Radiation doses of yttrium-90 citrate and yttrium-90 EDTMP as determined via analogous yttrium-86 complexes and positron emission tomography

Yttrium-90 is used for palliative therapy for the treatment of skeletal metastases, but because it is a pure - emitter, data on the pharmacokinetics and radiation doses to metastases and unaffected organs are lacking. To obtain such data, the present study employed yttrium-86 as a substitute for⁹⁰Y, with detection by positron emission tomography (PET). The study compared the properties of two different⁸⁶Y complexes —⁸⁶y-citrate and⁸⁶Y -ethylene diamine tetramethylene phosphonate (EDTMP) — in ten patients with prostatic cancer who had developed multiple bone metastases (the ten patients being divided into two groups of five). Early dynamics were measured up to 1 h post injection (p.i.) over the liver region, followed by subsequent whole-body PET scans up to 3 days p.i. Absolute uptake data were determined for normal bone, bone metastases, liver and kidney. Radiation doses were calculated according to the MIRD recommendations. Based on the pharmacokinetic measurements of the distribution of the⁸⁶Y complexes, it was possible to calculate radiation doses for the bone metastases and the red bone marrow delivered by complexes containing⁹⁰Y. In 1 cm³ of bone metastasis, doses of 26±11 mGy/MBq and 18±2 mGy/MBq were determined per MBq of injected⁹⁰Y- citrate and⁹⁰Y- EDTMP, respectively. The doses to the bone marrow were 2.5±0.4 mGy/MBq for⁹⁰Y- citrate and 1.8±0.6 mGy/MBq for⁹⁰Y-EDTMP.⁸⁶Y and PET provide quantitative information applicable to the clinical use of⁹⁰Y. This method may also be useful for the design of other⁹⁰Y radiopharmaceuticals and for planning radiotherapy dosages.     

Biokinetics and dosimetry in patients administered with 111In-DOTA-Tyr3-octreotide: implications for internal radiotherapy with 90Y-DOTATOC

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe¹-Tyr³-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with ⁹⁰Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 μg), labelled with 150–185 MBq of ¹¹¹In. Blood and urine samples were collected throughout the duration of the study (0–2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3–4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ μmol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for ¹¹¹In-DOTATOC in blood was 0.9±0.4 h. The injected activity excreted in the urine in the first 24 h was 73%±11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2±1.8 h in spleen, 1.7±1.2 h in kidneys, 2.4±1.9 h in liver, 1.5±0.3 h in urinary bladder and 9.4±5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03–6.50 h). Based on our findings, the predicted absorbed doses for ⁹⁰Y-DOTATOC would be 7.6±6.3 (spleen), 3.3±2.2 (kidneys), 0.7±0.6 (liver), 2.2±0.3 (bladder), 0.03±0.01 (red marrow) and 10.1 (range: 1.4–31.0) (tumour) mGy/MBq. These results indicate that high activities of ⁹⁰Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the disired therapeutic response desired would be obtained. Received 17 February and in revised form 22 April 1999     

Combined treatment of advanced oropharyngeal cancer with external radiotherapy and three-step radioimmunotherapy

The prognosis of patients with locally advanced head and neck cancer remains grim due to poor locoregional tumour control. In the attempt to eradicate residual disease, various novel modalities have been tested, among which radioimmunotherapy (RIT) has shown some potential. We present a case of locally advanced oropharyngeal carcinoma successfully treated with a combination of various treatments including surgery, radio-chemotherapy and three-step RIT, with the avidin-biotin pretargeting system. A partial tumour response was achieved after surgery and radio-chemotherapy; persistent disease was documented at computed tomography (CT), ultrasound (US) and immunoscintigraphy (ISG) 10 weeks after the end of chemo-radiotherapy. The good correlation between the tracer localization in the scintigraphic images and residual mass visualized at CT suggested the application of three-step RIT using systemic administration of yttrium-90 (py) biotin. At present, 17 months after RIT, the patient is alive with no evidence of disease as documented by magnetic resonance imaging (MRI) and US. This is the first case of complete clinical remission of a head and neck carcinoma induced by combined treatment including pretargeted RIT with ⁹⁰Y-biotin. Received 15 May and in revised form 22 May 1998     

Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-dPhe1-Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

[⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide ([⁹⁰Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [⁸⁶Y]DOTA-dPhe¹-Tyr³-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [⁸⁶Y]DOTA-dPhe¹-Tyr³-octreotide was administered at two different peptide concentrations, namely 2 and 100 μg peptide per m² body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [⁸⁶Y]DOTA-dPhe¹-Tyr³-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1–3.3 mGy per MBq [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide injected. For the 100 μg/m² SMT487 protocol with amino acid co-infusion this dose was about 20%–40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide, respectively. The average effective dose equivalent amounted to 0.23–0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [⁹⁰Y]DOTA-dPhe¹-Tyr³-octreotide in patients with somatostatin receptor-expressing tumours. Received 26 September and in revised form 18 November 1998     

