Alliance A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal
Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes.
In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org .
Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer.
Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).
Alvarez JA
，Shi Q
，Dasari A
，Garcia-Aguilar J
，Sanoff H
，George TJ
，Hong T
，Yothers G
，Philip P
，Nelson G
，Al Baghdadi T
，Alese OB
，Zambare W
，Omer D
，Verheij FS
，Bercz A
，Kim MJ
，Buckley J
，Williams H
，George M
，Garcia R
，Gallagher P
，O'Reilly EM
，Meyerhardt JA
，Crawley J
，Shergill A
，Horvat N
，Romesser PB
，Hall W
，Smith JJ
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《BMC CANCER》
Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.
Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC.
The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate.
From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%.
Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile.
ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.
Zhang W
，Zhou H
，Jiang J
，Zhu Y
，Zou S
，Jiang L
，Tang Y
，Liang J
，Sun Y
，Jiang Z
，Qu W
，Li Y
，Zhou A
... -
《BMC CANCER》
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.
Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control.
In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete.
Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression).
The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer.
Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.
Bahadoer RR
，Dijkstra EA
，van Etten B
，Marijnen CAM
，Putter H
，Kranenbarg EM
，Roodvoets AGH
，Nagtegaal ID
，Beets-Tan RGH
，Blomqvist LK
，Fokstuen T
，Ten Tije AJ
，Capdevila J
，Hendriks MP
，Edhemovic I
，Cervantes A
，Nilsson PJ
，Glimelius B
，van de Velde CJH
，Hospers GAP
，RAPIDO collaborative investigators
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ResearchGate
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