Infiltration of the prostatic ducts by prostatic adenocarcinoma occurs relatively frequently, being most commonly associated with high grade disease. It is now recognised that intraductal carcinoma ...of the prostate (IDCP) has an associated poor prognosis and this is reflected in its histological, molecular and immunohistochemical features. The current recommendation of the World Health Organization is that IDCP not be taken into consideration when grading prostate adenocarcinoma. It is apparent that Gleason did not differentiate between IDCP and stromal invasive carcinoma when developing and validating his grading system, and recent studies suggest that the incorporation of IDCP grading into the overall grading of the specimen provides additional prognostic information.
Purpose: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a ...continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx.
Patients and methods: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached.
Results: The median potential follow-up time was 53 months (range, 14–101). The DFS at 5 years was 41% (95% CI, 33–50%) for ART and 35% (95% CI, 27–43%) for CRT (
P=0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66–1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (
P=0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (
P=0.300). The respective hazard ratios were 0.88 (95% CI, 0.65–1.2) and 0.85 (0.62–1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%;
P<0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (
P<0.05), except for the mucous membrane where late effects were similar in both arms.
Conclusions: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy.
Purpose:
To assess dose delivery accuracy to clinically significant points in a realistic patient geometry for two separate pelvic radiotherapy scenarios.
Methods:
An inhomogeneous pelvic phantom was ...transported to 36 radiotherapy centers in Australia and New Zealand. The phantom was treated according to Phase III rectal and prostate trial protocols. Point dose measurements were made with thermoluminescent dosimeters (TLDs) and an ionisation chamber. Comprehensive site-demographic, treatment planning, and physical data were collected for correlation with measurement outcomes.
Results:
Dose delivery to the prescription point for the rectal treatment was consistent with planned dose (mean difference between planned and measured dose − 0.1 ± 0.3% std err). Dose delivery in the region of the sacral hollow was consistently higher than planned (+1.2 ± 0.2%). For the prostate treatment, dose delivery to the prostate volume was consistent with planned doses (−0.49 ± 0.2%) and planned dose uniformity, though with a tendency to underdose the PTV at the prostate-rectal border. Measured out-of-field doses were significantly higher than planned.
Conclusions:
A phantom based on realistic anatomy and heterogeneity can be used to comprehensively assess the influence of multiple aspects of the radiotherapy treatment process on dose delivery. The ability to verify dose delivery for two trials with a single phantom was advantageous.
Utilization of nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, can produce gastrointestinal ulceration. Thus, cyclooxygenase-2-selective inhibitors, such as celecoxib, and ...protective agents (e.g. rebamipide) have been employed to alleviate harmful NSAID effects. This study sought to explore the influence of rebamipide on the hepatic outcomes following administration of two commonly prescribed NSAIDs.
Rats were given either vehicle or rebamipide (30 mg/kg) orally twice daily for two days, then on the third day respective groups were dosed with either vehicle, celecoxib (40 mg/kg), or diclofenac (10 mg/kg) in addition to a respective dose of vehicle or rebamipide. Livers were collected on day 4 following euthanasia. Hepatic tissue was examined via histopathology and assayed for oxidative stress and specific NSAID concentration.
The liver sections were found to be free from structural changes. Oxidative stress biomarkers, reduced glutathione and malondialdehyde, were discovered to be unaltered among the groups tested. The hepatic NSAID concentrations were not significantly affected by the presence of rebamipide.
The concomitant administration of rebamipide does not influence the hepatic condition of rats administered either celecoxib or diclofenac at the dosages and over the time course examined.
