K. Nishiyama

Serum CA19-9 Alterations During Preoperative Gemcitabine-Based Chemoradiation Therapy for Resectable Invasive Ductal Carcinoma of the Pancreas as an Indicator for Therapeutic Selection and Survival

Objective:To evaluate serum CA19–9 alterations during preoperative gemcitabine-based chemoradiation therapy (CRT) for resectable pancreatic cancer (PC) in the earlier identification of patients who are likely to benefit from subsequent resection. Summary Background Data:One of the advantages of the preoperative CRT strategy for patients with advanced PC is that undetectable systemic disease may be revealed during preoperative CRT, thus avoiding unnecessary surgery. Serum CA19–9 has been evaluated as a predictive indicator of the treatment efficacy and outcome in various clinical settings. Methods:We retrospectively reviewed 64 consecutive patients with resectable PC (at diagnosis) who received preoperative CRT at our hospital between 2002 and 2008. Patients were divided into 2 groups (efficacy grouping) to evaluate the efficacy of preoperative CRT according to the clinical course. Group A included patients who were unable to receive the subsequent resection due to the development of unresectable factors during preoperative CRT and those who received the subsequent resection but developed recurrent disease within 6 months after surgery; group B included patients who received the subsequent resection and survived without recurrences for more than 6 months after surgery. We developed a new classification utilizing pretreatment CA19–9 and proportional alteration of CA19–9 2 months after the initiation of treatment. The categories were defined as: I (increased), MD (modestly decreased), and SD (substantially decreased). Clinicopathological variables and CA19–9 alteration status were correlated with the efficacy grouping and overall survival. Results:All of the category I patients were included in group A, 93.5% of the category SD patients in group B, and approximately half of the category MD patients in group A. CA19–9 alteration status was a single independent variable associated with efficacy grouping and overall patient survival, with the 1-year survival rate of category I patients, and the 4-year survival rate of category MD and SD patients being 22.2%, 34.1%, and 58.9%, respectively. Conclusions:CA19–9 alteration status is useful in identifying those who will benefit from the preoperative CRT and subsequent resection and those who will not; it was a significant predictor for patient prognosis in the setting of the preoperative CRT strategy for resectable PC.

Serum REG4 level is a predictive biomarker for the response to preoperative chemoradiotherapy in patients with pancreatic cancer.

Objectives: Preoperative chemoradiotherapy is one of the key strategies for the improvement of survival in pancreatic cancer; however, no method to predict the response has yet been established. The aim of this study was to prospectively evaluate the predictive value of REG4, a new member of the regenerating (REG) islet-derived family of proteins. Methods: Stably REG4-expressing cells were established from a pancreatic cancer cell line and exposed in vitro to &ggr;-ray or gemcitabine to investigate the relevance of REG4 to the resistance to chemotherapy or radiotherapy. In 23 patients with resectable pancreatic cancer, the serum concentration of REG4 was measured before preoperative chemoradiotherapy, and the histologic response was evaluated after the surgery. Results: A 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and fluorescence activated cell scanning (FACS) revealed that REG4-overexpressing cells were resistant to &ggr;-radiation but showed a modest resistance to gemcitabine. The patients with a higher REG4 level, but not carcinoembryonic antigen or CA-19-9, showed an unfavorable histologic response to chemoradiotherapy (Spearman, &rgr; = 0.439, P = 0.039). The patients showing a higher REG4 level experienced local recurrence postoperatively. Conclusions: These data demonstrated in vitro and in vivo that REG4 protein overexpression was associated with an unfavorable response to preoperative chemoradiotherapy. REG4 can clinically be used as a predictive biomarker.

