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.

Superiority of intensity-modulated radiotherapy over three-dimensional conformal radiotherapy combined with brachytherapy in nasopharyngeal carcinoma: a planning study.

A planning study was performed in order to investigate the potential benefits of intensity-modulated radiotherapy using a simultaneous integrated multi-target treatment technique (SIMT-IMRT) over highly optimized three-dimensional conformal radiotherapy combined with intracavitary brachytherapy (3D-CRT + IBT) for the treatment of nasopharyngeal carcinoma (NPC). The subjects were eight patients with Stages I-IV NPC. For each case, two sets of plans were prepared after delineation of gross tumour volumes, three planning target volumes (PTVs) and 17 organs at risk (OARs). Dose prescriptions for PTVs were 72.6 Gy, 66 Gy and 52.8 Gy in 33 fractions for SIMT-IMRT vs 72 Gy (66 Gy in 33 fractions for 3D-CRT and 3 Gy twice for IBT), 66 Gy (in 33 fractions) and 46 Gy (in 23 fractions) for 3D-CRT + IBT plans. Compared with the combined plans, SIMT-IMRT provided superior results for the primary tumour (PT) in terms of mean equivalent uniform dose (67 Gy vs 63.7 Gy, p = 0.016). IMRT plans increased the mean tumour control probability (TCP) values (both uncorrected and corrected for accelerated tumour repopulation after 28 days) for PT when compared with 3D-CRT + IBT (98% and 94.3% vs 95.8% and 89.9%, respectively, p = 0.016). Mean doses to middle/external ears, parotid glands and temporomandibular joints were significantly lower in IMRT plans. Our conclusion is that, for all stages of NPC, SIMT-IMRT was superior to highly optimized 3D-CRT + IBT in terms of tumour coverage, increased local TCP, and dose reduction to some OARs. We recommend that SIMT-IMRT should be considered as a first-line radiotherapy technique for NPC.

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.

Development and diseases of the pancreas.

The pancreas is a vital gland of exocrine and endocrine function. It is the target of two main affections: diabetes and pancreatic cancer. We describe the tissue interactions, signaling pathways and intracellular targets that are involved in the emergence of the pancreas primordium and its proliferation, morphogenesis and differentiation. It appears that several genes of developmental relevance have an adult function and are involved in pancreas affections. Embryological experimentation in animals contributed to provide candidate genes for human disease and holds promise for future treatments.

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.

[Destiny-zapping--medical education, students' world view and the ethical challenge]. / Skjebnezapping--medisinsk grunnopplaering, legestudenters dannelse og den etiske fordring.

Three medical students describe their search for professional and personal identity midway through medical school. The article focuses on their concrete experience of human suffering and vulnerability, which is set against elements from the relational ethics of Danish philosopher KE Løgstrup. Løgstrup's ontology is based on a relational understanding of being human, and implicitly opposes the strongly objectivating and individualised view of human existence promoted through the experiences of everyday medical education.

Normal tissue response to low doses of radiotherapy assessed by molecular markers--a study of skin in patients treated for prostate cancer.

The aim of this study was to evaluate normal tissue response by molecular markers to multifraction low doses of ionizing radiation, with the focus on changes in repopulation, estimated using Ki-67 as the proliferation marker, and on expressions of the p53 and p21 proteins, identified as key proteins in the DNA damage checkpoint. Repeated skin biopsies were taken from patients treated for prostate cancer with radiotherapy. The expressions of Ki-67, p53 and p21 of the keratinocytes in the basal cell layer of the epidermis were quantified immunohistochemically. The dose to the basal layer was 1.1 Gy per fraction, given five times per week for seven weeks. The indices of the three markers were determined over the whole period. A significant suppression of the Ki-67 index was observed during the first weeks, followed by a significant gradual increase in the Ki-67 index over the last weeks. The p53 and p21 protein levels were almost zero in the unirradiated skin. Upon irradiation, both the p53 and p21 index increased in a pattern very congruent to the Ki-67 index. In conclusion, daily fractions of about 1 Gy to the skin resulted in, for the keratinocytes in the basal layer, a cell growth arrest for a couple of weeks and a subsequent acceleration in repopulation during the following weeks of irradiation. The present findings also provided novel insights into the role of the p53/p21 pathway in the response of a normal epithelium to ionizing radiation as it is applied in radiotherapy.

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.

Correction factors for Farmer-type chambers for absorbed dose determination in 60Co and 192Ir brachytherapy dosimetry.

