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Purpose: Molecularly targeted agents will play a major role in the next generation of personalized cancer therapies. However, intrinsic and acquired resistance to targeted agents poses challenges to the success of such treatments. The Cancer Genome Atlas data suggest that both EGFR and PI3K pathways are reasonable targets in head and neck cancers (HNC). However, single agent treatment with EGFR inhibitor erlotinib or pan-PI3K inhibitor BKM120 fails to induce apoptosis of most HNC cell lines. We have previously reported that EGFR and PI3K co-targeting has synergistic antitumor effects both in vitro and in vivo and induces variable apoptosis. The purpose of the current study was to investigate the mechanism of intrinsic resistance to apoptosis induced by the combination of EGFR inhibitor erlotinib and PI3K inhibitor BKM120 and to sensitize the resistant cells with natural extracts. Methods: In a panel of 10 malignant and 1 premalignant HNC cell lines, we evaluated apoptosis by Annexin-V staining. Protein expression levels were measured by Western blotting. Small molecule chemical inhibitors and siRNA-mediated knockdown strategies were used to inactivate and shut down the expression of the relevant proteins, respectively. Results: The combination of erlotinib and BKM120 induced variable apoptosis. Some cell lines were very sensitive (Tu686, 686LN, 93-VU-147T), some were moderately sensitive (Fadu, SqCCy1, 1483, UMSSC90), and others were resistant (UD-SCC2, MSK-LEUK1, JHU022) to apoptosis induction. JHU022 and 1483 cell lines expressed very high levels of phosphorylated c-Met. Targeting c-Met with the small molecule inhibitor crizotinib or siRNA rendered these cell lines highly sensitive to erlotinib and BKM120 induced apoptosis. Moreover, inhibition of Src family kinases (SFK) with the small molecule inhibitor dasatinib or with c-Src-specific siRNA inhibited phosphorylated c-Met. In addition, inhibition of SFK in these cell lines conferred sensitivity to erlotinib and BKM120 induced apoptosis. We also screened several natural extracts isolated from microorganisms. We found that ACM, one of these extracts, strongly induced apoptosis of the resistant cell lines. Moreover, the extract inhibited constitutively active p-Met in the resistant cell line. Conclusions: Our results strongly suggest that some of the resistant cell lines expressed high levels of phosphorylated c-Met downstream of SFK. This confers resistance of these cells to the combination of erlotinib and BKM120 as inhibition of this pathway sensitizes the cells. Moreover, the bacterial extract ACM is a natural inhibitor of c-Met which sensitizes these resistant cell lines. It may be an excellent direction for further drug development. Citation Format: Asm Anisuzzaman, Abedul Haque, Brian Butler, ARM R. AMIN. A natural inhibitor of c-Met that sensitizes head and neck cancer cells resistant to EGFR and PI3K co-targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 706.

37 Background: Immune related adverse events still occur in up to 91% of patients receiving immunotherapy. Intratumoral administration is a potential solution to limit these events by reducing systemic exposure while increasing local concentration. However, intratumoral injection is hindered by rapid clearance of drug from the tumor. Our group has developed an intratumoral nanochannel implant for sustained delivery of immunotherapy (NDES) as a solution. Recent clinical and preclinical studies have found success in the combination of radiotherapy and immunotherapy in improving both local and distant tumor response. We propose a combination of radiotherapy followed by sustained intratumoral delivery of immunotherapy as a treatment regimen to improve tumor response and reduce side effects. Methods: Mice were implanted with the 4T1 murine mammary carcinoma and separated into treatment and control groups. CD40 agonist antibody was delivered intratumorally via NDES. Radiotherapy was administered at 8 Gy for three consecutive days and implantation of the NDES occurred the day after the final fraction of radiation. The tumor growth curve was plotted and tumor, spleen, lymph nodes, lungs, and blood were collected at the study endpoint for further flow cytometry and histological analysis. Results: The combination of radiotherapy and sustained intratumoral CD40 antibody showed significantly decreased tumor growth rates over radiotherapy or sustained intratumoral immunotherapy alone. Both intratumoral and systemic T-cell activation was observed. Mice treated with sustained intratumoral CD40 antibody showed decreased toxicity when compared to those receiving comparable systemic dosage. Conclusions: Radiotherapy combined with local sustained intratumoral immunotherapy is a potential strategy for improving treatment of solid tumors which currently show suboptimal response to current immunotherapy regimens and for inducing a systemic response to distant metastases while minimizing adverse side effects. The sustained delivery profile of the NDES presents an opportunity for practical intratumoral administration and avoidance of repeated invasive procedures in patients.

Advancements in molecular biology and the ability to prime the immune system to target cancer cells have opened new frontiers in anti-cancer therapy, particularly in the metastatic setting.

