ABSTRACT
BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.
Subject(s)
Intestinal Neoplasms , Neuroendocrine Tumors , Octreotide , Organometallic Compounds , Pancreatic Neoplasms , Stomach Neoplasms , Humans , Octreotide/therapeutic use , Octreotide/administration & dosage , Octreotide/analogs & derivatives , Octreotide/adverse effects , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Male , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/radiotherapy , Neuroendocrine Tumors/mortality , Female , Middle Aged , Organometallic Compounds/therapeutic use , Organometallic Compounds/administration & dosage , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Aged , Intestinal Neoplasms/drug therapy , Intestinal Neoplasms/pathology , Intestinal Neoplasms/radiotherapy , Intestinal Neoplasms/mortality , Adult , Radiopharmaceuticals/therapeutic use , Treatment Outcome , Neoplasm Grading , Progression-Free SurvivalABSTRACT
BACKGROUND: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS: Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Neuroendocrine Tumors/drug therapy , Octreotide/analogs & derivatives , Octreotide/administration & dosage , Organometallic Compounds/therapeutic use , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Delayed-Action Preparations , Disease-Free Survival , Drug Administration Schedule , Female , Gastrointestinal Neoplasms/mortality , Humans , Infusions, Intravenous , Kaplan-Meier Estimate , Male , Middle Aged , Nausea/chemically induced , Neuroendocrine Tumors/mortality , Octreotide/adverse effects , Octreotide/therapeutic use , Organometallic Compounds/adverse effectsABSTRACT
BACKGROUND: The identification of extrauterine disease is critical to the management of patients with high-risk endometrial cancer. The purpose of the current study was to determine the accuracy of preoperative positron emission tomography (PET)/computed tomography (CT) in the detection of extrauterine disease. METHODS: Women with high-risk endometrial cancer were enrolled prospectively and underwent preoperative PET/CT followed by surgery, including sentinel lymph node biopsy and lymphadenectomy. Primary tumor factors on PET/CT were correlated with lymph node pathology. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the detection of lymphadenopathy and peritoneal disease by PET/CT. RESULTS: A total of 112 patients were enrolled and underwent PET/CT between April 2013 and May 2016, 108 of whom were evaluable. On PET/CT, 21 patients (19.4%) were found to have extrauterine disease, 18 (17%) had positive lymph nodes, and 8 (7%) had peritoneal disease. A total of 108 patients underwent surgery, 103 of whom (95%) underwent lymphadenectomy. The sensitivity of PET/CT to detect positive lymph nodes was 45.8%, with a specificity of 91.1%, positive predictive value of 61.1%, and negative predictive value of 84.7%. The false-negative rate was 54.2%. There was no difference in primary tumor characteristics on imaging noted between patients with positive and negative lymph nodes. The sensitivity of PET/CT to detect peritoneal disease was 37.5%, with a specificity of 97.8%, positive predictive value of 75%, and negative predictive value of 90.0%. The false-negative rate was 62.5%. CONCLUSIONS: Preoperative PET/CT did not reliably predict the presence of extrauterine disease in women with high-risk endometrial cancer. Given the high false-negative rates, PET/CT should not be used in the preoperative treatment planning of these patients.
