Dose-dense temozolomide regimen for the treatment of brain metastases from melanoma, breast cancer, or lung cancer not amenable to surgery or radiosurgery: a multicenter phase II study

S Siena, L Crinò, M Danova, S Del Prete, S Cascinu, S Salvagni, I Schiavetto, M Vitali, E Bajetta, S Siena, L Crinò, M Danova, S Del Prete, S Cascinu, S Salvagni, I Schiavetto, M Vitali, E Bajetta

Abstract

Background: Brain metastases reduce survival because therapeutic options are limited. This phase II study evaluated the efficacy of single-agent therapy with alternating weekly, dose-dense temozolomide in pretreated patients with brain metastases prospectively stratified by primary tumor type.

Methods: Eligible patients had bidimensionally measurable brain metastases from histologically/cytologically confirmed melanoma, breast cancer (BC), or non-small-cell lung cancer (NSCLC). Prior chemotherapy, radiotherapy, and whole-brain radiotherapy (WBRT) were allowed. Patients received temozolomide 150 mg/m(2)/day (days 1-7 and 15-21 every 28- or 35-day cycle).

Results: In the intent-to-treat population (N = 157; 53 melanoma, 51 BC, and 53 NSCLC), one patient had complete response, nine (6%) had partial responses, and 31 (20%) had stable disease in the brain. Median progression-free survival was 56, 58, and 66 days for melanoma, BC, and NSCLC, respectively. Median overall survival was 100 days for melanoma, 172 days for NSCLC, and not evaluable in the BC group. Thrombocytopenia was the most common adverse event causing dose modification or treatment discontinuation. Grade 4 toxic effects were rare.

Conclusions: This alternating weekly, dose-dense temozolomide regimen was well tolerated and clinically active in heavily pretreated patients with brain metastases, particularly in patients with melanoma. Combining temozolomide with WBRT or other agents may improve clinical outcomes.

Figures

Figure 1.
Figure 1.
Kaplan–Meier estimates of progression-free (A) and overall survival (B) by tumor type.

