Toxicity and Tolerability of 177Lu-DOTA-TATE PRRT with a Modified Administered Activity Protocol in NETs of Variable Origin - A Phase 2 Registry Study.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) has been recently approved for advanced, metastatic, or progressive neuroendocrine tumors (NETs). OBJECTIVE: This study reports the adverse events (AEs) observed with patient-tailored administered activity. METHODS: Fifty-two PRRT naive patients were treated with 177Lu-DOTATATE. The administered activity ranges between 2.78 and 5.55 GBq/cycle using the patient's unique characteristics (age, symptoms, blood work, and biomarkers). RESULTS: The protocol was well tolerated with the overwhelming majority of participants being forty- six (88%), completing all 4 induction therapy cycles. The median cumulative administered activity was 19.6 GBq (ranged 3.8-22.3 GBq). A total of 42/52 (81%) reported at least one symptom, and 43/52 (83%) had evidence of biochemical abnormality at enrollment that would meet grade 1 or 2 criteria for AEs. These symptoms only slightly increase with treatment to 50/52 (96%) and 51/52 (98%), respectively. The most common symptoms were mild fatigue (62%), shortness of breath (50%), nausea (44%), abdominal pain (38%), and musculoskeletal pain (37%). The most common biomarker abnormalities were mild anemia (81%), reduced estimated glomerular filtration rate (eGFR) (58%), increased alkaline phosphatase (ALP) (50%), and leukopenia (37%). Of critical importance, no 177Lu-DOTATATE related grade 3 or 4 AEs were observed. CONCLUSION: Tailoring the administered activity of 177Lu-DOTATATE to the individual patient with a variety of NETs is both safe and well-tolerated. No patient developed severe grade 3 or 4 AEs. Most patients exhibit symptoms or biochemical abnormality before treatment and this only slightly worsens following induction therapy.

Survival predictors of 177Lu-Dotatate peptide receptor radionuclide therapy (PRRT) in patients with progressive well-differentiated neuroendocrine tumors (NETS).

PURPOSE: 177Lu-Dotatate is an emerging treatment modality for patients with unresectable or metastatic well-differentiated NETs. This study examines survival predictors in patients who received 177Lu-Dotatate. METHODS: A retrospective single-center review was conducted, examining 47 individuals with progressive well-differentiated NETs treated with 177Lu-Dotatate (four induction cycles of 5.5 GBq at 10-week intervals followed by eight maintenance cycles of 3.7 GBq at 6-month intervals). RESULTS: Median follow-up was 63.1 months with a median progression-free survival (PFS) of 34.1 months. However, median overall survival (OS) was not reached at the time of analysis. The presence of ≥ 5 bone metastases (hazard ratio HR 4.33; p = 0.015), non-gastroenteropancreatic (non-GEP) NETs (HR 3.22; p = 0.025) and development of interim ascites (HR 3.15; p = 0.047) independently predicted a worse OS. Patients with chromogranin A of ≥ 4 × upper limit of normal (ULN) had shorter OS (p < 0.001) and PFS (p = 0.004). Similarly, those with pre-existing ascites demonstrated a worse OS (p = 0.009) and PFS (p = 0.026). Liver metastases involving greater than 50% liver volume and the existence of unusual metastatic locations had a negative impact on OS (p = 0.033) and PFS (p = 0.026), respectively. CONCLUSION: High burden of skeletal and hepatic metastases, non-GEP-NETs, chromogranin A of ≥ 4 × ULN, unusual metastatic sites, pre-existing and interim ascites are predictors of poor outcomes in patients treated with 177Lu-Dotatate. These common indicators can be used for the risk stratification and identification of patients most likely to benefit from PRRT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02236910, Retrospectively registered on September, 2014.

Efficacy of 177Lu-Dotatate Induction and Maintenance Therapy of Various Types of Neuroendocrine Tumors: A Phase II Registry Study.

Peptide receptor radionuclide therapy (PRRT) has been recently established as a treatment option for progressive gastro-entero-pancreatic neuroendocrine tumors (NETs) including four 200 mCi induction cycles. The purpose of this phase 2 trial is to expand use of PRRT to different types of NETs with the application of dose adjustment and evaluate value of maintenance therapy in patients who had disease control on induction therapy. Forty-seven PRRT naïve NET patients with different primary origin received 177Lu-DOTATATE induction therapy, ranging from 75 to 150 mCi per cycle, based on patients' clinical status such as liver and renal function, extent of metastases, and previous therapies. Thirty-four patients underwent additional maintenance therapy (50-100 mCi per cycle) following induction course until they developed disease progression. The estimated median progression-free survival (PFS) was 36.1 months. The median PFS in our MNET subgroup was 47.7 months, which is markedly longer than NETTER-1 trial with median PFS of 28.4 months. The median PFS was significantly longer in patients who received PRRT as first-line treatment after disease progression on somatostatin analogs compared to patients who received other therapies first (p-value = 0.04). The total disease response rate (DRR) and disease control rate (DCR) was 32% and 85% based on RECIST 1.1 and 45% and 83% based on Choi criteria. This trial demonstrates longer PFS with the addition of low dose maintenance therapy to induction therapy compared to NETTER-1 trial that only included induction therapy. Also, we observed considerable efficacy of PRRT in various types of advanced NETs.

SPECT-based functional lung imaging for the prediction of radiation pneumonitis: a clinical and dosimetric correlation.