Preparation and evaluation of 89Zr-Zevalin for monitoring of 90Y-Zevalin biodistribution with positron emission tomography

Purpose To evaluate whether ⁸⁹Zr can be used as a PET surrogate label for quantification of ⁹⁰Y-ibritumomab tiuxetan (⁹⁰Y-Zevalin) biodistribution and dosimetry before myeloablative radioimmunotherapy.Methods Zevalin was labelled with ⁸⁹Zr by introducing N-succinyldesferal (N-sucDf) as a second chelate. For comparison of the in vitro stability of ⁸⁹Zr-Zevalin and ⁸⁸Y-Zevalin (as a substitute for ⁹⁰Y), samples were incubated in human serum at 37°C up to 6 days. Biodistribution of ⁸⁹Zr-Zevalin and ⁸⁸Y-Zevalin was assessed at 24, 48, 72 and 144 h p.i. by co-injection in nude mice bearing the non-Hodgkin’s lymphoma (NHL) xenograft line Ramos. The clinical performance of ⁸⁹Zr-Zevalin-PET was evaluated via a pilot imaging study in a patient with NHL, who had undergone [¹⁸F]FDG-PET 2 weeks previously.Results Modification of Zevalin with N-sucDf resulted in an N-sucDf-to-antibody molar ratio of 0.83±0.04. After radiolabelling and purification, the radiochemical purity and immunoreactivity of ⁸⁹Zr-Zevalin always exceeded 95% and 80%, respectively. ⁸⁹Zr-Zevalin showed the same stability in serum as ⁸⁸Y-Zevalin, with a radiochemical purity >95% during a period of 6 days. The co-injected ⁸⁹Zr-Zevalin and ⁸⁸Y-Zevalin conjugates showed a very similar biodistribution, except for liver and bone accumulation at 72 and 144 h p.i., which was significantly higher for ⁸⁹Zr than for ⁸⁸Y. PET images obtained after injection of ⁸⁹Zr-Zevalin showed clear targeting of all known tumour lesions.Conclusion ⁸⁹Zr-Zevalin and ⁸⁸Y-Zevalin showed a very similar biodistribution in mice, implying that ⁸⁹Zr-Zevalin-PET might be well suited for prediction of ⁹⁰Y-Zevalin biodistribution in a myeloablative setting.     

90Y树脂微球治疗在临床应用中的放射防护研究

目的 探讨⁹⁰Y树脂微球治疗在临床应用中的放射防护措施。方法 模拟⁹⁰Y树脂微球治疗手术流程,通过监测术前药物分装准备、药物转运、术中药物操作和输注、术后患者住院观察各个阶段周围剂量当量率水平,分析临床应用中所应采取的放射防护措施。结果 活性室周围剂量当量率水平为0.12~0.42 μSv/h,通风橱周围剂量当量率为1.04~3.32 μSv/h。数字减影血管造影(DSA)室在⁹⁰Y+DSA扫描时最高为0.78 μSv/h,在⁹⁹Tc^m+DSA时最高为 0.36 μSv/h; 透视防护区在⁹⁰Y药物时在第一术者位155 cm高度为13.19 μSv/h,而在⁹⁰Y+DSA扫 描时最高为80 cm高度处315.01 μSv/h。第二术者位在⁹⁰Y药物时最高为155 cm高度为6.28 μSv/h, ⁹⁰Y+DSA 扫描时最高为155 cm高度处291.03 μSv/h。患者病房周围剂量当量率为0.11~0.58 μSv/h。 结论 核医学科及介入室等原有屏蔽措施能够满足⁹⁰Y树脂微球治疗的放射防护要求,但仍需根据实际情况进行科学评估,同时应加强药物操作中的放射防护及表面污染处理措施。     

Cherenkov counting of yttrium-90 in the dry state; correlations with phosphorus-32 Cherenkov counting data

We present data that illustrate some advantages of Cherenkov counting for the radioassay of ⁹⁰Y in the dry state and provide recommendations concerning sample counting geometry. Slightly higher detection efficiencies and figures-of-merit were obtained when counting ⁹⁰Y in the dry state in polyethylene plastic counting vials compared to the counting of ⁹⁰Y in 20 ml of water in borosilicate glass vials. The effects of polyethylene plastic counting vials and sample counting geometry are compared to similar data obtained in the Cherenkov counting of ³²P. Data are presented to interpret the effects of polyethylene plastic and borosilicate glass on Cherenkov counting efficiency and background counts. Applications of the Cherenkov counting of ⁹⁰Y and ³²P in the dry state in the biological and radiopharmaceutical sciences are foreseen as well as applications in the analysis of ⁹⁰Sr(⁹⁰Y) and ³²P in health physics and environmental monitoring.     

