Rectal neoadjuvant EBRT pre-operative short-course

• Rectal adenocarcinoma.
• Lower edge of the tumour within 12 cm of anal verge/at or below the peritoneal reflection.
• MRI stage T3-4 and/or N1-2.
• Consider for full thickness low T2 lesions where R0 resectability or sphincter preservation is in doubt.
• Medically fit for combined therapy.
• Short-course neoadjuvant radiation therapy is generally given as part of a total neoadjuvant treatment (TNT) protocol, for patients deemed fit enough.

• ECOG 0-2.

Cautions

• Non-rheumatoid collagen vascular disorders.

• Inflammatory bowel disease and/or history of adhesions/bowel obstruction.

• Previous radiation therapy to the region of interest.

• Cardiac implantable electronic devices (CIEDs).

Exclusions

• Pregnancy.

Indications notes

• Consider omitting neoadjuvant therapy in select MRI 'good prognosis' T3a-b N0 tumours.^rr
• Traditionally, long-course chemoradiation therapy (LC-CRT) has been preferred over short-course radiation therapy (SCRT) in patients with locally advanced tumours whereby ‘downstaging’ is required to minimise the chance of a positive circumferential resection margin or maximise sphincter preservation.^r rrr This is likely to apply in the setting of TNT.
• In patients who would benefit from adjuvant therapy, it is preferred to administer chemoradiation therapy (CRT) in the pre-operative setting, given the proven improvement in locoregional control, sphincter preservation, and reduced acute and late toxicity compared to post-operative CRT.^rrrrr
• For rectal cancers with lower edge >12 cm from anal verge or above peritoneal reflection (‘high rectum’) where local recurrence rates are far lower, the role of pre-operative LC-CRT is controversial.^rrr It may be considered for selected locally advanced tumours where pelvic recurrence is a concern and neoadjuvant therapy is tolerable. The NSABP, MRC, Swedish, and Dutch trials all included rectal cancers up to 15 cm from the anal verge.^rrrr
• The use of a TNT approach with either SCRT or LC-CRT is favoured in those with mid-to-low rectal disease (T3/4, N0-2) and/or threatened margins. This preference is based on emerging evidence suggesting improved outcomes, including disease-free survival (DFS), reduced distant metastases (DM), and a higher potential for organ preservation in patients demonstrating a good response.^r
• The selection of radiation therapy regimen and its sequencing with systemic treatment should be tailored to individual risk factors, determined through a comprehensive multidisciplinary patient assessment.

• Timing of surgery should be at the discretion of the surgical team.
• Surgery can either be planned immediately (within 10 days of commencing radiation therapy) or delayed 4-8 weeks, with caution.^rrrr

• If a patient has severe obstructive symptoms, fistula or severe incontinence, they should be considered for a defunctioning stoma prior to starting radiation therapy.

• Consider genetic counselling and germline testing when appropriate.

• Anxiety and depression are common in patients with cancer. A referral to a psychosocial practitioner should be considered.

• Current smokers should be referred to a smoking cessation program.

Margin ranges have been agreed by the Radiation Oncology reference committee and reflect safe clinical practice.

Target volume notes

• Caution should be exercised using short-course radiation therapy when external iliac or inguinal nodal volumes need to be encompassed as there is a lack of data regarding toxicity in this setting.

Target volume guides

• International consensus guideline on CTV delineation in rectal cancer^r:
  • Link to guideline
  • Link to atlas
• National rectal cancer intensity-modulated radiation therapy (IMRT) guidance^r:
  • Link to guideline

OAR notes

• Minimal published guidelines or clinical trial protocols containing OAR constraints for short-course IMRT/VMAT exist. The above constraints are taken from the UK IMRT guidance document, in turn based on an in-house single institution protocol.^r
• It is reasonable to endeavour to treat as small a volume of small bowel as necessary to ensure adequate coverage of the PTVs.
• For tumours 6 cm or higher from the anal verge, efforts should be made to spare the anal canal as faecal incontinence is a well-recognised late toxicity of radiation therapy.^r

Suggested OAR contouring atlases and guidelines

• Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas.^r
• National rectal cancer intensity-modulated radiotherapy (IMRT) guidance^r

Target verification recommendations reflect the minimum imaging required for the safe delivery of this protocol.