Subject(s)
Endometrial Neoplasms/pathology , Lymphatic Metastasis/diagnostic imaging , Peritoneal Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography/statistics & numerical data , Preoperative Care/statistics & numerical data , Adult , Aged , Aged, 80 and over , Endometrial Neoplasms/surgery , Endometrium/pathology , Endometrium/surgery , False Negative Reactions , Feasibility Studies , Female , Fluorodeoxyglucose F18/administration & dosage , Humans , Hysterectomy , Middle Aged , Peritoneal Neoplasms/secondary , Predictive Value of Tests , Prospective Studies , Radiopharmaceuticals , Reproducibility of Results , Salpingo-oophorectomy , Sentinel Lymph Node/diagnostic imaging , Sentinel Lymph Node/pathology , Sentinel Lymph Node BiopsyABSTRACT
OBJECTIVE: To evaluate the patterns of (18)F-FDG uptake at the surgical margin after hepatectomy to identify features that may differentiate benign and malignant uptake. METHODS: Patients who had undergone a PET/CT after hepatectomy were identified. Delay between resection and PET/CT, presence of uptake at the surgical margin, pattern of uptake, and maximal standardized value were recorded. The PET/CT findings were correlated with contrast-enhanced CT or MRI. RESULTS: There were 26 patients with increased 18F-FDG uptake; uptake was diffuse in seven and focal in 19. Diffuse uptake was due to inflammation in all cases. Focal uptake was due to recurrence in 12 and inflammation in seven cases. Defining a focal pattern only as a positive for malignancy yielded 100 % sensitivity, 87 % specificity, 37 % false positive rate. As expected, SUVmax was significantly higher for recurrence than inflammation, but did overlap. Contrast-enhanced CT allowed differentiation between malignant and benign uptake in all cases. CONCLUSION: F-FDG uptake after hepatectomy does not equate to recurrence and yields a high false positive rate. Diffuse uptake did not require additional evaluation in our sample. Focal uptake, however, may be due to recurrence; differentiating benign and malignant nodular uptake relies on optimal contrast-enhanced CT or MRI. KEY POINTS: ⢠Marginal uptake exposes patients to the risk of false positive diagnosis of recurrence. ⢠Benign and malignant patterns of marginal uptake overlap. ⢠Diffuse marginal uptake in our experience, has a high chance to be inflammatory. ⢠Focal marginal uptake can be due to recurrent tumour or inflammation. ⢠Contrast-enhanced CT or MR allows the differentiation between benign and malignant uptake.
Subject(s)
Fluorodeoxyglucose F18/pharmacokinetics , Liver Diseases/diagnosis , Radiopharmaceuticals/pharmacokinetics , Adult , Aged , Aged, 80 and over , Diagnosis, Differential , Female , Humans , Liver Diseases/surgery , Magnetic Resonance Imaging/methods , Male , Middle Aged , Multimodal Imaging/methods , Positron-Emission Tomography/methods , Retrospective Studies , Sensitivity and Specificity , Tomography, X-Ray Computed/methodsABSTRACT
The prognostic value of interim positron emission tomography (PET) was evaluated after 2 cycles of doxorubicin, bleomycin, vinblastin and dacarbazine in classical Hodgkin lymphoma patients (n = 229), based on Deauville criteria. In early stage non-bulky disease, bulky stage II disease, advanced stage low International Prognostic Score (IPS ≤2) and advanced stage (IPS ≥3), 3-year progression-free survival rates in PET2-negative vs. PET2-positive groups were 95·9% vs. 76·9% (P < 0·0018), 83·3% vs. 20·0% (P = 0·017), 77·0% vs. 30·0% (P < 0·001) and 71·0% vs. 44·4%(P = 0·155), respectively. The outcome after positive PET2 was better than previously reported. The results from non-randomized studies of PET2-guided therapy would be valuable with careful interpretation.
Subject(s)
Hodgkin Disease/diagnostic imaging , Positron-Emission Tomography , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Hodgkin Disease/drug therapy , Hodgkin Disease/mortality , Humans , Male , Middle Aged , Prognosis , Proportional Hazards Models , Young AdultABSTRACT
We observed that some patients with well-differentiated neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with Lutetium-177 (177Lu) DOTATATE developed rapid disease progression with biopsy-proven histologic transformation to neuroendocrine carcinoma (NEC), an outcome that has not been previously described. Therefore, we conducted a retrospective review of all patients with well-differentiated G1-G2 NET who received at least one cycle of PRRT with (177Lu) DOTATATE at our center from January 2019 to December 2020. Among 152 patients, we identified 7 patients whose NET transformed to NEC. Median time from start of PRRT to transformation was 8.2 months (range: 2.6-14.4 months). All patients whose tumors underwent transformation had pancreatic tail as the primary site and had prior chemotherapy with temozolomide. No differences in the incidence of transformation were observed according to gender, race, original tumor grade, or number of prior therapies. Six patients received treatment with platinum and etoposide after transformation with two patients having partial response as best response. All patients with transformation died from progressive disease with median overall survival (OS) after transformation of 3.3 months (95% CI 2.1-4.4). Molecular testing of transformed NEC identified mutation(s) in TP53 and/or ATM in all cases. Transformation of NET to NEC following PRRT is associated with aggressive course and dismal prognosis. Patients with pancreatic tail as the primary site who had prior therapy with temozolomide may be at a higher risk. Further investigation is necessary to determine the best treatment sequence in this patient population.
