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INTRODUCTION: While [177Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [177Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter. METHODS: Ten mHSPC patients underwent two cycles of [177Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values. RESULTS: Kinetics of [177Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047). CONCLUSIONS: We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.
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Lutecio , Antígeno Prostático Específico , Neoplasias de la Próstata , Radiofármacos , Hormonas/metabolismo , Humanos , Lutecio/efectos adversos , Lutecio/farmacocinética , Lutecio/uso terapéutico , Masculino , Órganos en Riesgo/diagnóstico por imagen , Órganos en Riesgo/efectos de la radiación , Estudios Prospectivos , Antígeno Prostático Específico/efectos adversos , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/farmacocinética , Antígeno Prostático Específico/uso terapéutico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/secundario , Dosis de Radiación , Radiofármacos/efectos adversos , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoRESUMEN
INTRODUCTION: Patient eligibility for [177Lu]Lu-PSMA therapy remains a challenge, with only 40-60% response rate when patient selection is done based on the lesion uptake (SUV) on [68Ga]Ga-PSMA-PET/CT. Prediction of absorbed dose based on this pre-treatment scan could improve patient selection and help to individualize treatment by maximizing the absorbed dose to target lesions while adhering to the threshold doses for the organs at risk (kidneys, salivary glands, and liver). METHODS: Ten patients with low-volume hormone-sensitive prostate cancer received a pre-therapeutic [68Ga]Ga-PSMA-11 PET/CT, followed by 3 GBq [177Lu]Lu-PSMA-617 therapy. Intra-therapeutically, SPECT/CT was acquired at 1, 24, 48, 72, and 168 h. Absorbed dose in organs and lesions (n = 22) was determined according to the MIRD scheme. Absorbed dose prediction based on [68Ga]Ga-PSMA-PET/CT was performed using tracer uptake at 1 h post-injection and the mean tissue effective half-life on SPECT. Predicted PET/actual SPECT absorbed dose ratios were determined for each target volume. RESULTS: PET/SPECT absorbed dose ratio was 1.01 ± 0.21, 1.10 ± 0.15, 1.20 ± 0.34, and 1.11 ± 0.29 for kidneys (using a 2.2 scaling factor), liver, submandibular, and parotid glands, respectively. While a large inter-patient variation in lesion kinetics was observed, PET/SPECT absorbed dose ratio was 1.3 ± 0.7 (range: 0.4-2.7, correlation coefficient r = 0.69, p < 0.01). CONCLUSION: A single time point [68Ga]Ga-PSMA-PET scan can be used to predict the absorbed dose of [177Lu]Lu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of [177Lu]Lu-PSMA therapy.
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Radioisótopos de Galio , Neoplasias de la Próstata Resistentes a la Castración , Dipéptidos , Compuestos Heterocíclicos con 1 Anillo , Humanos , Lutecio , Masculino , Órganos en Riesgo/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/patología , Radiofármacos/uso terapéuticoRESUMEN
BACKGROUND: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with 177Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that 177Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using 177Lu-PSMA-I&T in a randomized multicenter setting. METHODS & DESIGN: This study compares 177Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on 18F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq 177Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another 18F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive 177Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show disease progression during the study follow up. A second primary objective is the time to disease progression. Disease progression is defined as a 100% increase in PSA from baseline or clinical progression. DISCUSSION: This is the first prospective randomized clinical study assessing the therapeutic efficacy and toxicity of 177Lu-PSMA-I&T for patients with oHSPC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04443062 .
