Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity.

BACKGROUND: To review treatment toxicity for patients with pancreatic and ampullary cancer treated with proton therapy at our institution. MATERIAL AND METHODS: From March 2009 through April 2012, 22 patients were treated with proton therapy and concomitant capecitabine (1000 mg PO twice daily) for resected (n = 5); marginally resectable (n = 5); and unresectable/inoperable (n = 12) biopsy-proven pancreatic and ampullary adenocarcinoma. Two patients with unresectable disease were excluded from the analysis for reasons unrelated to treatment. Proton doses ranged from 50.40 cobalt gray equivalent (CGE) to 59.40 CGE. RESULTS: Median follow-up for all patients was 11 (range 5-36) months. No patient demonstrated any grade 3 toxicity during treatment or during the follow-up period. Grade 2 gastrointestinal toxicities occurred in three patients, consisting of vomiting (n = 3); and diarrhea (n = 2). Median weight loss during treatment was 1.3 kg (1.75% of body weight). Chemotherapy was well-tolerated with a median 99% of the prescribed doses delivered. Percentage weight loss was reduced (p = 0.0390) and grade 2 gastrointestinal toxicity was eliminated (p = 0.0009) in patients treated with plans that avoided anterior and left lateral fields which were associated with reduced small bowel and gastric exposure. DISCUSSION: Proton therapy may allow for significant sparing of the small bowel and stomach and is associated with a low rate of gastrointestinal toxicity. Although long-term follow-up will be needed to assess efficacy, we believe that the favorable toxicity profile associated with proton therapy may allow for radiotherapy dose escalation, chemotherapy intensification, and possibly increased acceptance of preoperative radiotherapy for patients with resectable or marginally resectable disease.

Dosimetric comparison of doses to organs at risk using 3-D conformal radiotherapy versus intensity modulated radiotherapy in postoperative radiotherapy of periampullary cancers: implications for radiation dose escalation.

CONTEXT: Postoperative periampullary cancers with high risk features are managed with adjuvant chemo radiotherapy. Doses of 40-50 Gy have generally been used in conventional radiotherapy. Dose escalation with conventional radiotherapy has been restricted due to surrounding critical organs. OBJECTIVE: The objective of this dosimetric analysis was to evaluate the dose of radiation received by organs at risk using 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT). METHODS: Ten postoperative patients of periampullary cancers were selected for this dosimetric analysis. Planning CT scans films were taken with slice thickness of 2.5 mm and transferred to Eclipse treatment planning system. The clinical target volume (CTV) included the postoperative tumor bed and draining lymph nodal areas. A 1 cm margin was taken around the CTV to generate the planning target volume (PTV). Critical structures contoured for evaluation included bowel bag, bilateral kidneys, liver, stomach and spinal cord. IMRT plans were generated using seven field coplanar beams and 3DCRT planning was done using one anterior and two lateral fields. A dose of 45 Gy in 25 fractions was prescribed to the PTV. RESULTS: V45 for bowel bag was 212.3 ± 159.0 cc (mean volume ± standard deviation) versus 80.9 ± 57.4 cc in 3DCRT versus IMRT (P=0.033). The V28 dose analysis for bilateral kidneys showed a value of 32.7±23.5 cc (mean volume ± standard deviation) versus 7.9 ± 7.4 cc for 3DCRT versus IMRT, respectively (P=0.013). The D60 for liver using 3DCRT and IMRT was 28.4 ± 8.6 Gy (mean dose ± standard deviation) and 19.9 ± 3.2 Gy, respectively (P=0.020). CONCLUSIONS: Doses to bowel bag, liver and kidneys was significantly reduced using IMRT leaving ample scope for dose escalation.

Adjuvant chemo-radiotherapy in ampullary cancers.

