scholarly journals Neoadjuvant Chemotherapy and Concomitant Boost Radiotherapy in the Treatment of Locally Advanced Rectal Cancer

2021 ◽  
pp. 1-19
Author(s):  
Mai AbdAllah Abdelazez ◽  
Soumaya Mohamed Eteba ◽  
Eman Hamza Elzahhaf ◽  
Sameh Roshdy Abdel Aziz ◽  
Rehab Omar ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Three Dimensional ◽  
Conformal Radiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Radiation Dermatitis ◽  
Concomitant Boost ◽  
Three Dimensional Conformal Radiotherapy

Aims: This study aimed to examine the efficacy and toxicities of concomitant boost three-dimensional conformal radiotherapy along with multidrug chemotherapy (capecitabine and oxaliplatin) in neoadjuvant course for locally advanced rectal cancer (LARC). Study Design: A phase II interventional nonrandomized study. Place and Duration of Study: This Study was conducted at Clinical Oncology and nuclear medicine department of Mansoura University Hospitals (Egypt) between November 2016 and October 2019. Methodology: Thirty patients (18 women, 12 men; age range 18-75 years) with (cT3-T4 and/or cN+) histologically confirmed rectal adenocarcinoma located within 12 cm of the anal verge were included in this study. Patients received three-dimensional conformal radiotherapy (3DCRT) to the pelvis of 45 Gy and a concomitant boost of 10 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). Radical surgery was scheduled six to eight weeks after chemoradiation. Acute toxicities were recorded according to Common Terminology Criteria for Adverse Event (CTCAE) v5.0. Potential prognostic factors were evaluated using a binomial logistic regression. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test. Results: All patients received chemoradiation. Twenty-seven patients underwent surgical resection. Twenty-five patients underwent sphincter-sparing surgery (92.6%) and nine patients (33.3%) achieved pathological complete response (pCR). The incidences of grade III neutropenia, diarrhea, and radiation dermatitis were 6.7%, 6.7%, 3.3% respectively. The three-year local recurrence (LR), disease-free survival (DFS) and overall survival (OS) rates were 7.4%, 63% and 74.1%, respectively. We found pre-surgical negative nodal status to be significantly associated with pCR (p=0.009). The pathological nodal stage was an independent prognostic factor to DFS. Conclusion: The combination of oxaliplatin, capecitabine, and dose escalation using concomitant boost 3DCRT is safely administrated in patients with locally advanced rectal adenocarcinoma and it offers high pCR and sphincter preservation rate.

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.

Neoadjuvant XELOX vs. XELIRI in combination with concomitant boost 3D-conformal radiotherapy in locally advanced rectal cancer (LARC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3570-3570 ◽  
Author(s):  
G. Privitera ◽  
C. Spatola ◽  
G. Acquaviva ◽  
G. Di Franco ◽  
L. Raffaele ◽  
...  
Keyword(s):  
Systemic Disease ◽  
Locally Advanced ◽  
Conformal Radiotherapy ◽  
Distant Metastases ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Common Adverse Event ◽  
High Dose ◽  
Concomitant Boost ◽  
Interval Surgery

3570 Background: While several randomized trials have shown that preoperative chemoradiation reduces local recurrence in LARC, there is no standard chemoradiation schedule. The aim of this study was to compare capecitabine + oxaliplatin (XELOX) vs. capecitabine + irinotecan (XELIRI) in association with high-dose radiotherapy. Methods: Patients (pts) with histologically proven uT3–4 N-/+ or uT2 N+ LARC were randomized to receive capecitabine 1250mg/m2 bid d1–14 before chemoradiation and then 825mg/m2 bid d22–55 plus either oxaliplatin 130mg/m2 d1,22&43 (18 pts) or irinotecan 180mg/m2 d1,22&43 (18 pts). On d22 pts also received radiotherapy administered to the whole pelvis (maximum 45Gy; 1.8Gy/fraction), with a concomitant boost to the CTV (maximum 9Gy; 1.5Gy/fraction) during the last 6d of treatment with a 6h inter-fraction interval. Surgery was carried out 6–8w after chemoradiation by the same surgical team. Results: 36 pts (23M/13F, median age 59 years, ECOG PS 0–1) were enrolled between Jan03 and Jun05. No pt had systemic disease at the time of diagnosis. One pt in the XELIRI group discontinued chemoradiation because of GI toxicity; the other 35 pts (18 XELOX, 17 XELIRI) received 95% and 92% of the planned chemotherapy doses, respectively. The most common adverse event was grade 3/4 diarrhea (6% XELOX, 18% XELIRI). There was no relevant neurotoxicity. 12 pts (67%) on XELOX and 12 pts (71%) on XELIRI had clinical and pathological downstaging. There were no treatment-related deaths. A complete pathological remission was seen in 4 pts (22%) on XELOX and 5 pts (29%) on XELIRI. 25 pts (71%; 13 XELOX, 12 XELIRI) underwent sphincter-saving surgery and 10 pts had Miles abdomino-perineal resection. All pts are alive after a median follow-up of 20 months (range 7–36 months), but 4 (2 in each group) have developed distant metastases. Conclusions: XELOX and XELIRI are feasible and effective, with high efficacy comparable to that observed with other neoadjuvant regimens. XELOX was better tolerated, as diarrhea was seen more frequently in the XELIRI arm. Further studies of these regimens are warranted in this setting. No significant financial relationships to disclose.