Subject(s)
Carcinoma, Neuroendocrine , Lutetium , Neuroendocrine Tumors , Radioisotopes , Humans , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/radiotherapy , Temozolomide , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Neuroendocrine/radiotherapy , Biopsy , Receptors, PeptideABSTRACT
BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.
Subject(s)
Colorectal Neoplasms , Liver Neoplasms , Liver , Radiotherapy, Image-Guided , Tomography, Emission-Computed, Single-Photon , Humans , Male , Female , Liver Neoplasms/secondary , Liver Neoplasms/radiotherapy , Liver Neoplasms/diagnostic imaging , Middle Aged , Aged , Liver/diagnostic imaging , Liver/radiation effects , Radiotherapy, Image-Guided/methods , Colorectal Neoplasms/radiotherapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/diagnostic imaging , Organ Size , Radiotherapy Dosage , Tomography, X-Ray Computed , Radiotherapy Planning, Computer-Assisted/methods , AdultABSTRACT
Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.
Subject(s)
Intestinal Neoplasms , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Consensus , Intestinal Neoplasms/drug therapy , National Cancer Institute (U.S.) , Neuroendocrine Tumors/pathology , Octreotide/therapeutic use , Pancreatic Neoplasms/drug therapy , United States , Clinical Trials as TopicABSTRACT
PURPOSE: To evaluate the feasibility of fast Dixon whole-body (WB) magnetic resonance imaging (MRI) for detecting bone and liver metastasis in clinical patients and to compare its performance with skeletal scintigraphy (SS) for detecting bone metastases using reference imaging with >1 year follow-up as the gold standard. MATERIALS AND METHODS: Twenty-nine patients with bone metastases prospectively underwent WB MRI and SS. WB MRI included coronal T2, axial T1 with and without intravenous gadolinium (including triphasic liver sequences), and axial diffusion-weighted imaging, plus spinal sagittal postcontrast T1-weighted images. The skeleton was divided into 16 segments. Reviewers blinded to other images identified up to five lesions per segment and rated them using a five-point confidence scale for metastatic disease. Sensitivities and specificities were compared using the McNemar test. RESULTS: The sensitivity of WB MRI and SS in detecting bone metastases was 70.8% and 59.6% (P = 0.003), respectively; specificity was 89.1% and 98.7% (P < 0.0001). WB MRI detected all livers with metastases (n = 8). One focal nodular hyperplasia was classified as a metastasis on WB MRI. CONCLUSION: Fast Dixon WB MRI is feasible in clinical patients, highly specific, and more sensitive than SS in detecting bone metastases, and can detect metastases of the liver.
Subject(s)
Bone Neoplasms/secondary , Magnetic Resonance Imaging/methods , Neoplasm Metastasis/diagnosis , Whole Body Imaging , Adult , Aged , Contrast Media , Diffusion Magnetic Resonance Imaging , Feasibility Studies , Female , Humans , Male , Middle Aged , Neoplasm Metastasis/diagnostic imaging , Prospective Studies , Radionuclide Imaging , Sensitivity and Specificity , Tomography, X-Ray ComputedABSTRACT
The most common serious complication of yttrium-90 ((90)Y) therapy is gastrointestinal ulceration caused by extrahepatic microsphere dispersion. The authors describe the use of a balloon catheter for temporary occlusion of the common hepatic artery to reverse hepatoenteric flow for lobar administration of resin microspheres when coil embolization of a retroportal artery was impossible. At 9 months after treatment, the patient had no gastrointestinal side effects and showed a partial response.
