Jonathan Feddock

Stereotactic Body Radiation Therapy Can Be Used Safely to Boost Residual Disease in Locally Advanced Non-Small Cell Lung Cancer: A Prospective Study

PURPOSE To report the results of a prospective, single-institution study evaluating the feasibility of conventional chemoradiation (CRT) followed by stereotactic body radiation therapy (SBRT) as a means of dose escalation for patients with stage II-III non-small cell lung cancer (NSCLC) with residual disease. METHODS AND MATERIALS Patients without metastatic disease and with radiologic evidence of limited residual disease (≤5 cm) within the site of the primary tumor and good or complete nodal responses after standard CRT to a target dose of 60 Gy were considered eligible. The SBRT boost was done to achieve a total combined dose biological equivalent dose >100 Gy to the residual primary tumor, consisting of 10 Gy × 2 fractions (20 Gy total) for peripheral tumors, and 6.5 Gy × 3 fractions (19.5 Gy total) for medial tumors using the Radiation Therapy Oncology Group protocol 0813 definitions. The primary endpoint was the development of grade ≥3 radiation pneumonitis (RP). RESULTS After a median follow-up of 13 months, 4 patients developed acute grade 3 RP, and 1 (2.9%) developed late and persistent grade 3 RP. No patients developed grade 4 or 5 RP. Mean lung dose, V2.5, V5, V10, and V20 values were calculated for the SBRT boost, and none were found to significantly predict for RP. Only advancing age (P=.0147), previous smoking status (P=.0505), and high CRT mean lung dose (P=.0295) were significantly associated with RP development. At the time of analysis, the actuarial local control rate at the primary tumor site was 82.9%, with only 6 patients demonstrating recurrence. CONCLUSIONS Linear accelerator-based SBRT for dose escalation of limited residual NSCLC after definitive CRT was feasible and did not increase the risk for toxicity above that for standard radiation therapy.

3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation

UNLABELLED An appropriate representation of the tumor microenvironment in tumor models can have a pronounced impact on directing combinatorial treatment strategies and cancer nanotherapeutics. The present study develops a novel 3D co-culture spheroid model (3D TNBC) incorporating tumor cells, endothelial cells and fibroblasts as color-coded murine tumor tissue analogs (TTA) to better represent the tumor milieu of triple negative breast cancer in vitro. Implantation of TTA orthotopically in nude mice, resulted in enhanced growth and aggressive metastasis to ectopic sites. Subsequently, the utility of the model is demonstrated for preferential targeting of irradiated tumor endothelial cells via radiation-induced stromal enrichment of galectin-1 using anginex conjugated nanoparticles (nanobins) carrying arsenic trioxide and cisplatin. Demonstration of a multimodal nanotherapeutic system and inclusion of the biological response to radiation using an in vitro/in vivo tumor model incorporating characteristics of tumor microenvironment presents an advance in preclinical evaluation of existing and novel cancer nanotherapies. FROM THE CLINICAL EDITOR Existing in-vivo tumor models are established by implanting tumor cells into nude mice. Here, the authors described their approach 3D spheres containing tumor cells, enodothelial cells and fibroblasts. This would mimic tumor micro-environment more realistically. This interesting 3D model should reflect more accurately tumor response to various drugs and would enable the design of new treatment modalities.

Impact of post-radiation biopsies on development of fistulae in patients with cervical cancer

OBJECTIVE In the post-radiation patient, late vascular sequelae and fibrosis predispose women to poor tissue healing, such that small tissue injuries could theoretically evolve into much larger ones such as fistulae. We sought to determine if a correlation exists between invasive procedures such as post-treatment biopsies and the subsequent development of gynecologic fistulae. METHODS A retrospective review was performed evaluating all patients treated for cervical cancer at our institution between 1997 and 2010. Biopsies or pelvic surgeries were included if performed within the radiated field, and evaluated in a multivariate predictive model for development of gynecologic fistulae. RESULTS Out of 325 total patients, 27 patients with fistulae were identified (8.2%). 14 fistulae (51.9%) were considered toxicity-related, 6 (22.2%) resulted from primary disease, and 7 (25.9%) were attributable to recurrent disease. Eighty-nine patients underwent an invasive procedure (55 biopsies and 34 pelvic surgeries). Recurrent and/or residual cancer was found in 28 (31.5%) specimens, and of the 61 patients who underwent an invasive procedure and were not found to have evidence of recurrent disease, 9 (14.8%) subsequently developed a fistula at a median 3.08 months. An elevated dose of radiation to the rectum (OR 1.001 for dose >72 Gy, p=0.0005), advancing tumor stage (OR 5.38 for stage III, OR 10.47 for stage IV, p=0.0288), and a post-radiation biopsy (OR 5.27, p=0.013) were significantly associated with fistula development. CONCLUSIONS Performing a biopsy in an irradiated field is associated with a relatively low yield and significantly contributes to the risk for fistula development.

