Peptide receptor radionuclide therapy with 177Lu-DOTATATE for patients with somatostatin receptor-expressing neuroendocrine tumors: the first US phase 2 experience.

OBJECTIVE: Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium (177)(Lu) DOTATATE in patients with progressive NETs. METHODS: Thirty-seven patients with grade 1 and grade 2 disseminated and progressive gastroenteropancreatic NET were enrolled in a nonrandomized, phase 2 clinical trial. Repeated cycles of 200 mCi (7.4 GBq; ±10%) were administered up to the cumulative dose of 800 mCi (29.6 GBq; ±10%). RESULTS: Among 32 evaluable patients, partial response and minimal response to treatment were seen in 28% and 3%, respectively, and stable disease was seen in 41% of patients. A total of 28% had progressive disease. A response to treatment was significantly associated with lower burden of disease in the liver. No significant acute or delayed hematologic or kidney toxicity was observed. An impressive improvement of performance status and quality of life were seen after Lu-DOTATATE therapy. CONCLUSIONS: Treatment with multiple cycles of (177)Lu-DOTATATE peptide receptor radionuclide therapy is well tolerated. This treatment results in control of the disease in most patients, whereas systemic toxicities are limited and reversible. Quality of life is also improved.

An extended phase II trial of iodine-125 methylene blue for sentinel lymph node identification in women with breast cancer.

BACKGROUND: The aim of this study was to determine if an intraoperative injection of iodine-125-labeled methylene blue ((125)I-MB) is a sensitive and effective method for detecting SLNs in women with breast cancer. STUDY DESIGN: Sixty-two women were enrolled in an extended phase II trial using (125)I-MB to guide SLNB. All patients were anesthetized and then injected subcutaneously with 1 mCi (125)I-MB in the outer quadrant of the areola. RESULTS: Radioactivity was detected in the axilla within 3 to 5 minutes. Fifty-eight of 62 (94%) patients had SLNs detected during their procedure. Mean (±SD) number of SLNs per patient was 1.8 ± 1.3 (range 0 to 6). A total of 112 nodes were dissected from 58 women; 110 of these nodes were considered sentinel. One hundred and eight (98%) nodes were hot, 98 (89%) nodes were blue, and 96 (87%) nodes were both hot and blue. Two women had complications; 1 had superficial skin staining and 1 had a superficial skin slough. Both healed uneventfully. No allergic reactions were observed. No radioactive uptake in the thyroid was seen. CONCLUSIONS: Iodine-125-labeled methylene blue can be mixed and administered in the operating room, improving hospital efficiency. Patient satisfaction is higher with (125)I-MB than with the technetium 99m sulfur colloid procedure because (125)I-MB does not produce localized burning and other adverse reactions associated with the traditional method, and 125I-MB is administered with the patient under anesthesia. Iodine-125 emits a lower-energy gamma ray than technetium 99m, lowering the surgeon's radiation exposure. Iodine-125-labeled methylene blue SLN identification is safe, cost effective, and produces equivalent outcomes compared with the traditional technique, making it an attractive alternative.

Long-Term Survival, Toxicity Profile, and role of F-18 FDG PET/CT scan in Patients with Progressive Neuroendocrine Tumors Following Peptide Receptor Radionuclide Therapy with High Activity In-111 Pentetreotide.

AIM: To study the long term benefits, toxicity and survival rate in patients with neuroendocrine tumors receiving multiple cycles of high activity In-111 Pentetreotide therapy. Moreover, our secondary aim was to evaluate the value of F-18 FDG PET-CT scan as prognostic indicator in this group of patients. BACKGROUND: Neuroendocrine tumors are a heterogeneous group of malignancies which are usually metastatic at diagnosis. Standard chemotherapy in these patients is associated with appreciable adverse events and low effectiveness. Since 1990s, Peptide receptor radionuclide therapy (PRRT) with radio-labeled somatostatin analogues has been introduced as a new method of treatment in patients with unresectable and/or metastatic neuroendocrine tumors expressing high levels of Somatostatin receptors. METHODS: 112 patients with progressive disseminated and unresectable neuroendocrine tumor (stage III and stage IV) were enrolled in a non-randomized trial in an out-patient setting. High activity In-111 Pentetreotide (500 mCi (18.5 GBq) per cycle) was administered as an intravenous infusion over 3 hours and repeated therapy cycles every 9-12 weeks in eligible patients up to maximum of 4 cycles. Response to therapy was evaluated by clinical imaging using the RECIST criteria, metabolic criteria and patient's quality of life questionnaire. Dosimetry and biodistribution studies were also performed. Finally, Kaplan-Meier survival analysis was performed for patients followed for greater than 12 months. The relationship between pretreatment F-18 FDG PET-CT scan status and survival was determined by two-tailed Student's t-test in 42 patients who underwent pre-therapy PET scans. RESULTS: For an average of 25 (median 18.65) months following the therapy, patients were evaluated for any evidence of toxicity. No significant acute toxicity was observed in patients. Grade II or III hematological toxicity (7.6% of patients), liver toxicity (18.4%) and also grade I renal toxicity (6.1%) was observed in 92 evaluable patients. Radiological responses were evaluated for an average of 29 months following their last cycle of therapy and results were analyzed by the RECIST criteria. Majority (85%) of patients had stable disease (SD), partial response (PR) rate was 7.5% and progressive disease (PD) was observed in 7.5% of patients. The average survival was 24.67 months after 2 cycles of therapy, 30.53 months after 3 cycles of therapy and 30.19 months after 4 cycles of therapy. Of the 42 patients who had pretreatment PET-CT imaging, 31 patients had positive F-18 FDG scans (SUV > 2.5) with an average survival time of 18.9 months (range 1.4-45.8 months) and 11 patients had negative F-18 FDG scans (SUV ≤ 2.5) with an average survival time of 31.8 months (range 7.4-42.9 months). Survival times for FDG negative patients were significantly longer than those for FDG positive patients (p = 0.001 with 95% confidence). CONCLUSION: High activity In-111 therapy is a safe and effective therapy for patients with progressive disseminated neuroendocrine tumors. No major hematological, renal and hepatic toxicities were observed. There was an increase in survival time particularly in patients with lower degree of liver involvement as well as patients who received three or more cycles of therapy, as compared to historical data. Pre-treatment FDG status may be a predictor of survival following In-111 pentetreotide therapy.

