Rationale for superseding
In a phase 3 randomised control trial by Motzer et al. (2009)r, patients received either repeated 6-week cycles of sunitinib (at a dose of 50 mg orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alpha (IFN) (at a dose of 9 million international units subcutaneously three times weekly). The primary endpoint of the study was progression free survival, which was statistically better for sunitinib patients. Median progression-free survival was 11 months in the sunitinib group (95% CI, 10 to 12) and 5 months in the IFN group (95% CI, 4 to 6), and a hazard ratio of 0.42 (95% CI, 0.32 to 0.54; P<0.001). For this reason the Medical Oncology Reference Committee has superseded this protocol.
The Medical Research Council of the UK performed a randomised study of interferon alpha (IFN) or medroxyprogesterone (MPA) for patients with metastatic renal cell cancer (RCC). 335 patients were randomised and approximately 40% had not had a nephrectomy. MPA dose was 300 mg daily. IFN dose started at 5 million international units three times weekly and escalated to 10 million international units three times weekly. Both arms received 12 weeks of therapy. There was a survival advantage for IFN with a hazard ratio of 0·72 (95% CI 0·55-0·94; p=0·017). These rates are equivalent to an absolute improvement in 1-year survival of 12% (95% CI 3-22%)-1-year survival was 31% for MPA and 43% for interferon-a. The median survival time was 2·5 months (95% CI 0·5-5·0 months) longer for interferon-a than for MPA (8·5 vs 6 months).r
A US study randomly assigned 241 patients with metastatic renal-cell cancer to undergo radical nephrectomy followed by therapy with IFN or to receive IFN therapy alone. The median survival of 120 eligible patients assigned to surgery followed by IFN was 11.1 months, and among the 121 eligible patients assigned to IFN alone it was 8.1 months (P=0.05).r A smaller European study randomised 85 patients to nephrectomy plus IFN (5 million international units three times weekly) or IFN alone. Time to progression (5 vs 3 months, hazard ratio 0·60, 95% CI 0·36-0·97) and median duration of survival were significantly better in nephrectomy than in IFN alone patients (17 vs 7 months, 0·54, 0·31-0·94).r
13-cis retinoic acid + interferon
A recent EORTC study of 320 patients shows a survival advantage of the additional of 13 cis-retinoic acid (CRA) to IFN. Median overall survival was 17.3 months for patients on IFN and CRA, and 13.2 months for patients treated with IFN (P =0.048).r An earlier US study failed to show a survival benefit in 284 patients, median survival 15 months in both arms.r
© Lancet 1999
Overall survival of 335 patients with metastatic RCC treated with either medroxyprogresterone 300mg daily for 12 weekly or alpha interferon (INF) 10 million units three times weekly for 12 weeks. Significant survival advantage for INF with hazard ratio of 0·72 (95% CI 0·55?0·94; p=0·017)r
At 4 weeks, a larger proportion of IFN patients than of MPA patients reported moderate or severe symptoms: lack of appetite, tiredness, nausea, lack of energy, shivering, and dry mouth. Of the 167 patients assigned IFN, dose reduction was necessary in 24% of patients on IFN and 7% of patients on MPA. 23 (14%) continued to receive IFN after 12 weeks.
There is no clear evidence for a dose-response relationship for IFN. Doses can be escalated to toxicity but in practical terms lower doses are more tolerable, allow a longer period of treatment thereby allowing time for tumour response.
12 weeks of MPA
n=49 ( %)
|12 weeks of interferon
|Lack of appetite
This adverse event data is the proportions of patients reporting moderate or severe symptoms.r