Intrabeam radiotherapy system for adjuvant treatment of early breast cancer

The management of early invasive breast cancer

4.1 The committee heard from the clinical experts that usual clinical practice in the NHS is to give adjuvant radiotherapy to people with early invasive breast cancer after successful breast-conserving surgery (that is, removal of the tumour with clear margins). This is given by external beam radiotherapy (EBRT) using a linear accelerator delivering 40 grays in 15 fractions over 3 weeks in line with NICE's clinical guideline on early and locally advanced breast cancer (CG80). The committee heard from the clinical experts that there was some variation in clinical practice, with some oncologists recommending EBRT over 5 weeks but that, in general, most oncologists would recommend EBRT in line with CG80. An additional external radiotherapy boost dose to the site of the excised tumour lasting a further 1 week to 2 weeks could be offered to people with a higher risk of local recurrence. The committee noted comments from professional groups and also heard from the clinical experts that radiotherapy is constantly evolving. It also noted that there are several ongoing trials investigating, for example, whether the course of radiotherapy could be reduced from 3 weeks to 1 week, or whether radiotherapy is needed at all for patients considered to be at low risk of recurrence. The clinical experts suggested that the results of these trials may influence future clinical practice in the UK. The committee understood that clinical practice is evolving and that the delivery and use of external radiotherapy may change in the future, moving towards a more targeted approach in which patients have treatment based on their individual risks. The committee noted that Intrabeam could be used at the time of surgery as an alternative to postoperative treatment with EBRT. It also noted that, if adverse histological features are identified in the cancer cells at final pathology after treatment with Intrabeam, and subsequent EBRT is recommended, a further external boost dose would not be needed.

Potential benefits of Intrabeam

4.2 The committee noted that Intrabeam delivers a single dose of targeted low energy (X‑ray) radiation to the tumour bed. It can be used in an operating theatre as a single treatment at the same time as the surgery to remove the primary tumour. Patients at low risk of recurrence do not receive any further radiotherapy. However the committee was aware that patients with a higher risk of recurrence (for example, histopathology showing invasive lobular carcinoma, extensive intraductal component, node involvement, and close margins) may go on to receive an additional course of EBRT. For patients having EBRT, treatment can only begin after the surgical wound has healed and takes several weeks of daily therapy to complete. Intrabeam also has the theoretical advantage of having the source of radiation directly applied to the tumour bed. However, the committee heard from the clinical experts that there are now techniques allowing clinical oncologists to more accurately target the dose with EBRT, such as using clips during surgery to mark the site of the tumour. Although there is a risk of clips moving within the cavity, EBRT has evolved and is generally considered to be accurate for targeting the tumour site. The committee noted comments from professional groups that the main aim of radiotherapy after surgical removal of the tumour is to prevent local recurrence. A clinical expert confirmed that local recurrence is not related to an increased risk of metastatic disease or mortality in people with low-risk early breast cancer, such as those included in a randomised trial of breast cancer surgery with or without subsequent EBRT: the PRIME II study. This study included women aged 65 years or older with tumours no bigger than 3 cm that had not spread to the lymph nodes and that were hormone-receptor positive. All the patients received adjuvant hormone treatment. If there is local recurrence after breast-conserving surgery and EBRT, this is usually treated by mastectomy. However, for some patients, brachytherapy may be a suitable breast-conserving treatment instead of mastectomy. If there is recurrence after treatment with Intrabeam, further breast-conserving surgery and EBRT still remain a theoretical treatment option. The committee also heard from the patient expert that Intrabeam could be used when EBRT is unsuitable or not possible, for example, for those patients who are unable to raise their arm. The committee understood from the clinical experts that people for whom EBRT was not a suitable treatment would currently be offered mastectomy, and that Intrabeam might be an appropriate option for them. The committee concluded that Intrabeam, given at the same time as surgery, provided a potential advantage in delivering radiotherapy in direct contact with the tumour bed, and also represented an alternative treatment option for people for whom EBRT is not suitable, although for those people with a higher risk of recurrence an additional course of EBRT may still be required.

