Survival Benefit of Adjuvant Chemoradiotherapy in Patients With Ampulla of Vater Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis focusing on the impact of adjuvant radiotherapy (RT) on overall survival (OS) in ampulla of Vater (AoV) cancer. BACKGROUND: The adjuvant treatment for AoV cancer is a subject of controversy without convincing evidence from randomized study. METHODS: A comprehensive search was performed in the databases of EMBASE, PubMed, Web of Science, Cochrane Library, and Ovid from inception to July 2014. We included studies, which compared survival between patients with or without adjuvant RT after curative surgery solely for AoV cancer. Hazard ratio (HR) for OS was extracted, and a random-effects model was used for pooled analysis. RESULTS: Ten retrospective studies including 3361 patients met all inclusion criteria and were included for the final meta-analysis. Adjuvant RT was delivered with concurrent chemotherapy, mostly 5-fluorouracil, in all institutional studies. Generally, adjuvant RT groups included more patients with locally advanced disease or lymph node metastasis than did the surgery alone groups. The pooled results demonstrated that adjuvant RT significantly reduced the risk of death (HR = 0.75; P = 0.01). Exploratory analyses showed that patients with lymph node metastasis (HR = 0.52; P = 0.001) and locally advanced disease (HR = 0.42; P = 0.001) may also have survival benefit from adjuvant RT. No clear evidence of publication bias was found. CONCLUSIONS: This is the first meta-analysis evaluating the role of adjuvant RT in AoV cancer. Our results suggest the potential for survival benefit of adjuvant chemoradiotherapy. Further studies, preferably randomized clinical trials, are needed to confirm our results.

Prognostic stratification of brain metastases from hepatocellular carcinoma.

The aim of this study is to evaluate prognostic factors of brain metastases from hepatocellular carcinoma. Medical records of 95 patients who have been diagnosed of brain metastases from hepatocellular carcinoma between January 2000 and December 2011 were retrospectively reviewed. The median age at diagnosis of brain metastases is 56.1 years. Eighty-two patients were male. Median interval from diagnosis of hepatocellular carcinoma to brain metastases was 29.5 months. Eighty-eight patents had extracranial metastases, and the lung was the most frequent involved organ. Motor weakness was the most frequent presenting symptom (49.5%). Intracranial hemorrhage was present in 71 patients (74.7%). Brain metastases were treated with whole brain radiation therapy (WBRT) alone in 57 patients, radiosurgery alone in 18, surgery and WBRT in 6, surgery and radiosurgery in 3, surgery alone in 3, radiosurgery and WBRT in 2, and conservative management only in 6. Median overall survival was 3.0 months. Multivariate analysis showed ECOG performance status, Child-Pugh class, AFP level, number of brain lesions, and treatment modality were associated with survival (p < 0.05). When patients were stratified with four prognostic factors including ECOG performance status, Child-Pugh class, AFP level, and number of brain lesions, median survival time for patients with 0-1, 2, 3-4 risk factors were 5.8 months, 2.5 months and 0.6 months, respectively (p < 0.001). In conclusion, we can estimate the survival of patients by prognostic stratification, although overall prognosis of patients with brain metastases from hepatocellular carcinoma is poor.

Impact of multimodality approach for patients with leptomeningeal metastases from solid tumors.

The purpose of this study was to evaluate treatment patterns, outcome and prognosticators for patients with leptomeningeal metastases from solid tumor. Medical records of 80 patients from January 1, 2004 to May 31, 2011 were retrospectively reviewed. Most frequent site of origin was the lung (59%) followed by the breast (25%). Most patients were treated with intrathecal chemotherapy (90%) and/or whole brain radiotherapy (67.5%). Systemic therapy was offered to 27 patients (33.8%). Percentage of patients treated with single, dual, and triple modality were 32.5%, 43.8%, and 23.8%, respectively. Median survival was 2.7 months and 1 yr survival rate was 11.3%. Multivariate analysis showed that negative cerebrospinal fluid cytology, fewer chemotherapy regimen prior to leptomeningeal metastases, whole brain radiotherapy, systemic therapy, and combined modality treatment (median survival; single 1.4 vs. dual 2.8 vs. triple 8.3 months, P<0.001) had statistical significance on survival. Subgroup analysis of non-small cell lung cancer (NSCLC) patients showed that targeted therapy had significant independent impact on survival (median survival; 10.5 vs. 3.0 months, P=0.008). Unlike previous reports, survival of patients with NSCLC primary was comparable to breast primary. Furthermore, combined modality treatment for all patients and additionally targeted therapy for NSCLC patients should be considered in the treatment of leptomeningeal metastases from solid tumor.

