Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 57, Issue 1, pp 34–39 | Cite as

Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours

  • Michele CaragliaEmail author
  • Raffaele Addeo
  • Raffaele Costanzo
  • Liliana Montella
  • Vincenzo Faiola
  • Monica Marra
  • Alberto Abbruzzese
  • Giovannella Palmieri
  • Alfredo Budillon
  • Francesco Grillone
  • Salvatore Venuta
  • Pierosandro Tagliaferri
  • Salvatore Del Prete
Original Article

Abstract

Objective: A combination regimen of temozolomide (TMZ) and pegylated liposomal doxorubicin has been evaluated in the treatment of brain metastases from solid tumours. Study design: Nineteen consecutive patients (pts) have been enrolled in a prospective phase II trial and treated with TMZ 200 mg/m2 (days 1–5) and pegylated liposomal doxorubicin 35 mg/m2 (day 1) every 28 days. The study was prospectively projected according to the Simon’s two-stage optimal design. Results: Major toxicities have been grade III neutropenia and thrombocytopenia in one patient (pt) and grade III erythrodisesthesia in two pts. Three pts achieved a complete response (CR) and four a partial response (PR), for an overall response rate of 36.8% (95% CI: 19.1–59.2), which exceeded the target activity in the study design. A significant improvement in quality of life was demonstrated by FACT-G analysis. The median Progression Free Survival (PFS) was 5.5 (95% CI: 2.7–8.2) months while the median Overall Survival (OS) was 10.0 months (95% CI: 6.3–13.7). Conclusions: The TMZ/pegylated liposomal doxorubicin regimen was well tolerated with an encouraging activity in brain metastases from solid tumours.

Keywords

Brain metastases Pegylated liposomal doxorubicin Temozolomide Quality of life Phase II study 

Notes

Acknowledgements

This work was partially supported by grants from Italian Minister for Research (PRIN2003).

