New horizons in radiotherapy for older people

Abstract

Radiotherapy is an effective, albeit underutilised, treatment for cancer in older adults, especially for those who are surgically inoperable or for whom chemotherapy poses too great a risk. It is estimated that approximately half of patients with cancer could benefit from radiotherapeutic management. This article synthesises the basics of how radiotherapy works, recent developments in the field and considers how this treatment modality may be adapted in an older patient population or may evolve in the future.

Technological advances of relevance include Intensity Modulated Radiotherapy (IMRT), Volumetric Modulated Arc therapy (VMAT), Stereotactic Ablative Body Radiotherapy (SABR), proton therapy, MR guided radiotherapy, as well as better image guidance during irradiation in order to improve precision and accuracy.

New approaches for better integration of geriatric medicine principles into the oncologic assessment and workup will also be considered, in order to provide more age attuned care. For more informed decision making, a baseline assessment of older radiotherapy patients should encompass some form of Comprehensive Geriatric Assessment. This can facilitate the optimal radiotherapy regime to be selected, to avoid overly toxic regimes in patients with frailty.

The review discusses how these new initiatives and technologies have potential for effective oncologic management and can help to reduce the toxicity of treatment for older adults. It concludes by highlighting the need for more evidence in this patient population including better patient selection and support for treatment to enhance person-centred care.

radiotherapy, cancer, older, older people

Key points

• Radiotherapy is a valuable treatment option for older patients with cancer.

• New technologies which reduce toxicity and improve efficacy will expand treatment options.

• Assessment of potential for toxicity is particularly important for older people.

• Joint initiatives in education and research between geriatricians and oncologists will help to improve care.

Introduction

Radiotherapy is an effective treatment for many cancers, both in a curative and palliative setting [1]. It is estimated that around half of patients with cancer would benefit [2] but even in well-resourced countries, a proportion of those eligible are not treated [3]. Lower regional rates of access to radiotherapy have been associated with worse outcomes, e.g. in patients with non-small cell lung cancer [4].

Rates of radiotherapy usage decline in older patients, especially those over 85 years. This is in keeping with other cancer treatments such as chemotherapy and surgery [5]. There is considerable geographic variation both in access to treatment and cancer outcomes, which is so great it is unlikely to be explained by population differences alone [6, 7].

A recent multivariate analysis of patients treated with radiotherapy showed no association between survival and age in patients with palliative intent, and only small variation in those treated with radical intent [8, 9]. Historically, selection for intensive treatments, such as concurrent chemoradiotherapy, was based on strict age cut offs [10]. Older patients remain under represented in clinical trials and therefore evidence regarding optimum treatment is limited [11].

Many patients have limited knowledge of radiotherapy prior to treatment and may have negative perceptions based on stories from friends, family and the press [12]. In patients with breast cancer, the majority found that their fears were unfounded [13]. These misperceptions can also occur amongst medical students and other doctors, who often have limited experience of radiotherapy [14]. Radiotherapy delivery has significantly improved over the last 50 years, from the routine use of linear accelerators (Linacs) to stereotactic radiotherapy (high dose, highly localised radiotherapy).

Basic principles of radiotherapy

External beam radiotherapy (EBRT)

External beam radiotherapy uses high energy x-ray beams, shaped and targeted to deliver a high dose to the tumour, sparing normal tissue as much as possible. This leads to DNA damage and ultimately, to cell senescence or death. Tumour cells have defective repair mechanisms and are, in theory, less able to recover than normal cells. The total radiotherapy dose is delivered over a number of daily sessions, known as fractions, to allow repair of normal tissues [15].

Side effects depend on the total dose, the dose per fraction, the total treatment time, volume and site treated as well as patient factors. Traditional radiotherapy regimes are based on treatment on five weekdays with a 2-day break for the weekend. Additional unscheduled breaks may reduce efficacy, especially for squamous cell tumours, such as head and neck cancer. Palliative treatments are usually delivered in shorter courses, usually between one [16] and fifteen fractions, whereas curative treatment can extend up to 37 fractions or seven and a half weeks [17]. Radiotherapy can be combined with chemotherapy either sequentially or concurrently.