The influence of the treatment response on the impact of resection margin status after preoperative chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND: Circumferential resection margin (CRM) and distal resection margin (DRM) have different impact on clinical outcomes after preoperative chemoradiotherapy (CRT) followed by surgery. Effect and adequate length of resection margin as well as impact of treatment response after preoperative CRT was evaluated. METHODS: Total of 403 patients with rectal cancer underwent preoperative CRT followed by total mesorectal excision between January 2004 and December 2010. After applying the criterion of margin less than 0.5 cm for CRM or less than 1 cm for DRM, 151 cases with locally advanced rectal cancer were included as a study cohort. All patients underwent conventionally fractionated radiation with radiation dose over 50 Gy and concurrent chemotherapy with 5-fluorouracil or capecitabine. Postoperative chemotherapy was administered to 142 patients (94.0%). Median follow-up duration was 43.1 months. RESULTS: The 5-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) rates, and locoregional control rates (LRC) were 84.5%, 72.8%, 74.2%, and 86.3%, respectively. CRM of 1.5 mm and DRM of 7 mm were cutting points showing maximal difference in a maximally selected rank method. In univariate analysis, CRM of 1.5 mm was significantly related with worse clinical outcomes, whereas DRM of 7 mm was not. In multivariate analysis, CRM of 1.5 mm, and ypN were prognosticators for all studied endpoints. However, CRM was not a significant prognostic factor for good responders, defined as patients with near total regression or T down-staging, which was found in 16.5% and 40.5% among studied patients, respectively. In contrast, poor responders demonstrated a significant difference according to the CRM status for all studied end-points. CONCLUSIONS: Close CRM, defined as 1.5 mm, was a significant prognosticator, but the impact was only prominent for poor responders in subgroup analysis. Postoperative treatment strategy may be individualized based on this finding. However, findings from this study need to be validated with larger cohort.

Outcome analysis of salvage radiotherapy for occult cervical cancer found after simple hysterectomy.

OBJECTIVE: The objective was to analyze the outcomes of the patients, who received salvage radiotherapy for incidentally discovered cervical cancer following simple hysterectomy, and to identify the influence of intracavitary radiotherapy on treatment outcomes. METHODS: Data from 117 patients with occult cervical cancer who underwent simple hysterectomy followed by salvage radiotherapy from September 1979 to November 2010 were collected. All the patients received external beam radiotherapy with (n = 45) or without (n = 72) intracavitary radiotherapy. Local control, disease-free survival, overall survival and treatment-related toxicity were investigated. RESULTS: The median follow-up time was 75 months. The 5- and 10-year local control/disease-free survival/overall survival rates were 93/87/87% and 90/84/83%, respectively. Among 98 patients who had no residual disease and negative resection margin on surgical specimens, 32 (33%) received intracavitary radiotherapy and 66 (67%) did not. There were no differences in patient and tumor characteristics between patients treated with and without intracavitary radiotherapy. The 5-year local control rate for the non-intracavitary radiotherapy group was 93 versus 94% for the intracavitary radiotherapy group (P = 0.564); the disease-free survival rate was 88 versus 94% (P = 0.894); the overall survival rate was 95 versus 85% (P = 0.106), respectively. Among all patients, there were 5% of Grade 3 or higher late toxicities. CONCLUSIONS: Patients with occult invasive cervical cancer discovered following simple hysterectomy could be treated safely and effectively with salvage radiotherapy. For patients with no residual disease and negative resection margin, intracavitary radiotherapy could be omitted.

20 year experience of postoperative radiotherapy in IB-IIA cervical cancer patients with intermediate risk factors: impact of treatment period and concurrent chemotherapy.

