Short-Course Radiation Therapy and the RAPIDO Trial: Too Short, Too Soon?

Since the early 2000s, the standard of care management for patients with locally advanced rectal cancer included either preoperative long-course chemoradiation (LCCRT) or short-course radiation therapy (SCRT) followed by surgery, with the delivery of postoperative chemotherapy based upon clinical and pathologic risk factors. Such an approach was associated with favorable rates of R0 resection and locoregional recurrence (LRR) of approximately 5% to 10%. Multiple trials have compared preoperative LCCRT versus SCRT.1Bujko K Nowacki MP Nasierowska-Guttmejer A Michalski W Bebenek M Kryj M Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.Br J Surg. 2006; 93: 1215-1223Crossref PubMed Scopus (992) Google Scholar,2Ngan SY Burmeister B Fisher RJ et al.Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.J Clin Oncol. 2012; 30: 3827-3833Crossref PubMed Scopus (639) Google Scholar The Trans-Tasman Radiation Oncology Group (TROG) 01.04 trial and the Polish Trial compared 50.4 Gy in 28 fractions with concurrent 5-fluoruracil (5-FU) followed by surgery 4 to 6 weeks later versus 25 Gy in 5 fractions with immediate surgery. Each study demonstrated comparable rates of LRR, disease-free survival, and overall survival for each radiation therapy regimen. Despite favorable pelvic control, the competing risk of distant metastasis by 3 to 5 years has remained approximately 25% to 30%, thus suggesting the need for novel strategies targeted at reducing this risk. One such approach has been to intensify the preoperative regimen with the delivery of total neoadjuvant therapy (TNT) including both radiation therapy and systemic therapy before surgery.3Bahadoer 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. 2021; 22: 29-42Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar,4Conroy 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. 2021; 22: 702-715Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar The RAPIDO Trial included 920 patients with rectal cancer and high-risk features of cT4, extramural venous invasion (EMVI), cN2, compromised mesorectal fascia (MRF), or involved extramesorectal/lateral pelvic lymph nodes and compared preoperative LCCRT with postoperative chemotherapy delivered to 42% at investigator discretion versus a SCRT-TNT regimen of SCRT followed by either 9 cycles of FOLFOX or 6 cycles of capecitabine and oxaliplatin (CAPOX).3Bahadoer 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. 2021; 22: 29-42Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar,5Dijkstra 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 [e-pub ahead of print]. Ann Surg. doi:10.1097/SLA.0000000000005799, accessed April 27, 2023.Google Scholar SCRT-TNT was associated with improvement in pathologic complete response (28% vs 14%) and the primary endpoint of 3-year disease-related treatment failure (DrTF), a composite endpoint of rectal cancer recurrence, treatment-related death, or new colon primary cancer, primarily through a reduction in risk of distant metastasis (20% vs 27%). There was no difference in overall survival, and per the initial report, no difference in locoregional failure (LRF), with 8% versus 6% (P = .12) for the TNT and LCCRT arms, respectively. A recently published 5-year update of the RAPIDO trial evaluated the planned secondary endpoint of LRF, incorporating both early locoregional failure (eLRF) among patients who either did not have surgery or underwent R2 resection (3% of patients) and LRR among those who underwent R0 or R1 resection (97% of patients).5Dijkstra 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 [e-pub ahead of print]. Ann Surg. doi:10.1097/SLA.0000000000005799, accessed April 27, 2023.Google Scholar Amongst the overall cohort as analyzed per intent-to-treat, there was not a significant difference in LRF, with 11.7% versus 8.1% (P = .07) for SCRT-TNT versus LCCRT, respectively. Among the subset of patients who underwent R0 or R1 resection, SCRT-TNT was associated with a higher rate of LRR (10.2% vs 6.1%; P = .027). In addition to treatment allocation (SCRT-TNT vs LCCRT), involved lateral pelvic lymph nodes were also associated with LRR on multivariate analysis. It is not immediately clear why there was more LRR in the SCRT-TNT arm than in the LCCRT arm, which has both statistical and clinical implications. Although LRF among the overall cohort was a planned secondary endpoint, LRR among the R0 or R1 subset was an unplanned post hoc subset analysis. Additionally, there were changes in the study's primary endpoint (from disease-free survival to DrTF) and sample size calculations before completion of accrual, and it is unclear if or how the changes affected the power to evaluate LRR. Finally, some may propose that a 4% difference in LRR is of marginal clinical significance against a backdrop of a lower rate of distant metastasis, equivalent overall survival, significant increase in convenience, and reduced financial toxicity for SCRT-TNT. What could explain the difference in LRR? From a clinical perspective, baseline disease characteristics, including cT4, cN2, involved lateral pelvic lymph nodes, EMVI, involved MRF, and proportion with tumors less than 5 cm from the anal verge, were similar between treatment arms. Most metrics of local tumor response were improved with SCRT-TNT, including “good response” radiographically (80.1% vs 70.1%) and pathologically (93.0% vs 87.3%), factors that were associated with lower LRR (6.8% vs 12% and 6.9% vs 16.9%, respectively). There were no significant differences in type of operation with LAR (48.6% vs 47.5%) and APR (35.0% vs 40.0%) in the SCRT-TNT and LCCRT arms, respectively. However, among those who had LRR, there was both a greater proportion who underwent LAR and a higher proportion of anastomotic recurrence in the SCRT-TNT versus LCCRT arm, suggesting the possibility that the use of sphincter-sparing operations tailored per tumor response may have increased the risk of microscopic residual disease. SCRT-TNT was associated with a higher risk of mesorectum breach than LCCRT (11% vs 6%, P = .022), and among the subset with a breached mesorectum, LRR was more common in the SCRT-TNT group (21% vs 4%, P = .053). These data are consistent with prior studies suggesting that total mesorectal excision (TME) quality is associated with LRR.6Kitz J Fokas E Beissbarth T et al.Association of plane of total mesorectal excision with prognosis of rectal cancer: Secondary analysis of the CAO/ARO/AIO-04 phase 3 randomized clinical trial.JAMA Surg. 2018; 153e181607Crossref PubMed Scopus (73) Google Scholar,7Quirke P Steele R Monson J et al.Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: A prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial.Lancet. 2009; 373: 821-828Abstract Full Text Full Text PDF PubMed Scopus (831) Google Scholar Was this a surgical quality issue unrelated to preoperative intervention, or is it possible that SCRT-TNT with both heightened dose per fraction and a longer interval after SCRT was associated with tissue fibrosis that made surgical resection more challenging, thus increasing the risk of mesorectum breach? The authors also suggest an association between LRR and treatment with 3D conformal radiation therapy (3D-CRT) versus intensity modulated radiation therapy (IMRT). The use of 3D-CRT (68.6% vs 73.7%) and IMRT (31.2% vs 26.3%) was similar between the LCCRT and SCRT-TNT cohorts. Among the subset treated with 3D-CRT, LRR was more common in the SCRT-TNT versus LCCRT cohorts (11.6% vs 6.0%, P = .016). In contrast, among the subset treated with IMRT, LRR rates were similar in each treatment group (6.3% vs 6.2%). Notably, this analysis was performed assuming time-independence with a χ2 analysis rather than with survival methodology. Because the authors made these assumptions and reported sufficient detail of patient characteristics to reconstruct a limited data set, we performed additional exploratory multivariate logistic regression analyses to assess the association between treatment allocation and radiation therapy technique (3D-CRT vs IMRT) with LRR. Our exploratory analysis suggested that SCRT-TNT was associated with LRR (odds ratio, 1.73; 