Intensity modulated radiation therapy following lumpectomy in early-stage breast cancer: Patterns of use and cost consequences among Medicare beneficiaries.

PURPOSE: In 2013, the American Society for Radiation Oncology (ASTRO) issued a Choosing Wisely recommendation against the routine use of intensity modulated radiotherapy (IMRT) for whole breast irradiation. We evaluated IMRT use and subsequent impact on Medicare expenditure in the period immediately preceding this recommendation to provide a baseline measure of IMRT use and associated cost consequences. METHODS AND MATERIALS: SEER records for women ≥66 years with first primary diagnosis of Stage I/II breast cancer (2008-2011) were linked with Medicare claims (2007-2012). Eligibility criteria included lumpectomy within 6 months of diagnosis and radiotherapy within 6 months of lumpectomy. We evaluated IMRT versus conventional radiotherapy (cRT) use overall and by SEER registry (12 sites). We used generalized estimating equations logit models to explore adjusted odds ratios (OR) for associations between clinical, sociodemographic, and health services characteristics and IMRT use. Mean costs were calculated from Medicare allowable costs in the year after diagnosis. RESULTS: Among 13,037 women, mean age was 74.4, 50.5% had left-sided breast cancer, and 19.8% received IMRT. IMRT use varied from 0% to 52% across SEER registries. In multivariable analysis, left-sided breast cancer (OR 1.75), living in a big metropolitan area (OR 2.39), living in a census tract with ≤$90,000 median income (OR 1.75), neutral or favorable local coverage determination (OR 3.86, 1.72, respectively), and free-standing treatment facility (OR 3.49) were associated with receipt of IMRT (p<0.001). Mean expenditure in the year after diagnosis was $8,499 greater (p<0.001) among women receiving IMRT versus cRT. CONCLUSION: We found highly variable use of IMRT and higher expenditure in the year after diagnosis among women treated with IMRT (vs. cRT) with early-stage breast cancer and Medicare insurance. Our findings suggest a considerable opportunity to reduce treatment variation and cost of care while improving alignment between practice and clinical guidelines.

Long term follow-up of neoadjuvant chemotherapy for non-small cell lung cancer (NSCLC) investigating early positron emission tomography (PET) scan as a predictor of outcome.

BACKGROUND: Neoadjuvant chemotherapy is effective in improving survival of resectable NSCLC. Based on findings in the adjuvant and metastatic setting, FDG positron emission tomography (PET) scans may offer early prognostic or predictive value after one cycle of induction chemotherapy. METHODS: In this phase II non-randomized trial, patients with AJCC version 6 stage IB to IIIB operable NSCLC were treated with 3 cycles of cisplatin and pemetrexed neoadjuvant chemotherapy. Patients underwent FDG-PET scanning prior to and 18 to 21 days after the first cycle of chemotherapy. Investigators caring for patients were blinded to results, unless the scans showed evidence of disease progression. FDG-PET response was defined prospectively as a ≥ 20% decrease in the SUV of the primary lesion. RESULTS: Between October 2005 and February 2010, 25 patients enrolled. Fifty two percent were female, 88% white, and median age was 62 years. Histology was divided into adenocarcinoma 66%, not otherwise specified (NOS) 16%, squamous cell 12%, and large cell 4%. Stage distribution was: 16% IB, 4% IIB, and 79% IIIA. Treatment was well tolerated and only one patient had a grade 4 toxicity. The median follow up was 95 months. The 5 year progression free survival (PFS) and overall survival (OS) for the entire population were 54 and 67%, respectively. Eighteen patients had a baseline FDG-PET scan and a repeat scan at day 18-21 available for comparison. Ten patients (56%) were considered metabolic responders on the day 18-21 FDG-PET scan. Responders had a 5 year PFS and OS of 60 and 70%, respectively, while the percentage for non-responders was 63 and 75% (p = 0.96 and 0.85). CONCLUSIONS: This phase II trial did not demonstrate that a PET scan after one cycle of chemotherapy can predict survival outcomes of patients with NSCLC treated with neoadjuvant chemotherapy. TRIAL REGISTRATION: NCT00227539 registered September 28th, 2005.

Correlation of Functional Lung Heterogeneity and Dosimetry to Radiation Pneumonitis using Perfusion SPECT/CT and FDG PET/CT Imaging.