Histopathological effects of preoperative chemoradiotherapy for pancreatic cancer: An analysis for the impact of radiation and gemcitabine doses

BACKGROUND AND PURPOSEnHistopathological findings of patients who underwent resection for pancreatic adenocarcinoma (PC) after preoperative chemoradiotherapy (CRT) reportedly showed beneficial effects. The purpose of our study was to evaluate the correlation between histopathological effects (HE) of preoperative CRT and treatment parameters [radiation and gemcitabine (GEM) doses].nnnMATERIAL AND METHODSnHE of CRT were assessed on 158 primary lesions of 157 patients with PC who underwent pancreatic resection after preoperative CRT with GEM between January 2006 and December 2011. The radiation dose delivered to the primary tumor site and surrounding regional nodal areas was 50 Gy until September 2009 followed by the dose escalation of a 10 Gy boost added for delivery with the field-in-field technique to the roots of the celiac and superior mesenteric arteries. Intravenous administration of GEM (1000 /m(2)) was initiated concurrently on days 1, 8, and 15, every 4 weeks and generally repeated for 3 cycles. HE of CRT on the primary tumor were categorized based on the number of tumor cells destroyed.nnnRESULTSnThe median overall survival time was 74.5 months and 3-year and 5-year survival rates were 64.3% and 54.5%, respectively. Dose-volume parameters of radiation such as D33 with a cut-off value of 51.6 Gy were correlated significantly with HE (p=.0230). Lesions having received GEM>7625 mg/m(2) before surgical resection more frequently showed positive HE (p=.0002). Multivariate logistic regression analysis demonstrated that both D33 and cumulative GEM dose were significant predictors of definite HE (p=.0110 and <.0001, respectively).nnnCONCLUSIONSnOur retrospective analysis showed that dose intensity of radiation and GEM is significantly related to HE of preoperative CRT for PC.

Feasibility and Efficacy of Combination Therapy With Preoperative and Postoperative Chemoradiation, Extended Pancreatectomy, and Postoperative Liver Perfusion Chemotherapy for Locally Advanced Cancers of the Pancreatic Head

BackgroundThe outcome after resection of advanced pancreatic cancers is extremely poor because of the high incidence of the postoperative development of liver metastasis and local recurrence. We performed a combination of chemoradiation and liver perfusion chemotherapy and extended pancreatectomy.MethodsNineteen patients with T3 pancreatic head cancers were enrolled. A total of 24 Gy in 12 fractions of 10-MV x-rays with a concurrent intravenous infusion of 5-fluorouracil (5-FU; 3 g/12 days) was administered to the pancreatic head area. An extended pancreaticoduodenectomy was performed, and catheters were placed into the gastroduodenal artery and the superior mesenteric vein. During the first 28 postoperative days, 5-FU was continuously infused via the hepatic artery and portal vein (3.5 g/28 days × 2). Finally, 36 Gy in 18 fractions with 5-FU (3 g/6 days) was applied to the pancreatic bed.ResultsAfter preoperative chemoradiation, four patients did not undergo surgical resection because of distant metastases. Fifteen patients underwent pancreaticoduodenectomy, liver perfusion chemotherapy, and postoperative chemoradiation. No patient developed grade 3 toxicity as a result of preoperative chemoradiation, but one patient (7%) developed grade 3 leukopenia during the postoperative treatments. The morbidity rate was 20% (3 of 15 patients), and the mortality rate was 0%. The overall 3-year survival rate was 53%. The 3-year disease-free survival rate was 66% in patients who pathologically responded well (>50%), versus 0% in patients with poor responses (Pxa0=xa0.04).ConclusionsA combination of preoperative and postoperative chemoradiation plus postoperative liver perfusion chemotherapy with an extended pancreatectomy is feasible, and the long-term outcomes are also promising.

