Gregory Gagnon

AMP-activated protein kinase promotes human prostate cancer cell growth and survival

The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. AMP-activated protein kinase (AMPK) is a serine-threonine kinase that is activated in response to the hypoxic conditions found in human prostate cancers. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. Here, we report prevalent activation of AMPK in human prostate cancers and provide evidence that inhibition or depletion of AMPK leads to decreased cell proliferation and increased cell death. AMPK was highly activated in 40% of human prostate cancer specimens examined. Endogenous AMPK was active in both the androgen-sensitive LNCaP cells and the androgen-independent CWR22Rv1 human prostate cancer cells. Depletion of AMPK catalytic subunits by small interfering RNA or inhibition of AMPK activity with a small-molecule AMPK inhibitor (compound C) suppresses human prostate cancer cell proliferation. Apoptotic cell death was induced in LNCaP and CWR22Rv1 cells at compound C concentrations that inhibited AMPK activity. The evidence provided here is the first report that the activated AMPK pathway is involved in the growth and survival of human prostate cancer and offers novel potential targets for chemoprevention of human prostate cancer. [Mol Cancer Ther 2009;8(4):733–41]

Fractionated Stereotactic Radiosurgery for Reirradiation of Head-and-Neck Cancer

PURPOSE Stereotactic radiosurgery (SRS) is an appealing treatment option after previous radiotherapy because of its precision, conformality, and reduced treatment duration. We report our experience with reirradiation using fractionated SRS for head-and-neck cancer. METHODS AND MATERIALS From 2002 to 2008, 65 patients received SRS to the oropharynx (n = 13), hypopharynx (n = 8), nasopharynx (n = 7), paranasal sinus (n = 7), neck (n = 7), and other sites (n = 23). Thirty-eight patients were treated definitively and 27 patients with metastatic disease and/or untreated local disease were treated palliatively. Nine patients underwent complete macroscopic resection before SRS. Thirty-three patients received concurrent chemoradiation. The median initial radiation dose was 67 Gy, and the median reirradiation SRS dose was 30 Gy (21-35 Gy) in 2-5 fractions. RESULTS Median follow-up for surviving patients was 16 months. Fifty-six patients were evaluable for response: 30 (54%) had complete, 15 (27%) had partial, and 11 (20%) had no response. Median overall survival (OS) for all patients was 12 months. For definitively treated patients, the 2-year OS and locoregional control (LRC) rates were 41% and 30%, respectively. Multivariate analysis demonstrated that higher total dose, surgical resection, and nasopharynx site were significantly associated with improved LRC; surgical resection and nonsquamous histology were associated with improved OS. Seven patients (11%) experienced severe reirradiation-related toxicity, including one treatment-attributed death. CONCLUSION SRS reirradiation for head-and-neck cancer is feasible. This study demonstrates encouraging response rates with acceptable toxicity. Fractionated SRS reirradiation with concurrent chemotherapy in select patients warrants further study.

Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors

BackgroundRecent developments in radiotherapeutic technology have resulted in a new approach to treating patients with localized lung cancer. We report preliminary clinical outcomes using stereotactic radiosurgery with real-time tumor motion tracking to treat small peripheral lung tumors.MethodsEligible patients were treated over a 24-month period and followed for a minimum of 6 months. Fiducials (3–5) were placed in or near tumors under CT-guidance. Non-isocentric treatment plans with 5-mm margins were generated. Patients received 45–60 Gy in 3 equal fractions delivered in less than 2 weeks. CT imaging and routine pulmonary function tests were completed at 3, 6, 12, 18, 24 and 30 months.ResultsTwenty-four consecutive patients were treated, 15 with stage I lung cancer and 9 with single lung metastases. Pneumothorax was a complication of fiducial placement in 7 patients, requiring tube thoracostomy in 4. All patients completed radiation treatment with minimal discomfort, few acute side effects and no procedure-related mortalities. Following treatment transient chest wall discomfort, typically lasting several weeks, developed in 7 of 11 patients with lesions within 5 mm of the pleura. Grade III pneumonitis was seen in 2 patients, one with prior conventional thoracic irradiation and the other treated with concurrent Gefitinib. A small statistically significant decline in the mean % predicted DLCO was observed at 6 and 12 months. All tumors responded to treatment at 3 months and local failure was seen in only 2 single metastases. There have been no regional lymph node recurrences. At a median follow-up of 12 months, the crude survival rate is 83%, with 3 deaths due to co-morbidities and 1 secondary to metastatic disease.ConclusionRadical stereotactic radiosurgery with real-time tumor motion tracking is a promising well-tolerated treatment option for small peripheral lung tumors.

