Maps and atlases of cancer mortality: a review of a useful tool to trigger new questions.

In this review we illustrate our view on the epidemiological relevance of geographically mapping cancer mortality. In the first part of this work, after delineating the history of cancer mapping with a view on interpretation of Cancer Mortality Atlases, we briefly illustrate the 'art' of cancer mapping. Later we summarise in a non-mathematical way basic methods of spatial statistics. In the second part of this paper, we employ the 'Atlas of Cancer Mortality in the European Union and the European Economic Area 1993-1997' in order to illustrate spatial aspects of cancer mortality in Europe. In particular, we focus on the cancer related to tobacco and alcohol epidemics and on breast cancer which is of particular interest in cancer mapping. Here we suggest and reiterate two key concepts. The first is that a cancer atlas is not only a visual tool, but it also contain appropriate spatial statistical analyses that quantify the qualitative visual impressions to the readers even though at times revealing fallacy. The second is that a cancer atlas is by no means a book where answers to questions can be found. On the contrary, it ought to be considered as a tool to trigger new questions.

On smoothing trends in population index modeling.

In this article, we consider the U.K. Common Birds Census counts and their use in monitoring bird abundance. We use a state-space modeling approach within a Bayesian framework to describe population level trends over time and contribute to the alert system used by the British Trust for Ornithology. We account for potential overdispersion and excess zero counts by modeling the observation process with a zero-inflated negative binomial, while the system process is described by second-order polynomial growth models. In order to provide a biological motivation for the amount of smoothing applied to the observed series the system variance is related to the demographic characteristics of the species, so as to help the specification of its prior distribution. In particular, the available information on productivity and survival is used to formulate prior expectations on annual percentage changes in the population level and then used to constrain the variance of the system process. We discuss an example of how to interpret alternative choices for the degree of smoothing and how these relate to the classification of species, over time, into conservation lists.

The impact of lower urinary tract symptoms and comorbidities on quality of life: the BACH and UREPIK studies.

OBJECTIVES: To investigate the effect of lower urinary tract symptoms (LUTS) on quality of life (QoL) and to determine its extent across a variety of cultures, and the confounding effects of self-reported comorbidities and demographics. SUBJECTS AND METHODS: Data were obtained from two population-based studies in five cities: UREPIK (Boxmeer, the Netherlands; Auxerre, France; Birmingham, UK; and Seoul, Korea) and the Boston Area Community Health (BACH) study (Boston, USA). UREPIK used stratified random samples of men aged 40-79 years. BACH used a multistage stratified cluster sample to randomly select adults aged 40-79 years. QoL was assessed using a standard Medical Outcomes Study-Short Form 12 (SF-12, mental and physical health component scores); LUTS was assessed using the International Prostate Symptom Score (IPSS). The association between QoL and IPSS, associated illnesses, and lifestyle factors was investigated using weighted regression. RESULTS: The UREPIK studied 4800 men aged 40-79 years; BACH recruited 1686 men aged 40-79 years. The prevalence of LUTS, defined as an IPSS of > or =8, varied by city (P < 0.001), with Auxerre reporting a prevalence (SE) of 18.1 (1.2)%, Birmingham 25.6 (1.5)%, Boston 25.1 (1.6)%, Boxmeer 21.2 (1.3)%, and Seoul 19.0 (1.2)%. Overall, this was similar to the reported rate of high blood pressure. Severe LUTS, defined as an IPSS of > or =20, affected approximately 3.3% of the age group; this was roughly similar to stroke (2.2%), cancer (4.5%), or heart attack (4.5%) and less than half as much as diabetes (8.6%). A 10-point increase in IPSS was associated with a 3.3 (0.3)-point reduction in SF-12 physical health component score, with the same effect in all cities (P = 0.682 for the interaction test). This was more than the physical health component score reduction caused by cancer, diabetes, or high blood pressure (2 points each), but less than stroke or heart attack (6 points). The comorbidities had no significant impact on SF-12 mental health component score (other than a heart attack, that had a 1.8-point reduction). A 10-point increase in IPSS was associated with a 3.4 (0.6)-point reduction of the mental health component score in the four western cities and a 1.4 (0.3)-point reduction in Seoul. CONCLUSIONS: Increasingly severe LUTS is associated with a lower QoL. The effect of moderate LUTS on QoL physical health component score is similar to that of having diabetes, high blood pressure or cancer, while the effect of severe LUTS is similar to a heart attack or stroke. These changes were consistent across cultures. This analysis shows the magnitude and consistency of the effects of LUTS on QoL. While these patients might be seen by several types of practitioners, it is likely that urologists will be in the best position to recognize the true impact of LUTS on a patient's QoL, to be aware of the effects of therapies for LUTS on QoL, and to ensure that colleagues in other disciplines recognize the importance of these symptoms and their treatment.

