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Major depressive disorder (MDD) is a prevalent mood disorder that is associated with differential prefrontal brain expression patterns. Treatment of MDD includes a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for depressive episodes, and they are among the most prescribed medications in North America. Although antidepressants are clearly effective, particularly for moderate to severe depressive episodes, there is variability in how individuals respond to antidepressant treatment. Failure to respond has individual, economic and social consequences for patients and their families. Several lines of evidence demonstrate that genes are regulated through the activity of microRNAs (miRNAs), which act as fine-tuners and on-off switches of gene expression. Here we report on complementary studies using postmortem human brain samples, cellular assays and samples from clinical trials of patients with depression and show that miR-1202, a miRNA specific to primates and enriched in the human brain, is differentially expressed in individuals with depression. Additionally, miR-1202 regulates expression of the gene encoding metabotropic glutamate receptor-4 (GRM4) and predicts antidepressant response at baseline. These results suggest that miR-1202 is associated with the pathophysiology of depression and is a potential target for new antidepressant treatments.

Purpose: To study the relationship between the accuracy of the dose calculation in brachytherapy and the estimations of the radiosensitivity parameter, α/β, for prostate cancer., Methods and Materials: In this study, Monte Carlo methods and more specifically the code ALGEBRA was used to produce accurate dose calculations in the case of prostate brachytherapy. Equivalent uniform biologically effective dose was calculated for these dose distributions and was used in an iso-effectiveness relationship with external beam radiation therapy., Results: By considering different levels of detail in the calculations, the estimation for the α/β parameter varied from 1.9 to 6.3 Gy, compared with a value of 3.0 Gy suggested by the American Association of Physicists in Medicine Task Group 137., Conclusions: Large variations of the α/β show the sensitivity of this parameter to dose calculation modality. The use of accurate dose calculation engines is critical for better evaluating the biological outcomes of treatments., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This investigation reports on the biochemical and clinical outcomes of a newly created pan-Canadian Prostate Cancer Risk Stratification (ProCaRS) database developed by the Genitourinary Radiation Oncologists of Canada (GUROC). GUROC ProCaRS template-compliant data on 7974 patients who underwent radiotherapy were received from 7 unique databases. Descriptive analysis, Cox proportional hazards, and Kaplan-Meier analyses were performed using American Society for Radiation Oncology (ASTRO) biochemical failure-free survival (BFFS), prostate cancer-specific survival, and overall survival. Multivariable modeling for the primary ASTRO BFFS end point showed that age, prostate-specific antigen, T stage, and Gleason score and components such as hormonal therapy, and radiation treatment (brachytherapy with better outcome than external-beam) were predictive of outcome. Kaplan-Meier analysis of the existing GUROC and new NCCN classification system both showed good separation of all clinical outcome curves. The construction of a pan-Canadian database has informed important prostate cancer radiotherapy outcomes and risk stratification.

Objective: To describe treatment options for clinically localized prostate cancer: radical prostatectomy, prostate brachytherapy, external beam radiation, and active surveillance., Quality of Evidence: Prostate-specific antigen (PSA) outcomes presented are from non-randomized, cohort, and other comparisons trials (level II evidence). We describe PSA outcomes from Canadian centres when they are available. One small randomized controlled trial (level I evidence) in localized prostate cancer is available to compare radical prostatectomy with brachytherapy., Main Message: Treatment choice in prostate cancer is based on initial PSA level, clinical stage of disease, and Gleason score, together with baseline urinary function, comorbidities, and patient age. In this article, we describe patients' eligibility for and the common side effects of all treatment options. Prostate brachytherapy and active surveillance have evolved as new standard treatments of localized prostate cancer. We give a brief overview of the brachytherapy procedure, side effects, and PSA outcomes across Canada, as well as active surveillance guidelines., Conclusion: Prostate cancer treatment requires a multidisciplinary approach, with input from both urology and radiation oncology. Input from family physicians is often as important in helping guide patients through the treatment decision process.

Background: The Genitourinary Radiation Oncologists of Canada (GUROC) published a three-group risk stratification (RS) system to assist prostate cancer decision-making in 2001. The objective of this project is to use the ProCaRS database to statistically model the predictive accuracy and clinical utility of a proposed new multi-group RS schema., Methods: The RS analyses utilized the ProCaRS database that consists of 7974 patients from four Canadian institutions. Recursive partitioning analysis (RPA) was utilized to explore the sub-stratification of groups defined by the existing three-group GUROC scheme. 10-fold cross-validated C-indices and the Net Reclassification Index were both used to assess multivariable models and compare the predictive accuracy of existing and proposed RS systems, respectively., Results: The recursive partitioning analysis has suggested that the existing GUROC classification system could be altered to accommodate as many as six separate and statistical unique groups based on differences in BFFS (C-index 0.67 and AUC 0.70). GUROC low-risk patients would be divided into new favorable-low and low-risk groups based on PSA ⩽6 and PSA >6. GUROC intermediate-risk patients can be subclassified into low-intermediate and high-intermediate groups. GUROC high-intermediate-risk is defined as existing GUROC intermediate-risk with PSA >=10 AND either T2b/c disease or T1T2a disease with Gleason 7. GUROC high-risk patients would be subclassified into an additional extreme-risk group (GUROC high-risk AND (positive cores ⩾87.5% OR PSA >30)., Conclusions: Proposed RS subcategories have been identified by a RPA of the ProCaRS database., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Prostate brachytherapy can be used as a monotherapy for low- and intermediate-risk patients or in combination with external beam radiation therapy (EBRT) as a form of dose escalation for selected intermediate- and high-risk patients. Prostate brachytherapy with either permanent implants (low dose rate [LDR]) or temporary implants (high dose rate [HDR]) is emerging as the most effective radiation treatment for prostate cancer. Several large Canadian brachytherapy programs were established in the mid- to late-1990s. Prostate brachytherapy is offered in British Columbia, Alberta, Manitoba, Ontario, Quebec and New Brunswick. We anticipate the need for brachytherapy services in Canada will significantly increase in the near future. In this review, we summarize brachytherapy programs across Canada, contemporary eligibility criteria for the procedure, toxicity and prostate-specific antigen recurrence free survival (PRFS), as published from Canadian institutions for both LDR and HDR brachytherapy.