The patient pathway is shown in Figure 1. Following oncology review, a patient will undergo a CT planning scan in the position they will receive treatment. This is used to outline the area to be treated as well as normal structures to receive a limited dose.

Figure 1.

The external beam radiotherapy patient pathway. A – A radiotherapy mask used for treatment in the head and neck region. B – A simple CT based radiotherapy plan. C – A linear accelerator, showing patient positioning during radiotherapy treatment.

At this visit, patients will also have small permanent tattoos which are used to align and accurately position them for treatment. In some cases, patients require additional immobilisation during treatment, e.g. a plastic mesh mask or an arm rest. The planning process for curative treatments can take between 2 and 3 weeks. Palliative treatments are usually simpler and can often be designed in a few hours.

When patients come for treatment, they lie on a hard couch and are positioned by the radiographers, who then leave the room. The patient must then lie still for around 5–10 minutes, although this may be much longer for complex treatments.

Patients are usually supported with regular reviews during treatment to allow early detection and management of toxicity. There is a multidisciplinary approach including oncologists, therapy radiographers, clinical nurse specialists and other allied health professionals.

Brachytherapy

Brachytherapy is a localised treatment, where a radioactive source is applied directly on or into a tumour (usually under a general anaesthetic). There is a sharp drop off in radiation dose, so high doses can be delivered to the tumour while sparing normal tissue. The source can either be applied for a short period of time or permanently inserted. Treatment is usually carried out over a short number of sessions. Patients will need to stay alone in a room whilst radiation is delivered, with treatment time varying between five minutes to a few days.

Brachytherapy is used either alone or in combination with external beam radiotherapy to treat cancers including prostate cancer, cervical cancer, endometrial, rectal cancer and skin cancer [18].

Radioisotopes

Radioisotopes have an important role in diagnostics but are also used to treat a small number of cancers, most notably, radioiodine as an adjuvant treatment in thyroid cancer. Although this is generally a well-tolerated treatment, patients have to be isolated for radiation protection reasons for up to three days. This means it is not suitable for patients who need support with activities of daily living or have significant cognitive impairment [19].

A novel radiopharmaceutical is radium 223, an alpha-emitter, which is used in the treatment of prostate cancer with symptomatic bone metastases. There is a high level of uptake in osteoblastic bone lesions and the alpha particles have a very small range of 2-10 cells, leading to a highly targeted treatment. It is usually administered intravenously and patients are not isolated with minimal radiation precautions required for a week [20]. It has been shown to be equally effective in older patients [21].

Uses of radiotherapy

Radiotherapy is part of around 40% of curative cancer treatments, with 16% of cancer cases cured by radiotherapy alone [22]. In common with surgery, radiotherapy is a local treatment and is generally only curative in the absence of metastatic disease.

Table 1 outlines uses of radiotherapy in the curative setting in some common cancers. Radiotherapy can be particularly useful in the treatment of non-melanoma skin cancer in frail older patients, especially in lesions which would require extensive surgical reconstruction [23].

Table 1.

Uses of radiotherapy in common cancers

Cancer type	Curative (may be used in combination with chemotherapy)	Adjuvant
Breast	No	Majority of cases after breast conservation, some cases post mastectomy
Lung	In patients unsuitable for surgery or with locally advanced disease SABR* may be alternative to surgery	Uncommon
Prostate	Alternative to surgery Preferred in high risk disease	Uncommon, can be used as salvage treatment
Bowel cancer	No role, in rectal cancer deferred surgery considered in patient with complete response to treatment	No role except in rectal cancer, usually neo-adjuvant
Head and neck	Preferred treatment for some locally advanced cancers	Common
Oesophagus	Alternative to surgery in unsuitable patients	Can be used neo-adjuvant Adjuvant treatment uncommon
Non-melanoma skin cancer	Alternative to surgery	Common, indications include close margins
Uterine	No	Common, often brachytherapy
Bladder	Alternative to surgery in many patients	Uncommon

* SABR (stereotactic ablative body radiotherapy) is very high radiotherapy dose accurately delivered to a small area in a small number of sessions.

