CONVECTION-ENHANCED DELIVERY OF CINTREDEKIN BESUDOTOX (INTERLEUKIN-13-PE38QQR) FOLLOWED BY RADIATION THERAPY WITH AND WITHOUT TEMOZOLOMIDE IN NEWLY DIAGNOSED MALIGNANT GLIOMAS

Neurosurgery ◽  
2007 ◽  
Vol 61 (5) ◽  
pp. 1031-1038 ◽  
Author(s):  
Michael A. Vogelbaum ◽  
John H. Sampson ◽  
Sandeep Kunwar ◽  
Susan M. Chang ◽  
Mark Shaffrey ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Malignant Gliomas ◽  
External Beam Radiation ◽  
Newly Diagnosed ◽  
Convection Enhanced Delivery ◽  
Beam Radiation ◽  
Interleukin 13 ◽  
Grade 3 ◽  
Dose Limiting Toxicity ◽  
Final Cohort

Abstract OBJECTIVE Cintredekin besudotox (CB), a recombinant cytotoxin consisting of interleukin-13 and truncated Pseudomonas exotoxin, binds selectively to interleukin-13Rα2 receptors overexpressed by malignant gliomas. This study assessed the safety of CB administered by convection-enhanced delivery followed by standard external beam radiation therapy (EBRT) with or without temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) in patients with newly diagnosed malignant gliomas. METHODS After gross total resection of the tumor, two to four intraparenchymal catheters were stereotactically placed and CB (0.25 or 0.5 μg/mL) was infused for 96 hours. This was followed, 10 to 14 days later, by EBRT (5940–6100 cGy, 5 d/wk for 6–7 wk) with or without temozolomide (75 mg/m2/d, 7 d/wk during EBRT). Safety was assessed during an 11-week observation period after catheter placement RESULTS Twenty-two patients (12 men, 10 women; median age, 55 yr; 21 with glioblastoma multiforme and one with an anaplastic mixed oligoastrocytoma) were enrolled. None of the patients experienced dose-limiting toxicities in the first two cohorts (0.25 μg/mL CB + EBRT [n = 3] and 0.25 μg/mL CB + EBRT + temozolomide [n = 3]). One patient experienced a dose-limiting toxicity (Grade 4 seizure) in the third cohort (0.5 μg/mL CB + EBRT [n = 6]). Six patients in the final cohort (0.5 μg/mL CB + EBRT + temozolomide [n = 10]) completed treatment, and one patient experienced a dose-limiting toxicity (Grade 3 aphasia and confusion). Four patients were not considered evaluable for a dose decision and were replaced. CB related adverse events occurring in more than one patient were fatigue, gait disturbance, nystagmus, and confusion. No Grade 3 to 4 hematological toxicities were observed. CONCLUSION CB (0.5 μg/mL) administered via convection-enhanced delivery before standard radiochemotherapy seems to be well tolerated in adults with newly diagnosed malignant gliomas. Further clinical study assessment is warranted.

scholarly journals EPCT-18. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY FOR RECURRENT, REFRACTORY, OR PROGRESSIVE EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG) AND NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i50-i51
Author(s):  
Ashley Plant ◽  
Stewart Goldman ◽  
Sandi Lam ◽  
Michael DeCuypere ◽  
Gregory Stein ◽  
...  
Keyword(s):  
Specific Activity ◽  
Phase 1 ◽  
High Specific Activity ◽  
External Beam Radiation ◽  
Central Component ◽  
Normal Brain ◽  
Newly Diagnosed ◽  
Convection Enhanced Delivery ◽  
Beam Radiation ◽  
Dose Limiting Toxicity

Abstract Ependymoma, HGG, and DIPG are gliomas that are often difficult to treat, frequently aggressive, and often carry an extremely poor prognosis. While external beam radiation therapy (EBRT) remains a central component of the management of pediatric gliomas, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. In a Phase 1 trial in adults with recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor when coverage was 75% or greater (n=10) was 392 Gy (CI 306 – 478). Thus far, the therapy has been well tolerated, no dose-limiting toxicity has been observed, and no treatment-related serious adverse events have occurred despite markedly higher absorbed doses than typically delivered by EBRT (n=18). Methods This is a two-part, Phase 1 dose-finding study followed by an expansion cohort to explore efficacy. Part 1 will enroll up to 18 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by convection enhanced delivery (CED). Tumor size will be limited to a diameter of 4 cm in the longest axis and a volume of 34 mL. The dose limiting toxicity period (DLT) is 28 days post infusion. Part 2 will independently evaluate 186RNL in 3 different cohorts: Cohort A: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive ependymoma; Cohort B: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive HGG; Cohort C: up to 15 subjects with newly diagnosed DIPG. The primary endpoint is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. Secondary endpoints are PFS-24 and OS-24 in Cohort A and PFS-12 and OS-12 in Cohorts B and C. Planned enrollment will begin in H2 2021.

