With Covid secure radiotherapy delivery now critical in the present corona-virus crisis and hypo-fractionation all the rage, why is the ultimate hypo-fractionated and adaptive treatment, Intra-Operative Radiotherapy or IORT sometimes seen historically in our sector as sorcery!


I look at 2 key treatment areas and offer some thoughts on the future.

Introduction, well where do we start!

In the UK at least, it seems that IORT is still sadly an ‘outlier’ with the cost of equipment sometimes prohibitive and the MDT collaboration required to deliver this in theatre not facile.

However, it is in reality no more complex than an HDR treatment to all intents and purposes once treatment protocols are established, radiation risk assessments completed, shielding calculated and adequate training given.

Timing is also an important issue sometimes with some long surgical processes involved and so radiographic and physics staff have to be ‘on-call’ to deliver the treatment and sometimes in the evenings or weekends.

Also, and very importantly, IORT relies on the cooperation and close collaboration between radiographers, physicists, clinical oncologists and surgeons throughout the process, a key element allowing for the delivery of a highly accurate and critically, one-off course of high-dose adaptive radiotherapy.

Pic: You need to wed a surgeon to a clinical oncologist

The starting point to setting up a service aside from having the dedicated IORT equipment (we will come to this later) is the ‘marriage’ of a clinical oncologist and surgeon who both want to offer this treatment to their patients. Having been directly involved in IORT since 2010, I know that this is not that easy.

My experience to date shows that more surgeons than clinical oncologists are looking to drive IORT implementation which may alienate some of their peers in radiotherapy. There are various ways to look at this, one is that surgeons are often seen to be ‘delivering’ radiotherapy which is not true as a radiographer and physicist are always present and a dose prescription must have been signed under IRMER regulations by the clinical oncologist and be available in theatre as should they!

They need not attend every treatment, just as they don’t attend everyone now but certainly would be expected to advise if real time adaption of any agreed protocol was required. This could also be done virtually by in-theatre Zoom or Teams perhaps! Usually the clinical oncologist is the referrer, the radiographer and or physicist the operator and the surgeon can become the practitioner in many cases. A radiation protection supervisor or RPS must attend, this can be any trained person able to advise in theatre and the treatment is given under the remit of a radiation protection advisor or RPA, risk assessment, local rules and controlled area. This is a simplistic summary but covers most key areas.

Pic: IORT needs to be delivered in a controlled area within the theatre

Secondly, many IORT techniques are not ‘NICE-guided’ standards of care and so are given under the remit of research nor are NHS tariffs available for dedicated reimbursement and so IORT often takes place in the UK private sector (where insurance payments are allowed for early stage breast cancer by some insurers for example) or under the financial remit of UK charities who fund the capital cost of the machine and often its use.

It should be noted here that hypo-fractionated breast radiotherapy such as Fast-Forward is also not ‘NICE guided’ either but presently allowed due to a remit from the RCR so that under Covid19 restrictions this treatment can be used as long as the patient again meets certain selection criteria. Also most SABR techniques are reimbursed by ‘Commissioning through Evaluation’ or CtE and are also largely not NICE guided either and still presently research based but this may change shortly.

Lastly, some centres keen to start IORT do not have the blessing of the radiographic or radiotherapy physics departments who are often working at full capacity and have no spare time or resources to commit to implement and support IORT.

If you add to this some largely ageing arguments within radiotherapy as to whether IORT is a suitable treatment at all and that some clinical trials that have explored IORT and looked to set this up as a standard of care are somehow flawed, makes this a very difficult ‘sell’ in the UK. In the US and Europe IORT is far more popular however as reimbursement schemes persist there making the financial numbers add up overseas!

But, and this is important, in my opinion if you are a carefully selected early stage breast cancer patient for instance, meet very comprehensive selection criteria and are consented appropriately with the facts on treatment morbidity and recurrence rates, you may wish to wake up from your wide local excision (lumpectomy) having completed your treatment course and had your radiotherapy. If it simply comes down to patient choice at this stage then why not, especially if you have a very busy life or want to avoid attending a busy general hospital for radiotherapy.

We will look more closely at IORT for breast cancer shortly.

Pancreatic Cancer – some stats.

