Petersen’s hernia after laparoscopic distal gastrectomy with Roux-en-Y reconstruction for gastric cancer

Background

To decrease the incidence of internal hernia after laparoscopic Roux-en-Y gastric bypass, recent recommendations indicated closure of mesenteric defects and Petersen’s defect. Laparoscopic distal gastrectomy for gastric cancer is used increasingly, so the incidence of Petersen’s hernia can also increase, but the trend has not been studied.

Methods

This study retrospectively reviewed 358 consecutive patients who underwent laparoscopic distal gastrectomy for gastric cancer at one institution, with antecolic Roux-en-Y (RY) reconstruction.

Results

Petersen’s hernia occurred in 6 (2.2 %) of 268 patients whose Petersen’s defect was not closed by a mean of 351 days after surgery. All the patients underwent reoperation with reduction and repair of the hernia except the first case. In 90 subsequent cases, with closure of the Petersen’s defect, internal hernias did not occur (0/90 cases; p = 0.06). Focusing on the totally laparoscopic procedure, Petersen’s hernia occurred in 2 (5.1 %) of 39 patients, whereas in 81 subsequent cases, with closure of Petersen’s defect, internal hernias did not occur (0/81 cases; p = 0.03).

Conclusions

Based on the recent recommendations for bariatric surgery, closure of this potential hernia defect is necessary after laparoscopic distal gastrectomy with R-Y reconstruction for gastric cancer.     

Naso-gastric or naso-jejunal decompression after partial distal gastrectomy for gastric cancer. Final results of a multicenter prospective randomized trial

Background

Only a few, small, monocentric randomized controlled trials (RCTs) have compared routine vs. no placement of a nasogastric or nasojejunal tube decompression (NG/NJT) in patients undergoing partial distal gastrectomy (PDG) for gastric cancer. However, to our knowledge, no multicenter prospective RCT has analyzed the role of decompression after both the Billroth II (BII) procedure and Roux-en-Y (RY) gastrojejunostomy. The aim of this study was to determine whether NG/NJT prevents the consequences of postoperative ileus after PDG for gastric cancer after both BII reconstruction and RY.

Methods

Two hundred seventy patients undergoing PDG for gastric cancer were randomly assigned NG/NJT placement (NG/NJT group) or not (no-NG/NJT group) with either Billroth II gastrojejunostomy or Roux-en-Y gastrojejunostomy. The patients were monitored for postoperative complications, mortality, and postoperative course.

Results

By January 2010 to June 2012, among 270 patients undergoing PDG for gastric cancer, 134 were randomly assigned to NG/NJT placement (NG/NJT group) and 136 to no decompression (no-NG/NJT group). Time to passage of flatus was significantly shorter in the NG/NJT group than in the no-NG/NJT group, but only after RY reconstruction (3.3 ± 1.5 vs. 4.3 ± 1.6 days, P < 0.001, respectively). Postoperative abdominal distention was significantly lower in the NG/NJT group than in the no-NG/NJT group after both BII and the RY procedure (P < 0.001). No significant differences in postoperative mortality or morbidity, especially anastomotic leakage or intra-abdominal sepsis, were observed between the groups.

Conclusion

Routine placement of an NG/NJT after BII and RY PDG is not necessary in elective surgery for gastric cancer.     

Laparoscopy-assisted uncut Roux-en-Y operation after distal gastrectomy for gastric cancer

In order to prevent the Roux stasis syndrome that sometimes follows Roux-en-Y gastrojejunostomy after distal gastrectomy, a new type of reconstruction, called the uncut Roux-en-Y technique, has been reported. We successfully performed 42 laparoscopy-assisted uncut Roux-en-Y gastrojejunostomies. Here we describe our technique and the initial outcome.     

The role of neuropathology in the management of progressive glioblastoma

Question

1. What are the most important diagnostic considerations in reporting progressive glioblastoma?

Target population

These recommendations apply to adults with progressive glioblastoma

Recommendations

Level III

For patients who undergo biopsy or neurosurgical resection at the time of radiologic or clinical progression, it is recommended that the pathologist report the presence and extent of progressive neoplasm as well as the presence and extent of necrosis within the pathologic material examined. Furthermore, to ensure the proper interpretation of progressive glioblastoma, it is recommended that the pathologist take into account the patient’s previous diagnosis and treatment, as well as the current clinical and neuroimaging features that have led to a second biopsy or resection.