OBJECTIVE: To compare the long-term clinical outcomes of adjuvant radiotherapy (RT) versus concurrent chemoradiotherapy (CCRT) in cervical cancer patients with intermediate risk factors. METHODS: Between 1990 and 2010, 110 cervical cancer patients with 2 or more intermediate risk factors (deep stromal invasion, lymphovascular space invasion, and large tumor size) underwent adjuvant RT (n=56) or CCRT (n=54) following radical surgery. Because CCRT had been performed since 2000, patients were divided into 3 groups regarding treatment period and the addition of chemotherapy, RT 1990-1999 (n=39), RT 2000-2010 (n=17) and CCRT 2000-2010 (n=54). Majority of concurrent chemotherapeutic regimens were carboplatin and paclitaxel (n=48). RESULTS: Five-year relapse-free survival (RFS) rates for RT 1990-1999, RT 2000-2010 and CCRT 2000-2010 were 83.5%, 85.6% and 93.8%, respectively. CCRT 2000-2010 had a significant decrease in pelvic recurrence (p=0.012) and distant metastasis (p=0.027). There were no significant differences in overall survival and RFS between RT 1990-1999 and RT 2000-2010. Acute grade 3 and 4 hematologic toxicities were more frequently observed in CCRT 2000-2010 (p<0.001). However, acute grade 3 and 4 gastrointestinal (GI) and chronic toxicities did not differ between the groups. CONCLUSIONS: This study shows that the addition of concurrent chemotherapy to postoperative RT in cervical cancer patients with intermediate risk factors may improve RFS without increasing acute GI and chronic toxicities, although hematologic toxicities increased significantly.

High survivin expression as a predictor of poor response to preoperative chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: To evaluate seven molecular markers including cyclooxygenase -2, epidermal growth factor receptor, Ki-67, p21, survivin, thymidylate synthase, and vascular endothelial growth factor for prediction of response to preoperative chemoradiotherapy in locally advanced rectal cancer. MATERIALS AND METHODS: Fifty-four patients with clinical T3-4 and/or node-positive rectal cancer who underwent preoperative chemoradiotherapy followed by surgical resection were enrolled into this study. Preoperative chemoradiotherapy consisted of 50.4 Gy of pelvic irradiation with concomitant 5-fluorouracil or oral capecitabine. Expression of molecular markers in pretreatment paraffin-embedded tumor biopsy specimens was assessed by immunohistochemical staining on the tissue microarray. Tumor downstaging was used as an endpoint for evaluation of tumor response. RESULTS: Tumor downstaging was observed in 22 patients (41%), and pathologic complete remission in 7 patients (13%). Among seven molecular markers, only survivin expression was significantly related with tumor downstaging: 26% with high survivin expression (>75% in extent) vs. 72% with low survivin expression (p = 0.0011). However, other six molecular markers were found not to have any correlation with tumor downstaging. CONCLUSIONS: High survivin expression in pretreatment tumor biopsy was associated with less tumor downstaging after preoperative chemoradiotherapy for locally advanced rectal cancer.

Age <40Years is an independent prognostic factor predicting inferior overall survival in patients treated with breast conservative therapy.

To evaluate the effect of age at diagnosis on the treatment outcome after breast conservative therapy (BCT), retrospective analysis was done for 378 patients undergoing BCT for early breast cancer. Patients were divided into two groups according to their age: 'younger' (<40years, n=108) and 'older' (≥40years, n=270). Multivariate analysis was performed on the variables including tumor characteristics, the use of systemic therapy, and age to assess risk factors for local-regional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival rates (OS). The median follow-up duration was 94months. The 8-year LRRFS, DMFS, and OS for younger and older groups were 88.1% and 96.5% (p=0.0022); 85.7% and 93.7% (p=0.0310); 89.2% and 95.9% (p=0.0205), respectively. On multivariate analysis, younger age was the only significant predictor of poor LRRFS (p=0.0022). Younger age and ER negativity showed borderline significance for DMFS (p=0.0828 and 0.0618, respectively). Younger age had trend toward inferior OS (p=0.0702). In conclusion, age younger than 40years was associated with inferior LRRFS in early breast cancer patients treated with BCT. There was also a trend for inferior DMFS and OS in younger patients. Age at diagnosis should be considered for individualized patient management.

Impact of delayed radiotherapy on local control in node-negative breast cancer patients treated with breast-conserving surgery and adjuvant radiotherapy without chemotherapy.

