The year 2007 saw the introduction of targeted therapies for metastatic renal cell carcinoma (mRCC), heralding a new era in the battle against kidney cancer.
Prior to 2007, the standard treatment options for mRCC included nephrectomy and cytokine-based therapies such as interferon-£\ (IFN£\) and interleukin-2 (IL-2).
• Nephrectomy remains the standard cytoreductive approach before starting patients on systemic treatment.
• High-dose IL-2 is the only immunotherapy that is able to yield durable complete responses, whereas IFN£\ has an efficacy equivalent to low-dose IL-2.
Evolving treatment strategies are now targeting various growth and signaling pathways in RCC tumor genesis and new agents predominantly inhibit receptor tyrosine kinases (RTK) associated with the VEGF, PDGF, mTOR, c-KIT and c-MET pathways.
With increasing numbers of effective novel inhibitors approved for use in treating advanced RCC, investigations are underway to compare these agents in head-to-head trials and evaluate the benefits of sequential or combination therapies.
Sunitinib as First-line RCC Therapy
Among these new agents, sunitinib (Sutent®; Pfizer) has been hailed as the new standard of care for first-line RCC treatment. Sunitinib is an oral, multi-targeted RTK inhibitor (for VEGF, PDGF and c-KIT) with antiproliferative and antiangiogenic effects.
In the most recent results and analysis of a landmark randomized Phase III study comparing sunitinib (n =375) with IFN£\ (n = 375) for first-line treatment of mRCC in treatment-naive patients, the efficacy of sunitinib was reaffirmed to provide significant reduction in the risk of death or disease progression.
Both independent central review and investigators’ assessment found that the median progression-free survival (PFS) is 11 months (95% CI: 11, 13) for sunitinib versus 5 months (95% CI: 4, 6) for IFN£\ (Figure 2).
Sunitinib was associated with a significantly superior objective response rate (ORR) of 39%, compared with 8% for IFN£\ (95% CI; P < 0.000001) in the independent central review.
In addition, safety analysis of results from the pivotal Phase III trial demonstrated that the treatment-related side effects of sunitinib were manageable and reversible. Hence, patients consistently reported a better quality of life with sunitinib than with IFN£\ (P < 0.001).
Sunitinib remains the reference standard for first-line treatment of mRCC, with significant improvement in PFS and ORR compared with IFN£\. The benefit of sunitinib extends across all subgroups of patients with mRCC, indicating sunitinib as the optimum first-line treatment for patients with good or intermediate MSKCC† risk factors.
Sunitinib for Patients with Cytokine-refractory mRCC
Two independent, single arm, multicenter Phase II trials demonstrated that sunitinib is also effective as a second-line therapy for the treatment of patients with cytokine-refractory mRCC.
Sunitinib demonstrated high response rates (40–44%) and a time to response of 2.3 months. The antitumor activity of sunitinib was supported by a median progression-free survival of 8.8 months (95% CI: 11.2–16.3).
Advances in RCC: A Case Discussion
Below are two case study examples demonstrating the application of new RCC therapies in the clinical setting.
Case 1: A 63-year-old male presented with hematuria and no symptoms of metastatic disease or paraneoplasia. However, a chest CT scan revealed five bilateral lung lesions. The patient underwent laparoscopic radical nephrectomy with further findings as shown in Figure 3.
• In two randomized trials, cytoreductive nephrectomy was shown to provide a median survival advantage of 11.1 months (versus 8.1 months for IFN£\-2b alone)10 and 17 months (versus 7 months for IFN£\ alone).
Post-surgery, the patient began treatment with sunitinib 50 mg orally daily for 4 weeks with the subsequent 2-weeks off treatment. These 6-week cycles of sunitinib were continued until disease progression.
• While on sunitinib treatment, particularly during the first and second cyles of treatment, careful follow-up including CBC and platelet count monitoring at two weeks and four weeks following initiation of sunitinib treatment along with routine BP monitoring and appropriate CT/MRI scans to evaluate tumor response are recommended. Side effects are monitored and can be managed with dose titration and according to the patient’s condition.
The patient’s disease was stable for 13 months before progression. Second-line therapy with the mTOR inhibitor temsirolimus was then initiated.
• In an independent central review of the PFS for sunitinib versus IFN£\, sunitinib was found to have a median PFS of 11 months versus 5 months with IFN£\.
• With temsirolimus, a 3.6-month improvement in survival versus IFN has been demonstrated.
The patient developed a brain metastasis 3 months later. Treatment with corticosteroids and whole-brain irradiation failed and the patient died 3 weeks later.
Case 2: A 45-year-old male presented with pain, swelling and limited movement of his right wrist. Further investigations are as shown in Figure 4.
Nephrectomy was performed, as was surgery for an isolated wrist metastasis. The patient was then monitored for 23 months and has, to date, shown no evidence of cancer relapse.
• Surgical resection of isolated metastases provides substantial 5-year survival rates with possible repeat metastasectomy.
Conclusion
The management of advanced RCC along with expansion of treatment access to more patient groups is an ongoing challenge. As progress continues to be made in establishing carefully designed clinical trials to support basic and translational research in RCC, targeted therapy with agents such as sunitinib is expected to advance the future of RCC treatment and allow more patients to be treated successfully.
*VEGF = vascular endothelial growth factor; PDGF = platelet-derived growth factor; c-KIT = stem cell factor; c-MET = mesenchymal epithelial transition factor; mTOR = mammalian target of rapamycin
†MSKCC = Memorial Sloan-Kettering Cancer Center