Question

2. What techniques and ancillary studies are most useful in separating malignant progression from treatment effect?

Target population

These recommendations apply to adults with progressive glioblastoma

Recommendations

Level III

In the setting of prior radiation and chemotherapy, it is recommended to adhere to strict histologic criteria for microvascular proliferation and necrosis in order to establish a diagnosis of a glioblastoma. Immunohistochemistry and genetic studies are selectively recommended for distinguishing neoplastic cells from atypical reactive cells in progressive glioblastoma.     

Sarcoma de Ewing en la infancia: resultados terapéuticos a largo plazo

Fundamento

Hemos analizado los resultados terapéuticos obtenidos en pacientes pediátricos diagnosticados de sarcoma de Ewing en nuestro centro y la significación de los factures de riesgo al diagnóstico sobre la supervivencia.

Pacientes y métodos

Entre los años 1980 y 1995 han sido tratados 37 pacientes. Se consideraron factores de riesgo al diagnóstico la existencia de metástasis, volumen del tumor primario mayor de 100 ml y localización centro-axial del mismo.

Resultados

Con una mediana de seguimiento de 9 años están vivos y libres de enfermedad 25 pacientes (67,56%) y la supervivencia actuarial libre de enfermedad es del 64,86%. Los pacientes sin metástasis tuvieron una supervivencia libre de enfermedad del 74,4 frente al 16,6% de los que presentaron metástasis (p < 0,001). Los enfermos con volumen tumoral mayor de 100 ml tuvieron una supervivencia libre de enfermedad del 49,8%; no hubo ningÚn fallecimiento en el grupo de volumen tumoral menor de 100 ml. La supervivencia libre de enfermedad para los pacientes con localización periférica del tumor fue del 66,8 frente al 63% de los de localización centro-axial, diferencia que no fue estadísticamente significativa. El grupo tratado con cirugía asociada a quimioterapia obtuvo una mayor supervivencia, sin diferencias estadísticamente significativas.

Conclusiones

a) El tratamiento multidisciplinario del sarcoma de Ewing permite una curación en torno al 70% de los casos, yb) la existencia de metástasis al diagnóstico y un volumen tumoral superior a 100 ml son los dos factores de riesgo que influyen de manera significativa en la supervivencia     

The role of radiotherapy in the management of progressive glioblastoma

Question

Can re-irradiation (by using conventional radiotherapy, fractionated radiosurgery, or single fraction radiosurgery) be used in patients with progressive glioblastoma multiforme after the first adjuvant combined multimodality treatment with radiation and chemotherapy?

Target population

These recommendations apply to adult patients with progressive glioblastoma after first line combined multimodality treatment with chemotherapy and radiation.

Recommendations

Level III

When the target tumor is amenable for additional radiation, re-irradiation is recommended as it provides improved local tumor control, as measured by best imaging response. Such re-irradiation can take the form of conventional fractionation radiotherapy, fractionated radiosurgery, or single fraction radiosurgery.

Level III

Re-irradiation is recommended in order to maintain or improve a patient’s neurological status and quality of life prior to any further tumor progression.     

Population pharmacokinetic/pharmacodynamic modeling for the time course of tumor shrinkage by motesanib in thyroid cancer patients

Objective

To develop a population pharmacokinetic/pharmacodynamic model describing the relationship between motesanib exposure and tumor response in a phase 2 study of motesanib in patients with advanced differentiated thyroid cancer or medullary thyroid cancer.

Methods

Data from patients (n = 184) who received motesanib 125 mg once daily were used for population pharmacokinetic/pharmacodynamic modeling. Motesanib concentrations were fitted to a 2-compartment population pharmacokinetic model. Observed change in tumor size was the drug response measure for the pharmacodynamic model. Exposure measures in the pharmacokinetic/pharmacodynamic model included dose, plasma concentration profile, or steady-state area under the concentration versus time curve (AUC _ss ). A longitudinal exposure–tumor response model of drug effect on tumor growth dynamics was used.

