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S M Bentzen

Publications and source records attributed to S M Bentzen.

At least 19 recordsLinked to original sources
PubMed2004

Pre-treatment haemoglobin concentration in accelerated and conventional radiotherapy for non-small cell lung carcinoma.

Serum haemoglobin has been shown to be an independent prognostic factor for a number of cancers including head and neck, bladder, cervix and anal cancers. This study has investigated the prognostic significance of pre-treatment haemoglobin in 164 consecutive patients receiving radical radiotherapy for non-small cell lung cancer. Forty-six received conventional fractionation to 60 Gy in 30 fractions and the remainder received accelerated fractionation, either CHART, 54 Gy in 36 fractions over 12 days (27 patients) or CHARTWEL, 60 Gy in 40 fractions over 18 days (76 patients). Patients were divided into three equal groups by haemoglobin concentration. The median overall survival in each of the three groups from lowest to highest haemoglobin was 17.5 months (95% CI 7.9 25), 18.4 months (95% CI 15.0 25.9) and 16.3 months (95% CI 13.0-19.6). No significant effect of pre-treatment haemoglobin concentration was seen in predicting overall, local disease free or metastases free survival.

Adult↗
PubMed2004

Is sensitization with nicotinamide and carbogen dependent on nicotinamide concentration at the time of irradiation?

PURPOSE: To determine whether tumour radiosensitization and the therapeutic benefit of administering carbogen with nicotinamide depend upon irradiating at the time of peak drug concentration. MATERIALS AND METHODS: Local tumour control of CaNT tumours in CBA mice and acute skin reactions in albino WHT mice were assessed after treatment with 10 X-ray fractions in air, carbogen alone or combined with 0.1, 0.2 or 0.5 mg g(-1) nicotinamide, injected 15, 30 or 60 min before irradiation. Plasma and tumour drug pharmacokinetics were performed. RESULTS: Nicotinamide was rapidly taken up into tumours; a six- and threefold higher concentration was obtained with 0.5 mg g(-1) compared with 0.1 and 0.2 mg g(-1), respectively. Tumour, but not skin, radiosensitization increased as the dose of nicotinamide increased (p = 0.03), but at each dose level there was no significant difference in radiosensitivity when irradiations were done at or after the time of peak concentration. An almost eightfold increase in plasma levels increased tumour enhancement ratios from 1.74 to 1.92 (p < 0.0001). In tumours all schedules gave significant enhancement relative to carbogen alone (p < or = 0.04). CONCLUSIONS: Tumour and skin radiosensitivity was independent of time of nicotinamide administration. Higher drug concentrations were not mirrored by proportionally higher enhancement ratios. Lower plasma levels than previously suggested significantly enhanced tumour radiosensitivity relative to carbogen alone. The clinical implications of these findings are discussed.

Animals↗
PubMed2003

Altered fractionation and combined radio-chemotherapy approaches: pioneering new opportunities in head and neck oncology.

Squamous cell carcinoma of the head and neck (HNSCC) are increasingly treated by multimodality approaches combining surgery, radiotherapy and chemotherapy. Randomised controlled trials have demonstrated major improvements in loco-regional tumour control from altered fractionation radiotherapy, accelerated fractionation and hyperfractionation, as compared with conventional fractionation. This experience is summarised, and the limit as to how far these modifications can be taken is discussed. It is emphasised that radiation fractionation will need to be optimised separately in multimodality strategies. Combined chemotherapy and radiotherapy has also been shown in phase III trials to produce an improved survival and an improved disease control. Chemotherapy may be given as neoadjuvant, concurrent or adjuvant treatment and the biological rationales for each of these, and the data supporting them, are reviewed. Although, large meta-analyses have shown concurrent chemoradiation to be the most effective, there is still a strong rationale for trying to develop neoadjuvant and adjuvant schedules. New, more active drugs may be important in this context. As therapy is becoming more intense, a careful recording and reporting of treatment-related morbidity is a crucial element in estimating the therapeutic gain from competing therapeutic management strategies. Development of non-cytostatic drugs and individualization of therapy using molecular prognostic markers are exciting areas of research with a great potential for improving therapy in the next decade and these are briefly discussed. Finally, a number of avenues for further research are identified.

Antineoplastic Agents↗
PubMed2003

Repopulation in radiation oncology: perspectives of clinical research.

