Rinaa S. Punglia

Regulation of Vascular Endothelial Growth Factor Expression by Insulin-Like Growth Factor I

Insulin-like growth factor I (IGF-I) and vascular endothelial growth factor (VEGF) levels are correlated with retinal ischemia-associated intraocular neovascu-larization in humans. Since VEGF is required for iris and retinal neovascularization in animal models of retinal ischemia, we tested whether IGF-I could act as an indirect angiogenic factor by increasing VEGF gene expression. IGF-I increased retinal pigment epithelial (RPE) cell VEGF mRNA in a concentration-dependent manner with an EC50 of 7 nmol/l (53.6 ng/ml). RPE and bovine smooth muscle cells exposed to 50 nmol/1 (383 ng/ml) IGF-I achieved peak VEGF mRNA expression within 2 h. IGF-I-treated RPE cells increased VEGF protein levels in conditioned media and stimulated capillary endothelial cell proliferation. Blockade of the IGF-I receptor with a neutralizing antibody abrogated the VEGF increases in RPE cells. Further, hypoxia-mediated and IGF-I-mediated increases in VEGF mRNA and protein levels were additive in RPE cells, and the hypoxia-induced VEGF increases were independent of endogenous IGF-I. VEGF promoter activity was enhanced by IGF-I in RPE cells, but VEGF transcript half-life was unaltered. In summary, the supplementation of RPE and smooth muscle cell cultures with IGF-I at 5-100 nmol/1 increased VEGF mRNA and secreted protein levels. The VEGF increases in RPE cells occurred primarily through enhanced transcription of the VEGF gene and via the IGF-I receptor. Elevated IGF-I levels may promote neovascularization through increased retinal VEGF gene expression.

Adoption of intensity-modulated radiation therapy for breast cancer in the United States

BACKGROUND Although intensity modulation of the radiation beam has been shown to lower toxic effects for patients receiving whole-breast irradiation, relatively simple techniques may suffice. It is thus controversial whether such treatment justifies billing for intensity-modulated radiation therapy (IMRT). METHODS We used the claims data to determine billing for IMRT from Surveillance, Epidemiology, and End Results-Medicare records from 2001 to 2005 for 26,163 women aged 66 years or older with nonmetastatic breast cancer treated with surgery and radiotherapy. The impact of individual covariates (demographic, health services, tumor, and treatment factors) on cost of treatment was assessed using the Wilcoxon two-sample test. Two-sided multivariable logistic regression was used to identify predictors for IMRT use. Cost of radiation was calculated in 2005 dollars. All statistical tests were two-sided. RESULTS The number of patients with IMRT billing claims increased from 0.9% (49 of 5196) of patients diagnosed in 2001 to 11.2% (564 of 5020) in 2005. In multivariable analysis, IMRT billing was more likely for patients with left-sided tumors (odds ratio [OR] = 1.30, 95% confidence interval [CI] = 1.16 to 1.45), for those residing in a health service area with high radiation oncologist density (OR = 2.32, 95% CI = 1.47 to 3.68), for those treated at freestanding radiation centers (OR = 1.36, 95% CI = 1.20 to 1.53), or for those residing in regions where the Medicare intermediary allowed breast IMRT (OR = 10.87, 95% CI = 9.26 to 12.76, all P < .001). The mean cost of radiation was

Optimizing Adjuvant Endocrine Therapy in Postmenopausal Women With Early-Stage Breast Cancer: A Decision Analysis

7179 without IMRT and

Effect of Very Small Tumor Size on Cancer-Specific Mortality in Node-Positive Breast Cancer

15 230 with IMRT. IMRT adoption contributed to an increase in the mean cost of breast radiation from

Impact of interval from breast conserving surgery to radiotherapy on local recurrence in older women with breast cancer: retrospective cohort analysis.

6334 in 2001 to

Cost-Effectiveness Analysis of Computerized Tomography in the Routine Follow-Up of Patients After Primary Treatment for Hodgkin’s Disease

8473 in 2005. CONCLUSIONS IMRT billing increased 10-fold from 2001 through 2005, contributing to a 33% increase in the cost of breast radiation. These findings suggest that reimbursement policy and practice setting strongly influenced adoption of IMRT billing for breast cancer.