BACKGROUND: Immune checkpoint inhibitors (ICI) are an increasingly common therapy for metastatic solid tumors. Despite their efficacy, many patients develop brain metastasis requiring stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (SRT). Radiation necrosis (RN) is a known risk. Recent observations suggest that patients receiving SRT/ICI may experience synergism albeit with potential increased risk of symptomatic RN. The best treatment in this setting remains unknown. VEGF inhibitors have demonstrable efficacy in treatment of RN and may be beneficial in treating neurotoxicity associated with combination SRT/ICI. METHODS: Data were analyzed retrospectively from 169 consecutive patients at a single institution undergoing SRS/SRT for brain metastasis from 2015–2017. 10 patients were eligible for evaluation having received SRT and ICI within a 6 month timeframe and with a minimum 3 months survival for assessment of RN. 7 patients were treated for lung adenocarcinoma, 2 for high-grade neuroendocrine tumor, and 1 with triple-negative breast cancer. RESULTS: 10 patients were treated with SRS (90%), SRT (60%), both (50%), or SRS followed by whole-brain radiation (10%) to a total of 65 brain metastases. ICI (nivolumab, pembrolizumab, atezolizumab, ipilimumab) was administered before, during, or after SRS/SRT. 6 patients (60%) developed symptomatic grade ≥ 1 neurological adverse events. Of these 6, 4 (40%) developed grade 3 RN requiring bevacizumab. Symptoms resolved rapidly in 3 of 4 patients (75%), the 4(th) patient died of complications of disease shortly after bevacizumab administration. Mean 12 month survival from initial immunotherapy treatment was 89% and mean 18 month survival from initial SRT was 78%. CONCLUSION: Combination treatment with SRT/ICI for brain metastases appears to be associated with high rates of RN compared to historical standards. Given the prolonged survival seen, appropriate management of this complication is paramount. Short course bevacizumab appears highly effective in treating symptomatic RN associated with ICI. Further evaluation with a larger sample size is warranted.

The purpose of this study was to compare the traditional involved-field radiation therapy (IFRT) which includes all sites of initial disease to response-based IFRT which includes only sites of bulky disease for rapid early responders (RER) in high-risk Hodgkin lymphoma. IFRT treatment plans (one traditional and one response-based), each delivering 21 Gy, were designed for seven pediatric patients with stage IIIB/IVB Hodgkin lymphoma. Dose–volume histograms (DVH) were created to determine the dose to the clinical target volume (CTV) and each organ at risk (OAR) for each treatment plan. The average CTV for the traditional IFRT was 1,491.3 cm3 and for response-based IFRT was 566.7 cm3 (p = 0.02). Response-based treatment reduced the average dose to the lungs from 13.3 to 6.5 Gy (p = 0.006), heart from 17.2 to 6.5 Gy (p = 0.004), breasts from 9.8 to 2.5 Gy (p = 0.003), thyroid from 21.7 to 6.1 Gy (p = 0.003), parotid glands from 8.6 to 0.8 Gy (p = 0.01), kidneys from 5.2 to 0.4 Gy (p = 0.02), liver from 8 to 0.5 Gy (p = 0.005), and spinal cord from 17.5 to 5.7 Gy (p = 0.001). Treating response-adapted reduced IFRT to sites of initial bulky disease for RER resulted in significant volume and dose reductions to the CTV and OAR when compared to the traditional IFRT. This reduction of dose to OAR may translate to a reduction of normal tissue toxicity and radiation late effects.

Objectives/Hypothesis Develop a novel three-dimensional (3-D) anatomical model to assist in improving spatial knowledge of the skull base, paranasal sinuses, and adjacent structures, and validate the utilization of 3-D reconstruction to augment two-dimensional (2-D) computed tomography (CT) for the training of medical students and otolaryngology–head and neck surgery residents. Study Design Prospective study. Methods A study of 18 subjects studying sinus anatomy was conducted at a tertiary academic center during the 2011 to 2012 academic year. An image processing and 3-D modeling program was used to create a color coded 3-D scalable/layerable/rotatable model of key paranasal and skull base structures from a 2-D high-resolution sinus CT scan. Subjects received instruction of the sinus anatomy in two sessions, first through review of a 2-D CT sinus scan, followed by an educational module of the 3-D reconstruction. After each session, subjects rated their knowledge of the sinus and adjacent structures on a self-assessment questionnaire. Results Significant improvement in the perceived understanding of the anatomy was noted after the 3-D educational module session when compared to the 2-D CT session alone (P

Perifosine was developed as a membrane-targeted alkylphospholipid that inhibits the PI3K/AKT pathway and has been suggested as a favorable candidate for combined use of radiotherapy. To better define the optimal schedule for this combination, we investigated schedule-dependent cytotoxic effects of perifosine and radiotherapy against prostate carcinoma cell lines in vitro. Human prostate cancer cell line CWR22RV1 and LNCaP were incubated with perifosine (5, 20, 40 μM) and treated with radiation (2, 4, 6, 8 Gy). Three different schedules were used: simultaneous treatment (R + P), perifosine followed by radiotherapy (P → R), and vice versa (R → P). Cell growth inhibition was determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. The effects of drug combinations at the concentration producing 80 % cell growth inhibition were analyzed by the isobologram method (Steel and Peckham). Colony formation assay was also conducted to confirm the result of MTS assay. Western blot analysis was used to explore the molecular mechanism of action for the combination of perifosine and irradiation. The R → P schedule showed the most significant cell growth inhibition when compared to other schedules (p

Objectives To evaluate biochemical non-evidence of disease and adverse events of salvage intensity-modulated radiotherapy using an endorectal balloon for prostate cancer patients after radical prostatectomy. Methods Data of 107 patients (median age 65 years) with persistent (>0.1 ng/mL) or rising prostate-specific antigen after radical prostatectomy were retrospectively analyzed. The mean dose to clinical target volume was 70 Gy in 32 fractions (the equivalent dose in 2 Gy fraction is 73.2 Gy based on α:β = 2). Biochemical non-evidence of disease and predictive factors were assessed. Genitourinary toxicity and gastrointestinal toxicity were also evaluated using the Radiation Therapy Oncology Group toxicity criteria. Results The median follow up was 37 months (range 6–126 months). A total of 48 patients developed biochemical recurrence. The 3- and 5-year biochemical non-evidence of disease rates of all patients were 52.6% and 48.8%, respectively. The Gleason score (≥4 + 3, ≤3 + 4) and pre-intensity-modulated radiotherapy prostate-specific antigen level (≥0.5 ng/mL

This paper is a retrospective report of the treatment of six patients with severely resorbed maxillae. Patients were treated, based on the amount of maxillary retrognathia, with either a Le Fort I downfracture or a "horseshoe" interpositional sandwich osteotomy, along with sinus elevation. Recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier was used for grafting in all patients, either alone or in combination with other grafting materials. Implants were placed and the patients were restored with fixed prostheses. Both grafting techniques are described, and the treated patients are presented.

