Summary Background Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen ...and whether tamoxifen should be given concurrently or after chemotherapy. Methods We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov , number NCT00929591. Findings Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8·94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio HR 0·76, 95% CI 0·64–0·91; p=0·002) but only marginally for the secondary endpoint of overall survival (HR 0·83, 0·68–1·01; p=0·057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0·84, 0·70–1·01; p=0·061) or overall survival (HR 0·90, 0·73–1·10; p=0·30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Interpretation Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. Funding National Cancer Institute (US National Institutes of Health).
High-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose ...could be safely escalated.
A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine.
At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions.
Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.
Elevated histone deacetylase (HDAC) isoenzyme levels have been described in patients with carcinomas and leukemias. HDAC inhibitors (HDACi) have shown promise in the treatment of carcinomas and are ...currently under intense research. To make better use of HDACi in treating chronic lymphocytic leukemia (CLL), HDAC isoenzyme levels were studied.
Quantitative reverse transcriptase polymerase chain reaction for HDAC isoenzyme was measured in 32 patients with CLL and compared with 17 normal volunteer controls. ZAP-70, CD38 and CD44 were also assayed and correlated to HDAC isoenzyme levels.
The results showed: (1) HDAC isoenzyme levels in CLL were significantly increased in class I including HDAC1 and HDAC3, in class II including HADC6, HDAC7, HDAC9 and HDAC10, and in class III including SIRT1 and SIRT6; (2) higher expression of HDAC isoenzyme levels was found in ZAP-70+ compared to ZAP-70- patients, and CD44 expression levels were correlated with HDAC isoenzyme expression levels in the majority of HDAC classes.
These results suggest: (1) in CLL, elevated HDAC isoenzyme activity is not restricted to one class, and therefore, HDACi therapy may need to be directed to more than one specific class of HDAC; (2) higher HDAC expression activity may indicate a poor prognosis and more advanced disease stage (through indirect evidence), since higher values were found in patients with ZAP-70+ and higher CD44 expression levels.
Purpose: To determine the relation between the incidence of radiation pneumonitis and the three-dimensional dose distribution in the lung.
Methods and Materials: In five institutions, the incidence ...of radiation pneumonitis was evaluated in 540 patients. The patients were divided into two groups: a Lung group, consisting of 399 patients with lung cancer and 1 esophagus cancer patient and a Lymph./Breast group with 78 patients treated for malignant lymphoma, 59 for breast cancer, and 3 for other tumor types. The dose per fraction varied between 1.0 and 2.7 Gy and the prescribed total dose between 20 and 92 Gy. Three-dimensional dose calculations were performed with tissue density inhomogeneity correction. The physical dose distribution was converted into the biologically equivalent dose distribution given in fractions of 2 Gy, the normalized total dose (NTD) distribution, by using the linear quadratic model with an α/β ratio of 2.5 and 3.0 Gy. Dose–volume histograms (DVHs) were calculated considering both lungs as one organ and from these DVHs the mean (biological) lung dose, NTD
mean, was obtained. Radiation pneumonitis was scored as a complication when the pneumonitis grade was grade 2 (steroids needed for medical treatment) or higher. For statistical analysis the conventional normal tissue complication probability (NTCP) model of Lyman (with
n = 1) was applied along with an institutional-dependent offset parameter to account for systematic differences in scoring patients at different institutions.
Results: The mean lung dose, NTD
mean, ranged from 0 to 34 Gy and 73 of the 540 patients experienced pneumonitis, grade 2 or higher. In all centers, an increasing pneumonitis rate was observed with increasing NTD
mean. The data were fitted to the Lyman model with NTD
50 = 31.8 Gy and
m = 0.43, assuming that for all patients the same parameter values could be used. However, in the low dose range at an NTD
mean between 4 and 16 Gy, the observed pneumonitis incidence in the Lung group (10%) was significantly (
p = 0.02) higher than in the Lymph./Breast group (1.4%). Moreover, between the Lung groups of different institutions, also significant (
p = 0.04) differences were present: for centers 2, 3, and 4, the pneumonitis incidence was about 13%, whereas for center 5 only 3%. Explicitly accounting for these differences by adding center-dependent offset values for the Lung group, improved the data fit significantly (
p < 10
−5) with NTD
50 = 30.5 ± 1.4 Gy and
m = 0.30 ± 0.02 (± 1 SE) for all patients, and an offset of 0–11% for the Lung group, depending on the center.
Conclusions: The mean lung dose, NTD
mean, is relatively easy to calculate, and is a useful predictor of the risk of radiation pneumonitis. The observed dose–effect relation between the NTD
mean and the incidence of radiation pneumonitis, based on a large clinical data set, might be of value in dose-escalating studies for lung cancer. The validity of the obtained dose–effect relation will have to be tested in future studies, regarding the influence of confounding factors and dose distributions different from the ones in this study.