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Lutecio/administración & dosificación , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Radioisótopos/administración & dosificación , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/efectos adversos , Progresión de la Enfermedad , Hormonas/genética , Hormonas/metabolismo , Humanos , Lutecio/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Hormono-Dependientes/patología , Neoplasias Hormono-Dependientes/radioterapia , Supervivencia sin Progresión , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Calidad de Vida , Radioisótopos/efectos adversos , Radiofármacos/administración & dosificación , Resultado del TratamientoRESUMEN
PURPOSE: Tumor targeted optical imaging using antibodies labeled with near infrared fluorophores is a sensitive imaging modality that might be used during surgery to assure complete removal of malignant tissue. We evaluated the feasibility of dual modality imaging and image guided surgery with the dual labeled anti-carbonic anhydrase IX antibody preparation (111)In-DTPA-G250-IRDye800CW in mice with intraperitoneal clear cell renal cell carcinoma. MATERIALS AND METHODS: BALB/c nu/nu mice with intraperitoneal SK-RC-52 lesions received 10 µg DTPA-G250-IRDye800CW labeled with 15 MBq (111)In or 10 µg of the dual labeled irrelevant control antibody NUH-82 (20 mice each). To evaluate when tumors could be detected, 4 mice per group were imaged weekly during 5 weeks with single photon emission computerized tomography/computerized tomography and the fluorescence imaging followed by ex vivo biodistribution studies. RESULTS: As early as 1 week after tumor cell inoculation single photon emission computerized tomography and fluorescence images showed clear delineation of intraperitoneal clear cell renal cell carcinoma with good concordance between single photon emission computerized tomography/computerized tomography and fluorescence images. The high and specific accumulation of the dual labeled antibody conjugate in tumors was confirmed in the biodistribution studies. Maximum tumor uptake was observed 1 week after inoculation (mean ± SD 58.5% ± 18.7% vs 5.6% ± 2.3% injected dose per gm for DTPA-G250-IRDye800CW vs NUH-82, respectively). High tumor uptake was also observed at other time points. CONCLUSIONS: This study demonstrates the feasibility of dual modality imaging with dual labeled antibody (111)In-DTPA-G250-IRDye800CW in a clear cell renal cell carcinoma model. Results indicate that preoperative and intraoperative detection of carbonic anhydrase IX expressing tumors, positive resection margins and metastasis might be feasible with this approach.
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Anticuerpos Monoclonales , Carcinoma de Células Renales/diagnóstico , Diagnóstico por Imagen , Neoplasias Renales/diagnóstico , Neoplasias Experimentales , Imagen Óptica/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Línea Celular Tumoral , Diagnóstico Diferencial , Femenino , Fluorescencia , Ratones , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 (177Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 µg of G250 labeled with 10 MBq indium 111 (111In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177Lu-DOTA-G250, a control group received 13 MBq nonspecific 177Lu-MOPC21, and the second control group was not treated and received 20 MBq 111In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 µg G250. Treatment with 13 MBq 177Lu-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49-53 days, p â=â .015), indicating that RIT has potential in this metastatic ccRCC model.
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Anticuerpos Monoclonales/administración & dosificación , Carcinoma de Células Renales/radioterapia , Inmunoconjugados/administración & dosificación , Neoplasias Renales/radioterapia , Lutecio/uso terapéutico , Radioisótopos/uso terapéutico , Radiofármacos/administración & dosificación , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Complejos de Coordinación/uso terapéutico , Relación Dosis-Respuesta en la Radiación , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Xenoinjertos , Humanos , Inmunoconjugados/farmacocinética , Inmunoconjugados/uso terapéutico , Inyecciones Intraperitoneales , Neoplasias Renales/patología , Dosis Máxima Tolerada , Ratones , Trasplante de Neoplasias , Neoplasias Experimentales , Radioinmunoterapia , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Distribución TisularRESUMEN
BACKGROUND: Bone marrow toxicity in advanced prostate cancer patients who receive [177Lu]Lu-PSMA-617 is a well-known concern. In early stage patients; e.g. low volume metastatic hormone sensitive prostate cancer (mHSPC) patients, prevention of late bone marrow toxicity is even more crucial due to longer life expectancy. To date, bone marrow dosimetry is primarily performed using blood sampling. This method is time consuming and does not account for possible active bone marrow uptake. Therefore other methodologies are investigated. We calculated the bone marrow absorbed dose for [177Lu]Lu-PSMA-617 in mHSPC patients using SPECT/CT imaging and compared it to the blood sampling method as reference. METHODS: Eight mHSPC patients underwent two cycles (3 and 6 GBq) of [177Lu]Lu-PSMA-617 therapy. After each cycle, five time point (1 h, 1 day, 2 days, 3 days, 7 days) SPECT/CT was performed at kidney level. Bone marrow dosimetry was performed using commercial software by drawing ten 1.5 cm diameter spheres in the lowest ten vertebrae to determine the time-integrated activity. Simplified protocols using only 2 imaging time points and 3 vertebrae were also compared. Blood-based dosimetry was based on the blood sampling method according to the EANM guideline. RESULTS: Mean bone marrow absorbed dose was significantly different (p < 0.01) for the imaging based method (25.4 ± 8.7 mGy/GBq) and the blood based method (17.2 ± 3.4 mGy/GBq), with an increasing absorbed dose ratio between both methods over time. Bland Altman analysis of both simplification steps showed that differences in absorbed dose were all within the 95% limits of agreement. CONCLUSION: This study showed that bone marrow absorbed dose after [177Lu]Lu-PSMA-617 can be determined using an imaging-based method of the lower vertebrae, and simplified using 2 time points (1 and 7 days) and 3 vertebrae. An increasing absorbed dose ratio over time between the imaging-based method and blood-based method suggests that there might be specific bone marrow binding of [177Lu]Lu-PSMA-617.
