Targeted therapies are a relatively new treatment in the battle against cancer. They work by interfering with specific targeted molecules within the cancer cells, rather than just interfering with rapidly dividing cells like chemotherapy does.
Tyrosine Kinase Inhibitors (TKIs)
Tyrosine kinase inhibitors (TKIs) are a type of targeted therapy for renal cancer, and their discovery has led to some improved outcomes for renal cancer patients. Sunitinib (Sutent®) is one such TKI, and in a head-to-head trial against IFN-α had very promising outcomes. The objective response rate for sunitinib was 47% compared with 12% on IFN-α, and median progression free survival was 11 months on sunitinib compared with 5 months on IFN-α [1]. For this reason TKIs are now the recommended first line treatment of metastatic renal cancer in the UK including cabozantinib (cabometyx) and Tivozanib (Fotiva). TKIs are designed to block two processes that are essential for cancer cells to grow and spread; these are cell proliferation and angiogenesis. Without these two processes, tumours are unable to grow:
Proliferation – this is when a cell divides, creating two cells where there used to be only one. Like the other cells in your body, cancer cells divide too. The difference is that cancer cells divide in an uncontrolled way, more times than they should, forming a tumour. Targeted therapy may slow down this process.
Angiogenesis – this is the development and growth of new blood vessels. These new blood vessels deliver nutrients and oxygen to tumours to enable them to grow. Multi-targeted therapy helps to slow or stop both cell proliferation and angiogenesis by blocking the biochemical signals that cause them. The biochemical signals involved in cell proliferation and angiogenesis in renal tumours are called tyrosine kinases. TKIs bind to vascular endothelial growth factor (VEGF) receptors and thereby block the action of tyrosine kinases to stimulate cell proliferation and angiogenesis.
Like all drugs, TKIs will also affect healthy cells in the body, as well as the cancer cells, and this can cause side effects.
TKIs are given as an oral capsule or tablet, and it is very easy for the patient and carer to assume that as it is taken at home it can’t be too harmful or serious. It is important that the patient has a good baseline assessment prior to commencing the treatment. This includes blood pressure, cardiovascular assessment, weight, blood chemistry, thyroid function, and complete blood count (CBC). Important and potentially serious side effects should be discussed and details of how to get help from the people who are likely to know about the medication must be given to the patient and carer prior to the treatment starting. It has been demonstrated that good side effect management allows patients to tolerate the treatment better.
There are several different types of TKI for renal cancer; these include sunitinib (Sutent®), pazopanib (Votrient®), axitinib (Inlyta®), everolimus (Afinitor®) and sorafenib (Nexavar®). In the UK, sunitinib and pazopanib are used as first-line treatment for advanced RCC. – Cabozantinib and tivozanib were recommended by NICE in 2018 as a first line treatment for advanced renal cell carcinoma, and in 2020 axitinib with avelumab were also recommended. [1] Additional second line treatments for advanced renal cell carcinoma include cabozantinib (2017),and Axitinib (2015).[2]
Side Effects
All TKIs have similar side effects; managing the most common ones will be addressed here, but for the individual drug you should make sure you familiarise yourself with the side effects and how best to manage them.
Fatigue is a common side effect of many cancer treatments, and indeed a symptom of cancer itself. Patients need to be advised to allow time for plenty of rest, prioritise activities, make the best use of the time when they know they are likely to feel less tired, take regular light exercise, maintain a normal sleep pattern, accept help from others, use relaxation techniques, and not feel guilty about sitting down and reading, listening to music, watching TV. This is especially important before, during and after periods of treatment and/or surgery.
