The Impact of Academic Facility Type and Case Volume On Survival in Patients Undergoing Curative Radiotherapy for Muscle-Invasive Bladder Cancer

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Amishi Bajaj, Brendan Martin, Richa Bhasin, Courtney Hentz, Alec M. Block, Matthew M. Harkenrider, Abhishek A. Solanki
BackgroundBladder-preserving curative radiation therapy (RT) has been established as an excellent treatment option for select patients with muscle-invasive bladder cancer (MIBC). However, some clinicians have concern that good outcomes are only achievable at high volume facilities and academic centers, questioning successful reproducibility of curative RT at smaller centers. The present study sought to determine if treatment at academic centers (AC) or high-volume facilities (HVF) was associated with better overall survival (OS) than treatment at non-academic centers (NAC) or lower-volume facilities (LVF).Materials and MethodsWe performed a retrospective cohort study of National Cancer Database (NCDB) patients (n=2,763) with cT2-4 N0 M0 transitional cell MIBC who received curative RT (60-70 Gy) with or without concurrent chemotherapy. Cox proportional hazards models were used to estimate the instantaneous hazard of death as a function of univariable and multivariable patient characteristics and clinical measures.ResultsUnivariable analysis (UVA) demonstrated that academic facility type was significantly associated with improved OS (HR = 0.88, 95% CI: 0.79-0.98, p=.02), while higher case volume was not associated with improved survival (HR = 0.97, 95% CI: 0.92-1.01, p=.15). MVA revealed no differences in OS for treatment at AC vs. NAC (HR = 0.94, 95% CI: 0.84-1.06; p=.31) or HVF vs. LVF (HR = 0.99, 95% CI: 0.94-1.04; p = .60). 2-year OS was 54.5% (95% CI: 52.5-56.4%) and 5-year OS was 28.9% (95% CI: 27.0-30.8%).ConclusionsAlthough some providers are cautious about offering curative radiotherapy at all centers, this large hospital-based study suggests that facility type and volume are not significantly associated with OS for patients undergoing curative RT after accounting for other clinically relevant risk factors. The results of this study demonstrate that curative RT in the treatment of MIBC may be considered for patients regardless of facility type or volume.

Teaser

We conducted a retrospective cohort study of patients in the National Cancer Database with muscle-invasive bladder cancer undergoing curative radiotherapy to identify whether the facility type and treating facility's case volume impact survival outcomes. When controlling for disease extent and treatment characteristics, patients at academic and non-academic facilities and low and high volume facilities had similar survival outcomes. Thus bladder-sparing curative radiotherapy should be discussed and offered confidently at most centers.


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Carotid Dosimetry and the Risk of Carotid Blowout Syndrome Following Re-irradiation with Head and Neck Stereotactic Body Radiation Therapy

