NE Oncology Issue – February 2014

Lu YS, et al. ECC 2013:1878

Background

The management of brain metastasis of breast cancer progressing from whole brain radiotherapy remains a severe challenge. The investigators hypothesized that starting bevacizumab (BE) one day before chemotherapy could further enhance the activity of etoposide (E) and cisplatin (P), two of the cytotoxic agents that have moderate activity in brain metastases of breast cancer, by increasing drug delivery into tumour tissue via bevacizumab-induced vascular normalization. At ECC 2013, Lu and colleagues presented results of this multicentre phase II study.1

Study design

  • This trial is registered with ClinicalTrials.gov (NCT01281696).
  • Breast cancer patients with brain metastases and progression of brain lesions after whole brain radiotherapy were enrolled.
  • Treatment was given in 21-day cycles: patients received bevacizumab 15 mg/kg on day 1, etoposide 70 mg/m2/day from day 2 to day 4, and cisplatin 70 mg/m2 on day 2 (BEEP regimen), for a maximum of six cycles.
  • The primary end point was a centrally assessed objective central nervous system (CNS) response, defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of a new CNS lesion, or progressive neurologic symptoms, and no progressive extra-CNS diseases.
  • An objective CNS response rate of 30% was assumed and 15% as a minimum interest, using a Simon’s optimum two-stage design with a significance level α of 0.15 and a power of 80%, a total of 31 assessable patients are required.
  • Serial dynamic contrast enhancement-magnetic resonance imaging (DCE-MRI) one hour, 24 hours, and 21 days after bevacizumab infusion were performed in selected suitable patients who had consented to the DCE-MRI study.

Key findings

Baseline characteristics and disposition

  • A total of 35 patients were enrolled from January 2011 to January 2013.
  • All patients were included for safety and efficacy analysis (reported by intent-to-treat analysis). Data cut-off was July 31, 2013.
  • Some of the patients’ baseline clinical charasteristics included:
    • Median age: 54.3 (range: 33.4–75.0) years;
    • Estrogen receptor (ER)/human epidermal growth factor receptor 2 (HER2) status:
      • ER+HER2−: six patients;
      • ER+HER2+: nine patients;
      • ER–HER2+: 14 patients; and
      • ER−HER2−: six patients.
    • Eastern Cooperative Oncology Group Performance Status:
      • 0–1: 16 patients;
      • 2: eight patients;
      • 3: 11 patients.
    • Median number of extra-CNS metastatic sites: 2 (range: 0–3);
    • Median number of prior lines of chemotherapy in metastatic setting: 3 (range: 1–8);
    • Six patients had been exposed to cisplatin and four patients had been exposed to etoposide treatment for metastatic disease before entering this study.
  • The median number of treatment cycles delivered was six (range: 1–6).
  • Eighteen patients (51.4%) needed dose reductions of etoposide to 60 mg/m2 and cisplatin to 60 mg/m2, and three patients discontinued from treatment due to toxicity. (Table 1)

Safety

  • The most frequent grade 3/4 toxicities per treatment cycle included neutropenia (30.8%), leukopenia (16.0%), infection with normal absolute neutrophil count or grade 1/2 neutropenia (15.4%), thrombocytopenia (7.7%), and anemia (7.1%). (Table 1)
    • One patient died of infection and one patient died of tracheoesophageal fistula. The latter patient had extensive mediastinal lymph node metastases, but her CNS tumours completely resolved after three cycles of BEEP.
  • Due to the high incidence of grade 3/4 neutropenia, the protocol was amended to mandate prophylactic filgrastim 300 μg/day for three days after BEEP treatment. After the amendment, the incidence of grade 3/4 neutropenia decreased from 37% to 12% per cycle.

