Patient-reported sexual toxicity after radiation therapy in long-term prostate cancer survivors.

BACKGROUND: To present an overview of patient-reported sexual toxicity in sexually active long-term prostate cancer survivors treated with radiation therapy. METHODS: We used patient-reported outcomes from a study-specific questionnaire surveying symptoms after prostate cancer radiation therapy. Data from 518 men treated at the Sahlgrenska University Hospital in Sweden from 1993 to 2006 were analysed. The men had undergone primary or salvage external beam radiation therapy (EBRT) or EBRT combined with high-dose rate brachytherapy (BT). We also used information from 155 non-treated reference men from the general population with no history of prostate cancer, matched for age and residency. RESULTS: Median time from treatment to follow-up was 5 years (range: 1-14 years). Among the 16 investigated symptoms on erectile function, libido, orgasm, and seminal fluid, 9 symptoms in the primary EBRT group and 10 in both the salvage EBRT and the EBRT+BT groups were statistically significantly more prevalent in survivors than in reference men. Erectile dysfunction was influenced by both age and time to follow-up, whereas symptoms relating to orgasm and seminal fluid were influenced by time to follow-up only. Not being sexually active was almost one and a half times as common in survivors as in reference men. CONCLUSIONS: The presented symptom profiles can help to develop personalized therapy for prostate cancer through a better understanding of which radiation-induced toxicities to be addressed in the clinic and can also assist in identifying suitable interventions for existing symptoms.

A calibration study of SAPS II with Norwegian intensive care registry data.

BACKGROUND: Mortality prediction is important in intensive care. The Simplified Acute Physiology Score (SAPS) II is a tool for predicting such mortality. However, the original SAPS II is poorly calibrated to current intensive care unit (ICU) populations because it draws on data, which is more than 20 years old. We aimed to improve the calibration of SAPS II using data from the Norwegian Intensive Care Registry (NIR). This is the first recalibration of SAPS II for Nordic data. METHODS: A first-level customization was applied to improve calibration of the original SAPS II model (Model A). NIR data used covered more than 90% of adult patients admitted to ICUs in Norway from 2008 to 2010 (n = 30712). RESULTS: The modified SAPS II, Model B, outperformed the original Model A with respect to calibration. Model B gave more accurate predictions of mortality than Model A (Hosmer-Lemeshow's C: 22.01 vs. 689.07; Brier score: 0.120 vs. 0.131; Cox's calibration regression: α = -0.093 vs. -0.747, ß = 0.921 vs. 0.735, (α|ß = 1) = -0.009 vs. -0.630). The standardized mortality ratio was 0.73 [95% confidence interval (CI) of 0.70-0.76] for Model A and 0.99 (95% CI of 0.95-1.04) for Model B. Discrimination was good for both models (area under receiver operating characteristic curve = 0.83 for both models). CONCLUSIONS: As expected, Model B is better calibrated than Model A, and both models have similar uniformity of fit and equal discrimination. Introducing Model B into Norwegian ICUs may improve precision in decision-making. Units will have a more realistic benchmark for the assessment of ICU performance. Mortality risk estimates from Model B are better than previous SAPS II estimates have been.

Patient-reported genitourinary toxicity for long-term prostate cancer survivors treated with radiation therapy.

BACKGROUND: The objective of this study is to provide comprehensive overviews of patient-reported urinary symptoms for long-term prostate cancer survivors treated with radiation therapy and for untreated, healthy men. METHODS: We performed a population-based cross-sectional study using a study-specific postal questionnaire assessing symptoms among 1007 men consecutively treated at the Sahlgrenska University Hospital, Göteborg, Sweden from 1993-2006 (primary or salvage external beam radiation therapy (EBRT) or EBRT and high-dose rate brachytherapy). We also randomly recruited 350 non-pelvic-irradiated matched control men from the Swedish Total Population Register. Symptom prevalence and prevalence ratios were computed. RESULTS: Survey participation rate was 89% (874/985) for eligible survivors and 73% (243/332) for eligible controls. Median time from treatment to follow-up was 5 years (range, 1-14 years). Among the 21 investigated symptoms reflecting obstruction, frequency, urgency, pain and incontinence, we found significantly higher prevalence compared with controls for 9 symptoms in the EBRT group, 10 in the EBRT+brachytherapy group and 5 in the salvage EBRT group. The prevalence for a majority of the symptoms was stable over time. CONCLUSION: The presented toxicity profiles provide a thorough understanding of patient-reported urinary symptoms that can assist in developing personalised therapy for prostate cancer.