Cellular repopulation is one of the most important biological determinants of the clinical outcome of fractionated radiation therapy. A number of randomized controlled trials of altered dose-fractionation have been conducted in patients with squamous cell carcinoma of the head and neck (HNSCC) and the main biological lessons from these are summarised. Data for other tumour histologies are relatively sparse. Further progress in radiotherapy for HNSCC is unlikely to result from altered fractionation alone, but a number of novel strategies for overcoming or exploiting repopulation are being researched. In the next 5 years, the top priorities for clinical and translational research in this field should be the development of clinically applicable predictive assays, functional imaging as an aid to optimize the dose distribution, optimization of combined modality therapies and novel biological strategies specifically targeting tumour cell proliferation.

Carcinoma, Squamous Cell↗
PubMed2002

Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation.

Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery, the possibility that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and neck cancer was investigated. The value of T(pot) in predicting the treatment outcome and in selecting patients for accelerated fractionation was tested. Seventy patients with (T2/N1-N2) or (T3-4/any N) squamous cell carcinoma of the oral cavity, larynx and hypopharynx who underwent radical surgery, were randomized to either (a) accelerated hyperfractionation: 46.2 Gy per 12 days, 1.4 Gy per fraction, three fractions per day with 6 h interfraction interval, treating 6 days per week or (b) Conventional fractionation: 60 Gy per 6 weeks, 2 Gy per fraction, treating 5 days per week. The 3-year locoregional control rate was significantly better in the accelerated hyperfractionation (88 +/- 4%) than in the CF (57+/- 9%) group, P=0.01 (and this was confirmed by multivariate analysis), but the difference in survival (60 +/- 10% vs 46 +/- 9%) was not significant (P=0.29). The favourable influence of a short treatment time was further substantiated by demonstrating the importance of the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy. Early mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group; reflecting a faster rate of dose accumulation. Xerostomia was experienced by all patients with a tendency to be more severe after accelerated hyperfractionation. Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably represent consequential reactions. T(pot) showed a correlation with disease-free survival in a univariate analysis but did not prove to be an independent factor. Moreover, the use of the minimum and corrected P-values did not identify a significant cut-off. Compared to conventional fractionation, accelerated hyperfractionation did not seem to offer a survival advantage in fast tumours though a better local control rate was noted. This limits the use of T(pot) as a guide for selecting patients for accelerated hyperfractionation. For slowly growing tumours, tumour control and survival probabilities were not significantly different in the conventional fractionation and accelerated hyperfractionation groups. A rapid tumour growth was associated with a higher risk of distant metastases (P=0.01). In conclusion, tumour cell repopulation seems to be an important determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association between T(pot) and treatment outcome. In fast growing tumours accelerated hyperfractionation provided an improved local control but without a survival advantage. To gain a full benefit from treatment acceleration, the surgery-radiotherapy gap and the overall treatment time should not exceed 6 and 10 weeks respectively.

Adult↗
PubMed2002

How useful are observational reports in the evaluation of interventions for radiation morbidity?: an analysis of formalin therapy for late radiation proctitis.

BACKGROUND AND PURPOSE: Evidence-based medicine requires the systematic and critical evaluation of published and unpublished trials. Problems arise when a clinical condition is relatively rare and the only available data relate to experiential knowledge. The way forward would be to recommend the development of good quality randomized controlled studies. Until then, we are left with the situation where some information exists, albeit in the form of case reports and small series. Should this information be used and what features would determine its strength? METHODS: Using the example of formalin therapy in haemorrhagic radiation proctitis, a treatment for a rare condition, we were able to identify 16 published studies, 13 of which were retrospective and three of which were prospective. The quality of reporting detail was assessed by comparison to the features in a 'proposed minimum dataset' for an uncontrolled study addressing this topic. RESULTS: The mean score for quality of reporting detail for these studies was 50.6% (range 25-70%). Earlier studies reported a significantly higher response rate than subsequent studies and although there was a tendency for smaller studies to report higher response rates, this was not significant. The score for detail of reporting did not improve with year of publication and the correlation between the size of the study and the detail of reporting was not statistically significant. CONCLUSIONS: The information presented is of exceedingly variable quality. If these studies are to be used, where insufficient controlled trials are available, they should be scored for methodology, and these scores used to assist interpretation of results. This would be facilitated if an accepted reporting format including specific criteria was available.

Evaluation Studies as Topic↗
PubMed2002

Treatment-related morbidity and hospital league tables: experience from a national audit of radiotherapy-induced morbidity in cervical carcinoma.

