Cancer Chemotherapy and Pharmacology

, Volume 61, Issue 1, pp 125–131 | Cite as

A phase I study of capecitabine and a modulatory dose of irinotecan in metastatic breast cancer

Original Article

Abstract

Purpose

There is a need for chemotherapy regimens active against anthracycline- and taxane-refractory breast cancer. Data from preclinical and pilot studies performed at Roswell Park Cancer Institute (RPCI) suggested that when irinotecan (IRN) is given with 5-fluorouracil (5-FU) efficacy is affected by the sequence of drug administration. Pretreatment with IRN 24 h before 5-FU increased the number of tumor cells in S-phase and the antitumor activity in a preclinical system. These data provided the rationale for the evaluation of IRN and capecitabine, a 5-FU prodrug, sequentially administered in patients with metastatic breast cancer. The main objective of the study was to determine the MTD and identify dose-limiting toxicities (DLTs) of capecitabine and IRN. Additionally, the degree of accumulation of cells in S-phase in tumor biopsies obtained at 24 h after the first dose of IRN was measured in consenting patients.

Patients and methods

Metastatic breast cancer patients who experienced disease progression after at least one (taxane or anthracycline based) chemotherapy regimen and an expected survival of at least 3 months and ECOG performance status 0–2 were eligible. Twelve patients were enrolled and treated. The starting doses were IRN 80 mg/m2 given over 90 min on days 1, 8, 22, 29, and capecitabine 1,500 mg/m2/day given days 2–15 and 23–36. Evaluation for response was performed after the first cycle. Sequential tumor biopsies were performed on five patients.

Results

The first three patients treated exhibited modulation in cyclin A index on tumor biopsy as defined by the study, defining the modulatory dose of IRN as 80 mg/m2. Overall, 4/5 biopsies showed modulation. Dose Limiting Toxicities (DLTs) were assessed during the first cycle of therapy. Two DLTs (Grade 3 nausea vomiting and dehydration; grade 3 pneumonia, hypoxia, hypotension) were seen at dose level 2 of capecitabine (2,000 mg/m2/day) and the first cohort was expanded. There were no DLTs for patients treated at DL 1. No grade 3–4 toxicities occurred at DL 1. Seven patients were evaluable for response following one cycle of treatment (partial response 1, stable disease 4, progressive disease 2) Of the five inevaluable patients, two experienced DLT, one received 50% of the planned capecitabine dose, one progressed prior to evaluation, and one withdrew consent.

Conclusion

IRN 80 mg/m2 days 1, 8, 22, 29 in combination with capecitabine 1,500 mg/m2/day in divided dose days 2–15 and 23–36 has an acceptable toxicity profile and resulted in modulation of S-phase in 4/5 specimens examined. Further studies of the activity of this combination and modulatory effect of IRN are warranted.

Keywords

Metastatic breast cancer Chemotherapy Irinotecan Capecitabine S-phase modulation Phase I 

References

  1. 1.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics. CA Cancer J Clin 56(2):106–130PubMedGoogle Scholar
  2. 2.
    Perez EA, Hillman DW, Mailliard JA, Ingle JN, Ryan JM, Fitch TR, Rowland KM, Kardinal CG, Krook JE, Kugler JW, Dakhil SR (2004) Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22(14):2849–2855PubMedCrossRefGoogle Scholar
  3. 3.
    Margolin KA, Doroshow JH, Akman SA, Leong LA, Morgan RJ, Raschko JW, Somlo G, Blevins C (1992) Effective initial therapy of advanced breast cancer with fluorouracil and high-dose, continuous infusion calcium leucovorin. J Clin Oncol 10(8):1278–1283PubMedGoogle Scholar
  4. 4.
    Doroshow JH, Leong L, Margolin K, Flanagan B, Goldberg D, Bertrand M, Akman S, Carr B, Odujinrin O, Newman E, et al (1989) Refractory metastatic breast cancer: salvage therapy with fluorouracil and high-dose continuous infusion leucovorin calcium. J Clin Oncol 7(4):439–444PubMedGoogle Scholar
  5. 5.
    Loprinzi CL, Ingle JN, Schaid DJ, Buckner JC, Edmonson JH, Allegra CJ (1991) 5-Fluorouracil plus leucovorin in women with metastatic breast cancer. A phase II study. Am J Clin Oncol 14(1):30–32PubMedCrossRefGoogle Scholar
  6. 6.
    Swain SM, Lippman ME, Egan EF, Drake JC, Steinberg SM, Allegra CJ (1989) Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. J Clin Oncol 7(7):890–899PubMedGoogle Scholar
  7. 7.
    Cameron DA, Gabra H, Leonard RC (1994) Continuous 5-fluorouracil in the treatment of breast cancer. Br J Cancer 70(1):120–124PubMedGoogle Scholar
  8. 8.
    Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34(8):1274–1281PubMedCrossRefGoogle Scholar
  9. 9.
    Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45(4):291–297PubMedCrossRefGoogle Scholar
  10. 10.
    Pavillard V, Formento P, Rostagno P, Formento JL, Fischel JL, Francoual M, Etienne MC, Milano G (1998) Combination of irinotecan (CPT11) and 5- fluorouracil with an analysis of cellular determinants of drug activity. Biochem Pharmacol 56(10):1315–1322PubMedCrossRefGoogle Scholar
  11. 11.
    Cao S, Rustum YM (2000) Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose. Cancer Res 60(14):3717–3721PubMedGoogle Scholar
  12. 12.
    Ramnath N, Khushalani N, Toth K, Litwin AM, Intengan ME, Slocum HK, Pendyala L, Smith PF, Stewart CC, Hoffman JL, Javle MM, Berdzik J, Creaven PJ, Rustum YM (2005) S-phase modulation by irinotecan: pilot studies in advanced solid tumors. Cancer Chemother Pharmacol 56(5):447–454PubMedCrossRefGoogle Scholar
  13. 13.
    Cao S, Durrani FA, Rustum YM (2005) Synergistic antitumor activity of capecitabine in combination with irinotecan. Clin Colorectal Cancer 4(5):336–343PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • T. O’Connor
    • 1
  • Y. Rustum
    • 1
  • E. Levine
    • 1
  • P. Creaven
    • 1
  1. 1.Roswell Park Cancer InstituteBuffaloUSA

Personalised recommendations