Association of perineural invasion with outcomes after neodjuvant chemoradiation for locally advanced rectal adenocarcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 750-750
Author(s):  
Priyanka Vinod Chablani ◽  
Phuong Nguyen ◽  
Charles Andrew Robinson ◽  
Xueliang Jeff Pan ◽  
Steve Andrew Walston ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Perineural Invasion ◽  
Locally Advanced ◽  
Prognostic Significance ◽  
Rectal Adenocarcinoma ◽  
Residual Tumor ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Resected Specimen ◽  
Free Survival

750 Background: Perineural invasion (PNI) as a prognostic indicator has not been well studied in patients with rectal adenocarcinoma treated with neoadjuvant chemoradiation (nCRT). In this study, we investigated the incidence and prognostic significance of PNI in patients with stages II-III locally advanced rectal cancer treated with nCRT. Methods: We performed a retrospective study of 110 consecutive patients treated with nCRT for locally advanced rectal adenocarcinoma at a single institution from 2004 to 2011. 88 of these patients had residual tumor in the resected specimen after nCRT. We evaluated the association of PNI with clinical outcomes, including disease-free survival (DFS), distant-metastasis-free survival (DMFS), and overall survival (OS), using log-rank and Cox proportional hazard modeling. Results: Of the 88 patients with residual tumor at surgery, 14 patients (16%) had PNI and 74 patients (84%) did not. Baseline distribution of selected variables in the PNI+ and PNI- groups are shown in Table 1. Median follow-up was 27 months (range 0.9 to 84 months). The median DFS was 13.5 months for PNI+ patients and 39.8 months for PNI- patients (p<0.0001). The median DMFS was 13.5 months for PNI+ patients and median not reached (> 40 months) for PNI- patients (p<0.0001). We did not detect a significant association between the presence of PNI and worse OS, perhaps due to a high rate of censored patients in the OS analysis. In a multivariate model including pT stage, pN stage, tumor location, tumor size, type of surgery, and radial margin status, PNI remained a significant predictor of DFS (HR 16.8, 95% CI, 3.7–75.5, p<0.0002) and DMFS (HR 18.9, 95% CI, 4.4–81.9, p<0.0001). Conclusions: For patients with locally advanced rectal cancer treated with nCRT prior to surgical resection, PNI found at the time of surgery is significantly associated with worse DFS and DMFS. [Table: see text]

Short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 139-139
Author(s):  
Ali Shamseddine ◽  
Youssef Zeidan ◽  
Ibrahim Moustafa Khalifeh ◽  
Joseph Gergi Kattan ◽  
Rim Turfa ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Interim Analysis ◽  
Response Rate ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Pathologic Response ◽  
Short Course ◽  
Pathologic Response Rate

139 Background: Total neoadjuvant treatment (TNT) for locally advanced rectal cancer is becoming an accepted approach over the last few years with increasing pathologic complete response (pCR) and compliance of patients for chemotherapy in comparison with the current standard of care i.e., fluoropyrimidine based chemoradiation followed by surgery and adjuvant chemotherapy. Sequential use checkpoint inhibitors after radiation therapy (RT) has demonstrated synergistic effect in vivo leading to decrease in size of irradiated and non-irradiated secondary tumors outside the radiation field (abscopal effect). Methods: This is an investigator initiated; open-label, single-arm multicenter phase II study, adopting Simon’s two-stage aiming at evaluating the pCR rate and safety of using short-course radiation therapy (25 Grays in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus Avelumab (anti PDL1), then total mesorectal excision(TME) in patients with locally-advanced, potentially resectable rectal adenocarcinoma. Results: 13 out of 44 patients were accrued from 20, July till 28, Dec 2018 in the first stage of the study (30% from total sample size). They all met the inclusion criteria and received full protocol treatment. 12 out of the 13 completed TME. 1 of the 13 had progression of disease, so surgery was aborted and patient was dropped out the study. The sample consisted of 9 (69%) males and 4 (31%) females with median age of 62 (33.0, 73.0) years. The first interim analysis revealed 3 patients (25%) achieved pCR (tumor regression grade: TRG = 0) out of 12 as compared to the historical control group with pCR of 16%. For the rest of the patients, 3 (25%) had major pathologic response rate (pRR) with TRG = 1 (< 10% viable cells is tumor bed).In total, 6 out of 12 patients (50%) had major pathologic response rate. As for safety, no serious adverse events of grade 3 and 4 were reported. Conclusions: Based on the first interim analysis results, incorporation of Avelumab and short course radiotherapy is tolerable in patients with locally advanced rectal cancer treated with TNT. The study will resume recruitment to reach the target accrual. Clinical trial information: NCT03503630.

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.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4117-TPS4117
Author(s):  
Paul Bernard Romesser ◽  
Emma B. Holliday ◽  
Tony Philip ◽  
Barbara Sarholz ◽  
Mirjam Kuipers ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Phase Ii ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Phase Ib ◽  
To Receive

TPS4117 Background: Preoperative chemo-radiotherapy with or without sequential chemotherapy, followed by surgical intervention, is 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. 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. During open-label Phase Ib (open), 18–30 patients (n = 3 per cohort) are due to receive peposertib + capecitabine (orally, 825 mg/m2 twice daily [BID]) + RT (45–50 Gy), 5 days/week. Peposertib 50 mg once daily (QD) is the starting dose. Additional dose levels will be 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). One patient has received peposertib 50 mg QD and six patients have received peposertib 100 mg QD. Patients are currently receiving peposertib 150 mg QD. Clinical trial information: NCT03770689 .

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