Rivera et al. (2006)

Rivera et al. (2006)
Design: Retrospective case series (prognosis), evidence level: 3
Country: United States
Inclusion criteria:
Bidimensionally measurable brain metastasis from breast cancer
Newly diagnosed
Refused RT or were neurologically stable or had tumour progression or recurrence after WBRT or SR
Life expectancy of > 8 weeks
Zubrod performance status ≤ 2
Adequate renal, liver and bone marrow function (definitions given).
Exclusion criteria:
Prior treatment with temozolomide or capecitabine
Rapidly progressing visceral disease
Serious medical condition (not defined).
Population:
Number of patients = 24, age range 32 to 77 years, median age = 50 years
Interventions:
Capecitabine (C) given orally in 2 divided doses and Temozolomide (T) given orally once daily.
Concomitant daily doses were given on days 1–5 and 8–12 with cycles repeated every 21 days.
Patients were divided into treatment groups based on dosage:

Dose level 0 (n = 6): C at 1800 mg per m2 + T at 75 mg per m2
Dose level 1 (n = 6): C at 1800 mg per m2 + T at 100 mg per m2
Dose level 2 (n = 8): C at 2000 mg per m2 + T at 100 mg per m2
Dose level 3 (n = 4): C at 2000 mg per m2 + T at 150 mg per m2

Patients were treated until disease progression or unacceptable toxicity. Treatment was withheld for dose-limiting toxicities (defined) and was then resumed at the same or a lower dose level when the toxicity was resolved.
Outcomes:
Primary: to determine the maximum tolerated dose of temozolomide and capecitabine

Secondary: response rates, response duration (RD), tumour response: Complete response (CR), Partial response (PR), Minor response or stable disease (SD), Progressive disease (PD), Not evaluable (NE).
Follow up:
Before treatment patients were given a full clinical examination, assessment of performance status, radiological studies, MRI, complete blood count, urinalysis, blood chemistry, and pregnancy test.

Complete blood cell and differential counts were tested every week during the study and toxicity was assessed on day 1 of every three week cycle. Imaging (MRI) was repeated every 6 weeks. Neurocognitive functioning was tested by a trained psychometrician one month after treatment had begun and for some patients (n = 7) at the end of the study. Symptoms and quality of life were assessed during follow-up and at the end of the study.

17/24 patients were taken off study with disease progression in the brain and 5/24 for disease progression elsewhere. None were taken off for toxicity.
Results:
Median number of treatment cycles per patient = 4 (range: 1–16 cycles)

Tumour response:
Dose level 0 (n = 6): CR (n = 1) PR (n = 1) SD (n = 2) PD (n = 2) NE (n = 0)
Dose level 1 (n = 6): CR (n = 0) PR (n = 1) SD (n = 3) PD (n = 1) NE (n = 1)
Dose level 2 (n = 8): CR (n = 0) PR (n = 1) SD (n = 5) PD (n = 1) NE (n = 1)
Dose level 3 (n = 4): CR (n = 0) PR (n = 0) SD (n = 1) PD (n = 3) NE (n = 0)
Total CR = 1 (this patients had not received prior WBRT and was on dose level 0)
Total PR = 3 (1 of these patients had not received prior WBRT, 2 patients had received prior WBRT)
Total SD = 11
Total PD = 7
Total NE = 2

Grade 3/4 adverse events:
Dose level 0 (n=6): neutropenia (n=3), headache (n=1) constipation (n=1)
Dose level 1 (n = 6): fatigue (n = 1), vomiting (n = 1), headache (n = 1), constipation (n = 1)
Dose level 2 (n = 8): fatigue (n = 2), neutropenia (n = 2), thrombocytopenia (n = 2)
Dose level 3 (n = 4): fatigue (n = 2), vomiting (n = 2), neutropenia (n = 2), thrombocytopenia (n = 1)

Median RD = 8 weeks (range: 6–64)
Median TTP in brain = 12 weeks (range: 3–70)

Neurocognitive function:
Improvements were noted in attention span (P = 0.047) and emotional function (P = 0.016) but there were no significant differences between baseline and end-of-study assessments.
General comments:
This paper was primarily a prospective, phase I dose finding study but which included details of tumour response and adverse events. Patients were treated with chemotherapy at a single institution.

14/24 patients were newly diagnosed with brain metastases, all of whom had declined WBRT.
10/24 patients had recurrent metastases, 8 of whom had received prior WBRT. All patients had multiple metastases which were inoperable and not amenable to SR.

Although relatively small and not designed for the purpose, nevertheless this phase I study produced useful data regarding tumour response and adverse events. There were no statistical analyses and data were presented straightforwardly as point estimates with ranges. Unfortunately only a small sub-set of patients were examined at the end of the study period and there was no long term follow-up.

Authors conclude that this treatment regime may provide an active and well tolerated alternative to WBRT in the treatment of patients with multiple brain metastases.

From: Chapter 6, Management of specific problems

Cover of Advanced Breast Cancer
Advanced Breast Cancer: Diagnosis and Treatment.
NICE Clinical Guidelines, No. 81.
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