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A pilot study of thalidomide in patients with progressive metastatic renal cell carcinoma
Danai D Daliani1, Christos N Papandreou, Peter F Thall
1Department of Genitourinary Medical Oncology, M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ddaliani@notes.mdacc.org
Background:
The highly vascular nature of renal cell carcinoma (RCC) suggests that angiogenesis inhibition may be therapeutic for patients with this disease. Thalidomide inhibits basic fibroblast growth factor and vascular endothelial growth factor (VEGF)-induced angiogenesis.
Methods:
In a pilot study, we evaluated the safety and efficacy of escalating doses of thalidomide in patients with progressive metastatic RCC (mRCC), measurable disease, and good organ function. Patients received oral thalidomide starting at 200 mg per day and increasing by 100-200 mg per day weekly until a target dose of 1200 mg per day was reached. Study endpoints were objective tumor response and toxicity.
Results:
Of the 20 patients enrolled, 19 were evaluable for response. Eighteen achieved the target dose. The most common, but reversible, toxicities were constipation, somnolence, and fatigue. Peripheral neuropathy was seen after prolonged therapy, necessitating dose reduction. Two patients achieved a partial response and nine had stable disease for a median of 14 months (range, 3-17 months). Median time to progression was 4.7 months (range, 0.7-31.3 months). Fifteen patients died (median survival, 18.1 months; 95% lower confidence bound 10.7). Survival was significantly longer in patients with higher hemoglobin level and longer time from first metastasis to start of thalidomide, but significantly shorter in patients with multiple organ involvement and previous treatments.
Conclusions:
Thalidomide at this dose is associated with manageable acute toxicities but long-term dose-limiting neuropathy. Objective responses are rare in patients with mRCC and are characterized by delay in achieving maximum tumor reduction. Prolonged stable disease is seen in some patients, but the benefit of thalidomide, as well as other angiogenesis inhibitors, in that setting needs to be studied in controlled, randomized trials.
Insights
Thalidomide showed manageable acute side effects in metastatic renal cell carcinoma (mRCC) patients, but long-term use caused dose-limiting neuropathy. Objective responses were rare, though some patients experienced prolonged stable disease.
Area of Science:
- Oncology
- Pharmacology
- Nephrology
Background:
- Renal cell carcinoma (RCC) is highly vascular, suggesting anti-angiogenesis therapy is a potential treatment.
- Thalidomide inhibits angiogenesis by targeting basic fibroblast growth factor and vascular endothelial growth factor (VEGF).
Purpose of the Study:
- To evaluate the safety and efficacy of escalating thalidomide doses in patients with progressive metastatic RCC (mRCC).
Main Methods:
- A pilot study administered oral thalidomide, escalating doses weekly from 200 mg to a target of 1200 mg daily.
- Primary endpoints included objective tumor response and toxicity assessment in patients with measurable disease and good organ function.
Main Results:
- Of 20 patients, 19 were evaluable; 18 reached the target dose. Common reversible toxicities included constipation, somnolence, and fatigue. Peripheral neuropathy emerged with prolonged therapy, requiring dose reduction.
- Two partial responses and nine cases of stable disease (median 14 months) were observed. Median time to progression was 4.7 months. Survival was influenced by factors like hemoglobin levels, time to treatment, and prior therapies.
Conclusions:
- Thalidomide at the studied doses has manageable acute toxicities but poses a risk of long-term dose-limiting neuropathy.
- Objective responses in mRCC are infrequent and delayed. The benefit of thalidomide and other angiogenesis inhibitors requires further investigation in randomized controlled trials.