Data are now available from a U.K. audit of survival and late morbidity following curative radiotherapy for cancer of the cervix treated in 1993. The complication rate per centre ranges from 0 to 67%. Although the frequency of complications following curative radiotherapy for cancer of the cervix might be considered to be an indicator of clinical performance, variation in treatment outcomes can be explained by sampling variability rather than real differences in quality of care. In the present study we have asked the question: could the disparity in complication rates between centres be no more or less than would be expected by chance? Our analysis suggests that this is the case, and for this reason it would be premature to use such outcome data to produce league tables or to assess institutional differences. Thus, ranking centres according to complication rate would not be valid, as the differences in rates observed are probably not significantly different from the national average. It is important that audit data are not used inappropriately and this analysis further highlights the need for reliable prospective collection of clinical information and the importance of considering sampling variability in interpreting the results of such studies.

Female↗
PubMed2002

From CHART to CHARTWEL in non-small cell lung cancer: clinical radiobiological modelling of the expected change in outcome.

CHART (Continuous Hyperfractionated Accelerated Radiotherapy) has been shown to improve the tumour control probability and survival relative to conventional radiotherapy in patients with inoperable non-small cell lung cancer (NSCLC). CHARTWEL (CHART Weekend-less) is a further development of this schedule escalating the physical dose to 60 Gy while maintaining the low dose per fraction of 1.5 Gy. In this schedule, three fractions, with a minimum interval of 6 h between fractions, are delivered 5 days per week. This extends overall treatment time from the 12 days of CHART to 18 days. Radiobiological modelling is used to estimate the expected tumour control and normal tissue morbidity after CHARTWEL relative to CHART. The estimations are based on the outcome of the CHART trial and published values for dose-fractionation and dose-response parameters for human tissues and tumours. Two new estimates of quantitative radiobiological parameters for early normal-tissue morbidity after chest irradiation are reported here. For radiation pneumonitis, the dose recovered per day is estimated at 0.44 Gy/day with 95% confidence limits 0.07 Gy/day and 0.80 Gy/day. For oesophagitis, the normalized dose-response gradient, gamma50, is estimated at 2.1 with 95% confidence limits 1.4 and 3.6. With regard to normal tissue effects, the increase in total dose when going from CHART to CHARTWEL is moderated by the slightly longer overall treatment time in case of early morbidity while the introduction of the weekend gaps may moderate the effect for late-responding normal tissues with a long repair halftime. Tumour control at 3 years is expected to increase by some 7-14 percentage points (from 19% to 26-33%) whereas the incidence of moderate and severe early oesophagitis and pneumonitis is expected to increase by about 2 percentage points. The incidence of late morbidity, lung fibrosis and oesophageal strictures, is expected to increase by 3-4 percentage points. The analyses conclude that CHARTWEL is likely to improve the therapeutic ratio relative to CHART.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Failure-specific prognostic factors after continuous hyperfractionated accelerated radiotherapy (CHART) or conventional radiotherapy in locally advanced non-small-cell lung cancer: a competing risks analysis.

The aim of this study was to identify possible failure-specific prognostic factors in non-small-cell lung cancer. Clinical outcome was analysed in 549 patients participating in the randomized controlled trial of CHART vs conventional radiotherapy. Local failure and distant failure with or without concurrent local relapse were subjected to a competing risk analysis using an accelerated failure-time model with a log-logistic hazard function. Randomization to CHART (2 P = 0.005), increasing age (2 P = 0.036) and female sex (2 P = 0.09) was all associated with a prolonged interval to failure. Advanced clinical stage was associated with a decreased interval to failure (2 P = 0.004) and a significantly increased risk (2 P = 0.009) of failing in distant rather than in local position. From this model, prognostic indices for local and distant failure were estimated for each individual patient. Competing risk analysis allows identification of patients with different failure patterns, and may provide a means of stratifying patients for intensified local or systemic therapy.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Influence of plasma glutathione levels on radiation mucositis.

PURPOSE: To test the hypothesis that there is a link between plasma glutathione (GSH) or other antioxidants (uric acid, ascorbate) and the severity of radiation mucositis following radiation treatment of tumors of the head and neck. PATIENTS AND METHODS: Patients with carcinomas of the head-and-neck region were treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen (54 Gy in 36 fractions over 12 days). Samples of blood plasma were analyzed for GSH, cysteine, urate, and ascorbate by high-pressure liquid chromatography. Patients were graded for dysphagia and requirement for analgesics. The areas under the curves of scores over 2-6 weeks following treatment were computed, and Spearman's rank-correlation coefficient was used to test for an association between plasma GSH levels (or those of other antioxidants) and mucositis. RESULTS: The pretreatment plasma GSH level in 18 patients scored in the study was 1.0 +/- 0.7 M. Analysis of these and the dysphagia scores produced a correlation coefficient of 0.22 (confidence interval -0.28, 0.61; p = 0.39). No correlation was seen between mucositis severity and other measures of plasma antioxidants: cysteine (7.6 +/- 1.7 M), cysteine + GSH (8.6 +/- 1.9 M), uric acid (317 +/- 86 M), ascorbate (29 +/- 20 M), or whole-blood GSH concentrations (1,010 +/- 239 M). CONCLUSION: The measurements of approximately micromolar levels of plasma GSH, or about 10 M cysteine + GSH (almost all of the total nonprotein thiols), are consistent with most other published data for either healthy adults or cancer patients; however, the values reported in an earlier study, suggesting a link between GSH and mucositis, are much higher. The hypothesis of a possible link between radiation mucositis and plasma-free (nonprotein) thiols was not supported.