Neonates respond to hypoxia initially by increasing ventilation, and then by markedly decreasing both ventilation (hypoxic ventilatory decline) and oxygen consumption (hypoxic hypometabolism). This latter process, which vanishes with age, reflects a tight coupling between ventilatory and thermogenic responses to hypoxia. The neurological substrate of hypoxic hypometabolism is unclear, but it is known to be centrally mediated, with a strong involvement of the 5-hydroxytryptamine (5-HT, serotonin) system. To clarify this issue, we investigated the possible role of VGLUT3, the third subtype of vesicular glutamate transporter. VGLUT3 contributes to glutamate signalling by 5-HT neurons, facilitates 5-HT transmission and is expressed in strategic regions for respiratory and thermogenic control. We therefore assumed that VGLUT3 might significantly contribute to the response to hypoxia. To test this possibility, we analysed this response in newborn mice lacking VGLUT3 using anatomical, biochemical, electrophysiological and integrative physiology approaches. We found that the lack of VGLUT3 did not affect the histological organization of brainstem respiratory networks or respiratory activity under basal conditions. However, it impaired respiratory responses to 5-HT and anoxia, showing a marked alteration of central respiratory control. These impairments were associated with altered 5-HT turnover at the brainstem level. Furthermore, under cold conditions, the lack of VGLUT3 disrupted the metabolic rate, body temperature, baseline breathing and the ventilatory response to hypoxia. We conclude that VGLUT3 expression is dispensable under basal conditions but is required for optimal response to hypoxic stress in neonates.

Purpose: To present clinical outcomes and dose-volume histogram parameters of three-dimensional image-based high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with primary or recurrent gynecologic cancer unsuitable for intracavitary brachytherapy (ICB)., Methods and Materials: Records of 43 women treated between 2001 and 2009 with iridium-192 gynecologic HDR-ISBT boost, using a Syed-Neblett template and inverse planning simulated annealing dose optimization, were reviewed. Median HDR-ISBT dose was 30Gy, delivered in 4-6Gy/fraction. Dose-volume histogram parameters recommended by the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology for image-based ICB were analyzed. Total doses were normalized to 2Gy fractions (biologically equivalent dose in 2Gy fractions). Local control (LC) and survival were calculated using Kaplan-Meier method. Toxicities were defined according to Common Terminology Criteria for Adverse Events v3.0., Results: There were 34 primary malignancies (cervix=12, vagina=15, Bartholin's gland=5, and vulva=2) and 9 recurrences. International Federation of Gynecology and Obstetrics stage distribution for primary cancers was I=2, II=13, III=15, and IV=4. Median followup was 19.3 months (range, 0-92.2). Two-year LC was 87% for primary cancers, and 45% for recurrent cancers, respectively (p=0.0175). Median V(100), D(90), and D(100) for clinical target volume were 97.6%, 90.2, and 68.7Gy(10), respectively. Median bladder and rectal D(2)(cc) were 76.6 and 79.5Gy(3), respectively. Median urethral D(10) was 80.6Gy(3). Twelve patients experienced Grades 3 and 4 late morbidity, but toxicities were transient. Only 2 patients had persistent severe toxicities. A trend toward increased risk for vaginal necrosis was observed with a clinical target volume >84cc., Conclusions: HDR-ISBT may achieve good LC in gynecologic cancer unsuitable for ICB, especially in primary malignancies with a 2-year LC rate higher than 85%. Delivery of such high doses has potential advantages but may predispose to adverse effects, reversible in most cases., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: High dose-rate (HDR) brachytherapy is most commonly administered as a boost in two or more fractions combined with external beam radiotherapy (EBRT). Our purpose is to compare outcomes with a single fraction HDR boost to that with a standard fractionated boost in intermediate risk prostate cancer., Materials and Methods: Results of two sequential phase II clinical trials are compared. The Single Fraction protocol consists of 15 Gy HDR in one fraction followed by 37.5 Gy EBRT in 15 fractions over 3 weeks; the Standard Fractionation protocol consisted of two HDR fractions each of 10 Gy, 1 week apart, followed by 45 Gy EBRT in 25 fractions. Patients had intermediate risk disease, and were well balanced for prognostic factors. Patients were followed prospectively for efficacy, toxicity and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition, and by biopsy at 2 years., Results: The Single Fraction protocol accrued 123 patients and the Standard Fractionation protocol, 60. With a median follow-up of 45 and 72 months, respectively, the biochemical disease-free survival was 95.1% and 97.9% in the Single and Standard Fractionation trials (p=0.3528). Two-year prostate biopsy was positive in only 4% and 8%, respectively. There was no difference in late urinary or rectal toxicity rates, or in health-related quality of life between the two protocols., Conclusions: The Single Fraction HDR protocol results in high disease control rate and low toxicity similar to our previous protocol using two HDR insertions, with significant savings in resources. While mature results with longer follow-up are awaited, a single 15 Gy may be considered as a standard fractionation regimen in combination with EBRT for men with intermediate risk disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Erk4 and Erk3 are atypical members of the mitogen-activated protein (MAP) kinase family. The high sequence identity of Erk4 and Erk3 proteins and the similar organization of their genes imply that the two protein kinases are paralogs. Recently, we have shown that Erk3 function is essential for neonatal survival and critical for the establishment of fetal growth potential and pulmonary function. To investigate the specific functions of Erk4, we have generated mice with a targeted disruption of the Mapk4 gene. We show that Erk4-deficient mice are viable and fertile and exhibit no gross morphological or physiological anomalies. Loss of Erk4 is not compensated by changes in Erk3 expression or activity during embryogenesis or in adult tissues. We further demonstrate that additional loss of Erk4 does not exacerbate the fetal growth restriction and pulmonary immaturity phenotypes of Erk3(-/-) mice and does not compromise the viability of Erk3(+/-) neonates. Interestingly, behavioral phenotyping revealed that Erk4-deficient mice manifest depression-like behavior in the forced-swimming test. Our analysis indicates that the MAP kinase Erk4 is dispensable for mouse embryonic development and reveals that Erk3 and Erk4 have acquired specialized functions through evolutionary diversification.