Efficacy

The key evidence supporting the use of this protocol comes from a large number of trials demonstrating local control and disease specific mortality improvement with pre/post-operative (chemo-) radiation therapy vs surgery alone as summarised in the CCCG meta-analysis.^r The most notable of these studies demonstrating the benefit of adding pre-operative short-course radiation therapy to surgery are the MRC-CR07, Swedish, and Dutch total mesorectal excision (TME) studies.^rrr Superiority of pre-operative vs post-operative chemoradiation therapy is demonstrated in three phase III trials: the NSABP R-03, German CAO/ARO/AIO-94, and Korean randomised controlled trials (RCTs).^rrr The equivalence of long-course chemoradiation therapy (LC-CRT) and short-course RT (SCRT) for local control, disease-free survival (DFS), and overall survival (OS) is demonstrated in the Australian TROG 01.04 and two Polish RCTs, as well as a meta-analysis of the wider literature.^rrrr

Neoadjuvant short-course versus surgery alone

The Dutch Colorectal Cancer Group trial randomised 1,861 patients with resectable rectal cancer (tumours not further than 15 cm from the anal verge and below the level of S1-2) to receive either pre-operative radiation therapy (25 Gy in 5 fractions) followed by TME (n = 924) or TME alone (n = 937).^r 85 patients received post-operative radiation therapy. Locoregional recurrence was lower at 10 years with the addition of pre-operative radiation therapy (11 vs 5%, p<0.0001), but this did not translate to a difference in OS. Survival at 10 years was improved by SCRT in a subgroup of patients with negative circumferential resection margin and stage III disease (50 vs 40%, p = 0.032).

Figure 1: Local recurrence in the 1,748 eligible patients who underwent a macroscopically complete local resection.

RT = radiation therapy, TME = total mesorectal excision.

© Lancet Oncol 2011^r

The MRC CR-07 trial randomised 1350 patients to preoperative SCRT (25 Gy in 5 fractions) or selective-postoperative LC-CRT in patients with positive margins (45 Gy in 25 fractions with concurrent fluorouracil).^r TME was performed in 92% of patients. 53 patients received postoperative chemoradiation therapy and 7 received postoperative radiation therapy only. Pre-operative SCRT reduced 3-year local relapse rate (4.4% vs 10.6%, p<0.0001), 3-year DFS but did not lead to an OS benefit.

Long-course versus short-course pre-operative chemoradiation therapy

The Australian TROG 01.04 trial was a phase III multicentre randomised trial involving 326 patients comparing pre-operative LC-CRT and SCRT in patients with T3 rectal cancers.^r Between 2001 and 2006, 163 patients were randomised to LC-CRT (50.4 Gy in 28 fractions, 5 days per week, with continuous infusion fluorouracil, surgery was completed 4-6 weeks after CRT), and 163 patients were randomised to SCRT (25 Gy in 5 fractions, 5 days per week, with surgery 3-7 days later). Surgery was followed by six 28 day cycles of adjuvant fluorouracil and folinic acid given daily for 5 days, starting 4-6 weeks after surgery. There were no differences in the primary outcome of 3-year LR (4.4% vs 7.5% p = 0.24), or 5-year DR (27% SC vs 30% LC) or 5-year OS (74% SC vs 70% LC). There was a numerical increase in local recurrences for distal tumours that did not reach statistical significance; 6/48 SCRT patients and 1/31 LC-CRT patients (p = 0.21).

In a similar Polish RCT of LC-CRT (n = 157) vs SCRT (n = 155), Bujko et al reported no significant difference in sphincter preservation rates (58% vs 61%, p = 0.57), 4-year OS, DFS or local recurrence (14.2% vs 9.0%, p = 0.17).^r

More recent evidence drawing comparisons between short and long-course RT is in the setting of total neoadjuvant treatment and have compelled considerable changes in practice’.

Total neoadjuvant therapy

There is a growing body of evidence that select patients with locally advanced rectal cancer may benefit from upfront total neoadjuvant therapy (TNT), rather than standard of care (SOC) pre-operative CRT followed by surgery and adjuvant chemotherapy. The rationale for this approach includes earlier treatment of micro-metastatic disease, maximising ‘down-staging’ and resectability (and perhaps the chance of non-operative management), administering chemotherapy in the pre-operative setting when it is better tolerated, and perhaps reducing the time with a stoma. Total neoadjuvant therapy before or after pre-op LC-CRT or SCRT has been included in the recently updated NCCN guidelines for management of rectal cancer.^r 

