Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial

The traditional standard of care for treating locally advanced rectal cancer (LARC) patients consists of neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy.1,2 This combined modality approach has dramatically decreased the local recurrence risk of LARC in the past 2 decades.3–5 However, most clinical trials failed to demonstrate that the addition of radiotherapy to TME improved the patients’ survival, which could probably be due to inadequate systemic control.6–8 Novel strategies have been suggested but remain currently investigational.9 Under the conventional nCRT paradigm, systemic therapy is usually administered 4 to 5 months after diagnosis, which might result in tumor progression before surgery.10 Furthermore, low compliance with adjuvant chemotherapy also has an impact, as less than 50% of patients are unable to receive the planned dose of adjuvant chemotherapy due to toxicities, surgical complications, or good response to chemoradiotherapy (CRT).11,12 Early exposure to systemic chemotherapy was expected to result in improved control of micrometastases and better tolerance to systemic chemotherapy.13 The strategy of total neoadjuvant therapy (TNT), in which chemotherapy is administered before surgery, either before or after CRT, has been widely studied recently. The RAPIDO and PRODIGE 23 trials successfully demonstrated that compared with conventional CRT, the TNT approach significantly improved the disease-free survival (DFS) and pathologic complete response (pCR) in LARC.3,4 As a result, the TNT approach has become a new treatment of choice for patients with threatened mesorectal fascia (MRF) or locally unresectable tumor. For patients with cT3 disease and clear MRF or cT1-2N1-2, both the TNT approach and conventional long-course or short-course radiotherapy are recommended in the National Comprehensive Cancer Network guideline,14 probably due to the concerns of increased toxicities with the TNT approach and lack of benefit in patients without high-risk factors. Therefore, the optimal neoadjuvant strategy for LARC patients with clear MRF is still open to future research. Since radiotherapy is associated with radiation toxicities, higher surgical complications, and worse long-term functional outcomes,15,16 the necessity for radiation in unselected LARC patients is being questioned, especially in those without high-risk factors such as stage cT4b or involved MRF.17–19

Neoadjuvant chemotherapy (nCT) seems a promising alternative. It has been shown to overcome the above-mentioned drawbacks of the conventional nCRT, shorten the treatment period and improve cost effectiveness.20–25 Previous studies exploring the approach of neoadjuvant chemotherapy have observed promising results, with a pathologic complete response (pCR) rate from 3·7% to 25·0%, a good tumor downstaging from 27·2% to 56·3%, and a local recurrence rate from 0% to 10·0%.5,17,18,20,25 The FOWARC study even demonstrated that nCT with mFOLFOX6 regimens achieved similar 3-year DFS and local recurrence rate to conventional nCRT, although the sample size was relatively small and comprised of a mixed population cohort.5 However, it should be noted that the efficacy of neoadjuvant chemotherapy alone should not be over-emphasized since the downstaging effect in unselected population was unsatisfactory.26,27 Previous studies have demonstrated that MRF invasion was associated with worse biology, the lower response rate to treatment, and worse prognosis.28–30 Thus, we hypothesized that tumors with MRF involvement might benefit less from chemotherapy alone.

In this multicenter, noninferiority, randomized trial, the CONVERT study, we compared neoadjuvant chemotherapy with CAPOX alone to standard CRT with Capecitabine for LARC in LARC patients with uninvolved MRF. Here, we report the preliminary results on their related toxicity, treatment compliance, surgical events, and other efficacy data.

METHODS Study Design and Participants

The CONVERT trial is a phase III, open-label, multicenter, noninferiority, randomized trial performed at 21 hospitals across China from June 1, 2014 to October 1, 2020 (NCT02288195). The trial followed the Consolidated Standards of Reporting Trials reporting guideline. The protocol was approved by the central ethics committee of Sun Yat-sen University Cancer Center (Guangzhou, China), and local ethics committees of all participating hospitals. All participants provided written informed consent.