Purpose: To evaluate the efficacy of a seed-migration detector and to compare its performance to fluoroscopy and postoperative chest radiographs., Methods and Materials: A gamma scintillation survey meter was converted to a seed-migration detector by adding a shield on the probe detection window. The detector response to three (125)I seed activities was characterized for different source-to-detector distances in water. The detector was used to perform a chest evaluation on 737 patients at their first postoperative visit. When the detector showed positive activity, seed migration was confirmed by taking a chest radiograph and by looking at the region with fluoroscopy., Results: One hundred and three patients (14.0%) presented at least one embolized seed. This accounts for 123 of the 39,887 seeds. Eighty-seven, 12, and 4 patients had respectively one, two, and three seed embolization. Compared with the seed-migration detector, detection based on fluoroscopy would have led to 13 false-negative detections (of 103, or 12.6%), and the radiograph would have resulted in 31 or 30.1%. More important, standard chest X-ray would have required a survey and extra radiation dose to lung to 100% of the patients, rather than the 14% who required it., Conclusions: The usual recommendation to perform chest radiographs at the first follow-up visit to scan lungs for embolized seeds should be revised because of the high false-negative rate. Scintillator-based gamma counter detector provides superior detection sensitivity and should be adopted as a standard of practice. Chest X-ray could be limited to documenting cases of positive migration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: To estimate the rate of late Grade 3 or greater genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) after treatment with external beam radiotherapy and prostate high-dose-rate (HDR) brachytherapy., Methods and Materials: Each participating institution submitted computed tomography-based HDR brachytherapy dosimetry data electronically for credentialing and for each study patient. Patients with locally confined Stage T1c-T3b prostate cancer were eligible for the present study. All patients were treated with 45 Gy in 25 fractions using external beam radiotherapy and one HDR implant delivering 19 Gy in two fractions. All AEs were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Late GU/GI AEs were defined as those occurring >9 months from the start of the protocol treatment, in patients with ≥18 months of potential follow-up., Results: A total of 129 patients from 14 institutions were enrolled in the present study. Of the 129 patients, 125 were eligible, and AE data were available for 112 patients at analysis. The pretreatment characteristics of the patients were as follows: Stage T1c-T2c, 91%; Stage T3a-T3b, 9%; prostate-specific antigen level ≤10 ng/mL, 70%; prostate-specific antigen level >10 but ≤20 ng/mL, 30%; and Gleason score 2-6, 10%; Gleason score 7, 72%; and Gleason score 8-10, 18%. At a median follow-up of 29.6 months, three acute and four late Grade 3 GU/GI AEs were reported. The estimated rate of late Grade 3-5 GU and GI AEs at 18 months was 2.56%., Conclusion: This is the first prospective, multi-institutional trial of computed tomography-based HDR brachytherapy and external beam radiotherapy. The technique and doses used in the present study resulted in acceptable levels of AEs., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: To secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response., Methodology/principal Findings: Using en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25-50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice., Conclusions: These results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers.

Purpose: The purpose of this retrospective study is to evaluate the role of endobronchial brachytherapy in the palliation of lung cancer (or metastasis) symptoms and its potential impact on overall survival., Methods and Materials: Eighty-one patients were included in this study. Endobronchial brachytherapy catheter was placed under conscious sedation. The projection of the tumor was drawn by the bronchoscopist to help the radiation oncology team to perform the dosimetry. Patients were treated with iridium-192 high-dose rate afterloading unit. Patients were planned to receive 5 Gy in four fractions weekly for a total of 20 Gy., Results: Seventy-three percent of the patients were treated for primary lung cancer. The remaining patients were treated for lung metastasis of other primary. Most patients presented dyspnea, cough, or hemoptysis. These three main symptoms were relieved in 85%, 77%, and 100%, respectively. The median survival was 14.7 months and local progression-free survival at 12 months was 77% and at 24 months 64%, respectively., Conclusion: Endobronchial brachytherapy is a very effective palliative treatment for endobronchial lesions., ((c) 2010 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the biochemical failure-free survival (BFFS), GU toxicity and erectile dysfunction in intermediate risk prostate cancer treated with iodine 125 monotherapy (I125)., Patients and Methods: Between October 1994 and October 2007, 1282 patients were treated with I125 at the Hotel Dieu de Quebec. Two hundred patients were intermediate risk prostate cancer. One hundred and fifty-seven had enough follow-up to be evaluated in this study. Biochemical failure-free survival is reported using Phoenix definition. Acute and late GU toxicity was described using the International Prostate Symptoms Score (IPSS) as well as with the rate of bladder catheter. Erectile dysfunction was also reported., Results: The mean age of the patients was 65.6 years (S.D.=6 years) and the mean pretreatment PSA was 8.7ng/ml. About half of the patients (51%) were T2b/T2c. About 44.6% had a PSA greater than 10 and 4.5% had Gleason score of 7/10. More than half of the patients received a short course of hormones of less than 6 months for cytoreduction (57.4%). The median follow-up was 60 months. Biochemical failure-free survival at 60-month and 96-month were 87.1% and 81% according to Phoenix definition. The mean IPSS rose from 5 immediately after the implant to 15 1 month after and then slowly decreased to 8 at 24 months. Acute urinary retention with bladder catheter occurred in 10.9% of patients. Only 4.3% presented erectile dysfunction at 5 months post-implant., Conclusion: I125 monotherapy for intermediate risk prostate implant gives biochemical failure-free survivals at 5 years and 8 years comparable to those obtained with high dose external beam radiotherapy. GU toxicity and erectile dysfunction were low and acceptable. Therefore, the use of I125 alone in this group of patients could be presented and discussed with the patient in the waiting of phase III validation., (2010 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Purpose: Using real-time intraoperative inverse-planned permanent seed prostate implant (RTIOP/PSI), multiple core biopsy maps, and three-dimensional ultrasound guidance, we planned a boost volume (BV) within the prostate to which hyperdosage was delivered selectively. The aim of this study was to investigate the potential negative effects of such a procedure., Methods and Materials: Patients treated with RTIOP/PSI for localized prostate cancer with topographic biopsy results received an intraprostatic boost (boost group [BG]). They were compared with patients treated with a standard plan (reference group [RG]). Plans were generated using a simulated annealing inverse planning algorithm. Prospectively recorded urinary, rectal, and sexual toxicities and dosimetric parameters were compared between groups., Results: The study included 120 patients treated with boost technique who were compared with 70 patients treated with a standard plan. Boost technique did not significantly change the number of seeds (55.1/RG vs. 53.6/BG). The intraoperative prostate V150 was slightly higher in BG (75.2/RG vs. 77.2/BG, p = 0.039). Urethra V100, urethra D90, and rectal D50 were significantly lower in the BG. No significant differences were seen in acute or late urinary, rectal, or sexual toxicities., Conclusions: Because there were no differences between the groups in acute and late toxicities, we believe that BV can be planned and delivered to the dominant intraprostatic lesion without increasing toxicity. It is too soon to say whether a boost technique will ultimately increase local control.

