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Background: Breast-conserving therapy (BCT) has been shown to be as effective as mastectomy in the treatment of tumors 2 cm or smaller. However, evidence of its efficacy, over the long term, in patients with tumors larger than 2 cm is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried out a randomized, multicenter trial comparing BCT with modified radical mastectomy for patients with tumors up to 5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant metastasis, or time to locoregional recurrence.Methods: Of 868 eligible breast cancer patients randomly assigned to the BCT arm or to the modified radical mastectomy arm, 80% had a tumor of 2.1-5 cm. BCT comprised lumpectomy with an attempted margin of 1 cm of healthy tissue and complete axillary clearance, followed by radiotherapy to the breast and a supplementary dose to the tumor bed. The median follow-up was 13.4 years. All P values are two-sided.Results: At 10 years, there was no difference between the two groups in overall survival (66% for the mastectomy patients and 65% for the BCT patients; P =.11) or in their distant metastasis-free rates (66% for the mastectomy patients and 61% for the BCT patients; P =.24). The rate of locoregional recurrence (occurring before or at the same time as distant metastasis) at 10 years did show a statistically significant difference (12% of the mastectomy and 20% of the BCT patients; P =. 01).Conclusions: BCT and mastectomy demonstrate similar survival rates in a trial in which the great majority of the patients had stage II breast cancer. [ABSTRACT FROM AUTHOR]

Introduction. The EORTC 22922/10925 trial investigated the potential survival benefit and toxicity of elective irradiation of the internal mammary and medial supraclavicular (IM-MS) nodes Accrual completed in January 2004 and first results are expected in 2012. We present the toxicity reported until year 3 after treatment. Patients and methods. At each visit, toxicity was reported but severity was not graded routinely. Toxicity rates and performance status (PS) changes at three years were compared by x2 tests and logistic regression models in all the 3 866 of 4 004 patients eligible to the trial who received the allocated treatment. Results. Only lung (fibrosis; dyspnoea; pneumonitis; any lung toxicities) (4.3% vs. 1.3%; p < 0.0001) but not cardiac toxicity (0.3% vs. 0.4%; p = 0.55) significantly increased with IM-MS treatment. No significant worsening of the PS was observed (p = 0.79), suggesting that treatment-related toxicity does not impair patient's daily activities. Conclusions. IM-MS irradiation seems well tolerated and does not significantly impair WHO PS at three years. A follow-up period of at least 10 years is needed to determine whether cardiac toxicity is increased after radiotherapy. [ABSTRACT FROM AUTHOR]

To study whether the effects of prognostic factors associated with the occurrence of distant metastases (DM) at primary diagnosis change after the incidence of loco-regional recurrences (LRR) among women treated for invasive stage I or II breast cancer. The study population consisted of 3,601 women, enrolled in EORTC trials 10801, 10854, or 10902 treated for early-stage breast cancer. Data were analysed in a multivariate, multistate model by using multivariate Cox regression models, including a state-dependent covariate. The presence of a LRR in itself is a significant prognostic risk factor (HR: 3.64; 95%-CI: 2.02–6.5) for the occurrence of DM. Main prognostic risk factors for a DM are young age at diagnosis (≤40: HR: 1.79; 95%-CI: 1.28–2.51), larger tumour size (HR: 1.58; 95%-CI: 1.35–1.84) and node positivity (HR: 2.00; 95%-CI: 1.74–2.30). Adjuvant chemotherapy is protective for a DM (HR: 0.66; 95%-CI: 0.55–0.80). After the occurrence of a LRR the latter protective effect has disappeared ( P = 0.009). The presence of LRR in itself is a significant risk factor for DM. For patients who are at risk of developing LRR, effective local control should be the main target of therapy. [ABSTRACT FROM AUTHOR]

In this study, the formation of cisplatin-DNA adducts after concurrent cisplatin-radiation and the relationship between adduct-formation in primary tumor tissue and normal tissue were investigated. Three intravenous cisplatin-regimens, given concurrently with radiation, were studied: daily low-dose (6 mg/m2) cisplatin, weekly 40 mg/m2, three-weekly 100 mg/m2. A 32P-postlabeling technique was used to quantify adducts in normal tissue [white blood cells (WBC) and buccal cells] and tumor. Normal tissue samples for adduct determination were obtained from 63 patients and tumor biopsies from 23 of these patients. Linear relationships and high correlations were observed between the levels of two guanosine- and adenosine–guanosine-adducts in normal and tumor tissue. Adduct levels in tumors were two to five times higher than those in WBC ( P < 0.001). No significant correlations were found between adduct levels in normal tissues and primary tumor biopsies, nor between WBC and buccal cells. In concurrent chemoradiotherapy schedules, cisplatin adduct levels in tumors were significantly higher than in normal tissues (WBC). No evidence of a correlation was found between adduct levels in normal tissues and primary tumor biopsies. This lack of correlation may, to some extent, explain the inconsistencies in the literature regarding whether or not cisplatin-DNA adducts can be used as a predictive test in anticancer platinum therapy. [ABSTRACT FROM AUTHOR]

We hypothesised that gastric cancer outcome could be improved with more effective and intensified postoperative chemoradiotherapy. This phase I/II study was performed to determine the maximal tolerated dose (MTD) and toxicity profile of postoperative radiotherapy with concurrent daily cisplatin and capecitabine. Patients were treated with capecitabine 1000 mg m(-2) twice a day (b.i.d.) for 2 weeks. Subsequently, patients received capecitabine (250-650 mg m(-2) orally b.i.d., 5 days week(-1)) and cisplatin (3-6 mg m(-2) i.v., 5 days week(-1)) according to an alternating dose-escalation schedule. Radiotherapy was given to a total dose of 45 Gy in 25 fractions. Thirty-one patients completed treatment. During chemoradiotherapy, eight patients developed nine items of grade III and one episode of grade IV (mainly haematological) toxicity. The MTD was determined to be cisplatin 5 mg m(-2) i.v. and capecitabine 650 mg m(-2) b.i.d. orally. This phase I/II study demonstrated that chemoradiotherapy with daily cisplatin and capecitabine is feasible in postoperative gastric cancer at the defined dose level and is currently being tested in a phase III multicenter study. [ABSTRACT FROM AUTHOR]

Models estimating growth and yield of forest stands provide important tools for forest management. Pure stands have been modeled extensively and successfully for decades; however, relatively few models for mixed-species stands have been developed. A spatially explicit, mechanistic model (COMMIX) is presented that simulates growth of mixed-species forest stands, and takes account of the effects of management on stand dynamics.Previously, it was shown that COMMIX satisfactorily reproduced the development of monospecific stands. In the present study, the model was used to simulate growth and yield in mixed stands differing in the proportions of species present. The concept of a “replacement series” was used to compare productivities of the mixed stands. The model was also used to analyze effects of thinning regimes and stand composition on productivity. Model simulations indicate that productivity of a mixed stand will generally be intermediate between the productivities of monospecific stands of the contributing species. However, stand composition, and especially thinning regime, will strongly affect stand productivity. The simulations are discussed with reference to the effects of resource partitioning, canopy stratification, complementarity, spatial pattern, crown dynamics, and phenology on the growth and yield of mixed stands. The study highlights the value of using mechanistic approaches to predict mixed stand development in relation to management regime. [ABSTRACT FROM PUBLISHER]

Examines the correlation between dermal fibroblast differentiation characteristics in vitro and breast fibrosis in radiation-treated patients. Risk of subcutaneous fibrosis following radiotherapy; Clinical predictors of fibrosis; Occurrence of higher extracellular collagen deposition.

The article discusses a research on the possible clinical impact of predictive assays in their capacity to tailor the treatment to individual cancer patients. The mechanism of action and side-effects of cisplatin combined with radiotherapy in lung cancer patients are discussed. Observations that led to the development of accelerated fractionation, schedules aimed at reducing the overall treatment time of radiotherapy for head, neck and cervical cancer patients, were detailed in a clinical trial.

Purpose: To validate whether the number of aberrations could be used as a measure of the radiosensitivity of human tumour cells. If so, this would potentially provide a more rapid method than the colony assay to predict radiocurability in human tumour biopsy material. Materials and methods: A panel of 13 human tumour cell lines was investigated, covering a wide range of radiosensitivities. Fluorescence in situ hybridization (FISH) employing whole chromosome probes was used to detect aberrations. Results: A dose-dependent increase in radiation-induced chromosome aberrations was observed in all cell lines. A good correlation (r=0.90) was found between cell survival and total chromosome aberrations in 12 of the 13 cell lines (92%), with one exception. A poorer correlation was observed between cell survival and stable- (r=0.85) and unstable-type aberrations (r=0.81). Survival-aberration correlations for individual radiation doses were worse, although statistically significant. The exceptional cell line showed significantly more aberrations for a given level of cell kill than expected based on data for the other lines. Conclusion: This study indicates that radiation-induced chromosome aberrations can be used as a potential predictor of intrinsic radiosensitivity for the majority of human tumours when more than one dose level is tested. This could aid the design of radiotherapy schedules for each individual patient, or in the decision of whether to use an alternative therapy. [ABSTRACT FROM AUTHOR]

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In mechanistic growth models, the description of assimilate allocation or dry matter partitioning plays a key role. Although theoretical concepts of allocation exist, they include many parameters that cannot be quantified. Therefore, many growth models use descriptive keys that represent the proportions of dry matter or carbohydrates assigned to each plant component. I have developed a model to describe the dynamic partitioning of dry matter in individual trees, and used it to investigate the effects of growth conditions on the partitioning pattern in Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) and beech (Fagus sylvatica L.). The model estimates the fractions of total available dry matter that should go to certain plant parts, based on the concept of structural balances. Both mechanistic and allometric relationships between tree components are used to model conditions for the dynamic distribution of dry matter. The model was to used to estimate the effects of dominance position, site conditions, and thinning on growth partitioning. [ABSTRACT FROM PUBLISHER]

Purpose: To test whether the intrinsic radiosensitivity of skin fibroblasts from breast cancer patients correlates with the degree of breast fibrosis after breast conserving therapy. Methods: In a systematic study design, 79 patients were selected from an earlier study group of 385 patients based on observed fibrosis and seven identified clinical risk factors for fibrosis development. In vitro radiosensitivity of patients' dermal fibroblasts was determined by clonogenic assay of early passage cultures. Survival was determined after irradiation at 0, 2 and 4 Gy, given in two fractions of 2 Gy with a 6 h interval. Results: There was a significant inter-patient variation for SF2 values (coefficient of variation 40%). The ratio of SF2 values for fibroblasts from patients with breast fibrosis versus those without was 0.80 (95% CI: 0.60-1.07). This was a statistically non-significant trend ( p 0.13). The same ratio for a derived value for SF2 ((SF2 SF4)/2) was 0.88 ( p 0.19). Conclusions: A significant variation in intrinsic radiosensitivity of breast cancer patients' dermal fibroblasts was observed. However, the degree of radiosensitivity did not show a significant correlation with fibrosis development. This indicates that the use of fibroblast radiosensitivity will have a limited usefulness for predicting fibrosis following breast irradiation. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of cisplatin in mice with s.c. RIF 1 tumours was studied after intratumoural (i.t.) administration of drug in solution and in different slow-release devices. The data were compared with those obtained after i.p. administration of cisplatin. The slow-release devices under test were manufactured from either starch (ST) or polymeric hydrogels with different water uptakes (named T1, T2 and T3). In vitro release from these devices was approximately 100% in 2 h for starch rods, 100% in 24 h for T3 hydrogels, 45% in 4 days for T2 hydrogels and less than 10% in 4 days for T1 hydrogels. In vivo release rates agreed well with the in vitro data for T1 and T2 rods and were slightly slower in vivo for the T3 rods. The ST rods released the drug 6 times slower in vivo than in vitro. Plasma concentrations after i.t. administration were lower than those measured after i.p. administration. Systemic exposure to both total and free platinum was reduced to 70% for i.t. as compared with i.p. administration. Tumour concentrations were 4 times higher after i.t. than after i.p. administration. Tumour and peak plasma levels of platinum increased with increasing release rates. With the faster-releasing formulations (ST and T3), tumour platinum concentrations were 100 times higher than after i.p. administration. With the slower releasing formulations (T1 and T2), total tumour platinum concentrations were 2 and 9 times higher, respectively, than after i.t. administration of cisplatin in solution. Platinum distribution within the tumour was homogeneous after i.p. administration. After i.t. administration of cisplatin in solution, platinum concentrations in the centre of the tumour were approximately 4 times higher than in peripheral tumour tissue. Implantation of cisplatin in T2 and T3 hydrogel rods resulted in large concentrations of platinum in the centre of the tumour (the site of implant), which decreased steeply towards the tumour periphery. In summary, i.t. administration of cisplatin solution produced better results than did systemic (i.p.) administration in terms of tumour versus plasma drug-concentration ratios. Administration of drug in slow-release rods proved even more advantageous, although this was offset by inhomogeneous drug distributions within the tumour. [ABSTRACT FROM AUTHOR]

In this study we investigated the effect of the incorporation of cisplatin in slow-release systems on tumour response and animal toxicity after intratumoural (i.t.) administration. Solid slow-release rods with incorporated cisplatin were prepared either from starch or from three different polyether-hydrogel formulations. In vitro release rates from these rods were widely different. With the starch system, approximately 100% release was obtained in 2 h. For the hydrogel formulations, release was approximately 100% in 1 day for a formulation with 40% water uptake (T3), 45% within 4 days for a formulation with 14% water uptake (T2) and 8% within 4 days for a formulation with 4% water uptake (T1). The slow-release rods containing graded amounts of cisplatin were implanted i.t. in s.c. RIF1 murine tumours. The i.t. administration of cisplatin in starch rods did not reduce animal toxicity or increase tumour response relative to i.t. injections of cisplatin in solution. For the hydrogel rods, the tumour response and animal toxicity for a given dose of cisplatin decreased with decreasing release rate. Higher doses of cisplatin could therefore be delivered with the slower-releasing hydrogel formulations. The slowest-release hydrogel rods (T1) had very little effect on either tumour (growth delay) or host (animal weight loss), even at cisplatin doses 8 times that tolerated as an i.p. injection. The fast (T3)- and intermediate (T2)-release hydrogel rods resulted in dose dependent tumour growth delays that were longer than those obtained with i.p. or i.t. administration of cisplatin. The highest response, a tumour growth delay of 55 days, was obtained with the intermediate-release hydrogel rods (T2) at a cisplatin dose of 40 mg/kg. Analysis of tumour growth delay for a given level of toxicity indicated that the intermediate-release formulation (T2) was slightly better than the fast-release formulation (T3) and confirmed the therapeutic advantage of i.t. implants over systemic therapy. [ABSTRACT FROM AUTHOR]