Ascorbic Acid↗
PubMed2001

Value of epidermal growth factor receptor, HER2, p53, and steroid receptors in predicting the efficacy of tamoxifen in high-risk postmenopausal breast cancer patients.

PURPOSE: Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment. HER2, epidermal growth factor receptor (EGFR), and p53 have all been suggested as possible markers of tamoxifen resistance. The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR, HER2, and p53 in steroid receptor-positive patients. PATIENTS AND METHODS: A total of 1,716 high-risk postmenopausal breast cancer patients were randomly assigned to treatment with tamoxifen (868 women) or to observation (848 women) in a prospective trial (Danish Breast Cancer Cooperative Group's 77c protocol). The content of the steroid receptors and expression of p53, EGFR, and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue. The length of follow-up was 10 years. The end point for this analysis was disease-free survival. RESULTS: Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2-, EGFR-, and p53-positive, high-risk, steroid receptor-positive patients. Patients with steroid receptor-positive tumors and positive immunohistochemical staining for HER2, EGFR or p53 benefited from treatment with tamoxifen for 1 year, although the latter variable contained independent prognostic information by itself. CONCLUSION: With the statistical power of the present randomized study, we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor-positive patients with early-stage breast cancer. Thus, neither HER2, EGFR, nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen.

Aged↗
PubMed2001

Role of chance in familial aggregation of colorectal cancer.

A prospective population-based study recorded family trees of 77 colorectal cancer patients younger than 50 years of age. Using mathematical modeling of population age-incidence data, we estimate that 1 (95% confidence limits 0 and 3) of these families is expected to meet the Amsterdam criteria I for HNPCC due to chance clustering of colorectal cancer.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2001

The translational research chain: is it delivering the goods?

PURPOSE: To address whether the translational research chain has influenced clinical practice in radiation oncology. METHODS AND MATERIALS: Merits and limitations of the various steps of the translational chain, i.e., in vitro studies, animal experiments, biomathematical modeling, Phase I and II trials, and randomized Phase III trials are briefly reviewed. The process and value of translational research in radiation oncology are addressed using dose fractionation and the time factor in tumors as examples. RESULTS: The examples show that translational research may indeed change clinical practice in radiation oncology. However, it takes several decades and considerable efforts to define and test new strategies. The "translational process" is by no means unidirectional but a continuing multiway dialog among basic scientists, applied scientists, clinical scientists, and clinical oncologists. CONCLUSION: Translational research works in radiation oncology, and it is difficult to conceive a better alternative for future improvement of therapy. The slow speed of the translational process indicates that there is a need for improving the various steps of the translational network and the interaction as a whole. Massive investments in one part of the network are likely to be at least partly wasted unless the other links are strengthened as well.

Animals↗
PubMed2001

bcl-2 expression in head and neck cancer: an enigmatic prognostic marker.

PURPOSE: The role of bcl-2 overexpression in cancer presents a paradox. In some tumor types, it is associated with favorable outcome, whereas in others the reverse is true. The purpose of this study was to explore the influence of bcl-2 in a large series of head and neck cancer patients treated in the CHART randomized trial. METHODS AND MATERIALS: Histologic material was obtained from 400 patients; bcl-2 expression was assessed by immunohistochemistry as either positive or negative cytoplasmic staining. RESULTS: Positivity of bcl-2 was recorded in 12.8% (9.5-16.5%, 95% confidence limits) of tumors. There were significant differences in positive tumors within different sites with nasopharynx showing the highest incidence (46.2%). A multivariate logistic regression analysis showed that bcl-2 was strongly associated with histologic dedifferentiation, as well as increasing N stage and female gender. In univariate analyses, bcl-2 positive patients had a lower locoregional relapse rate (RR 0.57, p = 0.02) and improved survival (RR 0.49, p = 0.004) compared to bcl-2 negative patients; this became more significant in multivariate analysis. CONCLUSION: These data demonstrate that bcl-2 overexpression is a marker of what is considered to be more advanced and aggressive disease yet it is associated with a more favorable outcome irrespective of the treatment schedule.

