Ugur Selek

Stereotactic body radiation therapy for management of spinal metastases in patients without spinal cord compression: a phase 1-2 trial

BACKGROUND Spinal stereotactic body radiation therapy (SBRT) is increasingly used to manage spinal metastases, yet the techniques effectiveness in controlling the symptom burden of spinal metastases has not been well described. We investigated the clinical benefit of SBRT for managing spinal metastases and reducing cancer-related symptoms. METHODS 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) were given SBRT in a phase 1-2 study. Patients received a total dose of 27-30 Gy, typically in three fractions. Symptoms were measured before SBRT and at several time points up to 6 months after treatment, by the Brief Pain Inventory (BPI) and the M D Anderson Symptom Inventory (MDASI). The primary endpoint was frequency and duration of complete pain relief. The study is completed and is registered with ClinicalTrials.gov, number NCT00508443. FINDINGS Median follow-up was 15·9 months (IQR 9·5-30·3). The number of patients reporting no pain from bone metastases, as measured by the BPI, increased from 39 of 149 (26%) before SBRT to 55 of 102 (54%) 6 months after SBRT (p<0·0001). BPI-reported pain reduction from baseline to 4 weeks after SBRT was clinically meaningful (mean 3·4 [SD 2·9] on the BPI pain-at-its-worst item at baseline, 2·1 [2·4] at 4 weeks; effect size 0·47, p=0·00076). These improvements were accompanied by significant reduction in opioid use during the first 6 months after SBRT (43 [28·9%] of 149 patients with strong opioid use at baseline vs 20 [20·0%] of 100 at 6 months; p=0·011). Ordinal regression modelling showed that patients reported significant pain reduction according to the MDASI during the first 6 months after SBRT (p=0·00003), and significant reductions in a composite score of the six MDASI symptom interference with daily life items (p=0·0066). Only a few instances of non-neurological grade 3 toxicities occurred: nausea (one event), vomiting (one), diarrhoea (one), fatigue (one), dysphagia (one), neck pain (one), and diaphoresis (one); pain associated with severe tongue oedema and trismus occurred twice; and non-cardiac chest pain was reported three times. No grade 4 toxicities occurred. Progression-free survival after SBRT was 80·5% (95% CI 72·9-86·1) at 1 year and 72·4% (63·1-79·7) at 2 years. INTERPRETATION SBRT is an effective primary or salvage treatment for mechanically stable spinal metastasis. Significant reductions in patient-reported pain and other symptoms were evident 6 months after SBRT, along with satisfactory progression-free survival and no late spinal cord toxicities. FUNDING National Cancer Institute of the US National Institutes of Health.

Outcome Variation among “Radioresistant” Brain Metastases Treated with Stereotactic Radiosurgery

OBJECTIVE:To determine the influence of histopathological diagnosis on the outcome of “radioresistant” brain metastases treated with stereotactic radiosurgery (SRS). METHODS:Patients (n = 189) with “radioresistant” brain metastases (n = 264) were consecutively treated with SRS between August 1991 and July 2002. The primary site of brain metastases was melanoma (n = 103), renal cell carcinoma (n = 77), and sarcoma (n = 9). The median age of the patients was 52 years, and the median Karnofsky Performance Scale score was 80. Initial brain metastasis presentation was single in 112 patients (59%). The median SRS dose was 18 Gy (range, 10–24 Gy). The median tumor volume was 1.6 cm3 (range, 0.06–27.5 cm3). The median follow-up of all patients was 7.4 months (range, 0.16–52 mo). RESULTS:The actuarial freedom from progression after 1 year was 64% for renal cell carcinoma patients, 47% for melanoma patients, and 0% for sarcoma patients (P < 0.001). The median survival time for all patients from time of SRS was 7.5 months. The rate of 1-year survival was 40% for renal cell carcinoma patients, 25% for melanoma patients, and 22% for sarcoma patients (P = 0.0354). The incidence of neurological death was lower among patients diagnosed with renal cell carcinoma (31%) than among patients with melanoma (66%) or sarcoma (60%) (P = 0.001). CONCLUSION:Survival after SRS is significantly worse for patients with melanoma and sarcoma brain metastases compared with patients with renal cell carcinoma. Our data show that progressive brain metastases seem to cause most of the cancer-related deaths among patients with SRS-treated melanoma and sarcoma brain metastases. Future investigations using chemotherapy or novel agents to enhance the effectiveness of SRS to melanoma and sarcoma brain metastases seem warranted.