This paper presents experimentally determined correction factors for Farmer-type chambers for absorbed dose determination in 60Co and 192Ir brachytherapy dosimetry. The correction factors were determined from measurements made in a PMMA phantom and calculation of ratios of measured charges. The ratios were corrected for the different volumes of the ionization chambers, determined in external high-energy electron beams. The correction factors for the central electrode effect and the wall material dependency in 60Co brachytherapy dosimetry agree with those used in external 60Co beam dosimetry. In 192Ir dosimetry, the central aluminium electrode increases the response of an NE2571 chamber compared with that of a chamber with a central graphite electrode. The increase is 1.1 and 2.1% at 1.5 and 5.0 g cm(-2) distance, respectively. Similar values are obtained with an NE2577 chamber. The wall correction factor in 192Ir dosimetry for a chamber with an A-150 wall has been determined to be 1.018, independent of the measurement distance. For a graphite walled chamber, the correction factor is 0.996 and 1.001 at 1.5 and 5.0 g cm(-2) distance, respectively. The values of the wall correction factors are evaluated by a theory presented. If the chamber is used according to the 'large cavity' principle, the correction factor to account for the replacement of the phantom material by the ionization chamber was determined to be 0.982 for an NE2571 chamber when used with a Delrin cap, and 0.978 for an NE2581 when used with a polystyrene cap. The correction factors for the 'large cavity' principle are valid at both 60Co and 192Ir qualities.

Absorbed dose determination at short distance from 60Co and 192Ir brachytherapy sources.

This paper presents two methods for absorbed dose determination with ionization chambers at short distance from 60Co and 192Ir brachytherapy sources. The methods are modifications of the Bragg-Gray and large cavity principles given in the IAEA code of practice for high- and medium-energy photon beams. A non-uniformity correction factor to account for the non-uniform electron fluence in the air cavity is introduced into the methods. The absorbed dose rates were determined from ionization chamber measurements at distances between 1.5 and 5.0 cm from the brachytherapy sources. The agreement between the two methods is excellent in 60Co brachytherapy dosimetry. For 192Ir dosimetry, the difference is less than 2.5% at all distances. In absorbed dose rate calculations with the 60Co brachytherapy source, the ratios between calculated and experimentally determined absorbed dose rates are 0.987 and 0.994 depending on the method used for absorption and scatter correction. In 192Ir dosimetry, the large cavity principle gives almost identical values to those which can be obtained with the AAPM recommendations. Using the chambers according to the Bragg-Gray principle in 192Ir dosimetry, the agreement with AAPM calculated absorbed dose rates is within 2.5% at all distances. The uncertainty, expressed as one standard deviation, in the experimentally determined absorbed dose is estimated to be between 3 and 4%.

Calculation of absorbed dose distributions from dynamic wedges.

In radiotherapy with photon beams, the use of dynamic wedges, which are obtained by the movement of one of the jaws, offers an increasing flexibility relative to the traditional use of metal wedges. But it is a disadvantage for the measurement of absorbed dose distributions, because the absorbed dose at each measurement point can only be obtained after a complete movement of the jaw. Consequently, for radiotherapy planning, an algorithm should be available that does not require measurements for any specific dynamically wedged beam, but is based on only a modest number of measurements. In this paper, an algorithm for the calculation of the dose distribution from dynamic wedges is described. This algorithm uses the convolution of pencil beam kernels with a non-uniform field function. These pencil beam kernels are derived from empirical data resulting from measurements of the open beam only.

Dose accuracy check of the 3D electron beam algorithm in a treatment planning system.

The accuracy of the recently implemented three-dimensional electron beam dose calculating algorithm in CADPLAN version 2.62 manufactured by Varian Dosetek was investigated. The algorithm uses a generalized Gaussian pencil beam model and the dose distributions are calculated as the sum of three weighted Gaussians. To use the calculating program in an optimum way, one needs to know the dose calculation accuracy of the algorithm as well as its limitations. This investigation includes comparisons of measured relative dose distributions with calculated dose distributions and also comparisons of measured and calculated monitor units. The geometries tested were quadratic fields, irregularly shaped fields, oblique fields, irregularly shaped phantom surfaces and internal heterogeneities and were most often irradiated with 8 and 20 MeV electrons. The results indicate that the algorithm is well suited for clinical three-dimensional dose planning. Some deviations occurred but they were most often within the limits of international criteria of acceptability.

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.

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.

Practical implementation of enhanced dynamic wedge in the CadPlan treatment planning system.

The Varian CadPlan algorithm for computation of relative dose distributions and monitor unit calculations for Enhanced Dynamic Wedge (EDW) fields is based on a combination of open field beam data and Segmented Treatment data Tables. Calculation of dose by the pencil beam convolution model uses scatter kernels and boundary kernels to create the distribution. The principles of the pencil beam convolution model is presented. Comparison of measured and calculated monitor units and relative dose distributions showed good agreement and the deviations are within international accepted tolerans. Test results indicate that the EDW model works satisfactorily for all energies and wedge angles.