Introduction

The recent analysis of the GLOBOCAN database by ESTRO (European Society of Therapeutic Radiation Oncology)-HERO (Health Economics in Radiation Oncology) project is both compelling and thought provoking¹. The project seeks to predict the incidence of cancer across Europe for the next decade with a view to assess the future burden of cancer care.  The data, subdivided by tumor site and by European country, gives guidance on investment in services, equipment and for the training of dedicated personnel. This is necessary to adequately manage the increased oncology demands expected in the near future. The analysis is particularly relevant for Ireland with a projected increase in annual cancer incidence from 2012 to 2025 of over 35%¹. The projections are consistent with Irish longer terms projections data which projects new invasive cancer cases to increase by 84% for females and 107% for males between 2010 and 2040².

The projections from the ESTRO-HERO project are particularly interesting as they are being carried out in parallel with the evidence-based data on radiotherapy indications, which have dramatically increased over the past number of years. This is due to the significant growth in indications for stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). The purpose of this paper is the highlight the evolving literature and growing indications for precision and personalized radiotherapy specifically stereotactic radiosurgery and stereotactic body radiotherapy. We will also seek the highlight the economic benefits of these treatments.

Methods

A literature search was performed using PubMed, Google Scholar and ClinicalTrials.Gov including the terms ‘stereotactic radiosurgery’, ‘stereotactic body radiotherapy,’ ‘SRS’, ‘SBRT’, ‘’stereotactic ablative therapy, ‘SABR’, ‘indications’, ‘economic impact’ and incorporated boolean logic. For the purposes of this paper we focused on the most common indication for SRS specifically the management of brain metastasis³ and the most common indications of SBRT namely management of inoperable NSCLC, lung metastasis, primary and secondary liver tumors, spinal metastasis and prostate cancer^4-9.

Results

Stereotactic Radiosurgery (SRS)

SRS is a novel radiation technique developed by a Swedish neurosurgeon, Lars Leksell, for lesions not amenable to surgical resection². SRS is a distinct discipline that utilises x-rays to inactivate defined target(s) in the head and spine without the need to make an incision. The target is identified by high-resolution imaging. SRS is mainly performed in a single session, using an immobilisation device and a stereotactic image guidance system, but can be conducted up to a maximum of five. Currently, over one hundred Irish patients per year are now treated with intracranial SRS but this is projected to increase to over two hundred annually¹⁰.

Brain Metastasis

Brain metastases are a significant health care problem. As patients live longer with better systemic treatment options, approximately 20% to 40% of cancer patients will develop brain metastases during the course of their illness¹¹. The management of brain metastases requires multidisciplinary input for optimal patient management. Various treatment options exist, including whole brain radiotherapy (WBRT), systemic therapy, resection, stereotactic radiosurgery, and best supportive care with the use of steroids.

The management choice in patients with newly diagnosed brain metastases depends on number of brain metastasis, histological subtype, performance status, estimated prognosis, and extent of extracranial disease¹². Brain metastases tend to be spherical with sharp demarcation from brain tissue. They are thus ideal for SRS because precision targeting can be easily generated using radiosurgical systems¹³.  Compared with surgical resection, SRS is advantageous as it can treat surgically inaccessible lesions and multiple lesions. In general asymptomatic patients with up to four lesions smaller than 4 cm are regarded as suitable for SRS. Local tumor control rates with SRS are consistently greater than 80%. Patients with newly diagnosed brain metastases may be treated with whole-brain radiotherapy alone versus whole-brain radiotherapy and SRS boost¹⁴. In practice we tend to omit whole brain radiotherapy from this treatment paradigm due to enhanced toxicity, impact on quality of life and no improvement in overall survival. Whole brain radiotherapy is then reserved for future salvage use if required.

For patients with symptomatic lesions amenable to safe complete resection, surgery followed by adjuvant radiotherapy¹³ should be considered. Adjuvant radiotherapy may take the form of comprehensive whole brain radiotherapy or more targeted stereotactic radiotherapy to the resection cavity. In general, adjuvant stereotactic radiotherapy tends to be preferable as it has similar local control rates and fewer side effects. It also reserves more comprehensive whole brain radiotherapy for use in the future if needed. Surgery or SRS are salvage treatment options in patients who received prior WBRT with progressive intracranial disease¹³. SRS, unlike conventional whole brain radiotherapy, has the additional advantage of being able to integrate with systemic treatment. Patients with brain metastasis treated with SRS can be treated without chemotherapy treatment breaks thus optimizing extracranial disease control in addition to their intracranial disease.

Stereotactic Body Radiotherapy (SBRT)

Advances in radiation delivery and personalized image guidance have led to the development of SBRT. SBRT allows for delivery of high doses of radiation with precision accuracy to extracranial sites¹⁵. It has emerged as an important treatment strategy for a variety of cancers, as radiation is delivered with precision to the tumor, limiting damage to surrounding healthy tissue. The use of stereotactic radiotherapy for non-cranial indications is the natural evolution for delivering radiation. In the near future, there will be a significant increase in demand for SBRT. Evidence for SBRT is rapidly growing and constantly evolving. This technique will not apply to all tumors – many will be treated with conventional radiotherapy. However it is likely for a proportion of patients and tumors there may be significant benefits to precision SBRT over conventional treatment.

Tumor sites where SBRT has a role include lung cancer, spinal tumors, liver tumors, prostate cancer, pancreatic cancer, head and neck cancer, renal cancer and oligometastatic bone disease. It is expected that this evidence base will become stronger as this technique develops¹⁵. SBRT offers the opportunity for patients, who currently receive treatments which are prolonged, inconvenient and associated with risk, to be considered for a technique which may involve only 1 to 5 hospital visits with minimal toxicity and with potentially greater disease control rates. It is likely to form the backbone of personalized oncologic care because of its evolving efficacy, the limited number of hospital visits. In addition a number of studies are reporting on its cost effectiveness¹⁶.

