Rectal adjuvant EBRT chemoradiation post-operative

• Rectal adenocarcinoma
• Patients who have undergone total mesorectal excision (TME) or partial mesorectal excision (PME) for stage T3-4 and/or N1-3, excluding T3N0 with clear margins.
• Other factors favouring adjuvant radiation therapy such as:
  • close/positive (<1 mm)^r circumferential margin (more likely in lower tumours) or disrupted or incomplete mesorectal excision.
• Consider for patients with high risk T1 or T2 rectal adenocarcinoma after endoscopic mucosal resection (EMR) in patients who refuse or are unsuitable for completion TME. High risk features include:^r
  • size >3 cm
  • >pT1
  • Grade 3
  • lymphovascular invasion (LVI) positive
  • margin positive
  • tumour budding
  • lower third submucosa depth of invasion (SM3).
• Suitable for combined therapy.

• ECOG 0-2.

Cautions

• Non-rheumatoid collagen vascular disorders.

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

• Cardiac implantable electronic devices (CIEDs).

Exclusions

• Pregnancy.

• Previous high dose radiation therapy to the same site.

Indications notes

• In patients with T4 tumours, threatened/close/positive margins to the circumferential resection margin (CRM) and in some lower third tumours pre-operative treatment is recommended.^rr

• Pre-operative chemoradiation therapy has been found to have improved locoregional control with reduced acute and late toxicity compared to post-operative radiation therapy.^rr 

• Total neoadjuvant therapy (TNT), which consists of either pre-operative short course radiotherapy or long course chemoradiotherapy, and/or pre-operative chemotherapy alone, is now the recommended approach in patients with higher risk stage II-III rectal cancer.^r

• For rectal cancers with lower edge > 12cm from anal verge or above peritoneal reflection, the role of pre-operative long course chemoradiation therapy is controversial but should still be considered for selected locally advanced tumours.

• If post-operative RT is thought necessary, consider surgical techniques to keep small intestine out of pelvis.^r
• There is variability in the administration of adjuvant treatment. Some departments begin with chemoradiation therapy whilst others proceed to two cycles of chemotherapy prior to commencing chemoradiation therapy. There is evidence to recommend beginning with chemoradiation therapy in patients requiring abdominoperineal resection.^r 
• Radiation therapy ideally should commence 4-6 weeks post-surgery.

• 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

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.^r Bladder, genitalia/perineum, 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

Adjuvant treatment of rectal cancer has been largely superseded by neo-adjuvant therapy (link to eviQ ID 1863: Rectal neoadjuvant EBRT chemoradiation pre-operative long-course protocol).

Evidence to support this protocol predates the widespread adoption of total mesorectal excision (TME), a surgical technique that has significantly reduced locoregional recurrence rates.

In 1985, the landmark GITSG-7175 trial established the rationale for post-operative radiation therapy for rectal cancer.^r It randomised 227 patients to one of four arms (202 completed data collection) following complete surgical resection of Dukes stage B2 and C adenocarcinoma of the rectum:

1. No adjuvant therapy (n=58)
2. Radiation therapy (n=50)
3. Chemotherapy (n=48)
4. Radiation therapy and chemotherapy (n=46)

Median follow up was 6.5 years and 5 year disease free survival was 67% for the chemoradiation therapy arm vs 45% for surgery alone (p=0.0005). Overall survival was not significantly different between groups.

The Norwegian Adjuvant Rectal Cancer Project Group consolidated the results of GITSG-7175 by following 144 patients with Dukes B and C rectal cancer for a minimum of 4 years.^r Participants randomised to surgery alone had significantly higher rates of local recurrence compared with surgery and postoperative chemoradiation therapy using bolus fluorouracil (30% vs 12%, p=0.01). The 5-year recurrence free survival was 46% for surgery alone compared with 64% for surgery and chemoradiation therapy (p=0.01). Overall survival rates at 5 years were 50% for surgery alone and 64% after adjuvant treatment (p=0.05).

Figure 1: Recurrence-free survival and overall survival

© BR J SURG 1997^r

Currently, completion TME is considered standard of care after transanal excision for high risk (poorly differentiated, margin positive or with lymphovascular space invasion) rectal cancer. Adjuvant chemoradiation therapy in these patients should only be considered for patients on a clinical trial, or in those who refuse or are unsuitable for completion TME. The TESAR trial is currently underway to investigate whether adjuvant radiation therapy following EMR is non-inferior to TME in adequately resected intermediate risk T1-2 rectal cancer.^r

Timing of chemoradiation therapy

Variation exists in the sequence of adjuvant radiation therapy and chemotherapy for locally advanced rectal cancer. A study of 308 patients undergoing adjuvant rectal chemoradiation therapy found no difference in disease free survival at 10 years between patients who started radiation on day 1 of cycle 1 of chemotherapy compared with day 1 of cycle 3 of chemotherapy.^r For patients undergoing abdominoperineal resection though, subgroup analysis showed a significant improvement in 10 year disease free survival for the early radiation therapy group (63% vs 40%, p=0.043).^r

Toxicity

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

Figure 2: Grade 3 or 4 toxic effects of chemoradiation therapy, according to actual treatment given

© N Engl J Med 2004^r

Robust toxicity data following transanal excision and adjuvant radiation therapy is lacking. A meta-analysis by Cutting et al., summarises the current studies reported outcomes (Table 5 below).^r However more data is required to assess long term functional and quality of life outcomes.

Figure 3: Adverse events of adjuvant therapy

© Colorectal disease 2018^r