Late symptoms in long-term gynaecological cancer survivors after radiation therapy: a population-based cohort study.

BACKGROUND: We surveyed the occurrence of physical symptoms among long-term gynaecological cancer survivors after pelvic radiation therapy, and compared with population-based control women. METHODS: We identified a cohort of 789 eligible gynaecological cancer survivors treated with pelvic radiation therapy alone or combined with surgery in Stockholm or Gothenburg, Sweden. A control group of 478 women was randomly sampled from the Swedish Population Registry. Data were collected through a study-specific validated postal questionnaire with 351 questions concerning gastrointestinal and urinary tract function, lymph oedema, pelvic bones and sexuality. Clinical characteristics and treatment details were retrieved from medical records. RESULTS: Participation rate was 78% for gynaecological cancer survivors and 72% for control women. Median follow-up time after treatment was 74 months. Cancer survivors reported a higher occurrence of symptoms from all organs studied. The highest age-adjusted relative risk (RR) was found for emptying of all stools into clothing without forewarning (RR 12.7), defaecation urgency (RR 5.7), difficulty feeling the need to empty the bladder (RR 2.8), protracted genital pain (RR 5.0), pubic pain when walking indoors (RR 4.9) and erysipelas on abdomen or legs at least once during the past 6 months (RR 3.6). Survivors treated with radiation therapy alone showed in general higher rates of symptoms. CONCLUSION: Gynaecological cancer survivors previously treated with pelvic radiation report a higher occurrence of symptoms from the urinary and gastrointestinal tract as well as lymph oedema, sexual dysfunction and pelvic pain compared with non-irradiated control women. Health-care providers need to actively ask patients about specific symptoms in order to provide proper diagnostic investigations and management.

End-of-life decisions as bedside rationing. An ethical analysis of life support restrictions in an Indian neonatal unit.

INTRODUCTION: Hundreds of thousands of premature neonates born in low-income countries are implicitly denied treatment each year. Studies from India show that treatment is rationed even for neonates born at 32 gestational age weeks (GAW), and multiple external factors influence treatment decisions. Is withholding of life-saving treatment for children born between 28 and 32 GAW acceptable from an ethical perspective? METHOD: A seven-step impartial ethical analysis, including outcome analysis of four accepted priority criteria: severity of disease, treatment effect, cost effectiveness and evidence for neonates born at 28 and 32 GAW. RESULTS: The ethical analysis sketches out two possibilities: (a) It is not ethically permissible to limit treatment to neonates below 32 GAW when assigning high weight to health maximisation and overall health equality. Neonates below 32 GAW score high on severity of disease and efficiency and cost-effectiveness of treatment if one gives full weight to early years of a newborn life. It is in the child's best interest to be treated. (b) It can be considered ethically permissible if high weight is assigned to reducing inequality of welfare and maximising overall welfare and/or not granting full weight to early years of newborns is considered acceptable. From an equity-motivated health and welfare perspective, we would not accept (b), as it relies on accepting the lack of proper welfare policies for the poor and disabled in India. CONCLUSION: Explicit priority processes in India for financing neonatal care are needed. If premature neonates are perceived as worth less than other patient groups, the reasons should be explored among a broad range of stakeholders.

National HIV treatment guidelines in Tanzania and Ethiopia: are they legitimate rationing tools?

