This pooled analysis evaluated the outcomes of prophylactic cranial irradiation (PCI) in 739 small-cell lung cancer (SCLC patients with stable disease (SD) or better following chemotherapy ± thoracic ...radiation therapy (TRT) to examine the potential advantage of PCI in a wider spectrum of patients than generally participate in PCI trials.
Three hundred eighteen patients with extensive SCLC (ESCLC) and 421 patients with limited SCLC (LSCLC) participated in four phase II or III trials. Four hundred fifty-nine patients received PCI (30 Gy/15 or 25 Gy/10) and 280 did not. Survival and adverse events (AEs) were compared.
PCI patients survived significantly longer than non-PCI patients {hazard ratio HR = 0.61 95% confidence interval (CI): 0.52–0.72; P < 0.0001}. The 1- and 3-year survival rates were 56% and 18% for PCI patients versus 32% and 5% for non-PCI patients. PCI was still significant after adjusting for age, performance status, gender, stage, complete response, and number of metastatic sites (HR = 0.82, P = 0.04). PCI patients had significantly more grade 3+ AEs (64%) compared with non-PCI patients (50%) (P = 0.0004). AEs associated with PCI included alopecia and lethargy. Dose fractionation could be compared only for LSCLC patients and 25 Gy/10 was associated with significantly better survival compared with 30 Gy/15 (HR = 0.67, P = 0.018).
PCI was associated with a significant survival benefit for both ESCLC and LSCLC patients who had SD or a better response to chemotherapy ± TRT. Dose fractionation appears important. PCI was associated with an increase in overall and specific grade 3+ AE rates.
Wingless-type protein (Wnt)/β-catenin pathway alterations in non-small cell lung cancer (NSCLC) are associated with poor prognosis and resistance. In 598 stage III-IV NSCLC patients receiving ...platinum-based chemotherapy at the MD Anderson Cancer Center (MDACC), we correlated survival with 441 host single-nucleotide polymorphisms (SNPs) in 50 Wnt pathway genes. We then assessed the most significant SNPs in 240 Mayo Clinic patients receiving platinum-based chemotherapy for advanced NSCLC, 127 MDACC patients receiving platinum-based adjuvant chemotherapy and 340 early stage MDACC patients undergoing surgery alone (cohorts 2-4). In multivariate analysis, survival correlates with SNPs for AXIN2 (rs11868547 and rs4541111, of which rs11868547 was assessed in cohorts 2-4), Wnt-5B (rs12819505), CXXC4 (rs4413407) and WIF-1 (rs10878232). Median survival was 19.7, 15.6 and 10.7 months for patients with 1, 2 and 3-5 unfavorable genotypes, respectively (P=3.8 × 10(-9)). Survival tree analysis classified patients into two groups (median survival time 11.3 vs 17.3 months, P=4.7 × 10(-8)). None of the SNPs achieved significance in cohorts 2-4; however, there was a trend in the same direction as cohort 1 for 3 of the SNPs. Using online databases, we found rs10878232 displayed expression quantitative trait loci correlation with the expression of LEMD3, a neighboring gene previously associated with NSCLC survival. In conclusion, results from cohort 1 provide further evidence for an important role for Wnt in NSCLC. Investigation of Wnt inhibitors in advanced NSCLC would be reasonable. Lack of an SNP association with outcome in cohorts 2-4 could be due to low statistical power, impact of patient heterogeneity or false-positive observations in cohort 1.
The use of stereotactic radiosurgery to treat cerebral cavernous malformations (CMs) is controversial. To evaluate the efficacy and safety of CM radiosurgery, the authors reviewed the experience at ...the Mayo Clinic during the past 10 years.
