Mitomycin C and capecitabine in pretreated patients with metastatic gastric cancer: a multicenter phase II study

  • Manuel Barreto Miranda
  • Jörg Thomas Hartmann
  • Salah-Eddin Al-Batran
  • Melanie Kripp
  • Deniz Gencer
  • Andreas Hochhaus
  • Ralf-Dieter Hofheinz
  • Kirsten MerxEmail author
Original Article – Clinical Oncology



We conducted a multicenter phase II study to assess the toxicity and efficacy of a combination of mitomycin C (MMC) and capecitabine in pretreated patients with metastatic or locally advanced gastric cancer.


Thirty-nine patients (77 % male) between 33 and 78 years (median 66) with pretreated locally advanced or metastatic esophagogastric adenocarcinoma and eastern cooperative oncology group performance status of ≤2, measurable lesions, and adequate organ functions were recruited into the study. Eight patients (21 %) had received more than one prior chemotherapy regimen. Treatment consisted of three-weekly MMC 10 mg/m2 day 1 and capecitabine 2,000 mg/m2 (day 1–14; repeated day 22).


A median of three cycles of therapy was administered. Grade 3 toxicity occurred in 20 patients (54 %). Main grade 3 adverse events were thrombocytopenia (11 %, n = 4), fatigue (8 %, n = 3), and neuropathy (8 %, n = 3). Two events of grade 4 toxicity were reported (5 %) (dyspnea and elevation of alkaline phosphatase due to bone metastases). Partial remission was noticed in 10.3 % (n = 4), stable disease in 33.3 % (n = 13) adding to a tumor control rate of 43.6 %. The median progression-free and overall survival were 2.8 and 5.6 months, respectively.


The combination of MMC and capecitabine exhibited a favorable tolerability profile in pretreated patients with gastric cancer. The disease control rate compares adequately with that of other phase II and phase III trials for second-line therapy in gastric cancer. This regimen may be considered as an alternative second-line treatment, especially for patients not suitable for or pretreated with taxanes and/or irinotecan.