A phase II trial of radiation and cetuximab followed by irinotecan/cetuximab for children with newly diagnosed diffuse pontine tumors and high-grade astrocytomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10030-10030 ◽  
Author(s):  
Margaret Macy ◽  
Mark W. Kieran ◽  
Susan N. Chi ◽  
Kenneth J. Cohen ◽  
Tobey MacDonald ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase 1 ◽  
Progression Free Survival ◽  
External Beam Radiation ◽  
High Grade ◽  
Newly Diagnosed ◽  
Beam Radiation ◽  
Phase 2 Trial ◽  
Correlative Studies ◽  
Grade 3

10030 Background: Diffuse intrinsic pontine gliomas (DIPG) and high-grade astrocytomas (HGA) have dismal prognoses. We previously demonstrated in a phase 1 study that cetuximab and irinotecan was a safe and tolerable regimen. Consequently, we initiated this 2-strata phase 2 trial to investigate the safety and efficacy of weekly cetuximab given with involved field external beam radiation therapy followed by 10 cycles of cetuximab and irinotecan for DIPG and HGA as determined by the 1-year progression-free survival. Methods: Eligible patients aged 3-21 years with newly diagnosed HGA or DIPG were enrolled to parallel strata. All patients received radiation therapy (5940 cGy) with concurrent cetuximab at 250mg/m2 IV weekly for 6 weeks. Following radiation, patients received cetuximab (250mg/m2 IV) weekly and irinotecan (16mg/m2/day IV) daily x 5 for two weeks every 21 days for 30 weeks. Tumor, serum, and CSF samples were collected for correlative studies. Sera collected at the onset of rash were analyzed for inflammatory and immune-related cytokines. Results: Forty-eight patients (27 DIPG, 21 HGA) were enrolled and 45 were treated (median age 8 years; range: 3–19). Toxicities were manageable; the most common adverse events were fatigue, gastrointestinal complaints, neutropenia, rash, headache, electrolyte abnormalities, elevated ALT/AST, and fever. Grade 3-4 events in ≥10% of patients were hypokalemia and lymphopenia. 4 patients experienced cetuximab-related hypersensitivity reactions (2 grade 3 reactions). The median PFS was 9.5 months (95% CI: 7.0-12.2) for HGA and 7.8 months (7.0-8.6) for DIPG with a 1-year PFS±SE of 24±10% and 25%±10% respectively. The median OS for HGA was 17.7 months (95% CI: 14.1-18.0) and 11.5 months (8.8-14.2) for DIPG. Biological correlative studies will be presented. Conclusions: Cetuximab and radiation therapy followed by cetuximab and irinotecan is well tolerated in children. Based on the 1-year PFS, this regimen may deserve further investigation in patients with DIPG. Biological correlative studies will delineate the mechanisms of the rash and possible implications for EGFR-targeted therapeutics in such patients. Clinical trial information: NCT01012609.

scholarly journals 3D Conformal Radiotherapy and Cisplatin for Recurrent Malignant Glioma

2008 ◽  
Vol 35 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Lauren VanderSpek ◽  
Barbara Fisher ◽  
Glenn Bauman ◽  
David Macdonald
Keyword(s):  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Conformal Radiotherapy ◽  
Maximum Tolerated Dose ◽  
External Beam Radiation ◽  
Recurrent Malignant Glioma ◽  
Beam Radiation ◽  
Fractionated Radiotherapy ◽  
3D Conformal Radiotherapy ◽  
Grade 3

