Adding Three Cycles of CAPOX after Neoadjuvant Chemoradiotherapy Increases the Rates of Complete Response for Locally Advanced Rectal Cancer

Background and Objectives: the total neoadjuvant chemoradiotherapy (TNT) includes different strategies, but the most appropriate model remains uncertain. The purpose of this retrospectively study was to evaluate the safety and pathological response in the consolidation chemotherapy model. Methods: patients with cT3/T4 or TxN + M0 rectal cancer that were receiving neoadjuvant chemoradiotherapy (CRT) (50 Gy with oral capecitabine)/TNT (CRT followed by three cycles of CAPOX) during September 2017 to September 2019 in our department were included. All of the patients were recommended to receive radical surgery. Results: a total of 197 patients were included. Eighty-one patients received CRT, while one hundred and sixteen patients received TNT. Nine patients did not undergo surgery because of the distant metastases (one patient (1.2%) in CRT group, two patients (1.7%) in TNT group) or a refusal of resection (two patients in CRT group, four patients in TNT group). The pathological complete response (pCR) rate was 32.7% in TNT compared with 12.8% in CRT (p = 0.002). There was no statistically significant difference in grade 3 acute toxicities of neoadjuvant treatment and surgical complications between the two groups. Conclusions: the consolidation chemotherapy model is safe for patients with locally advanced rectal cancer and it has a high pCR rate. The long-term follow-up is necessary to be evaluated in a future prospective, randomized trial.

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Total neoadjuvant chemoradiotherapy (consolidation chemotherapy during the interval after chemoradiotherapy) for distal rectal cancer increases the rates of complete response

10.21203/rs.3.rs-19234/v1 ◽

2020 ◽

Author(s):

Zhiwei Zhai ◽

Kunning Zhang ◽

Chen Wang ◽

Jiagang Han ◽

Tian Zhang ◽

...

Keyword(s):

Rectal Cancer ◽

Pathological Complete Response ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Consolidation Chemotherapy ◽

Significant Difference

Abstract Objective To compare the safety and efficacy between neoadjuvant concurrent chemoradiotherapy (CRT) and total neoadjuvant chemoradiotherapy (TNT) in patients with locally advanced rectal cancer. Methods Patients with cT3/T4 or TxN+M0 rectal cancer were randomized to receive CRT/TNT. In CRT group, we planned pelvic radiotherapy (50.0Gy in 25 fractions) with two cycles of concurrent CAPOX followed by total mesorectal excision (TME). In TNT group, 3 cycles of CAPOX were administered 2 weeks after the completion of CRT before TME. The primary endpoints of my study were pathological complete response (pCR) rates in the two cohorts. Results A total of 197 patients were included in our study. Eighty-one patients received CRT while one hundred and sixteen patients received TNT (consolidation chemotherapy). Nine patients did not undergo surgery because of the distant metastases (1 patient (1.2%) in CRT group, 2 patients (1.7%) in TNT group) or clinical complete response (cCR) (2 patients in CRT group, 4 patients in TNT group). The rate of pathological complete response in TNT was significantly higher than the rate in CRT (32.7% vs12.8%, P =0.002). No grade 4 or serious adverse events were observed. There was no statistically significant difference in the grade 3 acute toxicities of neoadjuvant treatment and surgical complications between the two groups (all P >0.05). Conclusions Our data suggests that total neoadjuvant chemoradiotherapy (consolidation chemotherapy) is effective and safe for patients with locally advanced rectal cancer and is associated with high rates of pathological complete response. The long-term follow-up and survival outcomes for patients are necessary to be evaluated in future prospective randomized trial.

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One to Two Cycles of Consolidation Chemotherapy With Capecitabine After Neoadjuvant Chemoradiotherapy Does Not Benefit Low-Risk Patients With Locally Advanced Middle-Low Rectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.695726 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xueqing Sheng ◽

Shuai Li ◽

Yangzi Zhang ◽

Jianhao Geng ◽

Hongzhi Wang ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Multivariate Logistic Regression Analysis ◽