Lung

The signature indication for SBRT is a patient with medically inoperable early-stage lung non–small-cell lung cancer³. This population of patients frequently died of cancer if left untreated¹⁷. Studies from the Nordic Group and the Radiation Therapy Oncology Group (RTOG) have shown over 90% local lesion control and a 3-year overall survival of approximately 60%^18,19. The survival is roughly twice what was typically achieved historically. Trials are currently comparing SBRT to surgery in operable patients.

In patients with a limited number of lung metastasis SBRT may be used if surgical resection is not possible⁵. Similar to cranial SRS, SBRT across all tumor sites may be interdigitated between chemotherapy cycles thus ensuring no compromise in systemic disease control. In fact there is significant research interest in this particularly which it comes to utilizing new immunotherapy drugs²⁰. The so-called abscopal effect has been noted in numerous patients treated with immunotherapy and SBRT. The theory is that SBRT primes the immune system to promote a more robust immune response against the tumor²⁰. This effect is currently being researched across a number of clinical trials.

Liver

Liver metastasis is a common site of spread from breast, colorectal and numerous other cancers. Surgery is technically difficult and only 10%–20% of metastatic CRC patients are candidates for surgical resection. Treatment options in non-surgical candidates include radiofrequency ablation RFA, trans-arterial chemoembolization, and percutaneous ethanol injection. All these procedures require a certain amount of invasiveness. SBRT provides an alternative noninvasive precision therapy, by providing optimal local tumor control as well as limiting dose to healthy tissue, and potentially lower complication rates. The local control rate achievable with SBRT varies in the range of 57%–100%^4,7. However, the follow-up times of most studies were relatively short, typically 18 months. In the primary treatment of hepatocellular cancer, SBRT can serve as either primary treatment in unresectable patients or as a bridge to liver transplant⁷. A number of studies reported excellent outcomes with liver SBRT with a 3-year local control and overall survival rates of 91% and 70%, respectively^21,22

 

Spine

The precision of SBRT allows for optimal targeting of a spinal tumor, while limiting the dose to the spinal cord. The most robust series from Pittsburgh published a series of 500 metastatic spinal lesions⁶. Sixty-nine percent lesions had received previous radiotherapy, meaning conventional irradiation was not possible.  Patients received a single fraction of precision SBRT. With a median follow up was 21 months. LC was 90 % in patients with no prior radiotherapy, and 88 % overall. Long term pain improvement was seen in 86 % of patients in whom the indication for treatment was pain. There were no cases of radiation myelopathy observed. 

Prostate

Patients with low risk prostate cancer have a number of treatment options to manage their disease. Many undergo active surveillance rather than treatment. However many progress and require active treatment. Current treatment options include radical prostatectomy, seed implant, and conventionally fractionated intensity-modulated radiation therapy. SBRT has now entered the mix of available therapies in this setting. A pooled analysis of 1,100 patients enrolled on prospective trials of SBRT demonstrates biochemical relapse-free survival rates and quality-of-life outcomes that compare favorably with other definitive treatments for prostate cancer⁸. Conventional prostate radiotherapy requires 37-42 hospital visits. However with precision prostate SBRT efficacious treatment can be delivered in 4 to 5 treatments. An additional appeal of prostate SBRT is its cost-effectiveness relative to other forms of radiation therapy of prostate cancer^{23, 24}. However, some retrospective series have raised concerns about genitourinary toxicity after SBRT for prostate cancer relative to conventional treatment²⁵.Results from prospective studies will be important. With implementation of any new technology, there is likely a significant learning curve toward optimal utilization.

Discussion

SRS and SBRT share technological characteristics and are likely to form one of the pillars of precision medicine in the future. There is the opportunity for patients who currently cannot be considered for treatment to have the possibility of a relatively non-toxic and short course of radiotherapy. This may improve their outcomes either regarding survival, palliation or quality of life. In this setting growth in SBRT will be a new treatment rather than replace existing therapies, and as such would be an additional cost burden on the Irish health service. However it may well be that SBRT has the greatest role to play in these situations, for example enabling patients currently considered to be without treatment options, to be either treated, cured or palliated.

SRS and SBRT demonstrate their clinical and economic value often in comparison to long-standing and well-accepted treatment options. From a patient perspective, SRS and SBRT provide patient-friendly options compared to other treatment options such as conventional RT. This especially applies to those who live in rural areas or a great distance from treatment centres. SRS/SBRT offers a treatment option that is non-invasive and can be completed in the outpatient setting. It will help free up valuable hospital resources as well as allowing patients to resume their normal daily activity as quickly as possible. SRS and SBRT have been demonstrated to be clinically cost-effective¹⁵. SRS/SBRT reduces health care utilisation, lessens indirect costs, and saves patients additional financial resources¹⁵.  In times of increasing cancer incidence¹ as well as resource constraints, cost-effective and cost saving techniques are crucial for health systems. Techniques such as SRS/SBRT have the potential to be beneficial to patients and have the additional benefit of healthcare cost reductions.

Disclosures, conflicts of interest, and acknowledgements:

D. N. Cagney, reports contribution made by Richard Steevens Scholarship 2015 and St. Luke’s Institute of Cancer Research Scholarship 2016. J. G. Armstrong reports no conflict of interest

Correspondence:

Daniel N. Cagney, Department of Radiation Oncology, Brigham and Women’s Hospital, 75 Francis Street,, Boston, MA 02115

Email: [email protected]

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