Adjuvant treatment is delivered after surgery to reduce the risk of disease recurrence. In some cases, e.g. rectal cancer, radiotherapy is used prior to surgery which is known as ‘neoadjuvant treatment’. This can increase the likelihood of successful surgery. The length of treatment depends on the tumour site and treatment intent but in some cases there are a variety of acceptable schedules.

Palliative radiotherapy can be very effective in reducing the local symptoms of cancer. Benefits can include reduction in pain, tumour shrinkage, control of bleeding, prevention of neurological symptoms from brain metastases and spinal cord compression as well as reduction in cough and dysphagia. A common indication is the treatment of bone metastases, with around 60% of patients experiencing pain reduction with a single treatment [1].

Palliative radiotherapy is usually delivered daily but there are some effective schedules, which are based on treatment on alternate days or once a week [24]. Re-irradiation may be considered in some cases but can increase toxicity [1].

Side effects

Radiotherapy can be very well tolerated even in the oldest adults, with acceptable toxicity and an 85% treatment completion rate reported amongst nonagenarians [25].

Radiotherapy side effects are usually local to the area treated, although fatigue can occur with any treatment. Side effects usually build up over the course of treatment then gradually improve over the course of weeks. Short term (acute) side effects, which develop within 90 days following the start of treatment, are usually related to the inflammatory effects of radiotherapy. Long term (late) side effects are often due to fibrosis and changes in blood supply.

The improvements in radiotherapy, which are discussed in the subsequent section, have allowed a reduction in the dose to the normal tissues and therefore reduced side effects [26]. Treatment for breast and prostate cancer are generally very well tolerated.

Skin toxicity is a particular problem for tumours located near or on the skin, such as anal, vulval and head and neck cancer. Skin breakdown can occur quite early during treatment and patients may require opiate analgesia. Specific creams and dressings can be used on the advice of the treating department. Healing usually occurs two to three weeks following completion of radiotherapy. Patients with cancers of the head and neck or thorax can develop painful mucositis, requiring strong analgesia and nutritional support including enteral feeding [26].

Late effects are those that occur beyond 90 days after the onset of radiotherapy and can even develop many years later. It is important to elicit a past history of radiotherapy, as patients may present after discharge from oncology follow up.

Such late effects are site specific, and include a small increase in second malignancies, pelvic syndromes, pneumonitis, endocrine failure following radiotherapy to the brain and xerostomia [26]. These patients may benefit from specialist review e.g. by a gastroenterologist for patients with long term bowel problems following pelvic radiotherapy [27].

Efficacy and tolerability of radiotherapy in older people

There is limited evidence comparing the efficacy and tolerability of radiotherapy in younger and older patients and the focus is on age rather than functional status. The majority of studies are retrospective case series or subgroup analyses and therefore represent highly selected patients. In general, efficacy appears to be similar [9], with conflicting reports as to whether toxicity rates are increased in older patients. There is also a paucity of evidence examining the impact of radiotherapy on older patients’ function and independence [26].

There is particular concern about the risk of cognitive impairment following radiotherapy to the brain in older patients, especially when used in combination with chemotherapy. Specific radiotherapy schedules have been developed for older patients with glioblastoma multiforme [28].

Toxicity may overlap with geriatric syndromes, e.g. urinary incontinence and pelvic radiotherapy. Older patients are also more likely to have comorbidities that make it impossible to deliver curative doses of radiotherapy, such as impaired lung function in patients with lung cancer. It is important to proactively manage toxicities, such as diarrhoea, as they may be less tolerable in older patients with limited mobility or chronic kidney disease [26].

Recent advances in radiotherapy

Improved precision and accuracy

Traditionally radiotherapy was delivered using a small number of beams, producing box-like radiotherapy fields making it difficult to avoid high doses to nearby structures. Intensity Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) are modern techniques to deliver more conformal dose volumes using different beam intensities. This means that normal tissues can be spared from high doses, reducing toxicity and increasing the dose that can be safely delivered to tumours. There has been widespread uptake of these techniques, despite relatively limited prospective data. Trials have shown IMRT reduced dry mouth in patients with head and neck cancer and improved cosmesis in breast cancer [29, 30].