Gastric cancer Second-line chemotherapy Capecitabine Mitomycin C 


  1. Ajani JA, Fodor MB, Tjulandin SA, Moiseyenko VM, Chao Y, Cabral Filho S, Majlis 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(24):5660–5667CrossRefPubMedGoogle Scholar
  2. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S (2010) Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol 28(9):1547–1553CrossRefPubMedGoogle Scholar
  3. Al-Batran SE, Kerber A, Atmaca A, Dechow C, Reitsamer E, Schmidt S, Kolassa Y, Neumann A, Weidmann E, Hartmann JT, Jager E (2007) Mitomycin C, 5-fluorouracil, leucovorin, and oxaliplatin as a salvage therapy for patients with cisplatin-resistant advanced gastric cancer: a phase I dose escalation trial. Onkologie 30(1–2):29–34PubMedGoogle Scholar
  4. Al-Batran SE, Pauligk C, Homann N, Hartmann JT, Moehler M, Probst S, Rethwisch V, Stoehlmacher-Williams J, Prasnikar N, Hollerbach S, Bokemeyer C, Mahlberg R, Hofheinz RD, Luley K, Kullmann F, Jager E (2013) The feasibility of triple-drug chemotherapy combination in older adult patients with oesophagogastric cancer: a randomised trial of the Arbeitsgemeinschaft Internistische Onkologie (FLOT65 +). Eur J Cancer 49(4):835–842CrossRefPubMedGoogle Scholar
  5. Bamias A, Papamichael D, Syrigos K, Pavlidis N (2003) Phase II study of irinotecan and mitomycin C in 5-fluorouracil-pretreated patients with advanced colorectal and gastric cancer. J Chemother (Florence, Italy) 15(3):275–281CrossRefGoogle Scholar
  6. Chen JS, Lin YC, Liau CT, Wang CH, Liaw CC (2003) Mitomycin C (MMC) with weekly 24-hour infusions of high-dose 5-fluorouracil and leucovorin in patients with advanced gastric cancer. Chang Gung Med J 26(6):433–439PubMedGoogle Scholar
  7. Chong G, Cunningham D (2005) Can cisplatin and infused 5-fluorouracil be replaced by oxaliplatin and capecitabine in the treatment of advanced oesophagogastric cancer? The REAL 2 trial. Clin Oncol 17(2):79–80CrossRefGoogle Scholar
  8. Chong G, Dickson JL, Cunningham D, Norman AR, Rao S, Hill ME, Price TJ, Oates J, Tebbutt N (2005) Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. Br J Cancer 93(5):510–514CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chun JH, Kim HK, Lee JS, Choi JY, Hwangbo B, Lee HG, Park SR, Choi IJ, Kim CG, Ryu KW, Kim YW, Lee JS, Bae JM (2005) Weekly docetaxel in combination with capecitabine in patients with metastatic gastric cancer. Am J Clin Oncol 28(2):188–194CrossRefPubMedGoogle Scholar
  10. Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 26(4):404–413CrossRefGoogle Scholar
  11. Comella P, Lorusso V, Maiorino L, Casaretti R, Cannone M, Massidda B, Putzu C, Leo S, Roselli M, Mancarella S, Palmeri S, Greco E, Vessia G, Sandomenico C, Franco L (2009) Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the southern Italy cooperative oncology group. Cancer Chemother Pharmacol 64(5):893–899CrossRefPubMedGoogle Scholar
  12. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. New Engl J Med 358(1):36–46CrossRefPubMedGoogle Scholar
  13. Curran D, Pozzo C, Zaluski J, Dank M, Barone C, Valvere V, Yalcin S, Peschel C, Wenczl M, Goker E, Bugat R (2009) Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial. Qual Life Res 18(7):853–861CrossRefPubMedPubMedCentralGoogle Scholar
  14. Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, Mansoor W, Fyfe D, Madhusudan S, Middleton GW, Swinson D, Falk S, Chau I, Cunningham D, Kareclas P, Cook N, Blazeby JM, Dunn JA, Investigators C- (2014) Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol 15(1):78–86CrossRefPubMedGoogle Scholar
  15. Ferlay J SI, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM,, Forman D B, F (2013) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Available via International Agency for Research on Cancer.
  16. Gencer D, Al-Batran SE, Dada R, Hunerliturkoglu AN, Gonnermann M, Kegel T, Scheiber H, Jordan WO, Burkholder I, Kellermann L, Hofheinz RD (2013) Metastatic esophagogastric adenocarcinoma: trends in first-line treatment and predictive factors for the implementation of HER2 testing in clinical practice during the first year after trastuzumab market approval. J Cancer Res Clin Oncol 139(2):337–345CrossRefPubMedGoogle Scholar
  17. Giordano KF, Jatoi A, Stella PJ, Foster N, Tschetter LK, Alberts SR, Dakhil SR, Mailliard JA, Flynn PJ, Nikcevich DA (2006) Docetaxel and capecitabine in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction: a phase II study from the north central cancer treatment group. Ann Oncol 17(4):652–656CrossRefPubMedGoogle Scholar
  18. Giuliani F, Gebbia V, De Vita F, Maiello E, Di Bisceglie M, Catalano G, Gebbia N, Colucci G (2003) Docetaxel as salvage therapy in advanced gastric cancer: a phase II study of the gruppo oncologico italia meridionale (G.O.I.M.). Anticancer Res 23(5b):4219–4222PubMedGoogle Scholar
