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UROSCAN
Year : 2006  |  Volume : 22  |  Issue : 4  |  Page : 384-385
 

Is 13-CIS-retinoic acid effective in patients with metastatic renal cell carcinoma?


Department of Urology, Christian Medical College, Vellore, Tamil Nadu, India

Correspondence Address:
A Karthikeyan
Department of Urology, Christian Medical College, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Karthikeyan A, Kekre NS. Is 13-CIS-retinoic acid effective in patients with metastatic renal cell carcinoma?. Indian J Urol 2006;22:384-5

How to cite this URL:
Karthikeyan A, Kekre NS. Is 13-CIS-retinoic acid effective in patients with metastatic renal cell carcinoma?. Indian J Urol [serial online] 2006 [cited 2019 Sep 15];22:384-5. Available from: http://www.indianjurol.com/text.asp?2006/22/4/384/29137

Aass N, De Mulder PH, Mickish GH, Mulders P, van Oosterom AT, van Poppel H, et al. Randomized phase III trial of Interferon alpha-2a with and without 13-cis-retinoic acid in patients with progressive metastatic renal cell carcinoma: European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951). J Clin Oncol 2005;23:4172-8.



   Summary Top


The prognosis is often bleak in metastatic renal cell carcinoma (RCC). The authors have investigated the role of 13-cis-retinoic acid (13-CRA) in metastatic renal cell carcinoma (RCC) with or without interferon alpha-2a (INF-a-2a) in a randomized control trial.[1] Recruitment was done in two phases and patient entry was closed in January 2001. The inclusion criteria were histologically proven RCC, WHO performance status of 0 or 1, normal platelet and WBC count, normal renal and liver function tests. All patients had nephrectomy and disease progression prior to randomization. Three million units (MU) of INF-a-2a was administered subcutaneously every day and the dose was escalated by 3MU every seventh day. The maximum dose was 9MU. 13-CRA was administered orally (1 mg/kg/day) every day. If toxicity occurred, the dose of INF-a-2a and 13-CRA was adjusted or stopped according to the protocol, depending on the severity. According to the protocol the patients should receive at least three months of therapy. Optimally, the treatment could be continued for 12 months. All the patients were followed until death or until July 2003. The primary end point was overall survival. The secondary end points were rate of progression, progression-free survival and toxicity. Two hundred and ninety-six patients should be recruited and 252 deaths were required to show a hypothesized overall survival difference of 10% at one year between the two groups. The power of the study was 80%. Analysis was done with an intention to treat. Three hundred and twenty patients were randomly assigned and 23 were found to be ineligible. The median time from diagnosis to random assignment was 46 weeks. A few patients had received radiotherapy and hormonal therapy prior to randomization in both the groups. The median duration of treatment was 13 weeks for the combination group and 15 weeks for the INF-a-2a group. One hundred and fifty-five patients were treated for less than three months due to disease progression and toxicity and 158 were treated for more than three months but only 39 patients could receive the complete protocol treatment. Overall median survival was 17.3 months in the combination group and 13.2 months for patients treated with INF-a-2a ( P =0.048). Median time to progression and progression-free survival was statistically significant in patients receiving combination treatment.


   Comments Top


Treatment options for metastatic RCC are limited. Cytokine-based treatment has shown promising results in metastatic RCC. The response rate varies from 15-20%. Retinoic acid has been shown to be effective in the management of leukemia and has been tried in other solid organ malignancies. The authors have explored the therapeutic role of retinoids in a disease which has a very poor prognosis. The authors could demonstrate a survival benefit of four months in the combination group. This survival advantage is probably due to nephrectomy prior to randomization. The mortality was approximately 50% in both the arms at the end of one year. Disease progression was the most common cause for discontinuation of the treatment. The majority of the patients could not complete the protocol treatment. Drug toxicity was seen in both the arms. Treatment was abandoned due to toxicity in 22% of patients in the combination group and 16% in the INF-a-2a group. In the EORTC Phase II trial systemic toxicity of grades 2-4 was seen in 60% of patients.[2] Mortality due to drug toxicity was not reported in both the trials. In another study by Motzer et al[3] the median duration of response and progression-free survival was statistically significant in the combination arm but there was no difference in the overall survival. Median survival time for all patients was 15 months. In the present study[1] median time from diagnosis to random assignment was 46 weeks. If the treatment had been initiated immediately after nephrectomy there might have been a better overall survival in the combination group. Thalidomide as single agent has been found to be ineffective in a randomized trial.[4] Thalidomide was found to be effective in combination with interleukin -2 in a Phase II trial.[5] Quality of life should be considered before venturing into newer treatment modalities as the survival advantage is marginal with treatment in metastatic renal cell carcinoma. All these trials were performed in a select group of patients and the outcome of these trials does not favor its use outside the setting of a clinical trial. Due to the poor overall prognosis further research is required in the management of patients with metastatic renal cell carcinoma.

 
   References Top

1.Aass N, De Mulder PH, Mickish GH, Mulders P, van Oosterom AT, van Poppel H, et al . Randomized phase III trial of Interferon alpha -2a with and without 13-cis-retinoic acid in patients with progressive metastatic renal cell carcinoma: European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951). J Clin Oncol 2005;23:4172-8.  Back to cited text no. 1    
2.Fossa SD, Mickisch GH, De Mulder PH, Horenblas S, van Oosterom AT, van Poppel H, et al . Interferon alpha-2a with or without 13-cis retinoic acid in patients with progressive measurable metastatic renal cell carcinoma. Cancer 2004;101:533-40.  Back to cited text no. 2    
3.Motzer RJ, Murphy BA, Bacik J, Schwartz LH, Nanus DM, Mariani T, et al . Phase III trial of interferon alpha-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 2000;18:2972-80.  Back to cited text no. 3    
4.Lee CP, Patel PM, Selby PJ, Hancock BW, Mak I, Pyle L, et al . Randomized phase II study comparing thalidomide with medroxyprogesterone acetate in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:898-903.  Back to cited text no. 4    
5.Amato RJ, Morgan M, Rawat A. Phase I/II study of thalidomide in combination with interleukin-2 in patients with metastatic renal cell carcinoma. Cancer 2006;106:1498-506.   Back to cited text no. 5  [PUBMED]  [FULLTEXT]




 

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