Kidney absorbed radiation doses for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T determined by 3D clinical dosimetry.

PURPOSE: For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T, using an identical dosimetry protocol. We evaluated the absorbed doses of both 177 Lu-labelled radioligands in human kidneys. METHODS: 3D SPECT/computed tomography (CT) imaging of the kidneys was performed after PSMA-RLT in cancer patients with PSMA-positive disease and an adequate glomerular filtration rate (≥50 mL/min). Ten metastatic hormone-sensitive prostate cancer patients (mHSPC) were treated with [ 177 Lu]Lu-PSMA-617 and 10 advanced salivary gland cancer (SGC) patients were treated with [ 177 Lu]Lu-PSMA-I&T. SPECT/CT imaging was performed at five timepoints (1 h, 24 h, 48 h, 72 h, and 168 h post-injection). In mHSPC patients, SPECT/CT imaging was performed after cycles 1 and 2 (cumulative activity: 9 GBq) and in SGC patients only after cycle 1 (activity: 7.4 GBq). Kidney absorbed dose was calculated using organ-based dosimetry. RESULTS: The median kidney absorbed dose was 0.49 Gy/GBq (range: 0.34-0.66) and 0.73 Gy/GBq (range: 0.42-1.31) for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, respectively (independent samples t test; P = 0.010). CONCLUSION: This study shows that the kidney absorbed dose for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T differs, with a ~1.5x higher median kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T. This difference in the clinical setting is considerably smaller than observed in preclinical studies and may not hamper treatments with [ 177 Lu]Lu-PSMA-I&T.

Results of histopathological revisions of major salivary gland neoplasms in routine clinical practice.

AIMS: Salivary gland neoplasms are rare and are characterised by overlapping histopathological aspects. Therefore, the assessment of the correct histopathological diagnosis can be challenging. This study evaluated the frequency of pathology consultations and revisions for salivary gland neoplasms during routine clinical practice in the Netherlands. Furthermore, the concordance and discordance rates of these revisions are presented. METHODS: The Dutch Pathology Registry (PALGA) was searched for patients that underwent a resection of a major salivary gland neoplasm between 2006 and 2016. Frequencies of pathology consultations and revisions are presented and, in order to calculate the rates of concordance and discordance, the results of the initial histopathological review were compared with the results of the revision. RESULTS: Between 2006 and 2016, 13 441 major salivary gland neoplasms were resected in the Netherlands. 90% (n=12 082) of these tumours were diagnosed as benign and 10% (n=1359) as malignant. The initial pathologist requested a consultation in 3.3% of resections (n=439). Revision of the histopathological specimen was performed in 2.6% (n=350) of cases. Revisions were discordant in 8.3%; including 5.8% of the initially benign diagnosed lesions reclassified as malignant by the second expert pathologist and 8% of the revised malignant tumours that underwent a subtype change. CONCLUSIONS: The number of discordant histopathological revisions (8.3%) emphasises the complexity of the histopathological diagnosis of salivary gland neoplasms. An increase in consultations may improve the accuracy of the initial diagnosis and thus treatment in salivary gland tumours while lowering the need for revisions and the number of discordant revisions.

Exposure-toxicity relationship of cabozantinib in patients with renal cell cancer and salivary gland cancer.

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 µg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured Cmin at steady-state. The geometric mean (GM) Cmin at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM Cmin at the start dose was 1456 µg/L (95% CI: 1185-1789) vs 682 µg/L (95% CI: 572-812) (P < .001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (Cmin 971 µg/L [95% CI: 790-1193] vs 669 µg/L [95% CI: 568-788]) (P = .005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM Cmin at BTD were comparable between the SGC and the RCC group, 694 µg/L (95% CI: 584-824) vs 583 µg/L (95% CI: 496-671) (P = .1). The observed cabozantinib exposure at BTD of approximately 600 µg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity.

Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer.

AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively. CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

PSMA-RLT in Patients with Metastatic Hormone-Sensitive Prostate Cancer: A Retrospective Study.

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.

Case Report: Two Cases of Salivary Duct Carcinoma in Workers With a History of Chromate Exposure.