The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.

Purpose: To retrospectively evaluate the prognostic value of smoking and drinking status in patients with head-and-neck squamous cell carcinomas., Methods and Materials: All patients with all stages and sites were included if complete information was available on baseline smoking and alcohol behavior (never, former, active), disease stage, primary site, radiation dose, sex, and age. Treatment was radiotherapy in 973 patients, postoperative radiotherapy in 469, and chemoradiotherapy in 429. Statistical analysis was performed with Kaplan-Meier and Cox methods., Results: Data from 1,871 patients were available. At baseline, 9% of patients never smoked, 40% were former smokers, and 51% were active smokers; 20% never drank, 25% were former drinkers, and 55% were active drinkers. Smoking was associated with inferior local control and survival. For local control, the hazard ratio (HR) of active smokers vs. former smokers was 1.5 (p = 0.0001). For survival, the HRs of former smokers and active smokers vs. those who never smoked were also statistically significant (1.3 and 1.7, respectively, p = 0.000001). Alcohol drinking was associated with local control (p = 0.03), and was associated with survival. For survival, HRs of former and active drinkers compared with those who never drank were, respectively, 1.1 (p = 0.01) and 1.28 (p = 0.001). Adjusted 5-year local control and survival rates for those who never smoked and never drank were 87% and 77%, respectively, and for those who were both active smokers and active drinkers were 72% (p = 0.007) and 52% (p = 0.0009), respectively., Conclusion: Smoking and drinking at baseline were associated with poor outcomes in these patients.

Purpose: To evaluate the biochemical recurrence-free survival (bRFS), the 2-year biopsy outcome and the prostate-specific antigen (PSA) bounce in patients with localized prostate cancer treated with an inversely planned high-dose-rate (HDR) brachytherapy boost., Materials and Methods: Data were collected from 153 patients treated between 1999 and 2006 with external beam pelvic radiation followed by an HDR Ir-192 prostate boost. These patients were given a boost of 18 to 20 Gy using inverse-planning with simulated annealing (IPSA).We reviewed and analyzed all prostate-specific antigen levels and control biopsies., Results: The median follow-up was 44 months (18-95 months). When categorized by risk of progression, 74.5% of patients presented an intermediate risk and 14.4% a high one. Prostate biopsies at 2 years posttreatment were negative in 86 of 94 patients (91.5%), whereas two biopsies were inconclusive. Biochemical control at 60 months was at 96% according to the American Society for Therapeutic Radiology and Oncology and the Phoenix consensus definitions. A PSA bounce (PSA values of 2 ng/mL or more above nadir) was observed in 15 patients of 123 (9.8%). The median time to bounce was 15.2 months (interquartile range, 11.0-17.7) and the median bounce duration 18.7 months (interquartile range, 12.1-29). The estimate of overall survival at 60 months was 97.1% (95% CI, 91.6-103%)., Conclusions: Considering that inverse planned HDR brachytherapy prostate boosts led to an excellent biochemical response, with a 2-year negative biopsy rate, we recommend a conservative approach in face of a PSA bounce even though it was observed in 10% of patients.

Purpose: To investigate the effect of anemia on outcome of treatment with radiochemotherapy in patients with head-and-neck cancer., Methods and Materials: The data of 196 patients with Stage II-IV head-and-neck cancer treated with concomitant cisplatin-based radiochemotherapy were retrospectively reviewed. Anemia was defined according to World Health Organization criteria as hemoglobin <130 g/L in men and <120 g/L in women., Results: Fifty-three patients were classified as anemic, 143 as nonanemic. The 3-year local control rate of anemic and nonanemic patients was 72% and 85%, respectively (p = 0.01). The 3-year overall survival rate of anemic and nonanemic patients was 52% and 77%, respectively (p = 0.004). In multivariate analysis, anemia was the most significant predictor of local control (hazard ratio, 0.37, p = 0.009) and survival (hazard ratio, 0.47, p = 0.007). A dose-effect relationship was also found for local control (p = .04) and survival (0.04) when grouping by hemoglobin concentration: <120, 120-140, and >140 g/L., Conclusions: Anemia was strongly associated with local control and survival in this cohort of patients with head-and-neck cancer receiving radiochemotherapy.

Purpose: To investigate the treatment outcomes by concomitant radiochemotherapy (CHEMORAD), and by surgery and postoperative radiotherapy (PORT) in patients with locally advanced head and neck cancers., Method: A retrospective study included all patients with Stage III and IV (except T1-2 N1) diseases between 1989 and 2002 treated with CHEMORAD (163 patients) or PORT (424 patients) at the L'Hôtel-Dieu de Québec. Chemotherapy was realized with Cisplatin (DDP) 100 mg/m(2), d1, d23, and d45 during radiotherapy or weekly DDP 40 mg/m(2) for 6 weeks in case of patients with poor general condition. Neck dissection was performed if residual disease was diagnosed on CHEMORAD. For the PORT group, 410 patients had neck dissection before adjuvant treatment., Results: The 2-year loco-regional control was 82% for CHEMORAD, and 72% for PORT (P = 0.01). The 2-year disease-free survival was 72% for CHEMORAD, and 64% for PORT (P = 0.02). The results were further confirmed by a Cox proportional hazard model., Conclusion: The results indicated that CHEMORAD is a better approach than PORT in the management of locally advanced head and neck cancers. Further randomized study will be needed to compare radical CHEMORAD with surgery plus adjuvant CHEMORAD to determine an appropriate treatment in the management of locally advanced head and neck squamous cell carcinomas.

