Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy.

The choice of the appropriate model and parameter set in determining the relation between the incidence of radiation pneumonitis and dose distribution in the lung is of great importance, especially in the case of breast radiotherapy where the observed incidence is fairly low. From our previous study based on 150 breast cancer patients, where the fits of dose-volume models to clinical data were estimated (Tsougos et al 2005 Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy Phys. Med. Biol. 50 3535-54), one could get the impression that the relative seriality is significantly better than the LKB NTCP model. However, the estimation of the different NTCP models was based on their goodness-of-fit on clinical data, using various sets of published parameters from other groups, and this fact may provisionally justify the results. Hence, we sought to investigate further the LKB model, by applying different published parameter sets for the very same group of patients, in order to be able to compare the results. It was shown that, depending on the parameter set applied, the LKB model is able to predict the incidence of radiation pneumonitis with acceptable accuracy, especially when implemented on a sub-group of patients (120) receiving [see text]|EUD higher than 8 Gy. In conclusion, the goodness-of-fit of a certain radiobiological model on a given clinical case is closely related to the selection of the proper scoring criteria and parameter set as well as to the compatibility of the clinical case from which the data were derived.

Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer.

BACKGROUND: A phase II trial of alternating i.v. and oral vinorelbine in combination with cisplatin was designed to determine the response rate, safety profile, progression-free survival, overall survival and quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-six chemotherapy-naïve patients received cisplatin 100 mg/m(2) and i.v. vinorelbine 25 mg/m(2) on day 1, followed by oral vinorelbine 60 mg/m(2) on days 8, 15 and 22, every 28 days. RESULTS: After an independent review, the response rate was 33% [95% confidence interval (CI) 20% to 46%]. Median progression-free and overall survival were 5.5 months (95% CI 3.7-6.4) and 8.9 months (95% CI 8.8-11.7), respectively. The most frequent hematological toxicities were neutropenia (grade 3-4 in 73% of patients) and anemia (grade 3-4 in 11% of patients). Grade 3-4 infections and non-hematological toxicities occurred occasionally. QoL for lung cancer related symptoms was stable or improved. CONCLUSIONS: The efficacy and safety of the alternating vinorelbine schedule (i.v. on day 1, oral on days 8, 15 and 22) in combination with cisplatin in advanced NSCLC are similar to those of the standard regimen using exclusively i.v. vinorelbine, whereas ease of administration and patient comfort may favor the novel approach.

Quality assurance in radiotherapy of breast cancer--variability in planning target volume delineation.

The inter-physician and inter-patient variability in planning target volume delineation for the radiotherapy of breast cancer after conservative surgery is presented. Eleven experienced radiation oncologists determined the planning target volume (PTV) for four breast cancer patients. Delineation was based on CT slices taken at intervals of 15 mm. The variability in target volume delineation was determined by measuring the volumes in units of cc and the position of the drawn PTVs. Statistical analysis was based on X/R-charts and on Pareto chart and analysis. The maximum range in PTV for one patient was from 670 to 1,200 cc. The observations of three physicians were in excess of the warning limit altogether 18 times. The methods used in this study clearly reveal inter-physician variability in PTV delineation and widest variations found are not acceptable. Training targeted to some physicians and more detailed and unambiguous protocols for PTV delineation are needed.

CT lung densitometry in assessing intralobular air content. An experimental and clinical study.

PURPOSE: To introduce a parameter called "intralobular air content percentage" to replace the CT number of the lung and to establish a proper protocol for its assessment. MATERIAL AND METHODS: We calibrated the HU (Hounsfield unit) scale for low densities with foam and evaluated the influence of certain acquisition and reconstruction parameters on the accuracy of CT densitometry of the lungs. The reproducibility of the results obtained in human experiments and the intralobular air content percentage of normal and diseased lung tissue were assessed. RESULTS: Air content could be reliably derived from the calibrated CT number of an area within a secondary lobulus. The mean intralobular air content of normal lungs varied from 77.8% to 88.0% in full inspiration. Helical or axial recording with a 10-mm slice thickness, a standard or soft algorithm and high tube currents and voltage settings, was suitable for the measurements. CONCLUSION: Before absolute lung density measurements (as a HU number or an air content percentage), the CT equipment has to be calibrated for low densities. The intralobular air content percentages of cooperative patients were reliably reproducible.

