Intraoperative radiation after pelvic short course radiation-based total neoadjuvant therapy for patients with rectal adenocarcinoma at high risk for local recurrence.

692 Background: Retrospective case series suggest that watch-and-wait (WW) is a safe alternative to total mesorectal excision (TME) in selected patients with a clinical complete response (cCR) after chemoradiotherapy (CRT). Because treatment strategies vary widely and total numbers of patients treated at different institutions have not been reported, the proportion of rectal cancer patients who can potentially benefit from WW is not known. Here, we report the results of a treatment strategy incorporating WW in a cohort of rectal cancer patients treated with total neoadjuvant therapy (TNT). Methods: Consecutive patients with stage II/III (MRI staging) rectal adenocarcinoma treated with TNT from 2012 to 2017 by a single surgeon were included. TNT consisted of mFOLFOX6 (8 cycles) or CapeOX (5 cycles) either before or after CRT (5600 cGy in 28 fractions with sensitizing fluorouracil or capecitabine). Tumor response was assessed with a digital rectal exam, endoscopy, and MRI according to predefined criteria. Patients with a cCR were offered WW, and patients with residual tumor were offered TME. WW and TME patients were compared based on intention to treat, using the chi-square or rank sum test. Relapse-free survival (RFS) was evaluated by Kaplan-Meier analysis. Results: A total of 109 patients were identified. One patient died during CRT. Of the 108 patients, 64 (59%) had an incomplete clinical response; 4 of the 64 patients declined surgery or had local excision, and 60 underwent TME. The remaining 44 patients (41%) had a cCR and underwent WW. On average, patients in the WW group were older and had smaller, more distal tumors. Median radiation dose, number of chemotherapy cycles, number ofadverse events, or length of follow-up (28 months) did not differ between the TME and WW groups. Five (11%) of the 44 WW patients had local tumor regrowth, at a median of 14 (4–25) months after TNT; 2 of the 5 also had distant metastasis. Six (10%) of the 60 TME patients had a pathological complete response. RFS did not differ between the TME and WW groups (log rank P= 0.09). Conclusions: Approximately 40% of patients with stage II/III rectal cancer treated with TNT achieve a clinical complete response and can benefit from a WW approach with the aim of preserving the rectum.

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Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04

Journal of Clinical Oncology ◽

10.1200/jco.2012.42.9597 ◽

2012 ◽

Vol 30 (31) ◽

pp. 3827-3833 ◽

Cited By ~ 426

Author(s):

Samuel Y. Ngan ◽

Bryan Burmeister ◽

Richard J. Fisher ◽

Michael Solomon ◽

David Goldstein ◽

...

Keyword(s):

Rectal Cancer ◽

Overall Survival ◽

Local Recurrence ◽

Radiation Therapy Oncology Group ◽

Rectal Adenocarcinoma ◽

Late Toxicity ◽

Distant Recurrence ◽

Oncology Group ◽

Short Course ◽

Long Course

Purpose To compare the local recurrence (LR) rate between short-course (SC) and long-course (LC) neoadjuvant radiotherapy for rectal cancer. Patients and Methods Eligible patients had ultrasound- or magnetic resonance imaging–staged T3N0-2M0 rectal adenocarcinoma within 12 cm from anal verge. SC consisted of pelvic radiotherapy 5 × 5 Gy in 1 week, early surgery, and six courses of adjuvant chemotherapy. LC was 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks, with continuous infusional fluorouracil 225 mg/m2 per day, surgery in 4 to 6 weeks, and four courses of chemotherapy. Results Three hundred twenty-six patients were randomly assigned; 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range, 3.0 to 7.8 years). Three-year LR rates (cumulative incidence) were 7.5% for SC and 4.4% for LC (difference, 3.1%; 95% CI, −2.1 to 8.3; P = .24). For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence (P = .21). Five-year distant recurrence rates were 27% for SC and 30% for LC (log-rank P = 0.92; hazard ratio [HR] for LC:SC, 1.04; 95% CI, 0.69 to 1.56). Overall survival rates at 5 years were 74% for SC and 70% for LC (log-rank P = 0.62; HR, 1.12; 95% CI, 0.76 to 1.67). Late toxicity rates were not substantially different (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer G3-4: SC, 5.8%; LC, 8.2%; P = .53). Conclusion Three-year LR rates between SC and LC were not statistically significantly different; the CI for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected.

