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 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 German CAO/ARO/AIO-949 trial, NSABP R-03 and Korean RCT.rr The equivalence of LC-CRT and 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.rrr
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 (LR) and distant (DR) recurrence.
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), distant recurrence (10-year DR 29.8% vs 29.6%), or disease-free survival (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 2012r
The 2017 meta-analysis by Song et al included 1,273 patients across three randomised controlled trials comparing pre-operative and post-operative CRT.r Pre-operative CRT was found to improve locoregional control (HR 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.
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 local recurrence (14.2% vs 9% p = 0.17).r
Total neoadjuvant therapy
There is emerging 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 (C)RT 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 with FOLFOX or CAPOX before or after pre-op LC-CRT or SCRT has been included in the recently updated NCCN guidelines for management of rectal cancer.r
Earlier studies have demonstrated feasibility of the TNT approach, as well as increased pathologic complete response (pCR) rates over SOC. Three abstracts presented at ASCO 2020 supported the use (or at least further study) of TNT; the now published ‘RAPIDO’ phase III RCT 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 TNT consisting of SCRT followed by chemotherapy (CAPOX 6x, FOLFOX 9x) vs SOC.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. 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%. The OPRA phase II RCT did not prove its primary endpoint of a 10% improvement in 3-year DFS of TNT over SOC, but did demonstrate rates of organ preservation (non-operative management) following TNT of 43-59%, far higher than historical controls.r
Given the recency of this evidence for TNT and the uncertainties in patient selection and specifics of TNT protocol (e.g. choice of chemotherapy agent, SCRT vs LC-CRT, and sequencing of modalities), it has not been incorporated into the current protocol. It is anticipated that this area will become more well-defined in the next update. Based on the current available evidence, it is already reasonable to employ this approach in select patients after appropriate multidisciplinary team (MDT) discussion.
Timing of surgery post-chemoradiation therapy
The optimal timing of surgery following neoadjuvant CRT is not well defined. Longer intervals to surgery beyond the standard 6-8 weeks can result in high rates of pCR, but may also result in increased post-operative morbidity and more difficult surgical resection and no difference in LC/DFS/OS.rrrrr
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.rrrrrr 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.