Published in UAB Insight, Spring 2008
Treatment Strategies, NCCN Guidelines
In the last 2 years the Food and Drug Administration (FDA) has approved three promising drugs for renal cell carcinoma: sorafenib, sunitinib, and temsirolimus. While not curative, these agents improve quality of life and have the potential to prolong life for patients.
In 2007, an estimated 51,000 Americans were diagnosed with kidney cancer. Renal cell carcinoma (RCC) accounts for 90% of kidney cancers; 75% of RCCs are clear cell. Symptoms often do not manifest until advanced stages of disease, and many patients who seek medical advice already have metastatic RCC (mRCC). The 5-year survival rate for patients with mRCC is less than 10%.
Early-stage RCC is potentially curable with nephrectomy, but 20% to 30% of individuals who undergo the procedure progress to mRCC. Progression within 1 year after nephrectomy confers the same survival rate as stage IV disease without nephrectomy: a median survival of 10 months with a 3-year survival rate of 11%.
“New understanding of kidney cancer on the molecular level has ushered in a new age in treatment,” says UAB hematologist-oncologist Graeme B. Bolger, MD, referring to the recent addition of angiogenesis inhibitors, tyrosine kinase inhibitors, and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus to the armamentarium. “These drugs provide survival benefit and reduce toxicity compared with the older treatments interferon alpha [INF-α] and interleukin-2 [IL-2],” he says.
Bolger serves on the National Comprehensive Cancer Network (NCCN) panel that determines kidney cancer practice guidelines as part of the Clinical Practice Guidelines in Oncology. The guidelines are developed and updated through an evidence-based process. Multidisciplinary panels from 21 of the nations’ top cancer centers, including the UAB Comprehensive Cancer Center, review research and make recommendations. “These guidelines continuously incorporate important new medical therapies for the treatment of advanced kidney cancer,” says Christopher L. Amling, MD, director of UAB’s Division of Urology.
Although surgical excision is the only curative treatment for localized kidney cancer, some masses are too large to resect, and in some patients with mRCC, the risk of nephrectomy exceeds its benefits. For a solitary metastatic site, the panel recommends nephrectomy and surgical metastasectomy; for multiple metastatic sites, it advises cytoreductive nephrectomy prior to systemic therapy. NCCN guidelines place surgery as primary treatment for stage IV RCC in certain cases depending on symptoms and extent of metastatic disease. “Nephrectomy in patients with metastatic disease and high performance status can offer a survival advantage when combined with systemic therapy,” Amling says.
UAB surgeons use laparoscopic approaches and ablation for small renal tumors in some patients with advanced disease, but those with advanced disease and large tumors require open surgery. Removal of large renal tumors is complicated by their invasive nature, associated tumor thrombus, and close proximity to the spleen, liver, and colon, but Amling has successfully removed tumors up to 20 cm and those associated with large renal vein and inferior vena caval thrombi. “Because this procedure requires hypothermic cardiac arrest so the tumor thrombus can be removed in a relatively bloodless surgical field, only experienced surgeons at large academic medical centers can perform it,” Amling says.
In patients with metastatic disease, surgical resection also can reduce flank pain, hemorrhage, unremitting fever, or hypercalcemia. To shrink unresectable tumors, UAB interventional radiologists perform renal artery embolization, in which a catheter-based injection of a foam or small particles into the arteries feeding the tumor blocks blood flow.
For patients with relapsed, stage IV, or surgically unresectable tumors and predominant clear cell histology, treatment avenues include high-dose IL-2, sorafenib tosylate, sunitinib malate, temsirolimus, or bevacizumab plus IFN-α. For those with non–clear cell histology IL-2 is not an option. As disease progresses, NCCN advises crossover regimens and best supportive and palliative care. The NCCN urges participation in clinical trials for patients with disease at any stage, no matter how localized or advanced.
Cytokines
For more than a decade cytokines were the standard treatment for RCC. High-dose IL-2, FDA-approved since 1992 for mRCC, is effective for select patients. About 14% of patients achieve a complete response, but most cannot tolerate toxicities.
