Survival and organ preservation according to clinical response after total neoadjuvant therapy in locally advanced rectal cancer patients: A secondary analysis from the organ preservation in rectal adenocarcinoma (OPRA) trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3509-3509
Author(s):  
Hannah Thompson ◽  
Jin Ki Kim ◽  
Jonathan B. Yuval ◽  
Floris Verheij ◽  
Sujata Patil ◽  
...  
Keyword(s):  
Clinical Response ◽  
Neoadjuvant Therapy ◽  
Organ Preservation ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Response Assessment ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Total Neoadjuvant Therapy

3509 Background: Clinical response following neoadjuvant therapy is paramount to identifying locally advanced rectal cancer (LARC) patients suitable for Watch and Wait (WW). A 3-tier schema was devised to stratify clinical response. Patients with a complete clinical response (cCR) are considered for WW, while those with an incomplete clinical response (iCR) are recommended for total mesorectal excision (TME). A near complete response (nCR) tier captures patients with significant, but not complete, response to be considered for WW. This schema’s efficacy has yet to be validated. We investigated survival and organ preservation (OP) rates based on this 3-tier clinical response assessment in patients with LARC who underwent total neoadjuvant therapy (TNT) in a prospective, multi-center clinical trial. Methods: Patients with MRI stage II and III rectal adenocarcinoma were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX). At 8+/-4 weeks following TNT, response on digital rectal and endoscopic examinations was evaluated by the 3-tier schema. The date of this restaging clinical response assessment was used as time zero. The endpoints of rate of OP, disease-free survival (DFS), TME-free DFS, and overall survival (OS) were evaluated using the Kaplan-Meier method with differences analyzed by the log-rank test. Results: Clinical response assessments were available for 294 patients. The median time to assessment after neoadjuvant therapy was 7.9 weeks. Based on the 3-tier schema, 124 patients were categorized as cCR, 113 as nCR, and 57 as iCR. Baseline age, sex, average distance from the anal verge, clinical T classification, and clinical N classification were similar between the response groups. The table shows the 3-year rates of OP, DFS, TME-free DFS, and OS. The median follow-up was 2.36 years. Of the patients with a nCR, the 3-year TME rate was 48% compared with 21% in the cCR group. Conclusions: The 3-tier clinical response assessment has prognostic implications for OP and DFS in patients with LARC who underwent TNT. In patients with a nCR, more than half achieved OP at 3 years. This information should be utilized to counsel patients regarding their expected outcomes. Clinical trial information: NCT02008656. [Table: see text]

A single-institution experience using total neoadjuvant therapy to treat locally advanced rectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 64-64
Author(s):  
Tyler Friedrich ◽  
Ashley Elizabeth Glode ◽  
Robert William Lentz ◽  
Whitney Herter ◽  
S. Lindsey Davis ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Clinical Response ◽  
Treatment Response ◽  
Locally Advanced ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Operative Management ◽  
Locally Advanced Rectal Cancer ◽  
Complete Clinical Response ◽  
Total Neoadjuvant Therapy

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.

Total neoadjuvant therapy for locally advanced rectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 662-662 ◽  
Author(s):  
Andrea Cercek ◽  
Campbell SD Roxburgh ◽  
Paul Strombom ◽  
Jesse Joshua Smith ◽  
Larissa K. F. Temple ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Neoadjuvant Therapy ◽  
Treatment Strategy ◽  
Locally Advanced ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Current Therapy ◽  
Average Dose ◽  
Total Neoadjuvant Therapy

662 Background: Current therapy for locally advanced rectal cancer (LARC) consists of 6 months of perioperative therapy, either with pre-operative chemo-radiotherapy (CRT) and post operative adjuvant chemotherapy (PAC) or total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) followed by CRT then surgery. The aim of our study was to report on the safety, efficacy and complete response rates comparing TNT to PAC in a larger series of LARC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: Pts treated at MSKCC (2009-15) were analyzed based on the intended treatment schedule (TNT or PAC). 730 LARC pts were treated with CRT, of these 320 received neoadjuvant CRT and 308 received TNT. Results: In the TNT group 205 pts (73%) underwent surgery within 26 weeks of completion of treatment, of which 38 (19%) had a pCR. Of the 78 pts who did not undergo surgery within 26 weeks, 68 (87%) had a complete clinical response (cCR). In the PAC group 293 pts (92%) underwent surgery within 26 weeks and 45 (15%) had a pCR. Of the 27 pts who did not undergo surgery within 26 weeks 22 (81%) had a cCR. The median follow up was 25 mo in the TNT group and 29 mo in the PAC group. There was no statistically significant difference in the distant metastasis free survival between the treatment regimens, despite a higher number of cT4 and cN + tumors in the TNT group. Fewer distant recurrences were seen in pts who had evidence of T downstaging (P < 0.001), N downstaging (P < 0.005), the presence of a cCR (P = 0.005) or a pCR (P < 0.005). Of the pts who received all treatment at MSKCC, comparison of dose of 5-FU and oxaliplatin between the preoperative (N = 249) and postoperative regimens (N = 101) was notable for a higher average dose received of both 5FU and oxaliplatin (p < 0.005 and p < 0.001) in the ICT group. Conclusions: These data add weight to the evidence already included in the NCCN guidelines that pre-operative chemotherapy as part of TNT is a viable treatment strategy with superior compliance and delivery of systemic therapy. Given the high complete response rate, TNT may be used as part of an organ preservation treatment strategy.

