Pretreatment lactate dehydrogenase levels predict how well poor-risk patients with advanced kidney cancer respond to temsirolimus, according to a retrospective analysis of a phase-III trial.
If further studies confirm the finding, a low-cost blood test for the enzyme could make it the first biomarker for clinical prediction of kidney cancer patients’ response to a mammalian target of rapamycin (mTOR) inhibitor, such as temsirolimus (Torisel).
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Dr. Andrew Armstrong
"Being able to direct these patients to a treatment we know will help them would be a major advancement in their care," Dr. Andrew J. Armstrong of the Duke Cancer Institute, Durham, N.C, said in a written statement. "At the same time, patients who would not benefit from the treatment would be spared from undergoing a drug regimen with potential side effects that could diminish their quality of life."
Temsirolimus is approved for treatment of advanced kidney cancer. Alternatives to mTOR inhibition for this disease include cytokine therapy and agents targeting the vascular endothelial growth factor.
A widely expressed metabolic enzyme in tissues, lactate dehydrogenase (LDH) is a well-known prognostic biomarker in various types of cancers, including prostate cancer, lymphoma, melanoma, and renal cell carcinoma (RCC). Prognostic biomarkers help evaluate patient outcomes irrespective of treatment. No predictive biomarkers have been identified that can help select treatments for genitourinary malignancies, including RCC, Dr. Armstrong and his associates wrote in the Journal of Clinical Oncology.
The researchers used data from a phase-III randomized study (N. Engl. J. Med. 2007;356:2271-81) to compare 404 poor-risk patients with advanced RCC who were randomly assigned to temsirolimus (201 patients) or interferon alfa-2a (IFN-alpha) (203 patients). Overall survival rates among patients treated with temsirolimus were 53.7% at 6 months and 34.3% at 12 months, compared with 39.5% and 12.7 %, respectively, in the IFN-alpha group.
Stratifying patients by high LDH (defined as greater than 1 × the upper limit of normal [ULN]) and normal LDH (up to 1 × ULN), investigators calculated the multivariable hazard ratio for death was 2.81with high vs. normal LDH at baseline (P less than .001), they reported (J. Clin. Oncol. Aug. 13 [doi: 10.1200/JCO.2011.40.9631]).
The analysis showed that, within the high-LDH group, median overall survival was significantly longer in those treated with temsirolimus than in those treated with IFN-alpha (6.9 v. 4.2 months; HR=0.56; P less than .002.) Among patients with normal LDH, median overall survival was not significantly improved by temsirolimus, however (11.7 months vs. 10.4 months).
As secondary end points, the authors examined the predictive value of baseline LDH for progression-free survival and clinical benefit rate, but they found no predictive interaction.
Dr. Armstrong said in an interview that the study statistically proves that LDH is a predictive biomarker for advanced RCC, but the results have to be validated before major practice changes take place.
"The advantage of LDH as a predictive and prognostic biomarker rests in its ease of collection, cost, and its routine assessment as part of routine medical care in patients with RCC," the authors wrote.
The study has several limitations, they noted. For one, it was limited to poor-risk patients with RCC. Also, temsirolimus was only compared with IFN-alpha, which is no longer in widespread use. Also, the study was limited to temsirolimus, an mTOR/TORC1 inhibitor.
"Although other TORC1 inhibitors may have anticancer activity, it is unknown at this time whether LDH is predictive of improved outcomes with these agents," the authors wrote.
Dr. Armstrong has received honoraria and research funding from Pfizer, which makes temsirolimus and funded the study.