DNA flow cytometry in surgically treated lung cancer--prognostic significance.

Although DNA aneuploidy and high proliferative activity (S-phase fraction, SPF) of tumour cells, measured by flow cytometry, have proved to be indicators of poor prognosis in most solid tumours, there have been conflicting results in lung cancer studies. During a four-year period we studied the prognostic significance of DNA ploidy and SPF in 99 surgically treated lung cancer patients. Flow cytometric analysis was done from archival, formalin-fixed, paraffin-embedded tumour specimens. DNA index and SPF were determined, using MultiCycle software with sliced nuclear correction to compensate for debris. There were 61 DNA diploid and 38 DNA aneuploid tumours. The median SPF was 10.2%. Neither ploidy nor SPF was associated with previously known prognostic factors. Survival was poorer in patients with aneuploid tumours than in the other patients, but the difference was not statistically significant. DNA ploidy and SPF thus do not seem to be useful prognostic indicators in surgically treated lung cancer.

Quality control in health care: an experiment in radiotherapy planning for breast cancer patients after mastectomy.

PURPOSE: The importance of evaluating and improving quality in clinical practice is now generally acknowledged. In this study we estimated different sources of variation in radiotherapy planning for breast cancer patients after mastectomy and sought to test the applicability of a reproducibility and repeatability (R&R) study in a clinical context. METHODS: Eleven radiation oncologists planned radiotherapy three times for three different kinds of breast cancer patients without knowing they were handling the same patient three times. Variation was divided into different components: physicians as operators, patients as parts, and repeated measurements as trials. Variation due to difference across trials (repeatability), that across the physicians (reproducibility), and that across the patients (variability) were estimated, as well as interactions between physicians and patients. Calculation was based on the sum of squares, and analysis was supported by various graphical presentations such as range charts and box plots. RESULTS: Some parts of the planning process were characterized by higher and different kinds of variation than the others. Interphysician variation (i.e., reproducibility) was not high but there were some clearly outlying physicians. The highest variation was in repeatability (= intraphysician variation). The major part of the variation was, however, that from patient to patient: 33% of the total in Parameter 1 and 85% of the total in Parameter 2. CONCLUSIONS: R&R studies are applicable and are needed to evaluate and improve quality in clinical practice. This kind of analysis provides opportunities to establish which kinds of patients require particularly careful attention, which points in the process are most critical for variation, which are the most difficult aspects for each physician and call for more careful description in documents, and which physicians need further training.

Prognosis of surgically treated lung cancer.

BACKGROUND AND AIMS: This retrospective study clarifies the prognosis of surgically treated lung cancer in a teaching university hospital. MATERIAL AND METHODS: During a four year period 141 patients were operated for lung cancer in a teaching university hospital. After five years follow up the case records were analysed. The operative and microscopical findings were classified using the AJC pTNM staging system and WHO's histologic classification of lung tumours. There were 120 (85 %) male and 21 (15 %) female. The median age for males was 62 years and females 64 years; range was 29 to 76 years for both sexes. RESULTS AND CONCLUSIONS: The perioperative mortality of all patients was 5,0 %, of 84 patients operated with lobectomy 2.4 %, of 32 patients operated with pneumectomy 15,6 %, and of 25 patients operated with explorative thoracotomy 0 %, respectively. The five year survival of all patients was 33 % including perioperative mortality. The survival was significantly better for 83 patients with stage I disease (49 %) than 17 stage II (6 %), 24 stage IIIa (20.8 %), and 17 stage IIIb or IV disease (0 %). The survival was significantly better after lobectomy (44.1 %) than after pneumectomy (25.0 %) or explorative thoracotomy (8.0 %). Our study shows the good effect of surgery in stage I, and confirms it's usefulness in stage IIIa lung cancer. The histologic types of tumours did not affect survival.

Osteonecrosis during the treatment of childhood acute lymphoblastic leukemia: a prospective MRI study.

BACKGROUND: Since the survival rates of childhood leukemia have improved, attention is increasingly focused on the long-term effects of the treatment. Osteonecrosis may complicate the treatment of acute lymphoblastic leukemia (ALL). To have more information about the natural history and clinical course of the development of osteonecrosis, a prospective MRI study was designed. PROCEDURE: The development of osteonecrosis was studied prospectively in 24 consecutive children with ALL who underwent T1-weighted magnetic resonance imaging (MRI) scanning of the lower extremities at the beginning of, during, and at the cessation of the chemotherapy. The general bone marrow signal intensity was assessed together with focal lesions. Circumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. RESULTS: Nine of the 24 patients (rate 38%) developed osteonecrosis during the treatment. Six of them were asymptomatic. MRI lesions regressed in size in six patients, and in three patients the MRI finding returned to normal. No operative treatment was needed. The osteonecroses appeared immediately or within a few months after the delayed intensification phase with intensive dexamethasone medication. CONCLUSIONS: Corticosteroids have been considered to be the main pathogenetic factor in the development of osteonecrosis in children with malignancies, which was also suggested by our findings. However, there is a lack of systematic prospective studies concerning the natural history and long-term follow-up observations of the prognosis of osteonecrosis, especially in pediatric patients. Based on our results, the lesions are often asymptomatic and cause no disability, and spontaneous improvement or even resolution may occur.

High-resolution computed tomography for the diagnosis of community-acquired pneumonia.

We compared high-resolution computed tomography (HRCT) with chest radiography (CR) to determine if there is any advantage to using HRCT in the diagnosis of community-acquired pneumonia (CAP). Simultaneously obtained chest radiographs were compared with HRCT scans for 47 patients with clinical symptoms and signs suspicious for CAP, HRCT identified all 18 CAP cases (38.3%) apparent on radiographs as well as eight additional cases (i.e., 55.3%); P = .004. The corresponding figures for bilateral involvement were six by CR (33.3%) and 16 by HRCT (61.5%), P = .001. CR did not show changes particularly affecting the upper and lower lung lobes and the lingula. Bronchopneumonia was visualized by CR in 11 cases (61.1%) and by HRCT in 22 cases (84.6%). The corresponding figures for airspace pneumonia were four (22.2%) and one (3.8%), respectively. The use of HRCT seems to increase the number of CAP cases confirmed by imaging and to improve the accuracy of diagnosing and typing of CAP.

Bone marrow changes on MRI in children with acute lymphoblastic leukaemia 5 years after treatment.

T1-weighted magnetic resonance imaging (MRI) of the lower extremities was performed 5 years after the cessation of therapy on 25 children treated for acute lymphoblastic leukaemia (ALL). Signal intensity pathologies considered to be related with the leukaemia itself or the treatment of ALL were found in nine of 25 children (36%). Two of these children had findings of osteonecrosis, five had a patchy signal pattern, one had diffuse inhomogeneity of the bone marrow signal intensity in complete remission and one had diffusely decreased signal intensity preceding the diagnosis of relapse. MRI unexpectedly revealed many bone marrow pathologies in symptomless children successfully treated for ALL. Especially, osteonecrosis might cause significant disability, and the aetiology, clinical course and prognosis of this complication are not well known. The intensive dexamethasone medication included in the treatment protocols may be responsible for the development of osteonecrosis. However, the prognosis of osteonecrosis in the long run requires further studies.

Human plasma antioxidant capacity during radiotherapy for lung cancer: a clinical study.

Even though it is well established that oxygen-free radicals are the main mechanism responsible for the cytotoxicity produced during radiotherapy, the role of the human antioxidant defense system in clinical radiation oncology is still to be clarified. Changes in the human plasma total peroxyl radical trapping capacity (TRAP) and its individual components were followed during clinical radiotherapy for lung cancer. Sixteen patients receiving radical-aimed radiotherapy provided blood samples nine times during the treatment. Our hypothesis was that oxygen-free radical production increased by irradiation should decrease the plasma TRAP as a consequence of oxidative stress. Only a moderate reduction of the plasma TRAP was found during the therapy in the study group taken as a whole, but the development pattern of TRAP and its unidentified components were clearly different in those patients showing complete or partial response to the treatment and those in which the disease progressed unabated. Plasma ascorbate levels showed no significant changes during radiotherapy. A decrease in vitamin E concentrations was seen after 6 Gy (p=0.05). Uric acid concentrations increased towards the end of the radiotherapy in both response groups (p=0.02 at 50 Gy). In this study, 26.6% of the plasma TRAP was due to unidentified antioxidants (UNID).