Eligibility criteria included adults aged 18-75 years with pathologically confirmed rectal cancer diagnosis and no previous treatment. All patients were also required to have an Eastern Cooperative Oncology Group performance status ≤1 and adequate hematologic, liver, and renal function. Contrast-enhanced computed tomography (CT) scan of the chest and abdomen and pelvic magnetic resonance imaging (MRI) were performed before inclusion in the trial to exclude metastases. Pelvic MRI was required for all patients unless contraindicated, in which case pelvic CT scan and endoscopic ultrasound were used for evaluation. Baseline colonoscopy and pelvic MRI were performed to confirm that the tumor had a distal edge located between 5 and 12 cm from the anal verge in consideration of the lack of data on the efficacy of nCT in low rectal cancer. From April 2019, the protocol was revised to also enroll patients with tumors within 5 cm from the anal verge because the FOWARC study reported that tumor location did not impact the response to chemotherapy. The clinical T stage was estimated based on both MRI and endoscopic ultrasound according to the AJCC seventh edition, and discrepant estimates were consulted with the surgeons and radiologists. Patients were included if their imaging suggested clinical cT2N+ or cT3-4aNany disease. Patients were ineligible if their primary tumor was staged as cT4b or adjacent to the MRF and had symptomatic bowel obstruction. Patients were also excluded if they had chemotherapy or other invasive malignancy within 5 years before registration or any prior pelvic radiation.

Random Assignment and Masking

Patients were recruited and assessed for eligibility at the center they were diagnosed and treated. A stratified randomized block design was adopted to assign patients (1:1) to the nCT (4 cycles of CAPOX followed by surgery and adjuvant chemotherapy) or nCRT (chemoradiotherapy followed by surgery and adjuvant chemotherapy; Fig. 1) group. Random assignment was conducted centrally, and patients were assigned through a phone call or internet interface hosted by the Fudan University Shanghai Cancer Center (Shanghai, China). Stratification factors included tumor location and clinical nodal staging. Investigators and participants were not masked to treatment allocations.

F1FIGURE 1:

Study design. Patients were assigned (1:1) to the nCT (4 cycles of CAPOX followed by surgery and adjuvant chemotherapy) or nCRT (chemoradiotherapy followed by surgery and adjuvant chemotherapy) group.

Procedures Neoadjuvant Chemotherapy

Patients assigned to the nCT group received 4 cycles of CAPOX regimen (Oxaliplatin, 130 mg/m2 IV day 1 plus capecitabine, 1000 mg/m2 twice daily for 14 d, Q3W). The duration of nCT is 3 weeks for each cycle and 12 weeks in total for 4 cycles of neoadjuvant chemotherapy. Treatment doses were adjusted in response to toxicities according to a predefined protocol (see the Protocol as a supplemental file, Supplemental Digital Content 1, https://links.lww.com/SLA/E394).

Neoadjuvant Chemoradiotherapy

Patients assigned to the nCRT group received 825 mg/m² of oral capecitabine twice daily with concurrent radiation therapy 5 days/week for 5 weeks. The total radiotherapy dosage was 50 Gy in 25 fractions to the gross tumor volume and 45 Gy in 25 fractions to the clinical target volume delivered by intensity-modulated radiation.

Restaging After Neoadjuvant Therapy

Restaging assessments with pelvic MRI and endoscopic ultrasound were performed 1 week after the completion of chemotherapy for the nCT group and 5 weeks after the end of chemoradiotherapy for the nCRT group. Patients with evidence of local disease progression in the nCT group underwent chemoradiation as in the nCRT group before surgery. In addition, patients with distant metastases were treated with current standard therapy. The watch-and-wait strategy was recommended only for patients who were candidates for abdominoperineal resection and achieved clinical complete response (cCR).

Surgery

Patients without disease progression were scheduled for surgery with TME 2 to 4 weeks after chemotherapy for the nCT group and 6 to 10 weeks after chemoradiotherapy for the nCRT group. Preventive diverting ileostomy was performed at the discretion of the primary surgeon.

Adjuvant Therapy

Adjuvant chemotherapy started 3 to 4 weeks following surgery in both groups, regardless of pathologic response stage. Patients in the nCT group received 4 cycles of the CAPOX regimen, and patients in the nCRT group received 6 cycles of the CAPOX regimen. For patients with microscopic (R1) or macroscopic (R2) disease in the resected specimen, postoperative chemoradiation was administered.