Hand/foot syndrome (palmer-planter erythema) can be quite debilitating. It can be simply redness of the skin or minor dryness, but may become very painful, swollen, blistered and peeling if not treated promptly. Patients should be advised to use an emollient twice a day to keep the skin on their hands and feet well moisturised. They should examine their skin regularly and report any changes. Activities that may cause friction of the hands or feet should be avoided (such as jogging, using tools like screwdrivers). They should protect against irritants such as washing up liquid, avoid hot baths, showers and sun exposure. Well-fitting shoes, preferably low-heeled to distribute weight evenly should be encouraged, and the feet in particular should be kept cool when possible. If the feet should start to get sore the use of gel inserts in shoes may be helpful. Visits to a chiropodist/podiatrist should be encouraged, and blistered skin should be left to heal. If areas should become dry, chapped or sore, bathing with tepid water and Epsom salts may help. Tea tree oil, aloe vera gels and urea based creams can also be helpful for irritated skin, but should be avoided on broken skin. If the skin reaction becomes severe with broken, moist, painful areas it may be necessary to have a dose reduction or break in treatment and use analgesia or steroid creams.
Hypertension is fairly common and for this reason patients should have their blood pressure monitored regularly (weekly when treatment is first started, then monthly) and treated if necessary.
Sore mouth (stomatitis) and taste changes can be quite distressing for the patient. Prior to commencing the treatment the patient should be encouraged to visit the dentist for a check up, and continue regular checkups throughout treatment. They should be advised to use a soft toothbrush and baby toothpaste as this has less abrasive chemicals that may cause pain in the mouth. Keeping the mouth and lips moist by using lip salves, saliva replacement gels, and mouthwashes such as sodium bicarbonate in water or manuka honey should be encouraged. Commercial mouthwashes often contain alcohol and this can compound the problem so should be avoided. If the mouth becomes painful topical treatments such as Bonjela or Gelclear can be used, and some people may find relief from anti-inflammatory painkillers. Aspirin as a mouthwash or mucilage may help (but this should not be swallowed). Using a spoon to eat instead of a fork may help to reduce mucosal injury, and using a straw to drink delivers the fluid further back in the mouth where it may be less painful. It may be necessary to adjust diet, avoiding hot, spicy, acidic foods, and eating little and often. With regard to taste changes, careful use of herbs and flavors may help. Sucking on fresh or frozen pineapple just before eating may help to stimulate the taste buds, but if the mouth is painful this may aggravate things. Eating sweets such as ‘starburst’ will encourage saliva production and might also help. Oral thrush can also be a problem and should be treated with nystatin or fluconazole.
Dry skin/pruritus can occur. Skin should be kept moisturised, overheating should be avoided, a good fluid intake should be maintained. Emollients or urea based creams can help with itching.
Skin/hair colour changes can occur. This can be quite alarming so the patient should be warned about it beforehand. It is harmless, but if hair dye is used it should be done during the 2 week break in treatment.
Diarrhoea is not uncommon. Anti-diarrhoeal agents, such as loperamide, can be used. Patients should also be advised to maintain a good fluid intake (2-2.5 litres a day), to avoid spicy foods and foods high in fibre when they have diarrhoea. Live yogurt may be helpful.
Constipation can also occur; obviously anti-diarrhoeal agents should be stopped if this is the case and aperients used. A good fluid intake is again important, but high fibre foods should be encouraged in this situation.
Nausea can occur, but this can easily be helped with anti-emetics and often resolves as the treatment continues.
Hypothyroidism can occur. The patient should have their thyroid function checked at each clinic visit and hypothyroidism should be treated appropriately. Symptoms can include fatigue, periorbital oedema, dry skin and shortness of breath.
Haematological disturbances (neutrapoenia and thombocytopoenia) are fairly rare but can occur, for this reason a complete blood count should be checked at each clinic visit. Patients should be encouraged to report any unusual bleeding immediately. They should also be made aware that if their temperature goes above 38⁰C, or they start shivering and shaking they should report it immediately.
Clinical Chemistry Disturbances Pazopanib can adversely affect liver function and even lead to liver failure if abnormalities not detected and acted upon, therefore regular monitoring of lifer function tests is necessary for first 4 months on treatment at least.
All patients undergoing TKI therapy should have their side effects monitored and recorded according to a toxicity grading scale such as the National Cancer Institute Common Toxicity Criteria version 2.0, 1999. This basically grades the side effects as 1 = mild side effects, 2 = moderate side effects, 3 = severe side effects, 4 = life threatening side effects and 5 = fatal. In order to help reduce grade 3 side effects and keep the patient on an effective treatment it may be necessary to dose reduce or interrupt. When things settle again it is then possible to re-escalate the dose.