Risk factors for vertebral compression fractures in preoperative chemoradiotherapy with gemcitabine for pancreatic cancer

BACKGROUND AND PURPOSEnPreoperative chemoradiotherapy (CRT) with gemcitabine (GEM) for pancreatic cancer is often accompanied by vertebral compression fractures (VCFs). This study aimed to establish the incidence of VCFs and identify the related risk factors (RFs) to elucidate how to decrease the overall incidence of VCF.nnnMATERIAL AND METHODSnWe investigated 220 patients with resectable or borderline-resectable pancreatic cancers who had completed preoperative CRT between 2006 and 2011. The RFs associated with VCF were analyzed in a total of 1308 thoracolumbar vertebral bodies.nnnRESULTSnThirty-seven VCFs occurred in 25 patients (11%); the cumulative incidence at two years was 18.9%. Univariate analysis revealed female sex, age and high daily GEM concentration during radiotherapy as RFs for VCF. The multivariate mixed effects logistic regression model demonstrated that the most responsible factor was radiation dose (p<0.001). We estimated the radiation condition resulting in a fracture incidence of ⩽5% by counting the patients number of the three RFs. For patients with three factors, the mean vertebral dose was 22.0 Gy.nnnCONCLUSIONSnThe RFs for VCF after CRT were identified. The side effect of VCF might be avoided by regulating the radiation dose to neighboring vertebral bodies after considering the RFs.

Couch height–based patient setup for abdominal radiation therapy

There are 2 methods commonly used for patient positioning in the anterior-posterior (A-P) direction: one is the skin mark patient setup method (SMPS) and the other is the couch height-based patient setup method (CHPS). This study compared the setup accuracy of these 2 methods for abdominal radiation therapy. The enrollment for this study comprised 23 patients with pancreatic cancer. For treatments (539 sessions), patients were set up by using isocenter skin marks and thereafter treatment couch was shifted so that the distance between the isocenter and the upper side of the treatment couch was equal to that indicated on the computed tomographic (CT) image. Setup deviation in the A-P direction for CHPS was measured by matching the spine of the digitally reconstructed radiograph (DRR) of a lateral beam at simulation with that of the corresponding time-integrated electronic portal image. For SMPS with no correction (SMPS/NC), setup deviation was calculated based on the couch-level difference between SMPS and CHPS. SMPS/NC was corrected using 2 off-line correction protocols: no action level (SMPS/NAL) and extended NAL (SMPS/eNAL) protocols. Margins to compensate for deviations were calculated using the Stroom formula. A-P deviation > 5mm was observed in 17% of SMPS/NC, 4% of SMPS/NAL, and 4% of SMPS/eNAL sessions but only in one CHPS session. For SMPS/NC, 7 patients (30%) showed deviations at an increasing rate of > 0.1mm/fraction, but for CHPS, no such trend was observed. The standard deviations (SDs) of systematic error (Σ) were 2.6, 1.4, 0.6, and 0.8mm and the root mean squares of random error (σ) were 2.1, 2.6, 2.7, and 0.9mm for SMPS/NC, SMPS/NAL, SMPS/eNAL, and CHPS, respectively. Margins to compensate for the deviations were wide for SMPS/NC (6.7mm), smaller for SMPS/NAL (4.6mm) and SMPS/eNAL (3.1mm), and smallest for CHPS (2.2mm). Achieving better setup with smaller margins, CHPS appears to be a reproducible method for abdominal patient setup.

Accumulated Dose of Intensity-Modulated Radiotherapy for Head and Neck Cancer Using Deformable Registration of Two Sets of Computed Tomography Images