TNT vs standard of care long or short course radiation therapy

Several recently randomised phase III trials have compared TNT to standard of care pre-operative CRT for T/4 or N1-2 (locally advanced) rectal cancer. These include the PRODIGE-23, RAPIDO, and STELLAR trials.^rrr Earlier phase II studies have demonstrated feasibility of the TNT approach, as well as increased pathologic complete response (pCR) rates over SOC. In general, phase III RCT's have reinforced favourable outcomes with TNT approach, including non-inferiority or improvements in pCR, DFS, distant metastases and OS. These findings are supported by recent systematic reviews and meta-analyses demonstrating higher pCR with TNT.^rr There also appears to be improved compliance with neoadjuvant chemotherapy while it remains as safe as adjuvant chemotherapy.

The PRODIGE 23 phase III RCT assessed the efficacy of mFOLFIRINOX x6 followed by LC-CRT, TME, +/- adjuvant chemotherapy vs SOC.^r Despite a different TNT regimen to RAPIDO, it demonstrated similar 7% absolute improvements in 3-year DFS (75.7% vs 68.5%) and 3-year metastasis free survival (MFS) (78.8% vs 71.7%) and doubling of pCR to roughly 28%. Updated 7-year results were presented as an abstract at ASCO 2023 and have seen these trends maintained, including an absolute OS benefit at 7 years of 81.9% (TNT) vs 76.1% (CRT).^r

The RAPIDO phase III RCT randomised 912 patients with high-risk, locally advanced disease to SOC pre-operative treatment with LC-CRT followed by TME with optional adjuvant CAPOX/FOLFOX administered (given in 59% of cases) vs SCRT (25 Gy/5#) followed by CAPOX/FOLFOX prior to Total mesorectal excision (TME); 6-10 weeks following. At 3 years the experimental arm demonstrated decreased 3 year disease-related treatment failure (23.7% vs 30.4%, p = 0.019) distant metastases (20% vs 26.8%), and higher pCR (28% vs 14%), with similar OS for both arms.^r Updated 5-year data shows higher locoregional failure and locoregional recurrence rates amongst the experimental group vs SOC (12 vs 8%, p=0.07 and 10 vs 6%, p= 0.03).^r The 3 year results showed improved pathological complete response (pCR) with TNT, thus suggesting pCR is not necessarily a surrogate for local recurrence rates (LRR).^r However, there has been sustained significant reductions in disease-related treatment failure (DrTF) and DM at 5 years in the experimental group vs standard arm, and no difference seen in overall survival.^r There was no unexpected toxicity, and no differences in rates of R0 resection or close circumferential resection margin, post-operative complications or quality of life. Interpretation is limited by the optional nature of chemotherapy in this trial and consideration should be given to the advanced disease.

The STELLAR III non-inferiority RCT evaluated DFS in 599 patients with locally advanced rectal cancer (cT3-4, N+) comparing neoadjuvant TNT consisting of SCRT (25 Gy/5#) followed by CAPOX (x4), TME and CAPOX (x2) versus conventional LC-CRT followed by TME and CAPOX (x6).^r The TNT arm was non-inferior for DFS at 3 year follow up (65% vs 62%, p<0.001). Total pCR and sustained clinical complete response (cCR) was higher in the TNT arm vs LC-CRT (21.8% vs 12.3%, p=0.002). OS at 3 years (as a secondary endpoint, thus not powered to show this) was significantly higher in the TNT arm (87% vs 75%, p=0.033), despite no difference observed in 3 year outcomes for metastasis-free survival (MFS) or LRR. The cause is unclear and is likened to the Polish II trial initial OS benefit data.

Figure 2: Pathologic complete response with total neoadjuvant therapy versus standard chemoradiation.

© Ann Surg 2020^r

Induction vs. consolidation chemotherapy

The phase II OPRA trial evaluated organ preservation rates with chemotherapy before or after LC-CRT to SOC (LC-CRT alone) based on tumour response.^r Results suggest that initiating treatment with CRT may improve TME free survival (non-operative management). Recent 5-year follow-up data has seen this trend maintained (3 years = 41% vs 53%, 5 year = 39% vs 54%).^r CAO/ARO/AIO-12 a phase II trial, demonstrated higher pCR rates (17% vs 25%) in patients treated with LC-CRT followed by FOLFOX as opposed to FOLFOX followed by LC-CRT prior to surgery.^r In contrast to OPRA, nonoperative management was not included in the study protocol. There was no significant difference in 3 year oncological outcomes (DFS, LRR, DM), toxicity, quality of life or incontinence detected, though the study was not powered to detect these.^r

