Previously reported findings from a multicentre, randomised, open-label, phase III, UNICANCER-PRODIGE 23 study demonstrated improved disease-free survival (DFS) and metastatic-free survival (MFS) with total neoadjuvant therapy versus standard-of-care in patients with locally advanced rectal adenocarcinoma. In a long-term follow-up analysis of this study, neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved overall survival (OS) and confirmed long-term DFS and MFS benefits.
Neoadjuvant chemotherapy with mFOLFIRINOX should now be considered as one of the best option of care for patients with rectal cancer according to Prof. Thierry Conroy of the Department of medical oncology, Institut de cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France and colleagues, who published the findings on 7 July 2024 in the Annals of Oncology.
The authors wrote in the background that in Europe, the standard-of-care for the treatment of locally advanced rectal cancer consists in a multidisciplinary approach with preoperative chemoradiotherapy followed by surgery and adjuvant chemotherapy resulting in an excellent local disease control; however, metastasis rates remain high.
To overcome distant recurrences, the total neoadjuvant therapy that includes courses of chemotherapy and chemoradiotherapy given as neoadjuvant before surgery, has been tested in phase II and III studies. This approach has demonstrated benefits including the early treatment of micrometastases, higher rate of pathologic complete response, and longer DFS together with facilitating resection, and improving chemotherapy tolerance, compliance to chemotherapy, and organ preservation.
In the UNICANCER-PRODIGE 23 study, patients treated with neoadjuvant mFOLFIRINOX had a 31% reduction in the relative risk of disease recurrence based on a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.49-0.97; p = 0.034) for 3-year DFS. The study also demonstrated a significant improvement of MFS for patients treated with neoadjuvant mFOLFIRINOX.
Furthermore, compliance to adjuvant chemotherapy was increased. Grade >3 adverse events occurred in 46% of patients during neoadjuvant chemotherapy, but grade >3 adverse events rate significantly decreased in the neoadjuvant group during adjuvant chemotherapy compared with the standard-of-care. In addition, the neoadjuvant chemotherapy improved tumour-related symptoms associated with a transitory reduction of most functional scores.
The primary endpoint in the UNICANCER-PRODIGE 23 study was DFS. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate. At the time of the first analysis, OS data were not mature. In the latest article, published in the Annals of Oncology, the study team reports the long-term follow-up analysis of the UNICANCER-PRODIGE 23 study, including OS results.
This multicentre, randomised, open-label, phase III study investigated the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on MRI, and staged cT3/T4.
With a median follow-up of 82.2 months, the 7-year DFS were 67.6% (95% CI 60.7%-73.9%) and 62.5% (95% CI 55.6%-68.6%) with restricted mean survival time (RMST) difference of 5.73 months (95% CI 0.05-11.41; p = 0.048) in the neoadjuvant chemotherapy and the standard-of-care groups.
The 7-year MFS was 79.2% (95% CI 73.0%-84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8%-77.8%) in the standard-of-care group with RMST difference of 6.1 months (95% CI 0.93-11.37; p = 0.021). The 7-year OS was 81.9% (95% CI 75.8%-86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7-81.2) in the standard-of-care group with RMST difference of 4.37 months (95% CI 0.35-8.38; p = 0.033).
The safety profile remained unchanged since the previous analysis. The UNICANCER-PRODIGE 23 demonstrated an interesting safety profile of 3 months induction chemotherapy with mFOLFIRINOX showing acceptable occurrence of grade 3-4 adverse events including neutropenia and diarrhoea, decreased postoperative mortality, decreased neurotoxicity, and good compliance to adjuvant chemotherapy.
Furthermore, the study demonstrated an improved quality-of-life (QoL) of patients enrolled in the neoadjuvant group with buttock pain, blood and mucus in stool, flatulence, foecal incontinence, stool frequency, embarrassment, and rectal and anxiety symptoms improved during the chemotherapy, notwithstanding lower physical functioning, role functioning, and more fatigue.
Of note, 86% of the patients in both groups had sphincter-preserving surgery and 85.5% were stoma-free at 7 years. Low anterior rectal resection syndrome was not evaluated per se in the UNICANCER-PRODIGE 23 study; however, parameters affected by this syndrome (lower global QoL, lower emotional and social functions, and higher incidence of diarrhoea and foecal incontinence) were not affected in patients enrolled in the study.
The authors commented that two recent clinical trials investigating total neoadjuvant therapy in locally advanced rectal cancer, RAPIDO and UNICANCER-PRODIGE 23, demonstrated significant benefit to decrease the onset of metastases compared to standard-of-care. Similar to UNICANCER-PRODIGE 23 study results, in the RAPIDO study, the 5-year distant metastases rate was reduced in the neoadjuvant group compared with the standard-of-care group. However, the diminution of the occurrence of metastases in the neoadjuvant group was not associated with an OS increase in the RAPIDO study.
Furthermore, in the RAPIDO study, the locoregional recurrence rate at 5 years was significantly increased in the neoadjuvant group. In the UNICANCER-PRODIGE 23, there was no any increase in the proportion of patients with local relapses and the DFS benefit was constant over time. Less events, including metastases and death as first events, were observed in the neoadjuvant group compared with the standard-of-care group, strengthening the positioning of the induction chemotherapy for the treatment of patients with locally advanced rectal cancer.
In the RAPIDO study, the reduction of distant metastases did not translate into OS improvement partly due to the ATRESS phenomenon, a significantly shorter survival after the onset of distant metastases in the total neoadjuvant group compared with the control group. This phenomenon was not observed in the UNICANCER-PRODIGE 23 study with a median survival after distant recurrence of 36.5 months in the neoadjuvant group compared with 35.7 months in the standard-of-care group.
In the UNICANCER-PRODIGE 23 study, the protocol definition of DFS included all second cancers. This has not been the case in a number of recent studies in rectal cancer. In the UNICANCER-PRODIGE 23 study, gender is an independent prognostic factor for survival, with men having poorer prognosis than women. Population series and a meta-analysis have shown that mortality from rectal cancer was lower in women than in men in most countries. There were speculations that these outcome differences might be related to the extent of lateral clearance, given that wide lateral margins are more difficult to achieve in the narrower and deeper male pelvis.
In the UNICANCER-PRODIGE 23 study, the poorer prognosis of men might be related to coexisting comorbidities. All five postoperative deaths occurred in men, primarily due to cardiovascular risk factors as in the two cases of treatment-related cardiac deaths in the standard-of-care group. Of the seven secondary cancers leading to death, six occurred in men and were related to tobacco use. This emphasises the importance of identifying cardiovascular risk factors and promoting smoking cessation before initiating chemotherapy and surgery procedures.
Future development of total neoadjuvant therapy with mFOLFIRINOX includes de-escalation strategies to further validate omission of preoperative chemoradiotherapy or organ preservation approach in locally advanced rectal cancer.
This study was funded by grants from the French Ministry of Health, Institut National du Cancer, and the French National League against Cancer.
Reference
Conroy T, Castan F, Etienne P-L, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial. Annals of Oncology; Published online 7 July 2024. DOI: https://doi.org/10.1016/j.annonc.2024.06.019