95% CI, 1.05-2.87; P = .033). However, in contrast to the published χ2 analysis, the use of 3D-CRT was not associated with LRR (odds ratio, 1.43; 95% CI, 0.79-2.59; P = .238), nor was there a significant interaction between treatment cohort and radiation therapy technique (P = .264). The authors’ findings, however, do call for additional consideration. At first glance, a geographic miss or increased risk of marginal recurrence may be more likely with IMRT versus 3DCRT, as IMRT requires careful target delineation and planning, as it delivers radiation more conformally to the target. The study finds the opposite, however, with patients who underwent 3D-CRT having significantly higher rates of LRR, and, in particular, anastomotic recurrence centrally in the target. If the premise that radiation therapy technique is correlated with LRR is accepted, one possible explanation may have been the use of fixed anatomic landmarks for 3D-CRT planning, increasing the risk of a geographic miss. Could varying practices of image guidance also have contributed? Further radiation therapy quality analysis is needed to help clarify this finding. Although the authors offer several hypotheses for the higher LRR in the SCRT-TNT arm, one possibility not explicitly discussed is the lower radiation dose used with SCRT. Using an alpha/beta ratio of 10 Gy for tumor, the biologically effective dose of SCRT is 37.5 Gy, more than 20% lower than that of long-course chemoradiation (50 Gy). Could the lower dose have translated into more LRR despite a higher rate of pathologic complete response? Critics of this explanation would point to the pre-TNT era randomized studies comparing LCCRT versus SCRT that showed no difference in LRR between the 2 strategies.1Bujko K Nowacki MP Nasierowska-Guttmejer A Michalski W Bebenek M Kryj M Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.Br J Surg. 2006; 93: 1215-1223Crossref PubMed Scopus (992) Google Scholar,2Ngan SY Burmeister B Fisher RJ et al.Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.J Clin Oncol. 2012; 30: 3827-3833Crossref PubMed Scopus (639) Google Scholar However, in looking at the details of the Polish and TROG trials, there did appear to be local endpoints that were worse with SCRT. In the Polish trial, the SCRT group had higher rates of R1 resection (13% vs 4%), nonreversed stomas (20% vs 11%), and late stoma creation due to worse anorectal function or morbidity (9% vs 4%) compared with LCCRT. In the TROG study, a subgroup analysis showed higher rates of LRR for distal tumors with SCRT (13% vs 3%). Although these were unplanned subset analyses that were not statistically significant, they raise a concern for a potential detriment with SCRT that could potentially be detected in a larger sample size and/or a higher risk rectal cancer subgroup. With that background in mind, the RAPIDO trial, with close to 1000 patients (3 times the number included in the POLISH and TROG trials) each with high-risk disease, further supports the signals of worse LRR rates associated with SCRT in select patient subsets, acknowledging that it is not possible to uncouple the possible effect of SCRT from that of a TNT approach. Should this update to the RAPIDO trial lead to refinement of patient selection for SCRT in the context of TNT? Acknowledging that DrTF was lower in the SCRT-TNT group, even after accounting for LRR, and with multiple trials that predated the TNT era showing similar rates of LRR between SCRT and LCCRT, we cannot be sure that use of LCCRT would have reduced the LRR rate in the RAPIDO TNT arm.1Bujko K Nowacki MP Nasierowska-Guttmejer A Michalski W Bebenek M Kryj M Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer.Br J Surg. 2006; 93: 1215-1223Crossref PubMed Scopus (992) Google Scholar,2Ngan SY Burmeister B Fisher RJ et al.Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04.J Clin Oncol. 