  19. Giuliani F, Molica S, Maiello E, Battaglia C, Gebbia V, Di Bisceglie M, Vinciarelli G, Gebbia N, Colucci G, Gruppo Oncologico dell’ Italia M (2005) Irinotecan (CPT-11) and mitomycin-C (MMC) as second-line therapy in advanced gastric cancer: a phase II study of the Gruppo Oncologico dell’ Italia Meridionale (prot. 2106). Am J Clin Oncol 28(6):581–585CrossRefPubMedGoogle Scholar
  20. Glimelius B, Hoffman K, Graf W, Haglund U, Nyren O, Pahlman L, Sjoden PO (1995) Cost-effectiveness of palliative chemotherapy in advanced gastrointestinal cancer. Ann Oncol 6(3):267–274PubMedGoogle Scholar
  21. Glimelius B, Ekstrom K, Hoffman K, Graf W, Sjoden PO, Haglund U, Svensson C, Enander LK, Linne T, Sellstrom H, Heuman R (1997) Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer. Ann Oncol 8(2):163–168CrossRefPubMedGoogle Scholar
  22. Hamaguchi T, Shirao K, Ohtsu A, Hyodo I, Arai Y, Takiuchi H, Fujii H, Yoshida M, Saito H, Denda T, Koizumi W, Iwase H, Boku N, Gastrointestinal Oncology Study Group of Japan Clinical Oncology G (2011) A phase II study of biweekly mitomycin C and irinotecan combination therapy in patients with fluoropyrimidine-resistant advanced gastric cancer: a report from the gastrointestinal oncology group of the Japan clinical oncology group (JCOG0109-DI Trial). Gastric Cancer 14(3):226–233CrossRefPubMedGoogle Scholar
  23. Hartmann JT, Quietzsch D, Daikeler T, Kollmannsberger C, Mayer F, Kanz L, Bokemeyer C (1999) Mitomycin C continuous infusion as salvage chemotherapy in pretreated patients with advanced gastric cancer. Anticancer Drugs 10(8):729–733CrossRefPubMedGoogle Scholar
  24. Hartmann JT, Oechsle K, Quietzsch D, Wein A, Hofheinz RD, Honecker F, Nehls O, Kohne CH, Kafer G, Kanz L, Bokemeyer C (2003) Protracted infusional 5-fluorouracil plus high-dose folinic acid combined with bolus mitomycin C in patients with gastrointestinal cancer: a phase I/II dose escalation study. Br J Cancer 89(11):2051–2056CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hartmann JT, Pintoffl JP, Al-Batran SE, Quietzsch D, Meisinger I, Horger M, Nehls O, Bokemeyer C, Konigsrainer A, Jager E, Kanz L (2007) Mitomycin C plus infusional 5-fluorouracil in platinum-refractory gastric adenocarcinoma: an extended multicenter phase II study. Onkologie 30(5):235–240PubMedGoogle Scholar
  26. Hartung G, Hofheinz R, Buchheidt D, Rost A, Brecht A, Forche K, Schroder M, Wojatschek C, Fritze D, Hehlmann R, Queisser W (2000) Combination of bolus 5-fluorouracil, folinic acid and mitomycin C in advanced gastric cancer: results of a phase II trial. Onkologie 23(5):444–447PubMedGoogle Scholar
  27. Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I (2013) Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol 31(35):4438–4444CrossRefPubMedGoogle Scholar
  28. Hofheinz RD, Hartung G, Samel S, Hochhaus A, Pichlmeier U, Post S, Hehlmann R, Queisser W (2002) High-dose 5-fluorouracil/folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. Onkologie 25(3):255–260PubMedGoogle Scholar
  29. Hofheinz RD, Hartmann JT, Willer A, Oechsle K, Hartung G, Gnad U, Saussele S, Kreil S, Bokemeyer C, Hehlmann R, Hochhaus A (2004) Capecitabine in combination with mitomycin C in patients with gastrointestinal cancer: results of an extended multicentre phase-I trial. Br J Cancer 91(5):834–838PubMedPubMedCentralGoogle Scholar
  30. Janunger KG, Hafstrom L, Nygren P, Glimelius B (2001) A systematic overview of chemotherapy effects in gastric cancer. Acta Oncol (Stockholm, Sweden) 40(2–3):309–326CrossRefGoogle Scholar
  31. Kang JH, Lee SI, Limdo H, Park KW, Oh SY, Kwon HC, Hwang IG, Lee SC, Nam E, Shin DB, Lee J, Park JO, Park YS, Lim HY, Kang WK, Park SH (2012) Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 30(13):1513–1518CrossRefPubMedGoogle Scholar
  32. Kaplan ELM, Paul (1953) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53(282):457–481CrossRefGoogle Scholar
  33. Kim HS, Kim HJ, Kim SY, Kim TY, Lee KW, Baek SK, Kim TY, Ryu MH, Nam BH, Zang DY (2013) Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer: a meta-analysis. Ann Oncol 24:2850–2854CrossRefPubMedGoogle Scholar
  34. Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W (2004) Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol 15(3):478–483CrossRefPubMedGoogle Scholar
  35. Kretzschmar A, Reichardt P, Thuss-Patience PC, Hohenberger P, Benter T, Dorken B, Kohne CH (2000) Weekly 24-hour infusion of high-dose 5-fluorouracil plus folinic acid in combination with mitomycin C for the treatment of advanced gastric cancer. Oncology 59(1):14–17CrossRefPubMedGoogle Scholar