Seventeen patients underwent radiosurgery for high-surgical-risk CMs in the following sites: thalamus/basal ganglia (four patients), brainstem (12 patients), and corpus callosum (one patient). All patients had experienced at least two documented hemorrhages before undergoing radiosurgery. Stereotactic magnetic resonance (MR) imaging was used for target localization in all cases. The median margin radiation dose was 18 Gy and the median maximum dose was 32 Gy. The median length of follow-up review following radiosurgery was 51 months. The annual hemorrhage rate during the 51 months preceding radiosurgery was 40.1%, compared with 8.8% in the first 2 years following radiosurgery and 2.9% thereafter. In 10 patients (59%) new neurological deficits developed that were associated with regions of increased signal on long-repetition time MR imaging performed a median of 8 months (range 5-16 months) after radiosurgery. Three patients recovered, giving the group a permanent radiation-related morbidity rate of 41%. Compared with 31 patients harboring arteriovenous malformations (AVMs) of sizes and in locations similar to those of the aforementioned CMs, who underwent radiosurgery during the same time period, the patients with CMs were more likely to experience radiation-related complications (any complication, 59% compared with 10%; p < 0.001; permanent complication, 41% compared with 10%; p = 0.02).
It is impossible to conclude that radiosurgery protects patients with CMs against future hemorrhage risk based on the available data, although it appears that some reduction in the bleeding rate occurs after a latency interval of several years. The risk of radiation-related complications after radiosurgery to treat CMs is greater than that found after radiosurgery in AVMs, even when adjusting for lesion size and location and for radiation dose.
To describe the relationship between cigarette smoking and quality of life (QOL) among lung cancer survivors as measured by the lung cancer symptom scale (LCSS).
The LCSS was mailed to eligible ...patients (1,506 patients) between 1999 and 2002. LCSS scores (total and individual QOL components) were compared among different groups of cigarette smokers via univariate independent group testing and multivariate linear models. The modeling process examined group differences adjusted for age, gender, stage, and time of LCSS assessment. LCSS scores were transformed onto a scale of 0 to 100 points in which higher LCSS scores corresponded to a lower QOL. A 10-point difference between groups was defined a priori as being clinically significant.
At the time of lung cancer diagnosis, 18% of the patients were never-smokers, 58% were former smokers, and 24% were current smokers. Among survey respondents completing the LCSS at follow-up assessment (1,028 respondents), the mean age was 65.2 years (SD, 10.8 years) and 45% were women. Thirty percent of baseline current smokers continued to smoke at the time of the follow-up assessment (ie, persistent smokers). The adjusted mean total LCSS scores for never-smokers and persistent smokers were 17.6 (SD, 4.02) and 28.7 (SD, 5.09), respectively (p < 0.0001). Seven of the individual LCSS QOL components (ie, appetite, fatigue, cough, shortness of breath, lung cancer symptoms, illness affecting normal activities, and overall QOL) were clinically and statistically (p < 0.001) different between never-smokers and persistent smokers. No clinically significant differences were noted for pain or hemoptysis. Former smokers had intermediate LCSS scores. No dose-response trends were observed between the number of packs of cigarettes smoked per day or the total number of pack-years smoked and the adjusted scores.
The hypothesized relationship between smoking status and QOL was supported by this correlational study. Our findings suggest that persistent cigarette smoking after a lung cancer diagnosis negatively impacts QOL scores.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Previous studies have attempted to investigate the impact of smoking cessation on lung cancer survival but have been limited by small numbers of former smokers and incomplete data.
...Methods: Over a six-year period, 5229 patients with non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) were enrolled in a prospective cohort of whom 2052 were former smokers. Patient's characteristics were obtained from medical records and a baseline interview. Vital status was determined through multiple sources. Cox proportional hazards models were used to estimate the effect of smoking abstinence on post-diagnosis mortality.
Results: For all patients with NSCLC, the median survival among never, former, and current smokers was 1.4 years, 1.3 years, and 1.1 years, respectively (
P < 0.01). Female NSCLC patients had a significantly lower risk of mortality with a longer duration of smoking abstinence (RR per 10 years of smoking abstinence = 0.85; 95% CI: 0.75, 0.97). No effect of smoking abstinence on mortality was observed for women with SCLC or for men with either histologic group.
Conclusions: The identification of smoking history as a prognostic factor in lung cancer survival supports previous research suggesting a direct biologic effect of smoking on survival. However, this effect may vary by sex and type of lung cancer.