Post-treatment Surveillance

Post-treatment follow-up was performed every 3 months for the first 2 years and every 6 months for the next 3 years. Details of follow-up assessments, including CT scans or MRI, abdominal ultrasound, colonoscopy, carcinoembryonic antigen measurement, physical examination, and digital rectal examination, are provided in the protocol.

Safety

Laboratory and adverse event (AE) monitoring during perioperative therapy were done on day 1 of all cycles of nCT, weekly for nCRT, before and after surgery, and on day 1 of all cycles of adjuvant chemotherapy. The severity of AE and the laboratory findings were graded by the investigators according to Common Terminology Criteria for Adverse Events, version 4.

Outcomes

The primary end point is 3-year local-regional failure-free survival. Local-regional failure-free survival was defined as the time interval between the date of randomization and the date of local or regional progression/relapse or death, whichever occurred first. Secondary end points included 3-year DFS, pCR rate, tumor regression grade (TRG), pelvic R0 resection rate, overall survival, AE profiles, and rate of receiving preoperative or postoperative chemoradiation. R0 resection was defined as microscopic complete resection with adequate tumor-free margins confirmed by pathology based on a review by the study pathologist. pCR was defined as the absence of viable tumor cells in the primary tumor and lymph nodes (ypT0N0). cCR was assessed through digital rectal examination, colonoscopy, and radiographic images. TRG was assessed using the AJCC/CAP TRG system.31 The 4 categories of AJCC/CAP TRG system were classified as grade 0 (complete response), grade 1 (moderate response), grade 2 (minimal response), and grade 3 (poor response). All imaging, surgical, and pathology reports were assessed by independent masked central review.

Statistical Analysis

The use of a noninferiority margin of 1·6 for the hazard ratio and a type I error of 5 percent ensured 80 percent power to show noninferiority between the nCT and nCRT group. On the basis of the previous studies,7,32 assuming a 3-year local-regional failure-free survival of 93% for the nCRT group and allowing ~5 percent of patients to be excluded from the per-protocol population, an enrollment of 650 patients was planned.

The initial results in this report mainly focus on the pathologic findings and safety profiles of this trial. The analysis of these outcomes will be performed using the χ2 test and with 95% confidence interval of the difference between the 2 proportions. Categorical variables were compared using the χ2 or Fisher exact test, and continuous variables were compared using the t-test. A 2-sided P value <0·05 indicated statistical significance. Subgroup analysis of patients with tumors located within 5 cm from the anal verge was performed. All statistical analyses were performed using the SPSS software ( version 24·0; SPSS). A detailed description of the statistical analysis plan is provided as a supplemental file (Supplemental Digital Content 2, https://links.lww.com/SLA/E395).

RESULTS

From June 1, 2014, to October 1, 2020, 663 patients at 21 centers were recruited and randomly assigned to the nCT (n=331) or nCRT (n=332) group. Seventy-four patients were excluded, of whom 50 (7·5%) withdrew consent after enrollment, 18 (2.7%) violated the study protocol, and 6 (0·9%) did not meet the inclusion criteria. The remaining patients in the nCT (n=300) and nCRT (n=289) groups were included in the modified intention-to-treat (mITT) population (Fig. 2). Their baseline characteristics were well-balanced (Table 1).

F2FIGURE 2:

Trial profile. The ITT population comprised all patients who were were randomized to treatment. The mITT population comprised all patients who were randomized to treatment and received at least 1 dose of study treatment. The PP population comprised of patients who completed the neoadjuvant therapy without major protocol deviations. Ccr indicates clinical complete response; ITT, intention-to-treat; mITT, modified intention-to-treat; nCRT, neoadjuvant radiochemotherapy; nCT, neoadjuvant chemotherapy; PP, per-protocol; SAE, serious adverse event.