Safety and efficacy of radionuclide therapy with high-activity In-111 pentetreotide in patients with progressive neuroendocrine tumors.

The intent of this study was to evaluate the safety and efficacy of high-activity 111In-pentetreotide in patients with neuroendocrine tumors. Thirty-two patients with pentetreotide-avid neuroendocrine tumors received therapy from August 2005 to November 2006. Fourteen (14) patients received 1 treatment and 18 patients received 2 treatments. Patients were followed an average of 12.73 months (range 1.2-24.5). Seventeen (17) patients (53%) had grade I or II hematologic toxicities, and 1 patient had grade III thrombocytopenia. One patient had grade II liver toxicity, which appeared 4 weeks after therapy and resolved on week 5. No patient had renal toxicity. Of the patients who completed 2 treatment cycles, 2 of 18 patients had partial disease regression, and 16 of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. A decrease in serum tumor markers was observed in 14 of 18 patients given 2 therapies. A clinical response was achieved in 84% of the patients. Upon interim analysis, median survival was approximately 13 months (range 1.2-24.5). These results show that high-activity 111In-pentetreotide therapy is effective in patients with progressive disseminated neuroendocrine tumors.

A phase I/II trial of 125I methylene blue for one-stage sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node biopsy can be associated with delays in operating room schedule and with significant pain during the preoperative Tc colloid injection. To avoid these problems, we developed a novel radiolabeled blue dye that can be injected intraoperatively. METHODS: We performed a phase I/II trial (IND#70627) of sterile pyrogen-free I-methylene blue to identify sentinel nodes in patients with breast cancer. Twelve women were studied. Two women each were given peritumoral or circumareolar injections of 100, 200, 300, 400, 500, or 1000 microCi of I methylene blue. RESULTS: Sentinel nodes were detected in 11 of 12 patients, with a low-dose 200 microCi patient being the single exception. The number of sentinel nodes detected per patient ranged from 0 to 3 (mean = 1.66 nodes/case). Radioactivity at the tumor injection site [counts per second (cps) averaged over 10 seconds] ranged from 3346 to 47,300 cps and was highly dose-dependent (r = 0.90, P = 0.0002). In contrast, the in vivo node counts ranged from 0 to 1228 cps, while ex vivo counts ranged from 0 to 1516 cps. The in vivo nodal counts were dose-dependent (r = 0.67, and P = 0.0231). Radiation was carefully monitored inside the operating room and in pathology. Even with the 1-mCi dose, the radioactive blue dye produced significantly lower personnel exposure than historically seen with Tc. CONCLUSIONS: This method eliminates the painful preoperative injections of Tc colloid, is performed by the surgeon in the operating room, is associated with lower radiation exposures for personnel, and avoids the delays caused by nonoperating room personnel. These observations warrant a more extensive trial of this method using the 1000-microCi dose of I methylene blue dye for sentinel lymph node biopsies.

Development of 125I-methylene blue for sentinel lymph node biopsy.

BACKGROUND: Sentinel lymph node biopsy is an established alternative to complete lymph node dissection in some patients. We have developed a novel, radiolabeled methylene blue dye that may be a useful alternative to the traditional two-step procedure involving 99mTc-labeled colloid and unlabeled blue dye. We hypothesize that 125I-labeled methylene blue will be rapidly absorbed into the lymphatics and transported to the drainage basin containing the sentinel nodes. MATERIALS AND METHODS: Rabbits footpads were injected with 1 mCi of 125I-labeled methylene blue admixed with unlabeled dye. A hand-held gamma detection device allowed tracking of radiolabeled dye to nodes in the popliteal and inguinal regions. At pre-established time points animals were sacrificed, and the nodal basin dissected. Nodal radioactivity as well as uptake of blue dye was recorded. RESULTS: The spread of the radiolabeled methylene blue compound from the footpad to the popliteal lymph nodes occurred in 5-10 min. CONCLUSION: The radiolabeled dye rapidly progresses through lymphatics to the draining nodes. Use of radiolabeled methylene blue may be an attractive alternative to current two-step sentinel node techniques, as it may be less painful, and may reduce the cost associated with the time-delay between the injection of the radioactive compound and surgery.