A key area of international IORT interest is in pancreatic cancer where annually in the US there will be circa 53,000 cases diagnosed and 42,000 deaths from this disease. Pancreatic cancer is the fourth commonest cause of death from cancer in men and women and has the highest mortality rate of all major cancers.

Surgery offers the only potential cure for pancreatic cancer. Only a few patients present with tumours that are fully resectable and even after the resection of localised cancers, long-term survival is rare. Sadly, adenocarcinoma of the pancreas has a 5-year survival rate of only 4%. Despite the progress of surgical treatment that has resulted in increased resection rates and a decrease in treatment-related morbidity and mortality, resection has unfortunately failed to improve long-term survival.

Some further facts

At presentation, only 10% to 20% of patients with pancreatic cancer have potentially resectable disease, 40% have locally advanced unresectable tumours, and 40% have metastatic disease while 74% of patients overall die within the first year of diagnosis.

Worryingly, pancreatic cancer is one of the few cancers for which survival has not improved substantially for over 40 years and so is an interesting area for radiotherapy research work both with regards to IORT and also MR guided radiotherapy that we looked closely at in the last RadPro blog on disruptive technology that you can read here:

https://www.radpro.org.uk/2020/11/04/november-blog/

Locally advanced pancreatic cancer (LAPC) is a very poor prognosis group with no international gold standard treatment regimen or consensus with dismal outcomes and despite treatment with neoadjuvant chemotherapy and chemoradiation, few patients are able to proceed to surgical resection and survival is very poor.

Pic: Pancreatic cancer survival is extremely poor.

Most IORT research in this field has focussed on LAPC and borderline resectable pancreatic cancer (BRPC) whereby after neo-adjuvant therapy some cancers are found to be amenable to surgery even if diagnostic imaging suggests otherwise and so these cases can often be resected when ‘down-graded’ if that is the right word and IORT given to the tumour bed. That is as long as an IORT service actually exists in that theatre and hospital which is not easy as discussed at length earlier and very rare!

Any ‘on-table’ unresectable cases discovered after surgical assessment can have IORT palliatively when surgery is not possible and so assuming consent has been given this is a treatment that would otherwise not be possible and can provide some local control, pain relief and extend life by some months.

However, there is hope for these patients with the potential to offer IORT to the 10% to 20% of resectable cases who can be fast-tracked to theatre in a matter of days/weeks and given IORT as a primary treatment delivering perhaps up to 15Gy in one fraction with some flexibility to offer it to the ‘on-table’ unresectable cases too. One huge advantage is that there is no radiation induced damage to vessels that require anastomosis following lengthy and complex ‘Whipple’ procedures that might complicate the surgery if the patient has had up to 50Gy of EBRT at some stage prior to the operation.

What is IORT – a definition?

Intraoperative radiation therapy or IORT delivers a concentrated, high dose of radiotherapy to a tumour bed during surgery. This technology can kill microscopic disease in surgical margins, reduce radiation treatment times or provide an added radiation boost. With IORT, a clinical oncologist in partnership with a surgeon delivers a dose of radiation in a single treatment session, while also working to preserve healthy tissue. This helps to reduce side effects and sometimes the need to return to hospital for further radiotherapy. The tumour bed is typically at high risk for recurrence while traditional radiotherapy requires a recovery period after surgery, which potentially leaves microscopic disease in the body longer.
IORT helps spare healthy tissues and organs with simple shielding techniques or moving organs at risk from the treatment field making this a truly ‘real-time adaptive’ treatment.

Types of IORT and machines.

Electron IORT

While IORT was first used in clinical practice in 1905 the modern era of IORT began with the introduction of electron IORT in the mid-1960s by transporting patients from the theatre after the tumour was removed to the radiotherapy department to receive their electron IORT on a conventional Linac.

The breakthrough came in 1997 with the introduction of a miniaturized, self-shielded, high dose rate mobile-linear accelerator that can treat many indications in theatre.

X-Ray IORT

Early practitioners of IORT treated primarily abdominal malignancies using superficial x-rays and later orthovoltage x-rays prior to the advent of technology that enabled high energy electrons. For the first 75 years, X-Ray IORT was used mostly for palliation.

HDR Brachytherapy – IORT

This technique was developed in the late-1980s in an attempt to combine the dosimetric advantages of Ir192 based high-dose rate brachytherapy with the challenges of treating some complex anatomical structures and surfaces with IORT such as retroperitoneal sarcoma. However, its limitations are that it does require a shielded bunker to deliver the treatment within or a dedicated shielded structure in theatre and this is rare.

