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Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms

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Abstract

Purpose

A multicenter phase I trial to establish the recommended dose of CPT-11/docetaxel plus cisplatin in advanced esophagogastric cancer patients and to correlate the efficacy and toxicity with genetic polymorphisms in DNA repair genes (XPD and XRCC3) and the UGT1A1 gene.

Methods

Four dose levels with a fixed dose of cisplatin (60 mg/m2), day 1, and dose-escalation of CPT-11 (50–70 mg/m2) and docetaxel (25–30 mg/m2), days 1 and 8, every 3 weeks were planned. Polymorphisms of XPD (Asp312Asn and Lys751Gln), XRCC3 (Thr241Met) and UGT1A1*28 were examined in baseline peripheral blood.

Results

Twenty-eight patients were included at three different dose levels. Dose-limiting toxicities were febrile neutropenia and diarrhea; the recommended dose was established at CPT-11 60 mg/m2 and docetaxel 25 mg/m2 plus cisplatin 60 mg/m2. Objective response was observed in 13 patients (50%). Median time to progression was 6.6 months, and median survival was 11.3 months. Median time to progression was 9.7 months for patients harboring the XRCC3 Met241Met genotype versus 8.4 months for patients with Thr241Met and 3.1 months for those with Thr241Thr (P = .04).

Conclusions

CPT-11/docetaxel plus cisplatin is active in patients with advanced esophagogastric cancer. XRCC3 Met241Thr polymorphisms could be a useful marker to predict prognosis in patients treated with a cisplatin-based chemotherapy. However, these results are required to be confirmed with a great number of patients.

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References

  1. Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Filho SC, Maijlis A, Assadourian S, Van Cutsem E (2005) Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma. J Clin Oncol 23:5660–5667

    Article  PubMed  CAS  Google Scholar 

  2. Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Yoshinori Hasegawa Y (2000) Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60:6921–6926

    PubMed  CAS  Google Scholar 

  3. Boku N, Ohtsu A, Shimada Y, Narikazu Boku, Shirao K, Seki S, Saito H, Sakata Y, Hyodo I (1999) Phase II study of a combination of irinotecan and cisplatin against metastatic gastric cancer. J Clin Oncol 17:319–323

    PubMed  CAS  Google Scholar 

  4. De Laat WL, Jaspers NG, Hoeijmakers JH (1999) Molecular mechanism of nucleotide excision repair. Genes Dev 13(7):768–785

    Article  PubMed  Google Scholar 

  5. De las Peñas R, Sanchez-Ronco M, Alberola V, Taron M, Camps C, Garcia-Carbonero R, Massuti B, Queralt C, Botia M, Garcia-Gomez R, Isla D, Cobo M, Santarpia M, Cecere F, Mendez P, Sánchez JJ, Rosell R (2006) Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol 17:668–675

    Article  Google Scholar 

  6. Font A, Sanchez JM, Rosell R, Taron M, Martinez E, Guillot M, Manzano JL, Margeli M, Barnadas A, Abad A (2002) Phase I study of weekly CPT-11(irinotecan)/docetaxel in patients with advanced solid tumors. Lung Cancer 37:213–218

    Article  PubMed  CAS  Google Scholar 

  7. Font A, Sanchez JM, Taron M, Martinez-Balibrea E, Sanchez JJ, Manzano JL, Margelí M, Richardet M, Barnadas A, Abad A, Rosell R (2003) Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism. Invest New Drugs 21:435–443

    Article  PubMed  CAS  Google Scholar 

  8. Gagne JF, Montminy V, Belanger P, Journault K, Gaucher G, Guillemette C (2002) Common human UGT1A1 polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxicamptothecin (SN-38). Mol Pharmacol 62:608–617

    Article  PubMed  CAS  Google Scholar 

  9. Gagnon JF, Bernard O, Villeneuve L, Têtu B, Guillemette C (2006) Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer. Clin Cancer Res 12:1850–1858

    Article  PubMed  CAS  Google Scholar 

  10. Gurubhagavatula S, Liu G, Park S, Zhou W, Su L, Wain JC, Lynch TJ, Neuberg DS, Christiani DC (2004) XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy. J Clin Oncol 22:2594–2601

    Article  PubMed  CAS  Google Scholar 

  11. Ilson DH, Saltz L, Enzinger P, Huang Y, Kornblith A, Gollub M, O´Reilly E, Schwartz G, DeGroff J, Gonzalez G, Kelsen DP (1999) Phase II trial of weekly irinotecan plus cisplatin in advanced esophageal cancer. J Clin Oncol 17:3270–3275

    PubMed  CAS  Google Scholar 

  12. Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ (2004) Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382–1388

    Article  PubMed  CAS  Google Scholar 

  13. Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M, Lopez-Vivanco G, Camps C, Botia M, Nuñez L, Sanchez-Ronco M, Sanchez JJ, Lopez-Brea M, Barneto I, Paredes A, Medina B, Artal A, Lianes P (2004) Single nucleotde polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol 15:1194–1203

    Article  PubMed  CAS  Google Scholar 

  14. Iyer L, Hall D, Das S et al. (1999) Phenotype-genotype correlation of in-vitro SN-38 (active metabolite of irinotecan) and bilirubin glucoronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther 65:576–582

    Article  PubMed  CAS  Google Scholar 

  15. Marcuello E, Altés A, Menoyo A, Del Rio E, Gómez-Pardo M, Baiget M (2004) UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer Br J Cancer 91:678–682

