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Vascular and Interventional Radiology |
1 From the Department of Radiology, Royal Free Hospital, Pond St, London NW3 2QG, England. From the 2003 RSNA Annual Meeting. Received July 9, 2004; revision requested September 14; revision received October 27; accepted December 14. Address correspondence to M.E.C.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: The study was local ethics committee approved, and all patients gave informed consent. Twenty-three patients (13 men, 10 women; age range, 21–69 years; median age, 57 years) with histologically proved large-volume liver metastases from neuroendocrine cancers were treated. All patients had radiologic evidence of liver disease progression and high uptake of indium 111 (111In) pentetreotide at scintigraphy. Selective hepatic intraarterial injection of 90Y-DOTA-lanreotide (total of 36 treatments; median activity per dose, 1 GBq) was administered with or without embolization. Treatment cycles were performed in 8-week intervals. Clinical, biologic, and radiologic tumor responses were assessed 8–12 weeks after each treatment cycle. Objective tumor response was classified according to World Health Organization response criteria as complete regression, partial response, stable disease, or disease progression. Kaplan-Meier survival curves were used to calculate 1-year survivals.
RESULTS: Partial response to treatment was achieved in three (16%) of 19 patients, and stable disease was achieved in 12 (63%). Four (21%) of 19 patients had continued disease progression. Clinical improvement was reported by 14 (61%) of the 23 patients, and a reduction in biologic marker levels was observed in nine (60%) of 15 patients. Reversible hematologic toxicity (National Cancer Institute common toxicity criteria grade > 2) occurred in three patients. The 1-year survival rate was 63% (median survival time, 15 months).
CONCLUSION: Hepatic intraarterial injection of 90Y-DOTA-lanreotide is a safe and effective palliative treatment for patients with progressive large-volume somatostatin receptor–positive liver metastases from neuroendocrine tumors.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The majority of neuroendocrine tumors express more than one of the five somatostatin receptors, the most frequently expressed one being somatostatin receptor 2 (3,4). Knowledge of the somatostatin receptor properties of these tumors has been used to develop imaging techniques and therapeutic strategies. Radiolabeled somatostatin analogs such as indium (111In) pentetreotide have proved to be very useful for tumor scintigraphy of tumors expressing somatostatin receptor 2. When administered in a high dose to patients with disseminated neuroendocrine tumors, 111In-pentetreotide has been shown to have a short-term beneficial antitumor effect without substantial toxicity (5,6).
The recent introduction of the metal chelator tetraazacyclododecane tetraacetic acid (DOTA) has considerably improved the stability of somatostatin radioconjugates and made it possible to use a variety of radionuclides, such as yttrium 90 (90Y), which delivers higher-energy radiation, for receptor-targeted radionuclide therapy. DOTA chelated to the somatostatin analog lanreotide can be stably labeled with either diagnostic 111In or the ß-emitting therapeutic radionuclide 90Y. Both 111In-DOTA-lanreotide and 90Y-DOTA-lanreotide bind to somatostatin receptors 2–5 with high affinity and to somatostatin receptor 1 with low affinity (7). Preliminary results from phase IIa of the Multicenter Analysis of a Universal Receptor and Treatment Initiative, a European Study, or MAURITIUS, in which 154 patients with different types of progressive tumors that expressed somatostatin receptors received short-term intravenous infusions of 90Y-DOTA-lanreotide, were promising (8). After receiving cumulative treatment doses of 90Y-DOTA-lanreotide of up to 8.6 GBq (232 mCi), 14% of patients had regressive tumor disease and 41% had stable disease. The patients had no severe acute or chronic hematologic toxicities or changes in renal or liver function after the infusions.