A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.

Purpose: To evaluate the impact of adaptative image-guided brachytherapy on therapeutic outcome and toxicity in prostate cancer., Materials and Methods: The 1,110 first patients treated at the CHUQ-l'Hôtel-Dieu de Québec were divided in five groups depending on the technique used for the implantation, the latest being intra operative treatment planning. Biochemical disease free survival (5-bDFS), toxicities and dosimetric parameters were compared between the groups., Results: 5-bDFS (ASTRO+Houston) were of 88.5% and 90.5% for the whole cohort. The use of intra operative treatment planning resulted in better dosimetric parameters. Clinically, this resulted in a decreased use of urethral catheterism, from 18.8% in group 1 to 5.2% in group 5, and in a reduction in severe acute urinary side effects (21.3 vs 33.3% P=0.01) when compared with preplanning. There was also less late gastrointestinal side effects (groups 5 vs 1: 26.6 vs 43.2% P<0.05). Finally, when compared with preplanning, intra operative treatment planning was associated with a smaller reduction between planned D90 and the dose calculated at the CT scan 1 month after the implant (38 vs 66 Gy)., Conclusion: The evolution of prostate brachytherapy technique toward intra operative treatment planning allowed dosimetric gains which resulted in significant clinical benefits by increasing the therapeutic ratio mainly through a decreased urinary toxicity. A longer follow-up will answer the question whether there is an impact on 5-bDFS.

Purpose: To use the Monte Carlo (MC) method as a dose calculation engine for postimplant dosimetry. To compare the results with clinically approved data for a sample of 28 patients. Two effects not taken into account by the clinical calculation, interseed attenuation and tissue composition, are being specifically investigated., Methods and Materials: An automated MC program was developed. The dose distributions were calculated for the target volume and organs at risk (OAR) for 28 patients. Additional MC techniques were developed to focus specifically on the interseed attenuation and tissue effects., Results: For the clinical target volume (CTV) D(90) parameter, the mean difference between the clinical technique and the complete MC method is 10.7 Gy, with cases reaching up to 17 Gy. For all cases, the clinical technique overestimates the deposited dose in the CTV. This overestimation is mainly from a combination of two effects: the interseed attenuation (average, 6.8 Gy) and tissue composition (average, 4.1 Gy). The deposited dose in the OARs is also overestimated in the clinical calculation., Conclusions: The clinical technique systematically overestimates the deposited dose in the prostate and in the OARs. To reduce this systematic inaccuracy, the MC method should be considered in establishing a new standard for clinical postimplant dosimetry and dose-outcome studies in a near future.

Purpose: To report outcomes and toxicity of the first Canadian permanent prostate implant program., Methods and Materials: 396 consecutive patients (Gleason < or =6, initial prostate specific antigen (PSA) < or =10 and stage T1-T2a disease) were implanted between June 1994 and December 2001. The median follow-up is of 60 months (maximum, 136 months). All patients were planned with fast-simulated annealing inverse planning algorithm with high activity seeds ([gt] 0.76 U). Acute and late toxicity is reported for the first 213 patients using a modified RTOG toxicity scale. The Kaplan-Meier biochemical failure-free survival (bFFS) is reported according to the ASTRO and Houston definitions., Results: The bFFS at 60 months was of 88.5% (90.5%) according to the ASTRO (Houston) definition and, of 91.4% (94.6%) in the low risk group (initial PSA < or =10 and Gleason < or =6 and Stage < or =T2a). Risk factors statistically associated with bFFS were: initial PSA >10, a Gleason score of 7-8, and stage T2b-T3. The mean D90 was of 151 +/- 36.1 Gy. The mean V100 was of 85.4 +/- 8.5% with a mean V150 of 60.1 +/- 12.3%. Overall, the implants were well tolerated. In the first 6 months, 31.5% of the patients were free of genitourinary symptoms (GUs), 12.7% had Grade 3 GUs; 91.6% were free of gastrointestinal symptoms (GIs). After 6 months, 54.0% were GUs free, 1.4% had Grade 3 GUs; 95.8% were GIs free., Conclusion: The inverse planning with fast simulated annealing and high activity seeds gives a 5-year bFFS, which is comparable with the best published series with a low toxicity profile.

Purpose: The aim of this study was to demonstrate, based on clinical postplan dose distributions, that technology can be used efficiently to eliminate the learning curve associated with permanent seed implant planning and delivery., Methods and Materials: Dose distributions evaluated 30 days after the implant of the initial 22 consecutive patients treated with permanent seed implants at two institutions were studied. Institution 1 (I1) consisted of a new team, whereas institution 2 (I2) had performed more than 740 preplanned implantations over a 9-year period before the study. Both teams had adopted similar integrated systems based on three-dimensional (3D) transrectal ultrasonography, intraoperative dosimetry, and an automated seed delivery and needle retraction system (FIRST, Nucletron). Procedure time and dose volume histogram parameters such as D90, V100, V150, V200, and others were collected in the operating room and at 30 days postplan., Results: The average target coverage from the intraoperative plan (V100) was 99.4% for I1 and 99.9% for I2. D90, V150, and V200 were 191.4 Gy (196.3 Gy), 75.3% (73.0%), and 37.5% (34.1%) for I1 (I2) respectively. None of these parameters shows a significant difference between institutions. The postplan D90 was 151.2 Gy for I1 and 167.3 Gy for I2, well above the 140 Gy from the Stock et al. analysis, taking into account differences at planning, results in a p value of 0.0676. The procedure time required on average 174.4 min for I1 and 89 min for I2. The time was found to decrease with the increasing number of patients., Conclusion: State-of-the-art technology enables a new brachytherapy team to obtain excellent postplan dose distributions, similar to those achieved by an experienced team with proven long-term clinical results. The cost for bypassing the usual dosimetry learning curve is time, with increasing team experience resulting in shorter treatment times.

