Session 3: Intra‐operative radiotherapy – creating new surgical boundaries

In patients with advanced and recurrent colorectal cancer, surgical resection with clear margins is the greatest challenge and is limited by known anatomical constraints. Preoperative or intra‐operative assessment of the limits of surgical dissection may help to explore the possibility of improving resectability through either targeted external beam radiotherapy or intra‐operative radiotherapy. Professor Chang reviews the evidence base and potential advantages and disadvantages of this approach, whilst the expert panel agree a consensus on the evidence for assessment and therapy of such patients.

Intra-operative radiotherapy (IORT) is not a new concept. It was introduced in the 1970s and 1980s as a technique to improve local control in locally advanced and unresectable tumours. It is typically combined with pre-or postoperative external beam radiotherapy (EBRT). Today it is used in conjunction with preoperative and, at times, repeat preoperative pelvic radiation therapy which is then followed by IORT.
There are advantages of giving a higher effective dose directly to the at-risk target in a single fraction, usually 10-20 Gy; there are reports of giving up to 30 Gy [1]. However, there are toxicity limits once you exceed 20 Gy [2,3]. Effectively what we are delivering is two to three times the external beam dose by delivering it directly to the tissues. Furthermore, the depth of penetration is between 0.5 and 1.0 cm. This is a major advantage here in that nontarget irradiation can be avoided.
There are a number of ways to deliver IORT. Conventional linear accelerators are stationary, and the same devices used for the delivery of EBRT in radiation suites can be installed in the operating room (OR). This used to be our standard approach at The University of Texas, MD Anderson Cancer Center; however, it is cumbersome and occupies OR space. Furthermore, radiation is delivered to through collimators and can only target tissues that are directly in line with the radiation source.
Nowadays there are mobile systems that have a lower energy and lower depth of penetration. One of the major advantages in the case of a mobile device is that shielding of the OR is not necessary.
At MD Anderson, we utilize an intra-operative highdose brachytherapy delivery system using a Harrison-Anderson-Mick applicator. The advantage of this approach is that we can deliver radiation to target areas that are not in the direct line of sight from an external source, for example along the anterior pelvis in the supine position or against the prostatic bed during sphincter-preserving proctectomy. We can even use in it in combination with minimally invasive surgery. Figure 1 shows a patient who underwent a robotic multivisceral resection with IORT being delivered through a Pfannenstiel incision.

When to utilize IORT?
IORT is indicated for borderline-resectable tumours and tumours where the resection margin is predicted to be closefor both primary and recurrent cancers. It is useful when the resection margins, despite multivisceral or extended resection, are threatened. This is where we can start to think about some of the new frontiers, to utilize this as a method to improve resectability and for organ preservation. That is, to avoid multivisceral resection, such as of the bladder or prostate or sacral bone, in situations where we know that the reason for considering multivisceral resection is close proximity or adherence of the tumour, not infiltration by the tumour.
Could IORT be an alternative to preoperative external beam therapy? That is an even more controversial issue that depends on the intent and goal of radiotherapy.
One of the only randomized trials to test the question of intra-operative radiation has been conducted by a French multi-institutional group. Patients were randomized to EBRT AE IORT. It showed no difference in local control or disease-free survival among patients who received IORT vs standard EBRT alone [4]. But one has to remember that in a study like this a number of these patients actually did not have fixed tumours. Many T3, rather than T4, tumours were included and the baseline recurrence rate was low. This study also treated the presacral plane.
So, in terms of improving local control in standard tumours, I think we have done a good job of doing that already thanks to the work of many of the people in this room. There is probably no role for IORT in the routine setting.
The data from Erasmus further confirms that the primary determinant of outcome is the completeness of resection (Table 1) [5].
However, amongst patients with close resection margins, local control rates were much better with IORT (10 Gy) than without: 50% with IORT and no durable local control without. Now we are starting to identify a population of patients in whom IORT can make a difference.