TABLE 1 - Baseline Demographic and Clinical Characteristics in the mITT Population Treatment group, No. (%) Characteristics Neoadjuvant chemotherapy (n=300) Neoadjuvant chemoradiotherapy (n=289) Age, years  Median(range) 60 (31-75) 60 (28-75) Sex  Male 188 (62·7) 177 (61·2)  Female 112 (37·3) 112 (38·8) Clinical T category  cT2 16 (5·3) 11 (3·8)  cT3 201 (67·0) 202 (69·9)  cT4a 83 (27·7) 76 (26·3) Clinical N category  cN0 92 (30·7) 77 (26·7)  cN1 147 (49·0) 133 (46·0)  cN2 61 (20·3) 79 (27·3) Distance from the anal verge  >10 cm 10 (3·3) 8 (2·8)  5-10 cm 166 (55·3) 163 (56·4)  ≤5 cm 124 (41·3) 118 (40·8) EMVI by MRI  Positive 52 (17·3) 63 (21·8)  Negative 248 (82·7) 226 (78·2) Lateral lymph node by MRI  Positive 27 (9·0) 36 (12·5)  Negative 273 (91·0) 253 (87·5)

EMVI indicates extramural venous invasion; mITT, modified intention-to-treat.

In the nCT group, 300 patients received at least 1 dose of nCT, 291 (97%) completed the nCT without major protocol deviations, and 272 (90·7%) underwent TME surgery. The median time between randomization and surgery was 16 weeks (IQR 14·7–18·1). Two patients in the nCT group achieved cCR and were managed with the watch-and-wait approach. Four patients received salvage nCRT because of local disease progression. In the nCRT group, 289 patients received at least 1 dose of nCRT, 284 (98.3%) completed the nCT without major protocol deviations, and 261 (90·3%) underwent TME surgery. The median time between randomization and surgery was 16·3 weeks (IQR 14·3–19·1). Five patients in the nCRT group achieved cCR and were managed with the watch-and-wait approach.

Table 2 shows the pathologic findings of the 2 groups. The pCR rate in the nCT group and nCRT group was 11·0% (95% CI, 7·8-15·3%) and 13·8% (95% CI, 10·1-18·5%) (RR: 1.140, 95% CI, 0.8863-1.541; P=0·33). Their corresponding downstaging (ypStage 0 to 1) rates were 40.8% (95% CI, 35·1-46·7%) and 45·6% (95% CI, 39·7-51·7%) (RR: 1.101, 95% CI, 0.9305-1.310; P=0·27), and TRG 0-1 rate were 23·2% and 36·8% (P < 0·001), respectively. The perioperative distant metastases (metastases identified before or during surgery) rate of the nCT group was lower than the nCRT group (0·7% vs. 3·1%; P=0·03). Similar results were observed in the subgroup of patients with tumors located within 5 cm from the anal verge (eTable 1, Supplemental Digital Content 3, https://links.lww.com/SLA/E396).

TABLE 2 - Pathological Findings Treatment Group, No. (%) Variable Neoadjuvant chemotherapy (n=272) Neoadjuvant Chemoradiotherapy (n=261) P Pathologic T category — — 0·524  ypT0 32 (11·8) 36 (13·8) —  ypTis 1 (0·4) 3 (1·1) —  ypT1 15 (5·5) 11 (4·2) —  ypT2 73 (26·8) 76 (29·1) —  ypT3 110 (40·4) 107 (41·0) —  ypT4 41 (15·1) 28 (10·7) — Pathologic N category — — 0·038  ypN0 200 (73·5) 214 (82·0) —  ypN1 62 (22·8) 37 (14·2) —  ypN2 10 (3·7) 10 (3·8) — Pathologic complete response — — 0·333  Yes 30 (11·0) 36 (13·8) —  No 242 (89·0) 225 (86·2) — ypT0-2N0M0 — — 0·265  Yes 111 (40·8) 119 (45·6) —  No 161 (59·2) 142 (54·4) — Tumor regression grade — — <0·001  TRG 0 30 (11·0) 36 (13·8) —  TRG-1 33 (12·1) 60 (23·0) —  TRG-2 98 (36·0) 103 (39·5) —  TRG-3 111 (40·8) 58 (22·2) —  Missing 0 4 (1·5) — TRG 0-1 — — <0·001  Yes 63 (23·2) 96 (36·8) —  No 209 (76·8) 161 (61·7) —  Missing 0 4 (1·5) —

