Yaacov Richard Lawrence

Improving prognosis of glioblastoma in the 21st century: who has benefited most?

Glioblastoma multiforme (GBM) is the most frequent primary brain tumor in adults. Temozolomide was rapidly incorporated into first‐line treatment following the publication of the pivotal European Organization for Research and Treatment of Cancer–National Cancer Institute of Canada phase 3 trial in 2005. However, in the trial, enrollment was limited to younger patients with good performance status. Therefore, this study performed a population‐based survival analysis of patients with newly diagnosed GBM covering the period before and after the introduction of temozolomide.

mTOR is a selective effector of the radiation therapy response in androgen receptor positive prostate cancer

Ionizing radiation (IR) is used frequently in the management of multiple tumor types, including both organ-confined and locally advanced prostate cancer (PCa). Enhancing tumor radiosensitivity could both reduce the amount of radiation required for definitive treatment and improve clinical outcome. Androgen suppression therapy improves clinical outcomes when combined with radiation therapy but is associated with significant acute and chronic toxicities; hence, there is a clear need for alternative means to increase the therapeutic window of radiotherapy. Herein, it is demonstrated that the mammalian target of rapamycin (mTOR) inhibitors rapamycin (sirolimus) and temsirolimus limit both hormone therapy (HT)-sensitive and castration-resistant PCa (CRPC) cell proliferation as single agents and have a profound radiosensitization effect when used in combination with IR. Importantly, the observed radiosensitization was influenced by the treatment schedule, in which adjuvant administration of mTOR inhibitors was most effective in limiting PCa cell population doubling. This schedule-dependent influence on in vitro treatment outcome was determined to be the result of relative effects on the cell cycle kinetics. Finally, adjuvant administration of either mTOR inhibitor tested after IR significantly decreased clonogenic cell survival of both HT-sensitive and CRPC cells compared with IR alone. Taken together, these data demonstrate that inhibition of mTOR confers a radiosensitization phenotype that is dependent on relative cell cycle kinetics and provide a foundation for clinical assessment.

A Phase I Study of the Combination of Sorafenib With Temozolomide and Radiation Therapy for the Treatment of Primary and Recurrent High-Grade Gliomas

PURPOSE Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Changing prognosis of metastatic colorectal adenocarcinoma: Differential improvement by age and tumor location

Over the past 2 decades, significant progress has been made in the field of metastatic colorectal cancer (mCRC) regarding new imaging techniques, surgical interventions, and systemic therapy. It is not known whether the benefit from these interventions has extended overall survival (OS) within the general mCRC population. A population‐based survival analysis of newly diagnosed patients who presented with mCRC was therefore performed.

Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure?

Purpose: The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. Methods: This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center’s Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric &khgr;2 test was used to compare the initial and final treatment recommendations following choline PET/CT. Results: Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n=6), radiation therapy (RT) (n=6), brachytherapy (n=2), RP+salvage prostate fossa RT (n=14), and RP+salvage prostate fossa/lymph node RT (n=6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans. PET/CT altered treatment approach in 18 of 33 (55%) patients (P=0.05). Sixteen of 27 patients (59%) treated previously with radiation were retreated with RT and delayed or eliminated androgen deprivation therapy: 1 received salvage brachytherapy, 10 received salvage pelvic lymph node or prostate fossa irradiation, 2 brachytherapy failures received salvage prostate and lymph nodes IMRT, and 3 with solitary bone metastasis were treated with radiosurgery. Eleven of 16 patients retreated responded to salvage therapy with a significant PSA response (<0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500±447 days. Two of 6 patients with no prior RT were referred for salvage prostatic fossa RT: 1 received dose escalation for disease identified in the prostate fossa and another had inclusion of “hot” pelvic lymph nodes in the treatment volume. Conclusions: These early results suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines may change management and improve care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning, and delaying or avoiding use of androgen deprivation therapy.

Hsp90 inhibition enhances PI-3 kinase inhibition and radiosensitivity in glioblastoma.

AbstractPurpose Combined targeting with a PI3-kinase inhibitor, BKM120, and an Hsp90 inhibitor, HSP990, was investigated as a multi-targeted approach to potentiate cell death in glioblastoma (GBM). Additionally, the effect of dual drug treatment combined with cytotoxic stress (radiation therapy) was examined.MethodsFour human GBM cell lines containing wild-type or mutated PTEN and/or p53 were studied. The effects of drug treatments on cell viability, apoptosis induction, pAKt activity, cell cycle arrest, clonogenicity, and tumor growth delay were studied.ResultsCombined concurrent treatment with both drugs produced more cell killing in cell viability and apoptosis assays than either drug alone. BKM120 plus HSP990 induced suppression of baseline Akt signaling as well as radiation (RT)-induced pAkt signaling in all cell lines. Cell cycle analysis revealed that HSP990 and BKM120, singly or combined, induced G2/M arrest leading to apoptosis/necrosis and polyploidy. Additionally, the drugs radiosensitized GBM cells in clonogenic assays. In vivo tumor growth delay studies demonstrated the effectiveness of combined drug treatment with HSP990 and BKM120 over single drug treatment, as well as the effectiveness of combined drug treatment in enhancing the effectiveness of radiation therapy.ConclusionsIn conclusion, HSP990 and BKM120, with and without RT, are active agents against glioma tumors. The sensitivity to these agents does not appear to depend on PTEN/p53status in the cell lines tested. We suggest that the combined action of both drugs is a viable multi-targeted strategy with the potential to improve clinical outcome for patients with high-grade glioma.