Results

Motesanib oral clearance in patients with medullary thyroid cancer was 67% higher than in patients with differentiated thyroid cancer patients (73.7 vs. 44 L/h). Patients’ disease type (medullary thyroid cancer vs. differentiated thyroid cancer) was the most important covariate for explaining interpatient variability in clearance. The objective response rates were 14 versus 2% for differentiated thyroid cancer and medullary thyroid cancer, respectively. Motesanib exposure measures (AUC _ss or concentration profile) were better predictors of tumor response than motesanib dose. The estimated motesanib concentration yielding tumor stasis (1.9 ng/mL) was lower than the observed trough concentrations in differentiated thyroid cancer and medullary thyroid cancer patients.

Conclusions

Differences in motesanib pharmacokinetics likely explain the difference in tumor response observed between differentiated thyroid cancer and medullary thyroid cancer patients. The population pharmacokinetic/pharmacodynamic model provides a tool for predicting tumor response to the drug to support the dosing regimen of motesanib in thyroid cancer patients.     

The role of targeted therapies in the management of progressive glioblastoma

Question

What is the influence of targeted medical therapies on disease control and survival in the adult patient with progressive glioblastoma?

Targeted population

This recommendation applies to adult patients with progressive glioblastoma

Recommendations

Level III Treatment with bevacizumab is recommended as it provides improved disease control compared to historical controls as measured by best imaging response and progression free survival at 6 months. Given that there are a large number of therapies are available for progressive glioblastoma that may be applied under selected circumstances dependent on patient characteristics and treating physician judgment, it is strongly recommended that patients with progressive glioblastoma be enrolled in properly designed clinical investigations to provide convincing evidence of therapeutic value.     

9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma

Purpose

The delivery of drugs to the brain is a major obstacle in the design and development of useful treatments for malignant glioma. Previous studies by our laboratory have identified a series of 9-amino acridine compounds that block the catalytic cycle of topoisomerase II resulting in apoptosis and cell death in a variety of cancer cell lines.

Methods

This study reports the in vitro and in vivo activity of two promising lead compounds, [{9-[2-(1H-Indol-3-yl)-ethylamino]-acridin-4-yl}-(4-methyl-piperazin-1-yl)-methanone (1) and [9-(1-Benzyl-piperidin-4-ylamino)-acridin-3-yl]-(4-methyl-piperazin-1-yl)-methanone] (2), using an orthotopic glioblastoma mouse model. In addition, the absorption, distribution, and metabolism properties are characterized by determining metabolic stability, MDCK accumulation, Pgp efflux transport, plasma protein binding, and brain distribution in mouse pharmacokinetic studies.

Results

The efficacy results indicate low micromolar ED₅₀ values against glioma cells and a significant increase in the survival of glioma-bearing mice dosed with (2) (p?1 and 2 showed both compounds penetrate the blood–brain barrier yielding peak concentrations of 0.25?μM and 0.6?μM, respectively. Peak plasma concentrations were determined to be 2.25?μM (1) and 20.38?μM (2). The results were further compared with data collected using a 15?mg/kg intravenous dose of 2 which yielded a peak concentration in the brain of 1.7 μM at 2.0?h relative to a 2.04 μM peak plasma concentration. The bioavailability was calculated to be 83.8%.

Conclusion

Taken overall, the results suggest compounds in this series may offer new strategies for the design of chemotherapeutics for treating brain cancers with high oral bioavailability and improved efficacy.     

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer

Objective

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).

Patients and treatment

Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n?=?29; 100?%) and taxanes (n?=?11; 37.9?%) were treated with oral capecitabine 950?mg/m² twice daily on days 1?C14 and docetaxel 75?mg/m² on day 1 every 3?weeks. Nineteen (65.5?%) patients received this regimen as second line and 10 (34.5?%) as???3rd line of therapy. All patients were evaluable for response and toxicity.