Non-operative management ("Watch and wait")

For patients who achieve a clinical complete response to neoadjuvant CRT, there are a number of observational studies suggesting a "watch and wait" strategy is a feasible option, although non-operative management is not yet considered standard of care given the lack of data to show that long-term oncological outcomes are equivalent to the traditional approach involving primary surgery. Importantly these studies have not assessed short course radiation therapy in this setting. Given the absence of level I or II evidence, this approach should currently be reserved for selected patients who express a particular preference to avoid surgery, have had a careful discussion with the MDT as to their risk tolerance, and are preferably managed in the context of a protocolised setting.^r It should be accompanied by a robust surveillance program, including rectal MRI, CT abdomen/pelvis, and proctoscopy/sigmoidoscopy to permit early salvage of local tumour regrowth.^rrrrrrr Ongoing trials will assist in identifying a subgroup of patients in whom this strategy is most appropriate, as well as more definitely compare oncologic outcomes with a "watch and wait" approach versus standard surgical management. If a watch and wait approach is recommended, consider enrolling the patient in a clinical trial.

Omission of RT

There is emerging evidence to support that neoadjuvant chemotherapy alone may be effective in treating subpopulations with low to intermediate risk locally advanced rectal cancer (LARC), excluding those with T4, N2, <5 cm from anal verge, <3 mm radial margin and requiring APR. The randomised, phase III PROSPECT non-inferiority trial compared standard pre-operative LC-CRT followed by TME vs selective FOLFOX x6 followed by response assessment.^r Those patients with significant (at least 20%) tumour response proceeded to TME with omission of RT. Both arms involved adjuvant chemotherapy. Results were non-inferior, however neither approach is presently preferred with significant toxicities and adverse QoL data associated with both arms. The multi-institutional phase III Chinese FOWARC trial demonstrated neoadjuvant FOLFOX alone yielded lower pathological complete response than regimens that included RT or LC-CRT.^r There were no significant differences in 10-year survival outcomes (DFS, OS) between mFOLFOX with or without radiation, or with TNT (FOLFOX + CRT) vs CRT. The eviQ reference committee panel maintains caution towards recommending omission of RT as a standard approach given escalated systemic treatment and the associated potential toxicities versus the tolerability of RT. Again, these studies have not assessed short course radiation therapy in this setting.

Timing of surgery

Timing of surgery should be at the discretion of the surgical team. Surgery can either be planned immediately (within 10 days of commencing RT) or delayed 4-8 weeks to potentially facilitate downstaging and reduce post operative complications, however should be used with caution given the more recent evidence as summarised below.^rrrr

The Stockholm III trial randomised patients to immediate surgery (within a week after SCRT) or delayed surgery (4-8 weeks after SCRT or LC-CRT).^r Local control was non-inferior with the longer interval to surgery and there were also no significant differences in distant metastases or OS. Acute radiation induced toxicity was recorded in 1 (< 1%) of patients in the immediate surgery group and 23 (7%) in the delayed surgery arm. In a pooled analysis of the two short-course radiation therapy regimens, the risk of post-operative complications was significantly lower after short-course radiation therapy with delay to surgery (53% vs 41%, OR 0.61, p = 0.001).^r

A study by Pach et al. involved 154 patients randomly assigned to either a short interval (7–10 days) or a long interval (4–5 weeks) between RT and surgery.^r Over a 10-year follow-up, the cumulative incidence of local recurrence was significantly lower in the short interval group (1.3%) compared to the long interval group (11.7%), while the incidence of systemic relapse was higher in the short interval group (14.3% vs 9.1%). Overall, 10-year survival rates were similar between the groups (58% vs 61%). However, patients who experienced downstaging after RT had significantly better 10-year survival rates. The study concludes that while delayed surgery increases the risk of local relapse, it does not affect overall survival compared to immediate surgery.^r

SCRT with 4-8 week delay to surgery is an alternative to immediate surgery, and can have benefits in reducing surgical morbidity or for logistical considerations. It must be balanced between the possible detrimental effect of increasing locoregional recurrence^r and delaying the time to adjuvant chemotherapy (and therefore treatment of micrometastatic disease in high-risk patients). 

Toxicity

Acute and late toxicities in the pre-operative short-course radiation therapy arm of the Australian TROG 01.04 trial.

A summary of the most clinically significant toxicities associated with this protocol are included in the table below.