Electronic Brachytherapy based IORT (50 kV)

Available since 1999, a miniature and mobile X-ray source emits low energy X-ray radiation in an isotropic distribution. The radiation which is produced by low energy mobile radiation systems however has a limited range and commonly used in early stage breast cancer but can be used in most theatre environments without dedicated shielding.

A brief history of IORT – Pancreas

Even early studies in the 70’s and 80’s the University of Kyoto in Japan showed that resection and 25/30Gy of IORT gave improvement in survival and pain control.

The US National Cancer Institute ran a randomised prospective trial that showed improved local control and median survival when compared to external beam radiotherapy back in 1993 while many others observed that IORT is an “independent prognostic factor for local control” as IORT techniques allow an increase in the effective radiation dose.

It was also shown in some trials that IORT and surgery resulted in no additional surgical morbidity or mortality while stage 1 and 2 cases showed “significantly prolonged time to local failure” and “overall survival” and so a trend towards IORT combined with surgery looked promising but seemingly was not followed up or used clinically as a standard of care probably due to a lack of solid phase 3 data and that many small single site trials, observational studies and retrospective or non-randomised trials abound.

However, it has been shown that IORT is a safe addition to the treatment of pancreatic cancer and standard neoadjuvant or adjuvant therapies improving local control for patients with resectable disease.

Patients with unresectable pancreatic cancer experience pain relief and also improved local control. In some studies, the addition of IORT led to improved survival and so is a useful therapy and palliation option for a very difficult group of patients.

Improved outcomes with neoadjuvant chemotherapy regimens have recently refocused minds on the role of IORT as local tumour progression causes significant morbidity and mortality. By essentially ‘down-grading’ LAPC cases or BRPC patients prior to surgery with the above treatments, more resectable cases have been operated on resulting in better local control and survival rates as long as an IORT delivery facility is available as discussed earlier.

At the Massachusetts General Hospital in the US, work has been ongoing for some years delivering IORT to LAPC and BRPC cases after neoadjuvant chemoradiation. This is followed by surgery and electron beam IORT.

A prospective series of 48 BRPC patients was published in JAMA Oncology in 2018 that showed that progression free survival was reported at 37.7 months for all patients and notably for those patients able to undergo resection and IORT (around 67%) the progression free survival was reported at 48.6 months and so a marked improvement.

There were also no reported increases of toxicity or morbidity in patients treated with IORT and the total procedure only adds around 30 minutes to the complete surgical process. A similar study for LAPC patients is now ongoing.

In summary, IORT has a role to play in all stages of pancreatic cancer as long as you have access to the equipment and an enthusiastic MDT. There is as suggested some new light at the end of the tunnel for these cancer patients.

A useful resource for pancreatic cancer information is:

https://www.pancreaticcancer.org.uk

A brief history of IORT – Breast

The Targit-A trial

This trial was designed to look at the long-term survival and local control from single dose IORT or accelerated partial breast irradiation depending on your viewpoint, during wide local excision for early stage breast cancer. It was sponsored by a manufacturer who also provided the equipment and so that immediately divided opinion from the start!

The main objective was to determine whether ‘risk-adapted’ IORT could effectively replace 15 or 30 fractions of postoperative whole breast external beam radiotherapy or EBRT.

The trial started in 2000 and was prospective and randomised with 32 centres in 10 countries participating including the UK, Europe, Australia, the USA and Canada. It finished recruiting patients in 2012.

Circa 3,500 women aged 45 years and older with invasive ductal carcinoma up to 3.5 cm in size, and eligible for breast conservation surgery were randomised before wide local excision to either IORT or 3 to 6 weeks of external beam radiotherapy depending on that centres EBRT breast treatment fractionation protocol.

IORT was supplemented by EBRT when postoperative tumour sample assessment and histology found higher risk factors in around 20% of patients and so quite a high number.

The end point for the trial was to attempt to show ‘non-inferiority’ against conventional EBRT with a margin of 2.5% for the absolute difference between the five-year local recurrence rates of the two arms and long-term survival outcomes.