PURPOSE: To apply a previously designed framework for predicting radiation pneumonitis by using pretreatment lung function heterogeneity metrics, anatomic dosimetry, and functional lung dosimetry derived from 2 imaging modalities within the same cohort. METHODS AND MATERIALS: Treatment planning computed tomography (CT) scans were co-registered with pretreatment [99mTc] macro-aggregated albumin perfusion single-photon positron emission tomography (SPECT)/CT scans and [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans of 28 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥2 (Common Terminology Criteria for Adverse Events, v. 4). Anatomic dosimetric parameters (mean lung dose [MLD], volume receiving ≥20 Gy [V20]) were collected from treatment planning scans. Baseline functional lung heterogeneity parameters and functional lung dose-volume parameters were calculated from pretreatment SPECT/CT and FDG PET/CT scans. Functional heterogeneity parameters calculated over the tumor-subtracted lung included skewness, kurtosis, and coefficient of variation from perfusion SPECT and FDG PET and the global lung parenchymal glycolysis and mean standardized uptake value from FDG PET. Functional dose-volume parameters calculated in regions of highly functional lung, defined on perfusion (p) or SUV (s) images, included mean lung dose (pMLD, sMLD) and V20 (pV20, sV20). Fraction of integral lung function receiving ≥20 Gy (pF20, sF20) was also calculated. Equivalent doses in 2 Gy per fraction (EQD2) were calculated to account for differences in treatment regimens and dose fractionation (EQD2Lung). RESULTS: Two anatomic dosimetric parameters (MLD, V20) and 4 functional dosimetric parameters (pMLD, pV20, pF20, sF20) were significant predictors of grade ≥2 pneumonitis (area under the curve >0.84; P < .05). Dose-independent functional lung heterogeneity metrics were not associated with pneumonitis incidence. At thresholds of 100% sensitivity and 65% to 91% specificity, corresponding to maximum prediction accuracy for pneumonitis, these parameters had the following cutoff values: MLD = 13.6 Gy EQD2Lung, V20 = 25%, pMLD = 13.2 Gy EQD2Lung, pV20 = 15%, pF20 = 17%, and sF20 = 25%. Significant parameters MLD, V20, pF20, and sF20 were not cross-correlated to significant parameters pMLD and pV20, indicating that they may offer independently predictive information (Spearman ρ < 0.7). CONCLUSIONS: We reported differences in anatomic and functional lung dosimetry between patients with and without pneumonitis in this limited patient cohort. Adding selected independent functional lung parameters may risk stratify patients for pneumonitis. Validation studies are ongoing in a prospective functional lung avoidance trial at our institution.

Trimodality Treatment of Malignant Pleural Mesothelioma: An Institutional Review.

OBJECTIVE: Malignant pleural mesothelioma (MPM) is a deadly disease with varying treatment options. This study retrospectively describes treatment practices at the University of Washington Medical System from 1980 to 2011, and evaluates the impact of trimodality therapy and radiation (photon and neutron) on survival. METHODS: A retrospective study was conducted on patients treated for MPM. Univariate and multivariate methods were utilized to evaluate potential factors associated with survival. Treatments received and baseline characteristics were included. Survival analysis of trimodality therapy was performed using a propensity score method to control for baseline characteristics. RESULTS: Among 78 eligible patients, the median age at diagnosis was 59 years and the median survival was 13.7 months. On multivariate analysis, the significant predictors of improved survival were age, smoking history, location, and receipt of radiation therapy or chemotherapy. In the 48 patients receiving radiation therapy, the difference in survival between neutron therapy and non-neutron therapy patients was not statistically significant: hazard ratio, 1.20 (95% confidence interval, 0.68-2.13), P=0.52. Patients receiving trimodality therapy were more likely to have early-stage disease (60% vs. 30%) and epithelioid histology (86% vs. 58%). In a propensity score-weighted Cox proportional hazards model, trimodality therapy patients had improved overall survival, hazard ratio 0.45, P=0.004, median 14.6 versus 8.6 months. CONCLUSIONS: Trimodality therapy was significantly associated with prolonged survival in patients with MPM, even when adjusting for baseline patient factors. Radiation therapy was associated with improved survival, but the modality of radiation therapy used was not associated with outcome.

