Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of the bisphosphonate zoledronic acid (Zometa® , Novartis Oncology) suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented to scientists and other medical professionals gathered at the Henry B. Gonzales Convention Center in San Antonio to hear and present the latest scientific findings in breast cancer research during the CTRC-AACR San Antonio Breast Cancer Symposium (December 10-14, 2008 ).

There is substantial in vitro evidence that zoledronic acid has direct antitumour effects and synergy with chemotherapy agents. Bisphosphonates may therefore be an adjuvant therapeutic strategy of potential importance.

‘Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,’ explained Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom.

Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a prospective, randomised, open label, parallel group trial designed to to evaluate the effect of zoledronic acid on breast cancer. ‘Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be practice changing,' Coleman said.

The AZURE trial opened to recruitment in September 2003. Patients were recruited from 176 centres worldwide, completing accrual in January 2006, 8 months ahead of schedule, and enrolled 3,360 women with stage II/III breast cancer. The trial was set up to determine whether adjuvant treatment with 4 mg zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve the disease-free and bone metastasis-free survival of women with breast cancer at high risk of relapse.

Analysis of the characteristics of the study population shows that both groups are well
matched across all criteria. 51% of patients have T2 tumour at presentation, with 76.6% being ER positive. 60.6% and 33.2% had 1-3 and ≥4 axillary nodes involved respectively and 6.4% were treated in the neoadjuvant setting. Anthracyclines were administered to 92.6% and 22.7% received taxanes, in large part due to accrual into the TANGO trial concurrent with AZURE. Only 4.6% received endocrine therapy alone. Almost half of the patients (44.6%) were premenopausal at randomisation.

Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group.

After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8 percent in the chemotherapy arm and 10.9 percent in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9 percent in the chemotherapy group and 65.3 percent in the combination group. ‘Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,’ Coleman said.

For more information, read:

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101. Poster Session V: Treatment: Neoadjuvant Therapy. San Antonio Breast Cancer Symposium.

Also read:

• Click here for full prescribing information.
• The Institute of Cancer Research

Also read PubMed Abstracts:

• Lyseng-Williamson KA. Zoledronic Acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82
• Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006 Apr;33(2 Suppl 7):S13-7.

Immunochemotherapy with Fludarabine, Cyclophosphamide, and Rituximab Improves Response Rates and Progression-Free Survival of Previously Untreated Pat

Results from this multinational phase III clinical trial presented by during the 50th Annual Meeting of the American Society of Hematology (ASH) in San Francisco, CA (December 6 – 9) by Dr. Michael Hallek, MD from the University of Cologne, Cologne, Germany, and the German CLL Study Group, suggest that fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy may become the new standard first-line therapy for the treatment of advanced chronic lymphocytic leukemia.

In this study, a total of 817 patients with previously untreated chronic lymphocytic leukemia were randomized to receive six 28-day cycles of fludarabine (25 mg/m2 intravenously on days 1 to 3) and cyclophosphamide (FC) (250 mg/m2 intravenously on days 1 to 3) alone or FCR (375 mg/m2 intravenously at start of first cycle and 500 mg/m2 on day 1 for all subsequent cycles). The primary objective of the study was to determine response rates and progression-free survival.

After an average follow-up of 25.5 months, a total of 761 patients were evaluable for response and 787 were evaluable for progression-free survival and overall survival. The overall response rate was significantly higher in the FCR arm (95 percent) as compared with the FC arm (88 percent). The complete response rate was also significantly higher in the FCR arm (52 percent) as compared with the FC arm (27 percent).

At two years, the progression-free survival rate was 76.6 percent in the FCR arm as compared with 62.3 percent in the FC arm. While FCR was found to cause more neutropenia (33.6 percent versus 20.9 percent) and leukopenia (24 percent versus 12.1 percent), it did not increase the incidence of severe infections (18.8 percent versus 14.8 percent) as compared with FC. Taken together, treatment with fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy improves response rate (RR) and progression free survival (PFS) and can be considered a safe first-line treatment for chronic lymphocytic leukaemia.

For more information, read:

• Hallek M, Fingerle-Rowson G, Fink AM, Busch R, et al. Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL). (Oral Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #325

Also read PubMed Abstracts:

• Borthakur G, O’Brien S, Wierda WG, Thomas DA, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab--incidence and predictors. Br J Haematol. 2007 Mar;136(6):800-5.