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Brian J. Gebhardt, John A. Vargo, Diane Ling, Brianna Jones, Mary Mohney, David A. Clump, James P. Ohr, Robert L. Ferris, Dwight E. Heron
Background/PurposeStereotactic Body Radiation Therapy (SBRT) is an increasingly used technique for re-irradiation of recurrent head-and-neck cancers (rHNC). Rates of carotid blowout syndrome (CBOS), which is defined as rupture and hemorrhage from the carotid artery or its major branches following re-irradiation in the absence of residual or progressive disease, have varied from 0-17% occurring at a median of 4-5 months following SBRT. This has prompted some to aggressively spare the carotids or avoid SBRT in patients with arterial encasement. Our institutional practice has not excluded patients from SBRT based on extent of carotid involvement or carotid dose. Thus, we aimed to correlate carotid dose and risk of CBOS; hypothesizing that carotid dose does not correlate with CBOS.Methods/MaterialsWe retrospectively reviewed 186 patients with recurrent, previously-irradiated head-and-neck cancer treated between January 2008 and March 2013. Patients treated early in our experience with incomplete dosimetry were excluded from analysis (n=111). A total of 75 patients were identified providing 150 carotid arteries for analysis. Median follow-up was 8 months (range: 1-91) for all patients, and 37 months for surviving patients (range: 31-91]. Patients were treated with linear accelerator-based SBRT to a median dose up to 44Gy (range: 40-50 Gy) in 5 fractions delivered on a twice-weekly basis. Concurrent Cetuximab was utilized in 63 patients (84%). The bilateral common, internal, and external carotid arteries were delineated 2cm above and below the planning target volume. The maximum dose to 0.1cc (D0.1cc), 1cc (D1cc), 2cc (D2cc) of the carotid and the mean carotid dose from SBRT were recorded and analyzed for association with carotid bleeding events using binary logistic regression.ResultsMedian re-irradiation interval was 20 months (range: 3-423), median prior radiation dose was 70 Gy (range: 52.5-140). Sixteen patients (21.3%) received more than 1 course of SBRT, and the cumulative carotid doses from fused summary plans were recorded. The overall median D0.1cc, D1cc, D2cc, and mean carotid doses were 40.8 Gy [interquartile range (IQR): 21.6-47.6], 26.8 Gy [IQR: 14.1-42.1], 15.4 Gy [IQR: 8.4-32.7], and 15.0 Gy [IQR: 8.9-23.3], respectively. There were a total of 4 bleeding events (5.3%): 2 patients (2.7%) had mucosal bleeds that resolved following embolization of carotid branches, and 2 patients (2.7%) died from complications of CBOS. In the 2 patients suffering CBOS, the D0.1cc were 48.4 Gy and 47.6 Gy. There was no significant association between bleeding events and D1cc (p=0.280), D2cc (p=0.571), or mean dose (p=0.568). There was a trend toward increased risk of bleeding and D0.1cc (p=0.080).ConclusionsThese results demonstrate a low risk of bleeding following re-irradiation with SBRT when 5 fractions are delivered on non-consecutive days even when tumor is completely encasing the carotid artery. While limited by low number of events, no significant association was found between dose-volume parameters and the risk of carotid bleeding. No CBOS noted when D0.1cc was <47.6 Gy.

Teaser

Stereotactic body radiation therapy has emerged as a viable treatment option for recurrent head and neck cancers after prior irradiation, though carotid dose constraints are not defined. The maximum dose to 0.1cc, 1cc, 2cc of the carotid and the mean dose were analyzed for association with bleeding. No significant association was found between dose-volume parameters and risk of carotid bleeding, and no CBOS noted when D0.1cc was <47.6 Gy.


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Concurrent Immune Checkpoint Inhibitors and Stereotactic Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma

Publication date: Available online 5 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Linda Chen, Jacqueline Douglass, Lawrence Kleinberg, Xiaobu Ye, Ariel E. Marciscano, Patrick M. Forde, Julie Brahmer, Evan Lipson, William Sharfman, Hans Hammers, Jarushka Naidoo, Chetan Bettegowda, Michael Lim, Kristin J. Redmond
PurposeTo characterize the effect of concurrent stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) and immune checkpoint inhibitors (ICI) on patient outcome and safety in patients with brain metastases (BM).Materials/Methods: We retrospectively identified metastatic non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) patients who had BM treated with SRS/SRT from 2010-2016 without prior whole brain radiotherapy (WBRT). We included SRS/SRT patients who were treated with anti-CTLA4 (ipilimumab) and anti-PD-1 (nivolumab, pembrolizumab). Patients who were given ICI on active or unreported clinical trials were excluded, and concurrent ICI was defined as given within 2 weeks of SRS/SRT. Patients were managed with SRS/SRT, SRS/SRT with non-concurrent ICI, and SRS/SRT with concurrent ICI. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves, and cox proportional hazard models were used for multivariate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related adverse events (irAEs), and new BM.Results260 patients were treated with SRS/SRT to 623 brain metastases. 181 were treated with SRS/SRT only and 79 with SRS/SRT and ICI, with 35% of patients treated with concurrent SRS/SRT and ICI. Concurrent ICI was not associated with increased rates of irAEs or acute neurologic toxicity and predicted for a decreased likelihood of developing ≥ 3 new BM following SRS/SRT (p=0.045, OR 0.337). Median OS for patients treated with SRS/SRT, SRS/SRT and non-concurrent ICI, and SRS/SRT with concurrent ICI was 12.9, 14.5, and 24.7 months respectively. Concurrent SRS/SRT and ICI was associated with improved OS compared to SRS/SRT only (p=0.002, HR 2.69) and compared to non-concurrent SRS/SRT and ICI (p=0.006, HR 2.40) on multivariate analyses. The OS benefit of Concurrent SRS/SRT and ICI was significant in comparison to patients treated with SRS/SRT pre (p=0.002, HR 3.82) or post (p=0.021, HR 2.64) ICI.ConclusionDelivering SRS/SRT with concurrent ICI may be associated with decreased incidence of new BM and favorable survival outcomes without increased rates of adverse events.