TREATMENT OF SPINAL TUMORS USING CYBERKNIFE FRACTIONATED STEREOTACTIC RADIOSURGERY: PAIN AND QUALITY-OF-LIFE ASSESSMENT AFTER TREATMENT IN 200 PATIENTS

OBJECTIVEBenign and malignant tumors of the spine significantly impair the function and quality of life of many patients. Standard treatment options, including conventional radiotherapy and surgery, are often limited by anatomic constraints and previous treatment. Image-guided stereotactic radiosurgery using the CyberKnife system (Accuray, Inc., Sunnyvale, CA) is a novel approach in the multidisciplinary management of spinal tumors. The aim of this study was to evaluate the effects of CyberKnife stereotactic radiosurgery on pain and quality-of-life outcomes of patients with spinal tumors. METHODSWe conducted a prospective study of 200 patients with benign or malignant spinal tumors treated at Georgetown University Hospital between March 2002 and September 2006. Patients were treated by means of multisession stereotactic radiosurgery using the CyberKnife as initial treatment, postoperative treatment, or retreatment. Pain scores were assessed by the Visual Analog Scale, quality of life was assessed by the SF-12 survey, and neurological examinations were conducted after treatment. RESULTSMean pain scores decreased significantly from 40.1 to 28.6 after treatment (P < 0.001) and continued to decrease over the entire 4-year follow-up period (P < 0.05). SF-12 Physical Component scores demonstrated no significant change throughout the follow-up period. Mental Component scores were significantly higher after treatment (P < 0.01), representing a quality-of-life improvement. Early side effects of radiosurgery were mild and self-limited, and no late radiation toxicity was observed. CONCLUSIONCyberKnife stereotactic radiosurgery is a safe and effective modality in the treatment of patients with spinal tumors. CyberKnife offers durable pain relief and maintenance of quality of life with a very favorable side effect profile.

Single-session and multisession CyberKnife radiosurgery for spine metastases—University of Pittsburgh and Georgetown University experience

OBJECT The authors compared the effectiveness of single-session (SS) and multisession (MS) stereotactic radiosurgery (SRS) for the treatment of spinal metastases. METHODS The authors conducted a retrospective review of the clinical outcomes of 348 lesions in 228 patients treated with the CyberKnife radiosurgery at the University of Pittsburgh Cancer Institute and Georgetown University Medical Center. One hundred ninety-five lesions were treated using an SS treatment regimen (mean 16.3 Gy), whereas 153 lesions were treated using an MS approach (mean 20.6 Gy in 3 fractions, 23.8 Gy in 4 fractions, and 24.5 Gy in 5 fractions). The primary end point was pain control. Secondary end points included neurological deficit improvement, toxicity, local tumor control, need for retreatment, and overall survival. RESULTS Pain control was significantly improved in the SS group (SSG) for all measured time points up to 1 year posttreatment (100% vs 88%, p = 0.003). Rates of toxicity and neurological deficit improvement were not statistically different. Local tumor control was significantly better in the MS group (MSG) up to 2 years posttreatment (96% vs 70%, p = 0.001). Similarly, the need for retreatment was significantly lower in the MSG (1% vs 13%, p < 0.001). One-year overall survival was significantly greater in the MSG than the SSG (63% vs 46%, p = 0.002). CONCLUSIONS Single-session and MS SRS regimens are both effective in the treatment of spinal metastases. While an SS approach provides greater early pain control and equivalent toxicity, an MS approach achieves greater tumor control and less need for retreatment in long-term survivors.