Subject(s)
Balloon Occlusion/methods , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/radiotherapy , Yttrium Radioisotopes/administration & dosage , Aged , Female , Humans , Microspheres , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: This paper aims to evaluate the safety and efficacy of the temporary redirection of blood flow of hepatoenteric collaterals using a balloon catheter in the common hepatic artery (CHA) to prevent the nontarget deposition of 90Y microspheres. MATERIALS AND METHODS: In this retrospective single-center study of patients who received 90Y radioembolization (RE) from September 2010 to September 2015, diagnostic (67 patients) or treatment (72 patients) angiograms with the attempted use of a balloon catheter in the CHA to temporarily direct blood flow away from the hepatoenteric arteries were analyzed. SPECT/CT nuclear scintigraphy was performed after both diagnosis and treatment. RESULTS: Overall, only 12 hepatoenteric arteries in 11 patients required embolization due to persistent hepatoenteric flow despite the use of the balloon occlusion technique in a total of 86 patients. Physicians performed the 90Y RE using balloon occlusion with glass (n = 22) or resin (n = 50) microspheres. Over 80% administration of the prescribed 90Y dose was accomplished in 34 (67%) resin and 20 (95%) glass microsphere patients. Post-treatment 90Y RE scintigraphy confirmed the absence of extrahepatic activity in all patients. One grade 2 gastrointestinal ulcer was present after 90 days of follow-up. CONCLUSION: Temporary CHA occlusion with a balloon catheter is a reliable and reproducible alternative to the conventional coil embolization of hepatoenteric arteries during diagnostic Tc-99m macroaggregated albumin and therapeutic 90Y RE delivery.
Subject(s)
Embolization, Therapeutic , Liver Neoplasms , Humans , Liver Neoplasms/radiotherapy , Retrospective Studies , Embolization, Therapeutic/adverse effects , Embolization, Therapeutic/methods , MicrospheresABSTRACT
OBJECTIVE: The purpose of this article is to determine whether the average of N CT images acquired at a particular dose (D) has image noise equivalent to that of a single image acquired at a dose of N × D. MATERIALS AND METHODS: An electron density phantom, an image quality phantom, and an adult anthropomorphic phantom were scanned multiple times on a 16-MDCT scanner at five effective tube current-rotation time product (mAs) settings (130 kVp; 12, 24, 48, 72, and 144 mAs). Lower-mAs images were averaged to simulate higher-mAs images. Differences in CT number and image noise between simulated and acquired images were quantified using the electron density phantom. Image quality phantom images were scored by three physicists to investigate differences in low- and high-contrast resolution. A forced-choice observer study was performed with three radiologists using anthropomorphic phantom images to evaluate differences in overall image quality. RESULTS: The CT number was, on average, reproduced to within 1 HU, and image noise was reproduced to within 4%, which is below the threshold for visibly perceptible differences in noise. Low- and high-contrast resolution were not degraded, and simulated images were visually indistinguishable from acquired images. CONCLUSION: For the dose range studied, it was concluded that the image quality of a CT image produced by averaging multiple low-mAs CT images is identical to that of a high-mAs image acquired at equivalent effective dose, when all other acquisition and reconstruction parameters are held constant. Prospective CT dose-reduction studies may be feasible by acquiring multiple low-dose scans instead of a single high-dose scan. Simulated high-dose images could be interpreted clinically, whereas lower-dose images would be available for an observer study.
Subject(s)
Radiation Dosage , Radiographic Image Enhancement/methods , Tomography, X-Ray Computed/methods , Adult , Humans , Linear Models , Phantoms, Imaging , Poisson Distribution , Reproducibility of Results , Retrospective StudiesABSTRACT
ABSTRACT: A 74-year-old man with biochemical recurrent prostate cancer underwent 18F-fluciclovine PET/CT for restaging to determine subsequent treatment strategy. 18F-fluciclovine PET/CT imaging demonstrated incidental focal heterogeneous increased 18F-fluciclovine uptake corresponding to a soft tissue nodule within the musculature of the left anterior abdominal wall. Subsequent ultrasound-guided biopsy of the lesion revealed histopathology compatible with a desmoid tumor. Consequently, the patient underwent surgical resection with wide local excision of the lesion.
