Prostate cancer screening in Australasia.
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Australia↗
Biomedical subjects
J W Denham
Publications and source records attributed to J W Denham.
Fatigue during breast radiotherapy and its relationship to biological factors.
INTRODUCTION: Fatigue is commonly reported in patients receiving radiotherapy for breast conservation, but the underlying mechanisms remain unclear. METHODS: Patients with early breast cancer participating in a prospective study of the impact of inflammatory processes on early and delayed breast morbidity were assessed for fatigue levels using the Functional Assessment of Cancer Therapy (FACT) fatigue subscale before and at intervals during and after radiotherapy. Blood for analysis of a variety of circulating cytokines, coagulation factors, peripheral blood indices and biochemical factors was collected at the same time points. RESULTS: Fifty-two eligible patients were assessed. Twenty-one patients (43%) developed significant fatigue during radiotherapy, whereas 28 (54%) developed minimal or no fatigue. Fatigue appeared to plateau between week 4 of treatment and 2 weeks after treatment. The fatigue was beginning to settle by 6 weeks after treatment. Significant fatigue was predicted by a higher baseline fatigue score, red cell count, neutrophil count, and D-dimer level. Baseline fatigue correlated with higher body mass index, C-reactive protein, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, interleukin-6, ICAM-1, hemoglobin and red cell, monocyte, and neutrophil counts. There were also significant correlations between body mass index and tissue plasminogen activator, C-reactive protein, interleukin-6, ICAM-1, and red cell count. After these factors were controlled for, baseline fatigue was seen to be associated with higher body mass index, soluble thrombomodulin, tissue plasminogen activator, von Willebrand factor antigen, monocyte count, and neutrophil count. Multiple logistic regression procedures indicated that the most predictive factors for fatigue during radiotherapy were higher baseline fatigue level and higher baseline neutrophil and red cell counts. CONCLUSION: This study has shown that significant fatigue is common in patients receiving breast irradiation and is precipitated during radiotherapy in some patients but not others. The factors shown to be associated with fatigue in this study will be helpful in shaping future studies.
Adult↗
Relapse patterns after chemo-radiation for carcinoma of the oesophagus.
AIM: The detailed review of patterns of failure in this report was undertaken to identify the continuing obstacles to the successful management of oesophageal cancer, and to establish whether there is a case to compare definitive chemo-radiation (Def-CR) and surgery for patients with squamous cancer in a randomized controlled trial. MATERIALS AND METHODS: First and subsequent sites of failure were reviewed in 274 patients treated with Def-CR using two cycles of cisplatin, infusional fluorouracil and 60 Gy; and 92 patients with limited chemo-radiation (CR), using one cycle and 35 Gy, followed by surgery (CR-Surg). All were treated on prospective non-randomized trials run by the Trans-Tasman Radiation Oncology Group between 1985 and 1999. Failure patterns were analysed using competing risks methodology, and pre-treatment variables predicting survival were identified by proportional hazards modelling. RESULTS: Site, stage, performance status and gender were independently predictive of survival following Def-CR. Local failure was evident in 42.3% of patients, but distant failure in isolation occurred in an additional 18.1%. Lowest rates of local and distant failure at 5 years (29.9% and 26%) occurred in patients with squamous cancer (SCC) located in the upper-third, whose 5-year survival was also the most favourable (49.2%). Survival was least favourable in patients with adenocarcinoma (AC) in the lower two-thirds (18.1%) due to higher rates of local (51.5%) and distant (36.1%) failure. Local failure occurred in 31.5% of patients undergoing CR-Surg but distant failure in isolation was observed in a further 34.7%. Outcomes were least favourable in patients with AC of the lower-third in whom 57.7% failed distantly and 5-year survival was 3.8%. Response to pre-operative chemo-radiation was also strongly predictive of outcome. Patients with no residual cancer in the resection specimen had the lowest rates of local (0%) and distant (16.7%) failure and the best survival (64.9%). Survival in patients with residual cancer in nodes, however, was extremely poor (3.5%) with distant failure occurring in 66.7%. CONCLUSION: The concurrent administration of chemotherapy with radiotherapy seems to have improved loco-regional control and has exposed distant failure as an obstacle to further improvements in outcome. Site, histological subtype, gender and response to chemo-radiation may predict biological differences in oesophageal cancer (OC) that influence outcome. A good case for a randomized comparison between Def-CR and CR-Surg in patients with SCC in the lower two-thirds exists.