Risk Factors for Posttreatment Edema in Patients Treated With Stereotactic Radiosurgery for Meningiomas

BACKGROUND Peritumoral edema is a recognized complication following stereotactic radiosurgery (SRS). OBJECTIVE To evaluate the risk of posttreatment peritumoral edema following SRS for intracranial meningiomas and determine predictive factors. METHODS Between 2002 and 2008, 173 evaluable patients underwent CyberKnife or Gamma Knife SRS for meningiomas. Eighty-four patients (49%) had prior surgical resections, 13 patients had World Health Organization grade II (atypical) meningiomas, and 117 patients had a neurological deficit before SRS. Sixty-two tumors were in parasagittal, parafalcine, and convexity locations. The median tumor volume was 4.7 mL (range, 0.1-231.8 mL). The median prescribed dose and median prescribed biologically equivalent dose were 15 Gy (range, 9-40 Gy) and 67 Gy (range, 14-116 Gy), respectively. Ninety-seven patients were treated with single-fraction SRS, 74 received 2 to 5 fractions, and 2 received >5 fractions. RESULTS The median follow-up was 21.0 months. Thirteen patients (8%) developed symptomatic peritumoral edema, with a median onset time of 4.5 months (range, 0.2-9.5 months). The 3-, 6-, 12-, and 24-month actuarial symptomatic edema rates were 2.9%, 4.9%, 7.7%, and 8.5%, respectively. The crude tumor control rate was 94%. On univariate analysis, large tumor volume (P = .01) and single-fraction SRS (P = .04) were predictive for development of posttreatment edema. CONCLUSION SRS meningioma treatment demonstrated a low incidence of toxicity; however, large tumor volumes and single-fraction SRS treatment had an increased risk for posttreatment edema. Risk factors for edema should be considered in meningiomas treatment.

Stereotactic Body Radiation Therapy for Liver Metastases from Colorectal Cancer: Analysis of Safety, Feasibility, and Early Outcomes

Introduction: Colorectal cancer (CRC) is the third leading cause of cancer-related death in the U.S. Many patients with CRC develop hepatic metastases as the sole site of metastases. Historical treatment options were limited to resection or conventional radiation therapy. Stereotactic body radiation therapy (SBRT) has emerged as a rational treatment approach. This study reviews our experience with SBRT for patients with liver metastases from CRC. Materials and Methods: Fourteen histologically confirmed hepatic CRC metastases in 11 consecutive patients were identified between November, 2004 and June, 2009 at Georgetown University. All patients underwent CT-based treatment planning; a few also had MRI or PET/CT. All patients had fiducial markers placed under CT guidance and were treated using the CyberKnife system. Treatment response and toxicities were examined; survival and local control were evaluated. Results: Most patients were treated to a single hepatic lesion (n = 8), with a few treated to two lesions (n = 3). Median treatment volume was 99.7 cm3, and lesions were treated to a median BED10 of 49.7 Gy (range: 28–100.8 Gy). Median follow-up was 21 months; median survival was 16.1 months, with 2 year actuarial survival of 25.7%. One year local control was 72%. Among patients with post-treatment imaging, eight had stable disease (80%) and two had progressive disease (20%) at first follow-up. The most common grade 1–2 acute toxicities included nausea and alterations in liver function tests; there was one grade 3 toxicity (elevated bilirubin), and no grade 4–5 toxicities. Discussion: SBRT is safe and feasible for the treatment of limited hepatic metastases from CRC. Our results compare favorably with outcomes from previous studies of SBRT. Further studies are needed to better define patient eligibility, study the role of combined modality treatment, optimize treatment parameters, and characterize quality of life after treatment.