2012; 30: 3827-3833Crossref PubMed Scopus (639) Google Scholar As our field moves toward a greater use of risk stratification for neoadjuvant therapy choice, including possible omission of radiation therapy for patients with low-risk features per MRI, SCRT remains an important consideration. We encourage practitioners to consider multiple risk factors in assessing LRR (presence of T4 disease, threatened MRF, lateral or extramesorectal lymph nodes, low tumor <5 cm from anal verge) when deciding between SCRT and LCCRT.8Battersby NJ How P Moran B et al.Prospective validation of a low rectal cancer magnetic resonance imaging staging system and development of a local recurrence risk stratification model: The MERCURY II study.Ann Surg. 2016; 263: 751-760Crossref PubMed Scopus (216) Google Scholar, 9Bhoday J Balyasnikova S Wale A Brown G How should imaging direct/orient management of rectal cancer?.Clin Colon Rectal Surg. 2017; 30: 297-312Crossref PubMed Scopus (26) Google Scholar, 10Lord AC Corr A Chandramohan A et al.Assessment of the 2020 NICE criteria for preoperative radiotherapy in patients with rectal cancer treated by surgery alone in comparison with proven MRI prognostic factors: A retrospective cohort study.Lancet Oncol. 2022; 23: 793-801Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 11Ruppert R Junginger T Ptok H et al.Oncological outcome after MRI-based selection for neoadjuvant chemoradiotherapy in the OCUM Rectal Cancer Trial.Br J Surg. 2018; 105: 1519-1529Crossref PubMed Scopus (65) Google Scholar, 12Siddiqui MRS Simillis C Hunter C et al.A meta-analysis comparing the risk of metastases in patients with rectal cancer and MRI-detected extramural vascular invasion (mrEMVI) versus mrEMVI-negative cases.Br J Cancer. 2017; 116: 1513-1519Crossref PubMed Scopus (93) Google Scholar One such strategy for total neoadjuvant therapy that balances risk factors for local versus distant recurrence that is in use at the University of Colorado is shown in Table 1, with other risk-adapted strategies having recently been proposed.13Bedrikovetski S, Traeger L, Fitzsimmons T, et al. Personalized total neoadjuvant therapy versus chemotherapy during the 'wait period' versus standard chemoradiotherapy for locally advanced rectal cancer. ANZ J Surg. doi:10.1111/ans.18229, accessed April 27, 2023.Google Scholar,14Hui C Vitzthum LK Chang DT Pollom EL Neoadjuvant therapy in the post-German rectal trial era: Making sense in the absence of consensus.Pract Radiat Oncol. 2023; 13: e54-e60Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Given the results of the RAPIDO trial, for patients with high-risk features for LRR, LCCRT may be preferred.Table 1Risk-adapted total neoadjuvant therapy approach for patients with cT3+ or N+ rectal cancer per the University of ColoradoLocal risk features*Local risk features: T4, extramural venous invasion, mesorectal fascia threatened, <5 cm from anal verge, extramesorectal or lateral pelvic lymph nodes. presentDistant risk features†Local risk features: T4, extramural venous invasion, mesorectal fascia threatened, <5 cm from anal verge, extramesorectal or lateral pelvic lymph nodes. presentWatch-and-wait motivatedTreatmentAnyYesAnySCRT → chemotherapyYesNoAnyLCCRT → chemotherapyNoNoYesLCCRT → chemotherapyNoNoNoSCRT → chemotherapyAbbreviations: LCCRT = long-course chemoradiation; SCRT = short-course radiation therapy. Local risk features: T4, extramural venous invasion, mesorectal fascia threatened, <5 cm from anal verge, extramesorectal or lateral pelvic lymph nodes.† Local risk features: T4, extramural venous invasion, mesorectal fascia threatened, <5 cm from anal verge, extramesorectal or lateral pelvic lymph nodes. Open table in a new tab Abbreviations: LCCRT = long-course chemoradiation; SCRT = short-course radiation therapy. Finally, it is important to delineate at the treatment outset if the goal is watch and wait (W&W); W&W was not addressed by RAPIDO, which evaluated TNT with operative management. For patients under consideration for W&W, a greater volume of evidence currently exists for LCCRT, with SCRT not yet having been directly compared with LCCRT in this setting. It is hoped that the currently accruing ACO/ARO/AIO-18 trial, which randomizes patients to TNT regimens of SCRT versus LCCRT followed by chemotherapy, will bring much needed clarity to this decision.