PURPOSE: Patterns of failure following surgical treatment of ampullary cancers indicate that up to 45% of patients develop loco-regional recurrence. The effect of adjuvant chemo-radiotherapy on survival and loco-regional control is not yet established in this malignancy. PATIENTS AND METHODS: From January 1989 to December 2000, 113 patients underwent pancreatico-duodenectomy for ampullary cancer. One hundred and four patients who survived the operation were available for analysis to study the effect of adjuvant chemo-radiotherapy on survival and loco-regional control. Forty-nine patients received adjuvant chemo-radiotherapy (median dose 50.4 Gy with concurrent 5-Flurouracil) and long-term outcome in these patients was compared with those 55 who did not receive adjuvant therapy. RESULTS: The overall median survival was 30.1 (range 1.6-140.0) months with actuarial 1, 3 and 5-year survival rates of 79, 43 and 33%, respectively. No significant difference in median survival (34.6 vs 24.5 months; P=0.3) and actuarial 5-year survival rates (38 vs 28%) was seen between those who received and those who did not receive adjuvant therapy. Adjuvant chemo-radiotherapy did not influence the survival in high-risk patients (P=0.84), in various T and N stages and had no impact on loco-regional recurrence (P=0.6). CONCLUSIONS: Adjuvant chemo-radiotherapy did not improve the long-term survival or decrease recurrence rates in patients with ampullary cancers who had undergone pancreatico-duodenectomy.

Adjuvant chemoradiotherapy in periampullary cancers--Where does it stand with conformal radiotherapy: A single institution experience.

BACKGROUND: Treatment of periampullary cancer involves Whipple surgery, followed by adjuvant radiotherapy and chemotherapy. Postoperative radiotherapy is particularly useful in managing high-risk patients (tumors involving the pancreas, poorly differentiated histology, involved lymph nodes and positive margins). Here, we review our results of treatment of 84 patients treated by surgery and adjuvant radiotherapy and chemotherapy. MATERIAL AND METHODS: A retrospective analysis of 84 patients of periampullary cancers treated in our department between January 2007 and December 2012 was carried out. All patients underwent Whipples surgery followed by postoperative radiotherapy 45-50 Gy/25-28 number in those presenting with high-risk features. Radiotherapy was delivered using three-dimensional conformal technique with 6 MV photons using three field treatment plans. Chemotherapy was given for 6 cycles using gemcitabine and oxaliplatin regimen repeated 2 weekly. RESULTS: Eighty four postoperative patients with high-risk features were available for the final analysis. There were 69 males and 15 female patients. There were 34.5% stage I, 57.1% stage II and 8.3% stage III patients. At end of adjuvant treatment with radiotherapy and chemotherapy 70% patients had a complete response, 7.5% had residual disease, 15% showed progressive disease, 5% were dead and 2.5% defaulted the treatment. The mean number of chemotherapy cycles received was 2.6. At 1 year follow-up the probability of disease free survival was 80% for node-negative patients versus 73% for node-positive disease (P = 0.27). Patients with stage up to IIA had a 1 year disease free survival of 83% versus 40% for patients with stage beyond IIA (P = 0.024). CONCLUSIONS: Our results showed a trend favoring lymph node negative status with disease free survival. With computed tomography based planning, adequate delineation of draining nodes is possible, and radiation toxicity has significantly decreased. Adequate coverage of nodal basins during radiotherapy planning is important, and stage of the disease seems to be an important prognostic factor.

Radiation-induced changes in mouse duodenal papilla.

Radiation-induced changes in duodenal mucosal morphology as seen by scanning electron microscopy have been widely reported in the literature. However, no comment has previously been made on any post-irradiation alteration in the duodenal papilla. This paper describes the preliminary results of an investigation into the effects of X rays on the papilla. The duodenal papilla was difficult to find in untreated and sham irradiated mice. It was identified in only two of six mice examined and was located 5.37 and 4.43 mm from the gastroduodenal junction. Eighteen hours after irradiation with 15 Gy X rays, there was little change in position or prominence of the papilla. However, 3 days after treatment, the papilla was only 2.19-3.83 mm from the pylorus. It was also more prominent, being found in all three animals studied and having a widely dilated orifice in contrast to the closed structure seen in the unirradiated specimens. It is concluded that treatment with X rays alters the structure of the duodenal papilla. There may be implications for duodenal function in this marked change in the papilla, which controls the flow of pancreatic and biliary secretions.