The biodistribution of 90Y-DOTA-lanreotide after intravenous injection, however, includes marked renal uptake and clearance, and although this does not appear to result in toxicity, it means that around 30% of the injected activity is lost in the urine within the first few hours and does not contribute to the therapy. In patients with tumors that are primarily within the liver, it would be logical to deliver the 90Y-DOTA-lanreotide directly to the liver metastasis by means of hepatic intraarterial infusion, with the goal of achieving higher intratumoral concentrations of 90Y-DOTA-lanreotide and providing more effective treatment of somatostatin receptor–positive liver metastases from neuroendocrine tumors. Thus, the purpose of our study was to prospectively evaluate the safety and effectiveness of hepatic intraarterial injection of 90Y-DOTA-lanreotide as a treatment for patients with progressive large-volume somatostatin receptor–positive liver metastases originating from neuroendocrine tumors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Twenty-three patients (13 men, 10 women; mean age, 54 years; age range, 21–69 years) were treated between November 2000 and November 2003. Eighteen patients had metastatic carcinoid tumors, four had metastatic pancreatic neuroendocrine tumors, and one had a neuroendocrine tumor from an unknown primary cancer (Table 1). Nine of the 23 patients underwent polyvinyl alcohol (PVA) particle (Cook, Bloomington, Ind) embolization at the same time as 90Y-DOTA-lanreotide injection.
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Immediately before the 90Y-DOTA-lanreotide injection, hepatic angiography was performed to assess the arterial anatomy, tumor blood supply, and patency of the portal vein. The hepatic arteries (right, left, or common hepatic arteries) feeding the liver segment that contained the metastases were then selectively catheterized, and 90Y-DOTA-lanreotide was injected with or without embolization with 150–500-µm PVA particles. Two experienced interventional radiologists (J.M.T. and D.M.) who had 10 and 5 years experience performing angiography, respectively, performed the angiographic examinations and embolizations. Concurrent PVA particle embolization was performed if we believed that the tumor was sufficiently large such that the isotope concentration would be too small to act alone, if the portal vein was patent, and if the existing liver function was sufficient such that there was no risk of further compromise to liver function. Nine patients underwent concurrent PVA particle embolization. Intravenous amino acid solution was not coadministered because 90Y-DOTA-lanreotide administration was not expected to cause renal toxicity (9). Further treatment cycles were performed in intervals of at least 2 months.
Preparation and Administration of 90Y-DOTA-Lanreotide
We prepared the 90Y-DOTA-lanreotide within the radiopharmacy of the hospital by dissolving 100 µg of DOTA-lanreotide peptide residue (Biotechnica, Vienna, Austria) in 0.4 mL of 1 mol/L ammonium acetate buffer and using a low-metal needle for fluid transfer. After mixing the solution at room temperature for 3–5 minutes, we added it to a vial that contained 1.2 GBq of 90Y-chloride (Amersham Health, Amersham Berks, England; MDS Nordion, Three River Island, Quebec, Canada) and placed the vial in a boiling water bath for 10 minutes. Before the agent was administered, it was filtered through a 0.2-µm low protein–binding filter and its labeling efficiency was determined to be higher than 95% at both high-pressure liquid chromatography and thin-layer chromatography. The dose of 90Y-DOTA-lanreotide was standardized to 1 GBq and administered by an experienced nuclear medicine physician (J.R.B.) in a designated room in the radiology department. Variations in administered doses depended on the amounts of radioactivity from other sources the patients received during the week of treatment.
The patient was then nursed in a designated side room overnight after treatment if no PVA particles had been administered and for 2–3 days after treatment if particles had been administered. Because a pure ß emitter was used, the patient was isolated during the first 16 hours after the treatment, during which time there was some urinary excretion of the agent, in accordance with the legal requirements for radioactivity protection and scintigraphic localization control.
Assessment of Effectiveness
Radiologic tumor response.—Tumor response to 90Y-DOTA-lanreotide treatment was determined by using computed tomography (CT). CT scans obtained 8–12 weeks after each treatment cycle were compared with CT scans obtained up to 4 weeks before the first treatment cycle. One radiologist (M.W.) who had 5 years experience reading liver CT scans and was blinded to the treatment given interpreted the scans. At the end of the study, a second radiologist (D.M.) who had 10 years experience reading liver CT scans and was blinded to the treatment given reread all of the images. Agreement was reached regarding the interpretation of all cases. Objective tumor response was assessed according to standard World Health Organization criteria (10). Each tumor was measured in two dimensions: its maximal diameter in the transverse plane and its largest perpendicular diameter on the same image. These diameters were multiplied to yield a cross product. The pretreatment and posttreatment cross products were compared to yield a treatment response, which was classified into one of four categories: complete response, indicating tumor disappearance; partial response, indicating a greater than 50% reduction in the cross product; disease progression, indicating a greater than 25% increase in the cross product; or stable disease, indicating a less than 50% reduction to a less than 25% increase in the cross product. For patients with multiple lesions, the cross product of several indicator lesions was added to categorize the patient's tumor response.