The purpose of this study is to determine the impact of edema on the dose delivered to the target volume. An evaluation of the edema characteristics was first made, and then a dynamical dosimetry algorithm was developed and used to compare its results to a standard clinical (static) dosimetry. Source positions and prostate contours extracted from 66 clinical cases on images taken at different points in time (planning, implant day, post-implant evaluation) were used, via the mean interseed distance, to characterize edema [initial increase (deltar0), half-life (tau)]. An algorithm was developed to take into account the edema by summing a time series of dose-volume histograms (DVHs) with a weight based on the fraction of the dose delivered during the time interval considered. The algorithm was then used to evaluate the impact of edema on the dosimetry of permanent implants by comparing its results to those of a standard clinical dosimetry. The volumetric study yielded results as follows: the initial prostate volume increase was found to be 1.58 (ranging from 1.15 to 2.48) and the edema half-life, approximately 30 days (range: 3 to 170 days). The dosimetric differences in D90 observed between the dynamic dosimetry and the clinical one for a single case were up to 15 Gy and depended on the edema half-life and the initial volume increase. The average edema half-life, 30 days, is about 3 times longer than the previously reported 9 days. Dosimetric differences up to 10% of the prescription dose are observed, which can lead to differences in the quality assertion of an implant. The study of individual patient edema resorption with time might be necessary to extract meaningful clinical correlation or biological parameters in permanent implants.

This study compared the prevalence of psychological difficulties (i.e., anxiety and depression), psychophysiological problems (i.e., insomnia and fatigue), and sexual difficulties across three modalities of treatment for prostate cancer (radiotherapy, brachytherapy, and radical prostatectomy). A total of 861 men completed a battery of questionnaires assessing anxiety, depression, fatigue, insomnia, and quality of life. Patients who initially received radiotherapy had higher levels of depression, anxiety, and fatigue and a lower quality of life, and were more likely to report clinical levels of depression and fatigue. Patients who initially received surgery were more likely to report clinical levels of sexual difficulties but less likely to report clinical levels of depression and fatigue, while patients who received brachytherapy were less likely to report sexual difficulties. Although cross-sectional, these findings raise the possibility of a differential influence of treatments for prostate cancer on some aspects of psychological functioning.

Purpose: Many cancer patients take antioxidant vitamin supplements with the hope of improving the outcome of conventional therapies and of reducing the adverse effects of these treatments. A randomized trial was conducted to determine whether supplementation with antioxidant vitamins could reduce the occurrence and severity of acute adverse effects of radiation therapy and improve quality of life without compromising treatment efficacy., Patients and Methods: We conducted a randomized, double-blind, placebo-controlled trial among 540 head and neck cancer patients treated with radiation therapy. Patients were randomly assigned into two arms. The supplementation with alpha-tocopherol (400 IU/d) and beta-carotene (30 mg/d) or placebos was administered during radiation therapy and for 3 years thereafter. During the course of the trial, supplementation with beta-carotene was discontinued because of ethical concerns., Results: Patients randomly assigned in the supplement arm tended to have less severe acute adverse effects during radiation therapy (odds ratio [OR], 0.72; 95% CI, 0.52 to 1.02). The reduction was statistically significant when the supplementation combined alpha-tocopherol and beta-carotene for adverse effects to the larynx (OR, 0.38; 95% CI, 0.21 to 0.71) and overall at any site (OR, 0.38; 95% CI, 0.20 to 0.74). Quality of life was not improved by the supplementation. The rate of local recurrence of the head and neck tumor tended to be higher in the supplement arm of the trial (hazard ratio, 1.37; 95% CI, 0.93 to 2.02)., Conclusion: Supplementation with high doses of alpha-tocopherol and beta-carotene during radiation therapy could reduce the severity of treatment adverse effects. However, this trial suggests that use of high doses of antioxidants as adjuvant therapy might compromise radiation treatment efficacy.

Background and Purpose: The aim of this study is to evaluate the acute and late complications in patients who have received HDR implant boost using inverse planning, and to determine dose volume correlations., Patients and Methods: Between September 1999 and October 2002, 44 patients with locally advanced prostate cancer (PSA>/=10 ng/ml, and/or Gleason score>/=7, and/or Stage T2c or higher) were treated with 40-45 Gy external pelvic field followed by 2--3 fraction of inverse-planned HDR implant boost (6--9.5 Gy /fraction). Median follow-up time was 1.7 years with 81.8% of patients who had at least 12 months of follow up (range 8.6--42.5. Acute and late morbidity data were collected and graded according to RTOG criteria. Questionnaires were used to collect prostate related measures of quality of life, and international prostate symptom score (IPSS) before and after treatment. Dose-volume histograms for prostate, urethra, bladder, penis bulb and rectum were analyzed., Results: The median patient age was 64 years. Of these, 32% were in the high risk group, and 61% in the intermediate risk group. 3 patients (7%) had no adverse prognostic factors. A single grade 3 GU acute toxicity was reported but no grade 3--4 acute GI toxicity. No grade 3--4 late GU or GI toxicity was reported. Acute (late) grade 2 urinary and rectal symptoms were reported in 31.8 (11.4%) and 4.6% (4.6%) of patients, respectively. A trend for predicting acute GU toxicity is seen for total HDR dose of more than 18 Gy (OR=3.6, 95%CI=[0.96--13.5], P=0.058). The evolution of toxicity is presented for acute and late GU/GI toxicity. Erectile dysfunction occurs in approximately 27% of patients who were not on hormonal deprivation, but may be taking sildenafil. The IPSS peaked on averaged 6 weeks post-implant and returned to the baseline at a median of 6 months., Conclusions: Inverse-planned HDR brachytherapy is a viable option to deliver higher dose to the prostate as a boost without increasing GU or rectal complication. Further HDR dose escalation to the prostate is feasible.