In regard to patients who underwent TME, their R0 resection rate was similar between the 2 treatment groups (nCT vs. nCRT, 99·6% vs. 99·6%, P>0·99; Table 3). The rate of preventive ileostomy in the nCT group was lower than in the nCRT group (52·2% vs. 63·6%; P=0·008). Similar sphincter preservation rate was observed in the 2 groups (nCT vs. nCRT, 94·9% vs. 94·3%; P= 0·76) and the subgroup of patients with tumors located within 5 cm from the anal verge (nCT vs. nCRT, 88·0% vs. 88·6%; P=0·89; eTable 2, Supplemental Digital Content 3, https://links.lww.com/SLA/E396). The difference in postoperative complications, including anastomotic leak and abscess, was of marginal significance between the 2 groups (18·8% vs. 25·7%; P=0·05).

TABLE 3 - Summary of Surgical Outcomes Treatment Group, No. (%) Variable Neoadjuvant chemotherapy (n=272) Neoadjuvant chemoradiotherapy (n=261) P Surgical procedures — — 0·477  Low anterior resection 251 (92·3) 234 (89·7) —  Abdominoperineal resection 14 (5·1) 15 (5·7) —  Intersphincteric resection 6 (2·2) 8 (3·1) —  Others 1 (0·4) 4 (1·5) — Sphincter preservation — — 0·760  Yes 258 (94·9) 246 (94·3) —  No 14 (5·1) 15 (5·7) — Preventive diverting ileostomy — — 0·008  Yes 142 (52·2) 166 (63·6) —  No 130 (47·8) 95 (36·4) — Resection limits — — >0·99  R0 271 (99·6) 260 (99·6) —  R1 1 (0·4) 1 (0·4) — Postoperative morbidity (≤30 d) 51 (18·8) 67 (25·7) 0·054  Anastomotic leak 16 (5·9) 16 (6·1) 0·913  Clinical fistula 0 4 (1·5) 0·057  Abscess 5 (1·8) 5 (1·9) >0·99  Bowel obstruction 8 (2·9) 5 (1·9) 0·577  Intestinal function disorder 16 (5·9) 19 (7·3) 0·515  Septicemia 1 (0·4) 2 (0·8) 0·617  Wound infection 14 (5·1) 23 (8·8) 0·096  Urinary complications 3 (1·1) 4 (1·5) 0·720  Others 5 (1·8) 8 (3·1) 0·410 Postoperative mortality (≤60 d) 0 1 (0·4) 0·490

Of the mITT patients, 259 patients (86·3%) in the nCT group and 263 patients (91·0%) in the nCRT group received the full dose of nCT or radiation (P=0·07). The incidence of adverse events during neoadjuvant therapy was similar in the 2 groups (Table 4; eTable 3 and eTable 4 in the Supplement, Supplemental Digital Content 3, https://links.lww.com/SLA/E396). Grade 3 to 4 toxicities occurred in 37 patients (12·3%) in the nCT group and 24 patients (8·3%) in the nCRT group (P=0·11). The most common grade 3 to 4 toxicities were leukopenia, thrombocytopenia and anemia. The rates of grade 3 to 4 leukopenia (nCT vs. nCRT, 3·0% vs. 4·8%), thrombocytopenia (nCT vs. nCRT, 5·3% vs. 1·0%), and anemia (nCT vs. nCRT, 2·3% vs. 1·0%) did not differ significantly between two the groups.