Efficacy

  • In total, 27 patients (77.1%; 95% CI: 59.9–89.6) achieved an objective CNS response.
  • The best volumetric CNS responses were: (Table 2)
    • ≥80% reduction: 13 patients (37.1%);
    • 50–<80% reduction: 14 patients (40.0%);
    • 20–<50% reduction: six patients (17.1%);
    • Non-evaluable: two patients (5.7%).
  • Six patients had non-CNS disease progression while CNS tumours remained under control.
  • All patients were also evaluated by exploratory analysis for best CNS response according to modified Response Evaluation Criteria in Solid Tumours (RECIST):
    • 21 patients (60.0%) achieved an objective CNS response, with two (5.7%) complete responses and 19 (54.3%) partial responses.
    • 12 patients (34.3%) had stable disease, and tumour status was non-evaluable for two patients (5.7%).
  • Median progression-free survival (PFS) was 6.2 months (95% CI: 4.9–7.5) and six patients were censored. (Figure 1A)
  • Median CNS-PFS was 7.1 months (95% CI: 6.4–7.8) and seven patients were censored. (Figure 1B)
  • Median overall survival was 9.8 months (95% CI: 6.5–13.1) and 11 patients were censored. (Figure 1C)
  • Eight patients received serial DCE-MRI on the study.
  • In general, tumour vascular normalization could be observed at 2.5 hours after starting bevacizumab infusion (one hour after infusion completion), but became much more obvious at 24 hours after infusion, as demonstrated by changes in DCE-MRI parameters. (Table 3)

Key conclusions

  • Tumour vascular normalization effects were more obvious at 24 hours compared with that at 2.5 hours after bevacizumab infusion.
  • By giving bevacizumab one day before etoposide and cisplatin, the BEEP regimen appears highly effective in brain metastases of breast cancer progressing from previous whole brain radiotherapy.
  • Further studies of this concept are warranted.

Reference: 1. Lu YS, Chen WW, Lin CH, et al. Bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for brain metastases of breast cancer progressing from radiotherapy — result of a multi-center phase II study. ECC 2013:1878.

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Spotlight Article

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Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

 

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Laurie H. Sehn, MD, MPH
Dr. Laurie H. Sehn is a Clinical Assistant Professor at the BC Cancer Agency and the University of British Columbia in Vancouver. She has been a medical oncologist and clinical investigator with the Lymphoma Tumour Group since 1998. Dr. Sehn has served on the Board of Directors of Lymphoma Foundation Canada (LFC) since 2002 and is currently Director of Research Fellowships for the LFC. Dr. Sehn’s research interests include all of the lymphoid cancers, with particular interest in the biology and treatment of large-cell lymphoma, the application of new imaging techniques such as PET scanning to lymphoma management, and innovative new approaches to treatment.

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Matthew Seftel, MBChB, MPH, MRCP(U.K.), FRCPC

Dr. Seftel is a hematologist/oncologist based at Princess Margaret Hospital in Toronto. He is a member of the Leukemia Group and leads the Allogeneic Blood and Marrow Transplantation Program. He is an Associate Professor at the University of Toronto in the Division of Internal Medicine. He is actively involved in clinical trials and outcomes-based research related to hematological malignancies and blood and marrow transplantation.

Investigator Commentary

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Sunil Verma, MD, MSEd, FRCPC

Dr. Sunil Verma is a medical oncologist and the Chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Ontario. He is also an Associate Professor at the University of Toronto. Dr. Verma completed his medical degree and postgraduate training in internal medicine and medical oncology at the University of Alberta. He completed a fellowship in breast cancer at the University of Toronto and a master’s degree in medical education at the University of Southern California. Dr. Verma is internationally recognized for his educational leadership and research in breast and lung cancers. He has led and created numerous innovative educational projects in oncology and won several teaching and mentoring awards. Dr. Verma’s research interests include reducing the toxicity of systemic treatment, developing novel therapies for breast and lung cancers, and medical education. He is the principal investigator for many clinical trials in breast and lung cancers, including an international phase III trial in breast cancer, and has authored or co-authored articles appearing in publications such as the Journal of Clinical Oncology, Cancer, The Oncologist, Lancet Oncology, Lancet, and The New England Journal of Medicine.