What about patients who have already been preoperatively or previously irradiated? Figure 2 shows data from Dr Haddock at the Mayo Clinic in 51 patients who had been previously irradiated either as adjuvant therapy for the original operation or as neoadjuvant therapy for their recurrence [6]. Again, stratification is based on the completeness of resection.
The median IORT dose was 20 Gy, but up to 30 Gy. There is potential for increased toxicity, but this is perhaps acceptable with dose tailoring. The authors concluded that re-irradiation with EBRT and IORT appeared to improve local control, but there was no comparison with a non-IORT irradiated group within this study [6].
Expert centres like the Mayo Clinic have been among of the pioneers of IORT, yet this study highlights the challenges in studying this question. Because we have a very heterogeneous population of patients it is very difficult to make direct comparisons. Even so it is possible to start thinking about some of these questions. Table 2 shows data from Heidelberg where patients received either pre-or postoperative EBRT [7]. Among 97 patients with recurrent rectal cancer, 54 also received EBRT. Some patients received IORT alone. Patients were stratified by completeness of resection (R0, R1 or R2). Among those patients who had R1 resection, the combination of IORT with EBRT was associated with a significant improvement in disease control when compared with IORT alone, but it is unclear what the effect was on the R2 patients.
So this again begs the question: can we enhance our local control achieved with standard treatments by adding IORT? It also suggests that IORT alone is probably insufficient for such complex disease.
A systematic review and meta-analysis conducted by Alex Mirnezami in collaboration with our group (at MD Anderson), Paris Tekkis and others [1] again highlights the challenge. Twenty-nine studies were included in this review, yet only about six studies were available for meta-analysis. But what we can conclude, whether we are looking at local control, disease-free survival or overall survival, is that there is an apparent benefit of  (Fig. 3). There is a tremendous heterogeneity in this literature and it therefore has to be taken with a grain of salt. However, the summary statistics show a benefit.
The primary toxicity of IORT appears to be wound related with an increased risk of wound toxicity with the addition of IORT.
A study from Memorial Sloan Kettering Cancer Center reviewed outcomes among 300 patients who underwent IORT, mostly for recurrent disease. The patients were categorized as negative margins, positive margins and close margins [8]. Their outcomes were stratified according to the resection status. In combination with IORT, these data suggest that while we can get improved results in patients with recurrent cancer it is unclear whether we can correct for potential deficiencies at the time of surgery. That is, with a close margin, can we get the outcomes with IORT to be as good as for patients with a negative resection margin status?
So what do we do at MD Anderson?
Here are data ( Fig. 4) from 100 consecutive patients treated with IORT at MD Anderson. R0 resection was achieved for 54% of the patients and 46% were resected with R1, none were R2 [9]. Most of these patients had recurrent disease and most required multivisceral resection. With respect to either local recurrence or survival, the addition of IORT corrected the gap in outcomes. This would suggest that IORT was able to correct a close resection margin to improve resectability.
The follow-up data compare outcomes with and without IORT stratified by R0/R1 resection status [9]. The addition of IORT was associated with improved R0, complete resection; R1/R2, microscopic/macroscopic residual tumour; IORT, intra-operative radiotherapy; NS, not significant. *IORT added for patients with margins ≤ 2 mm, after 1997 [5].    local control, with R1 patients approaching similar rates of local control as R0 patients. Similar findings have been found by Professor Harm Rutten in Eindhoven. Positive margin patients have a high risk for local recurrence, whereas those achieving at least a 0-1 mm negative margin have similar rates of disease control with the addition of IORT. The addition of IORT seems to improve local control, although this study did not directly compare patients with IORT with those without [10].
So for patients who have a microscopically positive margin, we can see that the addition of IORT is perhaps one option that is available to improve resection outcomes. So now if we have a borderline resectable patient for whom, despite a radical extended resection, we know we are going to have a close margin, then perhaps the addition of IORT may be able to close that gap and expand our therapeutic window for surgery.
So the key questions that remain now are: • Can IORT improve outcomes following resection of borderline resectable tumours?
