Terence Z. Wong

Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study

PURPOSE To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. PATIENTS AND METHODS In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. RESULTS Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. CONCLUSION Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

Craniotomy for tumor treatment in an intraoperative magnetic resonance imaging unit.

OBJECTIVE The complex three-dimensional anatomic features of the brain and its vulnerability to surgical intervention make the surgical treatment of intracranial tumors challenging. We evaluated the surgical treatment of supratentorial tumors using intraoperative magnetic resonance imaging (MRI), which provides real-time guidance, allows localization of intracranial tumors and their margins, and facilitates continuous assessment of surgical progress. METHODS Sixty patients underwent craniotomies for tumor treatment in the General Electric intraoperative MRI unit at the Brigham and Womens Hospital (Boston, MA) during a 1-year period. The patients selected were those with intracranial tumors that were considered difficult to resect because of their locations or previous incomplete operations. Twenty-nine low-grade and 19 high-grade gliomas, 8 metastatic lesions, 2 meningiomas, 1 pineoblastoma, and 1 astroblastoma were resected. RESULTS Tumors were accurately localized and targeted, and the extent of resection, as well as any intraoperative complications, could be immediately assessed during surgery. Marked brain shifting occurred during the procedures, and repeated intraoperative imaging allowed surgical accommodation for this shifting. In more than one-third of the cases, intraoperative imaging showed residual tumor when resection appeared complete on the basis of surgical observation alone. CONCLUSION Intraoperative MRI is a revolutionary tool for the surgical treatment of brain tumors, providing observation of the procedure as it is being performed. With intraoperative MRI, tumor resection is safer, the extent of resection can be directly evaluated, and intraoperative complications can be noted if they occur. Outcomes after resection depend on minimizing injury to normal brain tissue and achieving maximal tumor resection. The use of intraoperative MRI directly affects these factors.

Phase II trial of murine 131I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas

PURPOSE To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. PATIENTS AND METHODS In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. RESULTS Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. CONCLUSION Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.

A Systematic Review of the Factors Affecting Accuracy of SUV Measurements

OBJECTIVE There is growing interest in using PET/CT for evaluating early response to therapy in cancer treatment. Although widely available and convenient to use, standardized uptake value (SUV) measurements can be influenced by a variety of biologic and technologic factors. Many of these factors can be addressed with close attention to detail and appropriate quality control. This article will review factors potentially affecting SUV measurements and provide recommendations on ways to minimize when using serial PET to assess early response to therapy. CONCLUSION Scanner and reconstruction parameters can significantly affect SUV measurements. When using serial SUV measurements to assess early response to therapy, imaging should be performed on the same scanner using the same image acquisition and reconstruction protocols. In addition, attention to detail is required for accurate determination of the administered radiopharmaceutical dose.

Progress Report of a Phase I Study of the Intracerebral Microinfusion of a Recombinant Chimeric Protein Composed of Transforming Growth Factor (TGF)-α and a Mutated form of the Pseudomonas Exotoxin Termed PE-38 (TP-38) for the Treatment of Malignant Brain Tumors

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-α and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25ng/mL to 100 with a 40mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Clinical Experience with α-Particle–Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6

α-Particle–emitting radionuclides, such as 211At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of α-particles than of β-particles, 211At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. Methods: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71–347 MBq of 211At by use of N-succinimidyl 3-[211At]astatobenzoate. Eighteen patients were treated with 211At-labeled ch81C6 (211At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial γ-camera imaging and blood sampling over 24 h were performed. Results: A total of 96.7% ± 3.6% (mean ± SD) of 211At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was ≤0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of 211At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. Conclusion: This study provides proof of concept for regional targeted radiotherapy with 211At-labeled molecules in oncology. Specifically, the regional administration of 211At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Salvage Radioimmunotherapy With Murine Iodine-131–Labeled Antitenascin Monoclonal Antibody 81C6 for Patients With Recurrent Primary and Metastatic Malignant Brain Tumors: Phase II Study Results

PURPOSE To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. PATIENTS AND METHODS In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. RESULTS With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. CONCLUSION In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses <or=100 ng/ml. CED has significant potential for enhancing delivery of therapeutic macromolecules throughout the human brain. However, the potential efficacy of drugs delivered by this technique may be severely constrained by ineffective infusion in many patients.

Prospective assessment of radiotherapy‐associated cardiac toxicity in breast cancer patients: Analysis of data 3 to 6 years after treatment

Radiation therapy (RT) to the left breast/chest wall has been linked with cardiac dysfunction. Previously, the authors identified cardiac perfusion defects in approximately 50% to 60% of patients 0.5 to 2 years post‐RT. In the current study, they assessed the persistence of these defects 3 to 6 years post‐RT.

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning

OBJECTIVE Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with 123I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of 123I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of 123I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery.