Tamer Refaat

Cancer active targeting by nanoparticles: a comprehensive review of literature

PurposeCancer is one of the leading causes of death, and thus, the scientific community has but great efforts to improve cancer management. Among the major challenges in cancer management is development of agents that can be used for early diagnosis and effective therapy. Conventional cancer management frequently lacks accurate tools for detection of early tumors and has an associated risk of serious side effects of chemotherapeutics. The need to optimize therapeutic ratio as the difference with which a treatment affects cancer cells versus healthy tissues lead to idea that it is needful to have a treatment that could act a the “magic bullet”—recognize cancer cells only. Nanoparticle platforms offer a variety of potentially efficient solutions for development of targeted agents that can be exploited for cancer diagnosis and treatment. There are two ways by which targeting of nanoparticles can be achieved, namely passive and active targeting. Passive targeting allows for the efficient localization of nanoparticles within the tumor microenvironment. Active targeting facilitates the active uptake of nanoparticles by the tumor cells themselves.MethodsRelevant English electronic databases and scientifically published original articles and reviews were systematically searched for the purpose of this review.ResultsIn this report, we present a comprehensive review of literatures focusing on the active targeting of nanoparticles to cancer cells, including antibody and antibody fragment-based targeting, antigen-based targeting, aptamer-based targeting, as well as ligand-based targeting.ConclusionTo date, the optimum targeting strategy has not yet been announced, each has its own advantages and disadvantages even though a number of them have found their way for clinical application. Perhaps, a combination of strategies can be employed to improve the precision of drug delivery, paving the way for a more effective personalized therapy.

Markov model and cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer.

Purpose:Metastatic breast cancer (MBC) remains an incurable disease despite advances in treatment modalities. In 2008, the FDA approved bevacizumab with paclitaxel for the initial treatment of HER2-negative MBC. The approval was then officially revoked by the FDA in November 2011. However, both the European Medicines Agency and NCCN still endorse bevacizumab for this indication. One of the greatest challenges facing health care worldwide is reconciling incremental clinical benefits with exponentially rising costs. This study aimed to assess the cost-effectiveness of bevacizumab with paclitaxel for HER2-negative MBC. Methods:A Markov decision tree using Data 3.5 (TreeAge Software Inc.) was created for decision and cost-effectiveness analyses of using bevacizumab plus paclitaxel versus paclitaxel alone as first-line chemotherapy in HER2-negative MBC using efficacy and toxicity data from the E2100 study. The model was designed from the patient and payer perspectives and sensitivity analyses were run. Results:The marginal cost between paclitaxel alone versus bevacizumab and paclitaxel was 86k with a marginal efficacy of 0.369 quality-adjusted life-years and marginal cost effectiveness of 232,720.72 USD. The expected outcome value was 1.86 for bevacizumab and paclitaxel and 1.67 for paclitaxel alone. The combination was not cost effective and only a marginal survival advantage was observed. Conclusions:This study demonstrates that, despite a significant progression-free survival advantage, the addition of bevacizumab to paclitaxel is not cost effective for the cohort of patients with HER2-negative MBC included in our analysis. Such data could be informative to policymakers who consider the health economics and incremental cost-effectiveness of medical therapies.

Thyroid V50 Highly Predictive of Hypothyroidism in Head-and-Neck Cancer Patients Treated With Intensity-modulated Radiotherapy (IMRT).

Objectives: Radiation-induced hypothyroidism affects a significant number of patients with head-and-neck squamous cell cancer (HNSCC). We examined detailed dosimetric and clinical parameters to better determine the risk of hypothyroidism in euthyroid HNSCC patients treated with intensity-modulated radiation therapy (IMRT). Materials and Methods: From 2006 to 2010, 75 clinically euthyroid patients with HNSCC were treated with sequential IMRT. The cohort included 59 men and 16 females with a median age of 55 years (range, 30 to 89 y) who were treated to a median dose of 70 Gy (range, 60 to 75 Gy) with concurrent chemotherapy in nearly all (95%) cases. Detailed thyroid dosimetric parameters including maximum dose, mean dose, and other parameters (eg, V50—percent volume receiving at least 50 Gy) were obtained. Freedom from hypothyroidism was evaluated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using Cox regression. Results: After a median follow-up period of 50 months, 25 patients (33%) became hypothyroid. On univariate analysis, thyroid V50 was highly correlated with developing hypothyroidism (P=0.035). Other dosimetric paramaters including mean thyroid dose (P=0.11) and maximum thyroid dose (P=0.39) did not reach statistical significance. On multivariate analysis incorporating patient, tumor, and treatment variables, V50 remained highly statistically significant (P=0.037). Regardless of other factors, for V50>60%, the odds ratio of developing hypothyroidism was 6.76 (P=0.002). Conclusions: In HNSCC patients treated with IMRT, thyroid V50 highly predicts the risk of developing hypothyroidism. V50>60% puts patients at a significantly higher risk of becoming hypothyroid. This can be a useful dose constraint to consider during treatment planning.

Hyperthermia and radiation therapy for locally advanced or recurrent breast cancer.

INTRODUCTION This study aims to report the outcome and toxicity of combined hyperthermia (HT) and radiation therapy (RT) in treatment of locally advanced or loco-regionally recurrent breast cancer. PATIENTS AND METHODS Patients treated with HT and RT from January 1991 to December 2007 were reviewed. RT doses for previously irradiated patients were > 40 Gy and for RT naïve patients > 60 Gy, at 1.8-2 Gy/day. HT was planned for 2 sessions/week, immediately after RT, for a minimum of 20 min and for > 4 sessions. Superficial or interstitial applicators were used with temperature measured by superficial or interstitial thermistors based on target thickness. HT treatment was assessed by thermal equivalent dose (TED), > 42.5 °C and > 43 °C. Endpoints included treatment response, lack of local progression (local control), and survival. RESULTS 127 patients received HT and RT to 167 sites. These included the intact breast (24.4%), chest wall/skin (67.7%), and breast/chest wall and nodes (7.9%). At a median follow-up of 13 months (mean 30 ± 38), improved overall survival was significantly associated with increasing RT dose (p < 0.0001), median TED 42.5 °C ≥ 200 min (p = 0.003), and local control (p = 0.0002). Local control at last follow-up was seen in 55.1% of patients. Complete response was significantly associated with median TED 42.5 °C ≥ 200 min (p = 0.002) and median TED 43 °C ≥ 100 min (p = 0.03). CONCLUSION HT and RT are effective for locally advanced or recurrent breast cancer in patients that have been historically difficult to treat by RT alone. Over 50% of patients achieved control of locoregional disease. Overall survival was improved with local control.

c-Met Overexpression in Cervical Cancer, a Prognostic Factor and a Potential Molecular Therapeutic Target.

Purpose: This study aimed to assess the association between pretreatment c-Met overexpression in local-regional advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), distant metastases (DM) control, and local-regional control (LC). Patients and Methods: This Institutional Review Board–approved study included cervical cancer patients treated definitively and consecutively with CRT. Evaluation of cytoplasmic immunoreactivity for c-Met was performed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes, and incorporated both the intensity and percentage of immunoreactivity in invasive carcinoma (H score). Treatment outcomes were reviewed and reported. Outcomes were stratified by c-Met overexpression and tumor characteristics. OS, PFS, LC, and DC rates were obtained via the Kaplan-Meier method and differences between groups were evaluated by the log-rank test. Hazard ratios were obtained via Cox regression for both univariate and multivariate analyses. Results: The 5-year OS, PFS, LC, and DC were 57.18%, 48.07%, 72.11%, and 62.85%, respectively. Ten (35.7%) and 18 patients (64.3%) had c-Met H index >30 and<30, respectively. c-Met overexpression was significantly associated with worse 3- and 5-year OS (P=0.003), PFS (P=0.002), LC (P=0.01), and DC (P=0.0003). Patients with c-Met overexpression had a hazard ratio of 6.297, 5.782, 6.28, and 18.173 for the risks of death, disease progression, local recurrence, and DM, respectively. Conclusion: c-Met overexpression could be a potential predictive marker and therapeutic target for local-regional advanced cervical cancer patients treated definitively with CRT.

Evaluation of Outcomes in Patients With Carcinoma of the Cervix Treated With Concurrent Radiation and Cisplatin Versus Cisplatin/5-FU Compared With Radiation Alone.

Objectives:The objective of this study was to compare outcomes for patients with cervical cancer treated with radiation concurrently with cisplatin, cisplatin/5-fluorouracil (5-FU), or without chemotherapy. Materials and Methods:We reviewed the records of eligible patients with locoregionally confined, stage IB1 through IVA, intact cervical cancer who were treated at Northwestern Memorial Hospital. All patients underwent definitive radiotherapy with combined external beam radiation—the majority with extended-field (62%)—and received low-dose rate brachytherapy. Results:A total of 236 patients were included: 99 had no concurrent chemotherapy, 95 were treated with concurrent cisplatin, and 42 were treated with cisplatin/5-FU. For all patients treated with or without chemotherapy, overall survival at 5 and 10 years was 64% and 59%, respectively. Patients treated with chemotherapy had a superior recurrence-free survival rate of 69% at 5 years versus 49% in patients who did not receive chemotherapy (P=0.09). Twenty-six percent of patients treated with cisplatin alone, 31% of patients treated with cisplatin/5-FU, and 45% of patients who did not receive chemotherapy experienced a disease recurrence. Adenosquamous histology conferred a higher rate of recurrence as compared with adenocarcinoma and squamous cell histologies (54% vs. 34%, respectively; P=0.05). Conclusions:Cisplatin-based concurrent chemoradiotherapy showed a trend toward improved recurrence-free survival survival in the definitive treatment of nonmetastatic cervical cancer. The addition of 5-FU to cisplatin did not appear to significantly impact survival or recurrence-free survival. Adenosquamous histology was associated with a higher risk of recurrence as compared with other histologic subtypes.

Volume-based pulsed-dose-rate brachytherapy boosting concurrent chemoradiation as a definitive treatment modality in cervical cancer

PURPOSE To report the treatment outcomes and treatment-induced adverse events (AEs) of concomitant chemoradiotherapy boosted with pulsed-dose-rate brachytherapy using volume-based two-dimensional planning in patients with cervical cancer. PATIENTS AND METHODS After obtaining the institutional review board approval, patients with FIGO Stages IB to IIIB cervical cancer, treated from January 2006 to December 2008 consecutively, were included. Volume-based planning was used and entailed defining an envelope around the tumor on a two-dimensional image and prescribing the dose to this envelope and reporting the dose of the isodose of 60 Gy. Patients and tumor characteristics, dosimetric parameters, AEs and treatment outcomes, local control rate, distant metastases rate, progression-free survival, and overall survival are reported. RESULTS The study included 95 patients; the median age is 50 years. The median tumor size is 50cc (range, 25-78cc). Median brachytherapy dose delivered to the envelope is 20 Gy (range, 15-35 Gy), and median volume encompassed by 60 Gy isodose curve is 137cc (range, 26-365cc). The 3-year overall survival, progression-free survival, local control rate, and distant metastases rate were 83.8%, 72.4%, 84.8%, and 15.4%, respectively. Gastrointestinal and genitourinary Grade 3 and 4 acute AEs were reported in 11.6% and 3.3% and chronic Grade 3 and 4 AEs were reported in 3.2% and 4.2% of all patients, respectively. CONCLUSIONS Chemoradiotherapy followed by pulsed-dose-rate brachytherapy boost is effective and tolerable treatment modality for locally confined cervical cancer.

Gamma Knife Stereotactic Radiosurgery for Grade 2 Meningiomas

Purpose This study aims to report long‐term clinical outcomes after Gamma Knife radiosurgery (GKRS) for intracranial grade 2 meningiomas. Methods In this Institutional Review Board approved study, we reviewed records of all patients with grade 2 meningiomas treated with GKRS between 1998 and 2014. Results A total of 97 postoperative histopathologically confirmed grade 2 meningiomas in 75 patients were treated and are included in this study. After a mean follow‐up of 41 months, 28 meningiomas had local recurrence (29.79%). Median time to local recurrence was 89 months (mean: 69, range: 47‐168). The 3‐ and 5‐year actuarial local control (LC) rates were 68.9 and 55.7%, respectively. The 3‐ and 5‐year overall survival rates were 88.6 and 81.1%, respectively. There was a trend toward worse LC with tumors treated with radiation doses ≤ 13 versus > 13 Gy. There was no radiation necrosis or second malignant tumors noted in our series. Conclusion This report, one of the largest GKRS series for grade 2 meningiomas, demonstrates that GKRS is a safe and effective treatment modality for patients with grade 2 meningiomas with durable tumor control and minimal toxicity. Adjuvant GKRS could be considered as a reasonable treatment approach for patients with grade 2 meningiomas.

Concomitant Chemoradiotherapy With Image-guided Pulsed Dose Rate Brachytherapy as a Definitive Treatment Modality for Early-stage Cervical Cancer.

Purpose:Concurrent chemoradiotherapy (CRT) is the standard of care for patients with bulky cervical cancer. This study aimed to determine the feasibility, tolerance, and effectiveness of pulsed dose rate (PDR) image-guided brachytherapy (IGBT), utilizing magnetic resonance imaging (MRI) planning after CRT for stages IB2 and II cervix cancer patients. Methods and Materials:This study planned to include patients with histologically confirmed stage IB2 and II cervical cancer who were treated with CRT followed by a PDR IGBT boost from January 2009 to December 2009 in our institution. All patients had at least a partial response after CRT before IGBT. The institutional review board approved the study. Patients received a 45-Gy external beam radiotherapy (EBRT) to the pelvis with concomitant weekly cisplatin (40 mg/m2) for 5 cycles. All patients then underwent reimaging using MRI before BT. The IGBT boost was accomplished with one insertion using an MRI-compatible tandem and ovoid applicator delivering 30 to 35 Gy to a high-risk clinical target volume. Treatment-induced adverse events (AEs), dose parameters, local control, progression-free survival, and overall survival are reported. Results:Forty patients were included in this study, with ages ranging from 31 to 65 years (median age, 45 y). Of all the patients, 12.5% and 5% experienced grade 3 to 4 acute gastrointestinal and genitourinary AEs, respectively, and 2.5% and 2.5% had grade 3 to 4 chronic gastrointestinal and genitourinary AEs, respectively. Within a median follow-up of 30 months (range, 7 to 40 mo), local control was 90%, progression-free survival was 87.5%, and overall survival was 100%. Conclusions:Intracavitary MRI PDR-IGBT boost after CRT is a feasible, tolerable, and effective treatment modality for patients with stages IB2 and II cervical cancer.

Development of a standardized method for contouring the larynx and its substructures

ObjectivesLimiting radiation dose to the larynx can diminish effects of laryngeal dysfunction. However, no clear guidelines exist for defining the larynx and its substructures consistently on cross-sectional imaging. This study presents computed tomography (CT)- and magnetic resonance imaging (MRI)-based guidelines for contouring laryngeal organs-at-risk (OARs).Materials and MethodsStandardized guidelines for delineating laryngeal OARs were devised and used to delineate on CT and MRI for head-and-neck cancer patients. Volumetric comparisons were performed to evaluate consistency and reproducibility of guideline-based contours.ResultsFor the initial 5 patients the mean CT and MRI based larynx volume did not differ significantly between imaging modalities; 34.39 ± 9.85 vs. 35.01 ± 9.47 (p = .09). There was no statistical difference between the CT based mean laryngeal volume in the subsequent 44 patients compared to the initial 5 patients outlined on CT and the MRI scan (p = 0.53 and 0.62). The OAR volume for laryngeal substructures were not statistically different among patients or between imaging modalities. Once established, the guidelines were easy to follow.ConclusionThe guidelines developed provide a precise method for delineating laryngeal OARs. These guidelines need to be validated and clinical significance of outlining laryngeal substructures and dose-volume constraints should be investigated before routine implementation in clinic practice.