Background: Although low dietary intakes of antioxidant vitamins and minerals have been associated with higher risks of cancer, results of trials testing antioxidant supplementation for cancer chemoprevention have been equivocal. We assessed whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer., Methods: We conducted a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial among 540 patients with stage I or II head and neck cancer treated by radiation therapy between October 1, 1994, and June 6, 2000. Supplementation with alpha-tocopherol (400 IU/day) and beta-carotene (30 mg/day) or placebo began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. In the course of the trial, beta-carotene supplementation was discontinued after 156 patients had enrolled because of ethical concerns. The remaining patients received alpha-tocopherol or placebo only. Survival was evaluated by Kaplan-Meier analysis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided., Results: After a median follow-up of 52 months, second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119 participants, respectively. The effect of supplementation on the incidence of second primary cancers varied over time. Compared with patients receiving placebo, patients receiving alpha-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88, 95% CI = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03). Similarly, the rate of having a recurrence or second primary cancer was higher during (HR = 1.86, 95% CI = 1.27 to 2.72) but lower after (HR = 0.71, 95% CI = 0.33 to 1.53) supplementation with alpha-tocopherol. The proportion of participants free of second primary cancer overall after 8 years of follow-up was similar in both arms., Conclusions: alpha-Tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival.

Online prostate positioning using gold markers and a standard video-based electronic portal imaging device is reported. The average systematic (random) errors have been reduced from 2.1 mm (2.7 mm) to 0.5 mm (1.5 mm) in AP direction, 1.1 mm (1.7 mm) to 0.7 mm (1.2 mm) SI and 1.2 mm (1.7 mm) to 0.6 mm (1.3 mm) LR.

Purpose: To measure the interfraction and intrafraction motion of the prostate during the course of external beam radiotherapy using a video electronic portal imaging device and three-dimensional analysis., Methods and Materials: Eighteen patients underwent implantation with two or three gold markers in the prostate before five-angle/11-field conformal radiotherapy. Using CT data as the positional reference, multiple daily sets of portal images, and a three-dimensional reconstruction algorithm, intrafraction translations, as well as interfraction and intrafraction rotations, were analyzed along the three principal axes (left-right [LR], superoinferior [SI], and AP). The overall mean values and standard deviations (SDs), along with random and systematic SDs, were computed for these translations and rotations., Results: For 282 intrafraction translational displacements, the random SD was 0.8 mm (systematic SD, 0.2) in the LR, 1.0 mm (systematic SD, 0.4) in the SI, and 1.4 mm (systematic SD, 0.7) in the AP axes. The analysis of 348 interfraction rotations revealed random SDs of 6.1 degrees (systematic SD, 5.6 degrees ) around the LR axis, 2.8 degrees (systematic SD, 2.4 degrees ) around the SI axis, and 2.0 degrees (systematic SD, 2.2 degrees ) around the AP axis. The intrafraction rotational motion observed during 44 fractions had a random SD of 1.8 degrees (systematic SD, 1.0 degrees ) around the LR, 1.1 degrees (systematic SD, 0.8 degrees ) around the SI, and 0.6 degrees (systematic SD, 0.3 degrees ) around the AP axis., Conclusion: The interfraction rotations observed were more important than those reported in previous studies. Intrafraction motion was generally smaller in magnitude than interfraction motion. However, the intrafraction rotations and translations of the prostate should be taken into account when designing planning target volume margins because their magnitudes are not negligible.

Background and Purpose: To validate the use of idealized seed orientations in conjunction with the line source formalism for post-implant dosimetry of permanent 125I prostate implants., Patients and Methods: Post-implant, a CT scan and three fluoroscopic images were obtained for 32 patients having undergone permanent implants. From these images, the seed positions and orientations (phi,theta) were determined (1625 individual seeds). Two different dosimetric calculations were done: one using real orientations and one using idealized orientations (seeds along the axis of implantation). Dose volume histograms (DVHs) and key dosimetric parameters were compiled for the prostate, urethra, rectum, bladder and penile bulb, to evaluate the difference between the two approximations., Results: The phi angle distribution (phi = 1.1 degrees; sigma phi = 22.9 degrees) and the theta angle distribution (theta= -4.29 degrees; sigma theta = 27.1 degrees) were found to be similar to the first order except for the pronounced peak of the phi angle distribution. The DVHs comparison and dosimetric parameters study reveal no significant difference between the two approximations. The difference in D90 for the prostate was only 0.02% (sigma = 0.91%) The differences were slightly higher in the case of the organs at risk, as expected from the dosimetric characteristics of the seed model used., Conclusions: The angular distributions (phi,theta) of individual seeds were determined. The dosimetric evaluation shows that line source formalism can be used in conjunction with an idealized seed configuration presented here to report prostate and organs at risk dose coverage.

An algorithm for the daily localization of the prostate using implanted markers and a standard video-based electronic portal imaging device (V-EPID) has been tested. Prior to planning, three gold markers were implanted in the prostate of seven patients. The clinical images were acquired with a BeamViewPlus 2.1 V-EPID for each field during the normal course radiotherapy treatment and are used off-line to determine the ability of the automatic marker detection algorithm to adequately and consistently detect the markers. Clinical images were obtained with various dose levels from ranging 2.5 to 75 MU. The algorithm is based on marker attenuation characterization in the portal image and spatial distribution. A total of 1182 clinical images were taken. The results show an average efficiency of 93% for the markers detected individually and 85% for the group of markers. This algorithm accomplishes the detection and validation in 0.20-0.40 s. When the center of mass of the group of implanted markers is used, then all displacements can be corrected to within 1.0 mm in 84% of the cases and within 1.5 mm in 97% of cases. The standard video-based EPID tested provides excellent marker detection capability even with low dose levels. The V-EPID can be used successfully with radiopaque markers and the automatic detection algorithm to track and correct the daily setup deviations due to organ motions.