AIM AND BACKGROUND: To evaluate the effect of the surgery-radiotherapy interval (SRI) on local control in node-negative breast cancer patients treated with breast-conserving surgery and adjuvant radiotherapy without chemotherapy. METHODS: From February 1992 to January 2002, 171 patients with node-negative breast cancer underwent breast-conserving surgery and adjuvant radiotherapy without chemotherapy. The whole breast was irradiated up to 50.4 Gy in 28 fractions followed by a 10-Gy boost to the tumor bed. Forty-four patients received tamoxifen in addition to radiotherapy. Patients were divided into 2 groups according to the length of SRI: <6 weeks (128 patients) versus ≥6 weeks (43 patients). The median follow-up period was 87 months (range, 22-167). RESULTS: The 8-year local control rates of patients with SRI <6 weeks and ≥6 weeks were 94.5% and 92.7%, respectively (P = 0.1140). When age, tumor size, resection margin status, combination with hormonal therapy, and SRI were incorporated into the Cox proportional hazards model, SRI <6 weeks and age at diagnosis ≥40 years were associated with increased local control (P = 0.0343 and 0.0264, respectively). In the subgroup analysis, SRI <6 weeks was correlated with a higher local control rate for patients aged <40 years (P = 0.0142). Among older patients, however, there was no statistical difference in local control according to SRI (P = 0.6655). Treatment interval had no impact on overall and distant metastasis-free survival. CONCLUSIONS: Early radiotherapy within 6 weeks of breast-conserving surgery is associated with increased local control in patients with node-negative breast cancer not undergoing chemotherapy.

Concurrent versus sequential administration of CMF chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer.

AIMS AND BACKGROUND: To compare the outcome of concurrent versus sequential administration of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy after breast-conserving surgery in early breast cancer. METHODS: From February 1992 to January 2002, 156 patients underwent CMF chemotherapy and radiotherapy, either concurrently (CCRT group, 88 patients) or sequentially (SCRT group, 68 patients). There was a predilection of patients with a larger tumor (P = 0.0035), with more frequent nodal involvement (P = 0.0686), and younger age (P = 0.0776) in the CCRT group. RESULTS: The planned radiotherapy was completed in every patient. No grade 3 or 4 late treatment-related toxicity was observed in the CCRT or SCRT group. Compliance to the treatment as well as cosmetic outcome of the two groups were comparable. Despite more adverse factors for local-regional recurrence in the CCRT group, the 5-year local-regional control rate of the CCRT group was similar to that of the SCRT group (97.7% vs 93.8%, respectively, P = 0.1688). On multivariate analysis, concomitant administration of chemotherapy and radiotherapy was associated with improved local-regional control (P = 0.0463). CONCLUSIONS: Concurrent administration of CMF chemotherapy and radiotherapy resulted in improved local-regional control over sequential administration without an increase in significant toxicity. Concurrent CMF chemoradiotherapy may serve as a viable option for patients at high-risk of local-regional relapse not suitable for anthracycline or taxane-based chemotherapy.

Phase II Trial of Postoperative Adjuvant Gemcitabine and Cisplatin Chemotherapy Followed by Chemoradiotherapy with Gemcitabine in Patients with Resected Pancreatic Cancer.

PURPOSE: Despite curative resection, the 5-year survival for patients with resectable pancreatic cancer is less than 20%. Recurrence occurs both locally and at distant sites and effective multimodality adjuvant treatment is needed. MATERIALS AND METHODS: Patients with curatively resected stage IB-IIB pancreatic adenocarcinoma were eligible. Treatment consisted of chemotherapy with gemcitabine 1,000 mg/m2 on days 1 and 8 and cisplatin 60 mg/m2 on day 1 every 3 weeks for two cycles, followed by chemoradiotherapy (50.4 Gy/28 fx) with weekly gemcitabine (300 mg/m2/wk), and then gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks for four cycles. The primary endpoint was 1-year disease-free survival rate. The secondary endpoints were disease-free survival, overall survival, and safety. RESULTS: Seventy-four patients were enrolled. One-year disease-free survival rate was 57.9%. Median disease-free and overall survival were 15.0 months (95% confidence interval [CI], 11.6 to 18.4) and 33.0 months (95% CI, 21.8 to 44.2), respectively. At the median follow-up of 32 months, 57 patients (77.0%) had recurrence including 11 patients whose recurrence was during the adjuvant treatment. Most of the recurrences were systemic (52 patients). Stage at the time of diagnosis (70.0% in IIA, 51.2% in IIB, p=0.006) were significantly related with 1-year disease-free survival rate. Toxicities were generally tolerable, with 53 events of grade 3 or 4 hematologic toxicity and four patients with febrile neutropenia. CONCLUSION: Adjuvant gemcitabine and cisplatin chemotherapy followed by chemoradiotherapy with gemcitabine and maintenance gemcitabine showed efficacy and good tolerability in curatively resected pancreatic cancer.