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BACKGROUND: Further stratification of the risk of recurrence of clear-cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) will facilitate selection of candidates for adjuvant therapy. OBJECTIVE: To assess the impact of tumor grade discrepancy (GD) between the primary tumor (PT) and VTT in nonmetastatic ccRCC on disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of a multi-institutional nationwide data set for patients with pT3N0M0 ccRCC who underwent radical nephrectomy and thrombectomy. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Pathology slides were centrally reviewed. GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS. RESULTS AND LIMITATIONS: We analyzed data for 604 patients with median follow-up of 42 mo (excluding events). Tumor GD between VTT and PT was observed for 47% (285/604) of the patients and was an independent risk factor with incremental value in predicting the outcomes of interest (all p < 0.05). Incorporation of tumor GD significantly improved the performance of the ECOG-ACRIN 2805 (ASSURE) model. A GD-based model (PT grade, GD, pT stage, PT sarcomatoid features, fat invasion, and VTT consistency) had a c index of 0.72 for DFS. The hazard ratios were 8.0 for GD = +2 (p < 0.001), 1.9 for GD = +1 (p < 0.001), 0.57 for GD = -1 (p = 0.001), and 0.22 for GD = -2 (p = 0.003) versus GD = 0 as the reference. According to model-converted risk scores, DFS, OS, and CSS significantly differed between subgroups with low, intermediate, and high risk (all p < 0.001). CONCLUSIONS: Routine reporting of VTT upgrading or downgrading in relation to the PT and use of our GD-based nomograms can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression. PATIENT SUMMARY: We developed a tool to improve patient counseling and guide decision-making on other therapies in addition to surgery for patients with the clear-cell type of kidney cancer and tumor invasion of a vein.
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Carcinoma de Células Renales , Neoplasias Renales , Trombosis , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Pronóstico , Estudios Retrospectivos , Invasividad Neoplásica/patología , Neoplasias Renales/cirugía , Trombosis/patología , Trombosis/cirugía , Sistema de RegistrosRESUMEN
BACKGROUND: Dosimetry in [177Lu]Lu-PSMA therapy is a valuable tool to assess treatment efficacy and toxicity. This study aims to develop a clinically implementable protocol to determine the absorbed dose in organs and tumor lesions after [177Lu]Lu-PSMA-617 therapy, by reducing the imaging time points and utilizing population-based kinetics with a single scan, with evaluation of its influence on the uncertainty in absorbed dose. METHODS: Ten patients with metastatic hormone-sensitive prostate cancer received two cycles of [177Lu]Lu-PSMA-617. Post-treatment imaging was performed at 1 h, 24 h, 48 h, 72 h and 168 h, consisting of three-bed positions SPECT/CT and a whole-body planar scan. Five-time point SPECT dosimetry was performed for lesions and organs with physiological uptake (kidneys, liver and salivary glands) and used as the reference standard. Absorbed dose values for various simplified protocols were compared to the reference standard. RESULTS: Accurate lesion dosimetry is possible using one-time point SPECT imaging at 168 h, with an increase in uncertainty (20% vs. 14% for the reference standard). By including a second time point, uncertainty was comparable to the reference standard (13%). Organ dosimetry can be performed using a single SPECT at 24 h or 48 h. Dosimetry based on planar scans did not provide accurate dose estimations. CONCLUSION: Accurate lesion dosimetry in [177Lu]Lu-PSMA therapy can be performed using a one- or two-time point protocol, making dosimetry assessments more suitable for routine clinical implementation, although dosimetry based om multiple time points is more accurate. Clinical trial registration This study was approved by the Medical Review Ethics Committee Region Arnhem-Nijmegen on January 23, 2018 and was registered on clinicaltrials.gov (NCT03828838).