Subject(s)
Carboxylic Acids/metabolism , Cyclobutanes/metabolism , Fibromatosis, Aggressive/diagnostic imaging , Fibromatosis, Aggressive/metabolism , Incidental Findings , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/diagnostic imaging , Aged , Biological Transport , Humans , Male , Prostatic Neoplasms/pathologyABSTRACT
Background: Glioblastomas are malignant, often incurable brain tumors. Reliable discrimination between recurrent disease and treatment changes is a significant challenge. Prior work has suggested glioblastoma FDG PET conspicuity is improved at delayed time points vs. conventional imaging times. This study aimed to determine the ideal FDG imaging time point in a population of untreated glioblastomas in preparation for future trials involving the non-invasive assessment of true progression vs. pseudoprogression in glioblastoma. Methods: Sixteen pre-treatment adults with suspected glioblastoma received FDG PET at 1, 5, and 8 h post-FDG injection within the 3 days prior to surgery. Maximum standard uptake values were measured at each timepoint for the central enhancing component of the lesion and the contralateral normal-appearing brain. Results: Sixteen patients (nine male) had pathology confirmed IDH-wildtype, glioblastoma. Our results revealed statistically significant improvements in the maximum standardized uptake values and subjective conspicuity of glioblastomas at later time points compared to the conventional (1 h time point). The tumor to background ratio at 1, 5, and 8 h was 1.4 ± 0.4, 1.8 ± 0.5, and 2.1 ± 0.6, respectively. This was statistically significant for the 5 h time point over the 1 h time point (p > 0.001), the 8 h time point over the 1 h time point (p = 0.026), and the 8 h time point over the 5 h time point (p = 0.036). Conclusions: Our findings demonstrate that delayed imaging time point provides superior conspicuity of glioblastoma compared to conventional imaging. Further research based on these results may translate into improvements in the determination of true progression from pseudoprogression.
ABSTRACT
Chimeric antigen receptor (CAR)-T cell therapy has revolutionized treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). However, since 36-60% of patients relapse, early response prediction is crucial. We present a novel population quantitative systems pharmacology model, integrating literature knowledge on physiology, immunology, and adoptive cell therapy together with 133 CAR-T cell phenotype, 1943 cytokine, and 48 metabolic tumor measurements. The model well described post-infusion concentrations of four CAR-T cell phenotypes and CD19+ metabolic tumor volume over 3 months after CAR-T cell infusion. Leveraging the model, we identified a low expansion subpopulation with significantly lower CAR-T cell expansion capacities amongst 19 NHL patients. Together with two patient-/therapy-related factors (autologous stem cell transplantation, CD4+/CD8+ T cells), the low expansion subpopulation explained 2/3 of the interindividual variability in the CAR-T cell expansion capacities. Moreover, the low expansion subpopulation had poor prognosis as only 1/4 of the low expansion subpopulation compared to 2/3 of the reference population were still alive after 24 months. We translated the expansion capacities into a clinical composite score (CCS) of 'Maximum naïve CAR-T cell concentrations/Baseline tumor burden' ratio and propose a CCSTN-value > 0.00136 (cells·µL-1·mL-1 as predictor for survival. Once validated in a larger cohort, the model will foster refining survival prediction and solutions to enhance NHL CAR-T cell therapy response.
ABSTRACT
We report the impact of 177Lu DOTATATE treatment on abdominal pain, diarrhea, and flushing, symptoms that patients with advanced midgut neuroendocrine tumors (NETs) often find burdensome. Methods: All patients enrolled in the international randomized phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial (177Lu-DOTATATE plus standard-dose octreotide long-acting repeatable [LAR], n = 117; high-dose octreotide LAR, n = 114) were asked to record the occurrence of predefined symptoms in a daily diary. Change from baseline in symptom scores (mean number of days with a symptom) was analyzed using a mixed model for repeated measures. Results: Patients (intent-to-treat) who received 177Lu-DOTATATE experienced a significantly greater decline from baseline in symptom scores than patients who received high-dose octreotide LAR. For 177Lu-DOTATATE, the mean decline in days with abdominal pain, diarrhea, and flushing was 4.10, 4.55, and 4.52 days per 4 weeks, respectively, compared with 0.99, 1.44, and 2.54 days for high-dose octreotide LAR. The mean differences were 3.11 days (95% confidence interval, 1.35-4.88; P = 0.0007) for abdominal pain, 3.11 days (1.18-5.04; P = 0.0017) for diarrhea, and 1.98 days (0.08-3.88; P = 0.0413) for flushing, favoring 177Lu-DOTATATE. A positive repeated measures correlation was found between diary-recorded symptom scores and questionnaire-recorded pain, diarrhea, and flushing. Conclusion: In addition to efficacy and quality of life benefits, symptom diaries from NETTER-1 demonstrated that treatment with 177Lu DOTATATE was associated with statistically significant reductions in abdominal pain, diarrhea, and flushing, constituting the core symptoms of patients with progressive midgut NETs, compared with high-dose octreotide LAR, supporting a beneficial effect of 177Lu DOTATATE on HRQoL.
ABSTRACT
PURPOSE: The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (90Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors. METHODS: We enrolled 38 Child-Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival. RESULTS: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III-IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8-14.4) and 13.2 months (95% CI 7.9-18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3-90) weeks, and average dose was 622 (466-800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment. CONCLUSION: This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01900002.
