The evidence supporting this protocol is provided by two phase III randomised trials by Wintonr et al 2005, & Douillardr et al 2005. The Winton study involved 482 patients and compared adjuvant vinorelbine plus cisplatin with observation. Patients with stage IB or stage II non-small cell lung cancer commenced treatment within 6 weeks of surgical resection. Patients were stratified according to nodal status (NO vs N1) and the presence of a ras mutation. Primary end point was overall survival, secondary endpoints included recurrence-free survival and the safety, toxicity and quality of life associated with this regimen.
The study enrolled patients over a period of 6 years and had a median follow up of approximately 5 years.r
The ANITA study (Douillard et al) was a prospective randomised phase III trial in patients with completely resected NSCLC, stages IB (T2N0), II or IIIA. Median follow-up 70 months.r
Efficacy
Patients in the Winton study had completely resected T2NO, T1N1, or T2N1 NSCLC with acceptable baseline characteristics and performance status of 0 or 1.
Overall survival was significantly prolonged in the chemotherapy arm (94 months vs 73 months for the observation arm) with a 31% reduction in risk of death (hazard ratio for death 0.69, 95% CI 0.52-0.91, P=0.04. This represented an absolute benefit in 5 yr overall survival of 15% (69% adjuvant chemotherapy vs 54% observation)
Chemotherapy significantly prolonged recurrence free survival compared with observation (hazard ratio for recurrence, 0.60; 95% CI, 0.45 to 0.79; P<0.001)
The median recurrence-free survival was 46.7 months (observation group) and had not been reached in the chemotherapy group.r
Anitar |
Observation |
Vinorelbine/cisplatin |
Median RFS |
20.7m (months) |
36.3m (p=0.002) |
Overall survival (OS) |
43.3m |
65.8m (p=0.013) |
2 year OS |
62.8% |
67.9% |
5 year OS |
42.6% |
51.2% |
Stage 11B median survival |
99.7m |
Not reached |
Stage 11 median survival |
36.5m |
65.8m |
Stage 11A median survival |
24.1m |
38.6m |
Both studies failed to demonstrate a statistically significant benefit for overall survival in the subgroup of patients with stage 1B.
Wintonr |
Vinorelbine, Cisplatin |
Observation only |
p-value |
5 year recurrence free survival |
61% |
49% |
.08 |
Overall survival |
94 months |
73 months |
.04 |
Survival:r
© N Engl J Med 2005
Toxicity
Two patients died due to treatment related toxicity one during CT from sepsis and one six months later due to interstitial lung disease, first documented during treatment.
77% had at least 1 dose modification or omission, and 55% required 1 dose delay or more, mostly related to neutropenia.
73% of patient had grade 3 or 4 neutropenia; G-CSF was administered to 15% of patients.
Drug-related adverse events among patients who received at least one dose of vinorelbine plus cisplatinr
Adverse eventr |
Vinorelbine plus cisplatin |
|
Any Grade (%) |
Grade 3 or 4 (%) |
Fatigue |
81 |
15 |
Anorexia |
55 |
10 |
Alopecia |
32 |
- |
Diarrhoea |
23 |
<1 |
Nausea |
80 |
10 |
Vomiting |
48 |
7 |
Constipation |
47 |
3 |
Infection |
22 |
1 |
Febrile neutropenia |
7 |
7* |
Hearing loss |
21 |
2 |
Sensory neuropathy |
48 |
2 |
Motor neuropathy |
15 |
3 |
Dyspnoea |
18 |
4 |
Thrombocytopenia |
32 |
1 |
Anaemia |
93 |
7 |
Neutropenia |
88 |
73 |
ALT elevation |
18 |
<1 |
Bilirubin elevation |
4 |
<1 |
Creatinine elevation |
16 |
<1 |
* 6% had febrile neutropenia after the dose of vinorelbine was reduced.