Prognostic Impact of Upfront Surgery for Locally Advanced Upper Rectal Adenocarcinoma

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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Capecitabine-induced myopericarditis – A case report and review of literature

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155218774871 ◽

2018 ◽

Vol 25 (4) ◽

pp. 1006-1010 ◽

Cited By ~ 2

Author(s):

Sydney Saunders ◽

Maria Anwar

Keyword(s):

Adverse Drug Reaction ◽

Drug Reaction ◽

Case Report ◽

Literature Search ◽

Case Reports ◽

Locally Advanced ◽

Rectal Adenocarcinoma ◽

Review Of Literature ◽

Medication Discontinuation ◽

Laboratory Investigations

Objective To describe a possible case of capecitabine-induced myopericarditis in a patient at the Cardio-Oncology Clinic in Calgary, AB. Design A literature search and adverse drug reaction assessment with the Naranjo tool was conducted. Results A 39-year-old male with recurrent locally advanced rectal adenocarcinoma presented two days after adjuvant treatment with capecitabine and oxaliplatin complaining of intermittent, severe interscapular pain. Based on symptoms, laboratory investigations, and imaging, the patient was diagnosed with acute myopericarditis. Management included aspirin, colchicine, and discontinuing adjuvant chemotherapy. A literature review revealed one case report of capecitabine-induced myopericarditis; however, more data were found regarding the cardiotoxicity of fluorouracil, for which capecitabine is a pro-drug. No case reports were found for oxaliplatin. Conclusion Due to the timeline of capecitabine administration, symptom onset, and improvement upon medication discontinuation, capecitabine is the probable cause of the myopericarditis. Although rare, it is important to consider the possibility of myopericarditis in patients receiving a fluoropyrimidine who present with cardiovascular symptoms.

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Prognostic impact of chemoradiation-related lymphopenia in patients with locally advanced pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.439 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 439-439

Author(s):

Daniel W Kim ◽

Grace Lee ◽

Colin D. Weekes ◽

David P. Ryan ◽

Aparna Raj Parikh ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cox Model ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Pancreatic Head ◽

Locally Advanced Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Prognostic Impact ◽

Entire Cohort ◽

Grade 3

439 Background: Chemoradiation (CRT) induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. The objective of this study was to evaluate the prognostic impact of lymphopenia in patients with nonmetastatic, unresectable pancreatic ductal adenocarcinoma (PDAC) treated by neoadjuvant FOLFIRINOX (5-fluorouracil [5FU]/leucovorin/irinotecan/oxaliplatin) followed by CRT. We hypothesized that severe lymphopenia would correlate with worse survival. Methods: The inclusion criteria for this single-institution retrospective study were: 1) biopsy-proven diagnosis of unresectable PDAC, 2) absence of distant metastasis, 3) receipt of neoadjuvant FOLFIRINOX followed by CRT, and 4) absolute lymphocyte count (ALC) available prior to and two months after initiating CRT. In general, CRT consisted of 5FU or capecitabine and RT with 58.8 Gy over 28 fractions. Lymphopenia was graded according to CTCAE v5.0. The primary variable of interest was lymphopenia at two months, dichotomized by ALC of < 0.5/μl (Grade 3 lymphopenia). The primary endpoint was overall survival (OS). Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results: A total of 138 patients were identified. Median follow-up for the entire cohort was 16 months. Median age was 65. Fifty-six percent were female, 86% were Caucasian, and 97% had ECOG ≤1. Median tumor size was 3.8 cm. Tumor location was pancreatic head in 63%, body in 22%, tail in 8%, and neck in 7%. Median baseline ALC for the entire cohort was 1.5 k/ul. Two months after initiating CRT, 106 (77%) had severe (Grade 3 or worse) lymphopenia. While there were no significant differences in baseline patient or disease characteristics, patients with severe lymphopenia received higher doses of RT with longer duration of treatment compared to those without severe lymphopenia. On multivariable Cox model, severe lymphopenia at two months was significantly associated with increased hazards of death (HR = 4.00 [95% CI 2.03-7.89], p < 0.001). Greater number of neoadjuvant FOLFIRINOX cycles received prior to CRT was associated with lower hazards of death (HR = 0.84 [95% CI 0.77-0.92], p < 0.001). The 12-month OS was 73% vs. 90% in the cohort with vs. without severe lymphopenia, respectively (log-rank p < 0.001). Conclusions: Treatment-related lymphopenia is common and severe lymphopenia may be a prognostic marker of poorer survival in locally advanced pancreatic cancer. Closer observation in high-risk patients and minimization of RT dose and duration are potential approaches to mitigating CRT-related lymphopenia. Our findings also suggest an important role of the host immunity in pancreatic cancer outcomes, supporting the ongoing efforts of immunotherapy trials in pancreatic cancer.

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