Teaser

Radiation is hypothesized to augment the immunogenicity of tumor cells. We retrospectively evaluated survival outcomes, incidence of new brain metastases, and treatment-related adverse events in patients who received stereotactic radiosurgery for brain metastases with concurrent immune checkpoint inhibition, with non-concurrent immune checkpoint inhibition, and with stereotactic radiosurgery alone. Delivering SRS with concurrent ICI may be associated with decreased incidence of new BM and favorable survival outcomes without increased rates of adverse events.


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Locally ablative radio therapy of a primary human small cell lung cancer tumor decreases the number of spontaneous metastases in two xenograft models

Publication date: Available online 6 December 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Thorsten Frenzel, Jordana Siekmann, Carsten Grohmann, Ursula Valentiner, Rüdiger Schmitz, Kristoffer Riecken, Boris Fehse, Udo Schumacher, Tobias Lange, Andreas Krüll
IntroductionCancer patients mainly die from distant metastases, for which small cell lung cancer (SCLC) serves as an instructive example. As it is still under debate whether radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT) or chemotherapy (ChT) may promote metastatic spread, we investigated the influence of these treatments on SCLC metastases in two xenograft models.Methods and materials1 x 10⁶ human SCLC cells (OH1, H69) were subcutaneously injected into SCID mice to form a local primary tumor node at the lower trunk. RT, OP, RChT, or ChT were started after development of palpable tumors. ChT was given as a single intraperitoneal injection of cisplatin. RT was 5 x 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control groups A) and at the end of the experiment (control groups B). Pro-apoptotic, anti-proliferative, anti-angiogenic, and hypoxic effects were assessed by Feulgen, Ki-67, S1P1 receptor, and HIF1α staining, respectively. Quantitative Alu-PCR was used to determine circulating tumor cells (CTCs) in the blood, and disseminated tumor cells (DTCs) in the lungs, bone marrow, liver, and brain.ResultsIn both xenograft models, RT and RChT abrogated local tumor growth indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination, but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in case of relapse-free surgery, similar effects could be achieved by OP.ConclusionOur models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regards to suppression of CTCs and DTCs.

Teaser

The influence of radiotherapy, surgery, chemotherapy, and radio-chemotherapy on local primary tumor growth and on spontaneous distant metastasis formation was investigated in two human small cell lung cancer xenograft mouse models. Local tumor control was most important to suppress metastasis formation. Most interestingly, radiotherapy was not only locally ablative and prevented spontaneous distant metastasis formation over time, but even reduced the metastatic cell load in distant organs pre-existing at the time of therapy induction.


