The neoadjuvant chemoradiotherapy (nCRT) might accentuate surgical complications and toxicity in the treatment of locally advanced rectal cancer (LARC) while neoadjuvant chemotherapy (nCT) alone shows promise as an alternative treatment. However, which patients deserve most from the nCT need further clarify. This trial aimed to assess the non-inferiority of nCT with capecitabine plus oxaliplatin (CAPOX) versus nCRT with capecitabine in LARC with uninvolved mesorectal fascia (MRF).
Patients with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to receive 4 cycles of CAPOX chemotherapy alone (nCT group) or CRT with concurrent Capecitabine (nCRT group). The primary end point is 3-year locoregional recurrence-free survival (LRRFS). Secondary end points, such as 3-year disease-free survival (DFS), 3-year overall survival (OS), and adverse events (AEs), were also reported.
A total of 663 patients were enrolled and 589 patients received the allocated treatment (nCT, n = 300; nCRT, n = 289). LRRFS was analyzed with a median follow-up of 48 months. 3-year LRRFS was 97.4% (95% CI, 95.5 to 99.3) in the nCRT group and 96.3% (95% CI, 94.0 to 98.6) in the nCT group, resulting in a hazard ratio (HR) of 1.40 (95% CI, 0.53 to 3.68). The nCT and nCRT achieved similar 3-year DFS (89.2% v 87.9%; HR, 0.88 [95% CI, 0.54 to 1.44]) and 3-year OS (95.0% v 94.1%; HR, 0.86 [95% CI, 0.42 to 1.76]). The nCT group showed a lower incidence of grade 2 to 4 long-term AEs (16.0% v 26.3%, P = 0.002) and proctitis (33.6% v 41.7%, P = 0.049) compared with nCRT group.
The non-inferiority of nCT was not confirmed with a very low incidence of local recurrence in both group. But nCT offers comparable DFS and OS while mitigating the burden of toxicity as compared to nCRT. These insights shed light on a potential paradigm shift in the treatment for LARC with uninvolved MRF.
FOLFOX is the way to go … as no significant difference was observed in the long-term survival outcome between mFOLFOX6 with and without radiation and fluorouracil plus radiation.
There is hope for organ preservation in rectal preservation. I believe the good news is that waiting is not as harmful. Those who underwent surgery after regrowth almost had the same disease-free survival (DFS) as those who had surgery after treatment because of incomplete response. The use of CtDNA (not analyzed in the trial) may play an even a bigger role where you may not have to wait for clinical regrowth to have the surgery, but of course more trials are needed to see if this will have clinical benefit. (Is the positive or rising CtDNA enough reason to have surgery vs imaging recurrence?)
Still, this is an exciting new era that will see change in treating early-stage colorectal cancer, recall the immunotherapy results in patients who were MMR deficient.
Tumor regression grade defined as the ratio between fibrosis and residual tumor, is routinely used to assess response to therapy and demonstrated to be an important predictor of patient’s outcome. In the era of TNT (total Neoadjuvant Therapy) this will help assess response to avoid surgery. It will be nice to add MRD testing in the blood as another tool.
Paradigm shift in rectal cancer therapy? Some may not need surgery, now some may not need radiotherapy.
Nice study showing a non-radiation approach to node-negative, earlier stage, low-lying rectal cancer, using FOLFOX/CAPEOX x 3 months followed by local excision for those with downstaging to T0/T1 disease. 79% of patients achieved organ preservation, and 2-year locoregional RFS was 90%. A good option for those who are not good candidates for radiation yet still want to avoid an APR-type surgery.