Purpose The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged γ-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

In certain ductal carcinoma in situ (DCIS) subpopulations, there is no consensus regarding whether to postoperatively irradiate; decisions are often made based on potential risk of cardiac toxicities. Given the utility of Surveillance, Epidemiology, and End Results (SEER) data for studying cardiac mortality in invasive disease, this is the first such study specific for DCIS patients, evaluating trends in cardiac mortality after left-sided radiotherapy (RT). The SEER database was queried for patients with DCIS that received RT and had known unilaterality. The central design of this study was to compare cardiac-specific mortality (CSM) between left- and right-sided DCIS patients as stratifying for “older” RT (1973–1982) versus more “modern” RT (1983–1992 or 1993–2002). Survival analysis was performed using Kaplan–Meier methodology and multivariate Cox regression modeling for factors associated with overall survival (OS) and CSS. Left- and right-sided patients were demographically balanced. CSM was worse for left-sided patients with DCIS diagnosed in 1973–1982 [hazard ratio (HR) 1.295; 95% confidence interval (CI) 1.182–1.420], but not in 1983–1992 (HR 1.022; 95% CI 0.949–1.100) or in 1993–2002 (HR 0.989; 95% CI 0.935–1.046)]. On multivariate analysis, laterality was not associated with OS in either decade. However, left-sided laterality was independently associated with CSM during the 1973–1982 time period, but not the more recent time periods. Examining temporal patterns in the 1973–1982 cohort, cardiac mortality was significantly increased during 10–19 and ≥20 years after diagnosis, but there was no significant increase in cardiac mortality for patients diagnosed up to 10 years after diagnosis. In the largest such DCIS series to date, left-sided RT was an independent risk factor for increased cardiac mortality from 1973 to 1982, but not after 1983. Using modern RT techniques and maintaining low heart doses, RT may not induce excess CSM in the DCIS population.

Purpose The standard treatment for stage IB1 and IIA1 cervical carcinoma is surgery. For non-operative cases, the National Comprehensive Cancer Network recommends definitive radiotherapy (RT) with or without chemotherapy. This study sought to determine whether the addition of chemotherapy to RT improved overall survival (OS) for patients with stage IB1 and IIA1 cervical cancer. Methods We used the National Cancer Data Base to identify patients with stage IB1 or stage IIA1 cervical cancer diagnosed in 2004 to 2012 who received definitive RT with or without chemotherapy. Patient, tumor, and treatment facility characteristics were assessed. Kaplan-Meier analysis was performed to compare overall survival (OS) between groups. Cox regression analysis was performed to identify factors associated with survival. Propensity-score matching was used to compare survival outcomes while accounting for indication bias. Results 825 patients met the specified criteria. 275 (33.3%) of patients received treatment with RT alone, whereas 550 (66.7%) were treated with CRT. The median OS in patients treated with RT alone was 121.1months, while the median OS for patients treated with CRT was not reached (hazard ratio [HR]=0.719; 95% confidence interval [CI] 0.549–0.945). Propensity-score matched analysis confirmed that CRT was superior to RT alone (HR=0.701; 95% CI 0.509 to 0.963). Conclusions Our study suggests the addition of chemotherapy to definitive RT in patients with stage IB1 or stage IIA1 cervical cancer is associated with an improvement in OS. Prospective studies are recommended to validate these results and to further investigate the quality of life differences associated with chemotherapy use.

Purpose: Accelerated partial breast irradiation (APBI) using a single-lumen device is associated with better cosmetic outcomes if the spacing between the applicator and skin is > 7 mm. However, there are no reports addressing the late toxicity and clinical outcomes in patients treated with single-entry multi-lumen/catheter applicators who had close skin spacing (7 mm or less). We undertook this study to report clinical outcome, acute and late toxicity as well as cosmesis of early stage breast cancer patients with close skin spacing treated with APBI using multi-lumen or multi-catheter devices. Material and methods : This is a retrospective study of all breast cancer patients who had undergone APBI using single-entry multi-lumen/catheter devices in a single institution between 2008 to 2012. The study was limited to those with ≤ 7 mm spacing between the device and skin. Results : We identified 37 patients and 38 lesions with skin spacing of ≤ 7 mm. Seven lesions (18%) had spacing of ≤ 3 mm. Median follow-up was 47.5 months. There was one case of ipsilateral breast recurrence and one ipsilateral axillary recurrence. Based on RTOG criteria, 22 treated lesions experienced grade 1 and 9 lesions experienced grade 2 toxicity. Twenty-one lesions experienced late grade 1 toxicity. One patient had to undergo mastectomy due to mastitis. Twenty-four treated breasts showed excellent and 11 had good cosmetic outcome. Overall cosmesis trended towards a significant correlation with skin spacing. However, all patients with ≤ 3 mm skin spacing experienced acute and late toxicities. Conclusions : Accelerated partial breast irradiation can be safely performed in patients with skin spacing of ≤ 7 mm using single-entry multi-lumen/catheter applicators with excellent cosmetic outcomes and an acceptable toxicity profile. However, skin spacing of ≤ 3 mm is associated with acute and late toxicity and should be avoided if possible.

