Samir Patel

Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle

Glucose-capped gold nanoparticles (Glu-GNPs) have been used to improve cellular targeting and radio-sensitization. In this study, we explored the mechanism of Glu-GNP enhanced radiation sensitivity in radiation-resistant human prostate cancer cells. Cell survival and proliferation were measured using MTT and clonogenic assay. Flow cytometry with staining by propidium iodide (PI) was performed to study the cell cycle changes induced by Glu-GNPs, and western blotting was used to determine the expression of p53 and cyclin proteins that correlated to cell cycle regulation. With 2 Gy of ortho-voltage irradiation, Glu-GNP showed a 1.5-2.0 fold enhancement in growth inhibition when compared to x-rays alone. Comparing the cell cycle change, Glu-GNPs induced acceleration in the G0/G1 phase and accumulation of cells in the G2/M phase at 29.8% versus 18.4% for controls at 24 h. G2/M arrest was accompanied by decreased expression of p53 and cyclin A, and increased expression of cyclin B1 and cyclin E. In conclusion, Glu-GNPs trigger activation of the CDK kinases leading to cell cycle acceleration in the G0/G1 phase and accumulation in the G2/M phase. This activation is accompanied by a striking sensitization to ionizing radiation, which may have clinical implications.

A treatment planning study comparing helical tomotherapy with intensity-modulated radiotherapy for the treatment of anal cancer

PURPOSE A planning study to compare helical tomotherapy (HT) and intensity-modulated radiotherapy (IMRT) for the treatment of anal canal cancer. MATERIALS AND METHODS Sixteen (8 males and 8 females) patients with anal cancer previously treated radically were identified. HT and IMRT plans were generated and dosimetric comparisons of the plans were performed. The planning goals were to deliver 54Gy to the tumor (PTV(54Gy)) and 48Gy to the nodes at risk (PTV(Node)) in 30 fractions. RESULTS PTVs: HT plans were more homogeneous for both men and women. Male patients: HT vs. IMRT: D(max): 55.87+/-0.58 vs. 59.17+/-3.24 (p=0.036); D(min): 52.91+/-0.36 vs. 44.09+/-6.84 (p=0.012); female patients: HT vs. IMRT: D(max): 56.14+/-0.71 vs. 59.47+/-0.81 (p=0.012); D(min): 52.36+/-0.87 vs. 50.97+/-1.42 (p=0.028). OARs: In general, HT plans delivered a lower dose to the peritoneal cavity, external genitalia and the bladder and IMRT plans resulted in greater sparing of the pelvic bones (iliac crest/femur) for both men and women. Iliac crest/femur: the difference was significant only for the mean V10Gy of iliac crest in women (p< or =0.012). External genitalia: HT plans achieved better sparing in women compared to men (p< or =0.046). For men, the mean doses were 18.96+/-3.17 and 15.72+/-3.21 for the HT and IMRT plan, respectively (p< or =0.017). Skin: both techniques achieved comparable sparing of the non-target skin (p=NS). CONCLUSIONS HT and IMRT techniques achieved comparable target dose coverage and organ sparing, whereas HT plans were more homogeneous for both men and women.

Phase I study of hypofractionated intensity modulated radiation therapy with concurrent and adjuvant temozolomide in patients with glioblastoma multiforme

