An elevated serum alkaline phosphatase level in hepatic metastases of grade 1 and 2 gastrointestinal neuroendocrine tumors is unusual and of prognostic value

Andriantsoa, Maeva; Hoibian, Solène; Autret, A.; Gilabert, Marine; Sarran, Anthony; Niccoli, Patricia; Raoul, Jean‐Luc

doi:10.1371/journal.pone.0177971

Cited by 9 publications

(11 citation statements)

References 12 publications

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“…Similar findings were observed with ALP elevation as with tumour burden, which is consistent with the association of ALP with tumour burden [10]. The HR for PFS benefit with 177 Lu-Dotatate versus high-dose octreotide in the high ALP group was nearly identical to the benefit in the normal ALP group.…”

Section: Discussionsupporting

confidence: 85%

“…In the phase 3 PROMID study (which randomised patients with midgut NET to octreotide long-acting release [LAR] versus placebo), liver tumour burden > 10% was associated with a hazard ratio (HR) for progression of 2.63 on multivariate analysis [2]. Another prognostic factor is serum alkaline phosphatase (ALP) [9][10][11][12][13], which may be elevated with extensive liver involvement and bone metastases [10,14]. In one series of metastatic gastrointestinal NET, ALP ≥ upper limit of normal (ULN) was associated with a median progression-free survival (PFS) of 10 months versus 33 months with normal ALP (multivariate HR, 2.49, P = 0.017) [10].…”

Section: Introductionmentioning

confidence: 99%

“…Another prognostic factor is serum alkaline phosphatase (ALP) [ 9 – 13 ], which may be elevated with extensive liver involvement and bone metastases [ 10 , 14 ]. In one series of metastatic gastrointestinal NET, ALP ≥ upper limit of normal (ULN) was associated with a median progression-free survival (PFS) of 10 months versus 33 months with normal ALP (multivariate HR, 2.49, P = 0.017) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Strosberg

Kunz

Hendifar

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177 Lu-Dotatate. Methods In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results Significantly prolonged median PFS occurred with 177 Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177 Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions 177 Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11 This article is part of the Topical Collection on Endocrinology.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Strosberg

Kunz

Hendifar

et al. 2020

Eur J Nucl Med Mol Imaging

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“…ALT and AST are found within the hepatocytes and are only released when there is liver damage although the cardiac muscles equally contain certain quantity of AST, while ALP is found in the cell lining of the hepatic biliary duct and released in large amount when there is hepatic biliary duct injury or obstruction [71][72][73][74]. ALP may also be profoundly elevated in metastatic hepatic carcinoma and metastatic colon carcinoma [75,76], lymphoma [77][78][79][80][81][82], osteosarcoma [83,84], or infiltrative diseases…”

Section: Discussionmentioning

confidence: 99%

Experimental Therapeutic Evaluation of the African Vegetables (Clerodendrum Volubile Leaf and Irvingia Gabonensis Seed Extracts) in Trastuzumab-Mediated Hepato-Renal Dysfunction in Wistar Rats

Adeneye

Olorundare

Akinsola

et al. 2021

Asian J Pharm Clin Res

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Objective: The use of trastuzumab (TZM) in the clinical management of human epidermal growth factor receptor 2 positive metastatic breast and gastric cancers, gastro-esophageal adenocarcinoma, and colorectal carcinoma has been limited by its off-target cardiac, hepatic, and renal toxicities which till date have no effective therapies in either their prevention or amelioration. Thus, the present study is designed at investigating the protective and therapeutic potentials of 400 mg/kg/day Clerodendrum volubile ethanol leaf extract (CVE) and Irvingia gabonensis ethanol seed extract (IGE) pretreatments in TZM-intoxicated Wistar rats based on their reported folkloric use in the local management of kidney and liver diseases and the previously reported therapeutic potential of these African vegetables in TZM cardiotoxicity. Methods: Forty-nine male Wistar rats were randomly allotted into seven groups of seven rats per group. Group I rats were treated with 10 ml/kg/day of 5% dimethyl sulfoxide (DMSO) sterile water p.o. and 1 ml/kg/day 5% DMSO sterile water i.p.; Groups II and III rats were orally pretreated with 400 mg/kg/day CVE and IGE, respectively, 3 h before 1 ml/kg/day/i.p. 5% DMSO sterile water; Group IV rats were orally pretreated with 10 ml/kg/day 5% DMSO sterile water 3 h before 2.25 mg/kg/day/i.p. TZM; and Groups V-VII rats were pretreated with 20 mg/kg/day Vit. C, 400 mg/kg/day CVE, and 400 mg/kg/day IGE all dissolved in 5% DMSO sterile water, respectively, 3 h before i.p. injections of 2.25 mg/kg/day TZM, all for 7 days. Liver function parameters, renal function parameters, oxidative stress markers, and histopathological investigations were the study measuring endpoints. Results: Oral pretreatment with 20 mg/kg/day Vit. C, 400 mg/kg/day CVE and IGE significantly ameliorated TZM-mediated hepatic and renal toxicities by effectively lowering the serum alanine transaminase, aspartate transaminase, alkaline phosphatase, creatinine, and urea levels. CVE and IGE pretreatments also significantly reversed TZM-induced decreases in the hepatic and renal tissue catalase, superoxide dismutase, and glutathione- S-transferase activities and reduced malondialdehyde levels. CVE and IGE pretreatments also improved TZM-induced hepatic and renal histological lesions. Conclusions: Overall, the chemotherapeutic/chemopreventive potentials of CVE and IGE in TZM-induced hepatorenal dysfunction were either wholly or partly mediated through free-radical scavenging and antioxidant activities.

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“…Creatinine is an established measure of kidney function, 19 and estimated glomerular filtration rate (eGFR) has been previously demonstrated to have a relationship with renal absorbed dose 10,11 . We included alkaline phosphatase, a reported prognostic marker of progression-free survival in patients with NETs, 20 to explore potential effects of tumor burden. Association of anemia, pancytopenia, bone marrow hypocellularity, and dysfunction of bone marrow–derived stromal cells with chronic kidney disease motivate the remaining factors 21–23 .…”

Section: Methodsmentioning

confidence: 99%

177Lu-DOTATATE Theranostics

et al. 2023

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PurposePretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression.Patients and MethodsPretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning–based tools. Dosimetry was performed by coupling the multi–time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD).ResultsThe median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2–1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models.ConclusionsPretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT.

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An elevated serum alkaline phosphatase level in hepatic metastases of grade 1 and 2 gastrointestinal neuroendocrine tumors is unusual and of prognostic value

Cited by 9 publications

References 12 publications

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Experimental Therapeutic Evaluation of the African Vegetables (Clerodendrum Volubile Leaf and Irvingia Gabonensis Seed Extracts) in Trastuzumab-Mediated Hepato-Renal Dysfunction in Wistar Rats

177Lu-DOTATATE Theranostics

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