[Possibilities of the treatment of biliary dyskinesia by laser irradiation]. / Vozmozhnosti lecheniia diskinezii zhelchevyvodiashchikh putei s pomoshch'iu lazernogo izlucheniia.

The examination of 68 patients with biliary dysfunction determined hypokinesia of the gallbladder in 40, sphincter of Oddi spasm in 15 and combination of the two conditions in 13 patients. Blood biochemical indices showed no differences in patients with biliary dyskinesia compared to normal subjects except for alkaline phosphatase levels elevated in 35.3% of patients. This suggests the development of biliary hypertension and cholestasis. All the patients demonstrated disturbed colloid stability of the bile, in those with combined dyskinesia it became lithogenic. Helium-neon and semiconductor laser radiation of biologically active points and the hepatic region, respectively, improved the patients' performance status. The pain and dyspepsia discontinued. The function of the gallbladder and sphincter of Oddi recovered. Positive changes occurred in the blood and bile biochemistry. Laser therapy promoted bilirubin and bile cholesterol decrease. Cholic acid concentration grew, lithogenic characteristics of the bile returned to normal. It is inferred that laser therapy of biliary dyskinesia proved effective.

Obstructive component analysis of radioactive stents and common plastic stents in the bile duct.

BACKGROUND: Endoscopic placement of a iodine-125 radioactive stent is useful to treat obstructive jaundice with unresectable periampullary tumors. This study aimed to retrospectively evaluate the obstructive component of biliary radioactive stents and discuss the different obstructive mechanism with common plastic stents. PATIENTS AND METHODS: Twenty consecutive patients with malignant obstruction underwent insertion of stents into the common bile duct, including 10 radioactive stents and 10 polyethylene stents. The radioactive stents were withdrawn after ∼3 months or earlier if clinical signs suggested stent clogging. Polyethylene stents were withdrawn after physical signs suggested stent clogging. Bacteriologic analyses included identification of aerobic and anaerobic bacteria. Stent surfaces were observed by scanning electron microscopy. Stent deposition was identified by Fourier-transformed infrared spectroscopy and pyrolysis derivatization/gas chromatography/mass spectrometry. RESULTS: Radioactive stent group and polyethylene stent group stents were placed for 86 days (interquartile range 62, 114) and 146 days (interquartile range 105, 181) respectively. The placement duration of the two types of stents was statistically significant. A variety of microorganisms were cultured from the stent deposits. Scanning electron microscope images showed a thicker necrotic layer on the external surface of polyethylene stent than the radioactive stent group. The proportions of obstructive components in each stent were different, but none of them were statistically significant. Necrotic tumor tissue was found in the radioactive stent group. CONCLUSION: Similar clogging events occurred in both radioactive stents and polyethylene stents. The median duration time of the radioactive stent was shorter, probably because of the smaller inner diameter, and the radioactive seeds exerted no beneficial effect in inhibiting microorganisms.

Defining the role of adjuvant external beam radiotherapy on resected adenocarcinoma of the ampulla of vater.

The role of adjuvant radiotherapy in the treatment of ampullary carcinoma (AC) remains unclear. We hypothesized that adjuvant radiotherapy (RT) does not improve survival following resection for AC. The SEER database was queried for patients with non-metastatic AC who underwent surgery (S) from 2004 to 2010. Propensity score (PS) modeling was applied to create balanced cohorts of patients that would be equally likely to receive RT. Cox proportional hazard models were used to compare survival. Of 1,287 patients, 329 (25.6%) received adjuvant RT. Unadjusted median overall survival (OS) for patients receiving adjuvant RT compared to S alone was 27 vs. 36 months (p = 0.14). Patients receiving RT were younger (63 vs. 69 years, p < 0.001), had more advanced tumors (69 vs. 53% T3/T4, p < 0.001), and had more frequent lymph node metastasis (73 vs. 40%, p < 0.001). Adjuvant RT failed to improve both overall survival (27 vs. 29 months, p = 0.58) and disease-specific survival (36 vs. 40 months, p = 0.92) in propensity-matched cohorts, although certain imbalances remained between treatment groups. Adjuvant RT does not confer a survival benefit for patients with ampullary tumors. The lack of disease-specific survival benefit suggests that it may also not be beneficial to prevent local recurrences.