Model-baseddose calculations (MBDCs) are performed using patient computed tomography (CT) data for patients treated with intraoperative (125)I lung brachytherapy at the Mayo Clinic Rochester. Various ...metallic artifact correction and tissue assignment schemes are considered and their effects on dose distributions are studied. Dose distributions are compared to those calculated under TG-43 assumptions.
Dose distributions for six patients are calculated using phantoms derived from patient CT data and the EGSnrc user-code BrachyDose. (125)I (GE Healthcare/Oncura model 6711) seeds are fully modeled. Four metallic artifact correction schemes are applied to the CT data phantoms: (1) no correction, (2) a filtered back-projection on a modified virtual sinogram, (3) the reassignment of CT numbers above a threshold in the vicinity of the seeds, and (4) a combination of (2) and (3). Tissue assignment is based on voxel CT number and mass density is assigned using a CT number to mass density calibration. Three tissue assignment schemes with varying levels of detail (20, 11, and 5 tissues) are applied to metallic artifact corrected phantoms. Simulations are also performed under TG-43 assumptions, i.e., seeds in homogeneous water with no interseed attenuation.
Significant dose differences (up to 40% for D(90)) are observed between uncorrected and metallic artifact corrected phantoms. For phantoms created with metallic artifact correction schemes (3) and (4), dose volume metrics are generally in good agreement (less than 2% differences for all patients) although there are significant local dose differences. The application of the three tissue assignment schemes results in differences of up to 8% for D(90); these differences vary between patients. Significant dose differences are seen between fully modeled and TG-43 calculations with TG-43 underestimating the dose (up to 36% in D(90)) for larger volumes containing higher proportions of healthy lung tissue.
Metallic artifact correction is necessary for accurate application of MBDCs for lung brachytherapy; simpler threshold replacement methods may be sufficient for early adopters concerned with clinical dose metrics. Rigorous determination of voxel tissue parameters and tissue assignment is required for accurate dose calculations as different tissue assignment schemes can result in significantly different dose distributions. Significant differences are seen between MBDCs and TG-43 dose distributions with TG-43 underestimating dose in volumes containing healthy lung tissue.
To evaluate the efficacy and toxicity of radiosurgery in the treatment of cranial base chordoma and chondrosarcoma.
We reviewed 29 patients with cranial base chordoma (n = 25) or chondrosarcoma (n = ...4) who underwent stereotactic radiosurgery between September 1990 and December 2002. The median patient age was 45 years (range, 10-81 yr). Nineteen patients also had radiation therapy before or in conjunction with radiosurgery (median dose, 50.4 Gy). The median tumor volume was 14.4 cm3 (range, 0.6-65.1 cm3). The median tumor margin dose was 15 Gy (range, 10-20 Gy); the median maximum radiation dose was 30 Gy (range, 20-40 Gy). Median clinical and imaging follow-up periods were 4.8 and 4.5 years, respectively.
Seven chordoma patients (28%) had tumor progression (in-field, n = 3; out-of-field, n = 4), whereas 18 had stable disease or tumor shrinkage. No patient with a chondroid chordoma had tumor enlargement. The actuarial tumor control rates were 89 and 32% at 2 and 5 years, respectively. All 4 patients with chondrosarcoma had tumor control. Clinically, 7 patients (24%) had improvement of pretreatment symptoms, 16 (55%) remained stable, and 6 (21%) worsened. Three patients with tumor progression died. Ten patients (34%) had radiation-related complications. Complications included cranial nerve deficits (n = 6), radiation necrosis (n = 5), and pituitary dysfunction (n = 3). Patients having radiosurgery alone had no toxicity.
Cranial base chordomas and chondrosarcomas remain a formidable management challenge. Radiosurgery as an adjunct to surgical resection provides in-field tumor control for some patients, but radiation-related complications are relatively high, especially when radiosurgery is combined with fractionated radiation therapy.