High glucose-induced apoptosis in bovine retinal pericytes is associated with transforming growth factor beta and betaIG-H3: betaIG-H3 induces apoptosis in retinal pericytes by releasing Arg-Gly-Asp peptides.

BACKGROUND: Transforming growth factor beta (TGF-beta) plays an important role in diabetic retinopathy. betaIG-H3 is a downstream target molecule of TGF-beta that may participate in the pathogenesis of diabetic retinopathy and in particular in the loss of pericytes during early pathological changes. METHODS: We observed bovine retinal pericytes apoptosis and the increased expression of TGF-beta and betaIG-H3 induced by high concentrations of glucose in the cell culture media. An anti-TGF-beta antibody was used to block glucose-induced retinal pericytes apoptosis. Retinal pericytes were also transfected with cDNA encodings either wild-type or mutant betaIG-H3 lacking Arg-Gly-Asp (RGD) sequences in order to validate the effects of betaIG-H3 and RGD signalling on retinal pericytes apoptosis. RESULTS: A cell death-detecting enzyme-linked immunosorbent assay revealed that 25 mM glucose significantly increased cell death compared with 5.5 mM glucose after 5 or 7 days of exposure (P < 0.01). High glucose significantly increased the TGF-beta levels as compared with 5.5 mM glucose after 5 days, and betaIG-H3 levels after 3, 5 and 7 days of exposure (P < 0.01). TGF-beta increased cell death and betaIG-H3 levels in a dose-dependent manner, with a maximal effect observed at 1 ng/mL. An anti-TGF-beta antibody nearly completely blocked high glucose-induced cell death. Wild-type betaIG-H3-transfected cells showed a significant increase in cell death as compared with mutant betaIG-H3-transfected (Mycb-c) cells, untransfected or mock-transfected cells. CONCLUSION: These results suggest that hyperglycaemia-induced expression of TGF-beta and betaIG-H3 contributes to accelerated retinal pericytes apoptosis. betaIG-H3 induces pericytes apoptosis through its RGD motif, which may constitute an important pathogenic mechanism leading to pericytes loss in diabetic retinopathy.

Prognostic value of p53 and bcl-2 expression in patients treated with breast conservative therapy.

Prognostic value of p53 and bcl-2 expression on treatment outcome in breast cancer patients has been extensively evaluated, but the results were inconclusive. We evaluated the prognostic significance of these molecular markers in patients treated with breast conserving surgery and radiotherapy. One hundred patients whose immunostaining of p53 and bcl-2 expression was available among 125 patients who underwent radiotherapy after breast conserving surgery and axillary lymph node dissection were enrolled into this study. Eighty-seven patients also received adjuvant chemotherapy and/or hormonal therapy. Conventional clinicopathologic variables and treatment-related factors were also considered. The 5-yr loco-regional relapse-free and distant metastasis-free survival rates were 91.7% and 90.9%, respectively. On univariate analysis, age, T stage and the absence of bcl-2 & estrogen receptor (ER) expression were associated with loco-regional relapse-free survival. When incorporating these variables into Cox proportional hazard model, only bcl-2(-)/ER(-) phenotype was an adverse prognostic factor (P=0.018). As for the distant metastasis-free survival, age, T stage, and p53 expression were significant on univariate analysis. However, p53 expression was the only prognosticator on multivariate analysis (P=0.009). A bcl-2(-)/ER(-) phenotype and p53 expression are useful molecular markers predicting loco-regional relapse-free and distant metastasis-free survival, respectively, in patients treated with breast conserving surgery and radiotherapy.

Ramosetron for the prevention of nausea and vomiting during 5-fluorouracil-based chemoradiotherapy for pancreatico-biliary cancer.

