RCC has peak incidence between 60 and 70 years of age and occurs most commonly in men, with a male to female ratio of 2:1; between 2008-2010 in the UK the number of new cases among men was 13-16 per 100,000 – twice the incidence rate reported for women. In 2014, RCC was the fifth most common cancer diagnosed in men and the tenth most common in women.¹ The incidence of renal cancer is race dependent with black men demonstrating a higher incidence than in men of all other races. Asians appear to have the lowest incidence of RCC.² 

Risk factors

The most common risk factors of RCC are smoking, obesity, hypertension, polycystic and horseshoe kidneys, and dialysis-dependent end-stage renal disease (ESRD) patients. Having a first-degree relative with kidney cancer also increases the risk of RCC.²

Genetic classification

Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome that occurs due to mutation of chromosome 3p, predisposing individuals with this condition to develop tumours in multiple organs including cerebellar haemangioblastoma, phaeochromocytoma and bilateral clear cell RCC.

Hereditary papillary RCC (HPRCC) is the second most common hereditary type of RCC. It is characterised by trisomy for chromosomes 7 and 17, as well as abnormalities on chromosomes 1, 12, 16, 20, and Y. In contrast to VHL, patients with HPRCC do not develop tumours in other organs. Other autosomal dominant conditions predisposing to RCC include Birt-Hogg-Dube syndrome and hereditary leiomyomatosis.³

Presentation

The classic triad of flank pain, gross haematuria and a palpable mass occurs only in less than 10% of patients and is a frequent manifestation of advanced disease. Paraneoplastic syndromes due to ectopic hormone secretion by the tumour occur in 25-30% patients. They include anaemia, hypercalcaemia, hypertension, polycythemia, Cushing’s syndrome and non-metastatic hepatic dysfunction. With routine use of CT scanning for evaluation of non-specific findings, asymptomatic renal tumours are increasingly detected incidentally (> 50%).²

Pathology 

Histologically, most RCCs are classified into the following subtypes: conventional clear cell, papillary, chromophobe, collecting ducts (Bellini) and medullary cell carcinoma.

• Clear cell (80%): It is usually well circumscribed, highly vascular, arise from proximal tubule and involves loss of VHL and other genes of chromosome 3. Patients with clear cell RCC have a worse prognosis compared with papillary or chromophobe RCC
• Papillary (10-15%): This shows trisomies of chromosomes 7 and 17 and the loss of chromosome Y and is most commonly seen in patients with end-stage renal disease
• Chromophobe (5%): as the name suggests it appears pale tan and arises from collecting duct. Most studies of the clinical behaviour of chromophobe RCC suggest a better prognosis for localised chromophobe RCC
• Bellini collecting duct and medullary cell types are the other types of RCC.⁴

Staging and survival

The tumour-node-metastasis (TNM) system more accurately classifies the extent of tumour involvement and is the currently used staging system. It is summarised in Table 1.

The percentage of people living five years or more following an RCC diagnosis has been estimated using the American Joint Committee on Cancer (AJCC) TNM staging system (see Table 2).

Renal tumour biopsy 

Percutaneous renal tumour biopsy should be performed in selected scenarios like choosing patients for active surveillance, prior to ablative treatments and to select the most suitable form of treatment strategy in the setting of metastatic disease.^6,7,8

Treatment of localised RCC

Initial active surveillance should be a first treatment option for small renal masses (< 4cm) in unfit patients or those with limited life expectancy.^9,10,11 

Surgical removal of the early-stage lesion (T1-T2) remains the only potential curative therapy available for RCC patients. Appropriate therapy depends almost entirely on stage of tumour at presentation and therefore requires a thorough staging evaluation. 

Radical or partial nephrectomies are the primary treatment of localised RCC. Partial nephrectomy (PN) is the established treatment for T1a tumours (< 4cm) and an emerging standard treatment for T1b tumours (4-7cm) provided that the operation is technically feasible and the tumour can be completely removed. Radical nephrectomy should be limited to those cases where the tumour is not amenable to nephron-sparing surgery.