References

    1. Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol. 2004;22:2865–2872.
    1. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer. 2002;94:2698–2705.
    1. Eichler AF, Loeffler JS. Multidisciplinary management of brain metastases. Oncologist. 2007;12:884–898.
    1. Lagerwaard FJ, Levendag PC, Nowak PJ, et al. Identification of prognostic factors in patients with brain metastases: a review of 1292 patients. Int J Radiat Oncol Biol Phys. 1999;43:795–803.
    1. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37:745–751.
    1. Gaspar LE, Scott C, Murray K, Curran W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys. 2000;47:1001–1006.
    1. Abrey LE, Olson JD, Raizer JJ, et al. A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol. 2001;53:259–265.
    1. Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol. 2001;12:249–254.
    1. Hedde J-P, Ko Y, Metzler U, et al. A phase I/II trial of topotecan and radiation therapy for CNS-metastases of patients with solid tumors. Proc Am Soc Clin Oncol. 2003;22(Suppl):111. (Abstr 444)
    1. Danson SJ, Middleton MR. Temozolomide: a novel oral alkylating agent. Expert Rev Anticancer Ther. 2001;1:13–19.
    1. Newlands ES, O'Reilly SM, Glaser MG, et al. The Charing Cross Hospital experience with temozolomide in patients with gliomas. Eur J Cancer. 1996;32A:2236–2241.
    1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996.
    1. Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999;17:2762–2771.
    1. Bignami M, O'Driscoll M, Aquilina G, Karran P. Unmasking a killer: DNA O(6)-methylguanine and the cytotoxicity of methylating agents. Mutat Res. 2000;462:71–82.
    1. Roos WP, Batista LF, Naumann SC, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene. 2007;26:186–197.
    1. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer. 2003;88:1004–1011.
    1. Brandes AA, Tosoni A, Cavallo G, et al. Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO) Br J Cancer. 2006;95:1155–1160.
    1. Wick A, Felsberg J, Steinbach JP, et al. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol. 2007;25:3357–3361.
    1. Bernardo G, Cuzzoni Q, Strada MR, et al. First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest. 2002;20:293–302.
    1. Cortes J, Rodriguez J, Aramendia JM, et al. Front-line paclitaxel/cisplatin-based chemotherapy in brain metastases from non-small-cell lung cancer. Oncology. 2003;64:28–35.
    1. Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer. 1999;85:1599–1605.
    1. Hedde JP, Neuhaus T, Schuller H, et al. A phase I/II trial of topotecan and radiation therapy for brain metastases in patients with solid tumors. Int J Radiat Oncol Biol Phys. 2007;68:839–844.
    1. Wong ET, Berkenblit A. The role of topotecan in the treatment of brain metastases. Oncologist. 2004;9:68–79.
    1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–214.
    1. Schadendorf D, Hauschild A, Ugurel S, et al. Dose-intensified bi-weekly temozolomide in patients with asymptomatic brain metastases from malignant melanoma: a phase II DeCOG/ADO study. Ann Oncol. 2006;17:1592–1597.
    1. Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol. 2004;22:2101–2107.
    1. Trudeau ME, Crump M, Charpentier D, et al. Temozolomide in metastatic breast cancer (MBC): a phase II trial of the National Cancer Institute of Canada–Clinical Trials Group (NCIC-CTG) Ann Oncol. 2006;17:952–956.
    1. Christodoulou C, Bafaloukos D, Linardou H, et al. Temozolomide (TMZ) combined with cisplatin (CDDP) in patients with brain metastases from solid tumors: a Hellenic Cooperative Oncology Group (HeCOG) Phase II study. J Neurooncol. 2005;71:61–65.
    1. Onyenadum A, Gogas H, Markopoulos C, et al. Mitoxantrone plus vinorelbine in pretreated patients with metastatic breast cancer. J Chemother. 2007;19:582–589.
    1. Kouvaris JR, Miliadou A, Kouloulias VE, et al. Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors. Onkologie. 2007;30:361–366.
    1. Lorusso V, Galetta D, Giotta F, et al. Topotecan in the treatment of brain metastases. A phase II study of GOIM (Gruppo Oncologico dell'Italia Meridionale) Anticancer Res. 2006;26:2259–2263.
    1. Chang JE, Khuntia D, Robins HI, Mehta MP. Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme. Clin Adv Hematol Oncol. 2007;5:894–902. 907–915.
    1. van Nifterik KA, van den Berg J, Stalpers LJ, et al. Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines. Int J Radiat Oncol Biol Phys. 2007;69:1246–1253.
    1. Langer CJ, Mehta MP. Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005;23:6207–6219.
    1. Antonadou D, Paraskevaidis M, Sarris G, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol. 2002;20:3644–3650.
    1. Addeo R, Caraglia M, Faiola V, et al. Concomitant treatment of brain metastasis with whole brain radiotherapy [WBRT] and temozolomide [TMZ] is active and improves quality of life. BMC Cancer. 2007;7:18.
    1. Suh JH, Stea B, Nabid A, et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol. 2006;24:106–114.
    1. Gori S, Rimondini S, De Angelis V, et al. Central nervous system metastases in HER-2 positive metastatic breast cancer patients treated with trastuzumab: incidence, survival, and risk factors. Oncologist. 2007;12:766–773.
    1. Kirsch DG, Ledezma CJ, Mathews CS, et al. Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol. 2005;23:2114–2116. author reply 2116–2117.
    1. Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol. 2004;15:1042–1047.
    1. Lin NU, Dieras VD, Paul D, et al. EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT) J Clin Oncol. 2007;25:35. (Abstr 1012)
    1. Pan M, Santamaria M, Wollman DB. CNS response after erlotinib therapy in a patient with metastatic NSCLC with an EGFR mutation. Nat Clin Pract Oncol. 2007;4:603–607.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj