Renal cell carcinoma (RCC) is the second most common urologic malignancy. Many patients are diagnosed at an advanced stage of disease, which has historically been resistant to both chemotherapy and radiation. However, management has undergone a paradigm shift in the last decade. A better understanding of disease biology has led to the introduction of small tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR). 

Sunitinib, pazopanib and bevacizumab, in combination with interferon, each have demonstrated efficacy in first-line therapy supported by level 1 evidence,^1-4 while temsirolimus has been shown to be effective in poor-risk patients.⁵

Despite these new active therapies, the disease will inevitably progress and median overall survival remains in the range of 22 months.⁶ The next steps involve deepening our understanding of disease biology and optimisation of currently available agents. 

Adjuvant therapy

In localised RCC, radical nephrectomy may be curative, however, relapses occur in 35-43%⁷ depending on the stage of disease. Features such as pathological tumour and nodal staging, size of tumour, nuclear grade and presence of histologic tumour necrosis have been recognised to influence the risk of recurrence.⁸

Adjuvant therapies after definite surgery with proven benefit to reduce recurrence are standard of care in cancers such as breast and colorectal.^9,10 Prior studies examining the role of adjuvant immunotherapy with or without chemotherapy have been negative in renal cancer.¹¹ The activity of VEGF TKIs and mTOR inhibitors in advanced disease has led to a number of major adjuvant studies: ASSURE (sunitinib versus sorafenib versus placebo for up to one year; NCT00326898); S-TRAC (sunitinib versus placebo for one year; NCT00375674); SORCE (sorafenib for one year versus three years versus placebo; NCT00492258); PROTECT (pazopanib versus placebo for one year; NCT01235962); and EVEREST (everolimus versus placebo for one year; NCT01120249) (see Table 1). 

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Results are not yet available from any of these studies, however, they apply differing pathologic inclusion criteria to determine eligibility. This may complicate comparison of efficacy between agents, and also reflects the lack of a universally accepted definition of high-risk RCC.¹² A recent analysis applied the differing entry criteria from these studies to over 1,300 patients from the nephrectomy registry of the Mayo Clinic and found that despite the variability in inclusion criteria, the studies had similar and relatively strong predictive accuracy for disease recurrence. Conversely, 6-18% of patients with a significant risk of recurrence were not eligible by these inclusion criteria.¹²

Cytoreductive nephrectomy

In the advanced disease setting, cytoreductive nephrectomy followed by interferon therapy was unequivocally shown to improve survival compared to interferon therapy only.¹³ Many observers proposed an immune-related mechanism although the precise mode of action remains unclear.¹⁴

Cytoreductive nephrectomy remains an effective palliative treatment option for tumour-related bleeding or intractable pain, however, the appropriateness of nephrectomy in the metastatic setting also depends on various patient and tumour-related factors.¹⁴ Relative contraindications include sarcomatoid histology, bulky osseous metastases, central nervous system or hepatic involvement and age over 75.¹⁴

Moreover, the role of cytoreductive nephrectomy in the era of active targeted therapies remains ill defined. Issues include the role of nephrectomy in improving survival in this era, the safety of surgery in anti-VEGF-treated patients, and the potential role of sunitinib and pazopanib as neoadjuvant therapy.

In a retrospective study, Margulis and colleagues found that pre-operative anti-VEGF therapy was safe and did not increase surgical morbidity or perioperative complications.¹⁵ However, these therapies appear to induce more shrinkage in the metastases rather than primary lesions,^16,17 calling into question their role in disease downstaging. 

Overall, the shrinkage of the primary lesion is in the order of 10%, which is insufficient to justify neoadjuvant therapy for downstaging.

A large multicentre analysis to identify prognostic factors for overall survival in patients treated with anti-VEGF therapies identified nephrectomy as a good prognostic indicator in univariate analysis but this significance was not retained in multivariate analysis.⁶

In a recently published retrospective study of over 300 patients, nephrectomy improved overall survival by 32% on multivariate analysis after controlling for other identified risk factors.¹⁸

Two currently-recruiting phase III trials aim to investigate the role of nephrectomy on survival in metastatic RCC treated with sunitinib (CARMENA; NCT00930033) and the role of delayed nephrectomy compared to immediate resection in patients treated with sunitinib (NCT01099423).