Purpose: To determine dosimetric predictors of late rectal toxicity after prostate radiotherapy, differentiating between dose to rectum and anal canal. Methods: Clinical and 3D dosimetric data for ...738 patients were prospectively collected in a clinical trial (TROG 03.04 “RADAR”) of variable‐duration hormone therapy with conformal radiotherapy using rectal DVH constraints of V65<40%, V70<30%, V75<5%. Dose‐volume histograms were generated for whole anorectum, anal canal, rectum and matched to longitudinal toxicity (measured 6‐monthly). Outcome measures were: bleeding, urgency/tenesmus (grade 1+, 2+, 3), pooled Common Toxicity Criteria version 2 proctitis (grade 1+, 2+), incontinence, bowel bother, diarrhea, and anorectal pain. Both prevalence (at 30 months post radiotherapy) and actuarial incidence (time‐to‐failure) endpoints were analyzed. Rectal mean dose and V5–V70 were used as factors in multivariate and univariate logistic regression (prevalence) and Cox proportional hazards (incidence) analyses. Results: Median follow‐up was 6.5 years post‐treatment. Multivariate models produced erratic effect estimates due to multicollinearity arising from constrained DVH shape as mandated by the trial protocol. Univariate analysis identified that pain, pooled proctitis, incontinence were predicted most by anal canal dose. Bleeding and diarrhea were not subvolume dependent. Bowel bother was not associated with any factor. Urgency/tenesmus association with subvolume depended on the outcome grade used. Conclusion: Doses to different subvolumes of the rectum are responsible for different types of toxicity. Different grades of the same toxicity are predicted by different subvolumes and DVH points. For datasets planned with dose constraints, multicollinearity of DVH points limits the usefulness of multivariate analysis. Further work will estimate DVH constraints to limit toxicity, and Lyman model parameters from the same data. Funding: National Health and Medical Research Council (Australian Government), Hunter Prostate Cancer Alliance, Trans‐Tasman Radiation Oncology Group. Conflicts of interest: none declared
Purpose: An anthropomorphic pelvic phantom was designed and constructed to meet specific criteria for multicenter radiotherapy dosimetric intercomparison.Methods: Three dimensional external and organ ...outlines were generated from a computed tomography image set of a male pelvis, forming the basis of design for an anatomically realistic phantom. Clinically relevant points of interest were selected throughout the dataset where point-dose values could be measured with thermoluminescence dosimeters and a small-volume ionization chamber. Following testing, three materials were selected and the phantom was manufactured using modern prototyping techniques into five separate coronal slices. Time lines and resource requirements for the phantom design and manufacture were recorded. The ability of the phantom to mimic the entire treatment chain was tested.Results: The phantom CT images indicated that organ densities and geometries were comparable to those of the original patient. The phantom proved simple to load for dosimetry and rapid to assemble. Due to heat release during manufacture, small air gaps and density heterogeneities were present throughout the phantom. The overall cost for production of the prototype phantom was comparable to other commercial anthropomorphic phantoms. The phantom was shown to be suitable for use as a “patient” to mimic the entire treatment chain for typical external beam radiotherapy for prostate and rectal cancer.Conclusions: The phantom constructed for the present study incorporates all characteristics necessary for accurate Level III intercomparison studies. Following use in an extensive Level III dosimetric comparison over a large time scale and geographic area, the phantom retained mechanical stability and did not show signs of radiation-induced degradation.
The intestine is often dose limiting during abdominal and pelvic radiation therapy. Delayed bowel toxicity is difficult to manage and adversely impacts the quality of life of long-term cancer ...survivors. Of the 8 to 9 million cancer survivors currently living in the United States, more than half have had abdominal or pelvic tumors, and about 60% of these patients have undergone or will undergo radiation therapy. Therefore, interventions that limit postradiation intestinal dysfunction would significantly improve outcomes in a large number of patients. Worthwhile steps toward reducing toxicity of treatments have been taken recently by introducing dose-sculpting treatment techniques. However, prophylactic or therapeutic approaches derived from an improved understanding of the pathophysiology of bowel injury will result in further advances. This article reviews current principles in the diagnosis and management of intestinal radiation injury. It also provides an overview of investigational strategies aimed at reducing radiation-induced bowel toxicity. These strategies include free radical scavengers, antioxidants, cytoprotective agents, cytokines, and enterotrophic interventions, as well as modulators of intraluminal factors, endothelial dysfunction, and neuroimmune interactions. Preclinical testing in clinically relevant animal models will facilitate translation of these strategies into the clinic and contribute to improving cancer cure rates and quality of life in cancer survivors.