A multicenter phase Ib/II study of DNA-PK inhibitor peposertib (M3814) in combination with capecitabine and radiotherapy in patients with locally advanced rectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS144-TPS144
Author(s):  
Paul Bernard Romesser ◽  
Emma B. Holliday ◽  
Tony Philip ◽  
Rocio Garcia-Carbonero ◽  
Jaume Capdevila ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Rectal Adenocarcinoma ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Ib

TPS144 Background: Perioperative radiotherapy and chemotherapy, followed by total mesorectal excision, is the standard of care for patients with locally advanced rectal cancer (LARC). However, 1/3 of these patients still develop distant metastases, indicating the need for more effective therapies. In addition, strategies that increase pathological complete response rates are needed to enable non-surgical management of LARC. DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage repair pathway for double-strand break repair. Peposertib (M3814), a potent, selective, orally administered DNA-PK inhibitor, has been shown to potentiate the effect of ionizing radiation in a human colon cancer xenograft model and several colon cancer cell lines. Peposertib is being investigated in several different trials across multiple indications. This Phase Ib/II study (NCT03770689) aims to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of the neoadjuvant treatment combination of peposertib, capecitabine, and radiotherapy (RT) in patients with LARC. Methods: Patients aged ≥18 years with histologically confirmed and resectable Stage II/III rectal adenocarcinoma are eligible. Induction chemotherapy is permitted, but residual disease must first be documented by MRI, digital rectal examination and endoscopy. Patients who received other anticancer therapies or those with prior pelvic RT are excluded. At open-label Phase Ib (open), 18–30 patients (n = 3 per cohort) will receive peposertib + capecitabine (orally, 825 mg/m2 twice daily [BID]) + RT (45–50.4 Gy), 5 days/week. Peposertib 50 mg once daily (QD) was the starting dose. Additional dose levels will range between 100─800 mg QD. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. At Phase II (planned), 150 patients will be randomized (1:1) to receive oral capecitabine (825 mg/m2 BID) + RT (45–50 Gy), with either oral peposertib (recommended phase II dose [RP2D] or placebo, QD for 5 days/week. Primary objectives are to define a maximum tolerated dose and RP2D (Phase Ib), and to evaluate the efficacy of peposertib + capecitabine + RT in terms of pathological/clinical complete response (Phase II). Secondary objectives include assessment of antitumor activity (Phase Ib), quality of life outcomes (Phase II), and PK of peposertib, and the safety and tolerability of the combination therapy (both phases). To date, one patient has received peposertib 50 mg QD, six patients peposertib 100 mg QD, three patients peposertib 150 mg QD, and three patients peposertib 250 mg QD. Clinical trial information: NCT03770689.

Randomized multicenter phase III trial comparing two neoadjuvant chemoradiotherapy (CT-RT) regimens (RT45-Cap versus RT50-Capox) in patients (pts) with locally advanced rectal cancer (LARC): Results of the ACCORD 12/0405 PRODIGE 2

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. LBA4007-LBA4007 ◽  
Author(s):  
J. Gerard ◽  
D. Azria ◽  
S. Gourgou-Bourgade ◽  
I. Martel-Laffay ◽  
C. Hennequin ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Neoadjuvant Chemoradiotherapy ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Concurrent Chemotherapy ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Total Mesorectum Excision

LBA4007 Background: Following the results of randomized trials FFCD 9203 and EORTC 2291, neoadjuvant CT-RT is considered standard treatment for LARC. The ACCORD 12/0405 PRODIGE 2 trial was initiated to optimize this regimen. Methods: Pts with T3 or resectable T4 N0–1-2 M0, rectal adenocarcinoma were randomized to arm A: concurrent RT 45Gy/25f/5 weeks (w) + capecitabine (800mg/m2/bid) or arm B: concurrent RT 50Gy/25f/5w + capecitabine (800mg/m2/bid/5/7days) + oxaliplatine 50mg/m2/w. Resection with Total Mesorectum Excision was scheduled 6 weeks after the end of CT-RT. Adjuvant chemotherapy was optional. 590 patients were needed to show an increase in the pathological complete response (Dworak) rate from 11% (arm A) to 20% (arm B). Circumferential positive rectal margin (CRM R1) was defined as the presence of residual cancer cells within 0 to 1 mm from the perirectal surface. Results: This trial closed in 07/2008 after randomization of 598 pts since 11/2005. Patients characteristics of 586 eligible pts were well balanced: male 66%, median age 61 years, 66% low rectum, 87% T3 stage. Data base was locked in March 2009. Results are reported in Table . Conclusions: The RT 50 capox regimen is compatible with surgery in 98% of cases with no increase in postoperative complication. In the RT 50 arm, there is a trend in favour of a higher rate of pathological complete sterilization and lower rate of positive CRM. These data could contribute to design a new standard preoperative regimen for LARC. 50 Gy/25 F/5 weeks combined with concurrent chemotherapy could be proposed as an efficient schedule. [Table: see text] No significant financial relationships to disclose.

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