Advances In Cancer Treatment

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POSTNOTENumber 598 April 2019Advances in Cancer TreatmentOverviewThe pace of innovation in cancer treatment israpid, with promising developments for patientsin terms of survival and quality of life. Researchin the fields of immunotherapy and radiotherapyhas shown positive results in treating somecancers where established treatments are noteffective. This POSTnote gives an overview ofrecent advances, the potential benefits and risks,and considers the opportunities and challengesof using new technologies in the NHS.BackgroundCancer is the leading cause of death in the UK for bothfemales (25.6%) and males (30.3%) when all cancers aregrouped together (around 164,000 deaths annually).1Prevention of cancer is a public health priority, in part due toincreased understanding about genetic, behavioural andenvironmental factors in causality and how to prevent them.2Technological advances mean that cancer treatment optionsare improving rapidly, and patients have better prospects,both in terms of clinical outcomes and quality of life. Canceris a key area for ongoing improvement for NHS England inthe NHS Long Term Plan (2019), which sets out itscommitments for cancer prevention, diagnosis andtreatment.3 NHS Scotland and NHS Wales also have cancerstrategies.4,5 The Department of Health in Northern Irelandrecently announced it will launch a similar strategy.More people in the UK are being diagnosed with cancerthan ever before, partly due to improved diagnosis andgreater public awareness. There are more than 360,000new cancer cases in the UK every year.6 At least half of allUK citizens born after 1960 will be diagnosed with someform of cancer during their lifetime.7 The rise in cancer New cancer treatment technologies haveshown promising results in clinical trials,particularly for difficult-to-treat cancers. Significant progress has been made incancer immunotherapies for specificcancers and patient populations. Researchinto the use of these therapies for othercancers and patients is ongoing. Advances in radiotherapy include improvedimaging and precision, proton beamtherapy, and molecular radiotherapy, all withpositive clinical results. Combination therapies, which combinedifferent types of immunotherapy, or drugand radiotherapies, are a research priority. New therapies require specialisedknowledge and resources. Stakeholdersagree that they should be delivered as partof a comprehensive multidisciplinary carepackage.diagnoses is also attributed to changes in demographicsand patterns of chronic disease. An ageing population,unhealthy eating habits, lack of exercise and poor sleeppatterns are predicted to cause a further 2% rise in cancerincidence by 2035.8,9 However, cancer survival in the UKhas doubled over the past 40 years, with half of peoplediagnosed surviving for 10 years or more.10 Some cancerswill become treatable as long-term chronic diseases astreatments improve.Current Treatment ApproachesThe current standard of care for cancer can involve a rangeof treatments, usually in combination.11 This might involve acombination of surgery to remove tumours, chemotherapyand/or conventional X-ray radiotherapy to kill cancer cells.Standard treatments are highly effective in treating somecancers, such as breast cancer, prostate cancer and sometypes of leukaemia. Other cancers are more difficult to treatdue to the location of the disease, its resistance to therapy,or the patient’s general health.12 These include tumours ofthe brain, lung, pancreas, oesophagus, head and neck,cancers diagnosed at a late stage, and those that havespread (metastasised).The Parliamentary Office of Science and Technology, Westminster, London SW1A 0AA; Tel: 020 7219 2840; email: [email protected]

POSTNOTE 598 April 2019 Advances in Cancer TreatmentWhile they are effective first-line treatments, chemotherapyand radiotherapy can cause serious side effects that impacton patients’ quality of life.13 For example, secondary cancersdevelop in around 5% of patients receiving conventional Xray radiotherapy due to the irradiation of surroundingtissue.14 Over the past decade, important progress has beenmade in “targeted” and “personalised” treatments.15 Usingadvances in physics and engineering combined with newdiagnostic capabilities and genome editing techniques,some treatments can now be tailored to specific patientsand specific types of cancer cells.16,17 This also means thatpatients for whom the treatment is unlikely to work will avoidunnecessary exposure to toxicity.Recent Advances in TreatmentThis note covers the following advances in specifictreatment areas that