Current agents: combination

The three main classes of drugs used in the management of advanced RCC – immunotherapy, anti-VEGF agents and mTOR inhibitors – have differing modes of action. This has led to interest in combination therapies, exemplified by the recent success of such a strategy in breast cancer.¹⁹

In two large randomised phase III studies, bevacizumab – an antibody against VEGF – in combination with interferon has been shown to confer superior progression-free survival compared to interferon alone.^1,3 Overall survival was not significantly different between arms but this was thought to be confounded by subsequent lines of active therapies. The toxicity of the combination is significant and may well be attributable to the interferon. Unfortunately, there are no data comparing bevacizumab monotherapy to the experimental arm in these studies. 

Temsirolimus – an intravenous mTOR inhibitor given weekly – has also been combined with interferon in a poor-risk population. The combination was associated with a higher rate of toxicity and no greater activity than temsirolimus alone.⁵ Combining VEGF tyrosine kinase inhibitors such as sorafenib and sunitinib with interferon led to a high rate of toxicity, even at low doses.²⁰

Attempts at combination of VEGF blockade and mTOR inhibition have also been met with limited success due to overlap in their toxicity profiles. The TORAVA study was a three-arm randomised phase II study pitting bevacizumab plus temsirolimus against sunitinib or bevacizumab plus interferon. The experimental arm reported inferior progression-free survival. Over 40% of patients stopped treatment secondary to toxicity, with a rate of grade 3 and 4 toxicity in excess of 70%.²¹

Ongoing trials such as INTORACT (NCT00631371), BeST (NCT00378703) and RECORD-2 (NCT00719264) are examining other combinations (see Table 2). The combination of bevacizumab with VEGF tyrosine kinase inhibitors is limited by a high rate of toxicities such as hypertension and proteinuria, as well as increased incidence of less common side-effects, such as micro-angiopathy, haemolytic anaemia and reversible posterior leukoencephalopathy syndrome.²⁰

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Bevacizumab and interferon aside, the combination approach remains unproven as yet and has faced criticism for unacceptably high toxicity requiring dose reduction and uncertainty about true drug resistance upon progression.²²

Current agents: sequencing

Due to the difficulties inherent in combining available agents, the sequential use of available agents has become standard care in everyday clinical practice. There is an accumulating evidence base derived from phase II and large randomised phase III studies including: the use of pazopanib after cytokines,⁴ sorafenib after immunotherapy in the TARGET study,²³ everolimus as second or third-line therapy in the RECORD-1 study,²⁴ and the recently published axitinib as second-line therapy in the AXIS study.²⁵

Based on the available evidence, the principle question remains whether to use sequential VEGF inhibition, or a switch to mTOR inhibition following first-line anti-VEGF failure. 

Moreover, the ideal sequencing of existing anti-VEGF TKIs remains uncertain. Although the target is the same, these drugs differ in their affinity for this target and also in their promiscuity for other targets. This is manifest in the toxicities associated with each VEGF TKI, which vary significantly. In addition to targeting VEGF, sorafenib also targets RAF kinase, which may be important in other cancer types. 

Retrospective data have indicated that within a sequential regimen, progression-free survival can be improved by using sorafenib as first-line therapy followed by sunitinib,^{20, 26, 27} rather than the other way around. This strategy is currently being evaluated further in the randomised phase III SWITCH study (NCT00732914).

Data are more limited on sequential use of other VEGF TKIs. The AXIS study compared axitinib with sorafenib as second-line therapy and recruited over 700 patients. Fifty-four per cent of patients on each arm received prior sunitinib and reported progression-free survival of 4.8 and 3.4 months respectively,²⁵ which was comparable to retrospective sorafenib data.^27-29 Other anti-VEGF molecules which have shown activity as second-line therapy included linifanib³⁰ and pazopanib;³¹ the latter is also the subject of an current phase II ICORG investigation (NCT01566747). 

