onc brain

Multicenter open-label randomized phase III noninferiority trial, 16 hospitals across 11 provinces of China, accrual August 2015 to August 2018, N=599 randomly assigned 1:1 (TNT 302, CRT 297). Stratified by tumor location, clinical stage and MRF status; median follow-up 35.0 months (range 8.3-63.9).

Age 18-70, ECOG 0-1, rectal adenocarcinoma of the distal or middle third (0-10cm from anal verge), cT3-4 and/or node-positive, no distant metastases, no prior anticancer treatment. Arms were balanced: cT4 15.9% v 12.8%, MRF involvement 56.3% v 56.2%, clinical stage III 85.8% v 83.5%.

TNT arm received 25Gy in 5 fractions over one week; CRT arm 50Gy in 25 fractions over 5 weeks with concurrent capecitabine 825mg/m2 twice daily. All patients received IMRT, a departure from RAPIDO, Polish II and PRODIGE 23. CTV covered mesorectum, presacral space, internal iliac, obturator nodes and ischiorectal fossa; superior border at the sacral promontory, inferior 2-3cm distal to the tumor, external iliacs added only for cT4b; CTV-to-PTV expansion 0.5-1.0cm.

TNT arm: 4 cycles CAPOX (oxaliplatin 130mg/m2 day 1, capecitabine 1,000mg/m2 twice daily days 1-14) starting 7-14 days after radiotherapy, then TME, then 2 further cycles. CRT arm: concurrent capecitabine during radiotherapy, then TME, then 6 cycles CAPOX. Total mesorectal excision was scheduled 6-8 weeks after preoperative treatment in both arms; a watch-and-wait pathway was permitted for clinical complete responders.

Primary: 3-year disease-free survival, noninferiority claimed if the upper bound of the 95% CI of the HR was at or below 1.43 (an 11% absolute margin against an assumed 65% CRT rate). Secondary endpoints were overall survival, metastasis-free survival, locoregional recurrence and surgical complications. Target accrual 600 with at least 194 DFS events for 80% power at one-sided alpha 0.05.

Acute grade III-V toxicity during preoperative treatment was 26.5% with TNT versus 12.6% with CRT (P<.001), driven almost entirely by hematologic events (grade 3-4 15.8% v 2.0%, P<.001) rather than by anything the radiotherapy added. Radiotherapy delivery itself was cleaner in the short-course arm, with no dose reductions at all, and grade III+ surgical complications were comparable (14.0% v 15.7%, P=.625). Grade III-IV toxicity during adjuvant chemotherapy ran lower after TNT (3.3% v 11.8%, P=.003).

STELLAR is the third randomized trial of short-course radiotherapy plus neoadjuvant chemotherapy against long-course CRT, after Polish II and RAPIDO, with PRODIGE 23 addressing the adjacent question of chemotherapy sequencing around long-course CRT. Its 3-year LRR of 8.4% with TNT sits alongside RAPIDO and PRODIGE 23 (4%-8.3%) and well below Polish II (21%-22%), which enrolled a heavier fixed cT3/cT4 population. Unlike RAPIDO and PRODIGE 23, STELLAR showed no reduction in distant metastasis (3-year DM 22.8% v 24.7%), and its OS advantage mirrors the early Polish II signal that later disappeared at 8 years.

The 11% noninferiority margin is wide, and the authors concede in retrospect that a narrower margin or larger sample would have been defensible given how close the arms proved. Distant metastasis, the endpoint short-course TNT was designed to move, did not separate at all (22.8% v 24.7%), which weakens the mechanistic case for the OS difference. Adjuvant chemotherapy completion also differed between arms (60.0% v 48.3%, P=.009), so postoperative treatment intensity is not held constant across the comparison.

The defensible read is the primary endpoint: 25Gy in 5 fractions followed by CAPOX delivers the same 3-year DFS and the same locoregional control as 50Gy in 25 fractions, in one week of radiotherapy instead of five. The 11.4-point OS separation is the number that will be quoted and the one least supported, since neither MFS nor LRR moved and the same pattern in Polish II did not survive longer follow-up. What transfers most reliably is the technique: full elective pelvic coverage with IMRT at 5x5Gy, delivered without a single dose reduction.

Prespecified noninferiority met on 3yr DFS with adequate accrual, but open-label, 35mo follow-up only, and the OS gain is a secondary endpoint unsupported by MFS or LRR.

Multicenter randomized phase III, N=458, accrual June 6, 2017 to December 27, 2023, median follow-up 51 months. Primary endpoint: DFS. Blinding is not reported and the two regimens are not maskable.

Stage II/III LARC aged 18 to 70 with at least one MRI high-risk feature (cT4a-b, cN2, mesorectal fascia involvement, or cT3c-d with EMVI). Baseline burden was heavy: cT4 47.82%, cN2 75.98%, threatened MRF 70.96%, EMVI 54.80%.

Experimental: one cycle induction CAPOX, LCRT with two cycles concurrent CAPOX, three cycles consolidation CAPOX, then surgery, so all cytotoxic therapy precedes resection. Control: LCRT with concurrent capecitabine, surgery, then six cycles adjuvant CAPOX at 4 to 8 weeks.

Long-course RT in both arms, so RT is the fixed element and the randomized variable is chemotherapy timing plus oxaliplatin exposure. Dose, fractionation, technique and target volume are not reported in the source text, nor is whether concurrent doublet chemotherapy altered RT delivery.

Primary: DFS. Secondary results reported here: MFS, pCR, locoregional failure, overall survival, grade ≥3 adverse events, major postoperative complications.

Primary endpoint met, with MFS moving in step and pCR strongly favoring the experimental arm, while locoregional failure and 3-year OS did not separate. See the efficacy table.

Grade ≥3 toxicity front-loads into the neoadjuvant phase with the doublet, but severe toxicity across the entire treatment course and major postoperative complications were comparable. Total mesorectal excision was performed in approximately 87% (TNT) and 90% (nCRT).

Sits alongside RAPIDO, PRODIGE-23 and STELLAR, the trials that established TNT, but keeps long-course chemoradiation as the RT backbone rather than short-course RT. Unlike RAPIDO's longer follow-up, intensification here did not increase locoregional failure.

Control-arm adjuvant CAPOX delivery and completion are not reported, and a TNT advantage partly reflects therapy planned but not received when postoperative chemotherapy under-delivers. Accrual spanned 2017 to 2023, during which TNT became routine, so control-arm contemporaneity drifted. Age was capped at 70.

The gain is distant, not local: MFS tracks DFS while locoregional failure is flat and low in both arms, which says long-course chemoradiation with a fluoropyrimidine is near its local ceiling in this population and the remaining room is systemic. The pCR tripling is the organ-preservation lever, but pCR is a resection-specimen endpoint and this trial did not test nonoperative management.

Randomized phase III, primary DFS met at 51mo median f/u, but TNT is already established by RAPIDO, PRODIGE-23, STELLAR; this refines regimen rather than the paradigm.