INTRODUCTION: When we irradiate lung cancer, the radiation dose that can be delivered safely is limited by the risk of radiation pneumonitis (RP) in the surrounding normal lung. This risk is dose-dependent and is commonly predicted using metrics such as the V20, which are usually formulated assuming homogeneous pulmonary function. Because in vivo pulmonary function is not homogeneous, if highly functioning lung can be identified beforehand and preferentially avoided during treatment, it might be possible to reduce the risk of RP, suggesting the utility of function-based prediction metrics. METHODS: We retrospectively identified 26 patients who received ventilation and perfusion single photon emission computed tomography (SPECT-CT) immediately prior to curative-intent radiation therapy. Patients were separated into non-RP and RP groups. As-treated dose-volume histogram (DVH), perfusion-SPECT-based and ventilation-SPECT-based dose-function histogram (DFH) parameters were defined for each group and were tested for differences. The relative utilities of ventilation-based and perfusion-based DFH metrics were assessed using receiver operating characteristic (ROC) analysis. RESULTS: The standard mean lung dose (MLD) was significantly higher in the RP group; the standard V20 and V30 were higher in the RP group but not significantly. Perfusion-weighted and ventilation-weighted values of the MLD, V20 and V30 were all significantly higher in the RP group. ROC analysis suggested that SPECT-based DFH parameters outperformed standard DVH parameters as predictors of RP. CONCLUSIONS: SPECT-based DFH parameters appear to be useful as predictors of RP.

Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain.

BACKGROUND: Samarium Sm 153 lexidronam (Sm-153) is an effective and well-tolerated treatment for painful bone metastases. The purpose of the analysis was to assess the safety and efficacy of repeated doses of Sm-153 in patients with metastatic bone pain. METHODS: Data were collected prospectively for 202 patients administered 1.0 mCi/kg of Sm-153. Particular emphasis was placed on analysis of data from 55 patients receiving > or = 2 doses. Pain scores, adverse events, and hematologic parameters were assessed after each dose. RESULTS: Mild, transient suppression of platelets and white blood cell counts was the most common adverse event after treatment. Nadirs were approximately half of baseline at 4 weeks after dosing with recovery by Week 8 in 90% of patients. Temporary grade 3 thrombocytopenia occurred in 11%, 12%, and 17% of patients after the first, second, and third drug administration, respectively. Grade 3 leukopenia occurred in less than 7% of patients independent of the number of administrations. Significant decreases in pain scores (P < .001) were observed at Week 4 after each of the first 3 doses and maintained at Week 8 after the first 2 doses (P < .003) but not the third. Decreases in pain scores were observed in 70%, 63%, and 80% of patients, respectively, at Week 4 after the first 3 administrations. CONCLUSIONS: Repeated dosing of 1.0 mCi/kg of Sm-153 was both safe and effective and is a reasonable treatment option in patients whose bone pain responds and then recurs after an initial dose provided that adequate hematologic function is present at the time of drug administration.

Prolonged deficits after focal inhibitory seizures.

INTRODUCTION: Seizures are most commonly associated with positive phenomena such as tonic, clonic or myoclonic movements, automatisms, paresthesias and hallucinations. Negative phenomena, however, are not an uncommon manifestation of seizure activity. Examples of negative seizure phenomena include speech arrest, aphasia, amaurosis, amnesia, numbness, deafness, neglect and atonic seizures. Less commonly described in the literature are focal inhibitory motor seizures. METHODS AND RESULTS: Two patients presenting with rapidly progressive, prolonged hemiparesis, sensory neglect and hemi-visual field obscuration are described. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain did not reveal progression of known structural lesions or new lesions. The superficial cortex of the hemisphere contralateral to the hemiparesis and sensory neglect enhanced diffusely with gadolinium on T1-weighted MRI images. Electroencephalography demonstrated periodic lateralized epileptiform discharges (PLEDs) in one patient and lateralized suppression and slowing in the other patient. Single photon emission computed tomography (SPECT) revealed hyperperfusion in the hemisphere contralateral to the hemiparesis and sensory neglect. The changes seen on MRI and SPECT resolved with resolution of the symptoms. CONCLUSION: Taken together with the clinical history, the results from these investigations suggest focal inhibitory seizure as the underlying etiology. A review of the literature and investigations helpful in making this difficult diagnosis are provided.

Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer.

OBJECTIVES: A Phase III randomized trial was designed to assess the effectiveness of samarium-153 (153Sm)-lexidronam for palliation of bone pain in patients with hormone-refractory prostate cancer. METHODS: A total of 152 men with hormone-refractory prostate cancer and painful bone metastases were enrolled in a prospective, randomized, double-blind trial comparing radioactive (153Sm) versus nonradioactive (152Sm) lexidronam complexes. Patients were randomized (2:1) to the radioactive (153Sm) agent. Patient diaries recording daily pain and analgesic use were completed during a planned 16-week evaluation period. Nonresponders were informed of the treatment received after 4 weeks of treatment and, if initially treated with placebo, were allowed to receive 153Sm-lexidronam in an open-label fashion. Pain was measured using validated patient-derived visual analog scales and pain descriptor scales. RESULTS: 153Sm-lexidronam had positive effects on measures of pain relief compared with placebo within 1 to 2 weeks. Reductions in opioid use were recorded at weeks 3 and 4. Because nonresponders were unblinded at week 4, statistical comparisons between the arms beyond week 4 were not possible. Mild, transient bone marrow suppression was the only adverse event associated with 153Sm-lexidronam administration. The mean nadir white blood cell and platelet count (3 to 4 weeks after treatment) was 3800/microL and 127,000/microL, respectively. Counts recovered to baseline after approximately 8 weeks. No grade 4 decreases in either platelets or white bloods cells were documented. CONCLUSIONS: These findings demonstrate that 1 mCi/kg 153Sm-lexidronam is both safe and effective for the palliation of painful bone metastases in patients with hormone-refractory prostate cancer.