Use of Rituximab for diffuse large B cell lymphoma (DLBCL) has improved outcomes and led to further questions regarding the benefit of consolidative radiation therapy (RT). This study sought to determine changes in RT utilization following the incorporation of Rituximab for treatment of early stage DLBCL and to examine survival outcomes.We included patients in the Surveillance, Epidemiology, and End Results database, diagnosed with Stage I-II DLBCL between 1992 and 2011. Linear regression was performed to determine rate of RT utilization over time during the pre- and post-Rituximab eras (1992-2001 vs. 2002-2011). Kaplan-Meier and Cox Regression were performed to compare overall survival (OS) for patients treated with or without RT. Propensity-score matching was used to compare survival outcomes to account for indication bias.34,680 patients met the specified criteria. RT utilization was 35.2% in the pre-Rituximab era and 29.9% in the post-Rituximab era (​P0.001). Linear regression revealed that in the pre-Rituximab era the slope of the best fit line for RT utilization by year was positive (m=0.01, ​P=0.0046), while the slope was negative in the post-Rituximab era (m=-0.008, ​P=0.0102). RT use was associated with improved OS in both the pre-Rituximab era (hazard ratio [HR]=0.797; 95% confidence interval [CI] 0.756-0.841) and the post-Rituximab era (HR=0.745; 95% CI 0.702-0.789). Propensity-score matched analysis confirmed that RT use improved OS in the pre-Rituximab era (HR=0.844; 95% CI 0.793-0.897) and post-Rituximab era (0.754; 95% CI 0.703-0.809).RT utilization has decreased following incorporation of Rituximab for first line treatment of DLBCL. RT use is associated with improved OS in both pre- and post-Rituximab eras, suggesting that RT should continue to be used for management of early stage DLBCL, even in the era of Rituximab.

The purpose of this study is to determine whether the use of helical tomotherapy can reduce dose to the heart, breast tissue, and thyroid gland in children receiving whole lung irradiation (WLI). Computed tomography simulation scans from nine pediatric patients previously treated with WLI were used for this dosimetry study. Each scan was alternatively planned using helical tomotherapy to minimize dose to surrounding critical structures. The clinical target volume (CTV) included both lungs. The ribs and spine in proximity to the lungs were included in the CTV to minimize bone asymmetry resulting from partial irradiation. The planning target volume (PTV) included the CTV with a 0.8-cm margin. The following structures were contoured: right atrium, left atrium, right ventricle, left ventricle, right and left breast, thyroid gland, and the humeral heads. Median dose (D med), minimum dose (D min), and maximum dose (D max) for the PTV, CTV, heart chambers, thyroid gland, right and left breast as well as right and left humeral heads were also obtained. The median PTV receiving the prescription dose was 97 %, with PTVs ranging from 95 to 99 %. The average D med for each of the four chambers of the heart ranged from 37 to 55 % of the prescription dose. The average D med for the breasts ranged from 88 to 95 % while for the thyroid gland was 10 % of the prescription dose. Helical tomotherapy can minimize the radiation dose delivered to nontarget organs such as the heart, breasts, and thyroid gland.

Owing to the liver’s integral role in biosynthesis and homeostasis, management of primary and secondary malignancies arising in this organ is of paramount oncologic significance. Over the past several decades, substantial progress has been achieved in the imaging and treatment of early and advanced hepatic malignancies. Radiation therapy (RT) has recently emerged as one of many local therapeutic options for both primary and metastatic liver cancer. Recent phase I and II studies describe promising efficacy and side effect profile; however, phase III studies are needed to establish RT among standard of care therapeutic modalities. In this review, we will describe (a) the scope, epidemiology, and standard treatment options for liver cancer; (b) relevant diagnostic imaging techniques; and (c) provide an in-depth review of RT treatment techniques, dose–volume limits of normal tissues, and results of both conventional and hypofractionated RT liver trials pertaining to primary and secondary liver cancers with emphasis on three-dimensional conformal radiation therapy (3DCRT) and stereotactic body radiotherapy (SBRT) studies.

Treatment for small-cell carcinoma of the bladder is largely guided by case reports, retrospective reviews, and small prospective trials. This study aimed to study outcomes using a large population-based database.The Surveillance, Epidemiology, and End Results-Medicare database (1991-2005) was used to analyze how different treatment combinations of specific bladder surgeries, chemotherapy, and radiation affected patient outcomes. Trends in the use of these combinations over time were also analyzed.A total of 533 patients were retrieved from the database. A bladder-sparing approach involving transurethral resection of the bladder tumor (TURBT) combined with chemotherapy and radiation yielded no significant difference in overall survival compared with patients undergoing at least a cystectomy (of whom over 90% received radical cystectomy) with chemotherapy (p0.05). The analysis of treatment trends indicated that these two general strategies for cure combined to account for fewer than 20% of patients. A majority of patients (54%) received TURBT as their only surgical treatment, and a subset analysis of these patients indicated that chemotherapy played a role in all stages of disease (p0.05) whereas radiation improved overall survival in regional-stage disease (p0.05).Relatively few patients with small-cell carcinoma of the bladder receive potentially curative therapies. Chemotherapy should be a major component of treatment. Cystectomy and bladder-sparing approaches represent two viable strategies and deserve further investigation to identify the patients who may benefit from organ preservation or not. In addition, the role of radiation in regional-stage disease should be investigated further, because it positively affects survival after TURBT.

Purpose The purpose of this study is to evaluate the relationship between testicular dose and serum testosterone (TE) level in low-risk prostate cancer patients treated with intensity-modulated radiotherapy (IMRT).