Adenocarcinoma↗
Clinical implications of mucosal regeneration.
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Dose Fractionation, Radiation↗
Prostate cancer: low alpha/beta the only consideration? In regard to Fowler, Chappell, and Ritter: the prospects for new treatments for prostate cancer.
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Clinical Trials as Topic↗
Extinction of the weakest.
PURPOSE: To examine whether changes in the effective doubling time of tumor cells during irradiation of head-and-neck cancer are linked to accumulating dose. METHODS AND MATERIALS: Optimal fitting of the results of four apparently iso-effective regimens in three recently reported randomized controlled trials (continuous hyperfractionated accelerated radiation therapy [CHART], Radiation Therapy Oncology Group [RTOG] 90-03, and Trans-Tasman Radiation Oncology Group [TROG] 91.01) was attempted using two different types of model of the change in effective doubling time that may occur during treatment. The first involved the traditional approach where doubling time changes at specific times after the start of treatment regardless of fractionation used (''fixed response time'' models). The second is where changes in doubling time are linked to accumulating biologic dose (''cellular depletion'' models). RESULTS: Changes in effective doubling time occur during radiotherapy for head-and-neck cancer. Data from the three trials can be fitted successfully by functions that imply a continuous reduction in effective doubling time. Models linking the reductions in effective doubling time to the cellular depletion that occurs in the tumor during radiotherapy fit the data satisfactorily. Effective doubling time ultimately reduces to 2 days, or slightly less, during high-dose radiotherapy regimens designed to cure squamous head-and-neck cancer. CONCLUSIONS: If the assumption of iso-effectivity is justified then this study indicates that the ''repopulation phenomenon'' may be best described by a function that depicts a reduction in effective tumor cell doubling time that decreases continuously during treatment down to a certain minimum value. Furthermore, this reduction may be linked to cellular depletion.
Cell Division↗
Is it time for a new formalism to categorize normal tissue radiation injury?
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Cells↗
A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study.
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.
Adult↗
Pilot study of high-frequency ultrasound to assess cutaneous oedema in the conservatively managed breast.
Cutaneous oedema is a relatively frequent complication in patients treated conservatively for breast cancer. The factors that contribute to this complication have not been precisely determined. We performed a pilot study to assess the usefulness of high-frequency ultrasound as a quantitative measure of cutaneous oedema. Eleven patients undergoing breast-conserving therapy for breast cancer were studied. Both the treated and untreated breasts were examined. Total cutaneous thickness provided a useful measure of cutaneous oedema. The treated breast was significantly thicker than the untreated breast (P < 0.001). The medial aspect of the breast was thicker than the lateral aspect in both the treated and untreated breast (P < 0.001). The increase in cutaneous thickness predated radiotherapy in those patients who had undergone an axillary dissection. Intrapatient variation in skin thickness was much less than interpatient variation in skin thickness (coefficient of variation 6.4% vs. 18.2% for the untreated breast; coefficient of variation 13.9% vs. 30.9% for the treated breast). Increasing cutaneous thickness was associated with decreasing cutaneous echodensity. We were unable to derive quantitative estimates of echodensity. Cutaneous oedema is an important outcome variable following conservative treatment of breast cancer. High-frequency ultrasound is able to quantify this accurately. It can readily detect changes invisible to the naked eye. High-frequency ultrasound should enable the effects of different treatment options (e.g., extent of surgery, radiotherapy, and chemotherapy) on cutaneous oedema to be differentiated and for the time course of oedema to be accurately characterised.
Aged↗
Treatment-time-dependence models of early and delayed radiation injury in rat small intestine.