Analysis of Variance↗
PubMed2001

Prognostic factor studies in oncology: osteosarcoma as a clinical example.

OBJECTIVE: Prognostic factor studies are abundant in oncology. Nevertheless, most of them have very limited impact on clinical practice, in part because many of them have a low statistical power. The importance of statistical power is illustrated using bootstrap resampling of data from a series of osteosarcoma patients. METHODS AND MATERIALS: Osteosarcoma is a rare disease, the incidence being just a few cases per million person-years in the Western World. Very few Phase III studies have been conducted in the disease, and much knowledge on therapeutic progress has come from Phase II studies. This has caused controversy concerning the validity of historical controls, which again has stimulated interest in the identification of prognostic factors in this disease. A literature search in the National Library of Medicine MEDLINE database was performed to identify prognostic factor studies in osteosarcoma published between 1975 and 1998. Monte Carlo methods, so-called bootstrap resampling, are used to investigate the importance of sample size based on survival data for a previously published series of 158 osteosarcomas treated with surgery alone. RESULTS: Most published studies are too small to provide useful information on prognostic factors in osteosarcoma. Three-quarters of the papers reviewed included less than 100 patients with osteosarcoma. More than 20 different potential prognostic factors were included in these papers. Inherent differences between studies and poor reporting hamper a synthesis of information from various studies. The results from the bootstrap resampling illustrate how the majority of published studies would miss even quite significant prognostic factors. CONCLUSIONS: An effort is needed to improve the design, conduct, and reporting of prognostic studies in oncology.

Bone Neoplasms↗
PubMed2001

Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial.

BACKGROUND AND PURPOSE: Early reactions after radiotherapy for head and neck cancer may become the limiting factor in current attempts to intensify loco-regional therapy through altered fractionation or combination of radiotherapy with chemotherapy. The aim of the present study was to quantify the dependence of early reactions on the dose-fractionation used in radiotherapy and on patients' age and radiation field size. PATIENTS AND METHODS: The data analyzed are from the randomized controlled trial of CHART (continuous hyperfractionated accelerated radiotherapy) vs. conventional radiotherapy in head and neck cancer. The trial accrued 918 patients from March 1990 to April 1995. Several early morbidity items were evaluated weekly for the first 8 weeks after the start of treatment. Weekly evaluation was continued in patients with early reactions extending beyond 8 weeks. Linear regression was used to analyze the time with reactions in individual patients. Polychotomous ordinal response regression was used to analyze the peak grade of early reactions in individual patients. RESULTS: The main findings of this analysis were as follows. (1) The incidence and peak prevalence of confluent mucositis was higher after CHART than after conventional radiotherapy. Therefore, the average time spent with confluent mucositis per patient treated was significantly longer after CHART than after conventional fractionation. (2) In patients who actually developed confluent mucositis, the average duration of this grade of reaction was not significantly different after CHART compared with conventional radiotherapy. (3) Confluent mucositis developed earlier after the start of treatment (2.9 vs. 4.9 weeks) but also started to improve sooner (5.4 vs. 7.5 weeks after the start of treatment) after CHART than after conventional radiotherapy. (4) The dose recovered per 1-day protraction of overall treatment time, D(prolif), was estimated at 0.80 Gy with 95% confidence limits 0.7 and 1.1 Gy/day for human mucosa. (5) For human skin erythema, the estimate of D(prolif) was 0.12 Gy/day with 95% confidence limits -0.12 and 0.22 Gy/day. (6) Highly significant relationships were found between the grade of morphological mucositis on one hand and dysphagia, pain on swallowing and prescribed analgesics on the other. Patients with confluent mucositis had fewer functional problems if this was confined to the larynx as compared with other subsites in the head and neck. (7) Although the incidence of confluent mucositis was higher in the oral cavity and oropharynx than in the hypopharynx and larynx, the radiobiological properties of mucosal reactions did not show significant variation among the various subsites within the head and neck region. (8) For a given dose and overall treatment time, a highly significant increase in incidence and severity of both mucositis and erythema was seen with increasing field size. Thus, a significant dose-volume or dose-area effect exists for both of these tissues. (9) Patients' age had no significant influence on the incidence and severity of mucositis or erythema. CONCLUSIONS: This study provides quantitative estimates of the dose-time and dose-volume relationships for human skin and normal mucosa in the head and neck region based on an analysis of data from 918 patients entered into a randomized-controlled trial of altered dose fractionation in radiotherapy.

Adult↗