Percent positive axillary lymph node metastasis predicts survival in patients with non-metastatic breast cancer

Purpose. We retrospectively evaluated the impact of percent positive axillary nodal involvement on the therapeutic outcomes in patients with non-metastatic breast cancer receiving postmastectomy radiotherapy and chemotherapy. Materials and methods. Between January 1994 and December 2002, the medical records of 939 eligible non metastatic breast carcinoma patients were analyzed. Chest wall radiotherapy was indicated in case of positive surgical margin, tumor size equal or more than 4 cm, skin-fascia invasion. Lymphatic irradiation was applied for more than three metastatic axillary lymph nodes, incomplete axillary dissection (<10 lymph nodes), extracapsular extension or perinodal fat tissue invasion. A total dose of 50 Gy was given to chest wall and lymph node regions with 2 Gy daily fractions. Statistical analyses were performed by Kaplan-Meier method, Log-rank test and Coxs regression analysis. Results. The median follow-up for all patients alive was 62 months. The 5-year overall survival (OS) and disease-free survival (DFS) for entire cohort were 81%, and 65%, respectively. Univariate analysis for OS revealed significance for tumour size (≤5 cm vs. >5cm, p<0.001), metastatic nodal involvement (0 vs. 1–3 vs. >4 LN, p<0.001), percent positive nodal involvement ([metastatic nodes/total nodes removed]×100; 0 vs.≤25% vs. 26–50% vs. >50%, p<0.001), surgical margin status (negative vs. positive, p=0.05), and hormonal treatment (present vs. absent, p=0.03). DFS had similarly significance for age (≤40 years vs. >40 years, p=0.006), tumour size (0.02), metastatic nodal involvement (p<0.001), percent positive nodal involvement (p<0.001), and perinodal invasion (present vs. absent, p=0.01). Multivariate analysis revealed significance for tumour size, percent positive nodal involvement, hormonal treatment, and surgical margin status for OS. Age and percent positive nodal involvement were found to be significant for DFS. Conclusion. Percent positive nodal involvement was found to be a significant prognostic factor for survival in all end-points.

Characteristics of Breast Cancer Patients with Central Nervous System Metastases: A Single-Center Experience

The aim of this study was to assess the characteristics of breast cancer patients with central nervous system (CNS) metastases and factors associated with survival after development of CNS metastasis. One-hundred-forty-four patients with brain metastases were retrospectively analyzed. Median age at the time of brain metastasis diagnosis was 48.9. Median time between initial diagnosis and development of brain metastasis was 36 months. Fourteen cases had leptomeningeal involvement. Twenty-two patients (15.3%) had single metastasis. Ten percent of the patients had surgery, 94% had radiotherapy and 63% had chemotherapy. Median survival after development of brain metastasis was 7.4 months. Survival of patients with single metastasis was significantly longer than those with multiple metastases (33.5 vs. 6.5 months, p = 0.0006). Survival of patients who received chemotherapy was significantly longer than those who received radiotherapy alone (9.9 vs. 2 months, p < 0.0001). In multivariate Cox regression analyses, presence of single metastasis and application of chemotherapy were the only significant factors associated with better survival (p = 0.047 and p < 0.0001, respectively). Age at initial diagnosis or at the time of brain metastasis, time from initial diagnosis to development of brain metastasis, menopausal status, tumor stage, grade, hormone receptor or HER2 status individually were not associated with survival. In this study, survival after the diagnosis of CNS metastases appeared to be affected by patient characteristics rather than biologic characteristics of the tumor. This is probably secondary to the lack of effective treatment options in these patients and overall poor prognosis.

Malignant Giant Cell Tumor of the Skull Base Originating From Clivus and Sphenoid Bone

SummaryWe present a case report of a giant cell tumor located in the skull base orginating from clivus and sphenoid bone treated by surgery and external beam radiotherapy (EBRT).

Comparison of intracavitary brachytherapy and stereotactic body radiotherapy dose distribution for cervical cancer.

