Jhe-Cyuan Guo

Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to co-administration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA double-strand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.

Association of radiotherapy with favorable prognosis in daily clinical practice for treatment of locally advanced and metastatic pancreatic cancer

Radiotherapy (RT) with or without chemotherapy is currently used in definitive therapy for advanced pancreatic cancer. We sought to evaluate the prognostic significance, pattern of care, and use of RT in locally advanced and metastatic pancreatic cancer.

Radiotherapy is associated with a favorable prognosis in daily clinical practice treating locally‐advanced and metastatic pancreatic cancer

Radiotherapy (RT) with or without chemotherapy is currently used in definitive therapy for advanced pancreatic cancer. We sought to evaluate the prognostic significance, pattern of care, and use of RT in locally advanced and metastatic pancreatic cancer.

Computed tomographic characteristics for patients with unresectable gastric cancer harboring low-volume peritoneal carcinomatosis

Although current staging workups could differentiate most patients with operable from inoperable advanced gastric cancers, there are still some patients with low-volume peritoneal carcinomatosis, defined as only metastasis with multiple subcentimeter lesions in peritoneum, receiving unnecessary open–close procedures. The computed tomography (CT) of the patients with unresectable advanced gastric cancer harboring low-volume peritoneal carcinomatosis was retrospectively identified and then thoroughly reviewed by two independent radiologists unaware of the peritoneal carcinomatosis status. Of the 798 patients with newly diagnosed gastric cancer between January 2007 and December 2010, 52 patients harboring advanced gastric cancer with low-volume peritoneal carcinomatosis receiving surgery with curative intent were identified. Descriptive statistic was used for the radiologic characteristics. The most common radiologic characteristic of CT was omental fat stranding (57.7%), followed by omental clustered subcentimeter nodules (53.8%), distant enlarged lymph node (40.4%), distant grouping of small lymph nodes (36.5%), peritoneal nodules or thickening (34.6%), minimal loculated ascites (21.2%), intestinal wall thickening or irregularity (9.6%), and hydronephrosis or hydroureter without stone or urothelial lesion (5.8%). Comprehensively reviewing the radiologic characteristics of CT may identify the patients harboring advanced gastric cancer with low-volume peritoneal carcinomatosis.

The recurrence patterns and post-recurrence survivals in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with preoperative paclitaxel/cisplatin-based chemoradiotherapy.

80 Background: More than half of patients (pts) with locally advanced ESCC would have disease recurrence after curative preoperative chemoradiation (CRT) followed by surgery. Whether recurrence pattern correlates with the post-recurrence survival remains uncertain. Methods: We included 131 pts with locally advanced ESCC (clinical T3N0-1M0 or T1-3N1M0 or M1a according to AJCC 6thedition) who were enrolled in 3 phase II clinical trials of preoperative CRT followed by surgery and had successfully completed CRT and surgery. These pts received preoperative twice weekly paclitaxel/cisplatin-based CRT with radiotherapy 40Gy given in 20 fractions followed by esophagectomy. When pts had first disease recurrence, we divided them into three groups according to their recurrence patterns: loco-regional recurrence (LRR), distant metastasis only (DM), and both LRR and DM (LRR+DM). Survival outcomes were compared using the Kaplan-Meier curves. Results: With a median follow-up of 34.8 months, 75 pts (57.3%) had disease re...

Postchemoradiotherapy Pathologic Stage Classified by the American Joint Committee on the Cancer Staging System Predicts Prognosis of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma

Introduction: To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing preoperative CRT followed by surgery. Methods: From three phase II trials of preoperative CRT for locally advanced ESCC, 140 patients were included. Preoperative CRT comprised twice weekly paclitaxel and cisplatin-based regimens and 40-Gy radiotherapy in 20 fractions. The post-CRT pathologic stage was classified according to the American Joint Committee on Cancer, 7th edition staging system. The prognostic effects of clinicopathologic factors were analyzed using Cox regression. Results: With a median follow-up of 61.9 months, the median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 24.5 and 30.9 months, respectively. The post-CRT pathologic stage was 0 in 34.5%, I in 12.9%, II in 29.3%, III in 13.6%, and ypT0N1-2 in 6.4% of the patients. The median PFS was 47.2, 25.9, 16.0, 9.4, and 15.1 months, and the median OS was 57.4, 34.1, 26.2, 14.1, and 17.6 months for patients with post-CRT pathologic stage 0, I, II, III, and ypT0N1-2, respectively. In multivariate analysis, performance status (p < 0.001), tumor location (p = 0.016), and extranodal extension (p = 0.024) were independent prognostic factors for PFS, whereas performance status (p < 0.001) and post-CRT pathologic stage (p = 0.027) were independent prognostic factors for OS. Conclusions: The post-CRT pathologic stage classified by American Joint Committee on Cancer, 7th edition staging system predicted the survival of locally advanced ESCC patients who underwent preoperative paclitaxel and cisplatin-based CRT followed by esophagectomy.