Biologic tumor response.—The biologic tumor response was determined by using serial measurements of plasma chromogranin A, plasma chromogranin B, 24-hour urinary 5-hydroxyindole acetic acid (5-HIAA) (for patients with carcinoid tumors only), and fasting gut hormones (for patients with biologically functioning pancreatic neuroendocrine tumors). In some patients, only the plasma chromogranin B levels were available for analysis because an established assay for chromogranin A level measurement was not available before the start of their treatments. The results were assessed (by M.K.G.M. and another physician) and reported as the change in the relevant biologic marker level between the pretreatment value and the value measured 8–12 weeks after the last treatment cycle.
Clinical response and performance status.—The patients assessed their treatments and clinical responses by completing a self-assessment questionnaire and during physician interviews conducted before the start of treatment and 8–12 weeks following each treatment cycle. The 10 clinical items they assessed included appetite; malaise; weight loss; and the presence and either the intensity or the frequency of abdominal pain, diarrhea, flushing, nausea and/or vomiting, fever, wheezing, and abdominal bloating. Any analgesic and somatostatin analog requirements before and after treatment were recorded in the physician notes. The patients' Eastern Cooperative Oncology Group performance status was assessed before and 8–12 weeks after treatment (by M.K.G.M., M.E.C., and J.R.B.).
Assessment of Safety
The monitoring of patients before treatment included complete blood counts, plasma creatinine and electrolyte level measurements, and liver function tests. These measurements were repeated at weekly intervals. Safety was assessed according to the degree of toxicity, which was graded by using National Cancer Institute common toxicity criteria (version 2.0). In patients who had grade 3 or greater hematologic toxicity (hemoglobin level < 8.0 g/dL, leukocyte count < 2.0 x 109/L, platelet count < 50 x 109/L), histologic examination of specimens obtained at trephine bone marrow biopsy was performed (by M.K.G.M., M.E.C., and J.R.B.).
Survival and Statistical Analyses
Kaplan-Meier survival curves were constructed by using statistical computer software (SPSS, version 11.0, 2001; SPSS, Chicago, Ill) to calculate the mean progression-free and overall survivals from the start of treatment. No control group was examined in this study; therefore, comparison with another treatment arm was not possible.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Treatment Effectiveness
Radiologic tumor responses.—At the initial CT assessment performed 3 months after the last treatment, three patients had a substantial reduction in tumor size (partial response), 12 had attained disease stability (ie, no change in the size of a previously growing tumor), and four had radiologic evidence of continued tumor progression (Table 2, Fig 2). The radiologic tumor response could not be assessed in the remaining four patients because they died before follow-up imaging could be performed. One of these patients (patient 9) had radiologic disease stabilization for 12 months following two cycles of therapy; however, the disease progressed clinically and the patient died 2 months after the third treatment, before he could undergo follow-up imaging. All four patients with nonassessable tumor response who died had clinical evidence of disease progression. One of the four patients who showed radiologic evidence of disease progression (patient 8) attained stabilization of the liver metastasis but developed progressive pelvic metastatic disease that required chemotherapy.
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After 12 months, one patient (patient 15) continued to have partial tumor response. Patient 1 developed tumor progression 9 months after treatment and died 2 months later. Six patients who had tumor stabilization at 3 months could be reassessed at 12 months following the last treatment: Patient 21 developed progressive pancreatic disease but continued to show liver metastasis tumor stability. Patient 5 had disease progression 6 months after treatment and died 1 month later. Patient 11 underwent PVA particle embolization at 9 months to control worsening symptoms of the carcinoid syndrome despite having no radiologic evidence of tumor progression. Patient 7 had radiologic evidence of disease progression after 12 months and underwent additional treatment with hepatic intraarterial 90Y-DOTA-lanreotide. The remaining two patients continued to have tumor stability.