4.3 The committee heard from the patient expert that the psychological burden of breast cancer is high for patients and their families. The patient expert explained that, when a patient is diagnosed with breast cancer, the thought of many radiotherapy sessions over a number of weeks can cause emotional stress and anxiety and is highly disruptive to daily living. The patient may need to stop working and face substantial travel costs, which can have a considerable financial and emotional impact on the patient and their family. The committee also heard from the patient expert that some patients who live a long distance from a radiotherapy centre may need to stay away from their home to be able to complete the course of radiotherapy. The patient and clinical experts highlighted that the time between diagnosis and the end of treatment is much reduced with Intrabeam compared with EBRT. This is because the patient has the treatment at the same time as surgery and, for most people, no further treatment is needed. The patient expert also considered that Intrabeam does not have the adverse effects that are associated with EBRT such as local tenderness, breast pain, swelling and reduced range of movement. However, the committee also heard from clinical experts that the adverse effects of EBRT are mainly fatigue and that only a few patients have radiosensitivity, which can cause swelling and weeping of the breast. The patient and the company expert stated that Intrabeam is associated with better cosmetic outcomes than EBRT, and that changes in breast appearance and texture can be avoided or reduced with Intrabeam. The patient expert highlighted that cosmetic outcomes have a big effect on patients' quality of life. However the committee heard differing opinions from the clinical experts as to whether the cosmetic outcome from Intrabeam is superior to modern EBRT because the cosmetic outcomes with EBRT have improved substantially in recent years. The committee heard from the clinical experts that breast fibrosis is more common with EBRT than with Intrabeam, but that both treatments are associated with a substantial increase in the occurrence of fibrosis in the breast. The committee noted comments from the company and patient groups stating that treatment with EBRT is associated with potential long-term damage to other organs including the heart, and that treatment with Intrabeam would reduce the radiation dose to adjacent tissues. However, a clinical expert stated that the radiation dose to the heart with modern EBRT is not clinically significant. The committee concluded that patients generally tolerate EBRT well, with good outcomes, but that avoiding multiple radiotherapy sessions by having a single treatment with Intrabeam at the same time as surgery would be considered a major advantage by some patients.

Clinical effectiveness

Cost effectiveness

4.11 The committee considered the cost-effectiveness evidence presented for Intrabeam compared with EBRT. It noted that both the company and the assessment group focused on the pre-pathology group of TARGIT‑A to develop their economic models. The committee noted that the results from both the company's and the assessment group's models estimated that the quality-adjusted life year (QALY) difference between Intrabeam and EBRT was very small. This was despite Intrabeam being associated with slightly more QALYs than EBRT in the company's model and being associated with fewer QALYs than EBRT in the assessment group's model. The committee also noted that the results from both the company's and the assessment group's models indicated that Intrabeam provided some cost savings compared with EBRT. However, these savings were higher in the company's model than in the assessment group's model. The committee also noted that the assumptions used by the company and the assessment group to develop their models were different, particularly for the costs associated with both technologies. When existing capital equipment is decommissioned or freed up for other use the best way to incorporate this into the economic modelling is not clear. The committee noted that section 5.5.8 of the NICE guide to the methods of technology appraisal (2013) states that, if introduction of the technology needs changes in infrastructure, costs and savings should be included in the analysis. Section 5.12.6 of the guide states that, if savings are anticipated, the extent to which these finances can actually be realised should be specified. The committee debated whether the costs for Intrabeam and linear accelerator equipment should be included in the same way in the economic model (that is, including the capital costs of equipment for both technologies), or whether only the tariff cost associated with each technology should be included. The committee considered that, if the capital cost of EBRT were included in the economic model, the cost savings associated with Intrabeam compared with EBRT would be greater. The committee agreed that both the company and the assessment group estimated the costs of Intrabeam treatment as lower than EBRT, but it concluded that the size of the cost savings was uncertain.