OBJECTIVE: To provide an ethical analysis of whether the Ethiopian and Tanzanian national HIV/AIDS treatment guidelines can be considered legitimate and fair rationing tools. METHOD: Qualitative study and ethical analysis involving guideline documents and interviews with nine key members involved in the development of the guidelines. The analysis followed an editing organising style. The theoretical framework was a guideline-specific framework based on theories of just resource allocation in healthcare and conditions that ensure fair processes in guideline development. According to this framework, legitimate rationing requires reasons for patient selection to be explicit, public and relevant, and decisions must be open to question and revision. RESULTS: The only explicit rationing criteria that both guidelines recommended were clinical antiretroviral treatment indications. Explicit non-clinical rationing criteria were expressed in a separate Ethiopian implementation guideline. Neither of the guideline development processes fully satisfies minimal requirements of procedural fairness. There is a lack of transparency. The reasons for decisions are rarely given and are not publicly available. This reduces the opportunity for public questioning, debate and revisions. The guidelines were based on expert opinion and consensus. Recommendations from the WHO were copied without much discussion, disagreement or adjustment. CONCLUSIONS: The two national HIV treatment guidelines discussed are de facto mechanisms for rationing but were developed using methods that do not fully satisfy the requirements of fair processes.

Beta-cell-targeted expression of a dominant-negative hepatocyte nuclear factor-1 alpha induces a maturity-onset diabetes of the young (MODY)3-like phenotype in transgenic mice.

Mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HNF-1 alpha) cause maturity-onset diabetes of the young 3, a severe form of diabetes characterized by pancreatic beta-cell dysfunction. We have used targeted expression of a dominant-negative mutant of HNF-1 alpha to specifically suppress HNF-1 alpha function in beta-cells of transgenic mice. We show that males expressing the mutant protein became overtly diabetic within 6 wk of age, whereas females displayed glucose intolerance. Transgenic males exhibited impaired glucose-stimulated insulin secretion, detected both in vivo and in the perfused pancreas. Pancreatic insulin content was markedly decreased in diabetic animals, whereas the glucagon content was increased. Postnatal islet development was altered, with an increased alpha-cell to beta-cell ratio. beta-Cell ultrastructure showed signs of severe beta-cell damage, including mitochondrial swelling. This animal model of maturity-onset diabetes of the young 3 should be useful for the further elucidation of the mechanism by which HNF-1 alpha deficiency causes beta-cell dysfunction in this disease.

Soft tissue sarcoma after treatment for breast cancer--a Swedish population-based study.

The aim was to quantify the risk of post-treatment sarcoma in breast cancer patients. All 122,991 women with a breast cancer from 1958 to 1992 in the Swedish Cancer Register were followed up for soft tissue sarcomas and 116 were found, giving a standardised incidence ratio of 1.9 (95% CI 1.5-2.2). The absolute risk was 1.3 per 10(4) person-years. The sarcomas were located in the breast region or on the ipsilateral arm in 63% (67/106). There were 40 angiosarcomas and 76 sarcomas of other types. In a case-control study, angiosarcoma correlated significantly with lymphoedema of the arm, odds ratio (OR) 9.5 (95% CI 3.2-28.0), but no correlation with radiotherapy was observed. For other types of sarcoma there was a correlation with the integral dose. The dose-response relationship indicated that the risk increased linearly with the integral dose to 150-200 J and stabilised at higher energies. The OR was 2.4 (95% CI 1.4-4.2) for an energy of 50 J, approximately corresponding to the radiation of the breast after breast-conserving surgery. Thus, only oedema of the arm correlated with angiosarcoma, but for other types of sarcoma the integral dose of radiotherapy was a predictor of the risk.

Clinical impact of dosimetry quality assurance programmes assessed by radiobiological modelling of data from the thermoluminescent dosimetry study of the European Organization for Research and Treatment of Cancer.

