Three months of neoadjuvant chemotherapy may downstage early-stage rectal cancer and thereby reduce the need for total mesorectal excisions (TMEs), resulting in higher rates of organ preservation.
For patients with clinical T1 to T3ab, node-negative, low- or mid-rectal adenocarcinoma eligible for endoscopic resection, 3 months of induction chemotherapy led to successful tumor downstaging and subsequent organ-sparing surgical strategies in more than half of patients analyzed, according to findings from the phase 2 NEO trial (NCT03259035).
Data showed that among 58 enrolled patients, there was an increase in protocol-specified organ preservation rate (psOPR), a reduction the need for total mesorectal excision (TMEs), minimal changes in quality of life and rectal function, and generally improved outcomes with modified folinic acid, fluorouracil, and oxaliplatin 6 (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX).
After chemotherapy, 33 patients had tumor downstaging to ypT0/1N0/X on surgical specimen, for a psOPR of 57% (90% CI, 45%-68%). The 23 remaining patients were recommended for TME per protocol, of whom 13 elected to proceed to observation, resulting in a 79% (90% CI, 69%-88%) observed organ preservation rate. Of the 10 remaining who proceeded to TME, 7 had no histopathologic residual disease. The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI, 86%-100%) for the observation group of 13 and 90% (95% CI, 58%-98%) for the TME group of 10. The combined group of 23 experienced no distant recurrences or deaths.
“To our knowledge, this is the first published study to describe organ-sparing outcomes of patients with stage I and early-stage II rectal cancer treated with induction chemotherapy and transanal surgical excision. More than half of the enrolled patients experienced complete or near-complete pathologic downstaging and met the protocol criteria for organ-sparing therapy,” the investigators wrote.
Accrual of patients for the trial lasted from August 2017 to May 2020, followed by database lock in January 2021. Most patients were men (71%) with a median age of 67 years (range, 31-83). All patients had well-to-moderately differentiated, nonmucinous rectal adenocarcinoma, with a median tumor height of 6.0 cm (range, 0-18). The most common cT stage by MRI was T2 (64%).
Chemotherapy regimens consisted of either 14-day cycles of mFOLFOX6 for 6 cycles or 21-day cycles of CAPOX for 4 cycles. Each cycle of mFOLFOX6 consisted of leucovorin at 400 mg/m2 and oxaliplatin at 85 mg/m2 as a single 2-hour infusion, bolus fluorouracil at 400 mg/m2 on day 1, and a 46-hour infusion of fluorouracil at 2400 mg/m2. Each cycle of CAPOX consisted of capecitabine at 1000 mg/m2 twice daily for 14 days and oxaliplatin 130 mg/m2 once on day 1. Nearly all mFOLFOX6 and CAPOX patients completed all planned cycles (91% and 89%, respectively). Patients with responsive tumors proceeded to TES between 2 to 6 weeks after their last cycle; patients with unresponsive tumors, or those with progression, were recommended for TME. Those assigned to observation were monitored for 36 months from the time of TES.
An important effect of the neoadjuvant chemotherapy treatment was the paucity of postoperative complications. According to early quality-of-life data, bowel function was minimally affected by TES and subsequently improved. The proportion of patients with low anterior resection syndrome (LARS) was 10% at baseline, 0% pre-excision, 22% at 6 months following excision, and 14% after 12 months. There were also minimal changes in fecal incontinence scores.
No unexpected toxicities occurred, and the most common adverse events resulting from chemotherapy were grade 3 gastrointestinal events, occurring in 22% of patients. There were no grade 5 events during the study.
“This study demonstrates the important role played by TES in accurately documenting the residual tumor burden, thereby informing provider and patient decision making about the need of subsequent therapy,” the investigators wrote.
This study comprised patients with MRI-staged early rectal cancer with no unfavorable histologic characteristics; therefore, a larger and more diverse study is required to support the hypothesis more fully in this patient population. Nonetheless, for this patient group, the results of this study indicate the potential benefits of neoadjuvant induction chemotherapy.
Kennecke HF, O’Callaghan CJ, Loree JM, et al. Neoadjuvant chemotherapy, excision, and observation for early rectal cancer: the phase II NEO trial (CCTG CO.28) primary end point results. J Clin Oncol. Published online August 18, 2022. doi: 10.1200/JCO.22.00184