OBJECTIVE: The aim of the study was to evaluate the role of ramosetron for the prevention of chemoradiotherapy-induced nausea and vomiting (CRINV) in patients receiving upper abdominal irradiation with concurrent 5-fluorouracil chemotherapy. METHODS: Between November 2006 and April 2007, 25 patients with pancreatico-biliary cancer underwent adjuvant chemoradiotherapy. A total dose of 40 Gy was delivered using 2 Gy/fraction, 5 days a week, with 2 weeks of planned rest after 20 Gy. Concomitant 5-fluorouracil (500 mg/m(2)/day i.v. bolus) was administered for the first 3 days of each split course. During the first course of chemoradiotherapy, all patients had prophylactic metoclopramide before treatment and those refractory to metoclopramide received rescue medication with ondansetron. During the second course of chemoradiotherapy, prophylactic ramosetron was given to patients who were refractory to ondansetron. Response to antiemetics was scored in four tiers: none, no CRINV; mild, did not interfere with normal daily life; moderate, interfered with normal daily life and severe, patient bedridden because of CRINV. RESULTS: Fifty-six percent of the patients (14 of 25) had moderate CRINV despite metoclopramide, and received ondansetron. Ten patients who experienced moderate CRINV despite the ondansetron had prophylactic ramosetron, and 60% of the patients (6 of 10) had the symptom improved. CONCLUSIONS: Ramosetron proved to be an effective alternative for the control of CRINV during upper abdominal irradiation with concurrent 5-fluorouracil chemotherapy.

Negative impact of heat exposure on cosmesis after conservative treatment for breast cancer.

AIM AND BACKGROUND: To identify the factors influencing cosmesis after conservative treatment in breast cancer. METHODS: Retrospective analysis was done on 424 patients who underwent postoperative radiotherapy after conservative surgery for breast cancer from February 1992 to January 2002. Most of the patients underwent quadrantectomy. Whole breast irradiation up to 50.4 Gy was delivered in 28 fractions followed by a 10 Gy boost in 5 fractions to the tumor bed. Regional lymph node irradiation was administered if indicated. Breast cosmesis was scored in 4 tiers. Breast symmetry was analyzed by the relative distance from the sternal notch to the nipple, using photos taken prior to radiotherapy and 2 years after its completion. Median follow-up was 64 months. RESULTS: Breast cosmesis was excellent in 15%, good in 63%, fair in 19%, and poor in 3% of the patients. In multivariate analysis, tumors >2 cm (P = 0.0109), lower quadrant location (P = 0.0026), lymph node irradiation (P = 0.0028), and heat exposure (P = 0.0152) were related to poor cosmesis. The cosmesis score after radiotherapy compared to the pre-radiotherapy score was deteriorated in patients who had undergone lymph node irradiation (P < 0.0001) and heat exposure (P = 0.0027). Breast symmetry was worse for patients who had tumors >2 cm (P < 0.0001), upper quadrant tumor location (P < 0.0001), chemotherapy in combination with radiotherapy (P = 0.0136), lymph node irradiation (P = 0.0006) and heat exposure (P = 0.0355). Changes in symmetry by radiotherapy were greater for lymph node-irradiated patients (P < 0.0001). CONCLUSIONS: With larger tumor size, lymph node irradiation, and chemotherapy in combination with radiotherapy, heat exposure was found to have a negative impact on cosmesis in patients undergoing conservative treatment for breast cancer. Patients should therefore be advised to avoid heat exposure after breast irradiation.

Impact of radiation dose in postoperative radiotherapy after R1 resection for extrahepatic bile duct cancer: long term results from a single institution.

PURPOSE: This study was conducted to evaluate the impact of radiation dose after margin involved resection in patients with extrahepatic bile duct cancer. METHODS: Among the 251 patients who underwent curative resection followed by adjuvant chemoradiotherapy, 86 patients had either invasive carcinoma (n = 63) or carcinoma in situ (n = 23) at the resected margin. Among them, 54 patients received conventional radiation dose (40-50.4 Gy) and 32 patients received escalated radiation dose (54-56 Gy). RESULTS: Escalated radiation dose was associated with improved locoregional control (5yr rate, 73.8% vs. 47.1%, p = 0.069), but not disease-free survival (5yr rate, 43.4% vs. 32.6%, p = 0.490) and overall survival (5yr rate, 40.6% vs. 29.6%, p = 0.348). In multivariate analysis for locoregional control, invasive carcinoma at the margin (HR 2.957, p = 0.032) and escalated radiation dose (HR 0.394, p = 0.047) were independent prognostic factors. No additional gastrointestinal toxicity was observed in escalated dose group. CONCLUSIONS: Delivery of radiation dose ≥ 54 Gy was well tolerated and associated with improved locoregional control, but not with overall survival after margin involved resection. Further validation study is warranted.

Phosphorylated Akt Expression as a Favorable Prognostic Factor for Patients Undergoing Curative Resection and Adjuvant Chemoradiotherapy for Proximal Extrahepatic Bile Duct Cancer.