Purpose: To present an exhaustive dosimetric comparison between three geometric optimization methods and our inverse-planning simulated annealing (IPSA) algorithm, with two different prescriptions for high-dose-rate (HDR) boost of the prostate. The objective of this analysis was to quantify the dosimetric advantages of the IPSA algorithm compared with more standard geometric optimizations., Methods and Materials: Between September 1999 and June 2001, 34 patients were treated to a dose of 40-44 Gy by external pelvic fields, followed by an HDR boost of 18 Gy in 3 fractions. The first 4 patients were treated with HDR using geometric optimization, and anatomy-based inverse-planning dose optimization was used for the remaining 30 patients. We retrospectively used the data from these 30 patients to create HDR dose distributions according to five different dose optimization protocols, including our IPSA algorithm. The various geometric optimization procedures differed in the way the dwell positions were activated and plan normalization was performed. Dose-volume histograms from all these plans were analyzed and multiple implant quality indexes extracted., Results: The IPSA algorithm provided better clinical tumor volume prescription dose coverage than did the geometric optimizations. The average prostate volume receiving 100% of the prescribed dose (V100) was 96.3% and 94.5% for IPSA with two different prescriptions compared with 92.1%, 92.6%, and 88.8% for the three geometric optimization schemes. The average urethra V150 value was 0.0% and 0.7% for IPSA with two different prescriptions, and the three geometric optimization protocols generated average values of 22.9%, 33.9%, and 38.8%. The bladder and rectal dose-volume histograms were similar, although the latest version of the IPSA algorithm slightly decreases the dose to these organs at risk because of organ-specific dose constraints included in the objective function., Conclusion: We found that planning an HDR prostate boost could be performed in a fast, secure, and effective manner with the IPSA algorithm. We demonstrated that our inverse-planning algorithm produces superior HDR plans than more conventional geometric optimizations for adenocarcinoma of the prostate. The organs at risk protection included in the objective function is a major feature of the algorithm and should allow us to escalate the HDR dose to the prostate without increasing undesirable side effects.

Purpose: The goal of this study is to evaluate the dosimetric impact on a pretreatment planning of prostatic volume and shape variations occurring between the moment of the volume study (preplanning) and just before a transperineal permanent seed implant procedure. Such variations could be an obvious source of misplacement of the seeds relative to the prostate gland and organs at risk. Other sources of dosimetric uncertainties, such as misplacement due to the procedure itself or edema, are eliminated by looking at these variations before the implant procedure., Methods and Materials: For 35 clinical cases, prostate contours were taken at preplanning time as well as in the operating room (OR) minutes before the procedure. Comparison of shape and volume between the two sets was made. The impact on V100 was evaluated by placing the seeds in their planned positions in the new volume (clinical situation) and also by performing a new plan with the second set of contours to simulate an intraoperative approach., Results: The volume taken in the OR remained unchanged compared to the pretreatment planning volume in only 37% of the cases. While on average the dose coverage loss from pretreatment planning due to a combination of variations of volume and shape was small at 5.7%, a V100 degradation of up to 20.9% was observed in extreme cases. Even in cases in which no changes in volume were observed, changes in shape occurred and strongly affected implant dosimetry., Conclusions: Variations of volume and shape between pretreatment planning and the implant procedure can have a strong impact on the dosimetry if the planning and the implant procedure are not performed on the same day. This is an argument in favor of performing implant dosimetry in the OR.

Purpose: To evaluate the dose distribution within the clinical target volume between two gynecologic brachytherapy systems---the tandem and ovoids and the Syed-Neblett gynecologic template---using a hypothetical computer model., Methods and Materials: Source positions of an intracavitary system (tandem and ovoids) and an interstitial system (GYN template) were digitized into the Nucletron Brachytherapy Planning System. The GYN template is composed of a 13-catheter implant (12 catheters plus a tandem) based on the Syed-Neblett gynecologic template. For the tandem and ovoids, the dwell times of all sources were evenly weighted to produce a pear-shaped isodose distribution. For the GYN template, the dwell times were determined using volume optimization. The prescribed dose was then normalized to point A in the intracavitary system and to a selected isodose line in the interstitial system. The treated volume in the two systems was kept approximately the same, and a cumulative dose-volume histogram of the treated volume was then generated with the Nucletron Brachytherapy Planning System to use for comparison. To evaluate the dose to a hypothetical target, in this case the cervix, a 2-cm-long, 3-cm-diameter cylinder centered along the tandem was digitized as the clinical target volume. The location of this hypothetical cervix was based on the optimal application of the brachytherapy system. A visual comparison of clinical target coverage by the treated volume on three different orthogonal planes through the treated volume was performed. The percentage dose-volume histograms of the target were generated for comparison. Multiple midline points were also placed at 5-mm intervals away from the tandem in the plane of the cervix to simulate the location of potential bladder and rectal dose points. Doses to these normal structures were calculated for comparison., Results: Although both systems covered the hypothetical cervix adequately, the interstitial system had a better coverage of the region lateral to the cervix. Smaller volumes of the vagina and uterine fundus received the full dose from the interstitial implant. The cumulative dose-volume histograms revealed larger high-dose regions within the treatment volume for the intracavitary system. The volumes receiving > or = 180% of the prescription dose were 31 cc and 17 cc for the intracavitary system and interstitial system, respectively. The isodose lines showed that most of this difference results from the high-dose region around the tandem. The percentage dose-volume histograms showed that a larger percentage of cervix received a higher dose in the intracavitary system. Fifty-two percent of the target volume received 200% or higher of the prescription dose with tandem and ovoids, compared with only 20% with the template system. Analysis of dose points outside of the 100% isodose lines showed a slightly more rapid dose drop-off with the interstitial system compared to the intracavitary system. Point doses at 20, 25, and 30 mm from the tandem in the interstitial system were 100%, 69%, and 51% of prescribed dose, and from the intracavitary system were 101%, 76%, and 58%, respectively., Conclusions: Our dosimetric analysis revealed a better coverage in the parametrial regions, but underdosage of the central cervical region, for the interstitial system. On the other hand, because of the increased distance of source to dose point, there is a more rapid dose drop-off outside the treated volume with the interstitial system, which has the potential to improve tissue sparing. Based on this analysis, we caution against using a radiotherapy system with a homogeneous central dose distribution when treating cervical cancer with an intact uterus. We recommend differential loading of the implant catheters with the majority of dose delivered from the tandem when using an interstitial GYN template with remote afterloader.