Ghosn M et al. (2008)

Ghosn M et al. (2008)
Design: Phase II study (prognosis), evidence level: 3
Country: Lebanon
Inclusion criteria:
Women of at least 18 years of age
Histologically proven MBC
WHO performance status < 2
At least one bi-dimensionally measurable lesion that had not been irradiated
Life expectancy > 3 months
Adequate bone marrow, liver and renal function (no parameters given)
Written informed consent
Ability to comply with the study protocol
Exclusion criteria:
Local disease only
Prior chemotherapy for MBC
Prior vinca alkaloid or capecitabine
Peripheral neuropathy in > 2 sites
Dysphagia or inability to swallow tablets
Malabsorption or other GI condition which would prevention drug absorption
Serious disease or significantly active infection
Pregnancy or lactation
CNS or leptomeningeal metastases
Use of the anti-viral agent sorivudine or related analogues
History of other malignancy within 5 years previously, except BCC cancer or CIS cervix.
Population:
Number of patients = 40. Age range 36 to 80 years, median age = 57 years
Interventions:
  1. Vinorelbine (VIN) at 25 mg per m2 given i.v. over 6–10 minutes on days 1 and 8 of a three- week cycle.
  2. Capecitabine (CAP) at 825 mg per m2 to be taken orally twice daily for the first 14 days of a three-week cycle.
Treatment was planned for four cycles after which responding patients received docetaxel (DOC) at 25 mg per m2 each week for 12 weeks. Patients who had progressed by the 2nd cycle of VIN + CAP were moved onto DOC and included in the ITT analysis.

Dose reductions or treatment delays occurred in response to (described) grade 3 or 4 haematological or non-haematological toxicities. For those patients who had disease progression after two cycles of VIN + CAP, the 1st injection of DOC was given at full dosage
Outcomes:
Primary objective: overall response rate (ORR), complete response (CR), partial response (PR) and stable disease (SD), clinical benefit ratio (CBR)

Secondary objective: evaluation of safety, overall survival (OS) and response duration (RD).
Follow up:
Baseline assessment were performed on all patients within three weeks of starting treatment including medical history, physical examination, assessment of performance status, pregnancy test (if needed), ECG, chest X-rays, tumour measurement, ultrasound and bone scans.

On day 1 of each treatment cycle, physical condition was evaluated along with performance status, haematological criteria and blood chemistries. On day 8 of each cycle, complete blood counts were determined. Tumour response was assessed every nine weeks until progression or earlier if progression was suspected.
Results:
Efficacy of VIN + CAP (ITT population) n=40:
CR = 2
PR = 20
ORR = 22 (55%)
SD = 13
CBR = 88%
PD = 5

Efficacy of DOC in those responding or stable with VIN + CAP (ITT population) n=40:
CR = 5
PR = 20
ORR = 25 (62.5%) (95%CI: 45.8–77.27)
SD = 3
PD = 12 (included 6 patients who did not receive DOC due to PD or death)

Efficacy of sequential treatment with VIN + CAP then DOC (ITT population) n=40:
CR = 5
PR = 20
ORR = 25 (62.5%)
SD = 5
CBR = 75%
PD = 9

ORR for patients previously treated with adjuvant anthracyclines = 68%
ORR for patients who were anthracycline naïve = 57.14%


Median TTP = 12.3 months (range: 1.5–48) (95% CI: 10.05–14.54)
Median OS = 35.8 months (range: 2–47)
1yr survival rate = 87.5%
2yr survival rate = 57.5%
3yr survival rate = 35%

Safety:
The median number of treatment cycles per patient was 4 (range: 1–5). CAP dose reduction was necessary for 5 patients and VIN dose reduction in 4 patients. DOC dose reduction was required for one patient.

Grade 3 or 4 events relating to VIN + CAP (n=40):
Anaemia = 1
Thrombocytopenia = 1
Neutropenia = 4
Febrile neutropenia = 3

Grade 3 or 4 events relating to DOC (n=35):
Anaemia = 1
Thrombocytopenia = 2
Neutropenia = 1
General comments:
This paper describes the long term results of a phase II study of VIN + CAP combined followed by DOC as 1st line therapy for advanced breast cancer. The study which was undertaken in 3 treatment centres in Lebanon. Patients were recruited between March 2002 and November 2003.

25/40 (62.5%) patients had been treated with anthracycline as adjuvant therapy. 61.3% of patients had visceral metastases and 75% had non-visceral metastases.

The addition of DOC to the combined regime of VIN + CAP did not significantly affect the overall response rate, even though it increased by 18.5%. The results from this trial encouraged the initiation of another randomised trial comparing VIN + CAP with or without sequential weekly DOC.

From: Chapter 4, Systemic disease-modifying therapy

Cover of Advanced Breast Cancer
Advanced Breast Cancer: Diagnosis and Treatment.
NICE Clinical Guidelines, No. 81.
National Collaborating Centre for Cancer (UK).
Copyright © 2009, National Collaborating Centre for Cancer.

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