Patients should be advised to avoid St John’s Wort and grapefruit juice when on TKIs as they will interfere with levels of the active drug in the blood stream. This is also true for certain medications, including types of antibiotics, so caution should be used in prescribing.
Monoclonal Antibodies
Bevacizumab (Avastin®) is a monoclonal antibody that is now licensed for use alongside INF-α to improve efficacy. It is an anti-vascular endothelial growth factor (VEGF) agent, and works as an anti-angiogenic cancer treatment. Tumour angiogenesis starts when cancer cells release various molecules, VEGF being the most significant, that send signals to nearby tissue. This signal activates certain genes in the nearby tissue that in turn make proteins that encourage the growth of new blood vessels. This is known as the ‘angiogenic switch’. Tumours can only grow to one or two millimetres without a blood supply, but once angiogenesis takes place can grow much larger and metastasise. Bevacizumab works by binding to VEGF thereby inhibiting the development of new blood vessels.
Bevacizumab is given as an infusion every two weeks, alongside the normal regime of IFN-α three times a week.
Patients having treatment with bevacizumab should avoid surgery as it will cause problems with wound healing. However, if surgery is required it can be stopped for 28 days prior to surgery.
Side effects
- Nose bleeds
- Headache
- Hypertension
- Proteinuria
- Taste changes
- Tear production disorder
- Diarrhoea
- Nausea
- Fatigue
- Haematological disturbances such as anaemia, thrombocytopaenia and neutropaenia
- Serious but rare side effects are GI perforation and severe bleeding.
Although bevacizumab is licensed for use alongside INF-α for the treatment of advanced RCC, the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) have not recommended bevacizumab as a treatment option in NHS England and NHS Scotland hospitals.
mTOR Inhibitors
The mammalian target of rapamycin (mTOR) pathway has been found to be dysregulated in many human tumours. mTOR is a protein kinase that is part of a signaling pathway with a central role in the control of cell proliferation, survival, mobility and angiogenesis, and is therefore an important target in the battle against cancer. Temsirolimus (Torisel ®) and everolimus (Afinitor ®) are examples of mTOR inhibitors licensed for use in the treatment of renal cancer. Temsirolimus is given as an infusion over 30-60 minutes once a week for as long as it is working, everolimus is an oral treatment and is taken once daily.
Side effects
- Rash; emollients can help
- Stomatitis
- Nausea
- Diarrhoea
- Fatigue
- Haematological disturbances such as anaemia, thrombocytopaenia and neutropenia; patients should be counselled to seek urgent medical attention if they have unexplained bleeding, high temperature, feel shivery and have flu-like symptoms. The importance of good hygiene should be stressed to them.
- Hyperglycaemia; patients should be advised to report excessive thirst or urinating more than usual.
- Non-infectious pneumonitis; patients should be counselled to report to their specialist team if they are regularly short of breath or have difficulty breathing, whether they have a cough or not.
- Wound healing complications; there may need to be dose interruption if surgery is planned.
Patients should be advised to avoid St John’s wort and grapefruit juice when on mTOR inhibitors. This is also true for certain medications, including various antibiotics, so caution – should be used in prescribing.
‘Lenvatanib combined with everolimus was recommended by NICE as second line treatment for advanced renal cell carcinoma in 2018 and everolimus on its own was also recommended as a second line treatment in 2017’.[2]
Reference
New treatments
- https://pathways.nice.org.uk/pathways/renal-cancer#content=view-node%3Anodes-first-line-treatment-for-advanced-and-metastatic-renal-cancer
- https://pathways.nice.org.uk/pathways/renal-cancer#content=view-node%3Anodes-second-line-treatment-for-advanced-and-metastatic-renal-cancer
http://www.macmillan.org.uk/cancerinformation/cancertreatment/treatmenttypes/biologicaltherapies/interferon.aspx accessed (14 september 2017)
Motzer, R J and Molina, A M (2009). Targeting Renal Cell Carcinoma. Journal of Clinical Oncology 27 (20), p.3274-76.