INF-α is still widely used as a single agent, with a 6% to 10% response rate in those with high performance status and nephrectomy. It provides a modest survival advantage. Influenza-like side effects decrease with time, but others such as weight loss, rashes, fatigue, and depression increase.
The Postcytokine Era
In 2005 the FDA approved bevacizumab, a monoclonal antibody that targets soluble vascular endothelial growth factor (VEGF) and prevents new blood vessel formation in tumors. It is approved for use in colorectal and breast cancer among others. In patients with RCC bevacizumab improves progression-free survival time but has yet to be proven to increase overall survival (N Engl J Med. 2003;349:427-434). However, a bevacizumab/INF-α combination doubles progression-free survival in mRCC and allows patients to reduce their interferon dose without lessening treatment benefit (Lancet. 2007;370:2103-2111).
The drugs sorafenib and sunitinib target the intracellular signaling pathways of VEGF receptors and inhibit their activation to stop cancer cell proliferation. They also target platelet-derived growth factor (PDGF) receptors and probably other kinases as well, Bolger says.
Sorafenib inhibits the VEGF receptor. It doubles the median time for tumor progression and won FDA approval in 2005 as second-line therapy (J Clin Oncol. 2006;24:2505-2512). The NCCN now recommends the drug as first-line therapy, partially based on evidence by Escudier et al (N Engl J Med. 2007;356:125-134). This trial found that in patients with advanced clear cell RCC resistant to standard therapy, progression-free survival was twice that in those receiving best supportive care. Treatment produced a number of toxic effects (diarrhea, rash, hand and foot skin reactions [redness, swelling, numbness, pain], and, more rarely, hypertension and cardiac ischemia).
Sunitinib has antitumor and antiangiogenic properties. In two phase 2 trials patients had partial responses or stable disease with no progression. The FDA approved it in 2006 for patients with mRCC who did not respond to cytokine therapy. In a phase 3 trial comparing sunitinib with IFN-α, patients receiving sunitinib had increased progression-free survival time and higher response rates. Patients reported a better quality of life than the INF-α group, and NCCN guidelines include the drug as a first-line therapeutic option.
Temsirolimus is the most recent addition to mRCC treatment choices and is the first targeted agent to demonstrate improvement in overall survival in patients with poor prognoses. It targets the mTOR kinase, which regulates cell growth and survival. Compared with INF-α the drug improves overall survival and progression-free survival in patients with high-risk advanced RCC. Combining temsirolimus and INF-α does not improve survival compared with INF-α alone (N Engl J Med. 2007;356[22]:2271-2281). The FDA approved temsirolimus in 2007 for advanced RCC.
Sequence, Timing of Therapies
“In this postcytokine age, we have new treatment options, but the optimal sequence and timing are undefined,” Bolger says. Clinical trials are in progress to compare combination therapies with single agents and to determine single agents’ efficacy as adjuvant therapy after nephrectomy.
“We have some idea of reasonable therapeutic strategies. Researchers have studied doublets containing INF-α, ultimately abandoning most of them because of toxicity. Almost all kinase inhibitor doublets require reduction of one or both drugs,” Bolger says. “The bevacizumab-containing doublets generally are well-tolerated and require less dose reduction.”
The BEST Trial
The BEST (bevacizumab, sorafenib, and temsirolimus) trial, a large multicenter study of the three drugs in patients with mRCC, should answer some outstanding questions. The four-arm trial will compare combinations of the drugs with bevacizu-mab alone. The first phase 3 adjuvant trial of multiple kinase inhibitor therapy in surgically resected RCC also is underway and is comparing sunitinib with sorafenib as adjuvant therapy.
“It is exciting to have the possibility of effective adjuvant therapy for patients who have large tumors and high risk for recurrent disease after nephrectomy, either because of tumor extending outside the renal capsule or vein involvement or extension,” says Amling.
“The more we understand the molecular pathways of RCC and how these new agents work, the closer we come to identifying additional therapeutic targets and devising strategies that further improve survival,” Bolger says.
For more information:
Dr. Christopher Amling
Dr. Graeme Bolger
1.800.UAB.MIST
mist@uabmc.edu