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Single-port (SP) robotic surgery is a novel technology and is at the beginning of its adoption curve in urology. The goal of this narrative review is to provide an overview of SP-robotic partial nephrectomy (PN) 4 years after the introduction of the da Vinci SP dedicated platform, focusing on perioperative outcomes, length of stay, and surgical technique. A nonsystematic review of the literature was conducted. The research included the most updated articles that referred to SP robotic PN. Since its commercial release in 2018, several institutions have reproduced robotic PN by using the SP platform, both via a transperitoneal and a retroperitoneal approach. The published SP-robotic PN series are generally based on preliminary experiences by surgeons who had previous experience with conventional multi-arms robotic platforms. The reported outcomes are encouraging. Overall, three studies reported that SP-robotic PN cases had nonsignificantly different operative time, estimated blood loss, overall complications rate, and length of stay compared to the conventional 'multi-arms' robotic PN. However, in all these series, renal masses treated by SP had overall lower complexity. Moreover, two studies underlined decreased postoperative pain as a major pro of adopting the SP system. This should reduce/avoid the need for opioids after surgery. No study compared SP-robotic versus multi-arms robotic PN in cost-effectiveness. Published experience with SP-robotic PN has reported the feasibility and safety of the approach. Preliminary results are encouraging and at least noninferior with respect to those from the multi-arms series. Prospective comparative studies with long-term oncologic and functional results are awaited to draw more definitive conclusions and better establish the more appropriate indications of SP robotics in the field of PN.
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Renal cell carcinoma (RCC) is characterized by its diverse histopathological features, which pose possible challenges to accurate diagnosis and prognosis. A comprehensive literature review was conducted to explore recent advancements in the field of artificial intelligence (AI) in RCC pathology. The aim of this paper is to assess whether these advancements hold promise in improving the precision, efficiency, and objectivity of histopathological analysis for RCC, while also reducing costs and interobserver variability and potentially alleviating the labor and time burden experienced by pathologists. The reviewed AI-powered approaches demonstrate effective identification and classification abilities regarding several histopathological features associated with RCC, facilitating accurate diagnosis, grading, and prognosis prediction and enabling precise and reliable assessments. Nevertheless, implementing AI in renal cell carcinoma generates challenges concerning standardization, generalizability, benchmarking performance, and integration of data into clinical workflows. Developing methodologies that enable pathologists to interpret AI decisions accurately is imperative. Moreover, establishing more robust and standardized validation workflows is crucial to instill confidence in AI-powered systems' outcomes. These efforts are vital for advancing current state-of-the-art practices and enhancing patient care in the future.
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Objective: No standard strategy for diagnosis and management of positive surgical margin (PSM) and local recurrence after partial nephrectomy (PN) are reported in literature. This review aims to provide an overview of the current strategies and further perspectives on this patient setting. Methods: A non-systematic review of the literature was completed. The research included the most updated articles (about the last 10 years). Results: Techniques for diagnosing PSMs during PN include intraoperative frozen section, imprinting cytology, and other specific tools. No clear evidence is reported about these methods. Regarding PSM management, active surveillance with a combination of imaging and laboratory evaluation is the first option line followed by surgery. Regarding local recurrence management, surgery is the primary curative approach when possible but it may be technically difficult due to anatomy resultant from previous PN. In this scenario, thermal ablation (TA) may have the potential to circumvent these limitations representing a less invasive alternative. Salvage surgery represents a valid option; six studies analyzed the outcomes of nephrectomy on local recurrence after PN with three of these focused on robotic approach. Overall, complication rates of salvage surgery are higher compared to TA but ablation presents a higher recurrence rate up to 25% of cases that can often be managed with repeat ablation. Conclusion: Controversy still exists surrounding the best strategy for management and diagnosis of patients with PSMs or local recurrence after PN. Active surveillance is likely to be the optimal first-line management option for most patients with PSMs. Ablation and salvage surgery both represent valid options in patients with local recurrence after PN. Conversely, salvage PN and radical nephrectomy have fewer recurrences but are associated with a higher complication rate compared to TA. In this scenario, robotic surgery plays an important role in improving salvage PN and radical nephrectomy outcomes.
