CT scan showing large kidney cancer (arrowed) destroying the kidney
The usual type of kidney (renal) cancer is a carcinoma. (Rarely, lymphomas and sarcomas occur).The commonest type is the clear cell type and this is the one associated with VHL (Von Hippel Lindau) gene mutations. However, a significant minority of cancers are of the papillary type and another subset arises from the pelvis: these almost invariably being of transitional cell histology.
The main risk factors for kidney cancer include obesity, hypertension, smoking and some genetic conditions, although none of these risk factors are particularly strong. There are geographic differences in the incidence such that the disease is rare in Japan compared with the Western world. There is a familial incidence of this disease in 2% of cases and the most importantly recognised is the association with von Hippel Lindau syndrome. In this syndrome renal cancer is associated with other disorders including retinal angioma, haemangioblastoma and phaeochromocytoma.
Cancer of the kidney accounts for 2% of all cancer deaths and the age range most at risk is 60-70 years. There is slight male dominance in incidence (male: female = 1.5:1). Approximately 2% of cases are associated with inherited syndromes.
Symptoms & diagnosis: kidney cancer
The most common presenting symptoms of advanced RCC are blood in the urine (haematuria), a palpable mass in the flank or abdomen and abdominal pain. Other non-specific symptoms include fever, night sweats, malaise and weight loss. Approximately 25% of patients present with advanced and/or metastatic disease.
CT scan showing a normal kidney (left arrow) and a large kidney cancer (right arrow)
An abdominal scan is the first test that indicates that there is a mass arising from the kidney, and an ultrasound scan tells whether it is truly solid and therefore likely to be a tumour.
The staging system is based on the combination of tumour size and extent of spread from the kidneys. The cancer spreads locally into the flank and then metastasises further afield, especially to the bones, lungs and also the brain and liver. 25% of patients present with metastatic disease. Symptoms of these metastatic sites of spread depend on the exact localisation of the spread, e.g. bone pain in the spine, pressure symptoms from brain metastases, coughing up blood from lung metastatic spread.
The staging therefore includes chest x-ray or CT scanning of the lungs as well as scanning of the abdomen. A whole body bone scan is also a part of the routine work-up. After CT scanning of the body and A PET scan or bone scan, the clinician should know whether the cancer has spread from the kidney.
Treatment & outcomes: Kidney cancer
chest x rays before (left panel )- showing advance lung metastases from kidney cancer, and after (right panel) successful immunotherapy.
A localised renal carcinoma is always considered for surgical removal; the whole kidney is removed (nephrectomy) so long as the other kidney is functioning normally and can take over the body’s overall renal function. If the tumour is localised to the kidney then such surgery may alone result in a 67% cure rate. The use of adjuvant systemic therapy (e.g. immunotherapy, see below) after the operation to try to reduce the subsequent incidence of relapse has not been proven and is not standard therapy. There may be a case for nephrectomy even if there is evidence of metastatic disease; some evidence having been assembled to suggest that, particularly lung, metastatic disease may be more likely to respond to other therapy (even to rarely involute without further therapy) if the large mass of primary tumour in the kidney is removed.
For metastatic spread, the options are limited as chemotherapy has a poor track record in this disease.
In recent years, new molecularly based therapies have been developed and the drugs sunitinib, pazopanib, cabozantinib and levatinibhave become established first line therapy for metastatic disease. They are tyrosine kinase inhibitors (TKI) that inhibit signalling pathways between aberrant oncogenes and cell mitotic activity.
In those whose tumours progress through the foregoing – usually sunitinib – the combination of everolimus (an M-TOR inhibitor) with another TKI is probably the best back-up regime to trial before immunotherapy.
With the realisation of the common involvement of the VHL (Von Hippel Lindau) gene, has come great interest in the therapeutic use of agents that inhibit VEGF and some of the cell growth promoting factors that are usually under the inhibitory control of the VHL gene. The TKI’s fulfill this function. They have replaced previous immunotherapies such as interferon and interleukin for first place systemic therapy in this disease – although the author has seen remarkable responses to interleukin in particular – for example those lung metastases illustrated above.
However, although interferon and interleukin are now rarely used in metastatic clear-cell renal/kidney cancer, other immunotherapy has proved very successful in treatment. The introduction of checkpoint inhibitor therapy with nivolumab or pembrolizumab after failure by TKI therapy brings another good form of systemic therapy for metastatic kidney cancer.
The mechanism of action of the checkpoint inhibitors is expanded in the treatment section of ‘Melanoma’ .
CT scan showing large liver metastasis from kidney cancer before (left panel) and after (right panel) three months on a TKI.
Chemotherapy has a poor track record for renal cancer
Following the observation that oestrogens could promote the incidence of renal carcinoma in hamsters, it was usual to prescribe hormonal therapy (particularly progestogens) in therapy of metastatic clear cell renal cancer and it is true that occasional responses have been well documented following this approach. However, it is a rare and poorly maintained response for the most part.
Occasionally, radiotherapy to the flank/loin after surgery is employed if the cancer is particularly aggressive in the flank region but it has not been shown to alter the survival statistics significantly.
Local radiotherapy for painful bony metastases or for brain metastases is good for the immediate problem that they bring but do not treat the problem as a whole. Focal radiation therapy options (Gamma Knife are indicated for small and even multiple brain metastases and can deliver obliterative doses without overdosing the surrounding brain
What to do if the renal cancer progresses despite all the foregoing?
It is recommended that there is a new tissue biopsy taken, or there is an analysis of cell-free DNA (cfDNA) from a blood draw (as dying cancer cells release DNA fragments into the blood stream after cell turnover/death and these can inform the oncologist of the mean genomics of the cancer at the time of the blood draw. All cancers are mutating as they are inherently unstable and the purpose of getting next generation sequencing on the cancer at the time of refractoriness to standard therapy is to find the new mutations that are driving the cancer cells to divide relentlessly. Not only is the cancer genome inherently unstable but the added pressure of previous therapies may enhance the Darwinian evolution of new cell clones that continue to be able to divide, due to mutations that allow escape from the growth inhibitory therapy under use at the time.
Next generation sequencing (most simply performed by cfDNA from a blood draw – if there is sufficient release) can allow the Oncologist to explore what genomically targeted options are left for the patient with refractory renal cancer.
The better understanding of the mutated VHL tumour suppressor gene in the causation of this disease is likely to bring better therapies for advanced disease.
Similarly, the undoubted important role of the immune system to treat advanced kidney cancer, will, in the future bring about better therapies – combination of checkpoint inhibition, together with others – CTL-4 inhibitors or others including interleukin -all being researched at present.
P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics … tel: +44-2076311632).
Left Panel: CT scan of chest showing multiple metastases affecting both lungs. Right Panel: CT scan of chest after immunotherapy demonstrating excellent response with clearance of all lung metastases.
Surgical nephrectomy stands a good chance of cure for localised disease but the disease will ultimately threaten life if metastatic at presentation. Nevertheless, with the use of the new breed of anti-cancer drugs outlined above, the patient with metastatic renal cancer is likely to lead a much prolonged life than a decade ago and the quality of life is also much better.
No screening tests are indicated as the disease is sufficiently unusual for the pick up rate on routine abdominal scanning – being so low as to not be feasible on health economics. There is one exception and that is the Von Hippel Lindau group of patients, who are sufficiently at high enough risk to warrant such screening by abdominal scanning.