Of the nine patients who underwent PVA particle embolization at the same time as 90Y-DOTA-lanreotide injection, eight underwent CT tumor response assessment. Two (25%) of these eight patients had a partial tumor response, and six (75%) had stable tumor disease. Of the 14 patients who underwent 90Y-DOTA-lanreotide intraarterial injection only, 11 underwent CT tumor response assessment: One patient (9%) had a partial response; six (54%), stable disease; and four (36%), progressive disease. In two of the 18 patients with metastatic carcinoid tumors and in two of the five patients with other tumor types, the tumor response could not be assessed at imaging. Of the three remaining patients with other tumor types, one had a partial response to therapy and two had progressive tumor disease.
Biologic tumor responses.—Five of the 23 patients had nonsecretory tumors and no elevation in tumor marker levels; therefore, their biologic responses to treatment could not be assessed. Three patients could not be assessed for biologic response because they died before a repeat measurement could be taken. Of the remaining patients, eight had reduced biologic marker levels only; four, increased biologic marker levels only; and three, decreased plasma chromogranin B levels but increased levels of vasoactive intestinal peptide, chromogranin A, or urinary 5-HIAA.
Clinical responses and performance status.—Of seven patients who reported having mild to severe abdominal pain before undergoing 90Y-DOTA-lanreotide treatment, four reported having reduced pain 8–12 weeks after the last treatment, with a reduction in analgesic medication requirements. All four of these patients had stable tumor disease. One patient reported having worse abdominal pain, and two reported having new abdominal pain; all three of these patients had progressive disease.
Ten patients reported having diarrhea (bowel movements more than three times a day) before undergoing treatment. Six of these patients were receiving somatostatin analogs. Seven of these patients, two of whom were receiving an increased dose of somatostatin analogs, reported having a reduced frequency of diarrhea after the final treatment. Of six patients who reported having flushing before undergoing treatment, four—two of whom were receiving an increased dose of somatostatin analogs—reported having a reduced frequency of flushing after treatment and two reported having no change in the frequency of flushing.
Three of seven patients who reported having weight loss before treatment gained weight after treatment. One patient with progressive disease reported new weight loss after the treatment. Four patients reported having an improved appetite, 13 reported having no change in appetite, and six reported having a reduced appetite following therapy. Three of 12 patients who reported having malaise before treatment reported having a reduced extent of this symptom, and one patient, who had progressive disease, described having new malaise. Only two patients reported having nausea and vomiting before undergoing treatment, and one of them reported having a lower degree of this symptom after treatment. Two patients had fevers before undergoing treatment, and in one of these patients, the fevers resolved after treatment. Only one patient reported having abdominal bloating before undergoing treatment, which did not lessen after treatment. No patient reported wheezing before undergoing treatment.
Four patients had an improved Eastern Cooperative Oncology Group performance status after treatment. Eleven patients had no change in performance status, and six—all of whom had progressive disease—had a lower performance status after treatment.
Safety
There were no serious periprocedural morbidities. After treatment with 90Y-DOTA-lanreotide, two patients (patients 1 and 9) developed acute renal impairment—probably secondary to sepsis—which was resolved by means of treatment with fluids, antibiotics, and intravenous N-acetylcysteine. After the procedure, five patients developed abdominal pain, nausea, pyrexia, and a transient elevation in liver enzymes (ie, postembolization syndrome) (11), which were probably secondary to tumor necrosis. All of these patients had undergone concurrent PVA particle embolization. Blood cultures obtained from these patients were negative for bacterial growth. These patients were treated with broad-spectrum antibiotics and analgesics and improved clinically within 72 hours. One patient developed atrial fibrillation with a fast ventricular response 2 hours after treatment. This patient also had undergone concurrent PVA particle embolization. Fourteen days after the 90Y-DOTA-lanreotide therapy, another patient who had undergone concurrent particle embolization required hospitalization for treatment of an infected necrotic liver metastasis, which resolved after administration of intravenous antibiotics.