Preparation and biodistribution of yttrium-90 Lipiodol in rats following hepatic arterial injection

In this study, we labelled Lipiodol with yttrium-90 and analysed the biodistribution in rats after intrahepatic arterial injection. An RP-18 column (E. Merck) was used to separate⁹⁰Y from strontium-90.⁹⁰Y was retained on the column, which had been pretreated with yttrium-selective extraction reagent, di(2-ethylhexyl) phosphate, while⁹⁰Sr was washed out. A hexadentate nitrogen-donor chelating ligandN,N,N,N-tetrakis(2-ben-zymidazolylmethyl)-1,2-ethanediamine (EDTB) was synthesized by condensation of 1,2-benzenediamine and ethylene diamine tetra-acetic acid (EDTA). Lipiodol was covalently conjugated with EDTB. The final product was obtained by eluting the retained⁹⁰Y from the RP-18 column with EDTB-Lipiodol. Sixteen male rats (Sprague-Dawley) were sacrificed at 1 h, 24 h, 48 h and 72 h (four rats at each time) after injection of approximately 0.1 mCi⁹⁰Y Lipiodol via the hepatic artery. Samples of liver, spleen, muscle, lung, kidney, bone, whole blood and testis were obtained and counted to calculate the tissue concentrations. In addition, labelling efficiency and in vitro stability were determined by ITLC methods. We found that at 1 h after intrahepatic injection, most of the radiotracer was retained in the liver, but it was eliminated gradually over a few days. The radioactivity level in the lung was fair at 1 h and remained at roughly the same level throughout the study. Radioactivity in the kidney and spleen reached a relatively high level at 24 h, but declined rapidly. Bone uptake was low initially but showed an increase between 24 h and 72 h. Low concentrations of radioactivity were noted in the muscle, testis and whole blood. In the study of in vitro stability, radiochemical purity and labelling efficiency were higher than 90%, indicative of good stability. These initial results indicate that Lipiodol may be a possible carrier agent for⁹⁰Y The retention of⁹⁰Y-Lipiodol in the normal liver is high initially; however, elimination occurs over a period of a few days. Future studies should assess the biodistribution of⁹⁰Y Lipiodol in an animal model with liver cancer.     

Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours

A uniform distribution of yttrium-90 (⁹⁰Y) microspheres throughout the entire liver has always been assumed for dose calculation in treating hepatic tumours. A simple mathematical model was formulated which allows estimation of the activities of a therapeutic dose of⁹⁰Y microspheres partitioned between the lungs, the tumour and the normal liver, and hence the radiation doses to them. The doses to the tumour and normal liver were verified by intra-operative direct beta-probing. The percentage of activity shunted to the lung and the tumour-to-normal tissue ratio (T/N) were obtained from gamma scintigraphy using technetium-99m-labelled macroaggregated albumin (MAA) which simulates the⁹⁰Y microspheres used in subsequent treatment. The intrahepatic activity was partitioned between the tumour and the normal liver based on the T/N and their masses determined from computerized tomography slices. The corresponding radiation doses were computed using the MIRD formula. The estimated radiation doses were correlated with the doses directly measured using a calibrated beta-probe at laparotomy by linear regression. The radiation doses to the tumour and the normal liver, estimated using the partition model, were close to that measured directly with coefficients of correlation for linear regression: 0.862 for the tumours and 0.804 for the normal liver compartment (P<0.001). The partition model permits a distinction between the radiation doses received by the tumour and the normal liver to be made and the doses thus estimated are close to the actual doses received. The optimal doses to the tumour and normal liver and hence the required quantity of⁹⁰Y microspheres to be administered can be easily predetermined.     

Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer

Radiation doses to the tumour and non-tumorous liver compartments from yttrium-90 microspheres in the treatment of hepatic cancer, as estimated by a partition model, have been verified by correlation with the actual doses measured with a beta probe at open surgery. The validity of the doses to the lungs, the tumour and non-tumorous liver compartment as estimated by the partition model was further evaluated in clinical settings. On the basis of the observation that one of three patients who received more than 30 Gy from a single treatment and one of two patients who received more than 50 Gy from multiple treatments developed radiation pneumonitis, it was deduced that an estimated lung dose <30 Gy from a single treatment and a cumulative lung dose <50 Gy from multiple treatments were probably the tolerance limits of the lungs. Three of five patients who received lung doses >30 Gy as estimated by the partition model and were predicted to develop radiation pneumonitis, did so despite the use of partial hepatic embolization to reduce the degree of lung shunting. Furthermore, a higher radiological response rate and prolonged survival were found in the group of patients who received higher tumour doses, as estimated by the partition model, than in the group with lower estimated tumour doses. Thus the radiation doses estimated by the partition model can be used to predict (a) complication rate, (b) response rate and (c) duration of survival in the same manner as the actual radiation doses measured with a beta probe at open surgery. The partition model has made selective internal radiation therapy using⁹⁰Y microspheres safe and repeatable without laparotomy.     

Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin

While the incidence of brain tumours seems to be increasing, median survival in patients with glioblastoma remains less than 1 year, despite improved diagnostic imaging and neurosurgical techniques, and innovations in treatment. We have developed an avidin-biotin pre-targeting approach for delivering therapeutic radionuclides to gliomas, using anti-tenascin monoclonal antibodies, which seems potentially effective for treating these tumours. We treated 48 eligible patients with histologically confirmed grade III or IV glioma and documented residual disease or recurrence after conventional treatment. Three-step radionuclide therapy was performed by intravenous administration of 35 mg/m² of biotinylated anti-tenascin monoclonal antibody (1st step), followed 36 h later by 30 mg of avidin and 50 mg of streptavidin (2nd step), and 18–24 h later by 1–2 mg of yttrium-90-labelled biotin (3rd step). ⁹⁰Y doses of 2.22–2.96 GBq/m² were administered; maximum tolerated dose (MTD) was determined at 2.96 GBq/m². Tumour mass reduction (>25%–100%), documented by computed tomography or magnetic resonance imaging, occurred in 12/48 patients (25%), with 8/48 having a duration of response of at least 12 months. At present, 12 patients are still in remission, comprising four with a complete response, two with a parital response, two with a minor response and four with stable disease. Median survival from ⁹⁰Y treatment is 11 months for grade IV glioblastoma and 19 months for grade III anaplastic gliomas. Avidin-biotin based three-step radionuclide therapy is well tolerated at the dose of 2.2 GBq/m², allowing the injection of ⁹⁰Y-biotin without bone marrow transplantation. This new approach interferes with the progression of high-grade glioma and may produce tumour regression in patients no longer responsive to other therapies. Received 9 September and in revised form 15 November 1998     

Mixed-ligand complexes of yttrium-90 dialkyldithiocarbamates with 1,10-phenanthroline as a possible agent for therapy of hepatocellular carcinoma

Yttrium-90 is a radioelement which has found wide use in targeted radionuclide therapy because of its attractive physical and chemical properties. Radioembolisation of hepatocellular carcinoma with radiolabelled Lipiodol is a method of choice. We have synthesised a series of alkyldithiocarbamate yttrium complexes, easily extracted into Lipiodol due to their high lipophilicity. Among the prepared series, a new radioconjugate, which is stable over an extended period of time, has been prepared, and could represent a potential treatment procedure for hepatocellular carcinoma.     

Phase I/II 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin’s lymphoma

Dosimetry studies in patients with non-Hodgkin’s lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from ⁹⁰Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of ⁹⁰Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received ¹¹¹In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of ⁹⁰Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of ¹¹¹In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n =56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2–7.8 Gy), 2.6 Gy to lungs (range 0.72–4.4 Gy), and 0.38 Gy to kidneys (range 0.07–0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8–67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T _1/2, blood AUC, plasma T _1/2, and plasma AUC. It is concluded that ⁹⁰Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T _1/2, reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population. Received 24 January and in revised form 20 March 2000     

Radioembolization with Yttrium-90 resin microspheres in treatment of HCC with or without PVT: Initial Egyptian experience

Background/Aim

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. Radioembolization with yttrium-90 (Y-90) microspheres is a new concept in radiation therapy for HCC. The aim of this study is to evaluate efficacy, side effects, and future direction of Y-90 therapy, using TheraSphere®, in patients with HCC with or without PVT.

Patients and methods

Forty patients were presented by hepatocellular carcinoma most of them with portal vein thrombosis and were treated with Y-90 resin microspheres (SIR-TeX®).

Results

At one month after treatment the overall response (complete or partial response) was exhibited by 9% of patients, stable disease exhibited by 80% of patients, progressive disease seen in 11% of patients.

Conclusion

Radioembolization with Y-90 resin microspheres offers a favorable risk/benefit profile for patients presenting with locally advanced unresectable HCC with or without PVT and good liver function.     

