The usual type of kidney (renal) cancer is a carcinoma. The commonest type is the clear cell type and this is the one associated with VHL gene mutations. However, a significant minority of cancers are of the papillary type and another subset arises, not from the parenchymal kidney, but from the pelvis; these usually 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.
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 bone scan, the clinician should know whether the cancer has spread from the kidney.
Treatment & outcomes: Kidney cancer
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. However, for some years, immunotherapy with interferon in particular has had some success with response rates of 15-20% in metastatic disease; the response of lung metastatic disease exceeds that of bone disease; the addition of interleukin probably improves the response rate of interferon alone. The figure shows (left panel) lung metastases from kidney cancer on a chest x-ray and their disappearance after immunotherapy (right panel), demonsatrating the very good (but temporary) responses that can be achieved. In recent years new molecularly based therapies have been developed and the drugs sunitinib and sorafenib and foremost amongst these. They are tyrosine kinase inhibitors that inhibit signalling pathways between aberrant oncogenes and cell mitotic activity.
With the realisation of the common involvement of the VHL 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. Thus, sunitinib and sorafinib are two such medical therapies that have replaced interferon and interleukin for first place systemic therapy in this disease.
Thus, the first systemic drug therapy for relapsed kidney cancer is now a tyrosine kinase inhibitor such as sunitinib or sorafenib (or newer tyrosine kinase inhibitors), followed by an m-TOR inhibitor, possibly backed up by a VEGF inhibitor such as bevacizumab. Immunotherapy is kept in reserve.
First line therapy would now usually be with sunitinib for all advanced clear cell kidney cancer patients. If the patient responds, he/she continues this therapy for a year or so – it is a simple tablet.
Bevacizumab is an antibody that inhibits tumour growth by blocking the formation of new tumour blood vessels. It can be considered for first-line therapy in combination with interferon-α in patients with advanced and/or metastatic RCC.
Sorafenib inhibits the development of tumour blood vessels and tumour cell proliferation. It may be considered for the treatment of patients with advanced RCC whose condition has failed to respond to interferon-α or interleukin-2 therapy or who are considered unsuitable for such therapy.
Sunitinib also inhibits the development of tumour blood vessels and tumour cell proliferation. Temsirolimus/ everolimus or other m-TOR inhibitors are selective inhibitors of a protein that regulates a signalling pathway controlling growth factor-induced cell proliferation. Sunitib and Temsirolimus may be considered for the treatment of patients with advanced and/or metastatic RCC, temsirolimus/everolimus usually being trialled after a trial period on sunitinib.
When/if the patient relapses after such therapy, there is little that alters the natural history of the disease further; thus far, conventional chemotherapy has not had success in treating this particular 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 disease 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.
Surgical nephrectomy stands a good chance of cure for localised disease but the disease is ultimately fatal if metastatic at presentation. Nevertheless, prolongation of life for patients who have relapsed after removal of their kidney for cancer (or for patients who present with inoperable or metastatic disease) is possible with immunotherapy and/or sorafinib/bevacizumab are the currently most successful.
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.
Questions & answers about kidney cancer
The patient (65 yr old male) had an ultra sound, and a cat scan which showed a soft tissue mass which was followed up by biopsy, It was decided that he had renal cell carcinoma. The cancer has spread to one lung, one bone in hip and to one lymph node.
He has been on sunitinib for 4 weeks. Following a two-week break this will continue for a further 4 weeks. Progress will then be assessed via a CT scan.
- Is this the appropriate treatment?
- What other treatments maybe right for him?
- Would you remove the diseased kidney?
This is an appropriate treatment for the stage of this disease. Sutent has shown significant activity in recent studies and has become a preferred drug for most oncologists in this situation. The response to sutent has to be measured over several months and may be evident by an improvement in the clinical condition but also by scanning.
Further treatments will need to be advised by the local oncologist. In light of his previous brain stem bleed there may have to be discussion as to whether other biological agents (temsirolimus, sorafenib) may be used. A number of drugs may not be readily available on the NHS as the benefits may not be sufficiently high. In selected patients there can be discussion of chemotherapy drugs but these can be toxic and again the local oncologist would need to balance the possible benefit from chemotherapy against side-effect profiles. Radiotherapy is a powerful localised treatment and can be used to alleviate pain from bone metastases.
In selected patients, removal of the kidney can be considered but if the disease has already spread there may be concern that such an operation may not be indicated. There are rare cases where removal of the kidney can lead to regression of the tumour but in general, this would not be advised if there is spread of the disease. Occasionally the kidney may need to be removed or other treatments such as embolisation considered if there are continued problems with bleeding.