The next step in rectal cancer treatment
Rectal cancer treatment is constantly evolving. Long course chemoradiotherapy (LCCRT, 25-28 fractions of 1.8 to 2Gy with concomitant fluoropyrimidine) followed by total mesorectal excision (TME) and adjuvant chemotherapy has been the conventional paradigm for stage II/III disease. Short course of radiotherapy (SCRT, 5 fractions of 5Gy) to the pelvis remains standard of care for patients with oligometastatic rectal cancer as well as frail patients with localised disease who are unable to undergo LCCRT or surgery.
Whilst historical studies have demonstrated non-inferiority of SCRT as compared to LCCRT in terms in the neoadjuvant setting (1-3), a post-hoc analysis of the RAPIDO trial, a phase III trial of patients with locally advanced rectal cancer, randomised to receive SCRT and consolidation chemotherapy versus LCCRT prior to radical TME surgery, showed a numerically higher local recurrence rate in the experimental arm (4). Postulated reasons for this include lower biologically equivalent dose (BED) of SCRT as compared to LCCRT, high proportion of T4b tumours and tumours involving the circumferential resection margin (CRM), high proportion of tumours located in the upper rectum exposed to greater positional variability, which combined with introduction of intensity modulated radiotherapy treatment (IMRT) employing tighter margins may have resulted in an increased risk of geographical miss.
Whilst short course radiotherapy delivered in 5 fractions over one week represents an optimal treatment option for patients with oligometastatic disease who benefit from minimal interruption of systemic therapy as well as patients who are too frail to be considered for LCCRT or surgery, there is an unmet need to optimise the delivery and improve efficacy of SCRT with the aim to improve local control especially as prognosis of patients with oligometastatic and polymetastatic rectal cancer continues to improve with the advance of novel systemic therapy options being employed in third line and beyond.
Introducing the MRIdian – an evidence-based treatment for rectal cancer
MR-guided adaptive radiotherapy has emerged in recent years as a promising modality in image guided radiotherapy, offering real-time high-resolution visualisation of the target and patient anatomy, allowing daily on-table adaptation and plan optimisation to reduce the dose to the organs at risk and improve tumour coverage.
MR-guided SCRT may allow safe radiotherapy dose escalation, better integration with intensified systemic chemotherapy and improved toxicity profile and tolerability in frail patients.
Here, we present a novel MR guided, daily adaptive dose escalated SCRT protocol and our institutional experience including planning data, early toxicity and patient related outcomes, effect on multimodality treatment (subsequent surgery and further systemic therapy) and local control.
Compared to conventional radiotherapy techniques, MRIgRT offers both reduced normal tissue toxicity – resulting in improved patient quality of life and long-term function – as well as improved oncological outcomes and organ preservation rates through selective dose escalation.
Various Phase II and III clinical trials6,7 and the global use of MRIgRT to treat other types of cancer, including prostate, kidney, lung and cervical, have generated valuable knowledge and a strong rationale for the use of short-course MRIgRT for patients with rectal cancer.
Having first introduced the MRIdian to the UK in 2019, we have treated more than 1500* patients using MRIgRT at our centres in Oxford and Cromwell Hospital London.
You can find out more about how to refer, eligibility criteria and the evidence base for MRIgRT and SCRT for rectal cancer below.
*figure accurate as of August 2024
Benefits of MRIdian
MRIdian combines a linear accelerator with an MRI scanner to deliver treatment with sub-millimetre accuracy. By using the most advanced imaging available, MRI-guided radiotherapy offers the potential for improved response through dose escalation compared to conventional techniques. This can provide a variety of benefits to patients.
Improved targeting
Improved soft tissue contrast by MRI scanning enables a clearer visualisation of the tumour site and reduces the planning target volume (PTV) margins.
Daily adjustments
MRIdian accounts for the variation in the target position, allowing clinicians to replan each fraction and enable dose escalation without increasing toxicity.
