Sequence of treatment in locally advanced and metastatic renal cell carcinoma

Abstract

The spectrum of drugs that have shown activity in advanced or metastatic renal cell carcinoma (RCC) has led to a debate on the optimal sequence of treatments. There is agreement on recommending targeted agents as the standard of care in this disease. Uncertainty, however, remains on the best first-line drug choice. Physicians and patients may select sunitinib, bevacizumab in combination with interferon-alpha (IFN-α), pazopanib, or-in poor risk patients-temsirolimus. There are also a variety of therapies with proven efficacy on hand in the second-line setting: sorafenib, pazopanib, axitinib, and everolimus. While most randomized RCC trials assessed progression free survival (PFS) as primary endpoint, some agents were shown to improve median overall survival (OS), and given in sequence they have extended the life expectancy of RCC patients from 13 months in the cytokine era to over 30 months. Despite the progress made, there are sobering aspects to the oncologic success story in RCC, as the new treatments do not obtain an objective response or disease stabilization (SD) in all patients. There are also as yet no predictors to select patients who might benefit and those who are primary resistant to specific drugs, and ultimately almost all patients will experience disease progression. Bearing inevitable treatment failure in mind, availability of further drugs and switching therapy while the patient is in a condition to continue pharmacotherapy is essential. Of note, depending on the setting, only 33-59% of patients receive second-line treatment. In this review we present data on first-, second-, and third-line treatment in RCC, and discuss the difficulties in their interpretation in the context of treatment sequence. We summarize biological aspects and discuss mechanisms of resistance to anti-angiogenic therapy and their implications for treatment selection.

Keywords: Algorithms; carcinoma; molecular targeted therapy; renal cell.

Figure 1

Possible treatment sequence. VEGF-TKI, vascular endothelial growth factor-tyrosine kinase inhibitors; mTOR, mammalian target of rapamycin.

Figure 2

Patient case 1. A 70-year-old male patient with primary metastatic RCC. The patient had a 10 cm renal mass and multiple pulmonary metastases. He underwent laparoscopic nephrectomy, histology showed clear cell RCC Fuhrman Grade 3, focally Grade 4. The patient had Memorial Sloan Kettering Cancer Center (MSKCC) intermediate risk (39) (1 risk factor). Treatment with the TKI pazopanib was initiated two months after surgery when progression of the lung metastases was seen. The patient had a dose reduction of pazopanib for nausea and hepatotoxicity. Nevertheless a PR was seen on CT. A recent CT scan shows sustained PR after 12 months of treatment. RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitors; PR, partial remission.

Figure 3

Patient case 2. A 48-year-old female patient with a history of breast cancer, which had been treated with surgery and adjuvant radiotherapy in 1997 in London. The patient presented with a 10 cm renal mass and disseminated lung metastases. She underwent nephrectomy, which revealed a clear cell RCC Fuhrman Grade 3, focally Grade 4. In addition, a wedge resection of a pulmonary metastasis was performed and confirmed RCC rather than metastatic breast cancer. The patient had MSKCC intermediate risk (2 risk factors). Postoperatively rapid disease progression was detected on a computed tomography (CT) scan 6 weeks after the initial CT and she was started on sunitinib. After the first 4-week cycle of treatment the patient had symptomatic and objective disease progression with bilateral pleural effusions, enlarged pulmonary metastases, a chest wall infiltration, and a newly diagnosed vena cava thrombosis. The patient was started on the mTOR inhibitor temsirolimus, which was available at the time. However, the patient died of progressive disease within 3 months of palliative nephrectomy. RCC, renal cell carcinoma; MSKCC, Memorial Sloan Kettering Cancer Center; mTOR, mammalian target of rapamycin.