Complete Response ◽

Low Risk ◽

Consolidation Chemotherapy ◽

Chemotherapy Group ◽

Significant Difference

Background and ObjectiveOrgan preservation can enable locally advanced rectal cancer (LARC) patients with clinical complete response (cCR) after neoadjuvant treatment to maintain quality of life. In this study, we aimed to evaluate whether one or two cycles of capecitabine after neoadjuvant chemoradiotherapy (NCRT) without extending the interval between the end of NCRT and surgery could increase the complete response (CR) rate in low-risk middle-low LARC patients.Material and MethodsWe retrospectively evaluated middle-low LARC patients with low risk defined as clinical T2-3b, mesorectal fascia-clear, and extramural vascular invasion-negative by magnetic resonance imaging (MRI), treated between January 2015 and July 2019. Patients were divided into two groups according to whether consolidation chemotherapy was administered after NCRT. Patients in the consolidation chemotherapy group received one or two cycles of capecitabine (1000 mg/m2 twice daily from days 1 to 14). The main outcome was the CR rate, including pathological CR (pCR) and cCR.ResultsA total of 169 patients, 105 in the consolidation chemotherapy group and 64 in the non-consolidation chemotherapy group, were included in the study, and the median follow-up was 37.2 months (range, 0.4–71.2 months). Seventeen patients achieved cCR and the remaining 152 underwent surgery after neoadjuvant treatment. There was no significant difference in the CR rate (39.0% vs. 35.9%, p=0.686), ypT0-2N0 rate (65.2% vs. 63.3%, p=0.812), or ypN0 rate (83.7% vs. 88.3%, p=0.503) between the consolidation chemotherapy and non-consolidation chemotherapy groups. Among the patients achieved cCR, 3 (17.6%) experienced regrowth in the rectum and 2 (11.8%) experienced distant metastasis. There was also no significant difference in the 3-year disease-free survival (87.4% vs 85.9%, p=0.971) in patients who underwent surgery between the two groups. Multivariate logistic regression analysis indicated that normal Carcinoma Embryonic Antigen (CEA) levels (p = 0.001) were associated with a higher CR rate. Moreover, there were no significant differences in the incidences of grade ≥2 acute toxicities during neoadjuvant treatment.ConclusionAlthough there was no increase in treatment-related toxicities between the two groups, simply adding one or two cycles of capecitabine after NCRT might be insufficient to benefit low-risk middle-low LARC patients.

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Deferral of rectal surgery following a continued response to preoperative chemoradiotherapy (Watch and Wait) study: A phase II multicenter study in the United Kingdom.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.489 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 489-489 ◽

Cited By ~ 11

Author(s):

S. K. Yu ◽

G. Brown ◽

R. J. Heald ◽

S. Chua ◽

G. Cook ◽

...

Keyword(s):

Rectal Cancer ◽

Surgical Resection ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Clinical Staging ◽

Pet Ct

489 Background: Neoadjuvant chemoradiotherapy (CRT) and surgical resection are standard components of therapy for patients locally advanced rectal cancer (T3,T4 or N+) in UK. In 15%-30% of patients treated pre-operatively with CRT will develop pathological complete response (CR). The time from completion of CRT to maximal tumour response is as yet unknown. This study is the first prospective study to attempt to identify the percentage of patients who can safely omit surgery and the safety of deferred surgery in patients who achieve clinical complete response post CRT. Of the 59 patients required for the study, this provides an update on 19 patients entered. Methods: Patients with locally advanced rectal cancer requiring neoadjuvant treatment are identified in the multidisciplinary meet (MDT). Patients undergo CRT using a minimum of 50.4Gy in 28 # daily conformal CT planned CRT with concomitant Capecitabine at 825mg/m2 BD. MRI pelvis and body CT are repeated 4 weeks post CRT and rediscussed at MDT. If there is a good partial response or CR, patients are considered for Deferral of Surgery Study. Based on the pre treatment clinical staging, patients are considered for adjuvant chemotherapy as per NICE guidance. At any point of the study, if there is histology proven tumour regrowth or progression, patient undergo surgery. Results: 10 (53%) patients remain in CR. 6 (32%) patients underwent surgical resection with clear margin after detection of tumour regrowth at from 2-23 months post CRT. 5 out of 6 of the patients with tumour regrowth underwent PET CT as per protocol, and all tumour regrowth in those 5 patients were detected by PET CT, i.e. FDG avid disease. The pathological stages on these 6 patients were ypT2N0 CRM negative in 5 and ypT3N0 CRM negative in 1. 3 (15%) patients with tumour regrowth refused surgery. Conclusions: In the 19 recruited patients, all the patients with tumour regrowth underwent surgical resection with clear margins. PET CT appears a useful tool for detecting tumour regrowth. The median time for tumour regrowth is 17.5 months post CRT. The trial will be successful if at least 11/59 patients are able to safely omit surgery. Accrual of patients continues. No significant financial relationships to disclose.

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Future of Radiotherapy Delivery in Rectal Cancer— European and US Approaches

Oncology & Hematology Review (US) ◽

10.17925/ohr.2014.10.2.139 ◽

2014 ◽

Vol 10 (02) ◽

pp. 139

Author(s):

Jordan A Torok ◽

Brian G Czito ◽

Christopher G Willett ◽

Manisha Palta ◽

◽

...