Abstract Objectives To examine the efficacy of prophylactic cranial irradiation (PCI) in elderly patients with small cell lung cancer (SCLC) (≥ 70 years of age) from a pooled analysis of four ...prospective trials. Materials & Methods One hundred fifty-five patients with SCLC (limited stage, LSCLC, and extensive stage, ESCLC) participated in four phase II or III trials. Ninety-one patients received PCI (30 Gy/15 or 25 Gy/10) and 64 patients did not receive PCI. Survival was compared in a landmark analysis that included only patients who had stable disease or better in response to primary therapy. Results Patients who received PCI had better survival than patients who did not receive PCI (median survival 12.0 months vs. 7.6 months, 3-year overall survival 13.2% vs. 3.1%, HR = 0.53 95% CI 0.36–0.78, p = 0.001). On multivariate analysis of the entire cohort, the only factor that remained significant for survival was stage (ESCLC vs. LSCLC, p = 0.0072). In contrast, the multivariate analysis of patients who had ESCLC revealed that PCI was the sole factor associated with a survival advantage (HR = 0.47 95% CI 0.24–0.93, p = 0.03). Grade 3 or higher adverse events (AEs) were significantly greater in patients who received PCI (71.4% vs. 47.5%, p = 0.0031), with non-neuro and non-heme being the specific AE categories most strongly correlated with PCI delivery. Conclusions PCI was associated with a significant improvement in survival for our entire elderly SCLC patient cohort on univariate analysis. Multivariate analysis suggested that the survival advantage remained significant in patients with ESCLC. PCI was also associated with a modest increase in grade 3 or higher AEs.
The voltage-dependent anion channel (VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. VDAC also interacts with antiapoptotic proteins from ...the Bcl-2 family, and this interaction inhibits release of apoptogenic proteins from the mitochondrion. We present the nuclear magnetic resonance (NMR) solution structure of recombinant human VDAC-1 reconstituted in detergent micelles. It forms a 19-stranded β barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion. In the presence of cholesterol, recombinant VDAC-1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. NMR measurements revealed the binding sites of VDAC-1 for the Bcl-2 protein Bcl-xL, for reduced β-nicotinamide adenine dinucleotide, and for cholesterol. Bcl-xL interacts with the VDAC barrel laterally at strands 17 and 18.
Patients with centrally located early-stage non-small-cell lung cancer (NSCLC) are at a higher risk of toxicity from high-dose ablative radiotherapy. NRG Oncology/RTOG 0813 was a phase I/II study ...designed to determine the maximum tolerated dose (MTD), efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for centrally located NSCLC.
Medically inoperable patients with biopsy-proven, positron emission tomography-staged T1 to 2 (≤ 5 cm) N0M0 centrally located NSCLC were accrued into a dose-escalating, five-fraction SBRT schedule that ranged from 10 to 12 Gy/fraction (fx) delivered over 1.5 to 2 weeks. Dose-limiting toxicity (DLT) was defined as any treatment-related grade 3 or worse predefined toxicity that occurred within the first year. MTD was defined as the SBRT dose at which the probability of DLT was closest to 20% without exceeding it.
One hundred twenty patients were accrued between February 2009 and September 2013. Patients were elderly, there were slightly more females, and the majority had a performance status of 0 to 1. Most cancers were T1 (65%) and squamous cell (45%). Organs closest to planning target volume/most at risk were the main bronchus and large vessels. Median follow-up was 37.9 months. Five patients experienced DLTs; MTD was 12.0 Gy/fx, which had a probability of a DLT of 7.2% (95% CI, 2.8% to 14.5%). Two-year rates for the 71 evaluable patients in the 11.5 and 12.0 Gy/fx cohorts were local control, 89.4% (90% CI, 81.6% to 97.4%) and 87.9% (90% CI, 78.8% to 97.0%); overall survival, 67.9% (95% CI, 50.4% to 80.3%) and 72.7% (95% CI, 54.1% to 84.8%); and progression-free survival, 52.2% (95% CI, 35.3% to 66.6%) and 54.5% (95% CI, 36.3% to 69.6%), respectively.
The MTD for this study was 12.0 Gy/fx; it was associated with 7.2% DLTs and high rates of tumor control. Outcomes in this medically inoperable group of mostly elderly patients with comorbidities were comparable with that of patients with peripheral early-stage tumors.
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