Frances McSherry

Concurrent Stereotactic Radiosurgery and Bevacizumab in Recurrent Malignant Gliomas: A Prospective Trial

PURPOSE Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Defining the Optimal Planning Target Volume in Image-Guided Stereotactic Radiosurgery of Brain Metastases: Results of a Randomized Trial

PURPOSE To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. METHODS AND MATERIALS Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). RESULTS Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. CONCLUSIONS SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.

Recurrent Glioblastoma Treated with Recombinant Poliovirus

BACKGROUND The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose‐finding and toxicity study in this population of patients, evaluating convection‐enhanced, intratumoral delivery of the recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast‐enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 107 and 1010 50% tissue‐culture infectious doses (TCID50), first in a dose‐escalation phase and then in a dose‐expansion phase. RESULTS From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level ‐1 (5.0×107 TCID50) was identified as the phase 2 dose. One dose‐limiting toxic effect was observed; a patient in whom dose level 5 (1010 TCID50) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose‐expansion phase, 19% of the patients had a PVSRIPO‐related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893.)

Phase II Trial of Upfront Bevacizumab, Irinotecan, and Temozolomide for Unresectable Glioblastoma

LESSONS LEARNED Trials focusing on unresectable multifocal glioblastoma are needed because of the extremely poor prognosis and challenges in receiving standard therapy, such as concurrent radiation and chemotherapy.Developing a strategy to chemically debulk tumors before radiation and/or surgery is warranted. BACKGROUND Extent of resection remains a key prognostic factor in glioblastoma (GBM), with gross total resection providing a better prognosis than biopsy or subtotal resection. We conducted a phase II trial of upfront therapy with bevacizumab (BV), irinotecan (CPT-11), and temozolomide (TMZ) prior to chemoradiation in patients with unresectable, subtotally resected, and/or multifocal GBM. METHODS Patients received up to 4 cycles of TMZ at 200 mg/m(2) per day on days 1-5 (standard dosing) and BV at 10 mg/kg every 2 weeks on a 28-day cycle. CPT-11 was given every 2 weeks on a 28-day cycle at 125 mg/m(2) or 340 mg/m(2) depending on antiepileptic drugs. Magnetic resonance imaging of the brain was done every 4 weeks, and treatment continued as long as there was no tumor progression or unmanageable toxicity. The primary endpoint was tumor response rate, with a goal of 26% or greater. RESULTS Forty-one patients were enrolled from December 2009 to November 2010. Radiographic responses were as follows: 9 patients (22.0%) had partial response, 25 (61.0%) had stable disease, and 2 (4.9%) had progression; 5 patients were not assessed. Cumulative response rate was 22%. Median overall survival was 12 months (95% confidence interval: 7.2-13.5 months). CONCLUSION Upfront treatment with BV, TMZ, and CPT-11 is tolerable and can lead to radiographic response in unresectable and/or subtotally resected GBM.

Patterns of failure for stage I ampulla of Vater adenocarcinoma: a single institutional experience.

BACKGROUND Ampullary adenocarcinoma is a rare malignancy associated with a relatively favorable prognosis. Given high survival rates in stage I patients reported in small series with surgery alone, adjuvant chemoradiotherapy (CRT) has traditionally been recommended only for patients with high risk disease. Recent population-based data have demonstrated inferior outcomes to previous series. We examined disease-related outcomes for stage I tumors treated with pancreaticoduodenectomy, with and without CRT. METHODS All patients with stage I ampullary adenocarcinoma treated from 1976 to 2011 at Duke University were reviewed. Disease-related endpoints including local control (LC), metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS Forty-four patients were included in this study. Thirty-one patients underwent surgery alone, while 13 also received adjuvant CRT. Five-year LC, MFS, DFS and OS for patients treated with surgery only and surgery with CRT were 56% and 83% (P=0.13), 67% and 83% (P=0.31), 56% and 83% (P=0.13), and 53% and 68% (P=0.09), respectively. CONCLUSIONS The prognosis for patients diagnosed with stage I ampullary adenocarcinoma may not be as favorable as previously described. Our data suggests a possible benefit of adjuvant CRT delivery.