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Same results, 20% of the cost: Short-course total neoadjuvant therapy

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2019.11.416 ◽

2020 ◽

Vol 106 (4) ◽

pp. 672-673

Author(s):

Parag J. Parikh ◽

William Chapman

Keyword(s):

Neoadjuvant Therapy ◽

Short Course ◽

Total Neoadjuvant Therapy ◽

The Cost

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NRG-GI002: A phase II clinical trial platform for total neoadjuvant therapy (TNT) in rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps3629 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS3629-TPS3629 ◽

Cited By ~ 2

Author(s):

Thomas J. George ◽

Greg Yothers ◽

Theodore S. Hong ◽

Marcia McGory Russell ◽

Y. Nancy You ◽

...

Keyword(s):

Clinical Trial ◽

Rectal Cancer ◽

High Risk ◽

Neoadjuvant Therapy ◽

Surgical Resection ◽

Phase Ii ◽

Locally Advanced ◽

High Risk Patient ◽

Randomized Phase Ii ◽

Total Neoadjuvant Therapy

TPS3629 Background: Improvements in outcomes for locally advanced rectal cancer (LARC) have plateaued due to an inability to consistently deliver adjuvant therapy (tx) and thus far ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms in LARC. The experimental arms are not intended for direct comparison, but to test a variety of sensitizers or hypotheses in a consistent and relatively homogenous high-risk patient (pt) population with correlative biomarkers. Success of any given experimental arm will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC as defined by any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. Based on promising phase I results, the first experimental arm will assess the activity of veliparib added to standard chemoRT (capecitabine + RT). Primary endpoint is to demonstrate improvement in Neoadjuvant Rectal Cancer (NAR) score for the experimental arm vs control representing 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, tx completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional arms added through rolling protocol amendments. NCT02921256. Support: U10 CA-180868, -20, 21, -22; UG-189867; AbbVie. Clinical trial information: NCT02921256.

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Total neoadjuvant therapy with short course radiation compared to concurrent chemoradiation in rectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.486 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 486-486 ◽

Cited By ~ 1

Author(s):

William Chapman ◽

Hyun Kim ◽

Philip Bauer ◽

Bilal Makhdoom ◽

Nikolaos Trikalinos ◽

...

Keyword(s):

Rectal Cancer ◽

Neoadjuvant Therapy ◽

Univariate Analysis ◽

Locally Advanced ◽

Complete Response ◽

Secondary Outcome ◽

Recurrence Rates ◽

Cancer Data ◽

Short Course ◽

Total Neoadjuvant Therapy

486 Background: Total Neoadjuvant Therapy (TNT), or delivery of all radiation and chemotherapy prior to surgery, has improved complete response and downstaging rates compared to adjuvant therapy in patients with rectal cancer. Data regarding the use of short course radiation in the setting of TNT (SC-TNT) are limited. This study compares the pathologic complete response rate (pCR), Neoadjuvant Rectal (NAR) Score – a validated predictor of outcome based on tumor downstaging, and recurrence rates for patients receiving SC-TNT versus chemoradiation (CRT). Methods: Patients who underwent neoadjuvant therapy followed by total mesorectal excision for Stage II or III rectal cancer from 2009 to 2018 were included in this retrospective cohort study. CRT recipients (50-55Gy/25-28 fx with concurrent 5-FU or capecitabine) comprised one cohort; the other included SC-TNT recipients (25-35Gy/5 fx followed by CAPOX or FOLFOX chemotherapy). The primary outcome of pCR rate was assessed in univariate analysis; the secondary outcome of NAR score was calculated and categorized as “Low” ( < 8), “Intermediate” (8–16), and “High” ( > 16). Finally, recurrence rates were measured and classified as local, distant, or both. Results: Of 388 eligible patients, 236 (60.8%) were treated with CRT and 152 (39.2%) underwent SC-TNT. On univariate analysis, the SC-TNT cohort had more advanced disease (77% Stage III disease vs. 67%, p = 0.04) and longer elapsed time between radiation completion and surgery (Median 131 vs. 63 days; p < 0.01). SC-TNT achieved a numerically higher pCR rate compared to CRT (25.0% vs. 19.1%, p = 0.16). Odds of achieving a “low” NAR Score trended higher among the SC-TNT cohort (OR 1.49, 95% CI 0.96 – 2.31). Recurrence rates were also similar (14.3% vs. 14.9%, p = 0.87) over comparable follow-up (CRT = 30.5 months [IQR 11.1 – 49.0]; SC-TNT = 22.3 months [IQR 10.8 – 61.0]; p = 0.82). Conclusions: SC-TNT yielded a pCR rate of 25% and overall recurrence rate of 14.9% among patients with locally advanced rectal cancer. Short course radiation with neoadjuvant multiagent chemotherapy is at least as effective as long-course CRT. [Table: see text]

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3509 ◽

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]

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