Automated beam gating
The MRIdian’s automated beam gating functionality allows radiotherapy to only be delivered when the target is within the treatment field, reducing toxicity.
Who to refer
At GenesisCare, we work with referring clinicians to make sure patients receive the most appropriate treatment for their condition.
We regularly review our treatment protocols and eligibility criteria and encourage all potential referrals to be submitted for peer review. Our current eligibility criteria are defined as follows:
- Aged 18 years or older
- WHO performance score 0-2 or Karnofsky performance status 70-100%
- Biopsy proven adenocarcinoma of the rectum
- All patients should be able to undergo MRI scans
Reviewed by a multidisciplinary team and external beam radiotherapy is an option for treatment
- Previous irradiation in the pelvic region
- Contraindications for MRI
- Patients who have electronic devices such as pacemakers or implanted defibrillators, deep brain stimulators, cochlear implants
- Patients who have a metallic foreign body in their eye
- Patients who have an aneurysm clip in their brain
- Patients with severe claustrophobia may not be able to tolerate an MRI scan
- Patients with inflammatory bowel disease
How to refer
We aim to make referrals to GenesisCare as rapid and straightforward as possible. For physicians with practising privileges, referrals can be made online here. Otherwise please contact us at your earliest opportunity at REM@genesiscare.co.uk.
The minimum data set required for MRIdian referrals is:
- Rectal radiotherapy consent form
- MR linac supplementary consent form
- Booking form (electronic/paper)
- Referral letter (letter referring the patient to the clinical oncologist)
- Histology report
- Rectal MRI report and images if possible
- GenesisCare MRIdian assessment pro forma
Please note, on occasions some insurers may ask for a medical report.
We’re recognised by all major insurers, including Bupa, AXA PPP, Aviva and Vitality, and can help with transport depending on treatment and locations, when required.
We also accept patients wishing to self-pay.
Evidence base
There has been an increasing evidence base for using the MRIdian system to treat rectal cancer.
Here are some of the key pieces of research to have been published over recent years across various topic areas.
Short-term vs. long-term radiotherapy as a treatment option in rectal cancer
Previously, neoadjuvant therapy for rectal cancer used long-course chemoradiation as standard, but a number of recently published trials have shown short-term radiotherapy to be a promising alternative.
Current guidelines from NICE do not make a recommendation on the duration or type of radiotherapy or chemotherapy to be used pre-operatively.
During the Stockholm III trial, short-course radiotherapy prior to surgery was shown to produce similar oncological outcomes to long-course radiotherapy. Delaying surgery for 4-8 weeks after short-course radiotherapy was also shown to have some safety advantages. Patients with biopsy-proven resectable adenocarcinoma of the rectum were randomised to one of three arms:
After 2-years, oncological outcomes were similar in the three treatment groups. At the 5-year follow-up, there were no statistically significant differences between the incidence of local recurrence, distant metastases or median overall survival, nor in HRQoL between either the three arms or in a comparison of the two SRT arms.11 |
The Phase III STELLAR trial demonstrated the effectiveness and acceptable toxicity of preoperative chemotherapy followed by surgery, along with short-term radiotherapy, in patients with locally advanced rectal cancer.
Patients with stage 3-4 primary tumour and/or regional lymph node-positive rectal cancer were randomly assigned to:
- Total Neoadjuvant Therapy (TNT) group (n=302): short-term radiotherapy (25 Gy in 5 fractions over 1 week) followed by 4 cycles of chemotherapy
- Chemoradiotherapy (CRT) group (n=297): 50 Gy in 25 fractions over 5 weeks concurrently with capecitabine
There was no significant difference in metastasis-free survival or locoregional recurrence between the treatment groups. The TNT group had better 3-year overall survival (86.5% vs. 75.1%, P=0.033). Acute grade 3-4 toxicities during preoperative treatment were higher in the TNT group vs. the CRT group (26.5% vs. 12.6%, P<0.001).