PurposeTo determine the safety and efficacy of hypofractionated intensity modulated radiation therapy (Hypo-IMRT) using helical tomotherapy (HT) with concurrent low dose temozolomide (TMZ) followed by adjuvant TMZ in patients with glioblastoma multiforme (GBM).Methods and materialsAdult patients with GBM and KPS > 70 were prospectively enrolled between 2005 and 2007 in this phase I study. The Fibonacci dose escalation protocol was implemented to establish a safe radiation fractionation regimen. The protocol defined radiation therapy (RT) dose level I as 54.4 Gy in 20 fractions over 4 weeks and dose level II as 60 Gy in 22 fractions over 4.5 weeks. Concurrent TMZ followed by adjuvant TMZ was given according to the Stupp regimen. The primary endpoints were feasibility and safety of Hypo-IMRT with concurrent TMZ. Secondary endpoints included progression free survival (PFS), pattern of failure, overall survival (OS) and incidence of pseudoprogression. The latter was defined as clinical or radiological suggestion of tumour progression within three months of radiation completion followed by spontaneous recovery of the patient.ResultsA total of 25 patients were prospectively enrolled with a median follow-up of 12.4 months. The median age at diagnosis was 53 years. Based on recursive partitioning analysis (RPA) criteria, 16%, 52% and 32% of the patients were RPA class III, class IV and class V, respectively. All patients completed concurrent RT and TMZ, and 19 patients (76.0%) received adjuvant TMZ. The median OS was 15.67 months (95% CI 11.56 - 20.04) and the median PFS was 6.7 months (95% CI 4.0 – 14.0). The median time between surgery and start of RT was 44 days (range of 28 to 77 days). Delaying radiation therapy by more than 6 weeks after surgery was an independent prognostic factor associated with a worse OS (4.0 vs. 16.1 months, P = 0.027). All recurrences occurred within 2 cm of the original gross tumour volume (GTV). No cases of pseudoprogression were identified in our cohort of patients. Three patients tolerated dose level I with no dose limiting toxicity and hence the remainder of the patients were treated with dose level II according to the dose escalation protocol. Grade 3–4 hematological toxicity was limited to two patients and one patient developed Grade 4 Pneumocystis jiroveci pneumonia.ConclusionHypo-IMRT using HT given with concurrent TMZ is feasible and safe. The median OS and PFS are comparable to those observed with conventional fractionation. Hypofractionated radiation therapy offers the advantage of a shorter treatment period which is imperative in this group of patients with limited life expectancy.

Treatment outcomes of squamous cell carcinoma of the oral cavity in young adults

OBJECTIVES The natural history of squamous cell carcinoma (SCC) of the oral cavity (OC) in young adults is unknown. We sought to provide an updated report on treatment outcomes of patients with OC SCC who were 40 years or younger. MATERIALS AND METHODS We performed a retrospective analysis of 124 consecutive patients with primary OC SCC treated at Mayo Clinic (1980-2014). Patient and tumor characteristics and treatment approach were abstracted from patient charts. RESULTS Median patient age was 35 years (range, 19-40 years). The most common primary site was oral tongue (107 patients; 86.3%). Most patients (101; 81.5%) underwent wide local excision. Surgery alone was curative in 77 patients (62.1%); 47 (37.9%) received radiotherapy, and 26 (21%) received chemotherapy. Five-year overall survival (OS) was 78.1%; 10-year OS was 76.9%. Five-year disease-free survival (DFS) was 66.6%; 5-year local control was 87.6%; and 5-year locoregional control was 78.5%. On multivariable analysis, factors associated with worse OS and DFS were higher pathologic T stage (P = .008), lymph node positivity (P < .001), and disease recurrence (P < .001). CONCLUSION Young adults with primary OC SCC may be treated with a similar treatment approach as older adults.

Choosing wisely after publication of level I evidence in breast cancer radiotherapy

Background Recent trials in early-stage breast cancer support hypofractionated whole-breast radiotherapy (WBRT) as part of breast-conserving therapy (BCT). Evidence also suggests that radiotherapy (RT) omission may be reasonable for some patients over 70 years. Among radiation-delivery techniques, intensity-modulated RT (IMRT) is more expensive than 3-dimensional conformal RT (3DCRT). Based on this evidence, in 2013, the American Society for Radiation Oncology (ASTRO) recommended hypofractionated schedules for women aged ≥50 years with early-stage breast cancer and avoiding routine use of IMRT for WBRT. To assess response to level I evidence and adherence to ASTRO recommendations, we evaluated the pattern of RT use for early-stage breast cancer at our National Comprehensive Cancer Network institution from 2006 to 2008 and 2011 to 2013 and compared the results with national trends. Methods Data from a prospective database were extracted to include patients treated with BCT, aged ≥50 years, with histologic findings of invasive ductal carcinoma, stage T1-T2N0M0, estrogen receptor-positive, and HER2 normal. We retrospectively reviewed the medical records and estimated costs based on 2016 Hospital Outpatient Prospective Payment System (technical fees) and Medicare Physician Fee Schedule (professional fees). Results Among 55 cases from 2006 to 2008, treatment regimens were 11% hypofractionated, 69% traditional schedule, and 20% RT omission (29% of patients were aged >70 years). Among 83 cases from 2011 to 2013, treatment regimens were 54% hypofractionated, 19% traditional schedule, and 27% RT omission (48% of patients were aged >70 years). 3DCRT was used for all WBRT treatments. Direct medical cost estimates were as follows: 15 fractions 3DCRT,

Palliative whole brain radiotherapy: Predictors of prescribing 5 versus 10 fractions.

7,197.87; 15 fractions IMRT,

A Phase I Study of Tomotherapy in Patients With Primary Benign and Low-grade Brain Tumors: Late Toxicity and Quality of Life.

11,232.33; 25 fractions 3DCRT,

Does expected survival influence palliative radiotherapy treatment recommendations

9,731.39; and 25 fractions IMRT,

Oropharyngeal Cancer Biology and Treatment: Insights From Messenger RNA Sequence Analysis and Transoral Robotic Surgery

16,877.45. Conclusion Despite apparent resistance to shorter radiation schedules in the United States, we demonstrate that rapid practice change in response to level I evidence is feasible. Wider adoption of evidence-based guidelines in early-stage breast cancer may substantially lower health care costs and improve convenience for patients without sacrificing oncologic outcomes.

Changes in Serial Magnetic Resonance Spectroscopy Predict Outcome in High-grade Glioma During and After Postoperative Radiotherapy

219 Background: The optimal dose for palliative whole brain radiotherapy (WBRT) continues to be debated. Common regimens include 20 Gy in five and 30 Gy in 10 fractions. We aimed to identify factors associated with WBRT dose schedules, hypothesizing that clinical prediction of survival (CPS) would influence prescribing practice. METHODS Demographic and clinicopathologic data were collected for consecutive patients with brain metastases receiving WBRT through a dedicated palliative radiation oncology clinic. At initial consultation, CPS were prospectively collected from treating radiation oncologists. Karnofsky performance status (KPS) and Mini-Mental Status Examination were available for 88.6% and 75.1%, respectively. Dose fractionation was collected and summary statistics calculated. Parameters were assessed for association with five fraction schedules using binary logistic regression, with odds ratios and 95% CI reported. RESULTS 193 patients underwent WBRT (N = 102 from 2010-2012; N = 91 from 2013-2014); 38/193 had 48 extracranial sites irradiated concurrently. 46.1% were male, mean age was 64.7 years (SD 11.6), and 63.7% had lung cancer. Median KPS was 70 (range 20-100) and median MMSE score was 27/30 (range 13-30). Median CPS and actual survival were 150 days (range 21-730d) and 96 days (range 11-1029d), respectively. 18.7% received WBRT within 30 days of death. 78.2% (151/193) and 17.6% (34/193) received five and 10 fractions, respectively; 8/193 were prescribed other schedules. On multivariate analysis, patients with KPS ≤ 70 were 5.93 times more likely to have received 5-fractions (95% CI 2.51-14.1; p < 0.0001). Those treated 2010-2012 were less likely to have received 5 fractions (OR 0.28; 95% CI 0.11-0.68; p = 0.005). CPS, age, gender, MMSE, histology, disease extent, and extracranial irradiation were not predictive of WBRT schedule. CONCLUSIONS Patients treated with WBRT with KPS ≤70 and those treated more recently were more likely to receive five fractions. Oncologist CPS was not a statistically significant predictor of schedule in this cohort.