Purpose:To determine the maximum tolerated dose of 3D conformal radiotherapy in combination with Cisplatin for patients with recurrent malignant gliomas.Methods:From 1999-2003, nine patients with recurrent malignant glioma received fractionated radiotherapy and Cisplatin (20 mg/m2/d IV on days 1-5) in a Phase I radiation dose escalation trial. Three sequential dose levels were evaluated: 25 Gy, 30 Gy, and 35 Gy, using 5 Gy fractions. All patients received prior external beam radiation (median dose 59.4 (20-60) Gy) and five patients received prior chemotherapy.Results:Six male and three female patients were enrolled with a median age of 52 years, and a median Karnofsky performance status score of 70. The median re-irradiated tumor volume was 18.9 (0.1-78.5) cm3 and the median follow-up was 8.8 (3.2-31.2) months. One patient (30 Gy/ 6 fractions) experienced medically reversible acute grade 3 toxicity. A second patient (35 Gy/ 7 fractions) experienced acute grade 2 toxicity and histology showed tumor and radiation effect. A third patient (25 Gy/ 5 fractions) experienced late grade 3 toxicity from radiation necrosis. The radiological responses consisted of complete response (1 patient), partial response (1 patient), and stable disease (2 patients). The median overall survival was 8.8 months (95% CI 8.0-9.9), and the median disease free interval was 2.0 months (95% CI 1.4-4.4). Seven patients received chemotherapy following re-irradiation and Cisplatin.Conclusion:The maximum tolerated dose of 3D conformal fractionated radiotherapy was 30 Gy in 6 fractions with low dose Cisplatin, which was well tolerated in terms of acute toxicity for our patient population. This regimen demonstrated only modest efficacy in the treatment of recurrent malignant glioma. Combinations of conformal re-irradiation and other systemic agents may merit investigation. Currently our recommended dose is 30 Gy in 6 fractions for selected patients.

Preoperative Paclitaxel and Concurrent Rapid-Fractionation Radiation for Resectable Pancreatic Adenocarcinoma: Toxicities, Histologic Response Rates, and Event-Free Outcome

2002 ◽  
Vol 20 (10) ◽  
pp. 2537-2544 ◽  
Author(s):  
Peter W. T. Pisters ◽  
Robert A. Wolff ◽  
Nora A. Janjan ◽  
Karen R. Cleary ◽  
Chusilp Charnsangavej ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Pancreatic Adenocarcinoma ◽  
External Beam Radiation Therapy ◽  
External Beam Radiation ◽  
Intraoperative Radiation Therapy ◽  
Preoperative Treatment ◽  
External Beam ◽  
Beam Radiation ◽  
Intraoperative Radiation ◽  
Grade 3

PURPOSE: To evaluate the toxicity of a preoperative regimen of paclitaxel and concurrent external-beam radiation therapy, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with localized, potentially resectable pancreatic adenocarcinoma were treated with 30 Gy external-beam radiation therapy and concomitant weekly 3-hour infusions of paclitaxel (60 mg/m2). Radiographic restaging was performed 4 to 6 weeks after chemoradiation, and patients with localized disease underwent pancreatectomy with EB-IORT. RESULTS: Thirty-five patients completed chemoradiation; 16 (46%) experienced grade 3 toxicity. Four patients (11%) required hospitalization for dehydration due to grade 3 nausea and vomiting. Twenty (80%) of 25 patients who underwent surgery underwent pancreatectomy; EB-IORT was used in 13 patients. There were no histologic complete responses to preoperative therapy; 21% of specimens demonstrated more than 50% nonviable cells (grade 2b treatment effect). With a median follow-up period of 46 months, the 3-year overall survival rate with chemoradiation and pancreatectomy was 28%. CONCLUSION: Preoperative paclitaxel-based concurrent chemoradiation is feasible. The toxicity of this regimen seems greater than that with fluorouracil. The histologic responses and survival are similar, suggesting no advantages to paclitaxel-based preoperative treatment.