The costs of conducting clinical research Emanuel, Ezekiel J; Schnipper, Lowell E; Kamin, Deborah Y ...
Journal of clinical oncology,
11/2003, Letnik:
21, Številka:
22
Journal Article
Recenzirano
Physicians frequently receive payment for enrolling subjects onto clinical trials. Some view these payments as conflicts of interest. Others contend that these payments are necessary reimbursements ...for conducting clinical research. We evaluated the clinical and nonclinical hours and costs associated with conducting a mock phase III clinical research trial.
We collected data from representatives of 21 clinical sites, on the numbers of hours associated with 13 activities necessary to the conduct of clinical research. The hours were based on enrolling 20 patients in a 12-month randomized placebo-controlled trial of a new chemotherapeutic agent. The outcome measures were disease progression and quality-of-life reports. These costs were evaluated for both government and pharmaceutical industry-sponsored trials.
On average, 4,012 hours (range, 1,512 to 13,319 hours) were required for a government-sponsored trial, and 3,998 hours (range: 1735 to 15,699) were required for a pharmaceutical industry-sponsored trial involving 20 subjects with 17 office visits, or approximately 200 hours per subject. Thirty-two percent of the hours were devoted to nonclinical activities, such as institutional review board submission and completion of clinical reporting forms. On average, excluding overhead expenses, it cost slightly more than 6,094 dollars (range, 2,098 dollars to 19,285 dollars) per enrolled subject for an industry-sponsored trial, including 1,999 dollars devoted to nonclinical costs.
Based on the results of our mock trial, the time required for nontreatment trial activities is considerable, and the associated costs are substantial.
Purpose: To analyze the failure patterns for patients with high-grade astrocytomas treated with high-dose conformal radiotherapy (CRT) using a quantitative technique to calculate the dose received by ...the CT- or MR-defined recurrence volume and to assess whether the final target volume margin used in the present dose escalation study requires redefinition before further escalation.
Methods and Materials: Between 4/89 and 10/95, 71 patients with high-grade supratentorial astrocytomas were entered in a phase I/II dose escalation study using 3-D treatment planning and conformal radiotherapy. All patients were treated to either 70 or 80 Gy in conventional daily fractions of 1.8–2.0 Gy. The clinical and planning target volumes (CTV, PTV) consisted of successively smaller volumes with the final PTV defined as the enhancing lesion plus 0.5 cm margin. As of 10/95, 47 patients have CT or MR evidence of disease recurrence/progression. Of the 47 patients, 36 scans obtained at the time of recurrence were entered into the 3-D radiation therapy treatment planning system. After definition of the recurrent tumor volumes, the recurrence scan dataset was registered with the pretreatment CT dataset so that the actual dose received by the recurrent tumor volumes during treatment could be accurately calculated and then analyzed dosimetrically using dose–volume histograms. Recurrences were divided into several categories: 1) “central,” in which 95% or more of the recurrent tumor volume (
V
recur) was within
D
95, the region treated to high dose (95% of the prescription dose); 2) “in-field,” in which 80% or more of
V
recur was within the
D
95 isodose surface; 3) “marginal,” when between 20 and 80% of
V
recur was inside the
D
95 surface; 4) “outside,” in which less than 20% of
V
recur was inside the
D
95 surface.
Results: In 29 of 36 patients, a solitary lesion was seen on recurrence scans. Of the 29 solitary recurrences, 26 were central, 3 were marginal, and none were outside. Multiple recurrent lesions were seen in seven patients: three patients had multiple central and/or in-field lesions only, three patients had central and/or in-field lesions with additional small marginal or outside lesions, and one patent had 6 outside and one central lesion. Since total recurrence volume was used in the final analysis, 6 of the 7 patients with multiple recurrent lesions were classified into central/in-field category.
Conclusion: Analysis of the 36 evaluable patients has shown that 32 of 36 patients (89%) failed with central or in-field recurrences, 3/36 (8%) had a significant marginal component to the recurrence, whereas only 1/36 (3%) could be clearly labeled as failing mainly outside the high-dose region. Seven patients had multiple recurrences, but only 1 of 7 had large-volume recurrences outside the high-dose region. This study shows that the great majority of patient recurrences that occur after high-dose (70 or 80 Gy) conformal irradiation are centrally located: only 1/36 patients (with 7 recurrent lesions) had more than 50% of the recurrence volume outside the region previously treated to high dose. Further dose escalation to 90 Gy (and beyond) thus seems reasonable, based on the same target volume definition criteria.
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