Background: Salivary duct carcinoma (SDC), one subtype of the 22 different salivary gland cancers, is a rare malignancy. Risk factors for the development of salivary gland cancer and SDC are largely unknown, although pollution has been described as one of the risk factors. In other cancers, especially in lung cancer, the carcinogenicity of chromium VI [Cr(VI)] is well-known. Here we report on two SDC patients who were occupationally exposed to Cr(VI) and discuss a potential relation between their Cr(VI) exposure and the occurrence of SDC. Case Presentation: The work history of two SDC patients was analyzed for chemical exposures. Both patients had a history of Cr(VI) exposure, with maintenance of military equipment considered as the source for this exposure. Inhalation of Cr(VI) containing particles from the removal of old paint by mechanical abrasion was identified as a probable source of exposure for both patients, and one of these patients also applied new paint. Both patients reported not to have used any respiratory protection which may have resulted in substantial inhalation of Cr(VI)-containing chromates. Furthermore, in one patient inhalation of fumes from soldering may have resulted in relevant co-exposure. Conclusion: A causal relation between Cr(VI) exposure and SDC, a rare cancer, cannot be demonstrated on an individual basis but detection in a population-based study is also unlikely because of the extremely low prevalence. Nevertheless, the work history is considered a relevant risk factor in the onset of SDC as occupational exposures to Cr(VI) occurred in poorly ventilated working environment and without using appropriate respiratory protective equipment.

Lutetium-177-PSMA-617 in Low-Volume Hormone-Sensitive Metastatic Prostate Cancer: A Prospective Pilot Study.

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.

Prognostic value of PSMA, c-MET and E-cadherin in salivary duct carcinoma.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC. MATERIALS AND METHODS: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied. RESULTS: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression. CONCLUSION: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC.

Impact analysis studies of clinical prediction rules relevant to primary care: a systematic review.

OBJECTIVES: Following appropriate validation, clinical prediction rules (CPRs) should undergo impact analysis to evaluate their effect on patient care. The aim of this systematic review is to narratively review and critically appraise CPR impact analysis studies relevant to primary care. SETTING: Primary care. PARTICIPANTS: Adults and children. INTERVENTION: Studies that implemented the CPR compared to usual care were included. STUDY DESIGN: Randomised controlled trial (RCT), controlled before-after, and interrupted time series. PRIMARY OUTCOME: Physician behaviour and/or patient outcomes. RESULTS: A total of 18 studies, incorporating 14 unique CPRs, were included. The main study design was RCT (n=13). Overall, 10 studies reported an improvement in primary outcome with CPR implementation. Of 6 musculoskeletal studies, 5 were effective in altering targeted physician behaviour in ordering imaging for patients presenting with ankle, knee and neck musculoskeletal injuries. Of 6 cardiovascular studies, 4 implemented cardiovascular risk scores, and 3 reported no impact on physician behaviour outcomes, such as prescribing and referral, or patient outcomes, such as reduction in serum lipid levels. 2 studies examined CPRs in decision-making for patients presenting with chest pain and reduced inappropriate admissions. Of 5 respiratory studies, 2 were effective in reducing antibiotic prescribing for sore throat following CPR implementation. Overall, study methodological quality was often unclear due to incomplete reporting. CONCLUSIONS: Despite increasing interest in developing and validating CPRs relevant to primary care, relatively few have gone through impact analysis. To date, research has focused on a small number of CPRs across few clinical domains only.

Degree of nephrotoxicity after intermediate- or high-dose cisplatin-based chemoradiotherapy in patients with locally advanced head and neck cancer.

BACKGROUND: The purpose of this study was to compare the occurrence of cisplatin-induced nephrotoxicity between concomitant chemoradiotherapy with high versus intermediate-dose cisplatin. METHODS: One hundred forty-four patients with locally advanced head and neck or nasopharyngeal cancer (NPC) were included; 40 patients received cisplatin 100 mg/m(2) (high dose) on days 1, 22, and 43, and 104 patients received cisplatin 40 mg/m(2) weekly (intermediate dose) during 6 weeks in combination with radiotherapy. RESULTS: During treatment with intermediate-dose cisplatin, 6.7% developed an increase of ≥50% serum creatinine versus 60.0% treated with high-dose cisplatin (p < .05). Nephrotoxicity (all grades) scored by Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 or CTCAE version 4.03 was 53% and 100% in the high-dose group and 4.8% and 68% in the intermediate-dose group, respectively. CONCLUSION: Significantly less nephrotoxicity occurs during chemoradiotherapy with intermediate-dose cisplatin compared with high-dose cisplatin. The CTCAE version 4.03 seems to be more appropriate in scoring nephrotoxicity than the CTCAE version 3.0. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1575-E1581, 2016.