Neoadjuvant Chemotherapy Elicits Necessary Responses for Organ-Sparing Surgery in Early-Stage Rectal Cancer

Hagen F. Kennecke, MD, MHA

Chemotherapy prior to transanal excision surgery demonstrated favorable responses that led to increased organ preservation rates among patients with early rectal cancer, according to findings from the phase 2 NEO trial (NCT03259035) published in the Journal of Clinical Oncology.

At a median follow-up of 15.4 months, and a database lock of January 20, 2021, the intent-to-treat, protocol-specified organ preservation rate was 57% (90% CI, 45%-68%), with 33 of 58 enrolled patients having tumor downstaging to ypT0/T1N0/X. The observed organ preservation rate was 79% (90% CI, 69%-88%), which included patients who declined their recommended surgery.

“Three months of induction chemotherapy with [modified leucovorin calcium, fluorouracil, and oxaliplatin 6 (mFOLFOX6) or capecitabine (Xeloda) plus oxaliplatin (CAPOX)] may successfully downstage a significant proportion of patients with favorable-risk, early-stage rectal cancer, allowing well-tolerated organ-preserving surgical therapy with minimal effect on organ function,” lead study author Hagen F. Kennecke, MD, MHA, the medical director of Gastrointestinal (GI) Oncology at Providence Cancer Institute in Portland, Oregon, and colleagues, wrote in a paper on the data. “Furthermore, recent work suggests transanal excision surgery can enhance the opportunity for organ preservation even in patients with locally advanced disease who achieve a near-complete response.”

Oncologic resection with total mesorectal excision (TME) is the current standard of care for patients with histologically high-risk, node-negative clinical T1 and T2 rectal tumors. However, this method results in issues with incontinence, bowel function, and sexual function, which are often further exacerbated by the addition of perioperative radiation.

Organ-sparing therapy in stage I/IIA rectal cancer can help patients avoid the adverse effects (AEs) associated with TME, such as permanent ostomy and low anterior resection syndrome. Additionally, neoadjuvant chemotherapy may reduce local and distal relapse in rectal tumors. The nonrandomized, open-label NEO trial aimed to determine the organ-sparing rate of patients in this population who were treated with neoadjuvant chemotherapy followed by transanal excision surgery.

Eligible patients included adults with invasive, well to moderately differentiated, clinical stage T1 to T3ab, node-negative, low- or mid-rectal adenocarcinoma confirmed by proctoscopy who were deemed eligible for endoscopic resection by the study surgeon. Additionally, patients needed to have a baseline ECOG performance score of 0 or 1, and adequate organ/hematologic function.

Patients were excluded if they had a history of external-beam pelvic radiation, prior therapy for rectal cancer, or metastatic disease.

Once enrolled, patients received 6 cycles of mFOLFOX6 or CAPOX, per investigator discretion. The mFOLFOX6 regimen was divided into 14-day cycles that consisted of 400 mg/m2 of leucovorin calcium and 85 mg/m2 of oxaliplatin in a 2-hour infusion, plus bolus fluorouracil at 400 mg/m2 once on day 1, and one 46-hour infusion of fluorouracil at 2,400 mg/m2. The CAPOX regimen was divided into 21-day cycles that consisted of capecitabine at 1000 mg/m2 twice daily for 14 days and oxaliplatin at 130 mg/m2 once on day 1.

Within 2 to 3 weeks after the last dose of chemotherapy, patients were assessed with pelvic MRI and proctoscopy. Within 2 to 6 weeks after the completion of chemotherapy, those who exhibited protocol-defined evidence of response to the neoadjuvant treatment proceeded to transanal endoscopic surgery. Patients who progressed or did not respond were recommended TME and preoperative pelvic radiation if they had clinical T3ab, clinical node-positive disease, or if they had involved or threatened circumferential radial margin.

Subsequent therapy was determined by local pathologic stage following systemic therapy prior to surgery. Investigators recommended observation for patients with node-negative yp stage T0 or T1 tumors with no poor prognostic features, and radical TME for patients with ypT1 tumors with poor prognostic features, ypT2 or T3 tumors, or any node-positive tumors. Poor prognostic features included lymphovascular invasion, poorly differentiated histology, and/or a positive margin within 1 mm.

The primary end point of the trial was protocol-specified organ preservation rate, defined as the proportion of patients who had tumor downstaging to ypT0/T1N0/X and who avoided radical surgery.

Per previously published literature, an organ preservation rate of 50% to 68% was expected among patients with clinical T1 to T3 node-negative rectal tumors who received chemoradiation and transanal endoscopic surgery. The experimental treatment would be considered promising if the organ preservation rate was 65% or higher, and of no interest if the organ preservation rate was 50% or lower.

Between August 22, 2017, and May 19, 2020, 58 patients were enrolled with a median age of 67 years (range, 31-38). Seventy-one percent of patients were male, 81% had an ECOG performance score of 0, and all had well or moderately differentiated, nonmucinous rectal adenocarcinoma. All patients received pelvic magnetic resonance imaging (MRI), as well as computed tomography (CT) scans of the chest, abdomen, and pelvis. MRI showed that 64% of patients had clinical tumor stage T2, and the median tumor height was 6.0 cm (range, 0-18).

All enrolled patients began chemotherapy, including 32 treated with mFOLFOX6 and 26 treated with CAPOX. In total, 91% of the mFOLFOX6 group and 89% of the CAPOX group completed all planned cycles of chemotherapy.