The relationship between cardiac radiation dose and mediastinal lymph node involvement in stage III non-small cell lung cancer patients.

PURPOSE: The results from Radiation Therapy Oncology Group (RTOG) 0617, a dose escalation trial that compared treatment with 60 Gy versus 74 Gy for patients with stage III non-small cell lung cancer (NSCLC), suggested that in these patients, the heart dose from radiation therapy correlates with survival. In particular, the study noted that patients with a high heart V5 and V30 had a poorer overall survival; however, the exact cause of this correlation is not known. We hypothesize that heart dose may be a surrogate for mediastinal nodal involvement, which has prognostic value in NSCLC. This study evaluates the relationship between heart dose and involvement of mediastinal lymph nodes in patients with stage III NSCLC treated with radiation therapy. METHODS AND MATERIALS: A total of 56 patients were identified and treated with definitive radiation therapy from 2007 to 2014. The heart was recontoured for every patient by a single physician, per the RTOG 1106 contouring atlas. We assessed lymph node station involvement using pretreatment data, and nodal coverage was confirmed on plan review. RESULTS: Mean heart dose was found to be significantly higher in patients with multinodal station and level 7 involvement. On Spearman's rank correlation, level 7 was significantly associated with all heart parameters tested (P < .001). Patients who had 2 or more lymph node stations involved were found to have significantly higher heart doses for all parameters tested when compared with those who had only one station involved or no nodal involvement. CONCLUSIONS: Our findings suggest that heart dose may be a surrogate for other prognostic factors in stage III NSCLC rather than an independent predictor of outcome.

Framework for radiation pneumonitis risk stratification based on anatomic and perfused lung dosimetry.

PURPOSE: To design and apply a framework for predicting symptomatic radiation pneumonitis in patients undergoing thoracic radiation, using both pretreatment anatomic and perfused lung dose-volume parameters. MATERIALS AND METHODS: Radiation treatment planning CT scans were coregistered with pretreatment [99mTc]MAA perfusion SPECT/CT scans of 20 patients who underwent definitive thoracic radiation. Clinical radiation pneumonitis was defined as grade ≥ 2 (CTCAE v4 grading system). Anatomic lung dose-volume parameters were collected from the treatment planning scans. Perfusion dose-volume parameters were calculated from pretreatment SPECT/CT scans. Equivalent doses in 2 Gy per fraction were calculated in the lung to account for differences in treatment regimens and spatial variations in lung dose (EQD2lung). RESULTS: Anatomic lung dosimetric parameters (MLD) and functional lung dosimetric parameters (pMLD70%) were identified as candidate predictors of grade ≥ 2 radiation pneumonitis (AUC > 0.93, p < 0.01). Pairing of an anatomic and functional dosimetric parameter (e. g., MLD and pMLD70%) may further improve prediction accuracy. Not all individuals with high anatomic lung dose (MLD > 13.6 GyEQD2lung, 19.3 Gy for patients receiving 60 Gy in 30 fractions) developed radiation pneumonitis, but all individuals who also had high mean dose to perfused lung (pMLD70% > 13.3 GyEQD2) developed radiation pneumonitis. CONCLUSIONS: The preliminary application of this framework revealed differences between anatomic and perfused lung dosimetry in this limited patient cohort. The addition of perfused lung parameters may help risk stratify patients for radiation pneumonitis, especially in treatment plans with high anatomic mean lung dose. Further investigations are warranted.

Theoretical effectiveness of cell survival in fractionated radiotherapy with hypoxia-targeted dose escalation.