PARTIAL-BREAST IRRADIATION VERSUS WHOLE-BREAST IRRADIATION FOR EARLY-STAGE BREAST CANCER: A COST-EFFECTIVENESS ANALYSIS

PURPOSE The optimal adjuvant endocrine strategy for postmenopausal breast cancer is unknown. Options include the antiestrogen tamoxifen, estrogen deprivation with aromatase inhibitors, and sequential therapy with tamoxifen and then an aromatase inhibitor. METHODS We developed Markov models to simulate 10-year disease-free survival among postmenopausal women with hormone receptor-positive breast cancer. The treatment strategies analyzed were 5 years of tamoxifen alone, 5 years of an aromatase inhibitor alone, and sequential treatment consisting of tamoxifen with cross over to an aromatase inhibitor at 2.5 or 5 years. Risk estimates were derived from reported randomized clinical trials. RESULTS Sequential therapy with tamoxifen followed by cross over to an aromatase inhibitor at 2.5 years yielded a modest improvement in disease-free survival compared with planned aromatase inhibitor monotherapy. At 10 years, the cross-over strategy yielded absolute disease-free survival rates of 83.7% and 67.6% for node-negative and node-positive patients, respectively, compared with 82.6% and 65.5%, respectively, for aromatase inhibitor monotherapy, which is a 6% relative risk reduction. Sequential therapy improved disease-free survival estimates by year 6 after treatment initiation. Later cross over from tamoxifen to an aromatase inhibitor at 5 years did not further improve 10-year disease-free survival estimates. Sensitivity analyses suggest that sequential treatment strategies optimized 10-year disease-free and distant disease-free survival independent of the degree of the beneficial carryover effect after aromatase inhibitor therapy or the ratio of local to distant tumor recurrence. CONCLUSION Modeling estimates suggest that sequential adjuvant therapy with tamoxifen followed by an aromatase inhibitor after 2.5 years yields improved outcomes compared with either drug alone or cross-over treatment after 5 years of tamoxifen.

Cost-effectiveness analysis of stereotactic body radiotherapy and radiofrequency ablation for medically inoperable, early-stage non-small cell lung cancer.

PURPOSE Traditionally, larger tumor size and increasing lymph node (LN) involvement have been considered independent predictors of increased breast cancer-specific mortality (BCSM). We sought to characterize the interaction between tumor size and LN involvement in determination of BCSM. In particular, we evaluated whether very small tumor size may predict for increased BCSM relative to larger tumors in patients with extensive LN involvement. PATIENTS AND METHODS Using Surveillance, Epidemiology and End Results registry data, we identified 50,949 female patients diagnosed between 1990 and 2002 with nonmetastatic T1/T2 invasive breast cancer treated with surgery and axillary LN dissection. Primary study variables were tumor size, degree of LN involvement, and their corresponding interaction term. Kaplan-Meier methods, adjusted Cox proportional hazards models with interaction terms, and a linear trend test across nodal categories were performed. RESULTS Median follow-up was 99 months. In multivariable analysis, there was significant interaction between tumor size and LN involvement (P < .001). Using T1aN0 as reference, T1aN2+ conferred significantly higher BCSM compared with T1bN2+ (hazard ratio [HR], 20.66 v 12.53; P = .02). A similar pattern was seen among estrogen receptor (ER) -negative patients with T1aN2+ compared with T1bN2+ (HR, 24.16 v 12.67; P = .03), but not ER-positive patients (P = .52). The effect of very small tumor size on BCSM was intermediate among N1 cancers, between that of N0 and N2+ cancers. CONCLUSION Very small tumors with four positive LNs may predict for higher BCSM compared with larger tumors. In extensive node-positive disease, very small tumor size may be a surrogate for biologically aggressive disease. These results should be validated in future database studies.