The largest dataset for mTOR inhibitors in sequence comes from the RECORD-1 study.³² Pre-planned subgroup analysis from the RECORD-1 study showed that everolimus demonstrated activity following either one or two lines of VEGF blockade³³ with progression-free survival similar to that seen with axitinib in second-line use. There are limited data on the efficacy of temsirolimus following failure of VEGF blockade, mostly restricted to small retrospective studies.^34,35 The largest series was reported by McKenzie and colleagues on 87 patients with intermediate-to-poor-risk renal cell carcinoma, with a time-to-progression of four months, suggesting activity.³⁶

For the proportion of patients who retain a good performance status, management upon progression beyond available agents poses a significant challenge. Small retrospective studies suggest that anti-VEGF rechallenge following everolimus resistance may be effective,^37,38 however, new agents with alternative mechanisms of action are required.

Refractory disease

Sunitinib and pazopanib are the most active single agents available for the management of advanced renal cell carcinoma in first-line treatment. Each confers a response rate of approximately 30% and disease stabilisation rates of 38-48%.^2,4 However, up to a quarter of all patients treated with VEGF tyrosine kinase inhibitors have progressive disease at first evaluation. These patients have uniformly poor responses to second-line VEGF blockade or indeed mTOR inhibition, and overall survival remains poor. 

Although this cohort contains many poor-risk patients and sarcomatoid tumours, approximately 50% of patients with primary refractory disease fall into good and intermediate risk groups. This suggests that the known clinical prognostic factors are not sufficiently robust to identify patients with primary refractory disease.³⁹ Anecdotal efficacy of cytotoxic chemotherapy in this cohort has been reported⁴⁰ and prospective studies for this substantial minority are needed. 

New agents

Axitinib, a TKI for VEGFR-1, -2 and -3, is the latest agent added to the armamentarium of therapies against advanced RCC.²⁵ Other anti-angiogenic agents in the advanced stage of development include tivozanib and dovitinib.⁴¹ The latter is of particular interest as it targets fibroblast growth factor receptor (FGFR) in addition to VEGF. FGFR is widely thought to be a tumour escape mechanism in response to sustained anti-VEGF therapy, and therefore responsible for the development of therapeutic resistance.⁴²

Nonetheless, it is becoming apparent that approaches which go beyond targeting VEGF will be required to enhance outcomes for patients with this disease. Strategies under evaluation include inhibition of the Ang/Tie2 pathway, immunotherapy with CTLA-4 inhibition or anti-PD1 inhibition and vaccine development.⁴³

Adjunctive therapies

Skeletal metastases affect up to one-third of all patients with metastatic renal cell carcinoma. In an analysis of over 800 patients, 32% of patients were afflicted with osseous metastasis, half of which were present at diagnosis and the remainder of which developed bony involvement during the course of their illness.⁴⁴ It was estimated that each patient with bone metastasis experienced 2.4 skeletal-related events, most commonly bony pain necessitating radiotherapy (60.9%), fractures (20%) and malignant cord or nerve root compression (11%).⁴⁴ Indeed, it has been suggested – based on analysis of over 200 cases of advanced disease – that osseous involvement by metastatic RCC is a poor prognostic indicator, predicting shorter progression-free survival and poorer overall survival.⁴⁵

Bisphosphonates such as zoledronic acid have been shown in multiple tumour types to reduce skeletal-related events. In a subset analysis of renal cell cancer cases, which constituted 10% of the entire cohort, zoledronic acid reduced the average rate of skeletal-related events and significantly prolonged time to first event.^46,47 Keizman and colleagues also reported that bisphosphonates in RCC might improve progression-free and overall survival in a retrospective study.⁴⁸

Conclusion 

The landscape of RCC has changed significantly since 2004, with the introduction of several active targeted therapies. As we move beyond the initial phase of familiarising ourselves with these new agents, their cytostatic properties and different side-effect profiles, larger questions have begun to present themselves. 

Adjuvant therapy has historically been ineffective in RCC, and the reproducibility of the activity of targeted therapies in the adjuvant setting remains to be elucidated. 

In the management of metastatic RCC, combination approaches have been confounded by limited efficacy and substantial toxicity. Sequential monotherapy has become the mainstay of day-to-day clinical practice, however, the correct sequencing remains uncertain. Primary refractory disease and osseous metastases have been recognised as poor prognostic indicators.

The treatment of advanced RCC appears set to become more complex with further anti-VEGF agents at an advanced stage, and new agents with different targets in development. While the goal of cure remains elusive, trials examining optimisation of existing agents and efficacy of new therapies represent a critical step forward.

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