The Brain Tumor Cooperative Group NIH Trial 87-01: A Randomized Comparison of Surgery, External Radiotherapy, and Carmustine versus Surgery, Interstitial Radiotherapy Boost, External Radiation Therapy, and Carmustine

Neurosurgery ◽  
2002 ◽  
Vol 51 (2) ◽  
pp. 343-357 ◽  
Author(s):  
Robert G. Selker ◽  
William R. Shapiro ◽  
Peter Burger ◽  
Margaret S. Blackwood ◽  
Melvin Deutsch ◽  
...  
Keyword(s):  
Median Survival ◽  
Malignant Gliomas ◽  
External Beam Radiation ◽  
Study Group ◽  
External Beam ◽  
Newly Diagnosed ◽  
Beam Radiation ◽  
Interstitial Radiotherapy ◽  
Treatment Groups ◽  
The Brain

Abstract OBJECTIVE The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas. METHODS The study involved a randomized comparison of surgery, external beam radiotherapy, and carmustine (BCNU) versus surgery, external beam therapy, interstitial radiotherapy boost, and BCNU in newly diagnosed malignant gliomas. 125I was chosen as best suited for this effort because it allowed preimplantation planning and postimplantation quality assurance review. Two hundred ninety-nine patients met the eligibility criteria and were randomized into the two arms of the study between December 1987 and April 1994. Follow-up continued for an additional 3 years. Twenty-nine patients were identified as having committed protocol violations and were excluded, resulting in 270 subjects in the Valid Study Group. One hundred thirty-seven patients received external beam radiation and BCNU, and 133 underwent the 125I implantation plus external beam radiation and BCNU therapy. RESULTS The overall median survival for the Valid Study Group was 64.3 weeks. The median survival for patients receiving additional therapy of 125I was 68.1 weeks, and median survival for those receiving only external beam radiation and BCNU was 58.8 weeks. The cumulative proportion surviving between the two treatment groups was not statistically significantly different (log-rank test, P = 0.101). As in other studies in the literature, age, Karnofsky score, and pathology were predictors of mortality. Additional analyses incorporating an adjustment for these prognostic variables, either in a stratified analysis or Cox proportional hazards model, did not result in statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups. CONCLUSION We conclude that there is no long-term survival advantage of increased radiation dose with 125I seeds in newly diagnosed glioma patients.

Phase I/II Study of Preoperative Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy in Patients With Locally Advanced Rectal Cancer: Cancer and Leukemia Group B 89901

2006 ◽  
Vol 24 (16) ◽  
pp. 2557-2562 ◽  
Author(s):  
David P. Ryan ◽  
Donna Niedzwiecki ◽  
Donna Hollis ◽  
Brent E. Mediema ◽  
Scott Wadler ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Continuous Infusion ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Grade 3 ◽  
Experienced Grade

Purpose The addition of oxaliplatin to fluorouracil in patients with advanced colorectal cancer improves survival. This phase I/II study evaluated the addition of weekly oxaliplatin to preoperative continuous infusion fluorouracil (FU) and external-beam radiation therapy (RT) in patients with locally advanced rectal adenocarcinoma. Patients and Methods Patients with clinical T3/T4 rectal adenocarcinoma and no evidence of metastases were treated with weekly oxaliplatin, continuous infusion FU 200 mg/m2 intravenously, and RT. A total of 6 weekly doses of oxaliplatin were planned. RT dose was 1.8 Gy/fraction to a total dose of 50.4 Gy. In the phase I portion, oxaliplatin was escalated from 30 to 60 mg/m2. Results Forty-four patients were entered onto the study, 18 on the phase I portion and 26 on the phase II portion. The maximum-tolerated dose (MTD) for oxaliplatin was determined to be 60 mg/m2. At the MTD, 12 patients experienced grade 3 or 4 diarrhea, two patients experienced grade 3 neutropenia, and one patient experienced grade 3 thrombocytopenia. Fifty-six percent of patients entered at the MTD completed all 6 weeks of oxaliplatin. Eight (25%) of 32 patients enrolled at the phase II dose experienced a pathologic complete response. Conclusion In this multicenter study, the addition of oxaliplatin to intravenous continuous infusion FU and RT for patients with locally advanced rectal cancer was associated with a high pathologic complete response rate but more toxicity than when FU is used alone. A regimen of weekly oxaliplatin, continuous infusion FU, and radiation therapy is now being evaluated by the National Surgical Adjuvant Breast and Bowel Project.