    PubMed  CAS  Google Scholar 

  16. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, Krogh V, Munnia A, Tumino R, Polidoro S, Piazza A,Vineis P (2001) XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis 22:1437–1445

    Article  PubMed  CAS  Google Scholar 

  17. Park DJ, Stoehlmacher J, Zhang W, Tsao-Wei DD, Groshen S, Lenz HJ (2001) A xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 61:8654–8658

    PubMed  CAS  Google Scholar 

  18. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  19. Ridwelski K, Gebauer T, Fahlke J, Kröning H, Kettner E, Meyer F, Eichelmann K, Lippert H (2001) Combination chemotherapy with docetaxel and cisplatin for locally advanced and metastatic gastric cancer. Ann Oncol 12:47–51

    Article  PubMed  CAS  Google Scholar 

  20. Ross P, Nicolson M, Cunningham D, Valle J, Seymour M, Harper P, Price T, Anderson H, Iveson T, Hickisk T, Lofts F, Norman A (2002) Prospective randomized trial comparing mitomycin, cisplatin and protracted venous-infusion fluorouracil (PVI 5-FU) with epirubicin, cisplatin, and PVI 5-FU in advanced esophagogastric cancer. J Clin Oncol 20:1996–2004

    Article  PubMed  CAS  Google Scholar 

  21. Roth AD, Maibach R, Martinelli G, Fazio N, Aapro MS, Pagani O, Morant R, Borner MM, Herrmann R, Honegger H, Cavalli F, Alberto P, Castiglione M, Goldhirsch A (2000) Docetaxel (Taxotere)-cisplatin (TC): an effective drug combination in gastric carcinoma. Swiss Group for Clinical Cancer Research (SAKK), and the European Institute Of Oncology (EIO). Ann Oncol 11:301–306

    Article  PubMed  CAS  Google Scholar 

  22. Ruzzo A, Graziano F, Kawakami K, Watanabe G, Santini D, Catalano V, Bisonni R, Canestrari E, Ficarelli R, Menichetti ET, Mari D, Testa E, Silva R, Vincenzi B, Giordani P, Cascinu S, Giustini L, Tonini G, Magnani M (2006) Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy. J Clin Oncol 24:1883–1891

    Article  PubMed  CAS  Google Scholar 

  23. Ruzzo A, Graziano F, Loupakis F, Santini D, Catalano V, Bisonni R, Ficarelli R, Fontana A, Andreoni F, Falcone A, Canestrari E, Tonini G, Mari D, Lippe P, Pizzagalli F, Schiavon G, Alessandroni P, Giustini L, Maltese P, Testa E, Menichetti ET, Magnani M (2007) Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J. doi:10.1038/sj.tpj.6500463

  24. Shirao K, Shimada Y, Kondo H, Saito D, Yamao T, Ono H, Yokoyama T, Fukuda H, Oka M, Watanabe Y, Ohtsu A, Boku N, Fujii T, Oda Y, Muro K, Yoshida S (1997) Phase I-II study of irinotecan hydrochloride combined with cisplatin in patients with advanced gastric cancer. J Clin Oncol 15:921–927

    PubMed  CAS  Google Scholar 

  25. Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, Guo Z, Lei L, Mohrenweiser H, Wei Q (2001) Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 61:1354–1357

    PubMed  CAS  Google Scholar 

  26. Toffoli G, Cecchin E, Corona G, Russo A, Buonadonna A, D¨Andrea M, Pasetto LM, Pessa S, Errante D, De Pangher V, Giusto M, Medici M, Gaion F, Sandri P, Galligioni E, Bonura S, Boccalon M, Biason P, Frustaci S (2006) The role of UGT1A*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol 24:3061–3068

    Article  PubMed  CAS  Google Scholar 

  27. Van Cutsem, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: A report of the V325 Study Group. J Clin Oncol 24:4991–4997

    Article  PubMed  CAS  Google Scholar 

  28. Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van Cutsem E, Planker M, Dos Santos JG, Piedbois P, Paillot B, Bodenstein H, Schmoll HJ, Bleiberg H, Nordlinger B, Couvreor ML, Baron B, Wils JA (2000) Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group. J Clin Oncol 18:2648–2657

    PubMed  CAS  Google Scholar 

  29. Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE (2006) Chemotherapy in advanced gastric cancer: A systematic review and meta-analysis based on aggregate data. J Clin Oncol 24:2903–2909

    Article  PubMed  CAS  Google Scholar 

  30. Webb A, Cunningham D, Scarffe JH, Harper P, Norman A, Joffe JK , Hughes M, Mansi J, Findlay M, Hill A, Oates J , Nicolson M, Hickish T, O’Brien M, Iveson T, Watson M, Underhill C, Wardley A, Meehan M (1997) Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J Clin Oncol 15:261–267

    PubMed  CAS  Google Scholar 

  31. Wöhrer SS, Raderer, Hejna M. (2004) Palliative chemotherapy for advanced gastric cancer. Ann Oncol 15:1585–1595

    Article  PubMed  Google Scholar 

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Correspondence to Albert Font.

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Font, A., Salazar, R., Maurel, J. et al. Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms. Cancer Chemother Pharmacol 62, 1075–1083 (2008). https://doi.org/10.1007/s00280-008-0700-3

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  • DOI: https://doi.org/10.1007/s00280-008-0700-3

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