Cervical cancer survival for patients referred to a tertiary care center in Kentucky

OBJECTIVES To identify prognostic factors influencing cervical cancer survival for patients referred to a tertiary care center in Kentucky. METHODS A cohort study was performed to assess predictive survival factors of cervical cancer patients referred to the University of Kentucky from January 2001 to May 2010. Eligibility criteria included those at least 18 years-old, cervical cancer history, and no prior malignancy. Descriptive statistics were compiled and univariable and multivariable Cox proportional hazard analysis were performed. RESULTS 381 patients met entry criteria. 95% were Caucasian (N=347) and 66% (N=243) lived in Appalachian Kentucky. The following covariates showed no evidence of a statistical association with survival: race, body mass index, residence, insurance status, months between last normal cervical cytology and diagnosis, histology, tumor grade, and location of primary radiation treatment. After controlling for identified significant variables, stage of disease was a significant predictor of overall survival, with estimated relative hazards comparing stages II, III, and IV to stage I of 3.09 (95% CI: 1.30, 7.33), 18.11 (95% CI: 7.44, 44.06), and 53.03(95% CI: 18.16, 154.87), respectively. The presence of more than two comorbid risk factors and unemployment was also correlated with overall survival [HR 4.25 (95% CI: 1.00, 18.13); HR 2.64 (95% CI 1.29, 5.42), respectively]. CONCLUSIONS Residence and location of treatment center are not an important factor in cervical cancer survival when a tertiary cancer center can oversee and coordinate care; however, comorbid risk factors influence survival and further exploration of disease comorbidity related to cervical cancer survival is warranted.

A feasibility study using TomoDirect for craniospinal irradiation

The feasibility of delivering craniospinal irradiation (CSI) with TomoDirect is investigated. A method is proposed to generate TomoDirect plans using standard three‐dimensional (3D) beam arrangements on Tomotherapy with junctioning of these fields to minimize hot or cold spots at the cranial/spinal junction. These plans are evaluated and compared to a helical Tomotherapy and a three‐dimensional conformal therapy (3D CRT) plan delivered on a conventional linear accelerator (linac) for CSI. The comparison shows that a TomoDirect plan with an overlap between the cranial and spinal fields might be preferable over Tomotherapy plans because of decreased low dose to large volumes of normal tissues outside of the planning target volume (PTV). Although the TomoDirect plans were not dosimetrically superior to a 3D CRT linac plan, the patient can be easily treated in the supine position, which is often more comfortable and efficient from an anesthesia standpoint. TomoDirect plans also have only one setup position which obviates the need for matching of fields and feathering of junctions, two issues encountered with conventional 3D CRT plans. TomoDirect plans can be delivered with comparable treatment times to conventional 3D plans and in shorter times than a Tomotherapy plan. In this paper, a method is proposed for creating TomoDirect craniospinal plans, and the dosimetric consequences for choosing different planning parameters are discussed. PACS number: 87.55.D‐

Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The ‘rigorous’ combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment.

Implementation and early clinical results utilizing Cs-131 permanent interstitial implants for gynecologic malignancies.

OBJECTIVE Permanent interstitial brachytherapy is an ideal yet underutilized treatment modality for accessible, small volume gynecological malignancies. We present early clinical results utilizing a new permanent isotope, Cs-131. METHODS A retrospective review was performed evaluating patients treated with Cs-131 permanent interstitial radiation at our institution from July 2011 through June 2013. Doses were most commonly prescribed and calculated to a depth of 5mm using Paterson-Parker planar implant rules for Au-198. This activity was converted to air-kerma strength (U). A conversion factor of 1.1 was applied based on RBE calculations, clinical observation and experience. RESULTS 14 patients were identified among whom 17 Cs-131 implants were performed. Seven patients were implanted as sole therapy, and a median dose of 50 Gy was delivered. Ten implants were performed as boost within a more extensive radiation treatment plan. In these patients, a median implant dose of 27.5 Gy was used and the median total dose delivered in combination was 78.25 Gy. After a median follow up of 12 months, the actuarial local control rate was 84.4%. A very low level of grade 1-3 reactions was observed with no fistula formations or other severe side effects. CONCLUSIONS Permanent interstitial brachytherapy with Cs-131 was well tolerated with favorable early results compared to other series. Cs-131 has multiple favorable properties, including minimal radiation exposure to treating staff, and should be considered as a therapeutic option in appropriately selected patients. A methodology for dose prescription, calculation of radioactivity required and distribution of the isotope is also presented.

Determination of prescription dose for Cs-131 permanent implants using the BED formalism including resensitization correction.