have recently shown promising resultsin clinical trials (Box 1) and/or in clinical practice. Immunotherapy Chimeric Antigen Receptor T-cell Therapy:engineers a patient’s T-cells so they will attack cancercells more efficiently Immune Checkpoint Inhibitors: block immune cellmechanisms, releasing the “brakes” on the immunesystem so that it can better kill cancer cells Radiotherapy Proton Beam Therapy (PBT): irradiates cancertumours with a beam of protons (small parts of atoms) Systemic Radiotherapy: involves infusing orinjecting radioisotopes into the patient to damagecancer cells Oncolytic Virus Therapy: uses viruses to kill cancercells and stimulate the immune response Combined ApproachesBox 1. The Clinical Trials ProcessTreatment development is a multi-stage process carried out byacademic research centres and, in the case of drugs, pharmaceuticalcompanies.18 Funding can come from government research grants,pharmaceutical companies and charities. Researchers at universitiesand research institutes normally carry out early stage lab-basedresearch into the cell and molecular biology of cancer. Newdiscoveries are tested for safety in animal models. Further large-scaletrials are then carried out to test for clinical efficacy and safety inhumans, usually conducted by pharmaceutical companies, who aredeveloping a particular drug, or by clinical academic centres, in thecase of radiotherapy.19 Further clinical trials determine the idealdosage or radioactivity; its use in different cancer types and differentpatient populations; and the potential for a treatment to be usedinstead of, or in combination with, existing approaches.At present, there are around 700 clinical trials into cancertreatments in the UK, many of which are testing theeffectiveness of combined treatment strategies.20 Trialinformation is available through the UK Clinical TrialsGateway.21 If successful in clinical trials, new treatments areassessed for clinical efficacy and cost-effectiveness by theNational Institute for Health and Care Excellence (NICE) foruse in the NHS in England and Wales.22Page 2Overall, recent advances in treatment have demonstratedpromising evidence of improvements in survival rates andquality of life for patients, and some improvements in sideeffects. Experts have cautioned that most of thesetreatments are approved as a second- or third-line treatmentfor specific cancers and patient subgroups. As they aretrialled for different indications they may become first-linetreatments. New technologies are generally more expensivethan standard treatments and require highly skilled clinicalstaff and specialised facilities to deliver them.23ImmunotherapiesCancer immunotherapy covers a range of technologies thatuse the patient’s own immune system to damage or killcancer cells. Most approaches involve adapting orengineering T-cells, a type of white blood cell that plays akey role in fighting infection and disease.24 Cancer cellsdeploy various tactics to prevent T-cells identifying anddestroying them. Immunotherapy research is focused onengineering the immune system to overcome these tactics.These therapies are for specific patient groups. They mayrequire a particular gene to be present to function, andpatients might need to be relatively healthy to withstandtreatment. A treatment might only work on a specific form ofcancer due to the varying ways the disease attacks healthycells. These treatments can have severe side effects,detailed below. They are also expensive, particularly if theyare personalised or genetically engineered treatments.Chimeric Antigen Receptor T-Cell (CAR T-cell)TherapyCAR T-cell therapy involves collecting, modifying and usinga patient’s own T-cells to treat their cancer. The biology ofthis process is complex (see Box 2). So far CAR T-cellshave been highly effective in treating a number of bloodcancers. Several hundred patients with B-cell leukaemia, Bcell lymphoma and myeloma have been successfully treatedin clinical trials.25 The first NHS patient was infused withCAR-T cells at Great Ormond Street Hospital in January2019.26 The associated clinical research team at UniversityCollege London leads the European field in CAR T-cellresearch, with ten trials currently recruiting.27 A metaanalysis of CAR T-cell therapy found that, 67% of bloodcancer patients survived without disease progression for atleast 6 months to 1 year.28 A future goal is to have universal“off the shelf” CAR T-cell therapy, which would be morecost-effective for drug developers, and potentially cheaperto provide on the NHS.29In 2018, NICE recommended CAR T-cell therapy for twopatient groups through the Cancer Drugs Fund (CDF) (seepage 4). According to current guidance it is not intended asa first-line treatment, but for patients for whom conventionalchemotherapy is not effective.30 A panel of clinicians makesdecisions about individual patient eligibility. The treatment isnow available on the NHS for the following patient groupswhile more clinical data on patient outcomes are collected:

POSTNOTE 598 April 2019 Advances in Cancer Treatment Children and young adults aged up to 25 years old withacute lymphoblastic leukaemia that has not respondedto standard treatment approaches.Adult patients with certain types of lymphoma, if two ormore previous therapies have failed.CAR T-cell therapy can have severe adverse effects.Between 50–80% of patients who have undergone systemicT-cell therapy experience cytokine release syndrome(influenza-like symptoms and high fever) and some haveneurological side effects, such as confusion.31 Research isbeing carried out on injecting CAR T-cell infusions directlyinto tumours, for cancers that are localised rather than thosethat affect the whole body. A trial at King’s College Londonhas found that this approach is safe and demonstratessome slowing of tumour growth in patients with difficult-totreat head and neck cancers.32Box 2. How Does CAR T-cell Therapy Work?T-cells have protein receptors on their surface that recognisefragments of protein (antigens) that are presented by other immunecells. When T-cell receptors detect these antigens, the T-cell “turnson”, releasing toxic chemicals to damage the cell, and recruiting otherimmune cells to the area.33 Cancer cells can disguise themselves ashealthy cells and block this immune response.In CAR T-cell therapy a sample of the patient’s T-cells are modified ina laboratory. An inactive virus is used to introduce genetic informationinto the T-cell so that they produce receptors that recognise andattach onto cancer antigens. These cells–now chimeric antigenreceptor T-cells–are stimulated to multiply rapidly and are infusedback into the patient in a single treatment. The receptors allow them tolocate and kill the cancer cells. Where therapy fails, it is usuallybecause CAR T-cells do not persist long-term, fail to reach the tumourin sufficient numbers, or the cancer cells have evolved.Immune Checkpoint Inhibitors (ICIs)Immune checkpoints are proteins on cell surfaces thatprevent the immune system attacking cells indiscriminately.These play an important role in deactivating the immuneresponse after a pathogen, such as a virus or bacteria, hasbeen destroyed. Cancer cells have molecules (known asligands) on their surface, which can bind with the checkpointproteins on T-cells, effectively pushing the “stop” button onthe immune system response.34 Immune checkpointinhibitors block this process, allowing T-cells to kill tumourcells by inducing apoptosis (programmed cell death).Examples of ICIs used in the UK are: Ipilimumab (Yervoy35) for advanced melanoma (skincancer). It was approved by NICE (see page 4) for usein the NHS in 2012.36 Pembrolizumab (Keytruda37) is offered on the NHS orthrough the Cancer Drugs Fund (see page 4) for arange of cancers and patient populations, sometimes incombination with ipilimumab or chemotherapy.38,39,40Side effects of ICIs are linked to their overall boosting of theimmune system. Common side effects (in around 10% ofpatients) can include pain and inflammation, fatigue,nausea, rashes and diarrhoea.41 The treatment can alsodisrupt the functioning of the liver, kidneys and thyroid.Page 3RadiotherapyRadiotherapy technology in the UK has improvedsignificantly over the past 20 years since becoming a priorityfor investment and development under NHS England’sCancer Strategy. There have been consistent advances inconventional external X-ray radiotherapy. The combinationof new imaging and patient immobilisation techniques, andimprovements in machine manoeuvrability, mean thatradiotherapy is a highly precise and effective treatment. Forexample, intensity modulated radiotherapy uses lead“leaves” to shape the beam precisely to the tumour.Stereotactic ablative radiotherapy allows for radiation beamsto be delivered from many different positions around thebody.42 The UK now has two Magnetic Resonance LinearAccelerator (MR Linac) machines in NHS hospitals, whichuse MRI scanners to account for organ movement duringand between appointments.43 The clinical role and value ofthese machines is an important clinical research question.Proton Beam Therapy (PBT)Proton beam therapy is a type of radiotherapy where abeam of high-energy protons is precisely targeted at atumour, which is newly available in the UK (see Box 3). 44Protons “drop off” faster than X-rays as