To investigate the utility of stereotactic body radiotherapy (SBRT) in the treatment of painful renal cell carcinoma (RCC) bone metastases, and for a possible dose effect on time to symptom relief.Eighteen patients with 24 painful osseous lesions from metastatic RCC were treated with SBRT. The most common treatment regimens were 24 Gy in 3 fractions and 40 Gy in 5 fractions. The times from treatment to first reported pain relief and time to symptom recurrence were evaluated. Median follow-up was 38 weeks (1-156 weeks).Seventy-eight percent of all patients had pain relief. Patients treated with a BED85 Gy achieved faster and more durable pain relief compared to those treated with a BED85 Gy. There was decrease in time to pain relief after a change in treatment regimen to 8 Gy × 5 fractions (BED = 86). There was only one patient with grade 1 skin toxicity. No neurological or other toxicity was observed.SBRT can safely and effectively treat painful RCC bony metastases. There appears to be a relationship between radiation dose and time to stable pain relief.

Stereotactic body radiation therapy (SBRT) is a promising treatment option for prostate cancer. Hypofractionation regimens, such as SBRT, may be more advantageous compared with conventional regimens because low α:β ratio of prostate cancer has high sensitivity to dose per fraction. In addition, a smaller and tighter margin with SBRT is expected to provide a low toxicity rate without reducing tumor control. The purpose of this article is to examine radiobiological, technical and clinical aspects of SBRT for prostate cancer.

Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit robust anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic drug-eluting seed (NDES). The NDES is inserted intratumorally using a minimally invasive trocar method similar to brachytherapy seed insertion and offers a clinical advantage of intratumoral drug elution. Drug diffusion from the NDES is regulated by physical and electrostatic nanoconfinement, thereby resulting in constant and sustained immunotherapeutic delivery without the need for repeated injections or clinician intervention. In this study, the NDES was utilized to deliver immunotherapeutics intratumorally in the 4T1 orthotopic murine mammary carcinoma model, which recapitulates triple negative breast cancer. We demonstrated that NDES-mediated intratumoral release of agonist immunotherapeutic monoclonal antibodies, OX40 and CD40, resulted in potentiation of local and systemic anti-tumor immune response and significant inhibition of tumor growth compared to control mice. Further, mice treated with NDES-CD40 demonstrated minimal liver damage compared to systemically treated mice. Collectively, our study highlights the NDES as an effective platform for sustained intratumoral immunotherapeutic delivery. The potential clinical impact is tremendous given that the NDES is applicable to a broad spectrum of drugs and solid tumors. Citation Format: Corrine Ying Xuan Chua, Priya Jain, Marco Folci, Andrea Ballerini, Jessica Rhudy, April Gilbert, Shail Shaibala, Giacomo Bruno, Carly S. Filgueira, Cassian Yee, E. Brian Butler, Alessandro Grattoni. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1708.

182 Background: In the treatment of gastroesophageal junction (GEJ) cancer, trimodality treatment with preoperative chemoradiation followed by surgery is the standard of care. However, predicting patient survival outcomes remains difficult. One possible means of predicting outcomes is comparing pre-treatment PET-CT with post-treatment PET-CT to see if a favorable response on imaging correlates with survival outcomes. Methods: We conducted a retrospective chart review of locally advanced GEJ cancer patients who underwent preoperative chemoradiotherapy followed by esophagectomy with negative margins. All patients underwent two PET-CT scans (before and after preoperative chemoradiation). We compared PET-CT imaging results and pathology results with survival outcomes. Values such as pre-treatment max SUV, post-treatment max SUV, change in max SUV, percent residual max SUV, complete response on PET-CT, and pathologic complete response were analyzed for potential impacts on recurrence rates and survival outcomes. Results: Forty patients had sufficient data to be included in our study. The median follow-up was 22.5 months. The majority of patients were male (82.5%), Caucasian (84.2%) and had adenocarcinoma histology (97.5%). Altogether, 75% of patients had stage III disease and 67.5% had locoregional nodal involvement. The majority (90%) of patients received some form of taxane and platinum based chemotherapy. Pre-treatment max SUV, post-treatment max SUV, change in max SUV, percent residual max SUV, and complete response on PET-CT were not associated with local recurrence, regional recurrence, disease-free survival, or overall survival. Pathologic complete response was associated with a decrease in the rate of distant metastasis ( P= 0.021) but not disease-free survival ( P= 0.411) or overall survival ( P= 0.878). Conclusions: Response on PET-CT after preoperative chemoradiation is not a predictive factor for recurrence, disease-free survival, or overall survival. Pathologic complete response predicted for a decrease in the rate of distant metastasis but not disease-free survival or overall survival.

Management of cT4b bladder cancer is poorly defined; national guidelines recommend chemotherapy (CT) alone or chemoradiation (CRT). Using a large, contemporary dataset, we evaluated national practice patterns as well as associated outcomes, especially with respect to radical cystectomy (RC) and CRT versus CT alone.The National Cancer Data Base was queried (2004-2013) for patients diagnosed with cT4bN0-3M0 bladder cancer. Patients were divided into 5 treatment groups: CT alone, CRT, RC (with/without CT/radiotherapy [RT]), other treatment (subtherapeutic RT with/without CT), or no treatment. Statistics included multivariable logistic regression to determine factors predictive of observation, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS.Of 896 total patients, 185 (20.6%) underwent CT alone, 80 (8.9%) CRT, 161 (18.9%) RC, 221 (24.7%) other treatments, and 249 (27.8%) observation. Differences in treatment paradigms were appreciated based on age, gender, nodal status, insurance, and facility-related parameters. Observation yielded a median OS of 3.7 months, lower than CT alone (P .001). As compared with the latter, CRT was associated with higher OS (10.5 vs. 12.1 months, P = .004). RC-based treatment displayed the numerically highest OS (14.2 months) and was statistically similar to CRT (P = .676). Treatment with any modality independently predicted for superior OS over observation.In the largest study of its kind, a surprisingly high proportion of patients underwent observation. CRT is associated with higher survival over CT alone, and carefully selected patients undergoing RC may experience prolonged survival.

Stereotactic radiosurgery (SRS) is one of the least invasive treatments for trigeminal neuralgia (TN). To date, most reports have been about Cobalt-based treatments ( i.e., Gamma Knife) with limited data on image-guided stereotactic linear accelerator treatments. We describe our initial experience of using BrainLAB Novalis stereotactic system for the radiosurgical treatment of TN. A total of 20 patients were treated between July 2004 and February 2007. Each SRS procedure was performed using the BrainLAB Novalis System. Thin cuts MRI images of 1.5 mm thickness were acquired and fused with the simulation CT of each patient. Majority of the patients received a maximum dose of 90 Gy. The median brainstem dose to 1.0 cc and 0.1 cc was 2.3 Gy and 13.5 Gy, respectively. In addition, specially acquired three-dimensional fast imaging sequence employing steady-state acquisition (FIESTA) MRI was utilized to improve target delineation of the trigeminal proximal nerve root entry zone. Barrow Neurological Index (BNI) pain scale for TN was used for assessing treatment outcome. At a median follow-up time of 14.2 months, 19 patients (95%) reported at least some improvement in pain. Eight (40%) patients were completely pain-free and stopped all medications (BNI Grade I) while another 2 (10%) patients also stopped medications but reported occasional pain (BNI Grade II). Another 2 (10%) patients reported no pain and 7 (35%) patients only occasional pain while continuing medications, BNI Grade IIIA and IIIB, respectively. Median time to pain control was 8.5 days (range: 1–70 days). No patient reported severe pain, worsening pain or any pain not controlled on their previously taken medication. Intermittent or persistent facial numbness following treatments occurred in 35% of patients. No other complications were reported. Stereotactic radiosurgery using the BrainLAB Novalis system is a safe and effective treatment for TN. This information is important as more centers are obtaining image-guided stereotactic-based linear accelerators capable of performing radiosurgery.

Combined modality treatment (neoadjuvant chemoradiotherapy followed by surgery) for locally advanced rectal cancer requires special attention to various organs at risk (OAR). As a result, the use of conformal dose delivery methods has become more common in this disease setting. Helical tomotherapy is an image-guided intensity modulated delivery system that delivers dose in a fan-beam manner at 7 degree intervals around the patient and can potentially limit normal tissue from high dose radiation while adequately treating targets. In this study we dosimetrically compare helical tomotherapy to 3D-CRT for stage T3 rectal cancer. The helical tomotherapy plans were optimized in the TomoPlan system to achieve an equivalent uniform dose of 45 Gy for 10 patients with T3N0M0 disease that was at least 5cm from the anal verge. The GTV included the rectal thickening and mass evident on colonoscopy and CT scan as well as with the help of a colorectal surgeon. The CTV included the internal iliac, obturator, and pre-sacral lymphatic chains. The OAR that were outlined included the small bowel, pelvic bone marrow, femoral heads, and bladder. Anatom-e system was used to assist in delineating GTV, CTV and OAR. These 10 plans were then duplicated and optimized into 3-field 3D-CRT plans within the Pinnacle planning system. The V[45], V[40], V[30], V[20], V[10], and mean dose to the OAR were compared between the helical tomotherapy and 3D-CRT plans. Statistically significant differences were achieved in the doses to all OAR, including all volumes and means except for V[10] for the small bowel and the femoral heads. Adequate dosimetric coverage of targets were achieved with both helical tomotherapy and 3D-CRT. Helical tomotherapy reduces the volume of normal tissue receiving high-dose RT when compared to 3D-CRT treatment. Both modalities adequately dose the tumor. Clinical studies addressing the dosimetric benefits are on-going.

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) programs to treat brain tumors were implemented when we first acquired the Brainlab Novalis system in 2003. Two years later, we started an extra-cranial stereotactic radio-ablation or more appropriately a stereotactic body radiation therapy (SBRT) program using the Brainlab Novalis image-guided system at The Methodist Hospital in Houston, Texas. We hereby summarize our initial experience with this system in delivering image-guided SBRT to a total of 80 patients during our first year of clinical implementation, from February 2005 to January 2006. Over 100 lesions in more than 20 distinct anatomical sites were treated. These include all levels of spine from cervical, thoracic, lumbar, and sacral lesions. Spinal lesions encompass intramedullary, intradural, extradural, or osseous compartments. Also treated were lesions in other bony sites including orbit, clavicle, scapula, humerus, sternum, rib, femur, and pelvis (ilium, ischium, and pubis). Primary or metastatic lesions located in the head and neck, supraclavicular region, axilla, mediastinum, lung (both central and peripheral), abdominal wall, liver, kidney, para-aortic lymph nodes, prostate, and pelvis were also treated. In addition to primary radiotherapy, SBRT program using the Brainlab Novalis system allows re-irradiation for recurrence and “boost” after conventional treatment to various anatomical sites. Treating these sites safely and efficaciously requires knowledge in radiation tolerance, fraction size, total dose, biologically equivalent dose (BED), prior radiotherapy, detailed dose volume histograms (DVH) of normal tissues, and the radiosensitive/radioresistant nature of the tumor. Placement of radio-opaque markers (Visicoil, Radiomed) in anatomical sites not in close proximity to bony landmarks (e.g., kidney and liver) helps in measuring motion and providing image guidance during each treatment fraction. Tumor/organ motion data obtained using 4D-CT while the patient is immobilized in the body cast aids in planning treatment margin and determining the need for respiratory motion control, e.g., abdominal compressor, gating, or active breathing control. The inclusion of PET/CT to the Brainlab treatment planning system further refines the target delineation and possibly guides differential fraction size prescription and delivery. The majority of the patients tolerated the SBRT treatment well despite the longer daily treatment time when compared to that of conventional treatment. All patients achieved good pain relief after SBRT. Compared to conventional standard radiotherapy of lower daily fraction size, we observed that the patients achieved faster pain relief and possibly more durable symptom control. Very high local control with stable disease on imaging was observed post SBRT. Our initial experience shows that the Brainlab Novalis system is very versatile in delivering image-guided SBRT to various anatomical sites. This SBRT approach can be applied to either primary or metastatic lesions in the primary, “boost,” or re-irradiation settings. The understanding of fraction size, total dose, BED, and DVH of normal tissues is very important in the treatment planning. Appropriate use of immobilization devices, radio-opaque markers for image-guidance, 4D-CT for tumor/organ motion estimates, and fusion of planning CT scans with biological/functional imaging will further improve the planning and delivery of SBRT, hopefully leading to better treatment outcome.

Renal cell carcinoma (RCC) is often regarded as a radiation-resistant tumor. However, radiation therapy (RT) in the form of stereotactic radiosurgery (SRS) or whole-brain irradiation has been used to treat brain metastases from RCC. To date, there have been no clinical pathologic correlative findings before and after RT. Herein, we present a case of a patient with brain metastases from RCC treated with SRS. The diagnosis of clear-cell RCC was made in 2001 after right radical nephrectomy. He was also found to have lung metastases at diagnosis. He presented with neurologic symptoms in 2004, and magnetic resonance imaging showed 3 brain lesions with a significant amount of edema consistent with brain metastases. The largest lesion caused a midline shift and was surgically resected. Pathology revealed metastatic RCC. The other 2 smaller brain lesions were treated at 20 Gy respectively with shaped-beam SRS using the BrainLab Novalis system. No whole-brain irradiation was delivered. However, the patient had difficulty weaning off his steroids, and a magnetic resonance imaging performed 6 months after SRS was read as "progression of the lesions." He then underwent resection of both the irradiated brain lesions. Pathologic examination revealed necrotic tissues without any viable tumor identified. The patient has since been doing very well, now 18 months after SRS and 5 years from the initial diagnosis. This is the first reported case that demonstrates that precise high-dose radiation in the form of SRS can cause significant tumor cell death (pathologic complete response) in radiation-resistant brain metastases from RCC. This finding also provides a rationale to deliver stereotactic body RT for primary and metastatic RCC extracranially. A prospective clinical trial using stereotactic body RT for primary and metastatic RCC is under way.

In situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult metastatic disease. We are currently conducting three clinical trials using in situ adenoviral vector mediated herpes simplex virus-thymidine kinase (HSV-tk) gene delivery followed by the HSV-tk prodrug ganciclovir (GCV) or valacyclovir (VCV). This study evaluates the systemic T-cell response after gene therapy in each trial.The study protocol included three separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in prostate cancer patients failing radiotherapy (36 patients), Trial B neoadjuvant gene therapy in pre-radical prostatectomy patients (22 patients), and Trial C gene therapy in combination with radiotherapy for prostate cancer (27 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward. A complete blood count was performed, and peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting after labeling with dual color-labeled antibody pairs.The pretreatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 12.23%, 16.72%, and 14.09% (Trials A, B, and C, respectively). Two weeks posttreatment, this increased to 22.87%, 26.15%, and 39.04% (Trials A, B, and C, respectively), and these increases were statistically significant (p = 0.0188, p = 0.0010, p0.0001, respectively). The increase of DR+CD8+ T cells was significantly larger in Trial C than in Trial A (p = 0.0044) or Trial B (p = 0.0288). Total CD8+ T cells significantly increased at 2 weeks posttreatment in Trial B and C (p = 0.0013, p = 0.0004, respectively). Interestingly, only in Trial C were significant increases in activated CD4+ T cells seen at 2 weeks (p = 0.0035).This is the first report of systemic T-cell responses after HSV-tk+GCV/VCV gene therapy under three clinical trial conditions. There was an increase in activated CD8+ T cells in the peripheral blood after vector injection, suggesting the potential for activation of components of cell-mediated immune response in all trial conditions. The addition of radiotherapy to in situ gene therapy seems to further increase the total CD8+ T cells and activated CD4+ T cells.

JAMES M. GALVIN D.SC.,* GARY EZZELL, PH.D., AVRAHAM EISBRAUCH, M.D.,* CEDRIC YU, D.SC., BRIAN BUTLER, M.D.,* YING XIAO, PH.D., ISAAC ROSEN, PH.D., JULIAN ROSENMAN, M.D.,* MICHAEL SHARPE, PH.D., LEI XING, PH.D., PING XIA, PH.D., TONY LOMAX, PH.D., DANIEL A. LOW, PH.D., AND JATINDER PALTA, PH.D. *American Society for Therapeutic Radiology and Oncology IMRT Scope Committee; American Association of Physicists in Medicine IMRT Subcommittee of the Radiation Therapy Committee

There is an evolving role for combining radiotherapy (RT) with gene therapy in the management of prostate cancer. However, the clinical results of this combined approach are much needed. The preliminary results addressing the safety of this Phase I-II study combining RT and gene therapy (adenovirus/herpes simplex virus-thymidine kinase gene/valacyclovir with or without hormonal therapy) in the treatment of prostate cancer have been previously reported. We now report the prostate-specific antigen (PSA) response and biopsy data.This trial was composed of three separate arms. Arm A consisted of low-risk patients (Stage T1-T2a, Gleason score7, pretreatment PSA10 ng/mL) treated with combined RT-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated RT. They also received adenovirus/herpes simplex virus-thymidine kinase/valacyclovir gene therapy. Arm B consisted of high-risk patients (Stage T2b-T3, Gleason score6, pretreatment PSA level10 ng/mL) treated with combined RT-gene therapy and hormonal therapy (luteinizing hormone-releasing hormone agonist [30-mg Lupron, 4-month depot] and an antiandrogen [flutamide, 250 mg t.i.d. for 14 days]). Arm C consisted of patients with Stage D1 (positive pelvic lymph nodes) who received the same regimen as Arm B with the addition of 45 Gy to the pelvic lymphatics. PSA determination and biopsy were performed before, during, and after treatment. The American Society for Therapeutic Radiology and Oncology consensus definition (three consecutive rises in PSA level) was used to denote PSA failure.Fifty-nine patients (29 in Arm A, 26 in Arm B, and 4 in Arm C) completed the trial. The median age was 68 years (range, 39-85 years). The median follow-up for the entire group was 13.5 months (range, 1.4-27.8 months). Only Arm A patients were observed to have an increase in PSA on Day 14. The PSA then declined appropriately. All patients in Arm A (median follow-up, 13.4 months) and Arm B (median follow-up, 13.9 months) had biochemical control at last follow-up. Three patients in Arm C (with pretreatment PSA of 335, 19.6, and 2.5 ng/mL and a combined Gleason score of 8, 9, and 9 involving all biopsy cores) had biochemical failure at 3, 3, and 7.7 months. Two patients had distant failure in bone and 1 patient in the para-aortic lymph nodes outside the RT portal. Six to twelve prostate biopsies performed in these 3 patients revealed no evidence of residual carcinoma. In Arm A, biopsy showed no evidence of carcinoma in 66.7% (18 of 27), 92.3% (24 of 26), 91.7% (11 of 12), 100% (8 of 8), and 100% (6 of 6) at 6 weeks, 4 months, 12 months, 18 months, and 24 months after treatment, respectively. In Arm B, no evidence of carcinoma on biopsy was noted in 96% (24 of 25), 90.5% (19 of 21), 100% (14 of 14), 100% (7 of 7), and 100% (2 of 2), respectively, in the same interval after treatment.This is the first reported trial of its kind in the field of prostate cancer that aims to expand the therapeutic index of RT by combining it with in situ gene therapy. The initial transient PSA rise in the Arm A patients may have been a result of local immunologic response or inflammation elicited by in situ gene therapy. Additional investigation to elucidate the mechanisms is needed. Hormonal therapy may have obliterated this rise in Arm B and C patients. The biopsy data were encouraging and appeared to show no evidence of malignancy earlier than historical data. Combined RT, short-course hormonal therapy, and in situ therapy appeared to provide good locoregional control but inadequate systemic control in patients with positive pelvic lymph nodes. Longer term use of hormonal therapy in addition to gene therapy and RT has been adopted for this group of patients to maximize both locoregional and systemic control.

Purpose A pilot study was designed to evaluate the safety and efficacy of a novel regimen of hypofractionated intensity-modulated radiotherapy (RT) in the adjuvant treatment of primary glioblastoma multiforme (GBM). The rationale of the study was to combine the potential radiobiologic advantage of hypofractionation to GBM with a highly conformal radiotherapeutic technique. The study was designed to measure the acute and chronic morbidity of patients treated with this regimen, response of GBM to the treatment, overall survival, and time to disease progression after therapy completion. Methods and materials Twenty eligible patients were accrued between February 1999 and May 2000 for the study. All patients had Karnofsky performance scores of ≥70. All patients were treated with intensity-modulated RT using the NOMOS Peacock system. A dose of 50 Gy was delivered in 5-Gy daily fractions within 2 weeks to enhancing primary disease, residual tumor, or surgical cavity. Simultaneously, 30 Gy was prescribed in 3-Gy daily fractions to surrounding edema. The time to progression was measured with serial neurologic examinations and MRI or CT scans after RT completion. Acute and late toxicity was graded using Radiation Therapy Oncology Group neurotoxicity scores. Results Of the 20 patients, 18 were evaluated for outcome. The median time to disease progression was 6 months after RT completion. The median overall survival was 7 months after treatment completion. All recurrences were within 2 cm of the operative bed. Neurotoxicity during therapy was minimal, with all patients experiencing Grade 0 or 1 toxicity. Late toxicity included 10 patients with Grade 0, 2 patients with Grade 2, and 3 patients with Grade 4 toxicity, manifesting as brain necrosis requiring surgical reexcision. The survival of the 3 patients with brain necrosis was 23, 20, and 9 months. Mortality in all cases was the result of tumor recurrence, with no mortality resulting from brain necrosis. Conclusion This regimen of hypofractionated intensity-modulated RT did not improve the time to disease progression or overall survival compared with historical experience using conventional fractionation. However, the treatment duration was reduced from 6 weeks to 2 weeks, which may be of palliative benefit in certain subsets of patients. This treatment regimen demonstrated a greater incidence of brain necrosis requiring surgical intervention; however, the 3 patients experiencing this toxicity had longer survival times. Future investigation may be useful to determine which fraction size may be optimal for GBM when highly conformal RT is used in the adjuvant setting.

Intensity modulated radiation therapy (IMRT) is gaining widespread use in the radiation therapy community. Prostate cancer is the ideal target for IMRT due to the growing body of literature supporting dose escalation and normal tissue limitations. The need for dose escalation and the limits of conventional radiation therapy necessitate precise patient and prostate localization as well as advanced treatment delivery. The treatment of prostate cancer has been dramatically altered by the introduction of technology that can focus on the target while avoiding normal tissue. IMRT is evolving as the treatment of the future for prostate cancer.