Abstract & Commentary
Synopsis: A phase II study is reported in patients with metastatic renal cell carcinoma using thalidomide. Patients were given doses up to 1200 mg if tolerable. A 5% objective response was observed with substantial toxicity. The true value of thalidomide in renal cell carcinoma has yet to be determined.
Source: Escudier B, et al. Ann Oncol. 2002;13:1029-1035.Angiogenesis has been recognized as a key factor in tumor progression and has become a target for anti-neoplastic drug development.1 Thalidomide, initially prescribed as a sedative and to ameliorate nausea in pregnancy in the 1950s, is known to have significant anti-angiogenic activity. Thalidomide demonstrated a capacity to eradicate experimental tumors in mice, to induce apoptosis of neovasculature established in experimental models, and to treat the vascular tumor, Kaposi’s sarcoma. Thalidomide has been shown to be active in the treatment of lepromatous leprosy and other dermatologic disorders such as cutaneous lupus erythematosus, recurrent erythema multiforme, prurigo nodularis, and aphthous ulcers. Recently, activity has been shown in inflammatory and autoimmune diseases such as Bechet’s syndrome, inflammatory bowel diseases, rheumatoid arthritis, sarcoidosis, and graft-versus-host disease. Thalidomide has also had activity in the treatment of chemoresistant multiple myeloma and gliomas.2,3
An investigation of thalidomide in renal cell carcinoma has been reported. Metastatic renal cell carcinoma is refractory to chemotherapy and median survival has been reported to range from 2-12 months. Both alpha-interferon and interleukin-2 have demonstrated some activity, both alone or combined, with objective response rates ranging from 5-40%. Forty patients were enrolled in the currently reported study. Eligibility included histologically confirmed metastatic renal cell carcinoma, an ECOG performance status 0-2, and adequate organ function. Thalidomide was administered nightly at 400 mg. The dose was increased to 800 mg after 6 weeks if disease was overtly progressive or after 12 weeks in the absence of an objective response. In patients whose disease continued to progress after 6 or 12 weeks at 800 mg, the dose was increased to 1200 mg if tolerated. The median age of the patients was 61 years and 80% had undergone nephrectomy. All but 6 had previously received immunotherapy.
The results were that no objective responses were observed at 12 weeks, but disease was stable in 11 patients. At 6 months, 2 patients achieved a partial response, corresponding to an overall response of 5%. These responses lasted 3 and 5 months. The 1-year survival rate was 38% and the median survival time was 10 months. Toxicity was significant, with fatigue and lethargy the most common. The fatigue score increased with time on therapy. Neurologic toxicity was substantial. Peripheral neuropathy was very common, with moderate at 20% and severe 15%. Thromboembolism was another significant toxicity. Nine patients had events during the first 12 weeks; 6 with deep venous thrombosis in the leg and 3 patients with vena cava thrombosis. Three patients also subsequently developed pulmonary embolism.
Comment by Stuart M. Lichtman, MD
Metastatic renal cell carcinoma continues to be an extraordinarily difficult problem in medical oncology. There are no standard therapies for the majority of patients with this disorder. Many patients are older and cannot tolerate therapy with high doses of interleukin-2. It was hoped that a less toxic, oral therapy such as thalidomide could provide some palliation for these patients. Unfortunately this is at least the second trial showing minimal to no clinical activity in this disease.4 The results in this study demonstrate that despite giving patients doses upwards of 1200 mg, no benefit was observed. Even more concerning was the substantial toxicity observed. This clearly negates any potential palliative benefit of stable disease. Because stable disease can occur as part of the natural history of metastatic renal cell carcinoma, any potential benefit of disease stabilization would need to be addressed in a randomized trial. It should also be noted that severe, unexpected toxicity resulted when thalidomide was combined with alpha-interferon.5
Thalidomide has a number of potential clinical applications. Some of these were mentioned previously. The drug has shown clear benefit in patients with multiple myeloma relapsing after transplant. Activity has also been demonstrated in glioma and the suggestion of some benefit in hepatocellular carcinoma. Thalidomide has been shown to ameliorate the toxicity of irinotecan in the treatment of metastatic colorectal carcinoma. Studies are ongoing to determine whether thalidomide can reverse the wasting syndrome associated with HIV infection.6
This and other studies have failed to demonstrate significant benefit of thalidomide in renal cell carcinoma and have been associated with substantial toxicity at the doses used in this trial. Despite the wide availability of the drug, patients should be encouraged to enroll on clinical trials to determine the true value of this medication in both the treatment of solid tumors and non-malignant disorders.
Dr. Lichtman is Associate Professor of Medicine, NYU School of Medicine, Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.
References
1. Escudier B, et al. Ann Oncol. 2002;13:1029-1035.
2. Singhal S, et al. N Engl J Med. 1999;341:1565-1571.
3. Fine HA, et al. J Clin Oncol. 2000;18:708-715.
4. Motzer RJ, et al. J Clin Oncol. 2002;20:302-306.
5. Nathan PD, et al. J Clin Oncol. 2002;20:1429-1430
6. Baidas S, et al. Cancer Invest. 2002;20:835-848.
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