Over the course of radiotherapy, between or even during fractions, the tumour and normal tissues can move due to changes such as breathing and bladder filling. Therefore, radiotherapy plans based on the initial planning CT may not accurately reflect organ position each day. New techniques, such as cone beam CT allows patients to have daily 3D imaging on the treatment machine. This ensures accurate patient setup as well as some correction to allow for daily changes to ensure target coverage and minimise dose to normal structures. This approach has been shown to decrease side-effects and improve recurrence free survival in patients with prostate cancer [31]. Imaging slightly increases the radiation dose, with a theoretical risk of second malignancy but this is unlikely to be significant in older patients.

Improved imaging has also facilitated novel techniques, such as ‘adaptive radiotherapy’. In the ‘plan of the day’ approach, a number of radiotherapy plans are developed before treatment and the one that fits best is chosen each day [24]. Deep inspiratory breath-hold whilst patients undergo radiotherapy for left sided breast cancer has been shown to reduce dose to the heart by moving it away from the radiotherapy field [32].

MR guided brachytherapy for cervical cancer increased the radiation dose to the tumour, whilst reducing the dose to normal tissues. This has been shown to improve local survival and reduce toxicity [33].

Reducing radiotherapy volumes

With improved image guidance and better patient selection, radiotherapy volumes have been reduced in a number of different tumour sites.

In the treatment of lymphoma, the traditional radiation field covered all lymph node areas on one side of the diaphragm. With the use of diagnostic PET scans, this has been safely reduced to cover only the involved nodal area [34].

Partial breast irradiation has also been shown to be safe in patients with low risk breast cancer after breast conserving surgery [35]. Omission of radiotherapy in low risk breast cancer patients over the age of 65 years can also be considered, as although radiotherapy reduced the risk of local recurrence, the absolute rate is less than 2% at five years [36].

Stereotactic radiotherapy

Stereotactic radiotherapy, also known as SABR (stereotactic ablative body radiotherapy) or SRS (stereotactic radiosurgery) is very high radiotherapy dose accurately delivered to a small area in a small number of sessions. It can be used to treat small areas of disease such as early stage lung cancer and brain metastases [37, 38]. Patients must be very still during delivery, either in a mask or using an arm rest. Lung cancer patients must have a regular breathing cycle to allow for correction of tumour movement.

The benefits of stereotactic treatment are both increased disease control as well as reduced toxicity compared to standard radiotherapy techniques. It has been shown to be well tolerated in older adults with early lung cancer and it is an excellent treatment option for those who do not want, or are unsuitable for, an operation. SABR avoids the metabolic and physiological stress of surgery and in preference to conventional EBRT can reduce normal tissue toxicity and specifically lung dose [38].

Hypofractionation

Hypofractionation is the use of slightly higher doses of radiation in each fraction of treatment, whilst reducing the total number of treatments. This has been shown to be possible in both breast and prostate cancer. For example, it is possible to reduce the length of treatment for patients with prostate cancer from 7 ½ to 4 weeks, without reducing efficacy or increasing side effects [39]. It may be possible to further reduce the number of treatments [40].

Radiotherapy is often delivered at supraregional centres and acceptance of treatment decreases as the distance to travel increases [22]. Reducing the number of visits required may decrease this effect particularly in older patients who may have limited access to transport.

A hypofractionated approach can also be useful in a palliative setting [24], limiting hospital visits and maximising resource utilisation.

Organ preservation; omitting surgery

Improving radiotherapy using drug modification, chemotherapy or combinations of external beam and brachytherapy can increase the chance of a cancer completely responding to treatment. This means in bladder or rectal cancer, if there is no evidence of residual cancer following radiotherapy, immediate surgery is replaced by surveillance and salvage approach [41].

Future developments

The first proton treatment centre has recently opened in the UK. Proton treatment leads to a different radiotherapy dose distribution, with a sharp cut off rather than a gradual fall off in dose, which can be useful in treating tumours near to critical structures such as the spinal cord. Currently, the main indications are for paediatric patients and there is a lack of evidence of benefit compared to standard radiotherapy for common cancers such as prostate cancer [42]. It is likely that this, as well as practical issues such as immobilisation and longer time on the radiotherapy couch will limit the use of proton radiotherapy in older patients.