Three patients developed hematologic toxicity (National Cancer Institute common toxicity criteria grade 3 or higher) owing to bone marrow suppression caused by 90Y-DOTA-lanreotide: Two of these patients had a carcinoid tumor, and one had a pancreatic endocrine tumor. One patient (patient 14) developed grade 3 anemia, grade 4 leukopenia, and grade 4 thrombocytopenia 3 weeks after treatment with 1.5 GBq of 90Y-DOTA-lanreotide. She presented with gum bleeding and required hospitalization for transfusion with red blood cells and platelets. Her hematologic indexes returned to normal completely within 8 weeks. A second patient (patient 1) developed grade 3 anemia and grade 3 thrombocytopenia a week after treatment. The low blood cell counts returned to normal within 4 weeks. The third patient (patient 12) developed grade 4 anemia, grade 3 leukopenia, and grade 3 thrombocytopenia 4 weeks after her second dose of 90Y-DOTA-lanreotide (1.2 GBq). She also required hospitalization for blood transfusion. Bone marrow trephine biopsy results confirmed hypocellularity. Her red and white blood cell counts returned to normal within 8 weeks; however, the thrombocytopenia persisted. This patient died 6 months after the last treatment.
Survival and Statistical Analyses
At 6 months after the start of therapy there were three deaths, all of which were due to disease progression. By 12 months, there were five more deaths, one (of patient 2) of which was not related to cancer. At the time of analysis, three additional deaths had occurred: One patient's (patient 9) death was related to hepatic decompensation secondary to tumor load, and the other two deaths were related to tumor progression. Therefore, a total of 11 (48%) of the 23 patients died during a 15-month period. At the time of analysis, from the start of 90Y-DOTA-lanreotide treatment, the median progression-free survival time was 9 months (mean, 12 months; standard error of the mean, 2 months) and the median survival time was 15 months (mean, 15 months; standard error of the mean, 2 months) (Fig 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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The selection of the carrier molecule lanreotide, a somatostatin analog that binds with high affinity to cell-surface somatostatin receptors 2–5, means that the therapeutic radioisotope selected must have a relatively long particle length to reach the nucleus and cause cell death. The high-energy ß emitter 90Y is an ideal labeling radioisotope: It has a particle length that extends across 50–70 cell diameters, and, thus, it can easily reach the nucleus and facilitate crossfire between adjacent cells. Intercell crossfire helps to overcome the problems encountered with heterogeneous radiopharmaceutical uptake that are caused by poor tumor vascularity, high interstitial pressure, and central necrosis in larger lesions.
All of the patients in this study had large-volume bilobar metastatic liver disease that was progressive in nature. At the time of analysis, three (16%) of the 19 patients in whom the tumor response was assessed at imaging had a partial response to the treatment of their liver metastasis with hepatic intraarterial 90Y-DOTA-lanreotide, and the response was maintained for a median period of 9 months (mean, 9 months ± 4). An additional 12 (63%) of the 19 patients had a period of tumor stability with no tumor growth for a median period of 14 months (mean, 13.2 months ± 6.1) after the last treatment. Therefore, almost 80% (15 of 19) of the patients showed some radiologic benefit from the treatment. These response rates are an improvement from the reported results of using intravenous 90Y-DOTA-lanreotide in the MAURITIUS study, in which 14% of the patients had regressive tumor disease and 41% had stable disease, and were achieved by using much lower cumulative treatment doses of 90Y-DOTA-lanreotide.
The subgroup of patients who underwent concurrent PVA particle embolization at the same time as 90Y-DOTA-lanreotide administration had a better tumor response rate than did the patients who underwent treatment with 90Y-DOTA-lanreotide only. These results indicate that tumor ischemia caused by concurrent embolization improves the response to 90Y-DOTA-lanreotide. Although it is known that small tumor foci surrounding the main embolized tumor may grow after embolization, in our study the 90Y-DOTA-lanreotide acted in an adjuvant setting, destroying nests of these cells and either preventing or slowing tumor regrowth. In this situation, it is not possible to know whether the isotope or the embolization produced the better response, and this was a limitation of the study. However, three of four patients in whom previous treatment with hepatic arterial embolization was ineffective went on to undergo hepatic intraarterial 90Y-DOTA-lanreotide injection only, and two of these patients had a stable tumor response; one patient's tumor response could not be assessed. Also, the patients who did not undergo concurrent embolization were in poorer physical condition—they often had larger hepatic tumor loads—than were the patients who received PVA particles, and this factor may have influenced responses to therapy.