The prevalence of urinary incontinence in community-dwelling married women: a matter of definition.

OBJECTIVE: To determine the prevalence of female urinary incontinence (UI) and its impact on quality of life. SUBJECTS AND METHODS: In a Dutch national postal questionnaire survey, 1460 spouses of 1771 men in the town of Boxmeer, age-stratified and randomly selected, were asked to participate. The prevalence of UI in the women was assessed in two ways. First, a total score on a short UI-specific questionnaire differentiated them into three groups, i.e. no symptoms (score 0-2), minimally (3-6) or severely incontinent (7-14). Second, a self-reported UI prevalence was calculated by asking respondents if they ever had urine loss. To conform to the International Continence Society standard definition, spouses were also asked to complete a general (Short Form-12) and lower urinary tract disease-specific quality-of-life questionnaire, and were asked about their need to seek help. RESULTS: The questionnaires were returned by 1071 women (mean age 57 years, range 29-79; response rate 73%); 34% were regarded as minimally and 12% as severely incontinent. The self-reported UI rate was 40%. Disease-specific and general quality of life was significantly lower for women with UI than for those with minimal or no urine loss; 38% of incontinent respondents had consulted a physician for their UI, and among respondents with minimal complaints this was 28%. CONCLUSIONS: Up to 46% of the married female population had some degree of UI, and severe UI significantly compromised their quality of life.

Mammaglobin expression in leukapheresis products is a predictive marker of poor prognosis in women with high-risk breast cancer.

PURPOSE: The purpose of this study was to investigate the incidence and prognostic relevance of tumor cell detection in granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cell collections (PBPCCs) using cytokeratin (CK), maspin (MAS), and mammaglobin (MAM) genes as epithelial cell markers. The population on which the study was conducted was drawn from stage III breast cancer patients undergoing high-dose chemotherapy and autologous transplantation with PBPCCs. EXPERIMENTAL DESIGN: One hundred and ninety-four patients were enrolled in the study and analyzed for tumor cell detection on the basis of 481 PBPCCs gathered before administration of chemotherapy. CK, MAS, and MAM gene expressions were investigated by means of the reverse transcription nested polymerase chain reaction, and those samples expressing CK were further hybridized with a radiolabeled internal probe to reduce false-positive results. Sensitivity and specificity were assessed on 37 controls (12 cell lines, 12 healthy donors, and 13 nonepithelial malignancies). Each of the known prognostic variables (age, stage, lymph node status, receptor status, c-ErbB2 status, and Ki67 status) was then analyzed (both individually and together with CK, MAS, and MAM expression on PBPCCs) in relation to patient overall survival (OS) and relapse-free survival (RFS). RESULTS: After a 3-year follow-up, an estimated 83% (95% confidence interval, 77.1-88.8%) of the patients were alive and an estimated 67% (95% confidence interval, 60.1-74.6%) were free of relapse. One hundred and seventy-six of the 194 patients (91%) had contaminated PBPCCs evidenced by at least one positive sample for any of the markers evaluated. The PBPCC frequency of CK, MAS, and MAM positivity (+) was 71%, 36%, and 16%, respectively. MAM expression on PBPCC was associated with an increased risk of relapse (P = 0.003), whereas CK and MAS expressions were not associated with changes in either RFS or OS. CONCLUSIONS: MAM gene expression on leukapheresis products of high-risk breast cancer patients is an indicator of poor prognosis. The method of evaluation is simple and reproducible and provides new tools for evaluating the role played by tumor cells in apheresis products and their potential in causing metastasis.

Hyperfractionated radiotherapy in locally advanced nasopharyngeal cancer. An analysis of 43 consecutive patients.