  36. Lorenzen S, Duyster J, Lersch C, von Delius S, Hennig M, Bredenkamp R, Peschel C, Lordick F (2005) Capecitabine plus docetaxel every 3 weeks in first- and second-line metastatic oesophageal cancer: final results of a phase II trial. Br J Cancer 92(12):2129–2133CrossRefPubMedPubMedCentralGoogle Scholar
  37. Maisano R, Caristi N, Mare M, Mafodda A, Carboni R, Montalto E, Iorfida M, Nardi M (2005) Mitomycin C and capecitabine combination (MiXe) in heavily pretreated metastatic breast cancer patients a dose-finding study. Anticancer Res 25(6C):4513–4517PubMedGoogle Scholar
  38. Massacesi C, La Cesa A, Marcucci F, Pilone A, Rocchi MB, Zepponi L, Santini D, Tonini G, Burattini L (2006) Capecitabine and mitomycin C is an effective combination for anthracycline- and taxane-resistant metastatic breast cancer. Oncology 70(4):294–300CrossRefPubMedGoogle Scholar
  39. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47(1):207–214CrossRefPubMedGoogle Scholar
  40. Mochizuki Y, Ohashi N, Kojima H, Ishigure K, Kinoshita T, Eguchi T, Fujitake S, Ito S, Fujiwara M, Kodera Y (2013) CPT-11 as a second-line treatment for patients with advanced/metastatic gastric cancer who failed S-1 (CCOG0702). Cancer Chemother Pharmacol 72(3):629–635CrossRefPubMedGoogle Scholar
  41. Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M (1993) Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 72(1):37–41CrossRefPubMedGoogle Scholar
  42. Park SH, Kim YS, Hong J, Park J, Nam E, Cho EK, Shin DB, Lee JH, Lee WK, Chung M (2008) Mitomycin C plus S-1 as second-line therapy in patients with advanced gastric cancer: a noncomparative phase II study. Anticancer Drugs 19(3):303–307CrossRefPubMedGoogle Scholar
  43. Pieters A, Laurent S, Dero I, Van Damme N, Peeters M (2008) The role of oral fluoropyrimidines in the treatment of advanced gastric cancer. Acta Gastroenterol Belg 71(4):361–366PubMedGoogle Scholar
  44. Pluschnig U, Schoppmann SF, Preusser M, Datler P, Asari R, Ba-Ssalamah A, Schwameis K, Birner P, Zacherl J, Hejna M (2013) Modified EOX (epirubicin, oxaliplatin and capecitabine) as palliative first-line chemotherapy for gastroesophageal adenocarcinoma. Anticancer Res 33(3):1035–1039PubMedGoogle Scholar
  45. Pyrhonen S, Kuitunen T, Nyandoto P, Kouri M (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71(3):587–591CrossRefPubMedPubMedCentralGoogle Scholar
  46. Salah-Eldin MA, Ebrahim MA, AL-A MS (2009) Phase II study of capecitabine plus cisplatin in patients with gastric cancer. Anticancer Drugs 20(3):191–196CrossRefPubMedGoogle Scholar
  47. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4(4):1013–1019PubMedGoogle Scholar
  48. Shimada S, Yagi Y, Kuramoto M, Aoki N, Ogawa M (2003) Second-line chemotherapy with combined irinotecan and low-dose cisplatin for patients with metastatic gastric carcinoma resistant to 5-fluorouracil. Oncol Rep 10(3):687–691PubMedGoogle Scholar
  49. Shitara K, Yuki S, Tahahari D, Nakamura M, Kondo C, Tsuda T, Kii T, Tsuji Y, Utsunomiya S, Ichikawa D, Hosokawa A, Ishiguro A, Sakai D, Hironaka S, Oze I, Matsuo K, Muro K (2014) Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Br J Cancer 110(2):271–277Google Scholar
  50. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10CrossRefPubMedGoogle Scholar
  51. Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, Dogan Y, Gebauer B, Schumacher G, Reichardt P (2011) Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer–a randomised phase III study of the arbeitsgemeinschaft internistische onkologie (AIO). Eur J Cancer 47(15):2306–2314CrossRefPubMedGoogle Scholar
  52. Ueda A, Hosokawa A, Ogawa K, Yoshita H, Mihara H, Ando T, Kajiura S, Fujinami H, Nishikawa J, Minemura M, Terada M, Kobayashi T, Horikawa N, Yabushita K, Note M, Sugiyama T (2013) Non-randomized comparison between irinotecan plus mitomycin C and irinotecan alone in patients with advanced gastric cancer refractory to fluoropyrimidine and platinum. Anticancer Res 33(11):5107–5111PubMedGoogle Scholar
  53. Van Cutsem E, 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(31):4991–4997CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Manuel Barreto Miranda
    • 1
  • Jörg Thomas Hartmann
    • 2
  • Salah-Eddin Al-Batran
    • 3
  • Melanie Kripp
    • 1
  • Deniz Gencer
    • 1
  • Andreas Hochhaus
    • 4
  • Ralf-Dieter Hofheinz
    • 1
  • Kirsten Merx
    • 1
    • 5
    Email author
  1. 1.III. Medizinische Klinik, Hämatologie und OnkologieUniversitätsmedizin MannheimMannheimGermany
  2. 2.Abteilung Hämatologie/OnkologieFranziskus HospitalBielefeldGermany
  3. 3.Krankenhaus NordwestUniversity Cancer Center (UCT)Frankfurt am MainGermany
  4. 4.Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin IIUniversitätsklinikum JenaJenaGermany
  5. 5.Department of Hematology and OncologyUniversity Hospital MannheimMannheimGermany

Personalised recommendations