The addition of amifostine to carboplatin and paclitaxel based chemoradiation in locally advanced non-small cell lung cancer: Long-term follow-up of Radiation Therapy Oncology Group (RTOG) randomized trial 9801

INTRODUCTION We report the long-term results of RTOG 9801, a randomized trial investigating the ability of amifostine, a radioprotector, to reduce chemoradiation-induced esophagitis. METHODS Patients with stages II and IIIA/B non-small-cell lung cancer received induction paclitaxel 225 mg/m2 intravenously (IV) and carboplatin area under the curve (AUC) 6 both days 1 and 22, followed by concurrent weekly paclitaxel (50 mg/m2) and carboplatin (AUC 2), with hyperfractionated radiation therapy (69.6 Gy at 1.2 Gy BID). Patients were randomly assigned to amifostine (AM) 500 mg IV four times per week or no-AM during chemoradiotherapy. Stratification factors included age (<70 vs. ≥70 years), stage and performance status. RESULTS 243 patients (pts) were enrolled; 120 received AM, 123 received no-AM. Two pts on each arm were found ineligible. Overall, 85% of patients were ≤70 years; 75% had a KPS ≥90. 34% had squamous histology. With median follow-up of 96.3 months (for patients still alive), overall survival was identical (hazard ratio 1.03 (0.79-1.34), NS): five-year survival 17% in both arms. The incidence of late grade 3-5 toxicities was 16% in the AM arm and 19% in the control arm (hazard ratio 1.24 (0.66-2.32), NS). There was no significant difference between the arms regarding overall survival, disease-free survival or long-term toxicity. CONCLUSION The chemoradiation regimen of carboplatin and paclitaxel produced long-term results in the multi-institutional setting comparable to other regimens. Amifostine did not appear to compromise survival. As done in RTOG 9801, more consistent reporting of long term toxicity is needed for comparison of different chemoradiation regimens.

Early toxicity predicts long-term survival in high-grade glioma.

Background:Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known.Methods:Acute and late ⩾ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable.Results:There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2–4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months).Interpretation:Acute NT is significantly associated with both late NT and overall survival.

Lymph node ratio predicts the benefit of post-operative radiotherapy in oral cavity cancer.

BACKGROUND The standard treatment for non-metastatic oral cavity squamous cell carcinoma (OCSCC) is surgical resection followed by post-operative radiotherapy (PORT) with/without chemotherapy in high risk patients. Given the substantial toxicity of PORT we assessed lymph node ratio (LNR) as a predictor of PORT benefit. DESIGN By using the Surveillance, Epidemiology and End Results (SEER) database, we analyzed all node positive OCSCC patients diagnosed between 1988 and 2007 who underwent neck dissection. LNR was categorized into three groups: < 6%, 6-12.5% and > 12.5%. RESULTS In 3091 subjects identified, median survival was 32, 25 and 16 months for LNR Groups 1, 2 and 3, respectively. On multivariate analysis, survival was associated with age, race, grade, tumor size, nodal stage, extra-capsular extension, use of PORT and LNR. When stratified by LNR group, PORT was associated with a survival benefit only in Group 3 (LNR > 12.5%): 2 year survival 25% vs 37%. No benefit to PORT was seen when the LNR ≤ 12.5%: 2 year survival 51% vs 54%. CONCLUSION A low LNR is associated with extended survival in LN positive OCSCC. The survival benefit associated with PORT in this disease appears to be limited to those with a LNR > 12.5%. Validation is required prior to the clinical implementation of our findings.

Predictors of Radiation Oncology Resident Research Productivity

PURPOSE Academic research is an essential part of residency training, yet resident productivity in research seems to be highly variable. The aim of this study was to determine the factors, both individual and institutional, that contribute to research output among radiation oncology residents. METHODS Newly practicing radiation oncologists and current senior residents were identified and invited via e-mail to complete a web-based survey. The survey addressed demographic factors, previous academic accomplishments, and residency program structure. The end point, research productivity, was defined as the number of first-author papers produced or research grants awarded on the basis of work initiated during residency. RESULTS Ninety-seven of the 232 senior residents and recently graduated radiation oncologists surveyed responded (a 42% response rate). The median number of publications produced on the basis of work during residency was 3 (range, 0-7). Twenty-one respondents indicated that they had received 1 or more grants. Forty-four respondents completed <6 months of research, while 53 completed ≥6 months of research. Univariate analysis revealed that a scientific college major and the amount of designated research time were positively correlated (P < .05) with first-author publications. Entering with a PhD, presenting research at an international meeting before residency, participation in the Holman Research Pathway, female gender, publications before residency, and the amount of designated research time were positively correlated (P < .05) with receiving a research grant. On multivariate regression analysis, the amount of designated research time was the sole determinant of first-author papers (P < .007), while participation in the Holman Pathway was the only surveyed factor that was correlated with research grants awarded (P < .001). CONCLUSIONS The amount of designated research time during residency training is the sole independent predictor of research productivity as measured by publications. Participation in the Holman Pathway is the sole detected item shown to be an independent predictor of achieving a peer-reviewed grant. Residency program structure has a major impact on the productivity of residents.