Conclusions

4.13 The committee discussed whether, based on the evidence available, it was reasonable to recommend Intrabeam for routine commissioning in the NHS in England. It considered that the clinical- and cost-effectiveness evidence for Intrabeam remained uncertain. The committee noted its previous conclusions that, even if the length of follow-up of patients in TARGIT‑A had been longer, the quality of the trial and particularly its generalisability to NHS clinical practice would still not have provided conclusive evidence to establish the relative clinical and cost effectiveness of Intrabeam compared with EBRT as delivered in the NHS. The committee also noted that the rate of local recurrence with Intrabeam may be higher than with EBRT. However, it took into account that Intrabeam may provide benefits that some patients would consider substantial and that there are some patients who could particularly benefit from Intrabeam, such as people for whom EBRT is not suitable. The committee recognised its role of not recommending treatments for routine use if the benefits to patients are unproven, or if the treatments are not cost effective, in line with section 6.1.2 of the guide to the methods of technology appraisal (2013). However, it understood that, to have the benefits of Intrabeam, some patients may be willing to accept a treatment that may be associated with a higher risk of local recurrence. It noted several benefits highlighted by the patient and clinical experts in terms of improving patients' quality of life, which could not be captured in the QALY calculation. It also noted that, although non-inferiority for Intrabeam compared with EBRT was unproven for local recurrence, the rates of recurrence in the Intrabeam group in the pre-pathology group were low. The committee understood the concerns raised by the clinical experts and the comments from professional groups that it is crucial to offer informed choice in clinical practice. The committee accepted that individual patient preference is important and agreed with the patient and clinical experts that patients should be fully informed of the evidence and treatment options available. The committee concluded that, given the difficulty in interpreting the evidence (particularly when specialist clinicians do not agree), patient selection for Intrabeam radiotherapy, if made available, should be done by multidisciplinary teams experienced in managing early invasive breast cancer including breast surgeons, clinical oncologists and radiotherapy physics experts in brachytherapy. The committee agreed that clinicians wishing to carry out Intrabeam radiotherapy should ensure that patients understand the uncertainties about the procedure, and inform them about alternative treatment options. It also agreed that patients should be given written information, from NICE, on the evidence of the risks and benefits of all available treatment options to help with shared decision-making.

4.14 The committee understood that, if treatment with Intrabeam became widespread, considerable investment in equipment would be needed. However, if Intrabeam results were subsequently found to be unfavourable, this would be associated with irrecoverable costs to the NHS and potentially with overall worse outcomes at a population level. However, the option of localised single treatment with Intrabeam is welcomed by patients and, if its clinical and cost effectiveness can be confirmed, it could be beneficial for both patients and the NHS. Taking these factors into account, the committee considered that it is a technology worthy of further evaluation. The committee concluded that, because of the uncertainty in the evidence available, the Intrabeam radiotherapy system cannot be recommended for routine commissioning for adjuvant treatment of early invasive breast cancer during breast-conserving surgery to remove the tumour.

4.15 The committee heard from the clinical experts that there are 6 Intrabeam devices in the UK, which were used in TARGIT‑A but are not all being used at the moment. The committee considered that, given these existing resources, including staff trained in using Intrabeam, it would be reasonable to continue to use those devices that are available until further data is collected. The committee understood that there is considerable pressure on the existing NHS infrastructure for providing radiotherapy. As demand continues to rise the NHS will have to make further investment in new radiotherapy resources, taking into account emerging evidence on optimum pathways of care. The committee considered that collecting information about all patients having treatment with Intrabeam at a national level will allow the evidence from TARGIT‑A to mature while further data are collected in the NHS in a carefully controlled manner. The committee therefore concluded that it can only recommend the use of the Intrabeam radiotherapy system using only machines that are already available and only in conjunction with NHS England specified clinical governance, data collection and submission arrangements. These providers will also be required to comply with any NHS England service specifications pertaining to the delivery of intra-operative radiotherapy.

4.16 The committee recommended that further data collection in the NHS should include, as a minimum, a national collection of data from all patients having the Intrabeam radiotherapy system for adjuvant treatment of early invasive breast cancer in the NHS and it be recorded in the national radiotherapy dataset. Clinicians should audit, review and document clinical outcomes (described in section 6) locally, and consider the relationship between outcomes and patients' characteristics.

4.17 The committee discussed the technical requirements for Intrabeam and noted comments received from professional groups. It heard from the clinical experts that, although staff training is needed for Intrabeam, this will not necessarily mean there will be an increase in the number of staff or staff time, rather a change in their responsibilities and duties. The committee agreed with the clinical experts and concluded that the Intrabeam radiotherapy system should only be used by clinicians with specific training in its use.

Equalities issues

4.18 The committee considered whether NICE's duties under the equalities legislation required it to alter or to add to its recommendations. A committee member raised the question of whether there is the potential for some patients to be disadvantaged by the recommendations, if they lack the capacity to understand the information provided by the clinician and to make an informed choice (such as people with learning disabilities or communication difficulties). The committee considered that patients would not be disadvantaged by the recommendations, providing that clinicians act in the interest of their patients, in line with their usual responsibilities, and tailor their explanation to each patient's level of understanding, and discuss the risks and benefits with the patient's carers when applicable. The committee concluded that there was no need to alter or add to its recommendations.

Summary of appraisal committee's key conclusions