• Can it facilitate organ preservation? For example, can an anterior tumour threatening the prostate or a posterior tumour abutting the sacral bone be resected using IORT in order to avoid the morbidity of exenteration or composite bone resection?
• Are there circumstances in which a single IORT fraction may be considered?
I would like to address these points briefly with this recent case, the kind of case we often see (Fig. 5). We know that despite extended resection in the lateral pelvis we are going to be dealing with a very close margin. Figure 6 shows the intra-operative photographnot dissimilar to what you have seen. This resection resulted in a 1-mm negative margin which was treated with IORT. So we could not do anything further than what we have done in this operation without dramatically altering the resection. Yet we may be able to augment our result with the addition of IORT.
What about the issue of a single dose?
I just want to touch briefly upon radiation biology. There are two mechanisms of cell deatheither mitotic death due to DNA injury or direct apoptosis with a high dose. The principle here is that cells that are producing DNA in S-phase are the most sensitive to radiation and not all cells will be in S-phase at the same time. So the concept of fractionation and delivery over a long course is that we are allowing an opportunity to hit the cells as they go through this cycle. But if we give radiation only once then there is going to be a population of cells that are not in the S-phase. So clearly there has to be another mechanism for those patients.
The TARGET A trial [11], with which I am sure those of you who are from London are quite familiar, is a trial that randomized women undergoing breast conservation therapy for early invasive ductal carcinoma: 20 Gy at 1-cm depth in a single intra-operative fraction with selective EBRT vs routine EBRT. There were two groups of patients in a pragmatic design. Patients received either IORT at the time of surgery or, if it was not known that they would need it, if the pathology details needed to be present and the system did not allow for that treatment at the time of surgery, patients received it at a second operation. The  Intra-operative photograph. There has been ligation of the internal iliac vessels; the sacral nerve roots yielding the sciatic nerve and the spinous process of the ischium can be seen.
wound was re-opened and radiation therapy was administered.
What we see here, if we just focus on the graphs (Fig. 7) of the patients who had pre-treatment assessment, is that patients who underwent EBRT vs singledose IORT had local control rates that were not significantly different. In fact, the EBRT patient group actually had more deathsalthough the difference was not statistically significant.
So it begs the question: if we have a situation such as that in Fig. 8 (a para-aortic recurrence) and we are going to approach this with surgery as part of a multimodality approach, there are a number of challenges with abdominal EBRT. EBRT to the abdomen may be a therapy that results in toxicity that is worse than the disease we are treating; but perhaps we can consider a multimodal treatment strategy of preoperative chemotherapy followed by lymph node dissection and high-dose IORT. Does that provide an opportunity for managing that kind of disease?   • The biological process behind IORT is not well understood.
• There are some data to support re-irradiation for patients with locally recurrent rectal cancer.
• The UK does not currently have IORT facilities; stereotactic ablative EBRT as a boost may be an alternative.
• Radiologists, irrespective of whether they work in an exenteration centre, should report the structures into which the tumour invades and which compartments would need to be resected to achieve an R0 margin.
• Imaging provides the 'pathological anatomy' following which a surgical decision regarding the extent of resectability should be made with the findings of clinical examination and an assessment of the general health and condition of the patient.

Audience voting
Question: Preoperative EBRT of margins at risk should be considered equivalent in effect to IORT for centres without access to IORT in order to increase the R0 resection rate or indeed organ preservation rates in exenterative type surgery. Agree or disagree? Strongly agree: 8% Agree: 22% Neutral: 44% Disagree: 20% Strongly disagree: 6% Editors note: There was no consensus on the use of EBRT. The audience required clarification of the term 'local recurrence' and it was felt that the distinction between EBRT and IORT was not required as these are both adjuncts. The question was rephrased to determine whether if IORT is not available is re-irradiation a sensible way to approach, i.e. can SBRT become equivalent of IORT?
Question: A trial is needed to test whether SBRT irradiation is equivalent in effect to IORT for centres without access to IORT to increase R0 resection rates? Agree or disagree?