One critical anomaly was that while around half the women had EBRT and half IORT, a large cohort of the IORT arm had IORT delivered at a later date, post initial surgery when they had no in-theatre access to the treatment machine. This was called the post-pathology group. This required a separate surgical procedure and involved reopening the wound. This arm of the trial had inferior results and so this was the next issue that adversaries of IORT used to lower their flag. Recurrence rates in the post-pathology arm were ‘out-with’ the non-inferiority goal but did have less need for post-op EBRT for obvious reasons.

IORT in the pre-pathology arm was found to be ‘non-inferior to EBRT’ and the local recurrence risk at five-year follow-up was 2.11% for IORT (pre-pathology arm) compared with 0.95% for EBRT and so within the prescribed non-inferiority window. However, mortality from other causes was ‘significantly lower’ and widely stated to be due to reduced cardiac toxicity when compared to EBRT however no subsequent data was analysed in detail to prove this.

Therefore, this was also claimed to be a trial anomaly by opponents and so largely ignored in the radiotherapy community despite the many recent advances in breath-hold systems for left breast cancer treatment and the inherent cardiac shielding applied by modern IMRT techniques!

Pic: Conventional 3D v IMRT plan for L Breast RT

There are other international breast IORT trials, one called ELIOT that uses electrons and not 50kV X-rays while both ASTRO and ESTRO have released guidance on patient selection criteria making this a safe treatment option. The initial results of ELIOT show that while the IORT arm overall meets the prespecified ‘equivalence’ margin of the trial, the recurrence rate was higher than with external beam radiotherapy but overall survival did not differ between groups. However, ELIOT patients with invasive cancer fitting the “suitability” criteria had a very low rate of recurrence once again pointing out the importance of strict patient selection criteria in line with the above guidance.

Other patients who might benefit from breast IORT are the very elderly, infirm, those shielding from Covid and also those who could not undertake, for various health reasons, a course of EBRT such as mental health issues or inability to raise their arms for instance.

My conclusion simply as a radiographer is that IORT is a suitable treatment for early stage breast cancer as long as the patient meets the strict acceptance criteria, is consented appropriately and is offered the choice of this versus 3 weeks of EBRT (or one week with the Fast-Forward trial for which data is still largely immature but subject to a Covid-19 roll out but where the patient is still exposed presently to busy hospitals and coronavirus) and can make up their own mind. Getting access to IORT machines is not without difficulty as suggested but some private centres in the UK still offer it while reimbursement codes and insurance companies still support and pay for it.

Lastly and on an important note, one key advantage of IORT over EBRT is that if you are unlucky enough to have a recurrence then a full course of EBRT can be given post IORT and after recurrence resection, the IORT is then deemed to have been an initial boost. However, after EBRT as the primary treatment, recurrence leads to mastectomy usually and so salvage after IORT is potentially less impactful.

If you Google Targit-A or ELIOT for early stage breast cancer there is lots of information out there for you to make up your own mind!

A useful resource for breast cancer is:

https://breastcancernow.org/

Other current areas of IORT research are:

Colorectal – patients with locally advanced or locally recurrent rectal cancer and/or following pelvic exenteration techniques.

Sarcoma – both extremity and retro-peritoneal soft tissue sarcomas.

Brain – glioblastoma and other tumours

Head and neck cancers – various sites

Locally advanced primary or recurrent gynaecological cancers

Spinal metastases and sacral tumours

The future of IORT – a few thoughts.

The use of a dedicated ‘in-theatre’ CT scanner will allow for the acquisition of images for ‘Image Guided IORT’ or IGIORT with the input of these images into a 3D treatment planning system with real time, on the fly dosimetry now possible.

One previously unhelpful issue that IORT has had is that it is difficult to obtain a delivered “treatment-plan” or patient record of the actual given treatment showing combined anatomy and dose. The above developments allow for this and so would be a big step forward.

Another area within electron IORT development is to allow for high-dose Flash RT to potentially be available in one mobile machine and or in-theatre. One US company has developed electron Flash RT that preclinically has shown an improved therapeutic index, while protecting normal tissue and a reported dose rate of up to 400 Gy/sec.

There is also it seems some potential out there for developing technologies using protons or similar ions suitable for IORT delivery or the creation of new IORT treatments in combination with targeted immune system adjustments, radiobiology research or even using radiosensitive nanoparticles amongst others that could perhaps lead to an increase in the use of IORT in the future, who knows!

Duncan Hynd – January 2021