The relative dose intensity (RDI) of oxaliplatin was at least 90% in 59% of patients, 80% to less than 90% in 22% of patients, and 60% to less than 80% in 19% of patients. The RDI of infusional 5-fluorouracil was at least 90% in 53% of patients, 80% to less than 90% in 22% of patients, and 60% to less than 80% in 19% of patients. The RDI for capecitabine was reduced to 80% to less than 90% in 50% of patients, 60% to less than 80% in 22% of patients, and less than 60% in 19% of patients.

In all, 56 patients received transanal endoscopic surgery in the form of minimally invasive surgery or transanal endoscopic microsurgery (n = 53) or open local excision (n = 3). In total, 93% (n = 52) had an R0 excision, 3.5% (n = 2) had an R1 excision, and 3.5% (n = 2) had an R2 excision.

Two patients did not proceed to transanal endoscopic surgery after chemotherapy. One had an initial node-negative clinical T1 tumor that progressed to clinical T3b after chemotherapy and proceeded directly to TME, with a specimen that showed a node-negative ypT2 tumor with a negative circumferential margin. The second patient had an initial node-negative clinical T2 tumor, did not respond to chemotherapy, and received standard-dose pelvic chemoradiation, which elicited a clinical tumor response that allowed them to schedule organ-sparing transanal endoscopic surgery.

In total, 23 patients were recommended for TME based on protocol requirements, which 10 patients received, including 7 with no histopathologic residual disease and 2 with pathologically node-positive tumors.

Additionally, 13 patients declined excision and proceeded to observation. Among these patients, 1 had a T1 tumor with histologic high-risk features, 11 had T2 tumors, and 1 had a T3 tumor. The patients in the observation group were followed for 36 months from the time of transanal endoscopic surgery and received proctoscopy, pelvic MRI, and carcinoembryonic antigen every 6 months, as well as contrast CT of the chest, abdomen, and pelvis annually for 3 years. Pelvic MRI could be substituted with pelvic CT at months 12, 24, and 36.

Among tumor stage subgroups, the protocol-specified organ preservation rate was 63% (n = 8) in the clinical T1 group, 54% (n = 37) in the clinical T2 group, and 62% (n = 13) in the clinical T3ab group.

During follow-up, the investigators recorded 2 locoregional recurrences, including 1 in a patient from the observation group. Both these patients were diagnosed with MRI-stage clinical T2, low-lying tumors at enrollment. One had residual ypT2, and one had ypT1 on their transanal endoscopic surgery specimen after chemotherapy.

The 1- and 2-year locoregional relapse-free survival rates were 98% (95% CI, 86%-100%) and 90% (95% CI, 58%-98%), respectively. The investigators observed minimal changes in quality of life (QOL) and rectal function scores, and no distant recurrences or deaths were reported.

Tumor genotyping with FoundationOne CDx was conducted in 53 patients with sufficient tissue. The investigators found no association between RAS mutation status and tumor downstaging after chemotherapy. In all, 49% (n = 16/33) of RAS-mutant tumors downstaged to ypT0 or T1, vs 60% (n = 12/20) in the RAS wild-type group (P = .57). No BRAF V600E mutations were reported.

Mismatch repair (MMR) status by immunohistochemistry (IHC) or next-generation sequencing (NGS) assay was available in 55 patients. All 55 patients had tumors with preserved MMR, with 100% (n = 30/30) concordance between IHC and NGS in patients with overlapping assays. ERBB2 amplification was observed in 5.7% (n = 3/53) of patients, all of whom had tumor downstaging and a protocol-specified organ preservation rate of 67%.

AEs were analyzed in the treated population. The toxicity profile for the chemotherapy was as expected, with the most common grade 3 or 4 AEs being GI AEs (grade 3, n = 13; grade 4, n = 1); hematologic AEs (grade 3, n = 5; grade 4, n = 4); biochemistry AEs (grade 4, n = 3); musculoskeletal AEs (grade 3, n = 2); and blood and lymphatic system AEs (grade 3, n = 1). No grade 5 AEs were reported.

Regarding AEs associated with transanal excision surgery, the estimated blood loss was 5 cc (range, 0-300). Additionally, 1 patient had intraoperative injury, and 1 patient needed admittance to an intensive care unit (ICU). No patients in this group required transfusion. The median hospitalization length of stay in this group was 0 days (range, 0-2).

Regarding TME AEs, the estimated blood loss was 65 cc (range, 10-3000), 2 patients required transfusion, 2 had intraoperative injury, and 2 needed to go to an ICU. The median hospitalization length of stay in this group was 5 days (range, 4-17). No patients died from surgery in either group.

All enrolled patients complied with QOL and rectal function instruments at baseline, 89% complied pre-excision, 85% complied at 6 months, and 86% complied at 12 months. At baseline, 10% of patients had major low anterior resection syndrome, and no patients had major low anterior resection syndrome pre-excision. The proportion of patients with major low anterior resection syndrome was 22% and 14% at 6 months and 12 months, respectively.

Throughout the study, only minimal changes from baseline fecal incontinence QOL lifestyle and depression/self-perception scales were observed.

“This study demonstrates the important role played by transanal excision surgery in accurately documenting the residual tumor burden, thereby informing provider and patient decision making about the need of subsequent therapy. This approach offers a much-desired organ-sparing option and warrants further investigation,” the study authors concluded.

Reference

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