BACKGROUND: Despite numerous randomized trials suggesting a benefit of unconventional fractionation in locally advanced head and neck cancer, the role of this approach in nasopharyngeal carcinoma is debatable. Based on the current clinical experience, the authors introduced hyperfractionated irradiation in the treatment of locally advanced head and neck cancer, including nasopharyngeal tumors. The preliminary results of this treatment approach in nasopharyngeal cancer patients are presented, with special focus on the pattern of failure and toxicity. PATIENTS AND METHODS: 43 patients with nasopharyngeal cancer (stage II-IV, TNM 1997) underwent hyperfractionated irradiation. In 34 cases, radiotherapy was preceded by a median of three cycles of cisplatin-based induction chemotherapy. Irradiation was delivered using a shrinking-field technique up to a total dose of 74.4 Gy in 62 fractions of 1.2 Gy twice daily (minimum 6-h interval)/5 days/week. RESULTS: Acute toxicity of hyperfractionated radiotherapy was significant but tolerable. Mucositis proved the most common side effect (grade 3: 24 patients, grade 4: three patients). Severe late toxicity was not observed. 30 of 34 patients (88%) responded to induction chemotherapy. At 6 weeks after completion of radiotherapy, complete response was seen in 35 patients (81%), partial response in five (12%), stable disease in one, and progressive disease in two. After a median follow-up of 32 months, 18 patients (41%) developed progressive disease. Primary tumor progression was observed in three patients, and seven patients each showed regional lymph node progression and distant metastases. In one case both regional lymph node progression and distant metastases were diagnosed. The 2-year progression-free survival and overall survival rates were 58% and 84%, respectively. CONCLUSION: Hyperfractionated radiotherapy seems a feasible and active regimen in locally advanced nasopharyngeal carcinoma. Accompanying acute and late toxicity is acceptable and does not compromise delivery of the planned irradiation dose. This regimen is associated with a high local control rate; relatively high nodal and distant failure, however, call for further treatment modifications, e. g., optimization of irradiation technique and/or dose escalation as well as improved systemic therapies.

Receptor radionuclide therapy with 90Y-DOTATOC in patients with medullary thyroid carcinomas.

UNLABELLED: Metastatic medullary thyroid cancer (MTC) shows a progressive course. Surgery is the only curative treatment. In advanced disease, chemo- and radiotherapy show poor results. Newly developed somatostatin analogue [DOTA0,Tyr3]octreotide (DOTATOC) labeled to 90Y is administered in patients with endocrine tumors expressing somatostatin receptors, like MTC. Preliminary studies demonstrated that 90Y-DOTATOC could be safely administered, resulting in objective responses in 27% of patients. AIMS: To evaluate the efficacy of 90Y-DOTATOC therapy in metastatic MTC patients with positive OctreoScan, progressing after conventional treatments. Twenty-one patients were retrospectively evaluated after therapy, receiving 7.5-19.2 GBq in 2-8 cycles. RESULTS: Two patients (10%) obtained a complete response (CR), as evaluated by CT, MRI and/or ultrasound, while a stabilization of disease (SD) was observed in 12 patients (57%); seven patients (33%) did not respond to therapy. The duration of the response ranged between 3-40 months. Using biochemical parameters (calcitonin and CEA), a complete response was observed in one patient (5%), while partial response in five patients (24%) and stabilization in three patients (14%). Twelve patients had progression (57%). Complete responses were observed in patients with lower tumor burden and calcitonin values at the time of the enrollment. CONCLUSIONS: This retrospective analysis is consistent with the literature, regarding a low response rate in medullary thyroid cancers treated with 90Y-DOTATOC. Patients with smaller tumors and higher uptake of the radiopeptide tended to respond better. Studies with 90Y-DOTATOC administered in earlier phases of the disease will help to evaluate the ability of this treatment to enhance survival. New more specific peptides and new isotopes will also represent the key of a better treatment of MTC.

Androgen ablation therapy does not increase the risk of late morbidity following 3D-conformal radiotherapy of organ-confined prostate cancer: the experience of the European Institute of Oncology.