The RAPIDO Phase III trial2 involved 920 patients with newly diagnosed, primary, locally advanced rectal adenocarcinoma from 54 centres in Europe and the USA. The patients were randomly assigned to either the experimental treatment group or the standard of care group.
- Experimental treatment group
Short-course radiotherapy (5 x 5 Gy over minimum 8 days) followed by chemotherapy (6 cycles of CAPOX chemotherapy or 9 cycles of
FOLFOX4 at physician discretion or hospital policy) and TME (total mesorectal excision)|
- Standard of care group
Standard chemoradiotherapy, TME and optional adjuvant chemotherapy 28 x 1.8 Gy daily up to 50.4 Gy or 25 x 2.0 Gy up to 50.0 Gy with concomitant twice-daily capecitabine 825 mg/m2 followed by TME (and adjuvant chemotherapy of CAPOX or FOLFOX according to hospital policy).
After three years, patients in the experimental group had a significantly lower probability of disease-related treatment failure, mainly due to fewer distant metastases (23.7% vs. 30.4%, P=0.019), and double the pathological complete response rate (28% vs. 14%, P<0.0001) compared to the standard of care group.
However, at the 5-year follow-up, the experimental group had an increased risk of locoregional recurrence (10% vs. 6%, P=0.027).5
Short-course radiotherapy for organ preservation
There has been growing interest in treatment strategies aimed at organ preservation. One such strategy is neoadjuvant chemoradiotherapy, which can lead to a pathological or clinical complete response, offering the possibility of postponing or even avoiding surgery.
Recently, two trials have reported experience of using short-course radiotherapy as an organ preservation strategy in rectal cancer:
During a study of patients with stage I-III rectal adenocarcinoma, short-course radiation therapy was administered (25 Gy in 5 fractions), followed by consolidation chemotherapy.12 43 patients with a clinical complete response (cCR) underwent nonoperative management and 43 patients with a non-clinical complete response underwent surgery.
In the cCR group, 2-year local regrowth-free survival was 81% and all patients with local regrowth were successfully salvaged.
Patients with cCR had improved 2-year regional control, distant metastasis-free survival, disease-free survival and overall survival compared with those with a non-cCR. No late grade 3+ GI or GU toxicities were observed.
In a single-arm prospective study, 19 patients with non-metastatic rectal adenocarcinoma were treated with short-course radiotherapy (25 Gy in 5 fractions) followed by FOLFOX x8 or CAPOX x5 cycles.
The 1-year clinical complete response (cCR) rate was 68%. At median follow-up of 27.7 months, 18 patients were alive with no evidence of disease.
Patients with cCR had improved 2-year disease-free survival, distant metastasis-free survival and overall survival. There were no severe late effects.
MRI-guided radiotherapy for rectal cancer
Dose escalation using MRI guidance offers a potential method of increasing the likelihood of complete response whilst maintaining a favourable toxicity profile.
Experience of treating prostate cancer using MRI-guided radiotherapy provides further rationale for this strategy.
The first clinical experience of MRI-guided radiotherapy for rectal cancer was reported in 2019.
Considered a basis for further investigation into the potential advantages of MRIgRT technology, MRIgRT was found to be a feasible option in the treatment of rectal cancer.
This was due to MRIgRT’s ability to better define the target treatment area, reducing the likelihood of inter- and intra-fractional error.14
Five patients with distal rectal tumours were treated in a feasibility study .
Each patient received 45 Gy in 25 fractions to the mesorectum and internal iliac lymph nodes and a simultaneous integrated boost to the primary tumour of 50 Gy in 25 fractions using a conventional linac. An MR-Linac also delivered weekly response-adaptive boost fractions of 3 Gy per fraction.
Treatment was shown to be well-tolerated, and four patients had a clinical complete response, with quality of life and continence scores comparable to baseline.