PURPOSE To compare the dose distribution characteristics of stereotactic body radiotherapy (SBRT) with intracavitary high-dose-rate (HDR) brachytherapy in patients with cervical carcinoma. METHODS AND MATERIALS HDR intracavitary brachytherapy treatment plans for 11 women with cervical carcinoma were evaluated in this analysis. The total HDR brachytherapy dose was 28Gy given in four fractions. HDR brachytherapy was delivered with the microSelectron HDR therapy unit (Nucletron B. V., Veenendaal, The Netherlands). SBRT plans for each patient were generated with MultiPlan for CyberKnife Robotic Radiosurgery System (Accuray Inc., Sunnyvale, CA). The dose distributions, dose-volume histograms, and maximum dose points of the target and critical organs were recorded for both plans. RESULTS SBRT yielded significantly better target coverage; the median target coverage for the 100% isodose line was 50.7% for HDR brachytherapy plans, whereas it was 99.1% for SBRT plans. The dose distributions for critical organs were similar in both types of plans. The exceptions were the 25% isodose being significantly better in brachytherapy plans for rectum, and the 100% isodose exposure being higher in brachytherapy plans for rectum, bladder, and sigmoid colon. Some significant differences were also found in maximum doses received by a 2-cc volume of bladder in favor of SBRT plans. In addition, maximum bone marrow doses were significantly higher in SBRT plans. CONCLUSION SBRT plans achieved better target coverage and better dose distributions to critical organs except bone marrow compared with HDR brachytherapy plans in patients with locally advanced cervical cancer.

Impact of Weight Change During the Course of Concurrent Chemoradiation Therapy on Outcomes in Stage IIIB Non-Small Cell Lung Cancer Patients: Retrospective Analysis of 425 Patients

PURPOSE We retrospectively investigated the impact of weight change (WC) during concurrent chemoradiation therapy (C-CRT) on clinical outcomes of stage 3B non-small cell lung cancer (NSCLC) patients. METHODS AND MATERIALS A total of 425 patients treated with C-CRT were included. All patients received 60 to 66 Gy of thoracic radiation therapy concurrently with 1 to 3 cycles of platinum-based chemotherapy. Pre- and posttreatment weight measurements on first and last days of C-CRT were used for WC. Patients were divided into 2 groups: group 1=weight loss (WL); group 2=weight preservation/gain (WP) for comparative analyses. RESULTS Following C-CRT, 252 patients (59.3%) experienced WL, while 89 patients (20.9%) and 84 patients (19.8%) showed WP or WG. At median 24.2 months of follow-up, 142 patients (33.4%) were alive (84 WP [48.6%] and 58 WL [23.0%]), and 58 (13.6%) of them were free of disease progression (41 [23.7%] for WP and 17 [6.7%] for WL). Median overall survival (OS), locoregional progression-free survival (LRPFS), progression-free survival (PFS), and distant metastases-free survival (DMFS) for the entire population were 22.8, 14.4, 10.6, and 11.7 months, respectively. Intergroup comparisons between WP and WL cohorts revealed significantly superior OS, LRPFS, PFS, and DMFS in WP patients (P<.05 for each). On multivariate analyses, only WL and advanced T stage were associated with poor prognosis (P<.05). CONCLUSIONS Present results in 425 stage 3B NSCLC patients demonstrated that WL during C-CRT is strongly associated with inferior survival outcomes compared to WP. This emerging finding might be useful by forming an encouraging basis for future investigations in facilitating a way to improve the outcomes of these patients experiencing WL during C-CRT.

Prognostic value of gross tumor volume delineated by FDG-PET-CT based radiotherapy treatment planning in patients with locally advanced pancreatic cancer treated with chemoradiotherapy