A retrospective safety and efficacy analysis of combination therapy using Gliadel wafers plus external beam radiation therapy with concurrent temozolomide in newly diagnosed glioblastoma multiforme patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 12510-12510
Author(s):  
E. Pan ◽  
S. B. Mitchell ◽  
J. S. Tsai
Keyword(s):  
Glioblastoma Multiforme ◽  
Clinical Outcomes ◽  
Multimodal Therapy ◽  
Small Sample ◽  
External Beam Radiation ◽  
Newly Diagnosed ◽  
Beam Radiation ◽  
Safety And Efficacy ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3

12510 Background: Safety and efficacy of malignant glioma treatment with carmustine-containing biodegradable implants (Gliadel® Wafers) followed by conventional radiotherapy (RT) and treatment with RT and concomitant temozolomide have both been well established. Multimodal therapy combining Gliadel® Wafers, RT, and temozolomide has recently demonstrated significant improvements in clinical outcomes of newly-diagnosed glioblastoma multiforme (GBM) patients. However, Gliadel® Wafer implantation in newly-diagnosed GBM patients is limited by the suspected risk of toxicities associated with multimodal therapy. Thus, the safety of multimodal therapy with Gliadel® Wafers, RT, and temozolomide needs to be determined. Methods: We conducted a retrospective analysis of medical records of 21 Florida Hospital Neuro- Oncology Center patients who were newly diagnosed with GBM from January 2003 to December 2005 and initially received multimodal therapy. All systemic and local toxicities were graded according to CTC AE v.3.0. Results were compared to historical data. Results: Our study population did not differ significantly from prior study populations with regard to patient demographics. 4 of 21 (19%) patients had grade 3 toxicities, which may have been related to multimodal therapy. None of the 21 patients had grade 4 toxicities. Median time to progression from initial surgery was 12.8 months (range 2–24 months). Median overall survival was 17 months (95% CI of 15–25 months). Conclusion: The addition of Gliadel® Wafers to concurrent RT and temozolomide did not result in a notable increase in grade 3 and 4 toxicities but did produce clinical outcomes comparable with those found in prior studies. The small sample size does not allow for definitive conclusions regarding efficacy. However, the addition of Gliadel® Wafers to concurrent RT and temozolomide appears to be safe in newly-diagnosed GBM patients. [Table: see text] No significant financial relationships to disclose.

Impact of histological grade on oncologic outcomes in clinical stage I patients with endometrial carcinoma patients after definitive primary radiation therapy

2019 ◽  
Vol 29 (5) ◽  
pp. 890-896
Author(s):  
Adria Suarez Mora ◽  
Zachary Horne ◽  
Sarah Taylor ◽  
Alexander Babatunde Olawaiye ◽  
Sushil Beriwal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Radiation Therapy ◽  
Histological Grade ◽  
Endometrial Adenocarcinoma ◽  
External Beam Radiation Therapy ◽  
Stage I ◽  
External Beam Radiation ◽  
External Beam ◽  
Beam Radiation ◽  
Grade 3

ObjectivesTo determine the impact of histological grade on overall survival in patients with clinical stage I endometrioid endometrial adenocarcinoma when radiation therapy is used as primary definitive treatment.MethodsPatients with stage I endometrioid endometrial adenocarcinomas who underwent definitive radiation therapy with brachytherapy ± external beam radiation therapy were identified from the National Cancer Database. Overall survival was estimated using the Kaplan-Meier method. Univariable and multivariable analyses were performed to determine factors affecting overall survival. Inverse probability of treatment weights were also used in multivariable analysis to estimate casual effects of external beam radiation therapy.ResultsA total of 947 patients were identified. Median overall survival for grade 1, grade 2, and grade 3 tumors was 62 months (95% CI 53.8 to 70.2), 48.5 months (95% CI 38.2 to 58.8), and 33.5 months (95% CI: 23.1 to 43.8), respectively. Grade, age, and insurance status were associated with overall survival in univariate analysis with only grade and age remaining significant in multivariate analysis. Brachytherapy with external beam radiation therapy was not associated with survival in comparison with brachytherapy alone. Compared with grade 1 tumors, patients with grade 3 (HR 1.4, 95% CI 1.15 to 1.89), but not grade 2 (HR 1.0, 95% CI 0.82 to 1.26), had an increased risk of death, which persisted in an inverse probability of treatment weights-adjusted model (HR 1.56, 95% CI 1.21 to 1.93).ConclusionsPatients with grade 3 stage I endometrioid endometrial adenocarcinoma treated with primary definitive radiation therapy have worse survival than those with lower grade tumors. Addition of external beam radiation therapy to brachytherapy did not affect survival.

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