Commentary by Michael Seidman MD, Chief Oncology Fellow
New treatment options for both early and advanced Renal Cell Cancer have recently been published. Traditionally, treatment for early stage disease was partial or radical nephrectomy. In the metastatic setting, treatment options were limited to toxic cytokine therapy with IFN or IL-2.
Some recent literature has suggested that small, incidentally found renal tumors can safely be watched without the need for invasive surgery. Remzi et al  retrospectively reviewed 287 tumor bearing kidneys 4cm or less detected by imaging and surgically removed. High grade (poorer prognostic) tumors were seen in 4.2%, 5%, and 25.5% of tumors measuring 2 cm or less, 2.1-3.0 cm, and 3.1 to 4.0 cm respectively. Distant metastases were seen in 2.4% of tumors 3.0 cm or less compared to 10.8% of tumors 3.1-4.0 cm.
Schlomer et al  examined 349 renal masses form 331 patients. Malignant tumors were seen in 72.1% of tumors less than 2 cm compared to 93.7% of tumors greater than 7cm. The mean size of tumors in patients with symptoms at the time of diagnosis was 6.2cm compared to 3.7cm for tumors discovered incidentally. High grade histology was more common in larger tumors, occurring in 52 % of tumors >4cm compared to 7% and 29% in tumors measuring <2.0 cm and 2-4cm respectively.
These recent reports support the notion that most small renal tumors, especially those <3.0 cm are indolent in nature. In older patients, and those with multiple comorbidities, watchful waiting is an option. Newer technologies, specifically cryoablation and radiofrequency ablation, can provide good disease control with a less invasive procedure than nephrectomy. Matin et al  reported on 616 patients who underwent RFA and cryoablation. 10% of the patients had residual or recurrent disease after primary therapy. After salvage ablative therapy, failure was seen in only 4.2% of patients treated. 2 yr overall survival in patients with recurrent or residual disease was 82.5% with a 97.4% 2-year metastasis-free survival.
The past year has seen the FDA approval of 2 new therapies for advanced renal cell carcinoma. RCC has been a particularly chemoresistant disease and treatment with cytokines have been rather disappointing and quite toxic. Exploiting biologic pathways that contribute to the pathogenesis of RCC has led to the development of new “targeted” therapies.
Motzer et al  compared IFN, which was the standard of care, to sunitinib as first-line therapy for advanced RCC. Sunitinib is a tyrosine kinase inhibitor against the VEGF and PDGF receptors. These receptors initiate intracellular signals for growth and angiogenesis, necessary for tumor survival. A response rate of 31% was seen with sunitinib compared to 6% for IFN. Progression free survival was significantly longer in the sunitinib arm, 11 months vs. 5 months. This study has changed the standard of care for treatment of metastatic RCC, with sunitinib now recommended as first-line therapy.
Sorafenib, a tyrosine kinase inhibitor of the VEGF and PDGF receptors as well as the signaling protein raf, is also approved for metastatic Renal Cell Cancer. This approval is based on a recently published Phase III study of sorafenib compared to placebo after failure of 1 prior therapy . Patients on sorafenib had an improved progression free survival form 2.8 months to 5.8 months. Sorafenib produced a nonsignificant trend toward improved median survival.
These therapies, while much easier to administer, do have some unique and significant side effects. More common adverse effects include rash, fatigue, diarrhea, hypertension, proteinuria, and hand-foot syndrome (redness and cracking of skin of hands and feet).
Additional investigations continue into targeting different signaling pathways and combining agents with different mechanisms of action to improve on current treatments for Renal Cell Cancer.
 Remzi M et al. Are small renal tumors harmless? Analysis of histopathological features according to tumors 4 cm or less in diameter. J Urol 2006 Sep; 176:896-9. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:16890647&_char_set=utf8
 Schlomer B et al. Pathological features of renal neoplasms classified by size and symptomatology. J Urol 2006 Oct; 176:1317-20. http://sfx.med.nyu.edu/sfxlcl3?genre=article&date=2006&rft.jtitle=Journal of Urology&volume=176&spage=1317&epage=1320
 Matin SF et al. Residual and recurrent disease following renal energy ablative therapy: A multi-institutional study. J Urol 2006 Nov; 176:1973-7. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:17070224&_char_set=utf8
 Motzer R et al. N Engl J Med 2007;356:115-124.
 Escudier B et al. N Engl J Med 2007;356:125-134. http://sfx.med.nyu.edu/sfxlcl3?genre=article&id=pmid:17215530&_char_set=utf8
Image courtesy of National Library of Medicine
2 comments on “Recent Developments in the Treatment of Renal Cell Carcinoma”
An additional treatment for metastatic renal cell cancer was approved by the FDA today based on a Phase III randomized trial published in the May 31, 2007 NEJM. This trial investigated treatment of poor prognostic metatstaic renal cell carcinoma with either interferon alfa, temsiroliums, or the combination. Temsirolimus inhibits the mamalian target of rapamycin kinase(mTOR). This kinase is involved in intracellular signalling of pathways promoting growth and proliferation of cells.
Median overall survival was 10.9 months for the temsirolimus arm, compared to 7.3 months for the interferon arm and 8.4 months for the combination arm. Progression free survival was improve from 3.1 month in the interferon arm to 5.5 months in the temsirolimus arm.
This study is significant for two reasons. First, this is the first targeted therapy to show a statistically significant improvement in overall survival. More impressive is that this was a poor prognostic group of metatstatic reanal cell patients (based on MSKCC prognostic model). This is the third recent drug approval for metatstatic renal cell cancer.
From Hudes et. al N Engl J Med 2007; 356:2271-2281
The temsirolimus trial was important since the point estimate for non clear cell RCC (which were mostly papillary ans some chromophobes) favors temsirolimus. This is apparent from the forest plot. Narrow CIs which does not cross the line of no difference. Take home point: All patients with non clear cell RCC should be treated with a mTOR inhibitor or reffered for a clinical trial
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