Portable chest radiographs in the intensive care units: referral patterns and estimated cumulative radiation exposures.

The objective of this article was to determine the frequency of referrals for portable chest radiographs from medical and (noncardiac) surgical intensive care units (NICU and SICU) and their respective stepdown units (NICA and SICA). Additionally, the cumulative entrance skin exposure (ESE) using an ion chamber was determined. We retrospectively reviewed the medical records of all adult patients admitted to the MICU, SICU, MICA, and SICA at a tertiary referral center during a 6-month interval. The duration of stay and the number of portable chest radiographs were determined for each patient. The measured ESEs from all portable radiography units ranged from 5 to15 mR (average: 10mR). The cumulative radiation exposure for each patient was calculated. There were 567 patients admitted to the units: 146 surgical and 421 medical. Their ages ranged from 15 to 87 years. The duration of stay varied from 1 to 68 days. A total of 3,794 portable chest radiographs were obtained. The number of radiographs per patient varied from 1 to 94. The number of radiographs and the corresponding cumulative radiation doses were as follows: 406 patients (72%) had fewer than five radiographs (<50 mR); 76 (13%) had five to 10 radiographs (<100 mR); 35 (6%) had 11 to 20 (<200 mR); and 50 (9%) had more than 20 chest radiographs (>200 mR). The cumulative ESE ranged from 10 to 940 mR. It exceeded 450 mR in only nine (1.5%) patients. Most (73%) patients undergoing intensive care undergo fewer than five radiographs during their stay in the units. Patient exposure from portable chest radiographs in this population is less than the average annual exposure from background radiation in the USA (450-500 mR), and is much less than the average annual exposure from teratogenic radiation.

Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies.

Somatostatin and its analogues bind to somatostatin receptors (sst) 1 through 5 that are overexpressed in neuroendocrine neoplasms such as gastroenteropancreatic (GEP) malignancies. After ligand-receptor binding, a fraction of the ligand-receptor complexes internalize. This internalization process is an effective means of delivering cytotoxic radiolabeled somatostatin analogues, especially those emitting short-range decay particles such as Auger electrons, to the neoplastic cell nucleus. Indium-111-pentetreotide, an sst 2 preferring somatostatin analogue with gamma and Auger electron decay characteristics, is commonly used for the scintigraphic evaluation and management of neuroendocrine cancer patients. This clinical trial was performed to determine the effectiveness and tolerability of therapeutic doses of (111)In-pentetreotide in patients with GEP tumors. GEP tumor patients who had failed all forms of conventional therapy, with worsening of tumor-related signs and symptoms and/or radiographically documented progressive disease, an expected survival less than 6 months, and sst positivity as determined by the uptake on a 6.0 mCi (111)In-pentetreotide scan (OctreoScan; Mallinckrodt Medical, Inc, St. Louis, MO), were treated with at least 2 monthly 180-mCi intravenous injections of (111)In-pentetreotide. Baseline clinical assessments, serum chemistries, and plasma pancreastatin levels were measured and repeated before each (111)In-pentetreotide treatment. From February 1997 to February 1998, 27 GEP (24 carcinoid neoplasms with carcinoid syndrome and 3 pancreatic islet cells) patients were accrued, with 26 patients evaluable for clinical and radiographic responses, 21 patients evaluable for biochemical assessments, and 27 patients evaluable for survival analysis and safety. Toxicity was evaluated by using standard National Cancer Institute (NCI) Common Toxicity Criteria guidelines. Clinical benefit occurred in 16 (62%) patients. Pancreastatin levels decreased by 50% or more in 81% of the patients. Objective partial radiographic responses occurred in 2 (8%) patients, and significant tumor necrosis (defined by 20 Hounsfield units or greater decrease from baseline) developed in 7 (27%) patients. The following transient Grades 3/4 NCI Common Toxicity Criteria side effects were observed, respectively: leukocyte: 1/1; platelets: 0/2; hemoglobin: 3/0; bilirubin: 1/3; creatinine: 1/0; neurologic: 1/0. Myeloproliferative disease and/or myelodysplastic syndrome have not been observed in the 6 patients followed-up for 48+ months. The median survival was 18 months (range, 3-54+ mo). Two doses (180 mCi) of (111)In-pentetreotide are safe, well-tolerated, and improve symptoms in 62% of patients, decrease hormonal markers in 81% of patients, decrease Hounsfield units on computed tomography (CT) scans in 27% of patients, with 8% partial radiographic responses and increased expected survival in GEP cancer patients with somatostatin receptor-expressing tumors. The maximal tolerated dose of (111)In-pentetreotide and the optimal dosing schedules remain under investigation.