Treatment of malignant tumors of the skull base with multi-session radiosurgery

ObjectiveMalignant tumors that involve the skull base pose significant challenges to the clinician because of the proximity of critical neurovascular structures and limited effectiveness of surgical resection without major morbidity. The purpose of this study was to evaluate the efficacy and safety of multi-session radiosurgery in patients with malignancies of the skull base.MethodsClinical and radiographic data for 37 patients treated with image-guided, multi-session radiosurgery between January 2002 and December 2007 were reviewed retrospectively. Lesions were classified according to involvement with the bones of the base of the skull and proximity to the cranial nerves.ResultsOur cohort consisted of 37 patients. Six patients with follow-up periods less than four weeks were eliminated from statistical consideration, thus leaving the data from 31 patients to be analyzed. The median follow-up was 37 weeks. Ten patients (32%) were alive at the end of the follow-up period. At last follow-up, or the time of death from systemic disease, tumor regression or stable local disease was observed in 23 lesions, representing an overall tumor control rate of 74%. For the remainder of lesions, the median time to progression was 24 weeks. The median progression-free survival was 230 weeks. The median overall survival was 39 weeks. In the absence of tumor progression, there were no cranial nerve, brainstem or vascular complications referable specifically to CyberKnife® radiosurgery.ConclusionOur experience suggests that multi-session radiosurgery for the treatment of malignant skull base tumors is comparable to other radiosurgical techniques in progression-free survival, local tumor control, and adverse effects.

Scoring system predictive of survival for patients undergoing stereotactic body radiation therapy for liver tumors.

BackgroundStereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumors. This study evaluated outcomes after SBRT to identify prognostic variables and to develop a novel scoring system predictive of survival.MethodsThe medical records of 52 patients with a total of 85 liver lesions treated with SBRT from 2003 to 2010 were retrospectively reviewed. Twenty-four patients had 1 lesion; 27 had 2 or more. Thirteen lesions were primary tumors; 72 were metastases. Fiducials were placed in all patients prior to SBRT. The median prescribed dose was 30 Gy (range, 16 – 50 Gy) in a median of 3 fractions (range, 1–5).ResultsWith median follow-up of 11.3 months, median overall survival (OS) was 12.5 months, and 1 year OS was 50.8%. In 42 patients with radiographic follow up, 1 year local control was 74.8%. On univariate analysis, number of lesions (p = 0.0243) and active extralesional disease (p < 0.0001) were predictive of OS; Karnofsky Performance Status (KPS) approached statistical significance (p = 0.0606). A scoring system for predicting survival was developed by allocating 1 point for each of the three following factors: active extralesional disease, 2 or more lesions, and KPS ≤ 80%. Score was associated with OS (p < 0.0001). For scores of 0, 1, 2 and 3, median survival intervals were 34, 12.5, 7.6, and 2.8 months, respectively.ConclusionsSBRT offers a safe and feasible treatment option for liver tumors. A prognostic scoring system based on the number of liver lesions, activity of extralesional disease, and KPS predicts survival following SBRT and can be used as a guide for prospective validation and ultimately for treatment decision-making.

Robotic stereotactic body radiation therapy for elderly medically inoperable early-stage non-small cell lung cancer.

INTRODUCTION Stereotactic body radiation therapy (SBRT) is being increasingly applied in the treatment of non-small cell lung cancer (NSCLC) because of its high local efficacy. This study aims to examine survival outcomes in elderly patients with inoperable stage I NSCLC treated with SBRT. METHODS A total of 31 patients with single lesions treated with fractionated SBRT from 2008 to 2011 were retrospectively analyzed. A median prescribed dose of 48 Gy was delivered to the prescription isodose line, over a median of four treatments. The median biologically effective dose (BED) was 105.6 (range 37.50-180), and the median age was 73 (65-90 years). No patient received concurrent chemotherapy. RESULTS With a median follow up of 13 months (range, 4-40 months), the actuarial median overall survival (OS) and progression-free survival (PFS) were 32 months, and 19 months, respectively. The actuarial median local control (LC) time was not reached. The survival outcomes at median follow up of 13 months were 80%, 68%, and 70% for LC, PFS, and OS, respectively. Univariate analysis revealed a BED of >100 Gy was associated with improved LC rates (P = 0.02), while squamous cell histology predicted for worse LC outcome at median follow up time of 13 months (P = 0.04). Increased tumor volume was a worse prognostic indicator of both LC and OS outcomes (P < 0.05). Finally, female gender was a better prognostic factor for OS than male gender (P = 0.006). There were no prognostic indicators of PFS that reached statistical significance. No acute or subacute high-grade toxicities were documented. CONCLUSION SBRT is a safe, feasible, and effective treatment option for elderly patients with inoperable early stage NSCLC. BED, histology, and tumor size are predictors of local control, while tumor size and gender predict OS.