OBJECTIVES: To evaluate the prognostic significance of phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expressions in patients undergoing adjuvant chemoradiotherapy (CRT) for proximal extrahepatic bile duct (EHBD) cancer. METHODS: Sixty-three patients with proximal EHBD cancer who underwent curative resection followed by adjuvant CRT were enrolled into this study. Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to a median of 40 Gy (range, 40 to 54 Gy). Fifty-nine patients also received fluoropyrimidine chemotherapy as a radiosensitizer. p-Akt, p-mTOR, and PTEN expression were assessed with immunohistochemical staining on the tissue microarray. RESULTS: p-Akt, p-mTOR, and PTEN were expressed in 23 (36.5%), 17 (27.0%), and 24 patients (38.1%), respectively. p-Akt expression was associated with distant metastasis and overall survival (OS), but not with locoregional recurrence. The 5-year distant metastasis-free and OS rates were 25.8% versus 58.2% (P=0.007), and 27.5% versus 50.2% (P=0.0167) in patients with negative and positive expression, respectively. On multivariate analysis, nodal involvement was the only significant prognosticator predicting inferior distant metastasis-free survival (P=0.0105), whereas p-Akt expression had a borderline significance (P=0.0541). As for OS, p-Akt expression was a marginally significant prognosticator (P=0.0635), whereas other risk factors lost the statistical significance. CONCLUSION: p-Akt expression tended to be associated with a favorable prognosis in patients undergoing curative resection followed by adjuvant CRT for proximal EHBD cancer.

Outcome Analysis of Chemoradiation in Unresectable Pancreatic Cancer Focusing on Treatment Sequencing Strategy.

AIM: To analyze the outcomes of patients with unresectable pancreatic cancer after chemoradiotherapy (CCRT), focusing on sequencing strategy. PATIENTS AND METHODS: Data of 144 patients treated from January 1989 to December 2013 were retrospectively analyzed. Patients were divided into the scheduled group (N=27), salvage group (N=37) and upfront group (N=80) per CCRT and chemotherapy sequence. RESULTS: With a median follow-up of 10.4 months (range=1.4-164.2), median overall survival (OS) was 13.5 months. Patients in the upfront group had inferior performance status and received a lower radiation dose (p=0.007 and p<0.001, respectively). Higher radiation dose (≥45 Gy) was the sole prognosticator related with improved survival in multivariate (p=0.001) analysis, whereas treatment sequence was not a significant prognostic factor (p=0.409). CONCLUSION: No difference was found among tested sequencing strategies that were all well-tolerated, despite skewed distribution for performance and radiation dose. An upfront approach may be a viable option for patients with limited performance to undergo more active systemic chemotherapy.

Prognostic Significance of Nodal Ratio in Patients Undergoing Adjuvant Chemoradiotherapy After Curative Resection for Ampullary Cancer.

OBJECTIVES: To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients METHODS: : Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors. RESULTS: There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients.

Postoperative chemoradiotherapy of pancreatic cancer: what is the appropriate target volume of radiation therapy?

AIMS AND BACKGROUND: To evaluate the influence of radiation therapy target volume on the treatment outcome of adjuvant chemoradiotherapy for pancreatic cancer after curative resection. METHODS: Between February 1987 and July 2001, 70 patients treated with curative resection and adjuvant chemoradiotherapy for pancreatic adenocarcinoma were analyzed. There were 49 males and 21 females, with a median age of 57 years. Whipple's operation was performed in 44 patients, pylorus-preserving pancreaticoduodenectomy in 14, distal pancreatectomy in 9, and subtotal pancreatectomy in 3. Postoperative adjuvant radiotherapy was given up to 40 Gy at 2 Gy per fraction with a two-week planned rest. Intravenous 5-fluorouracil (500 mg/m2/day) was given on days 1 to 3 of each split course of radiotherapy. Until 1991, whole pancreas or preoperative tumor volume and retroperitoneal lymph nodes were irradiated (extended field, n=14). Thereafter, the target volume included the retroperitoneal lymph nodes and the involved pancreatic resection margin (limited field, n=56). The median follow-up period of all the patients was 16 months (range, 2-99). RESULTS: The overall 2- and 5-year survival rate of all patients was 29.7% and 14.0%, respectively. According to the radiotherapy target volume, the median survival time was 14 months in the extended field group and 16 months in the limited field group (P = 0.65). CONCLUSIONS: From the viewpoint of the target volume of radiotherapy, a limited field did not worsen the treatment outcome, although the survival rate was poor in both groups.