TABLE 4 - Safety Summary During Neoadjuvant Therapy Treatment Group, No. (%) Neoadjuvant chemotherapy (n=300) Neoadjuvant chemoradiotherapy (n=289) Event Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4 Any event 174 (58·0) 37 (12·3) 163 (56·4) 24 (8·3) Hematologic  Leukopenia 95 (31·7) 9 (3·0) 114 (39·4) 14 (4·8)  Anemia 44 (14·6) 7 (2·3) 43 (14·9) 3 (1·0)  Thrombocytopenia 43 (14·3) 16 (5·3) 18 (6·2) 3 (1·0) GI  Nausea 75 (25·0) 3 (1·0) 38 (13·1) 0  Vomiting 43 (14·3) 1 (0·3) 24 (8·3) 0  Diarrhea 12 (4·0) 4 (1·3) 20 (6·9) 1 (0·3) Laboratory  Aminotransferase 28 (9·3) 2 (0·7) 26 (9·0) 0  Alkaline phosphatase 5 (1·7) 0 5 (1·7) 0  Bilirubin 8 (2·7) 0 22 (7·6) 3 (1·0) Genitourinary 0 0 10 (3·5) 3 (1·0) Neurological 63 (21·0) 3 (1·0) 18 (6·2) 0 Cardiac 3 (1·0) 1 (0·3) 0 0 Mucositis 0 0 0 0 Allergic reaction 0 0 0 0 Palmar-plantar erythrodysaesthesia 12 (4·0) 1 (0·3) 19 (6·6) 1 (0·3) Alopecia 4 (1·3) 0 0 0 Other events 11 (3·7) 0 0 0

GI indicates gastrointestinal.

In the neoadjuvant phase, 2 deaths were observed in the nCT group, of whom 1 died from serve infection during neoadjuvant therapy, and the other died from unexplained sudden death during neoadjuvant therapy. One patient in the nCRT group died from multiple organ dysfunction caused by anastomotic leakage after surgery.

Among the patients who underwent surgery, 235 (86·4%) of 272 patients in the nCT group and 222 (85·0%) of 261 patients in the nCRT group received adjuvant chemotherapy (P=0·69). One patient in the nCT group with postoperative pathologically confirmed positive margins were given adjuvant radiotherapy and chemotherapy. The reasons for not undergoing adjuvant chemotherapy were as follows: 35 patients (13·0%) refused adjuvant chemotherapy and 2 patients (0·7%) did not receive the allocated adjuvant chemotherapy in the nCT group. And 34 patients (13·0%) refused the therapy, four patients (1·5%) did not receive the allocated adjuvant chemotherapy, and 1 patient (0·4%) died from SAE in the nCRT group. In addition, full-dose adjuvant chemotherapy was administered to 52·8% and 44·1% of the patients in the nCT and nCRT group (P=0·07; eTable 5, Supplemental Digital Content 3, https://links.lww.com/SLA/E396).

DISCUSSION

The preliminary results from the CONVERT trial demonstrated that for patients with MRF-negative LARC, neoadjuvant chemotherapy with CAPOX achieved similar downstaging rate and pCR rate, and was associated with lower risk of perioperative metastasis and preventive ileostomy compared with nCRT with capecitabine. These results suggest nCT with CAPOX alone as an effective alternative treatment to conventional nCRT in LARC with uninvolved MRF.

Previous studies explored the possibility of avoiding routine pelvic radiation by using systemic chemotherapy for LARC.17–19 Schrag and colleagues first reported a pilot study using nCT (FOLFOX + bevacizumab) for highly selected LARC. In their study, patients with cT4 diseases, MRF threatened, and fixed or deemed unresectable tumor before neoadjuvant therapy were excluded. They found that nCT demonstrated promising results with a pCR rate of 25%, good downstaging rate of 56·3%, 4-year local recurrence rate of 0%, and 4-year disease-free survival of 84%.18 Similarly, the GEMCAD 0801 study recruited patients with cT3 and MRF-negative LARC and observed a pCR rate of 20% with nCT (CAPOX + bevacizumab).17 The FOWARC study compared nCT with mFOLFOX6 regimens to fluorouracil-radiotherapy as neoadjuvant therapy for unselected LARC. Similar successful downstaging rate (35·5% vs. 37·1%) was observed between the 2 groups. However, the pCR rate was much lower in the chemotherapy group (6·6% vs. 14·0%).33 Likewise, the CORONA I study used the CAPOX regimen as neoadjuvant therapy for unselected LARC, and the patients achieved a pCR rate of 12% and a good downstaging rate of 29·3%. In this present study, the downstaging (40·8% vs. 45·6%) and pCR (11·0% vs. 13·8%) rates of nCT were similar to nCRT. This wide range of pCR rates in different studies could be due to the different criteria in patient selection. In a study by Schrag et al,

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