Biopsy of enlarging lesions after stereotactic radiosurgery for brain metastases frequently reveals radiation necrosis

Background Stereotactic radiosurgery (SRS) offers excellent local control for brain metastases (BM) with low rates of toxicity. Radiation necrosis (RN) may occur after treatment and is challenging to distinguish from local recurrence (LR). We evaluated enlarging brain lesions following SRS that were subsequently biopsied to differentiate RN versus LR. Methods This study reviewed patients receiving SRS for BM between 2008 and 2012 who underwent a biopsy for suspicion of RN versus LR on MRI. Data collection included demographics, radiation parameters, imaging findings, and post-biopsy pathology. Kaplan-Meier methods determined overall survival. Fishers exact test assessed for association between lesion biopsy result and variables of interest. Results Thirty-four patients with 35 biopsied BM were included. Lesions were biopsied a median of 8.8 months after SRS. Most patients had primary lung cancer (11; 31.4%). Eleven (31.4%) biopsies were positive for LR and 24 (68.6%) showed RN only. Median overall survival was longer for patients with RN (31.0 mo) than for patients with LR (14.5 mo; P = 0.135). Time from SRS to biopsy was significantly different between RN and LR groups; 10 lesions (52.5%) biopsied ≤9 months after SRS showed LR, whereas 1 lesion (6.3%) biopsied >9 months after SRS showed LR (P = 0.004). For 16 (65.7%) lesions, management was changed or directed by the biopsy results. Conclusions Stereotactic biopsy for accessible enlarging lesions after SRS appears diagnostically valuable in patients with few lesions and changes clinical management. RN should be suspected in patients with an enlarging lesion more than 9 months post-SRS.

Immune Activation in Early Stage Non-Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab

Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non–small cell lung cancer (NSCLC) patients. Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB–IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles. Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs. Conclusions: This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies. Clin Cancer Res; 23(24); 7474–82. ©2017 AACR.

A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab

Purpose Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan–bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2–5), overall CINV CR (days 1–5), and QoL, fatigue, and toxicity. Materials and methods A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL–DEX. Validated surveys assessed fatigue and QoL. Results A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL–DEX dose administrations 1–3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL–DEX treatment-related toxicities. Conclusion Data suggest that PAL–DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.

Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma

Abstract Lessons Learned. Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival. Disease‐expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis. Background. Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3–11 months with bevacizumab (BEV)‐containing regimens. BEV in rMG has 6‐month progression free survival (PFS‐6) of ∼40% and an objective response rate of 21.2%. BEV‐containing regimens improve PFS‐6 to 42.6%–50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c‐Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth. Methods. Thirty‐six BEV‐naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro‐Oncology [RANO] criteria), PFS‐6, overall survival (OS), and toxicity. Results. Median patient follow‐up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%–44.1%). Median OS was 11.2 months (95% CI: 7–17.5). PFS‐6 was 41.7% (95% CI: 25.6%–57.0%). Most frequent treatment‐related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism. Conclusion. Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens.

Single fraction stereotactic radiosurgery for multiple brain metastases

Introduction Due to the neurocognitive side effects of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) is being used with increasing frequency. The use of SRS is expanding for patients with multiple (>4) brain metastases (BM). This study summarizes our institutional experience with single-fraction, linear-accelerator-based SRS for multiple BM. Methods and materials All patients who were treated between January 1, 2013, and September 30, 2015, with single-fraction SRS for ≥4 BM were included in this institutional review board–approved, retrospective, single-institution study. Patients were treated with linear accelerator–based image guided SRS. Results A total of 59 patients with ≥4 BM were treated with single-fraction SRS. The median follow-up was 15.2 months, and the median overall survival for the entire cohort was 5.8 months. The median number of treated lesions per patient was 5 (range, 4-23). Per patient, the median planning target volume (PTV) was 4.8 cc (range, 0.7-28.8 cc). The prescribed dose across all 380 BM for the 59 patients ranged from 7 to 20 Gy. The median of the mean dose to the total PTV was 19.5 Gy. Although the number of treated lesions (4-5 vs ≥6) did not influence survival, better survival was noted for a total PTV <10 cc versus ≥10 cc (7.1 vs 4.2 months, respectively; P = .0001). A mean dose of ≥19 Gy to the entire PTV was also associated with increased survival (6.6 vs 5.0 months, respectively; P = .0172). Patients receiving a dose of >12 Gy to ≥10 cc of normal brain had worse survival (5.1 vs 8.6 months, respectively; P = .0028). Conclusion In single-fraction SRS for patients with multiple BM, smaller total tumor volume, higher total dose, and lower volume of normal brain receiving >12 Gy were associated with increased survival. These data suggest that using SRS for the treatment of multiple BM is efficacious and that outcomes may be affected more by total tumor volume than by the number of lesions.