PURPOSE: The goal of this article is to compute the cell survival during fractionated radiotherapy with non-uniform hypoxia-targeted dose distribution relative to cell survival for a uniform dose distribution with equal integral tumor dose. The analysis is performed for different parameters of radiotherapy with conventional and hypofractionated dose regimens. METHODS: Our analysis is done using a parsimonious tumor response model that describes the major components of tumor response to radiotherapy such as radiosensitivity, cell proliferation, and hypoxia using as few variables as possible. Two levels of oxygenated and hypoxic cells with the survival curves described by the linear quadratic (LQ) model are implemented in the model. The model allows for analytical solutions for relative cell survival in a single fraction simulation which can be used for additional validation of our numerical simulations. The relative cell survival was computed for conventional and hypofractionated dose regimens in a model problem with radiobiological parameters for the non-small-cell lung cancer. Sensitivity of cell survival to different parameters of radiotherapy such as the relative volume of hypoxic fraction, boost dose ratio, re-oxygenation rate, and delivery errors was investigated. RESULTS: Our computational and analytical results show that relative cell survival for non-uniform and uniform dose distributions is larger than 1.0 during the first few fractions of radiotherapy with conventional fractionation. This indicates that the uniform dose distribution produces a higher cell killing effect for the equal integral dose. This may stem from domination of linear contribution to the cell killing effect seen in the dose range of 1-2 Gy and a steeper slope of survival curve in the oxygenated tumor region. This effect can only happen if the distribution of clonogens is nearly uniform; therefore, after the first few fractions, the non-uniform dose distributions outperform the uniform dose distribution and relative cell survival becomes less than 1.0. However, re-oxygenation and delivery errors can also reduce the effectiveness of hypoxia-targeted non-uniform dose distributions toward the end of treatment. For hypofractionated radiotherapy with fractional dose >3 Gy, the relative cell survival was always below 1.0, which means the non-uniform dose distributions produced higher cell killing effect than the uniform dose distribution during the entire treatment. CONCLUSION: The data obtained in this work suggest that non-uniform hypoxia-targeted dose distributions are less effective at cell killing than uniform dose distributions at the beginning of radiotherapy with conventional fractionation. However; non-uniform dose distributions can outperform uniform dose distribution by the end of the treatment if the effects of re-oxygenation and delivery errors are reduced. In hypofractionated radiotherapy, non-uniform hypoxia-targeted dose distributions are more efficient than uniform dose distributions during the entire treatment.

Fast neutron radiotherapy in the treatment of malignant pleural mesothelioma.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a fatal disease lacking standardized treatment. We describe the use of fast neutron radiation therapy in MPM patients referred to the Department of Radiation Oncology at the University of Washington Medical Center. MATERIALS AND METHODS: Retrospective chart review of MPM patients receiving neutron radiotherapy treatment from 1980 to 2012. RESULTS: A total of 30 MPM patients received fast neutron radiotherapy as part of their treatment regimen. Median age at diagnosis was 59.6 years (range, 46.6 to 72.3 y). Eighteen patients received fast neutron radiotherapy as a component of trimodality treatment. Median overall survival was 20.3 months (range, 5.5 to 73.3 mo) with 1 patient censored at 34.8 months and all other patients with confirmed dates of death. One patient receiving radiotherapy alone as a palliative measure died during radiation treatment. One patient was unable to tolerate radiotherapy and stopped before completing prescribed treatment. On univariate analysis, Brigham Stage at presentation was a significant predictor of survival (P<0.01). No significant differences in survival were observed when comparing patients who received trimodality treatment compared to those who did not. CONCLUSIONS: Fast neutron radiotherapy may be utilized in the management of MPM patients. However, treatment with fast neutron radiotherapy did not significantly improvement outcome, even when used in a trimodality regimen.

Challenges and opportunities in patient-specific, motion-managed and PET/CT-guided radiation therapy of lung cancer: review and perspective.

The increasing interest in combined positron emission tomography (PET) and computed tomography (CT) to guide lung cancer radiation therapy planning has been well documented. Motion management strategies during treatment simulation PET/CT imaging and treatment delivery have been proposed to improve the precision and accuracy of radiotherapy. In light of these research advances, why has translation of motion-managed PET/CT to clinical radiotherapy been slow and infrequent? Solutions to this problem are as complex as they are numerous, driven by large inter-patient variability in tumor motion trajectories across a highly heterogeneous population. Such variation dictates a comprehensive and patient-specific incorporation of motion management strategies into PET/CT-guided radiotherapy rather than a one-size-fits-all tactic. This review summarizes challenges and opportunities for clinical translation of advances in PET/CT-guided radiotherapy, as well as in respiratory motion-managed radiotherapy of lung cancer. These two concepts are then integrated into proposed patient-specific workflows that span classification schemes, PET/CT image formation, treatment planning, and adaptive image-guided radiotherapy delivery techniques.