Accelerated Partial Breast Irradiation Using Brachytherapy for Breast Cancer: Patterns in Utilization and Guideline Concordance

Objectives To determine if the length of interval between breast conserving surgery and start of radiotherapy affects local recurrence and to identify factors that might be associated with delay in older women with breast cancer. Design Retrospective cohort analysis with Cox proportional hazards models to study the association between time to radiotherapy and local recurrence, and propensity score and instrumental variable analyses to confirm findings. Logistic regression investigated factors associated with later start of radiotherapy. Setting Linked database (Surveillance, Epidemiology, and End Results Program-Medicare) in the United States Participants 18 050 women aged over 65 with stage 0-II breast cancer diagnosed in 1991-2002 who received breast conserving surgery and radiotherapy but not chemotherapy. Main outcome measure Local recurrence. Results Median time from surgery to start of radiotherapy was 34 days, with 29.9% (n=5389) of women starting radiotherapy after six weeks. Just over 4% (n=734) of the cohort experienced a local recurrence. After adjustment for clinical and sociodemographic factors, intervals over six weeks were associated with increased likelihood of local recurrence (hazard ratio 1.19, 95% confidence interval 1.01 to 1.39, P=0.033). When the interval was modelled continuously (assessing accumulation of risk by day), the effect was statistically stronger (hazard ratio 1.005 per day, 1.002 to 1.008, P=0.004). Propensity score and instrumental variable analysis confirmed these findings. Instrumental variable analysis showed that intervals over six weeks were associated with a 0.96% increase in recurrence at five years (P=0.026). In multivariable analysis, starting radiotherapy after six weeks was significantly associated with positive nodes, comorbidity, history of low income, Hispanic ethnicity, non-white race, later year of diagnosis, and residence outside the southern states of the US. Conclusions There is a continuous relation between the interval from breast conserving surgery to radiotherapy and local recurrence in older women with breast cancer, suggesting that starting radiotherapy as soon as possible could minimise the risk of local recurrence. There are considerable disparities in time to starting radiotherapy after breast conserving surgery. Regions of the US known to have increased rates of breast conserving surgery had longer intervals before radiotherapy, suggesting limitations in capacity. Given the known negative impact of local recurrence on survival, mechanisms to ameliorate disparities and policies regarding waiting times for treatment might be warranted.

Cost-effectiveness of CT and PET-CT for determining the need for adjuvant neck dissection in locally advanced head and neck cancer

PURPOSE To estimate the clinical benefits and cost effectiveness of computed tomography (CT) in the follow-up of patients with complete response (CR) after treatment for Hodgkins disease (HD). PATIENTS AND METHODS We developed a decision-analytic model to evaluate follow-up strategies for two hypothetical cohorts of 25-year-old patients with stage I-II or stage III-IV HD, treated with doxorubicin, bleomycin, vinblastine, and dacarbazine-based chemotherapy with or without radiation therapy, respectively. We compared three strategies for observing asymptomatic patients after CR: routine annual CT for 10 years, annual CT for 5 years, or follow-up with non-CT modalities only. We used Markov models to calculate life expectancy, quality-adjusted life expectancy, and lifetime costs. Baseline probabilities, transition probabilities, and utilities were derived from published studies. Cost data were derived from the Medicare fee schedule and medical literature. We performed sensitivity analyses by varying baseline estimates. RESULTS Annual CT follow-up is associated with minimal survival benefit. With adjustments for quality of life, we found a decrement in quality-adjusted life expectancy for early-stage patients followed with CT compared with non-CT modalities. Sensitivity analyses showed annual CT for 5 years becomes more effective than non-CT follow-up if the specificity of CT is 80% or more or if the disutility associated with a false-positive CT result is less than 0.01 quality-adjusted life years (QALYs). For advanced-stage patients, annual CT for 5 years is associated with a very small quality-adjusted survival gain over non-CT follow-up with an incremental cost-effectiveness ratio of 9,042,300 dollars/QALY. CONCLUSION Our analysis suggests that routine CT should not be used in the surveillance of asymptomatic patients in CR after treatment for HD.