdikleri yanıtları araştırmak üzere planlanmıştır. Gereç ve Yöntemler: 2013-2017 yılları arasında takip edilen 35 hasta çalışmaya dahil edilerek tıbbi kayıtları incelendi. Bulgular: Cerrahi grubun progresyonsuz sağkalımı medyan 10 aydı. De novo metastatik grupta progresyonsuz sağkalım medyan 6 aydı (tablo 2). Cerrahi grupta progresyonsuz sağkalım de novo metastatik gruba göre istatistiksel olarak anlamlı uzundu (p: 0,033). Cerrahi grup genel sağkalım 20 ay iken de novo metastatik grup genel sağkalımı 7 aydı. Cerrahi grubun genel sağkalımı de novo metastatik gruba göre istatistiksel olarak anlamlı derecede daha uzundu (p: 0,020). Sonuç: Çalışmamızın sonuçlarına göre FOLFIRINOX tedavisi, primer pankreas tümörü opere edilen ve ardından metastaz gelişen pankreas duktal adenokarsinomlu hastalarda daha etkilidir. Bu nedenle, performansa bakılmaksızın FOLFIRINOX uygulaması cerrahi yapılmış hastalarda uygun olabilir. Ayrıca hastalık yükünü azaltmak için opera edilen hastalarda daha iyi sonuçlar alınması nedeniyle, hastalık yükünü azaltmak için cerrahi tedaviler metastatik hastalarda uygulanabilir. Sonuçlarımızın valide edilebilmesi için daha geniş hasta popülasyonları ile randomize çalışmalar yapılmasına ihtiyaç bulunmaktadır.

Anahtar Kelimeler

• pancreatic caner
• FOLFIRINOX
• surgery

Kaynakça

1. Rahib, L, Smith, B.D, Aizenberg, R, Rosenzweig, A.B, Fleshman, J.M, Matrisian, L.M, Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States, Cancer Research, 2014, 74, 2913-21.
2. Siegel, R.L, Miller, K.D, Jemal, A, Cancer statistics, 2019, A Cancer Journal for Clinicians, 2019, 69:7.
3. Neoptolemos, J.P, Stocken, D.D, Friess, H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer, The New England Journal of Medicine, 2004, 350, 1200-10.
4. Oettle, H, Neuhaus, P, Hochhaus, A, et al., Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial, JAMA Oncology, 2013, 310, 1473-81.
5. Oettle, H, Post, S, Neuhaus, P, et al., Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative- intent resection of pancreatic cancer: a randomized controlled trial, JAMA Oncology, 2007, 297, 267-77.
6. Neoptolemos, J.P, Stocken, D.D, Bassi, C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial, JAMA Oncology, 2010, 304, 1073-81.
7. Sinn, M, Bahra, M, Liersch, T, et al., CONKO-005: adjuvant chemotherapy with gemcitabine plus erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a multicenter randomized phase III trial, Journal of Clinicial Oncology, 2017, 35, 3330-7.
8. Von Hoff, D.D, Ervin, T, Arena, F.P, et al., Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine, The New England Journal of Medicine, 2013, 369, 1691–703.

9. Conroy, T, Desseigne, F, Ychou, M, et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer, The New England Journal of Medicine, 2011, 364, 1817–25.
10. Rasheed, Z.A, Matsui, W, Maitra, A, Pathology of pancreatic stroma in PDAC. In: Grippo PJ, Munshi HG (eds), Pancreatic Cancer and Tumor Microenvironment, Transworld Research Network: Trivandrum, India, 2012.
11. Schober, M, Jesenofsky, R, Faissner, R, et al., Desmoplasia and chemoresistance in pancreatic cancer, Cancers, 2014, 6, 2137–2154.
12. Apte, M.V, Park, S, Phillips, P.A, et al., Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells, Pancreas, 2004, 29, 179–187.
13. Kozono, S, Ohuchida, K, Eguchi, D, et al., Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells, Cancer Research, 2013, 73, 2345–2356.
14. Stylianopoulos, T , Martin, J.D , Chauhan, V.P , Jain, S.R , Diop-Frimpong, B , Bardeesy, N , et al., Causes, consequences, and remedies for growthinduced solid stress in murine and human tumors, Proceedings of the National Academy of Sciences, 2012, 109, 15101 – 8.
15. Chauhan, V.P , Boucher, Y , Ferrone, C.R , Roberge, S , Martin, J.D, Stylianopoulos, T , et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fl uid pressure, Cancer Cell, 2014, 26, 14 – 5.
16. Alvarez, R , Musteanu, M , Garcia-Garcia, E , Lopez-Casas, P.P, Megias, D , Guerra, C , et al., Stromal disrupting effects of nab-paclitaxel in pancreatic cancer, British Journal of Cancer, 2013, 109, 926 – 33.
17. Hidalgo, M, Von Hoff, D.D, Translational therapeutic opportunities in ductal adenocarcinoma of the pancreas, Clinical Cancer Research, 2012, 18, 4249 – 56.
18. Chauhan, V.P , Martin, J.D, Liu, H, Lacorre, D.A, Jain, S.R , Kozin, S.V, et al., Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels, Nature Communications, 2013, 4, 2516.
19. Endrich, B, Reinhold, H.S, Gross, J.F, Intaglietta, M, Tissue perfusion inhomogeneity during early tumor growth in rats, Journal of the National Cancer Institute, 1979, 62, 387 – 95 .
20. Conroy, T, Hammel, P, Hebbar, M, et al., FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer, The New England Journal of Medicine, 2018, 379, 2395-406.
21. Conroy, T, Desseigne, F, Ychou, M et al., FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, The New England Journal of Medicine, 2011, 364, 1817-25.