BackgroundWe aimed to assess whether gross tumor volume (GTV) determined by fusion of contrast-enhanced computerized tomography (CT) and 18F-fluoro-deoxy-D-glucose positron emission tomography-CT (FDG-PET-CT) based radiotherapy planning could predict outcomes, namely overall survival (OS), local-regional progression-free survival (LRPFS), and progression-free survival (PFS) in cases with locally advanced pancreas cancer (LAPC) treated with definitive concurrent chemoradiotherapy.MethodsA total of 30 patients with histological proof of LAPC underwent 50.4 Gy (1.8 Gy/28 fractions) of radiotherapy concurrent with continuously infused 5-FU followed by 4 to 6 courses of maintenance gemcitabine. Target volume delineations were performed on FDG-PET-CT-based RTP. Patients were stratified into 2 groups: GTV lesser (GTVL) versus greater (GTVG) than cut off value determined by receiver operating characteristic (ROC) analysis, and compared in terms of OS, LRPFS and PFS.ResultsMedian GTV delineated according to the FDG-PET-CT data was 100.0 cm3. Cut off GTV value determined from ROC curves was 91.1 cm3. At a median follow up of 11.2 months, median OS, LRPFS and PFS for the entire population were 10.3, 7.8 and 5.7 months, respectively. Median OS, LRPFS and PFS for GTVL and GTVG cohorts were 16.3 vs. 9.5 (p = 0.005), 11.0 vs. 6.0 (p = 0.013), and 9.0 vs. 4.8 months (p = 0.008), respectively.ConclusionsThe superior OS, LRPFS and PFS observed in GTVL patients over GTVG ones suggests a potential for FDG-PET-CT-defined GTV size in predicting outcomes of LAPC patients treated with definitive C-CRT, which needs to be validated by further studies with larger cohorts.

Proton Beam Radiation Therapy for Head and Neck Malignancies

Proton beam radiation therapy (PBRT) has unique physical properties (e.g., Bragg Peak) that limit the amount of normal tissue irradiated in the head and neck region while maximizing the radiation delivered to the tumor. Radiation therapy is commonly used in both the primary and adjuvant setting for many head and neck malignancies. Limiting the unnecessary radiation to normal tissues within the head and neck region can result in a profound improvement in quality of life during and after treatment. Although PBRT was initially developed in the 1950s, recent technological advances have permitted the development of hospital-based facilities for proton delivery. PBRT has been shown to improve outcomes for patients with sinonasal tumors, chordomas, chondrosarcomas, ocular, and periocular malignancies. Further development of intensity-modulated proton therapy will permit comprehensive treatment for head and neck tumors.

GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro

STUDY QUESTION Is there any in vitro evidence for or against ovarian protection by co-administration of a GnRH agonist with chemotherapy in human? SUMMARY ANSWER The co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not preserve ovarian reserve in vitro. WHAT IS KNOWN ALREADY Randomized controlled trials of the co-administration of gonadotrophin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to preserve ovarian function have shown contradictory results. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRH agonist (GnRHa) places this approach as a fertility preservation strategy under scrutiny. We therefore aimed in this study to provide in vitro evidence for or against the role of GnRHa in the prevention of chemotherapy-induced damage in human ovary. STUDY DESIGN, SETTINGS, SIZE AND DURATION This translational research study of ex vivo and in vitro models of human ovary and granulosa cells was conducted in a university hospital between 2013 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian cortical pieces (n = 15, age 14-37) and mitotic non-luteinized (COV434 and HGrC1) and non-mitotic luteinized human granulosa cells (HLGC) expressing GnRH receptor were used for the experiments. The samples were treated with cyclophosphamide, cisplatin, paclitaxel, 5-FU, or TAC combination regimen (docetaxel, adriamycin and cyclophosphamide) with and without GnRHa leuprolide acetate for 24 h. DNA damage, apoptosis, follicle reserve, hormone markers of ovarian function and reserve (estradiol (E2), progesterone (P) and anti-mullerian hormone (AMH)) and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy + GnRHa groups. MAIN RESULTS AND THE ROLE OF CHANCE The greatest magnitude of cytotoxicity was observed in the samples treated with cyclophosphamide, cisplatin and TAC regimen. Exposure to these drugs resulted in DNA damage, apoptosis and massive follicle loss along with a concurrent decline in the steroidogenic activity of the samples. GnRHa co-administered with chemotherapy agents stimulated its receptors and raised intracellular cAMP levels. But it neither activated anti-apoptotic pathways nor prevented follicle loss, DNA damage and apoptosis induced by these drugs. LIMITATIONS, REASONS FOR CAUTION Our findings do not conclusively rule out the possibility that GnRHa may offer protection, if any, through some other mechanisms in vivo. WIDER IMPLICATIONS OF THE FINDINGS GnRH agonist treatment with chemotherapy does not prevent or ameliorate ovarian damage and follicle loss in vitro. These data can be useful when consulting a young patient who may wish to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy-induced damage.