The European Organization for Research and Treatment of Cancer (EORTC) Radiotherapy Group initiated its mailed thermoluminescence dosimetry (TLD) programme in 1986. The aim of the present study was to evaluate the clinical relevance of variations in beam output detected in the period 1993 to 1996. A total of 140 beam outputs were checked (26 for cobalt-60 units and 114 for linear accelerators) in 35 centres. Clinical dose-response data for tumour control and normal tissue morbidity were used to assess the variation in clinical outcome resulting from variability in beam output. For 75 checked beams with nominal accelerating potentials (n. a.p.) of 6 MV or less the mean ratio, +/- standard deviation (S.D.) of measured to stated output was 1.004+/-0.020. For 65 beams with n. a.p. of 8 MV or more, the ratio was 1.009+/-0.021. Even with this relatively high level of precision, broad distributions of estimated tumour control or normal tissue morbidity were found. In the 10% of the beams with the most pronounced underdosage, the loss in tumour control probability was estimated at 7-8 percentage points. Likewise, in the 10% of the beams with the most pronounced overdosage, the increase in mild/moderate morbidity was 19-22 percentage points. For severe morbidity the same beams raised the estimated incidence of severe complications from 5% to 9-10%. An estimation of the loss of uncomplicated cure probability was about 1% for both high and low energy beams. Sequential mailings considerably improved the uniformity of clinical outcome. We conclude that small deviations in beam output may lead to clinically important variations in outcome. Substantial reductions in the variation between measured and stated output can be achieved by sequential mailings. Mailed TLD checks should be an integral part of a continuously ongoing quality assurance activity in radiotherapy.

The Quality Assurance programme of the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC): a critical appraisal of 20 years of continuous efforts.

In 1982, the European Organization for Research and Treatment of Cancer (EORTC) Radiotherapy Group established the Quality Assurance (QA) programme. During the past 20 years, QA procedures have become a major part of the activities of the group. The methodology and steps of the QA programme over the past 20 years are briefly described. Problems and conclusions arising from the results of the long-lasting QA programme in the EORTC radiotherapy group are discussed and emphasised. The EORTC radiotherapy group continues to lead QA in the European radiotherapy community. Future challenges and perspectives are proposed.

Profile of radiotherapy departments contributing to the Cooperative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.

PURPOSE: Since 1982, the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC) is carrying out a Quality Assurance program that includes the evaluation of the structure and human resources of 50 centers actively participating in protocols of clinical research in radiotherapy. METHODS AND MATERIALS: One or two site visits were made by a team of radiation physicists and physicians. A detailed questionnaire was circulated to these radiotherapy centers to collect and update standardized figures on the status and activities of each center, to clarify some obscurities encountered during on-site visits, and to extend investigations to issues that were not addressed during local audits. RESULTS: This article reports on departmental infrastructure, staff and equipment workload, and quality control procedures carried out by single institutions. Large variations in equipment and staff are observed among participating centers. Comparisons between data collected in the early 1980s and during a recent update show no difference in workload per megavoltage equipment and per simulator. The number of cancer patients treated per year per radiotherapist seems to slightly diminish, especially in centers that experienced a considerable staff shortage a few years ago. The most significant improvement is observed for the number of cases treated per year per member of the radiation physics team. The radiographer's workload shows an opposite trend. CONCLUSIONS: Our database provides participating centers with strong comparative arguments to correct staff and equipment unbalances and to convince administrative authorities of priorities in decision making. The current analysis shows that the situation for equipment is unchanged in comparison with that observed 6 years ago. Efforts have to be put forth in some institutions to reduce the workload at simulators. A tentative profile and guidelines for minimum recommendations for European radiotherapy departments involved in clinical research are presented.

Quality audit of radiotherapy with EORTC mailed in water TL-dosimetry.

A mailable TL-dosimetry (LiF) system has been designed and tested for the EORTC Radiotherapy Group for periodic monitoring of radiation therapy machines between and prior to on-site visits. Three TL-dosimeters were enclosed in a capsule which was placed in a holder and irradiated in photon beams in a water phantom. The institutes were instructed to irradiate the capsule to an absorbed dose of 2 Gy. After the irradiation, all capsules with dosimeter, the holder and completed data sheets were returned to Gothenburg for evaluation. The heating procedure used for reading the dosimeters was optimised regarding fading and reproducibility (less than 0.5%, 1. S.D.). The fading of the TL-signal was eliminated by adding an external annealing to the heating procedure. Both supralinearity and energy dependence were tested and routinely corrected for. The dosimeters were individually calibrated. During 1987, 1988 and the first part of 1989, dosimeters were mailed to 22 institutes, participating in clinical trials organised by the Radiotherapy Group. Of the 178 beams measured, 89% were within acceptable levels of variation for the absorbed dose states (less than or equal to 4%). The photon results gave a mean of 1.012 and a standard deviation of 0.025.