References

  1. 1.
    Abrey LE, Christodoulou C (2001) Temozolomide for treating brain metastases. Semin Oncol 28:34–42CrossRefPubMedGoogle Scholar
  2. 2.
    Awada A, Gil T, Sales F, Dubuisson M, Verecken P, Klastersky J, Moerman C, de Valeriola D, Piccart MJ (2004) prolonged schedule of temozolomide (Temodal) plus liposomal doxorubicin (Caelyx) in advanced solid cancers. Anticancer Drugs 15:499–502CrossRefPubMedGoogle Scholar
  3. 3.
    Berk L (1995) An overview of radiotherapy trials for the treatment of brain metastases. Oncology 9:1205–1219PubMedGoogle Scholar
  4. 4.
    Bleehen NM, Newlands ES, Lee SM, Thatcher N, Selby P, Calvert AH, Rustin GJ, Brampton M, Stevens MF (1995) Cancer research campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13:910–913PubMedGoogle Scholar
  5. 5.
    Bower M, Newlands ES, Bleehen NM, Brada M, Begent RJ, Calvert H, Colquhoun I, Lewis P, Brampton MH (1997) Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 40:484–488CrossRefPubMedGoogle Scholar
  6. 6.
    Britten CD, Rowinsky EK, Baker SD, Agarwala SS, Eckardt JR, Barrington R, Diab SG, Hammond LA, Johnson T, Villalona-Calero M, Fraass U, Statkevich P, Von Hoff DD, Eckhardt SG (1999) A phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies. Clin Cancer Res 5:1629–1637PubMedGoogle Scholar
  7. 7.
    Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J (1993) The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 11:570–579PubMedGoogle Scholar
  8. 8.
    Danson SJ, Middleton MR (2001) Temozolomide: a novel oral alkylating agent. Expert Rev Anticancer Ther 1:13–19CrossRefPubMedGoogle Scholar
  9. 9.
    Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM (1988) Identification and characterization of the blood vessels of solid tumours that are leaky to circulating macromolecules. Am J Pathol 133:95–109PubMedGoogle Scholar
  10. 10.
    Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clin Pharmacokinet 42:419–436PubMedCrossRefGoogle Scholar
  11. 11.
    Gordon AN, Granai CO, Rose PG, Hainsworth J, Lopez A, Weissman C, Rosales R, Sharpington T (2000) Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 18:3093–3100PubMedGoogle Scholar
  12. 12.
    Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312–3322PubMedGoogle Scholar
  13. 13.
    Huang GS, Juretzka M, Ciaravino G, Kohler S, Teng NN (2002) Liposomal doxorubicin for treatment of metastatic chemorefractory vulvar adenocarcinoma. Gynecol Oncol 87:313–318CrossRefPubMedGoogle Scholar
  14. 14.
    Koukourakis MI, Koukouraki S, Fezoulidis I, Kelekis N, Kyrias G, Archimandritis S, Karkavitsas N (2000) High intratumoural accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer 83:1281–1286CrossRefPubMedGoogle Scholar
  15. 15.
    Koukourakis MI, Romanidis K, Froudarakis M, Kyrgias G, Koukourakis GV, Retalis G, Bahlitzanakis N (2002) Concurrent administration of Docetaxel and Stealth liposomal doxorubicin with radiotherapy in non-small cell lung cancer: excellent tolerance using subcutaneous amifostine for cytoprotection. Br J Cancer 87:385–392CrossRefPubMedGoogle Scholar
  16. 16.
    Leighl NB, Burkes RL, Dancey JE, Lopez PG, Higgins BP, David Walde PL, Rudinskas LC, Rahim YH, Rodgers A, Pond GR, Shepherd FA (2003) A phase I study of pegylated liposomal doxorubicin hydrochloride (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small-cell lung cancer. Clin Lung Cancer 5:107–112PubMedGoogle Scholar
  17. 17.
    Mintz AH, Kestle J, Gaspar L, Gaspar L, Hugenholtz H, Fisher B, Duncan G, Skingley P, Foster G, Levine M (1996) A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with single cerebral metastasis. Cancer 78:1470–1476CrossRefPubMedGoogle Scholar
  18. 18.
    Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH (1992) Phase I trial of temozolomide (CCRG81045: M and B 39831: NSC 362856). Br J Cancer 65:287–291PubMedGoogle Scholar
  19. 19.
    O’Reilly SM, Newlands ES, Glaser MG, Brampton M, Rice-Edwards JM, Illingworth RD, Richards PG, Kennard C, Colquhoun IR, Lewis P (1993) Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer 29A:940–942CrossRefGoogle Scholar
  20. 20.
    Parney IF, Chang SM (2003) Current chemotherapy for glioblastoma. Cancer J 9:149–156PubMedCrossRefGoogle Scholar
  21. 21.
    Posner JB (1992) Management of brain metastases. Rev Neurol 148:477–487PubMedGoogle Scholar
  22. 22.
    Rivera E, Valero V, Arun B, Royce M, Adinin R, Hoelzer K, Walters R, Wade JL III, Pusztai L, Hortobagyi GN (2003) Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. J Clin Oncol 21:249–3254CrossRefGoogle Scholar
  23. 23.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10CrossRefPubMedGoogle Scholar
  24. 24.
    Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn M, Brandes AA, Cairncross G, Lacombe D, Mirimanoff RO (2004) Concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM). Conclusive results of a randomized phase III trial by the EORTC Brain & RT groups and ncic clinical trial group. Proc Am Soc Clin Oncol 22:(Abst 2)Google Scholar
  25. 25.
    Vantongelen K (eds) (1994) A practical guide to EORTC studies: evaluation, criteria, scoring scales and instruments. EORTC, BrusselsGoogle Scholar
  26. 26.
    Vecht CJ, Haaxma-Reiche H, Noordijk EM, Padberg GW, Voormolen JH, Hoekstra FH, Tans JT, Lambooij N, Metsaars JA, Wattendorff AR (1993) Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery. Ann Neurol 33:583–590CrossRefPubMedGoogle Scholar
  27. 27.
    Volm M, Oratz R, Pavlick A (2000) A phase I study of liposomal doxorubicin and temozolomide in patients with advanced cancer. Proc Am Soc Clin Oncol 19:(Abst 872)Google Scholar
  28. 28.
    Walker AE, Robins M, Weinfeld FD (1985) Epidemiology of brain tumours: the national survey of intracranial neoplasms. Neurology 35:219–226PubMedGoogle Scholar
  29. 29.
    Wollina U, Dummer R, Brockmeyer NH, Konrad H, Busch JO, Kaatz M, Knopf B, Koch HJ, Hauschild A (2003) Multicenter study of pegylated liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 98:993–1001CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Michele Caraglia
    • 1
    • 2
    Email author
  • Raffaele Addeo
    • 1
  • Raffaele Costanzo
    • 1
  • Liliana Montella
    • 1
  • Vincenzo Faiola
    • 1
  • Monica Marra
    • 3
  • Alberto Abbruzzese
    • 3
  • Giovannella Palmieri
    • 4
  • Alfredo Budillon
    • 2
  • Francesco Grillone
    • 5
  • Salvatore Venuta
    • 5
  • Pierosandro Tagliaferri
    • 5
  • Salvatore Del Prete
    • 1
  1. 1.Oncology Department“S.Giovanni di Dio” HospitalFrattaminoreItaly
  2. 2.Experimental Pharmacology UnitNational Institute of Tumours “Fondazione G. Pascale” of Naples Italy
  3. 3.Department of Biochemistry and BiophysicsII University of Naples Italy
  4. 4.Department of Molecular and Clinical Endocrinology and OncologyUniversity “Federico II” of Naples Italy
  5. 5.Department of Experimental and Clinical Medicine“Magna Græcia University” of Catanzaro Italy

Personalised recommendations