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Objective: The role of lymph node dissection (LND) is still controversial in patients with renal cell carcinoma undergoing surgery. We aimed to provide a comprehensive review of the literature about the effect of LND on survival, prognosis, surgical outcomes, as well as patient selection and available LND templates. Methods: Recent literature (from January 2011 to December 2021) was assessed through PubMed and MEDLINE databases. A narrative review of most relevant articles was provided. Results: The frequencies in which LNDs are being carried out are decreasing due to an increase in minimally invasive and nephron sparing surgery. Moreover, randomized clinical trials and meta-analyses failed to show any survival advantage of LND versus no LND. However, retrospective studies suggest a survival benefit of LND in high-risk patients (bulky tumors, T3-4 stage, and cN1 patients). Moreover, extended LND might provide important staging information, which could be of interest for adjuvant treatment planning. Conclusion: No level 1 evidence of any survival advantage deriving from LND is currently available in literature. Thus, the role of LND is limited to staging purposes. However, low grade evidence suggests a possible role of LND in high-risk patients. Randomized clinical trials are warranted to corroborate these findings.
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BACKGROUND: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients. METHODS: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. RESULTS: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1-6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2-7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1-2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3-4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09-19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. CONCLUSIONS: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up.
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BACKGROUND: PSMA-PET is a novel imaging modality for the staging of prostate cancer (PCa). While there are several PSMA ligands available, F-18-PSMA-1007 is particularly of interest as it is not renally excreted and therefore does not impair the imaging of the pelvic area. Hence, this study aimed to investigate the F-18-PSMA-1007-PET for the primary staging of PCa and compared it to multi-parametric (mp) MRI and histopathology. METHODS: A retrospective study was performed of men with intermediate and high-risk PCa patients that underwent a F-18-PSMA-1007-PET after mpMRI with subsequent MR-guided target biopsy (MRGB). Suspicious mpMRI lesions and F-18-PSMA-1007-PET were simultaneously reviewed on both a per patient and per-lesion basis. Results were subsequently evaluated with histopathological outcome of MRGB, and if performed, the radical prostatectomy specimen. RESULTS: A total of 66 suspicious mpMRI lesions were identified in 53 patients and underwent MRGB. Two lesions had a maximum standardized uptake value (SUVmax) less than the mean SUVmax of healthy prostate tissue and were considered as non-PSMA-expressing. All PSMA avid tumors had higher SUVmax than the mean SUVmean of the bladder/urine, therefore all lesions were clearly distinguishable in the pelvic area. Twenty-three patients received a radical prostatectomy of which the histopathology specimens were evaluated. F-18-PSMA-1007-PET/CT correctly staged seminal vesicle invasion (i.e. pT3b) more often than mpMRI (90 vs. 76%), whereas mpMRI more accurately detected extracapsular extension (i.e. pT3a) compared to F-18-PSMA-1007-PET (90% vs 57%). CONCLUSIONS: The present study of a selected cohort suggest that dual imaging with mpMRI and F-18-PSMA-1007-PET may improve staging of primary PCa. F-18-PSMA-1007-PET/CT had low renal clearance, which could assist the evaluation of tumors in proximity of the bladder.
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Fluorodesoxiglucosa F18/metabolismo , Niacinamida/análogos & derivados , Oligopéptidos/metabolismo , Neoplasias de la Próstata/patología , Anciano , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Imágenes de Resonancia Magnética Multiparamétrica , Niacinamida/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Prostatectomía , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/cirugía , Radiofármacos/metabolismo , Estudios RetrospectivosRESUMEN
PURPOSE: [177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC. PATIENTS AND METHODS: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS. RESULTS: All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III-IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease. CONCLUSIONS: 177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.