Ablative therapies can also be an alternative to surgical options. These include cryoablation and radiofrequency ablation. These come with a risk of inferior metastasis-free survival rate, overall survival rate and increased local recurrences.^3,12 

Treatment of advanced/metastatic RCC 

Cytoreductive nephrectomy (CN) resection of tumour is curative only if all tumour deposits are removed. For most patients with metastatic disease, CN is palliative and systemic treatments are necessary. Patient selection for CN should include good performance status, the ability to debulk at least 75% of the tumour burden, no symptomatic metastatic disease, and predominant clear cell pathology. Two randomised controlled trials, SWOG and EORTC, compared CN plus interferon alpha (IFNa) versus IFNa alone. Both trials reported significant improvement in overall survival and time to progression in patients who had CN+IFNa.¹³

Patient selection 

The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) scoring models are the two important tools used in selecting patients for systemic therapy. European Association of Urology (EAU) guidelines prefer the use of the IMDC model (see Table 3).

Systemic therapy for RCC

Understanding the molecular biology of RCC leads to a multimodal approach in terms of treating RCC. These modalities include: 

• Immunotherapy (interferon-alpha, interleukin-2 [IL-2])
• Anti-vascular endothelial growth factor (anti-VEGF) (sunitinib, sorafenib, pazopenib)
• Checkpoint inhibitors (nivolumab, ipilimumab)
• Mammalian target of rapamycin (mTOR) (temsirolimus, everolimus).

First-line therapy

For patients with good-risk disease, anti-VEGF therapy is the primary option rather than immunotherapy. Other options for good-risk patients include checkpoint inhibitor immunotherapy (nivolumab/ipilimumab). 

For patients with intermediate- or poor-risk disease, immunotherapy with the combination of nivolumab plus ipilimumab rather than targeted anti-VEGF therapy is recommended. Targeted cabozantinib or nivolumab monotherapy are alternatives if the combination of nivolumab plus ipilimumab is not available.^15,16

Second-line therapy

For patients who have progressed after initial treatment with VEGF inhibitor, treatment with nivolumab or a combination of nivolumab plus ipilimumab is suggested.^15,16 For patients who progress after immunotherapy, anti-VEGF targeted therapy is advised.

Third-line therapy 

Patients who have progressed following an initial molecularly targeted agent and immunotherapy may benefit from treatment with an alternative targeted agent. These can be mTOR inhibitors, such as everolimus, or other anti-VEGF agents, including axitinib and cabozantinib.^15,16 

Treatment of advanced non-clear cell RCC

In advanced non-clear cell RCC, anti-VEGF directed therapy rather than immunotherapy is the recommended first-line treatment. Sunitinib is the preferred agent.

Cytotoxic chemotherapy with platinum-based agents such as gemcitabine plus cisplatin is preferred in collecting duct RCC or renal medullary carcinoma.¹⁷

Clinical trials

Important current advances in systemic therapy are mentioned below:

• CARMENA – Phase III trial of cytoreductive nephrectomy plus sunitinib vs sunitinib alone. Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic RCC who were classified as having intermediate-risk or poor-risk disease¹⁸
• CABOSUN – Phase III trial of cabozantinib vs sunitinib in intermediate/poor risk RCC patients. Cabozantinib was shown to increase progression-free survival (PFS) and overall survival (OS) benefit. Bone metastasis responded well to cabozantinib¹⁹
• CheckMate 214 – Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced RCC²⁰
• InMotion 151 – Bevacizumab/atezolizumab vs sunitinib. The bevacizumab/atezolizumab combination was shown to improve PFS²¹
• METEOR – Phase III trial of cabozantinib vs everolimus. Cabozantinib showed improved PFS, overall survival, and objective response rate.²²

Radiation therapy

RCC has been characterised as a radioresistant tumour. The use of radiotherapy in the management of RCC comes in the form of treating the metastases and is mainly used to treat brain metastases, painful bone metastases and recurrences in the renal bed.¹²

Conclusion

With the introduction of several new targeted agents for systemic therapy and risk stratification of patients there is improvement in long-term survival for more patients with metastatic disease. Surgery still remains a cornerstone in treatment of early tumours.

References

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