Results

Complete response occurred in two (6.9?%) patients and partial response in eleven (37.9?%) for an overall response rate of 44.8?% (95?% CI 26.7?C62.9?%). Eleven women (37.9?%) had stable disease and five (17.2?%) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5?%) responded to DC combination. The median duration of response was 5.7?months (range 3.4?C64.2), the median time to disease progression 9.3?months (range 1.2?C58), and the median overall survival 25.5?months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6?% of patients and three of them (10.3?%) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9?% of the patients, fatigue in 3.4?%, and neurotoxicity in 3.4?%.

Conclusion

The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.     

Metabolic factors and risk of thyroid cancer in the Metabolic syndrome and Cancer project (Me-Can)

Objective

To investigate metabolic factors and their possible impact on risk of thyroid cancer.

Methods

A prospective cohort study was conducted based on seven population-based cohorts in Norway, Austria, and Sweden, in the Metabolic syndrome and Cancer project (Me-Can). Altogether 578,700 men and women with a mean age of 44.0 years at baseline were followed for on average 12.0 years. Relative risk of incident thyroid cancer was assessed by levels of BMI, blood pressure, and blood levels of glucose, cholesterol, triglycerides, and by a combined metabolic syndrome (MetS) score. Risk estimates were investigated for quintiles, and a z score distribution of exposures was analyzed using Cox proportional hazards regression.

Results

During follow-up, 255 women and 133 men were diagnosed with thyroid cancer. In women, there was an inverse association between glucose and thyroid cancer risk, with adjusted RR: 95% CI was 0.61 (0.41?C0.90), p trend = 0.02 in the fifth versus the first quintile, and a positive association between BMI and thyroid cancer risk with a significant trend over quintiles. There was no association between the other metabolic factors, single or combined (Met-S), and thyroid cancer.

Conclusion

In women, BMI was positively, while blood glucose levels were inversely, associated with thyroid cancer.     

Potentially fatal complications for elderly patients after laparoscopy-assisted distal gastrectomy

Background

The safety of surgery for gastric cancer in the elderly has been shown previously. However, potentially fatal complications based on an established severity grading system were not well described, and associated risk factors have not been assessed. The present study sought to examine severity-dependent postoperative complications after laparoscopy-assisted distal gastrectomy (LADG) in elderly patients and risk factors of potentially fatal postoperative complications.

Methods

The study included 189 patients aged 70 years or older and who underwent LADG for early gastric cancer. Patient characteristics, perioperative outcomes, postoperative complications including severity assessment using the Clavien–Dindo classification, and risk factors related to postoperative complications were analyzed.

Results

The overall complication rate was 24.9 % (47/189). The most frequent complication was abdominal fluid collection (9 cases, 4.8 %). Severe complications classified as grade III or above in the Clavien–Dindo grading system were found in 20 (10.6 %) patients. Multivariate analysis identified preoperative serum albumin concentration (odds ratio, 5.200; 95 % CI, 1.706–15.850), Roux-en-Y reconstruction (odds ratio, 3.611; 95 % CI, 1.103–11.817), and simultaneous cholecystectomy (odds ratio, 5.008; 95 % CI, 1.378–18.201) as independent predictors of a higher rate of severe postoperative complications after LADG in elderly patients.

Conclusion

The incidence of severe complications after LADG in the elderly was quite acceptable considering the risks associated with radical surgery with extensive lymphadenectomy. Preoperative serum concentrations of albumin (<4.0 g/dl), Roux-en-Y reconstruction, and simultaneous cholecystectomy are independent risk factors for severe postoperative complications in these patients.     

A comparison of postoperative quality of life and dysfunction after Billroth I and Roux-en-Y reconstruction following distal gastrectomy for gastric cancer: results from a multi-institutional RCT

Background

Both Billroth I (B-I) and Roux-en-Y (R-Y) reconstructions are commonly performed as standard procedures, but it has yet to be determined which reconstruction is better for patients. A randomized prospective phase II trial with body weight loss at 1?year after surgery as a primary endpoint was performed to address this issue. The current report delivers data on the quality of life and degree of postoperative dysfunction, which were the secondary endpoints of this study.

Methods

Gastric cancer patients who underwent distal gastrectomy were intraoperatively randomized to B-I or R-Y. Postsurgical QOL was evaluated using the EORTC QLQ-C30 and DAUGS 20.