Purpose: The aim of this study was, using deformable image registration (DIR), to evaluate alteration of dose distribution caused by patient’s anatomical structure changes during a two-phase intensity-modulated radiotherapy (IMRT). nMethods: IMRT consisted of an initial plan delivering 53 Gy to gross tumor volume (GTV) and 45 Gy to elective volumes and a boost plan delivering 16.96 Gy to GTV. The subjects were 10 patients with head and neck cancer who underwent computed tomography (CT) scans twice (first CT before treatment and second CT before boost). A sum of the initial and the boost plans for the first CT was Original total plan. Using DIR, the original boost and a modified new boost plan were recalculated on the second CT and summed with the initial plan to create total plans: DIR plan and modified DIR plan. nResults: Mean dose (Dmean) of the ipsilateral and contralateral parotids were increased by 8.0% (P<0.01) and 6.8% (P<0.05) in DIR plan compared with Original total plan. Compared with DIR plan, modified DIR plan reduced Dmean of the ipsilateral parotid (P<0.01). Dose to 95% of the volume (D95) to clinical target volume for GTV (CTV1) of DIR plan was significantly higher than that of Original total plan (P<0.01) and modified DIR plan (P<0.01). nConclusions: Dose summation using DIR demonstrated that the body shrinking during IMRT significantly increased the doses of both parotids and CTV1. Modified DIR plan compensated the increases in doses of the ipsilateral parotid and CTV1.

Prospective small bowel mucosal assessment immediately after chemoradiotherapy of unresectable locally advanced pancreatic cancer using capsule endoscopy: a case series

In this case series, three consecutive patients with unresectable locally advanced pancreatic cancer (ULAPC) underwent capsule endoscopy (CE) before and after chemoradiotherapy (CRT) to evaluate duodenal and jejunal mucosa, and to examine the relationship between CE findings and dose distribution. CE after CRT showed duodenitis and proximal jejunitis in all three patients. The most inflamed region was the third part of the duodenum, and in dose distribution, this was the closest region to the center of irradiation. This case series shows that CE can safely diagnose acute duodenitis and proximal jejunitis caused by CRT for ULAPC, and that dose distribution is possible to predict the degree of duodenal and jejunal mucosal injuries.

Maximum Intensity Projection (MIP) and Average Intensity Projection (AIP) in Image Guided Stereotactic Body Radiation Therapy (SBRT) for Lung Cancer

Maximum Intensity Projection (MIP) and Average Intensity Projection (AIP) in Image Guided Stereotactic Body Radiation Therapy (SBRT) for Lung Cancer K. Shirai, K. Nishiyama, T. Katsuda, Y. Ueda, M. Miyazaki, K. Tsujii, and S. Ueyama; Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3, Nakamichi, Higashinari-ku, Osaka, Japan, National Cerebral and Cardiovascular Center, 5-7-1, Fujishirodai, Suita-City, Osaka, Japan

Prior splenic irradiation reduces hematologic adverse events during chemotherapy in pancreatic tail cancer: a report of a patient with liver cirrhosis

Thrombocytopenia is a major complication of liver cirrhosis that often limits the use of anticancer drugs. In this report, we describe a thrombocytopenic patient with liver cirrhosis who developed pancreatic tail cancer and underwent splenic irradiation. Particular emphasis was placed on the impact of irradiation on thrombocytopenia. A 73-year-old male with liver cirrhosis was diagnosed with pancreatic tail cancer infiltrating the splenic hilum by computed tomography (CT) and pancreatic juice cytology. His baseline platelet count was 84xa0×xa0103/mm3. A total of 50xa0Gy of irradiation to the pancreatic tail and splenic hilum was carried out as local therapy for pancreatic cancer. Splenic irradiation was also expected to reverse liver cirrhosis-related thrombocytopenia, which was making systemic chemotherapy difficult to administer in this patient. One month later, systemic gemcitabine chemotherapy was commenced. At the start of chemotherapy, his platelet count remained at 93xa0×xa0103/mm3, but rose to 246xa0×xa0103/mm3 2.5xa0months later, which allowed the administration of chemotherapy without any remarkable hematologic toxicities. Post-irradiation CT revealed a low density area indicating irradiation-induced necrotic tissue that had expanded into the surrounding non-tumorous spleen parenchyma, and which may have impacted positively on the thrombocytopenia. Our case report suggests that splenic irradiation may be a potential therapeutic option for liver cirrhosis-related thrombocytopenia, especially in patients who require systemic chemotherapy for cancer.