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Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Andrógenos/uso terapéutico , Dipéptidos/efectos adversos , Compuestos Heterocíclicos con 1 Anillo/efectos adversos , Hormonas/uso terapéutico , Humanos , Masculino , Proyectos Piloto , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Calidad de Vida , Radioisótopos , RadiofármacosRESUMEN
BACKGROUND: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. CHANGES IN METHODS AND MATERIALS: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; "Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer" and is now partly supported by Advanced Accelerator Applications, a Novartis Company. CONCLUSIONS: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. TRIAL REGISTRATION: ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020.
Asunto(s)
Antagonistas de Andrógenos , Neoplasias de la Próstata Resistentes a la Castración , Hormonas , Humanos , Lutecio/efectos adversos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , RadioisótoposRESUMEN
UNLABELLED: Despite advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC), there is still an unmet need in the treatment of this disease. A phase 2 radioimmunotherapy (RIT) trial with lutetium 177 ((177)Lu)-girentuximab was initiated to evaluate the efficacy of this approach. In this nonrandomized single-arm trial, patients with progressive metastatic ccRCC who met the inclusion criteria received 2405 MBq/m(2) of (177)Lu-girentuximab intravenously. In the absence of persistent toxicity and progressive disease, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. A total of 14 patients were included. After the first therapeutic infusion, eight patients (57%) had stable disease (SD) and one (7%) had a partial regression. The treatment was generally well tolerated but resulted in grade 3-4 myelotoxicity in most patients. After the second cycle, continued SD was observed in five of six patients, but none were eligible for retreatment due to prolonged thrombocytopenia. In conclusion, RIT with (177)Lu-girentuximab resulted in disease stabilization in 9 of 14 patients with progressive metastatic ccRCC, but myelotoxicity prevented retreatment in some patients. PATIENT SUMMARY: We investigated the efficacy of lutetium 177-girentuximab radioimmunotherapy in patients with metastatic kidney cancer. The treatment resulted in disease stabilization in 9 of 14 patients. The main toxicity was prolonged low blood cell counts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02002312 (https://clinicaltrials.gov/ct2/show/NCT02002312).
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/radioterapia , Neoplasias Renales/radioterapia , Lutecio/uso terapéutico , Radioinmunoterapia , Radioisótopos/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Anhidrasa Carbónica IX/inmunología , Carcinoma de Células Renales/secundario , Supervivencia sin Enfermedad , Humanos , Neoplasias Renales/patología , Lutecio/efectos adversos , Neutropenia/inducido químicamente , Ensayos Clínicos Controlados no Aleatorios como Asunto , Radioinmunoterapia/efectos adversos , Radioisótopos/efectos adversos , Retratamiento , Trombocitopenia/inducido químicamenteRESUMEN
UNLABELLED: Near-infrared dye-tagged antibodies can be used for the sensitive detection of tumor tissue in vivo. Surgery for clear-cell renal cell carcinoma (ccRCC) might benefit from the use of optical imaging to facilitate the intraoperative detection of carbonic anhydrase IX (CAIX)-expressing tumor lesions with chimeric monoclonal antibody (mAb) girentuximab, which has been shown to have excellent imaging capabilities for ccRCC. Here we studied the potential of fluorescence imaging to detect ccRCC tumors in nude mice with RCC xenografts by using mAb girentuximab conjugated with IRDye800CW; SPECT imaging was used as a reference. METHODS: Groups of athymic BALB/c mice with subcutaneous CAIX-positive SK-RC-52 ccRCC tumors were injected intravenously with (125)I-labeled girentuximab-IRDye800CW or (125)I-labeled girentuximab. For determination of the specificity of the accumulation of the anti-CAIX antibody conjugate in ccRCC, separate groups of mice bearing a CAIX-positive tumor (SK-RC-52) and a CAIX-negative tumor (SK-RC-59) received (125)I-girentuximab-IRDye800CW or (125)I-labeled MOPC21-IRDye800CW (control mAb). Optical images and micro-SPECT images were acquired until 3 d after injection. Mice were euthanized after the last imaging session, and the biodistribution of the radiolabeled antibody preparations was determined. RESULTS: Optical imaging and micro-SPECT imaging at 1 d after the injection of (125)I-girentuximab-IRDye800CW showed clear delineation of the CAIX-expressing ccRCC xenografts, and image contrast improved with time. Fluorescence imaging and biodistribution studies showed high and specific uptake of (125)I-girentuximab-IRDye800CW in CAIX-positive ccRCC xenografts (SK-RC-52, 31.5 ± 9.6 percentage injected dose per gram [%ID/g] at 72 h after injection). Tumor uptake was specific, as very low uptake of (125)I-girentuximab-IRDye800CW was noted in the CAIX-negative SK-RC-59 tumor (4.1 ± 1.5 %ID/g), and no uptake of (125)I-MOPC21-IRDye800CW (control mAb) was noted in the CAIX-positive SK-RC-52 tumor (1.2 ± 0.1 %ID/g). CONCLUSION: Subcutaneous CAIX-expressing ccRCC xenografts were visualized by optical imaging with (125)I-girentuximab-IRDye800CW. Optical images showed good concordance with micro-SPECT images. The accumulation of (125)I-girentuximab-IRDye800CW in ccRCC tumors was high and specific. Girentuximab-IRDye800CW potentially could be used for the intraoperative detection of CAIX-expressing tumors and the assessment of residual tumor in resection margins or metastatic lesions in patients with ccRCC.