ABSTRACT
PURPOSE: To assess the overall survival (OS) and progression-free survival (PFS) of unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass-microsphere transarterial radioembolization (TARE) with and without concurrent sorafenib. METHODS: OS and PFS were analyzed in 55 patients with an intrahepatic tumor (IHT) ≤50% without advanced or aggressive disease features (ADFs), which was referred to presence of infiltrative/ill-defined HCC, macrovascular invasion, or extrahepatic disease treated with only TARE (TARE_alone) and in 74 patients with IHT ≤50% with ADFs or IHT >50% treated with TARE and sorafenib (TARE_sorafenib). Prognostic factors for OS and PFS were identified using univariate and multivariate analyses. RESULTS: Median OS and PFS of TARE_alone patients were 21.6 (95% CI 6.1-37.1) and 9.1(95% CI 5.2-13.0) months, respectively, and for TARE_sorafenib patients 12.4 (95% CI 9.1-15.6) and 5.1 (95% CI 2.6-7.5) months, respectively. Better OS was associated with serum AFP <400 (HR 0.27, p=0.02) in TARE_alone, and IHT ≤50% (HR 0.39, p=0.004) and AFP <400 (HR 0.5, p=0.027) in TARE_sorafenib. Unilobar involvement (HR 0.43, p=0.029) and AFP <400 ng/mL (HR 0.52, p=0.015) correlated with better PFS in TARE_alone and TARE_sorafenib, respectively. Adverse events (AEs) were more frequent in TARE_sorafenib than TARE_alone (92.4 vs 80.3%), but only 9.3% were grade 3 or higher AEs. CONCLUSION: TARE_alone provided the most prominent survival benefit in IHT ≤50%-without ADF patients who had unilobar HCC and serum AFP <400 ng/mL. TARE and sorafenib yielded the best outcomes in patients with IHT ≤50% and serum AFP <400 ng/mL, with some additional grade 1-2 AEs compared to TARE only.
ABSTRACT
BACKGROUND: Radium-223 dichloride (Ra-223) is a targeted alpha therapy that induces localized cytotoxicity in bone metastases. We evaluated the efficacy and safety of Ra-223 plus hormonal therapy in hormone receptor-positive (HR+), bone-dominant metastatic breast cancer. METHODS: In this single-center phase II study, 36 patients received Ra-223 (55 kBq/kg intravenously every 4 weeks) up to 6 cycles with endocrine therapy. The primary objective was to determine the clinical disease control rate at 9 months. Secondary objectives were to determine (a) tumor response rate at 6 months, (b) progression-free survival (PFS) durations, and (c) safety. RESULTS: The median number of prior systemic treatments for metastatic disease was 1 (range, 0-4). The disease control rate at 9 months was 49%. The tumor response rate at 6 months was 54% (complete response, 21%; partial, 32%). The median PFS was 7.4 months (95% CI, 4.8-not reached [NR]). The median bone-PFS was 16 months (95% CI, 7.3-NR). There were no grade 3/4 adverse events. CONCLUSIONS: Ra-223 with hormonal therapy showed possible efficacy in HR+ bone-dominant breast cancer metastasis, and adverse events were tolerable. We plan to further investigate the clinical application of Ra-223 in these patients. (NCT02366130).
Subject(s)
Alpha Particles/adverse effects , Antineoplastic Agents, Hormonal/administration & dosage , Bone Neoplasms/therapy , Breast Neoplasms/therapy , Chemoradiotherapy/methods , Radium/administration & dosage , Adult , Aged , Antineoplastic Agents, Hormonal/adverse effects , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Bone and Bones/diagnostic imaging , Breast/diagnostic imaging , Breast/pathology , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Chemoradiotherapy/adverse effects , Denosumab/administration & dosage , Denosumab/adverse effects , Female , Fulvestrant/administration & dosage , Fulvestrant/adverse effects , Humans , Injections, Intravenous , Middle Aged , Positron Emission Tomography Computed Tomography , Progression-Free Survival , Radioisotopes/administration & dosage , Radioisotopes/adverse effects , Radium/adverse effects , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tamoxifen/administration & dosage , Tamoxifen/adverse effectsABSTRACT
Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10-149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.