Another new technology is an MR linac, combining MR scanning with radiotherapy. This is useful for increasing doses to cancers in the abdomen such as pancreatic cancer, which is difficult to visualise on standard machines [43].

Other areas of research include the use of SABR for oligometastatic disease, where metastatic spread is limited to a small number of sites. This approach can delay the need for systematic therapy and leads to long term survival in a proportion of patients [40]. There have also been promising results combining radiotherapy and immunotherapy treatment but toxicity is a potential concern in older patients [44].

Practical issues in delivering radiotherapy for older patients

There are few data describing older patients’ experiences of radiotherapy or the barriers to treatment but there are some issues that can limit access to treatment in older patients.

Daily attendance may be difficult due to caring responsibilities or limited transport so temporary accommodation close to the treatment centre could be considered. Care needs should be assessed, with home support tailored to treatment times and accounting for potential increased need due to toxicity.

Patients with cognitive impairment must be carefully assessed to ensure it is safe and practical for them to be alone, lie still and follow instructions during radiotherapy delivery. Guidelines aimed at making radiotherapy departments more dementia-friendly have been developed, summarised in Figure 2 [45].

Figure 2.

Recommendations for people with dementia undergoing radiotherapy.

It is important to assess a patient’s mobility prior to treatment, as they generally must be able to transfer to the treatment couch with assistance. They may also have to maintain a position such as arm raised behind their head or hold their breath for a period of time e.g. to ensure treatment delivery for breast cancer. This ensures optimal access of radiotherapy beams to the breast with a breath hold technique reducing radiation to the heart and lungs. In this situation, conditions reducing shoulder mobility can be problematic.

Prior to radiotherapy, it is important to optimise the treatment of movement disorders, orthostatic hypotension and vertigo. Delivering therapy can be practically challenging for patients with contractures or kyphosis. However it is not impossible, and various methods of immobilisation are available in order to assist in more challenging scenarios e.g. using vacuum fix bags and increased cushioning.

CGA in a radiotherapy setting

Consensus guidelines from the International Society of Geriatric Oncology (SIOG) [46], the National Comprehensive Cancer Network (NCCN) [47] and European Organisation for Research and Treatment of Cancer (EORTC) [48], recommend Comprehensive Geriatric Assessment (CGA) for all cancer patients. A baseline assessment including at least some, but preferably all CGA domains supports informed decision making, reducing the risk of under-treatment of fit patients as well as sparing frail patients toxic treatment.

There is currently no standardised approach to assessing fitness for radiotherapy (or other cancer directed) treatment in older patients with cancer [49], although it is recognised that chronological age is not enough. In contrast to medical and surgical oncology, there is a lack of integration of CGA into clinical practice. A recent systematic review identified only twelve small non randomised studies, highlighting a sparsity of high-quality literature [50].

Many reasons have been put forward for the lack of clinical implementation of CGA, including that it is time-consuming, resource intensive and geriatricians are in short supply [51]. Questions include the interplay of frailty and radiotherapy parameters as well as the optimum assessment approach.

Vision for the future

Radiotherapy is a very valuable treatment option for older patients with cancer. Although many patients benefit, areas for improvement include better patient selection and support during treatment.

The application of new technologies which reduce toxicity and improve efficacy, will expand the options that are available to older patients in a curative and palliative setting. Toxicity reduction is important for all patients but particularly those who are older with less reserve.

What is less clear is the impact of CGA deficits on patient outcomes or ability to tolerate treatment and this should be the focus of future research. Increased cooperation between oncologists, general practitioners and geriatricians should also improve outcomes for older patients. Joint educational initiatives such as the SIOG Advanced Course in Geriatric Oncology can help to promote collaboration and networking [52] and help to build interdisciplinary teams capable of delivering both research and treatment that are right for older people with cancer.

Declaration of Conflict of Interest: None.

Declaration of Sources of Funding: The Christie NHS Foundation Trust is a member of the Elekta Atlantic MR-linac Consortium and has received research funding from Elekta, Sweden which has partially supported A.C.‘s salary. This grant was unconditional and Elekta had no input into the concept, content or submission of this article.