Postoperative radiotherapy in periampullary cancers: a brief review.

BACKGROUND: The treatment of periampullary cancers is complex and challenging. Adjuvant therapy for resected periampullary and pancreatic cancers has been the subject of intense clinical investigations for several decades. Periampullary cancer management has often been clubbed with pancreatic cancers. DISCUSSION: Following surgery, adjuvant chemoradiotherapy has been widely accepted as standard of care in the USA, although different prospective and retrospective studies have shown conflicting results. Controversy regarding the effectiveness of chemoradiotherapy exists in the literature, both in terms of survival as well as toxicity. However, conventional postoperative radiotherapy practice needs to be reviewed in view of changes and developments in radiation techniques in the last decade. In this article, we review the management of periampullary cancers with special emphasis on the adjuvant postoperative radiotherapy.

Endobiliary stent: marker for patient alignment in image-guided radiotherapy in pancreatic and periampullary cancers.

PURPOSE: The aim of this study was to analyse the possibility of using stent in pretreatment megavoltage computed tomography (MVCT) images with respect to that on planning kilovoltage computed tomography as tumour surrogate during matching for daily registration in cases of pancreatic and periampullary cancer treated on a TomoTherapy Hi-Art system. METHODS: Planning CT and pretreatment MVCT of the first and then after every three fractions were transferred to a FocalSim workstation for ten patients. Planning CT of each patient was independently fused with each of the seven MVCT images of that patient. The stent was contoured on all of the eight images for each patient. The difference between the three co-ordinates of centre of mass (CM) of the stent on the planning CT and seven MVCT images was found. The difference between CM of the liver and stents on the planning CT as well as on the MVCT for all seven fractions was also calculated. The mean of these differences across all patients was calculated and analysed. RESULTS: The mean difference in planning and MVCT CMs for stents in the X, Y and Z directions was 0.13 cm (±0.4), 0.16 cm (±2.2) and 0.35 cm (±0.7), respectively. Average difference between CM of the liver and stent on the planning CT in the X, Y and Z directions was found to be 1.832 cm (±1.64), 5.34 cm (±1.33) and 0.54 cm (±0.26), respectively. Average difference between CM of the liver and CM of stent on the MVCT for that day in the X, Y and Z directions was found to be 1.93 cm (±1.5), 4.6 cm (±1.03) and 0.654 cm (±0.35), respectively. CONCLUSIONS: Endobiliary stents are stable tumour localisation surrogates and can be used to correct for interfraction target motion.

Cholangiocarcinoma: clinical significance of tumor location along the extrahepatic bile duct.

PURPOSE: To define the criteria for resection and/or radiation therapy (RT) of extrahepatic bile duct cancer. MATERIALS AND METHODS: Of 81 patients with extrahepatic bile duct cancer treated from 1983 to 1992, those with proximal duct lesions (n = 56) underwent RT and/or resection or palliative care, and those with distal lesions (n = 25) underwent resection with or without RT. Follow-up was available 3-114 months (median, 28 months). RESULTS: Patients with distal bile duct cancer lived longer than patients with proximal bile duct cancer (survival with Kaplan-Meier analysis, 53% vs 13% at 5 years, respectively, P < .01). Median survival in patients with proximal cancer after RT was more than double that without RT (17 months vs 6 months, respectively, regardless of stage [P = .01]); survival was not significantly different after resection. In patients with distal cancer, RT after resection made no significant difference in median survival (68 months). CONCLUSION: Patients with proximal cancer should undergo primary RT, and expectations should be limited. Patients with distal cancer should undergo resection, and RT may not be needed.