BACKGROUND: The present study modeled data from a large series of experiments originally designed to investigate the influence of time, dose, and fractionation on early and late pathologic endpoints in rat small intestine after localized irradiation. The objective was to obtain satisfactory descriptions of the regenerative response to injury together with the possible relationships between early and late endpoints. METHODS: Two- and 26-week pathologic radiation injury data in groups of Sprague-Dawley rats irradiated with 27 different fractionation schedules were modeled using the incomplete repair (IR) version of the linear-quadratic model with or without various time correction models. The following time correction models were tested: (1) No time correction; (2) A simple exponential (SE) regenerative response beginning at an arbitrary time after starting treatment; and (3) A bi-exponential response with its commencement linked to accumulated cellular depletion and fraction size (the 'intelligent response model' [INTR]). Goodness of fit of the various models was assessed by correlating the predicted biological effective dose for each dose group with the observed radiation injury score. RESULTS: (1) The incomplete repair model without time correction did not provide a satisfactory description of either the 2- or 26-week data. (2) The models using SE time correction performed better, providing modest descriptions of the data. (3) The INTR model provided reasonable descriptions of both the 2- and 26-week data, confirming a treatment time dependence of both early and late pathological endpoints. (4) The most satisfactory descriptions of the data by the INTR model were obtained when the regenerative response was assumed to cease 2 weeks after irradiation rather than at the end of irradiation. A fraction-size-dependent delay of the regenerative response was also suggested in the best fitting models. (5) Late endpoints were associated with low-fractionation sensitivity and treatment-time dependence even in animal groups that exhibited minimal early mucosal reactions. CONCLUSION: Radiation injury scores in this rat small intestinal experimental model cannot be adequately described without time correction. 'Consequential' mechanisms contribute to the development of late effects, even in animals that do not develop severe early mucosal injuries. The initiation of the regenerative response is subject to a fraction-size-dependent mitotic delay and is linked to the level of accumulated cellular depletion. The response does not cease at the end of therapy but probably continues until maximal healing has taken place.
Animals↗
Influence of dose-rate on inflammatory damage and adhesion molecule expression after abdominal radiation in the rat.
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Animals↗
Decision-making models in the analysis of portal films: a clinical pilot study.
Portal films continue to play an important role in the verification of radiotherapy treatment. There is still some discussion, however, as to what action should be taken after a port film has shown a radiation field deviation from the prescribed volume. It was the aim of the present pilot study to investigate the performance of three decision-making models ('Amsterdam', 'Quebec' and 'Newcastle') and an expert panel basing their decision on intuition rather than formal rules after portal film acquisition in a clinical setting. Portal films were acquired on every day during the first week of treatment for five head and neck and five prostate cancer patients (diagnostic phase). If required, the field position was modified according to our normal practice following the recommendation of the expert panel. In order to analyse the results of the models, however, additional port films were taken in the following 3 treatment weeks with the patient moved as required by the different models (intervention phase). The portal films were taken over 4 consecutive days, positioning the patient according to each of the different models on one day each. None of the models diagnosed a field misplacement in the head and neck patients, while the 'Amsterdam' and 'Quebec' models predicted a move in one prostate patient. The 'Newcastle' model, which is based on Hotelling's T2 statistic, proved to be more sensitive and diagnosed a systematic displacement for three prostate patients. The intervention phase confirmed the diagnosis of the model, even if the three portal films taken with the patient position adjusted as required by the model proved to be insufficient to demonstrate an improvement. The 'Newcastle' model does not rely on assumptions about the random movement of patients and requires five portal films before a decision can be reached. This approach lends itself well to incorporation into electronic portal imaging 'packages', where repeated image acquisitions present no logistical difficulty.
Decision Support Techniques↗
Is there more than one late radiation proctitis syndrome?
PURPOSE: To investigate the significance of the various late rectal symptoms that appear after radical prostatic irradiation. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Aged↗
Do acute mucosal reactions lead to consequential late reactions in patients with head and neck cancer?
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 b.i.d 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.
Acute Disease↗
Causes for increased myelosuppression with increasing age in patients with oesophageal cancer treated by chemoradiotherapy.