AIMS AND BACKGROUND: Androgen ablation therapy in conjunction with radiotherapy--neoadjuvant and adjuvant--has consistently been shown to be associated with improved biochemical and local control, whereas controversy still remains as regards its benefit in terms of overall survival. The objective of this study is to determine the impact of androgen ablation in combination to 3D-conformal radiotherapy on late treatment-related toxicity. METHODS: 236 patients were treated with 3D-conformal radiotherapy to a total dose ranging from 70 and 78.6 Gy. Fifty-six patients did not receive any form of androgen ablation whereas 176 were given at least 3 months of neoadjuvant androgen ablation. Of these, 64 stayed on androgen ablation for a median time of 6 months post-radiotherapy. Acute toxicity was evaluated weekly during the course of treatment. Late toxicity was assessed at 3-months intervals during the follow-up. Toxicity was scored according to the RTOG criteria. RESULTS: The median follow-up was 24.6 months (range, 12-62). The incidence of late genitourinary toxicity was: 3% G2, 3.5% G3, 0.5% G4. The incidence of late gastrointestinal toxicity was: 12% G2, 2% G3, 1% G4. No association was observed between the use of androgen ablation and late treatment-related toxicity. High-risk patients who continued on androgen ablation long-term were not found to have an increased risk of developing late toxicity with respect to those who never had any form of androgen ablation or those only treated neoadjuvantly. CONCLUSIONS: In our experience, the use of androgen ablation does not impact on late toxicity following high dose 3D-conformal radiotherapy for prostate cancer.

Finding dose-volume constraints to reduce late rectal toxicity following 3D-conformal radiotherapy (3D-CRT) of prostate cancer.

BACKGROUND AND PURPOSE: The rectum is known to display a dose-volume effect following high-dose 3D-conformal radiotherapy (3D-CRT). The aim of the study is to search for significant dose-volume combinations with the specific treatment technique and patient set-up currently used in our institution. PATIENTS AND METHODS: We retrospectively analyzed the dose-volume histograms (DVH) of 135 patients with stage T1b-T3b prostate cancer treated consecutively with 3D-CRT between 1996 and 2000 to a total dose of 76 Gy. The median follow-up was 28 months (range 12-62). All late rectal complications were scored using RTOG criteria. Time to late toxicity was assessed using the Kaplan-Meyer method. The association between variables at baseline and > or=2 rectal toxicity was tested using chi(2) test or Fisher's exact test. A multivariate analysis using logistic regression was performed. RESULTS: Late rectal toxicity grade > or=2 was observed in 24 of the 135 patients (17.8%). A 'grey area' of increased risk has been identified. Average DVHs of the bleeding and non-bleeding patients were generated. The area under the percent volume DVH for the rectum of the bleeding patients was significantly higher than that of patients without late rectal toxicity. On multivariate analysis the correlation between the high risk DVHs and late rectal bleeding was confirmed. CONCLUSIONS: The present analysis confirms the role of the rectal DVH as a tool to discriminate patients undergoing high-dose 3D-CRT into a low and a high risk of developing late rectal bleeding. Based on our own results and taking into account the data published in the literature, we have been able to establish new dose-volume constraints for treatment planning: if possible, the percentage of rectal volume exposed to 40, 50, 60, 72 and 76 Gy should be limited to 60, 50, 25, 15 and 5%, respectively.

Intravascular ultrasound based dose assessment in endovascular brachytherapy.

BACKGROUND: the role of endovascular brachytherapy in restenosis prevention is well documented. Dose is usually prescribed at a fixed distance from the source axis by angiographic quantification of vessel diameter. Recently, intravascular ultrasound (IVUS) was introduced in dose prescription, allowing a better evaluation of the vessel anatomy. This study retrospectively explores the difference between prescription following angiographic vessel sizing and delivered dose calculated with IVUS. METHODS AND RESULTS: Seventeen lesions were studied with IVUS, identifying on irradiated segment, three sections on which measuring minimal and maximal distance from the centre of IVUS catheter to the adventitia; using dedicated software, corresponding doses were calculated. The dose ranged widely, with maximal and minimal values of 71.6 and 4.9 Gy; furthermore, heterogeneity in dose among different sections was observed. In the central section, the maximal dose was 206% of the one prescribed with the QCA model at 2 mm from the source axis, while the minimal dose was 96%. In proximal and distal sections, respective values were 182, 45, 243, and 122%. CONCLUSIONS: Our analysis confirmed the dose inhomogeneity delivered with an angiographic fixed-dose prescription strategy. A dose variation was found along the irradiated segment due to the differences in vessel thickness. IVUS emerged as an important tool in endovascular brachytherapy, especially for irregular-shaped vessels.