Overall objective partial tumor response rates of 33%–86% have been reported for patients with liver metastases from neuroendocrine tumors following treatment with hepatic arterial embolization performed either alone or in combination with chemotherapy (2,11–19). However, a direct comparison between the results of our study and those of the other studies was not possible because most of the other investigations included patients at all stages of disease and some of them included patients who did not have radiologic evidence of disease progression.
In this series, 60% (nine of 15) of the patients who could be assessed had reduced biologic marker levels at 8–12 weeks after 90Y-DOTA-lanreotide therapy. Sixty-one percent (14 of 23) of the patients reported having clinical improvements after treatment. Of the patients who reported having abdominal pain, diarrhea, and flushing before undergoing treatment, 57% (four of seven), 70% (seven of 10), and 67% (four of six), respectively, reported improvements. These subjective response rates compare favorably with those reported following treatment for advanced progressive neuroendocrine tumors with high-dose 90Y-DOTA tyrosine 3 (3Tyr)-octreotide, which also yielded high subjective response rates (reduced diarrhea in 83% of cases and reduced flushing in 46% of cases) (20).
The number of patients enrolled in the study was small. This factor was a limitation of the study and makes it difficult to perform further subgroup comparisons between the patients with carcinoid tumors and those with pancreatic neuroendocrine tumors and between the patients who underwent concurrent PVA particle embolization and those who underwent hepatic intraarterial 90Y-DOTA-lanreotide injection only. However, neuroendocrine tumors are relatively rare, and this investigation was an initial pilot study. An additional limitation was the fact that there was no control group for statistical comparison. A comparison between the patients and control subjects from other studies was not attempted because of the inherent problems of performing this type of comparison, particularly differences in case mix.
The 90Y-DOTA-lanreotide treatments were generally well tolerated. Five (56%) of nine patients who underwent concurrent PVA particle embolization developed the postembolization syndrome. These minor side effects are common following embolization and can usually be easily controlled, but they may persist for several days (11). Reversible hematologic toxicity (National Cancer Institute common toxicity criteria grade 3 or 4) due to bone marrow suppression occurred in three (13%) patients. Two of these three patients previously had undergone multiple treatment cycles with intravenous 90Y-DOTA-lanreotide or intravenous 90Y-DOTA-octreotide, and one patient was undergoing concurrent treatment with interferon alfa. All high-activity radionuclide therapies result in some degree of reversible myelosuppression, the rate of recovery of which is partly dose related but depends more on the underlying bone marrow reserve (21). Increased toxicity is therefore more likely to occur in patients who have extensive bone metastases; in patients who have been heavily pretreated with chemotherapy, intravenous targeted radiation therapy, and/or external-beam radiation therapy; and in patients who are undergoing concurrent therapy with interferon alfa. The development of hematologic toxicity in these two patients was therefore not surprising.
Waldherr et al (20) also observed hematologic toxicity following treatment with high-dose 90Y-DOTA 3Tyr-octreotide: 23% of patients developed National Cancer Institute common toxicity criteria grade 3 or 4 lymphopenia, and 3% developed grade 3 anemia. de Jong et al (22) reported the development of a myelodysplastic syndrome in 7.5% of patients with different types of somatostatin receptor–positive tumors who were treated with high-dose 111In-diethylenetriaminepentaacetic acid–octreotide. There were no treatment-related deaths, and this finding compares favorably with the reported mortality rates in other studies of hepatic intraarterial particle embolization of neuroendocrine metastases (1,18).
In conclusion, hepatic intraarterial injection of 90Y-DOTA-lanreotide is a safe and effective palliative treatment for patients with progressive large-volume somatostatin receptor–positive liver metastases from neuroendocrine tumors. Further investigations that include comparative dosimetry with intravenous 90Y-DOTA-lanreotide therapy, as well as studies to compare the effectiveness of 90Y-DOTA-lanreotide with that of chemoembolization, are appropriate.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: DOTA = tetraazacyclododecane tetraacetic acid • 5-HIAA = 5-hydroxyindole acetic acid • PVA = polyvinyl alcohol
Authors stated no financial relationship to disclose
Author contributions: Guarantors of integrity of entire study, M.E.C., J.R.B.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, M.K.G.M., M.E.C., J.R.B.; clinical studies, all authors; statistical analysis, M.K.G.M., J.R.B.; and manuscript editing, M.K.G.M., M.W., M.E.C., J.R.B.
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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