Asunto(s)
Anticuerpos Monoclonales , Anhidrasas Carbónicas/inmunología , Carcinoma de Células Renales/diagnóstico , Imagen Óptica/métodos , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Bencenosulfonatos/química , Transporte Biológico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Humanos , Indoles/química , Marcaje Isotópico , Masculino , Ratones , Ratones Desnudos , Distribución TisularRESUMEN
UNLABELLED: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of (111)In-labeled girentuximab. METHODS: (111)In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of (111)In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single (111)In-girentuximab injection and scintigraphy without any treatment. Distribution of (111)In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue. RESULTS: Treatment with sorafenib resulted in a marked decrease of (111)In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, -38.4%; range, +9.1% to -79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients. CONCLUSION: Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of (111)In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/tratamiento farmacológico , Radioisótopos de Indio/farmacocinética , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Anciano , Sinergismo Farmacológico , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Niacinamida/uso terapéutico , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Cintigrafía , SorafenibRESUMEN
BACKGROUND: Improved and more frequent radiologic evaluation has resulted in increased identification of renal masses of unknown origin, which frequently pose a diagnostic dilemma for urologists. OBJECTIVE: Carbonic anhydrase IX (CAIX) is an antigen ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). The specific and high level of expression in ccRCC makes CAIX an excellent target for imaging ccRCC lesions. We present our experience with immuno-single-photon emission computed tomography (immunoSPECT) imaging with the indium-111 ((111)In)-labeled anti-CAIX antibody girentuximab in patients presenting with either a primary renal tumor or a history of ccRCC and lesions suspect for metastases during follow-up. DESIGN, SETTING, AND PARTICIPANTS: Twenty-nine patients received 100-200 MBq (111)In-labeled girentuximab. Whole-body and single photon emission computed tomography (SPECT) images were acquired after 4-7 d. INTERVENTION: Injection with (111)In-girentuximab and image acquisition after 4-7 d. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Accuracy of (111)In-girentuximab immunoSPECT. RESULTS AND LIMITATIONS: Distinct uptake of (111)In-girentuximab was seen in 16 of 22 patients presenting with a renal mass. All renal masses proven to be ccRCC after resection (n=15) were detected with (111)In-girentuximab. Suspect lesions of six patients showed no uptake of (111)In-girentuximab. In these patients, ccRCC was not found, nor progression occurred. Seven patients with a history of ccRCC and possible metastatic lesions on follow-up computed tomography scans were imaged with (111)In-girentuximab. In four of these patients, the lesions showed preferential uptake of (111)In-girentuximab and local or systemic treatment was initiated. In three other cases, no (111)In-girentuximab targeting was seen. During follow-up of these three patients, one showed progression, for which systemic treatment was started. In the two other patients, no progression occurred, suggesting a benign nature. CONCLUSIONS: (111)In-girentuximab immunoSPECT can be used to detect ccRCC lesions in patients with a primary renal mass and to clarify the nature of lesions suspect for metastases in patients with a history of ccRCC.