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Characterization of PD-L1 expression in Chinese non-small cell lung cancer patients with PTEN expression as a means for tissue quality screening

Abstract

The goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN IHC showed that 108 TMA samples and 105 whole-section samples qualified for PD-L1 IHC. With a clinically relevant cutoff, 41.7% of the TMA samples were PD-L1 positive. PD-L1 level was much lower in EGFR-mutant patients and seemed to be a favorable prognostic factor for both overall survival (OS) and recurrence-free survival (RFS). These findings were confirmed in the whole-section samples except that their survival data were not mature enough for correlation analysis. In summary, PD-L1 expression was detected in approximately 40% of PTEN-qualified Chinese NSCLC samples, negatively correlated with EGFR mutation and seemed to be a favorable prognostic factor for both OS and RFS. Notably, the different results from PTEN-qualified and PTEN-disqualified samples underscore the importance of tissue quality control prior to biomarker testing.

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Comparative gene co-expression network analysis of epithelial to mesenchymal transition reveals lung cancer progression stages

Abstract

Background

The epithelial to mesenchymal transition (EMT) plays a key role in lung cancer progression and drug resistance. The dynamics and stability of gene expression patterns as cancer cells transition from E to M at a systems level and relevance to patient outcomes are unknown.

Methods

Using comparative network and clustering analysis, we systematically analyzed time-series gene expression data from lung cancer cell lines H358 and A549 that were induced to undergo EMT. We also predicted the putative regulatory networks controlling EMT expression dynamics, especially for the EMT-dynamic genes and related these patterns to patient outcomes using data from TCGA. Example EMT hub regulatory genes were validated using RNAi.

Results

We identified several novel genes distinct from the static states of E or M that exhibited temporal expression patterns or 'periods' during the EMT process that were shared in different lung cancer cell lines. For example, cell cycle and metabolic genes were found to be similarly down-regulated where immune-associated genes were up-regulated after middle EMT stages. The presence of EMT-dynamic gene expression patterns supports the presence of differential activation and repression timings at the transcriptional level for various pathways and functions during EMT that are not detected in pure E or M cells. Importantly, the cell line identified EMT-dynamic genes were found to be present in lung cancer patient tissues and associated with patient outcomes.

Conclusions

Our study suggests that in vitro identified EMT-dynamic genes capture elements of gene EMT expression dynamics at the patient level. Measurement of EMT dynamic genes, as opposed to E or M only, is potentially useful in future efforts aimed at classifying patient's responses to treatments based on the EMT dynamics in the tissue.

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Leukocytoclastic vasculitis complicating cisplatin + radiation treatment for laryngeal cancer: a case report

Abstract

Background

Leukocytoclastic vasculitis is typically mediated by deposition of immune complexes and is related to many causes, including medication. To the best of our knowledge, leukocytoclastic vasculitis related to cisplatin has not yet been described in the scientific literature.

Case presentation

We report a rare case of leukocytoclastic vasculitis after the first cycle of high-dose cisplatin chemotherapy in a patient with larynx carcinoma. A 48-year-old Caucasian man with larynx carcinoma received a high-dose of cisplatin monochemotherapy (100 mg/m² every 21 days), along with 70 Gy of radiotherapy divided into 35 sessions, as a therapeutic schedule. Twelve days after the first chemotherapy administration and after 8 sessions of radiotherapy (total of 16 Gy), the patient presented with acute onset of palpable purpura in the lower limbs. The patient was hospitalized for 10 days, and during this period, he underwent several examinations to rule out infectious, autoimmune, and neoplastic disorders. A skin biopsy showed leukocytoclastic vasculitis with a positive pattern for IgM and C3, as detected through direct immunofluorescence. Twenty-five days after cisplatin administration, the chemotherapy regimen was changed to carboplatin AUC 5, and the episodes of purpura ceased, reinforcing the hypothesis of an adverse reaction to cisplatin.

Conclusions

Cisplatin can induce leukocytoclastic vasculitis and clinicians should be aware of this potential effect for better case management and diagnosis.

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