Pierga et al. (2004)

Pierga et al. (2004)
Design: Phase II study (therapy), evidence level: 3
Country: France
Inclusion criteria:
Females (and males) with MBC who had enrolled on a compassionate use study. All patients registered on this study were required to have failed taxane therapy and anthracycline therapy (or have anthracycline contra-indicated).
Exclusion criteria:
None stated
Population:
Number of patients = 197. Age range 31 to 88 years, median age = 56 years
Interventions:
Recommended treatment regime was 2500 mg per m2 divided into two daily doses for 14 days every 21 days. Treatment may have been discontinued, or the dose reduced, at the physician or patient’s discretion and further appropriate treatment may be have been administered. Standard dose reductions were employed in the event of toxicity.
Outcomes:
Primary outcomes: time to progression (TTP) and overall survival (OS).

Secondary outcomes: complete response (CR), partial response (PR), stable disease (SD), and overall response rate (ORR).
Follow up:
Median follow-up by study cut-off: 8.5 months (range: 0.3–24.6)
Results:
Patient characteristics:
Performance status n (%):
0–1 = 109 (60%)
2 = 39 (21%)
≥ 3 = 34 (19%)
NK = 15 (−)

Menopausal at diagnosis n (%):
Yes = 92 (47%)
No = 102 (53%)
NK = 3 (−)

Primary tumour n (%):
T1–2 = 140 (79%)
T3–4 = 38 (21%)
NK = 19 (−)

Scarff-Bloom-Richardson (SBR) grade n (%):
1–2 = 54 (49%)
3 = 57 (51%)
NK = 86 (−)

Hormonal status n (%):
ER +ve = 148 (80%)
PR +ve = 140 (76%)
Both +ve = 68%

Median time from diagnosis to metastatic disease = 44.9 months (range 0.7–331.3)
Median time from metastatic disease to treatment initiation = 34.6 (range 0.3–270.6)

Sites of disease n (%):
Bone = 116 (59%)
Liver = 86 (44%)
Lung = 76 (39%)
Skin = 59 (30%)
Lymph nodes = 52 (26%)
Pleura = 46 (23%)

Chemotherapy n (%):
Adjuvant = 118 (61%)
Palliative = 189 (96%)
Hormonal therapy n (%):
Adjuvant = 67 (35%)
Palliative = 138 (71%)

Number of lines of palliative chemotherapy n (%):
0 = 6 (3%)
1 = 19 (10%)
2–3 = 97 (49%)
≥ 4 = 75 (38%)

Chemotherapy agents n (%):
Taxanes = 158 (81%)
Anthracyclines = 122 (62%)
Vinorelbine = 111 (57%)
5-FU protracted = 28 (14%)
5-FU other = 25 (13%)

Efficacy n (%):
CR = 1 (1%)
PR = 29 (15%)
SD = 66 (34%)
PD = 76 (39%)
Not assessable = 24 (12%)
NK = 1 (1%)
ORR = 15% (95%CI: 11–21%)

Median duration of response = 8.9 months (95%CI: 6.1–11.7)
Median duration of SD = 6.6 months (95%CI: 5.1–8.0)
Median TTP = 4.8 months (95%CI: 4.1–5.0)(n=152)
Median OS = 14.7 months (95%CI: 9.6–19.8)

Safety:
Patients received a median of 5 cycles of treatment. 32% of patients received dose reduction, mostly for toxicity. 32 patients discontinued treatment because of toxicity.

Grade 3–4 adverse events:
Haematological n (%):
Anaemia = 7 (4%) (n=180)
Leukopenia = 11 (6%) (n=180)
Thrombocytopenia = 5 (3%) (n=180)
Febrile neutropenia = 1 (1%) (n=NK)

Gastrointestinal n (%):
Diarrhoea = 12 (7%) (n=174)
Mucositis = 10 (6%) (n=177)
Nausea = 6 (3%) (n=175)
Vomiting = 4 (2%) (n=173)
Hand-foot syndrome = 29 (16%) (n=177)
Asthenia = 15 (9%) (n=159)
General comments:
Study was undertaken between September 1998 and January 2001 in 32 secondary care facilities (some of these centres may have been tertiary).

Recruitment: Patients were recruited onto a compassionate use study. The only criteria were that they should have MBC and no other inclusion or exclusion criteria were enforced. The sample size is high.

122 (62%) patients received anthracyclines and 158 (81%) taxanes, as palliative therapy. It is not recorded how many patients had received both drugs in this setting.

Allocation: The treatment is assumed to be according to license but this is not formally recorded and was only recommended.

Maintenance: Drop-out rates are not recorded in this retrospective data analysis.

Median follow-up period with 95%CI was recorded. Whilst median OS had been reached in the entire study population this was not true of the responding patients who had a significantly longer survival time than non-responders (P < 0.0001).

Using univariate and multivariate analysis, the authors identified several prognostic factors of ORR, TTP and OS. Response to treatment was strongly prognostic for OS with non-responders (SD and not evaluated) having a 5-fold risk of death compared with responders (CR and PR).

Measurement: No patient data were collected or monitored prospectively but rather were extracted from records with the co-operation of treating physicians. Derived data from missing information were not used, with the exception of hormone receptor status, which was assumed to be positive if patients were treated with hormone therapy.

There is an assumption by the authors, having studied case notes, that tumour response was assessed according to WHO criteria and adverse events were graded according to NCI-CTC standards.

Authors detailed the following outcomes: TTP and OS.

It seems likely, given the programme in which these patients were enrolled, that many would have had a poor prognosis and, in the light of this, a low OS and higher TTP might be expected, compared with other studies. The result may, if anything, perhaps underestimate the efficacy of capecitabine as treatment of the MBC population as a whole. Nonetheless, given the high patient number, the fairly wide CI may be reflecting the very heterogeneous background of this study group.

From: Chapter 4, Systemic disease-modifying therapy

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