Background and purpose: The relationship between acute and late mucosal reactions remains ill defined but is of considerable relevance to efforts to produce therapeutic gains through the use of ...altered fractionation schemes and concurrent chemotherapy. We therefore investigated whether acute mucosal reactions in patients treated with an accelerated and a conventionally fractionated radiotherapy regime predicted the severity of late mucosal reactions.
Patients and methods: The study population consisted of 191 patients randomised on a prospective trial comparing conventional fractionation at 2 Gy/fraction per day, 70 Gy over 47 days with an accelerated regimen of 59.4 Gy, 1.8 Gy BID over 24 days for Stage III–IV carcinoma of the head and neck. Acute and late mucosal reactions were scored according to RTOG/EORTC criteria and analyzed using multiple regression techniques.
Results: The duration of time spent by patients at the acute confluent mucositis grade 3 level was inversely related to the time to onset of the reaction for both fractionation schedules. Time to onset was more rapid for patients treated on the accelerated schedule but time spent at the reaction grade did not differ significantly between the schedules. After correction for treatment and patient related factors, anatomical site (oral cavity/oropharynx versus hypopharynx/larynx) and increasing duration of confluent mucositis emerged as independent predictors of the hazard of late mucosal reactions with the latter effect being more pronounced in the accelerated treatment arm. The expected reduction in late mucosal effects in the accelerated fractionation arm, predicted by the LQ model for late effects was identified only in patients whose acute confluent mucosal reactions lasted less than 20 days.
Conclusions: The presence of individual patient susceptibility factors that determine the severity of acute mucosal reactions is suggested. A link between severe and prolonged acute reactions and the risk of developing late mucosal reactions that is independent of biological dose, has also been found. Purpose designed prospective studies of these issues are necessary.
To investigate the significance of the various late rectal symptoms that appear after radical prostatic irradiation.
Patients with localised prostate cancer treated between 1987 and 1994 at the Mater ...Hospital, Newcastle with radical megavoltage irradiation were recalled for examination and to complete a detailed questionnaire concerning late radiation-induced symptoms and their effects on normal daily life. The influence of patient age treatment related variables and acute proctitis symptoms occurring during therapy or the late symptoms recorded were assessed and the relationship between late symptoms and late EORTC/RTOG score and impact on normal daily life were studied.
The presence of symptoms of acute proctitis was the only factor to predict any of three late symptoms (urgency, frequency and diarrhoea) and late EORTC/RTOG score in this series (odds ratios: 1.7-2.57, P-values: 0.009-0.0007). Cluster and discriminant function analyses revealed the presence of five subgroups of patients with varying permutations of different late rectal symptoms, including one group with minimal symptoms (P < 0.0001). While bleeding and rectal discharge were the major contributors to late EORTC/RTOG score (P < 0.0001 and 0.04), faecal urgency and bleeding were the most important factors to impact on normal daily life (P < 0.0001 and P < 0.0003). A relatively low concordance was found between late EORTC/RTOG score and the patients' self assessment on the effect of their symptoms on their normal daily lives. Some late symptoms, including bleeding and rectal discharge become less prevalent after 3 years of follow-up with a resulting improvement in EORTC/RTOG score.
There may be more than one late (chronic) proctitis syndrome which may be linked in greater or lesser degrees to acute proctitis symptoms occurring during therapy. Urgency is a common late symptom which often has an important impact on normal daily life and deserves recognition in late normal tissue scoring systems. Assessment of the incidence of bleeding as a measure of late rectal morbidity following prostate irradiation may underestimate the impact of these chronic effects. Confirmatory studies are necessary.