Results

Between August 2005 and December 2008, 332 patients were enrolled in a randomized trial comparing B-I versus R-Y. A mail survey questionnaire sent to 327 patients was completed by 268 (86.2%) of them. EORTC QLQ-C30 scores were as follows: global health status was similar in each group (B-I 73.5?±?18.8, R-Y 73.2?±?20.2, p?=?0.87). Scores of five functional scales were also similar. Only the dyspnea symptom scale showed superior results for R-Y than for B-I (B-I 13.6?±?17.9, R-Y 8.6?±?16.3, p?=?0.02). With respect to DAUGS 20, the total score did not differ significantly between the R-Y and B-I groups (24.8 vs. 23.6, p?=?0.41). Only reflux symptoms were significantly worse for B-I than for R-Y (0.7?±?0.6 vs. 0.5?±?0.6, p?=?0.01).

Conclusions

The B-I and R-Y techniques were generally equivalent in terms of postoperative QOL and dysfunction. Both procedures seem acceptable as standard reconstructions after distal gastrectomy with regard to postoperative QOL and dysfunction.     

Long-term outcomes of Roux-en-Y and Billroth-I reconstruction after laparoscopic distal gastrectomy

Background

Laparoscopic distal gastrectomy (LDG) is an established procedure for the treatment of early gastric cancer. Roux-en-Y (R-Y) or Billroth-I (B-I) reconstruction is generally performed after LDG in Japan. The aim of this retrospective cohort study was to compare the effectiveness of R-Y and B-I reconstructions and thereby determine which has better clinical outcomes.

Methods

We analyzed data from 172 patients with gastric cancer who underwent LDG. Reconstruction was done by R-Y in 83 patients and B-I in 89. All patients were followed up for 5 years. Evaluated variables included symptoms, nutritional status, endoscopic findings, gallstone formation, and later gastrointestinal complications.

Results

Scores for the amount of residue in the gastric stump, remnant gastritis, and bile reflux, calculated according to the “residue, gastritis, bile” scoring system, were significantly lower in the R-Y group (score 0 vs. 1 and more; p = 0.027, <0.001, and <0.001, respectively). The proportion of patients with reflux esophagitis was significantly lower in the R-Y group (p < 0.001). Relative values (postoperative 5 years/preoperative) for body weight, serum albumin level, and total cholesterol level were similar in the two groups (p = 0.59, 0.56, and 0.34, respectively). Gallstone formation did not differ between the groups (p = 0.57). As for later complications, the incidence of gastrointestinal ulcer was 4.5 % in the B-I group, and that of ileus was 3.6 % in the R-Y group, but differences between the groups were not significant (p = 0.12, 0.11, respectively).

Conclusions

As compared with B-I, R-Y was associated with lower long-term incidences of both bile reflux into the gastric remnant and reflux esophagitis.     

Feasibility of laparoscopy-assisted total gastrectomy in patients with clinical stage I gastric cancer

Background

Laparoscopy-assisted total gastrectomy (LATG) for gastric cancer is not yet widespread because of the technical difficulty of reconstruction. We have performed LATG on 100 patients with clinical stage I gastric cancer. This study investigated the short-term outcomes of LATG.

Methods

Between September 2001 and September 2012, 100 patients with clinical stage I gastric cancer underwent LATG with D1 plus beta or D2 lymphadenectomy. Roux-en-Y esophagojejunostomy was performed intracorporeally using end-to-side anastomosis with a circular stapler (the purse-string suture method). The primary endpoint was the proportion of postoperative complications during hospitalization.

Results

Mean operation time was 249 min; mean blood loss was 182 ml. There were no conversions to open surgery. According to the Clavien–Dindo classification, there were 8 grade II (8 %) and 10 grade IIIa/b (10 %) complications. There were no treatment-related deaths or grade IV complications. The most frequent complication was anastomotic or stump leakage (6 %), followed by pancreatic fistula (5 %). Reoperations were required in two patients with leakage.

Conclusions

The short-term outcomes of LATG in our study involving 100 patients were outlined. LATG for gastric cancer patients should be attempted preferably in a clinical trial setting by surgeons with sufficient experience in laparoscopic gastrectomy.     