PURPOSE The current widely used biological equivalent dose (BED) formalism for permanent implants is based on the linear-quadratic model that includes cell repair and repopulation but not resensitization (redistribution and reoxygenation). The authors propose a BED formalism that includes all the four biological effects (4Rs), and the authors propose how it can be used to calculate appropriate prescription doses for permanent implants with Cs-131. METHODS A resensitization correction was added to the BED calculation for permanent implants to account for 4Rs. Using the same BED, the prescription doses with Au-198, I-125, and Pd-103 were converted to the isoeffective Cs-131 prescription doses. The conversion factor F, ratio of the Cs-131 dose to the equivalent dose with the other reference isotope (Fr: with resensitization, Fn: without resensitization), was thus derived and used for actual prescription. Different values of biological parameters such as α, β, and relative biological effectiveness for different types of tumors were used for the calculation. RESULTS Prescription doses with I-125, Pd-103, and Au-198 ranging from 10 to 160 Gy were converted into prescription doses with Cs-131. The difference in dose conversion factors with (Fr) and without (Fn) resensitization was significant but varied with different isotopes and different types of tumors. The conversion factors also varied with different doses. For I-125, the average values of Fr/Fn were 0.51/0.46, for fast growing tumors, and 0.88/0.77 for slow growing tumors. For Pd-103, the average values of Fr/Fn were 1.25/1.15 for fast growing tumors, and 1.28/1.22 for slow growing tumors. For Au-198, the average values of Fr/Fn were 1.08/1.25 for fast growing tumors, and 1.00/1.06 for slow growing tumors. Using the biological parameters for the HeLa/C4-I cells, the averaged value of Fr was 1.07/1.11 (rounded to 1.1), and the averaged value of Fn was 1.75/1.18. Fr of 1.1 has been applied to gynecological cancer implants with expected acute reactions and outcomes as expected based on extensive experience with permanent implants. The calculation also gave the average Cs-131 dose of 126 Gy converted from the I-125 dose of 144 Gy for prostate implants. CONCLUSIONS Inclusion of an allowance for resensitization led to significant dose corrections for Cs-131 permanent implants, and should be applied to prescription dose calculation. The adjustment of the Cs-131 prescription doses with resensitization correction for gynecological permanent implants was consistent with clinical experience and observations. However, the Cs-131 prescription doses converted from other implant doses can be further adjusted based on new experimental results, clinical observations, and clinical outcomes.

SU-E-T-114: Dose Modification for Cs-131 Permanent Implants Using Resensitization-Corrected Normal Tissue BED

PURPOSE To apply resensitization (redistribution and reoxygenation) correction to normal tissue BED calculation and have it verified with clinical outcomes. METHOD AND MATERIALS The BED formalism without resensensitization for permanent implants was BED = D*RE - BF, where D is the prescribed dose, RE = 1 + (β/α)R0/(μr+λ), BF = K*Teff, K = ln(2)/(αTp), and Teff = Taveln(αDTp/T1/2). α and β are LQ parameters, R0 the initial dose rate, μr the repair constant, λ the source decay constant, and Tp the repopulation time. Resensitization can be included in the extended LQ equation (LQR) S = exp[-αD - βG(Tr)D2 + 1/2σ2 G(Ts)D2 + Teff/Tp], where G(Tr) and G(Ts) describe repair and resensitization, and 1/2σ2 represents cell-to-cell diversity. Combining Dales formalism with LQR led to RE = 1+(β/α)R0/(μr+λ)-(1/2σ2 /α)R0/(μs+λ), where μs is the resensitization constant. We used this formula to calculate the BED for normal tissue based on the prescribed dose for Au-198 GYN permanent implants from which we have gained extensive clinical experience. Then, we calculated the dose with Cs-131 which has the equal BED as Au-198. RESULTS The prescribed doses for Au-198 ranged from 10 to 120 Gy. The converted doses for Cs-131 implants ranged from 9 to 161 Gy (without resensitization correction) and 8.9 to 156 Gy (with resensitization correction), which resulted in the average value of dose conversion factor, Fn (no resensitization correction) = 1.14, and 1.10 for Fr (with resensitization correction) which agreed with the results from the calculation for tumor. The doses derived with 1.10 reduced the complications such as brisk moist desquamation in actual clinical cases. CONCLUSION Resensitization correction in BED for normal tissues led to significant reduction in prescription dose and thus in toxicity. The results further show that resensitization correction is needed for permanent implant dose calculation.

No cookie-cutter oncology: individualized treatment approaches for women with corpus endometrial cancer.

>Endometrial adenocarcinoma is the most common gynecologic malignancy and, for the majority of patients who present with stage I (∼70%) or stage II (∼10%) disease, 5-year overall survival rates approach 85%. However, the complicated mix of medical comorbidities, the broad spectrum of techniques and treatment modalities and controversial clinical trial outcomes makes treating this heterogeneous group of patients unique and challenging. Similar management controversies exist and, when one factors in histologic variability, no flow-chart treatment algorithm can be easily constructed. This article will discuss data from key clinical trials, consider the role of routine lymphadenectomy as a component of surgical staging, discuss the heterogeneity of stage III patients in both presentation and response to treatment, review options for medically inoperable patients and reflect on current and upcoming protocols