Osteonecrosis in children treated for acute lymphoblastic leukemia: a magnetic resonance imaging study after treatment.

The purpose of the study was to find out the prevalence of osteonecrosis in children with acute lymphoblastic leukemia (ALL) in complete bone marrow remission at the end of the treatment. Twenty-eight children with ALL underwent MRI of the upper and/or lower extremities. Bone marrow signal intensity was analyzed on T1-weighted images, where circumscribed lesions with a rim of low signal intensity were considered typical of osteonecrosis. Osteonecrosis was found in 9 of the 28 children (32%, 95% CI 16% to 52%). Five of them were asymptomatic. They had been treated with high risk and intermediate risk protocols, both of which include a delayed intensification phase with dexamethasone. None of the patients with standard risk ALL were found to have developed osteonecrosis. Osteonecroses occurred unexpectedly in symptomless patients and in patients with mild transient symptoms treated with high risk and intermediate risk protocols. Our study suggests that the intensification phase of the treatment protocols with intensive dexamethasone medication might be responsible for the development of osteonecrosis.

Abdominal ultrasound findings during and after treatment of childhood acute lymphoblastic leukemia.

BACKGROUND: The treatment of acute leukemia in childhood has been increasingly successful. Concurrently, severe leukemia-related gastrointestinal complications have become more common. METHODS: We evaluated the findings of the abdominal ultrasound (US) examinations of 52 children with acute lymphoblastic leukemia (ALL) who had severe clinical symptoms indicating infection or abdominal complication during chemotherapy treatment or after the cessation of such treatment and assessed the impact of these findings on patients' subsequent treatment and survival. RESULTS: Our study presents ten cases of typhlitis with a prevalence of 9%, all of which were rapidly diagnosed by US and had a favourable outcome. We also found focal intra-abdominal parenchymal lesions in six children, five of them due to fungal infection and one due to leukemic infiltration. Several other intra-abdominal pathologies significant for the patients' treatment are also reported. DISCUSSION: We believe that abdominal US is a useful, rapid, safe, and accurate imaging method for children with ALL suspected to suffer from leukemia- or chemotherapy-related gastrointestinal complications. More invasive imaging methods are seldom needed. CONCLUSIONS: According to our results, abdominal US gives the necessary information in most of the cases and provides prompt diagnosis, which may prevent possible fatal complications.

Flow cytometric analysis of tumor DNA profile related to response to treatment and survival in small-cell lung cancer.

Flow cytometric (FCM) analysis of tumor DNA ploidy and S-phase fraction (SPF) has been widely used to predict prognosis and treatment response in many malignant tumors, but rarely in small-cell lung cancer (SCLC). In the present study, tumor DNA ploidy and SPF were measured from paraffin-embedded tumor biopsy samples of 36 small-cell lung cancer patients treated with combination chemotherapy and radiotherapy. Aneuploidy was detected in 69% of the tumors. There was a statistically non-significant trend towards more aneuploidy among extensive disease (ED) patients as compared to patients with limited disease (LD): 80% versus 65%, respectively (p = 0.69). The mean SPF was 21.3% (+/-7.6) in patients with LD and 29.0% (+/-5.3) in patients with ED, the difference (7.6%) being statistically significant (p = 0.008, 95% CI for the difference 2.2-13.1). No significant differences was detected in the survival of aneuploid and diploid patients or patients with low (< or = 24.9%) and high (> 24.9%) SPF. Similarly, no significant difference was observed between aneuploid and diploid cases in relation to response to treatment or response duration. It is concluded that the difference detected in the SPF with LD and ED of SCLC may indicate the biological aggressiveness of extensive SCLC.

Abdominal sonographic findings at primary diagnosis of acute lymphoblastic leukemia in children: a comparison with different clinical risk factors.

We evaluated the presence of abdominal organomegaly and lymphadenopathy with ultrasound in 92 children with acute lymphoblastic leukemia (ALL) prior to chemotherapy, and compared these findings with the different immunophenotypes, age groups, and white blood cell (WBC) counts as well as the survival of the patients and the clinical findings of organomegaly. All the patients (n = 13) with a WBC higher than 50/microL showed intra-abdominal pathology compared with the patients with a low WBC, of whom 37% (n = 18) had normal scans. The children with a high WBC count also had hepatomegaly (P = 0.003) and splenomegaly (P = 0.06) significantly more often, and showed high echogenicity of the kidneys (P = 0.001). Lymphadenopathy was found significantly more often in children with T-cell leukemia (P = 0.005). The younger age groups (0 to 2 and 2 to 5 years of age) had hepatomegaly significantly more often (P = 0.02), and the youngest age group (0 to 2 years) showed increased echogenicity of the kidneys more often (P = 0.04). Ultrasound showed hepatomegaly in 14 patients and splenomegaly in 23 patients who were assessed clinically as normal. According to our results, abdominal ultrasound is a useful tool for evaluating abdominal organomegaly and the extramedullary leukemic burden and can give information that is not available in clinical examination. There was no statistical association between the primary ultrasonographic findings and the patients' later survival.

Carboplatin and etoposide in extensive small cell lung cancer.

The combination of carboplatin and etoposide was evaluated in 61 previously untreated patients with extensive small cell lung cancer. Treatment was given at four-week intervals with 450 mg/m2 of carboplatin intravenously (i.v.) on day 1 and etoposide 100 mg/m2 i.v. on days 1-3. The response was complete in 5 (9%) and partial in 28 (50%) of the 56 evaluable patients (overall response rate 59%). The median time to progression after response as well as the median survival time in all evaluable patients was 4.6 months. WHO grade 3 and 4 leukopenia and thrombocytopenia occurred in 8% and 11% of the courses respectively. Two treatment-related deaths were registered. The combination of carboplatin and etoposide used in the present study produced acceptable response rate and toxicity, but duration of response and median survival were shorter than expected from earlier studies.

Effects of simulated herbivory on tillering and reproduction in an annual ryegrass,Lolium remotum.

This study examined the overall impact of simulated herbivory on tillering and reproductive performance of an annual ryegrass,Lolium remotum. The interaction between herbivore damage and intraspecific competition and the effect of the timing of damage were also studied. The experimental plants were sown at two densities and were randomly assigned to eight different damage treatments consisting of artificial leaf area removal by clipping with scissors or removal of one-third of the ripening seeds. The treatments were executed at two flowering stages. The pattern of tiller development differed significantly among treatments and between densities. At the lower density, earlier treatments delayed tiller development more than the same treatments executed later. At the higher density, all treatments delayed tiller development. The density effect was significant for all reproductive traits measured. The reproductive output of plants grown at the higher density was lower and the negative treatment effects were stronger than at the lower density. The treatment effect was significant for seed dry weight per plant and individual seed weight but not for number of seeds per plant. There were no statistically significant interaction effects between the damage treatments and density, suggesting that the plants responded to the damage similarly, irrespective of the density. The plants did not totally compensate for losses due to damage at either density, even though they slightly increased their resource allocation to sexual reproduction at the higher density.

Radical radiotherapy of inoperable non-small cell lung cancer. Irradiation techniques and tumor characteristics in relation to local control and survival.

The relation between tumor characteristics, irradiation technique, local tumor control and survival was retrospectively studied in 323 patients with non-small cell lung cancer who started radical radiotherapy in 1974-1981. At that time three non-randomized different fractionation schedules were used: 16 x 3.25 Gy, total dose 52 Gy, 3 fractions/week (schedule 1), 11 x 4 Gy, total dose 44 Gy, 2 fractions/week (schedule 2) and 25 x 2 Gy, total dose 50 Gy, 5 fractions/week (schedule 3). The highest survival rates were observed in the patient group treated according to schedule 2. The 2-year survival rate was 30% compared with 18% and 6% in the patients treated according to schedule 1 and 3 respectively. However, this can at least partly be explained by patient selection. A correlation between size of the tumor, target volume and survival was observed: the larger the tumor, the poorer the survival. Pleural effusion showed to be an unfavorable prognostic factor. The prognosis of inoperable lung cancer on the whole remained poor: the 1-year survival rate was 43% and 2-year survival rate 16%. Only 3% of the patients lived at least five years.