Meta-analysis for psychological impact of breast reconstruction in patients with breast cancer

Aims

This meta-analysis aimed to evaluate the impact of breast reconstruction on the psychological aspects in patients with breast cancer.

Methods

A literature search on PubMed, Embase, ScienceDirect and Google scholar databases was conducted up to September 2017. The pooled risk radio (RR) or standard mean difference (SMD) and the corresponding 95% confidence intervals (CIs) were calculated using the RevMan 5.3 software.

Results

A total of 5 studies were included in this meta-analysis. There were 551 breast cancer patients receiving mastectomy plus breast reconstruction and 574 breast cancer patients receiving mastectomy alone. The results showed that breast reconstruction can significantly decrease the incidence of anxiety (RR = 0.62, 95% CI 0.47–0.82, P = 0.0006)/depression (RR = 0.54, 95% CI 0.32–0.93, P = 0.02) and scale score for evaluating anxiety (SMD = ? 0.20, 95% CI ? 0.37 to ? 0.03, P = 0.02)/depression (SMD = ? 0.22, 95% CI ? 0.39 to ? 0.66, P = 0.007) compared with mastectomy alone.

Conclusions

Breast reconstruction after mastectomy was benefit for improving the psychological damages in patients with breast cancer.

     

Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development

Purpose

Tumor suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer development. The aim of this study was to assess the extent of methylation of the RASSF1A and APC TSG promoters in ovarian epithelial adenomas, low malignant potential tumours and carcinomas in order to reveal a role for epigenetic TSG silencing in the development of these ovarian malignancies.

Method

The promoter methylation status of the RASSF1A and APC genes was assessed in 19 benign cystadenomas, 14 low malignant potential (LMP) tumours, and 86 carcinomas using methylation specific PCR (MSP).

Results

The methylation frequencies of the RASSF1A and APC gene promoters in benign cystadenomas were found to be 37?% and 16?%, respectively. The LMP tumours exhibited RASSF1A and APC gene promoter methylation frequencies of 50?% and 28?%, respectively, whereas the carcinomas exhibited methylation frequencies of 58?% and 29?%, respectively. Methylation of either the RASSF1A or the APC gene promoter was encountered in 58?% of the invasive carcinomas.

Conclusion

The observed aberrant methylation frequencies of the RASSF1A and APC gene promoters indicate that an accumulation of epigenetic events at these specific TSG promoters may be associated with the malignant transformation of benign cystadenomas and LMP tumours to carcinomas.     

Association of HTLV1 Infection and Esophageal Squamous Cell Carcinoma

Background

Both esophageal carcinoma and HTLV-1 (Human T cell lymphotropic virus 1) have high prevalence in northeastern of Iran.

Objective

To assess the presence of HTLV-1 genome in esophageal cancerous tissue and in tissues from non cancerous individuals.

Methods

Eighty five patients with esophageal squamous cell carcinoma and 48 non-cancerous control patients that underwent esophagogasteroscopy for other reasons were included in this study. All selected subjects are residing in northeastern part of Iran. All specimens were studied histopathologically by H&E staining and were evaluated for HTLV-1 by PCR method. In PCR, the presence of tax, pol, env and LTR segments of HTLV-1 genome were detected.

Results

Male to female ratio in the case group was 3 to 5. Average age and standard deviation in case and control group were 56?±?17 and 54?±?21 years, respectively; which did not have any significant differences. All the patients came from the same area in the northeastern part of Iran. HTLV-1 genome was found in two subjects with esophageal cancer and in one subject in the control group. Statistical analysis showed no significant differences between the two groups (chi square = 0.26, Fisher exact test P value = 0.7, Odd ratio = 1.13 [0.08?<?OR?<?32.46]).

Conclusion

HTLV-1 infection and esophageal squamous cell carcinoma did not appear to have a significant correlation.     

A two-part Phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics

Background

Cediranib (RECENTIN?) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers.

Methods

Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF).

Results

In part A, plasma AUC and C _max of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12?C34% and C _max, 20?C43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30?mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16?weeks, with significant reductions in DCE-MRI parameters and CT EnF.

Conclusions

It is recommended that cediranib be administered at least 1?h before or 2?h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.