The aim of this study was to identify why increasing myelosuppression accompanies increasing age in patients treated for oesophageal cancer by chemoradiation. Weekly neutrophil and platelet counts were obtained throughout treatment in 86 patients undergoing chemoradiation without surgery for oesophageal cancer. One or two cycles of cisplatin 80 mg/m2/day followed by 5-fluorouracil 800 mg/m2/day for 4-5 days were administered during the first and fourth or fifth week of radiotherapy using 2 Gy daily fractions. 44 of the patients underwent 5-fluorouracil pharmacokinetic studies. Multiple regression procedures were used to determine the strength of factors that contribute to initial and nadir neutrophil and platelet counts. The kinetics of myeloid response were evaluated from the rates of disappearance and re-appearance of neutrophils and platelets during treatment. Age, fluorouracil dose (or AUC), baseline body weight and neutrophil (or platelet) count were found to be powerfully and independently predictive of both first neutrophil and platelet nadir count. Baseline neutrophil and platelet counts were also found to correlate negatively with advancing age independently of other factors. The rate of descent of both indices, however, was independent of age, baseline count and fluorouracil dose suggesting that variations in the size of the myeloproliferative compartment prior to treatment were responsible for interpatient variations. In addition, the rate of recovery of both indices was not influenced by age amongst patients in whom data was assessable suggesting that proliferation of surviving marrow elements is not compromised by age. These data are compatible with the hypothesis that a progressive depletion of the myeloid stem cell compartment accompanies advancing age, and that this is responsible for increasing myelotoxicity.
Adult↗
A generalized F mixture model for cure rate estimation.
Cure rate estimation is an important issue in clinical trials for diseases such as lymphoma and breast cancer and mixture models are the main statistical methods. In the last decade, mixture models under different distributions, such as exponential, Weibull, log-normal and Gompertz, have been discussed and used. However, these models involve stronger distributional assumptions than is desirable and inferences may not be robust to departures from these assumptions. In this paper, a mixture model is proposed using the generalized F distribution family. Although this family is seldom used because of computational difficulties, it has the advantage of being very flexible and including many commonly used distributions as special cases. The generalised F mixture model can relax the usual stronger distributional assumptions and allow the analyst to uncover structure in the data that might otherwise have been missed. This is illustrated by fitting the model to data from large-scale clinical trials with long follow-up of lymphoma patients. Computational problems with the model and model selection methods are discussed. Comparison of maximum likelihood estimates with those obtained from mixture models under other distributions are included.
Confidence Intervals↗
Long-term results of accelerated radiation treatment for advanced head and neck cancer.
BACKGROUND AND PURPOSE: This report presents long-term follow-up data from a prospective but unrandomized trial of a continuous 3.5-week course of accelerated radiation treatment (ART) used as primary treatment for patients with loco-regionally advanced head and neck cancer. MATERIALS AND METHODS: Ninety-three patients in three centres in New Zealand and Australia were treated with ART (59.40 Gy in 33 fractions over 24-25 days). Their disease originated from three anatomical regions (oral cavity, 35 patients; pharynx, 31 patients; larynx, 27 patients). Seventy-nine of these patients had stage III or IV cancers. RESULTS: Follow-up ranged from 68 to 203 months (median 139 months). Loco-regional (LR) failure occurred in 52 patients leading to a 10-year actuarial expectation of LR control of 38%. The actuarial expectation of LR control at 10 years was highly dependent on stage and for stage III, IVA and IVB patients it was 57+/-8.1%, 32+/-1.7% and 7+/-0.5%, respectively. Multivariate analysis could not confirm an independent impact of primary site or histological differentiation on LR failure. Two patients died of acute toxicity of treatment and six patients developed grade 3/4 late complications affecting soft tissues only, yielding an actuarial expectation of complications of this severity at 5 years of 9%. No cases of osteoradionecrosis or myelitis were observed. CONCLUSION: This ART, which has proved easy to use at a number of large and small centres, has produced encouraging long-term LR control at a cost of limited soft tissue morbidity.
Adolescent↗