Rectal neoadjuvant EBRT chemoradiation pre-operative long-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
• Long course neoadjuvant chemoradiation therapy (CRT) is generally given as part of a total neoadjuvant therapy (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 high dose radiation therapy to the same site.

• 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.

• Where surgery is planned, it should be performed within 6-12 weeks after LC-CRT is completed. Higher pathological complete response (pCR) and ‘tumour downstaging’ is achieved with intervals longer than the ‘standard’ 6 weeks taken from the seminal German CAO/ARO-AIO-94 trial, however they have not been shown to translate into better oncologic outcomes.^rr

• 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.

OR

Prescription notes

• Multiple planning studies demonstrate improved conformality and significantly reduced doses to organs at risk using IMRT or VMAT vs 3DCRT. The evidence for improved dosimetry translating to clinical outcomes is more variable; two prospective phase 2 RTOG studies of IMRT for lower GI cancers (0529 and 0822) failed to achieve their primary endpoints of reduced grade 2+ acute gastrointestinal (+/- genitourinary) toxicity, while a meta-analysis of retrospective data showed major improvements in these same measures.^rrr The ASTRO 2021 clinical practice guideline issued a conditional recommendation for IMRT/VMAT with appropriate daily image guidance, acknowledging these techniques are less robust to daily variations in setup.^r

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

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

• Constraints are for plan optimisation rather than strict constraints and target coverage is generally prioritised.^r Bladder, and femoral head/neck constraints may be difficult to achieve. 

Suggested OAR contouring atlases and guidelines

• National rectal cancer intensity-modulated radiation therapy (IMRT) guidance^r:
  • Link to guideline
• Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas.^r
• Suggested article: Clinical Target Volume Delineation for Rectal Cancer Radiation Therapy: Time for Updated Guidelines?^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 number of trials demonstrating local control and disease specific mortality improvement with pre/post-operative chemo-radiation therapy (CRT) as summarised in the CCCG meta-analysis.^r Superiority of pre-operative vs post-operative chemoradiation therapy is demonstrated in three phase III trials: the NSABP R-03, German CAO/ARO/AIO-949 trial, and Korean RCT.^rrr The equivalence of long-course CRT LC-CRT and short-course radiation therapy (SCRT) for local control, disease-free survival (DFS), and overall survival (OS) is demonstrated in the Australian TROG 01.04 and two Polish randomised control trial's (RCT's), as well as a meta-analysis of the wider literature.^rrrr

Pre-operative chemoradiation therapy vs post-operative chemoradiation therapy

The German CAO/ARO/AIO-94 trial was a multicentre phase III randomised trial involving 823 patients comparing pre-operative chemoradiation therapy (CRT) with post-operative CRT in patients with stage II to III rectal cancer.^r In this study 421 patients were randomised to receive pre-operative CRT (with surgery completed 6 weeks after CRT) and 402 patients were randomised to post-operative CRT. In both arms patients received CRT of 50.4 Gy in 28 fractions, 5 days per week, a 120-hour fluorouracil infusion on weeks 1 and 5 and one month after surgery patients received four 5-day cycles of fluorouracil. In the post-operative treatment group patients also received a 5.4 Gy boost to the tumour bed. Primary endpoint was OS and the secondary endpoints included DFS and cumulative incidences of local recurrence (LR) and distant recurrence (DR).

Pre-operative CRT improved local control compared to post-operative CRT (10-year cumulative incidence of LR 7.1% vs 10.1%) with reduced rates of acute toxicity. There was no difference in OS (10-year OS 59.6% vs 59.9%, p = 0.85), DR (10-year DR 29.8% vs 29.6%), or DFS (10-year DFS 68.1% vs 67.8%). An early publication reported a statistically significant improvement in sphincter preservation rate for patients requiring abdominoperineal excision in the pre-operative CRT arm, compared to the post-operative CRT arm (39% vs 19% p = 0.0004​).^r

Figure 1: Cumulative incidence of LR among the 799 patients randomly assigned to pre-operative or post-operative CRT, according to an intention-to-treat analysis.

© JCO 2012^r

The 2017 meta-analysis by Song et al included 1,273 patients across three RCT's comparing pre-operative and post-operative CRT.^r Pre-operative CRT was found to improve locoregional control (Hazard Ratio = 0.59) with reduced acute toxicity and higher conversion from abdominoperineal resection (APR) to low anterior resection. No significant differences were observed in OS, relapse free survival, distant recurrence rates, sphincter preservation rates and chronic toxicity.^r

Although the German trial established the standard for pre-operative CRT in rectal carcinomas, the chemotherapy regimen used in that trial has been largely replaced by oral capecitabine, which has demonstrated non-inferior (if not superior) oncologic outcomes. Link to ID 73 Rectal locally advanced fluorouracil (protracted infusion) chemoradiation and ID 84 Rectal locally advanced capecitabine chemoradiation.

Long-course vs 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 long-course chemoradiation therapy (LC-CRT) and short-course radiation therapy (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% SCRT vs 30% LC-CRT) or 5-year OS (74% SCRT vs 70% LC-CRT). 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 (157) vs SCRT (155), Bjuko et al. reported no significant difference in sphincter preservation rates, (58% vs 61% p = 0.57), 4-year OS, DFS or LR (14.2% vs 9% p = 0.17).^r

More recent evidence drawing comparisons between short and long-course radiotherapy 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 ‘downstaging’ 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 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 T3/4 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 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 local recurrence rates (LRR). The cause is unclear and is likened to the Polish II trial initial OS benefit data.^r

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. 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 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.

Toxicity

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