Mailed TL dosimetry programme for machine output check and clinical application in the EORTC radiotherapy group.

The Radiotherapy group of the European Organisation for Research and Treatment of Cancer (EORTC-RT) has been performing quality assurance with mailed TL dosimetry since 1986. The programme consists of therapy machine output checks, in vivo measurements, and dosimetry for brachytherapy. The therapy machine output checks have revealed a few large deviations (greater than 7%) between EORTC-measured and institute-stated dose, but also shown an improvement in the dosimetry of the participating institutes as a result of consecutive mailings. The use of in vivo dosimetry with mailed TLD has proven that it is feasible to detect deviations of +/- 5%. The results have shown deviations within +/- 5% for dosimeters located well within the radiation field for internal measurements in the pelvic region. Dosimetry of brachytherapy has been performed for low dose rate 192Ir sources. Differences of 14% can be seen between the participating centres.

Quality assurance control in the EORTC cooperative group of radiotherapy. 3. Intercomparison in an anatomical phantom.

Two papers concerning the quality control study organised by the EORTC (European Organisation for Research on Treatment of Cancer) Cooperative Group on Radiotherapy have been published. The medical profile (part 1) and the dosimetric intercomparison (part 2) of the participating institutions were presented. This part (paper 3) presents an integrated clinical and dosimetric investigation in an anatomical phantom. A tonsillar tumour and a homolateral subdigastric node were marked in an anatomical phantom. The institutions were asked to treat the phantom once like an ordinary patient. The phantom was loaded with dosimeters and irradiated. From the results obtained, it can be concluded that we did not find any major dosimetric problem related to absorbed dose calibration or calculation in the phantom. However, several major problems were related to non-optimal planning, treatment technique and dose distribution. The investigation shows the importance of a quality assurance programme for cooperative groups.

The influence of irradiation time per treatment session on acute and late skin reactions: a study on human skin.

A comparison of the radiation effect of altering the treatment time per session in fractionated radiotherapy was performed on human skin with 12 MeV electrons. Four fractions of 7.2 Gy were given within 22 days, once a week. The dose per fraction was administered in 4 min and 32 min, respectively. The dose rate was about 2 Gy/min and the prolonged treatment time was achieved by dividing each dose fraction into three equal subfractions with intervals of 14-15 min. Prolongation of the treatment time resulted in a significant reduction of the skin erythema (p less than 0.001), pigmentation (p less than 0.05) and the degree of telangiectasia at 5 years (p less than 0.001). The relative biological effectiveness (RBE) for the prolonged (32 min), in relation to that of the short (4 min) treatment time, RBE4 min/32 min, was 1.09-1.10 for erythema and 1.07-1.12 for telangiectasia. These findings indicate that prolongation of the treatment time per session has to be adjusted for in clinical radiation oncology.

The programme of quality assurance of the EORTC radiotherapy group. A historical overview.

A quality assurance programme was activated in 1982 in the EORTC Cooperative Group of Radiotherapy. Definitions and contents of quality assurance and quality control, definitions of errors and deviations (systematic, occasional) are given. The methodology and steps of the quality assurance programme adopted over the past ten years are briefly described. The need for an interaction between national and international networks is emphasized. Consensus statements on quality assurance in radiotherapy provided during the January 1993 Geneva meeting conclude this introduction to the detailed reports on the quality assurance programme of the EORTC Cooperative Group of Radiotherapy.

EORTC radiotherapy group quality assurance: mechanical checks and beam alignments of megavoltage equipment.

In 1987 mechanical checks of megavoltage units and simulators were included in the on-site physics program of the EORTC. The results reported were obtained in 16 different centres and concern 23 accelerators, 14 cobalt units and 14 simulators. In general, the deviations observed for accelerators and simulators are smaller than for cobalt units. A single score, based on the deviations observed for the mechanical checks, is attributed to each centre.

Entrance and exit TL-dosimetry in the conservative treatment of breast cancer: a pilot study for the EORTC-Radiotherapy Cooperative Group.