Keyword(s):

Rectal Cancer ◽

Radiation Therapy ◽

Randomized Clinical Trials ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Significant Difference ◽

Long Course

Neoadjuvant radiation therapy is integral in the management of patients with localized rectal cancer. In parts of Europe, patients with operable rectal cancer are treated with short-course radiation therapy delivered in five daily, 5 Gy fractions to a total dose of 25 Gy, followed by surgery within 1 week. In the US, the standard for locally advanced rectal cancer is neoadjuvant chemoradiotherapy. This approach is principally based on the results of the German Rectal Cancer Study Group trial evaluating preoperative compared with postoperative chemoradiation. Surgery is typically performed at 4–8 weeks following completion of long-course chemoradiotherapy, facilitating tumor downstaging, and potential sphincter sparing surgery. No significant difference in clinical outcomes has been observed between these two approaches in two randomized clinical trials; however, further follow-up of these studies and new results from ongoing trials are anticipated to further clarify the optimal neoadjuvant treatment strategy.

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Future of Radiotherapy Delivery in Rectal Cancer—European and US Approaches

European Oncology & Haematology ◽

10.17925/ohr.2014.10.2.45 ◽

2015 ◽

Vol 11 (1) ◽

pp. 45

Author(s):

Jordan A Torok ◽

Brian G Czito ◽

Christopher G Willett ◽

Manisha Palta ◽

◽

...

Keyword(s):

Rectal Cancer ◽

Radiation Therapy ◽

Randomized Clinical Trials ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Significant Difference ◽

Long Course

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The consensus Immunoscore adapted to biopsies in patients with locally advanced rectal cancer: Potential clinical significance for a “Watch and Wait” strategy.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2628 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2628-2628

Author(s):

Carine El Sissy ◽

Amos Kirilovsky ◽

Marc Van Den Eynde ◽

Alfredo Romero ◽

Florence Marliot ◽

...

Keyword(s):

Rectal Cancer ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Reliable Estimate ◽

Watch And Wait ◽

Significant Difference

2628 Background: We investigated whether an adaptation to rectal biopsies of the recently validated consensus Immunoscore, could predict the response to neoadjuvant treatment and delineate clinical responders that could benefit from a “Watch and Wait” (W&W) strategy with acceptable outcomes. Methods: Initial biopsies from 273 patients with locally advanced rectal cancer (LARC) treated by neoadjuvant chemoradiotherapy (nCRT) followed by Total Mesorectal Excision (TME), were immunostained for CD3+ and cytotoxic CD8+ T cells and quantified by digital pathology to determine the Immunoscore within pre-treatment Biopsy (ISB). Expression level of 44 immune related genes post-neoadjuvant treatment was investigated by Nanostring technology (n = 64 patients). Results were correlated with response to neoadjuvant treatment, disease free survival (DFS) and time to recurrence (TTR). Prognostic performance of ISB was finally assessed in 73 LARC treated by W&W strategy. Results: ISB Low, Intermediate and High were respectively observed in 23.3, 50.4 and 26.3 % of the cohort. ISB was positively and significantly correlated with the response to nCRT, as evaluated by Dworak classification (P = .0034), ypTNM (P = .0003), down-staging (P = .0014), and neoadjuvant rectal (NAR) score, (P < .0001). ISB status was also positively associated with the degree of local immune activation post-neoadjuvant treatment. ISB High patients were at low risk of relapse, with 5-year DFS rates of 81.1 % (CI, 71.3-92.1 %) as compared to 57.8 % (CI, 45.9-72.9 %) in ISB low patients. In multivariate analysis, ISB was the only significant parameter at presentation associated with DFS (High vs Low: P = .001). Among W&W patients, significant difference was observed for TTR according to ISB status (High vs Low: P = .025). Conclusions: ISB could provide a reliable estimate of the response to nCRT and risk of recurrence in LARC patients' treated by TME or W&W strategy.

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Consolidation Chemotherapy May Improve Pathological Complete Response For Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy: Evidence From Real-World Data

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2020.07.1928 ◽

2020 ◽

Vol 108 (3) ◽

pp. e640-e641

Author(s):

J. Cui ◽

X. Dou ◽

Y. Sun ◽

J. Yue

Keyword(s):

Rectal Cancer ◽

Real World ◽

Pathological Complete Response ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Consolidation Chemotherapy ◽

Real World Data

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Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer

Cells ◽

10.3390/cells10061539 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1539

Author(s):

Virgílio Souza e Silva ◽

Emne Ali Abdallah ◽

Bianca de Cássia Troncarelli Flores ◽

Alexcia Camila Braun ◽

Daniela de Jesus Ferreira Costa ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Transforming Growth Factor ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-β receptor I (TGF-βRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS− was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-βRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps144 ◽

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.

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