While dose escalation has been shown to increase response rate, reducing the PTV planning margins has the potential to lower toxicity.9
A feasibility study explored how daily online adaptation of the clinical target volume (CTV) enabled margin reduction of the PTV.9
43 patients with rectal cancer received 25 Gy in 5 fractions. For 18 patients, margins were reduced. The median in-room time was also recorded as 48 minutes per fraction
Definitions of radiotherapy for rectal cancer
Short-course radiotherapy
A treatment schedule used in rectal cancer where radiotherapy of 25 Gy in 5 fractions is delivered in 1 week.
Long-course radiotherapy
A treatment schedule used in rectal cancer. The typical dose is 45 Gy in 25 fractions, delivered over 5 weeks.
Hypofractionated radiotherapy
A term used to describe radiotherapy where the overall dose is delivered in a smaller number of fractions over a shorter period of time, with a higher fraction per dose. It is used when the dose per fraction is >2 Gy or more. Short-course radiotherapy is a form of hypofractionated radiotherapy.
MRIdian specialists at GenesisCare
At GenesisCare, radiotherapy treatment is delivered by a multidisciplinary team of specialists including clinicians, radiographers and technologists. Our team combine their many years of experience in treating rectal cancer with expertise in all forms of radiotherapy, including MRIdian MRIgRT.
Meet our SABR advisory team
Our SABR reference group is an advisory team of leading NHS clinicians who provide clinical oversight for the SABR service across the GenesisCare network.
The group work to improve patient access to SABR, oversee training and contribute to the evidence base through supporting research, thanks to our academic collaboration with the University of Oxford.
- Glynne-Jones R, Wyrwicz L, Tiret E, et al: Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv263, 2018
- Bahadoer RR, Dijkstra EA, van Etten B, et al: Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 22: 29-42, 2021
- Jin J et al. Multicenter, Randomized, Phase III Trialof Short-Term Radiotherapy Plus ChemotherapyVersus Long-Term Chemoradiotherapy in LocallyAdvanced Rectal Cancer (STELLAR). J Clin Oncol 40, 1681–1692 (1011).
- Conroy T, Bosset JF, Etienne PL, et al: Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 22: 702-715, 2021
- Dijkstra EA, Nilsson PJ, Hospers GAP, et al: Locoregional Failure During and After Short-course Radiotherapy followed by Chemotherapy and Surgery Compared to Long-course Chemoradiotherapy and Surgery - A Five-year Follow-up of the RAPIDO Trial. Ann Surg, 2023
- Brand, D. H. et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol 20, 1531–1543 (2019).
- Kishan, A. U. et al. Magnetic Resonance Imaging–Guided vs Computed Tomography–Guided Stereotactic Body Radiotherapy for Prostate Cancer. JAMA Oncol (2023) doi:10.1001/jamaoncol.2022.6558.
- Boldrini, L., Intven, M., Bassetti, M., Valentini, V. & Gani, C. MR-Guided Radiotherapy for Rectal Cancer: Current Perspective on Organ Preservation. Front Oncol 11, (2021).
- Intven, M. P. W. et al. Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience. Radiotherapy and Oncology 154, 172–178 (2021).
- NICE (National Institute for Health and Care Excellence). Colorectal cancer NICE guideline. www.nice.org.uk/guidance/ng151 (2020).
- Erlandsson, J. et al. Radiotherapy regimens for rectal cancer: long-term outcomes and health-related quality of life in the Stockholm III trial. BJS Open 5, (2021).
- Chin, R. I. et al. Clinical Complete Response in Patients With Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Nonoperative Management. Int J Radiat Oncol Biol Phys 112, 715–725 (2022).
- Kim, H. et al. Nonoperative Rectal Cancer Management With Short-Course Radiation Followed by Chemotherapy: A Nonrandomized Control Trial. Clin Colorectal Cancer 20, e185–e193 (2021).
- Chiloiro, G. et al. MR-guided radiotherapy in rectal cancer: First clinical experience of an innovative technology. Clin Transl Radiat Oncol 18, 80–86 (2019).
- Boeke, S. et al. Online MR guided dose escalated radiotherapy for organ preservation in distal rectal cancer. Clin Transl Radiat Oncol 37, 153–156 (2022).