Mailed dosimetry, using thermoluminescent dosimeters, can play an important role in quality assurance procedures in radiotherapy. In 1989, a pilot study was started with the main aim to show the feasibility of this method for the multicentre EORTC trial 22881 on the conservative management of breast carcinoma. Two anthropomorphic breast phantoms and six patients with breast carcinoma were irradiated according the prescriptions of the protocol. TLD measurements of the entrance and exit dose were performed in 6 MV tangential X-ray beams. It proved to be possible to correlate the dose measured in the entrance and exit points of the beams to the calculated dose closely under the surface. A thickness of at least 5 mm bolus material must be applied over the dosimeters and a distance of at least 3 cm from the lateral and medial field borders must be maintained in order to reach a clinically acceptable accuracy in the measurements.

Soft tissue sarcoma after treatment for breast cancer.

In a register study all women in the West of Sweden Health Care Region with a breast cancer diagnosed between 1960 and 1980 (n = 13,490) were followed up in the Swedish Cancer Register to the end of 1988 for later occurrence of a soft tissue sarcoma (STS). Nineteen sarcomas were reported, whereas 8.7 were expected and the relative risk (RR) was 2.2 (CI 95% 1.3-3.4). The absolute risk was 1.7/10(4) person years (PY) in comparison with 0.8 expected. To obtain a more detailed analysis of the associations between arm lymphoedema, radiotherapy and STS development, and to control the quality of the register data, a case control study was also performed. Clinical records from the different hospitals in the region were collected for all the 19 cases as well as for three selected controls per case. The histopathology of the cases were reviewed, and one of the cases was reclassified as a malignant melanoma and excluded from further analysis. Thirteen of the cases were clustered around the treated breast area. To quantify the exposure to radiotherapy, the integral dose was estimated. The presence of lymphedema was included as a binary variable in the analysis. The exact conditional randomisation test indicated a significant correlation between the integral dose and the development of an STS (p = 0.008) and this association was still significant after stratification for arm oedema. A conditional logistic regression analysis with STS as the dependent variable and the integral dose as the explanatory variable gave an odds ratio (OR) of 5.2/100 J (CI 95% 1.3-21.2), and if this regression was restricted only to the STS developing in the radiation fields the OR was 3.2/100 J (CI 95% 0.8-12.9). Thus, the excess of STS in this breast cancer cohort was very low (0.9/10(4) PY). However the integral dose correlates well to the development of STS and can be useful in quantifying even small risks of secondary malignancies in the breast cancer population.

Potential advantages of protons over conventional radiation beams for paraspinal tumours.

BACKGROUND AND PURPOSE: Conformal treatment planning with megavoltage X-rays and protons was studied in an attempt to determine if there are advantage of boost therapy with protons instead of X-rays for a patient with a tumour growing around the cervical spinal cord. MATERIALS AND METHODS: A patient with a Ewing sarcoma was selected for the model study. The proton boost plan was realised with a six beam patched technique. Several X-ray boost techniques were planned, some not yet practically realisable. The techniques giving the best dose distributions and the best tumour control probabilities in the absence of significant late toxicity were looked for. The boost techniques were added to two large lateral X-ray beams covering the planning target volume (PTV) and the main risk organ, the spinal cord. The evaluation was made with two biological models, i.e. the tumour control probability (TCP) model, proposed by Webb and Nahum (Webb, S. and Nahum, A.E. A model for calculating tumour control probability in radiotherapy including the effect of inhomogeneous distributions of dose and clonogenic cell density. Phys. Med. Biol. 38: 653-666, 1993), and the normal tissue complication probability (NTCP) model, first derived by Lyman (Lyman, J.T. Complication probability as assessed from dose-volume histograms. Radiat. Res. 104: s13-s19, 1985). RESULTS: The comparison showed small but clear advantages of protons for the boost. At 1% NTCP in the spinal cord, the calculated TCP was on average 5% higher. However, depending on the values of the parameters chosen in the biological models, the gain for protons varied from 0-10%. The smallest gains were seen in radiosensitive tumours for which the TCP was close to 100% with any of the techniques and in radioresistant tumours for which neither technique resulted in any appreciable probability of local cure. CONCLUSION: Protons appear to have therapeutic advantages over conventional radiotherapy in tumours with relatively high radiosensitivity situated close to the spinal cord.