Indium-111-labelled liposomes: dosimetry and tumour detection in patients with cancer

Neutral phospholipid vesicles (VesCan), which had been prepared for clinical use, were loaded with 37 MBq indium-111 and administered to seven patients with malignant tumours. The median lipid dose was 2.0 mg/kg. Sequential images showed rapid blood clearance at the early stage, with homogeneous uptake of ¹¹¹In-labelled VesCan (¹¹¹In-labelled V-liposomes) in the liver and spleen. Dosimetric estimates for these organs were 1.2 and 1.5 mGy/MBq, respectively, with a whole-body exposure dose of 0.076 mGy/MBq. Total renal excretion of ¹¹¹In was less than 10% of the injected dose, occurring mainly as ¹¹¹In-EDTA in three patients. Gamma camera images 24–48 h after administration revealed increased activity in the tumours of four patients. ¹¹¹In-labelled V-liposomes may enable the demonstration of the tumour site without toxicity and with radiation doses comparable to other radionuclide imaging techniques. Correspondence to: A. Kubo     

Sector analysis of dosimetry of prostate cancer patients treated with low-dose-rate brachytherapy

PurposeBrachytherapy is an effective single treatment modality for low- and intermediate-risk prostate cancer. Here, we compare the radiation doses in different prostate sectors between the preimplant planning images and the postimplant dosimetry.Methods and MaterialsTwo hundred fifteen consecutive patients treated for prostate cancer by ¹²⁵I seed brachytherapy were assessed. Pretreatment plans using transrectal ultrasound images of the prostate were compared with the dose calculated on posttreatment MRI and CT scans obtained 1 month after seed implantation. Twelve sectors were generated by dividing the prostate base, midgland, and apex into four quadrants each. Pretreatment and posttreatment dosimetry were compared between the 12 different sectors of the prostate.ResultsAverage V₁₀₀ (percentage of prostate volume that receives 100% of the prescribed dose) in the preimplant planning images of the prostate was 99.9 ± 0.25% compared with postimplant V₁₀₀ of 94.8 ± 3.77% (p < 0.0001). Prostate V₁₀₀ in the postimplant dosimetry was >91% in all sectors, except the anterior base sector, in which it was 64.87 ± 20.96%. Average 1-month D₉₀ (the dose to 90% of the prostate volume) was 114.5 ± 10.55%. D₉₀ at 1 month compared with preimplant planning was lower in the prostate base and higher in the prostate apex (p < 0.001).ConclusionsOur results show that in ¹²⁵I seed brachytherapy, prostate base receives a lower dose and apex receives a higher dose compared with preimplant planned dose coverage.     

Radioembolization with 90Y Microspheres: Angiographic and Technical Considerations

The anatomy of the mesenteric system and the hepatic arterial bed has been demonstrated to have a high degree of variation. This is important when considering pre-surgical planning, catheterization, and trans-arterial hepatic therapies. Although anatomical variants have been well described, the characterization and understanding of regional hepatic perfusion in the context of radioembolization have not been studied with great depth. The purpose of this review is to provide a thorough discussion and detailed presentation of the angiographic and technical aspects of radioembolization. Normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors are discussed. Furthermore, the principles described here apply to all liver-directed transarterial therapies. R.S. and J.-F.G. are consultants for MDS Nordion. R.M., D.L., L.B., and J.I.B. are proctors for Sirtex Medical. A.S.K. has received honoraria from MDS Nordion and Sirtex Medical. This work was not funded.     

Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer

Purpose

Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies (bsMAb) and a radiolabeled peptide reduces the radiation dose to normal tissues. Here we report the accuracy of an ¹¹¹In-labeled pretherapy test dose for personalized dosing of ¹⁷⁷Lu-labeled IMP288 following pretargeting with the anti-CEA × anti-hapten bsMAb, TF2, in patients with metastatic colorectal cancer (CRC).

Methods

In 20 patients bone marrow absorbed doses (BMD) and doses to the kidneys were predicted based on blood samples and scintigrams acquired after ¹¹¹In-IMP288 injection for individualized dosing of PRIT with ¹⁷⁷Lu-IMP288. Different dose schedules were studied, varying the interval between the bsMAb and peptide administration (5 days vs. 1 day), increasing the bsMAb dose (75 mg vs. 150 mg), and lowering the peptide dose (100 μg vs. 25 μg).

Results

TF2 and ¹¹¹In/¹⁷⁷Lu-IMP288 clearance was highly variable. A strong correlation was observed between peptide residence times and individual TF2 blood concentrations at the time of peptide injection (Spearman’s ρ?=?0.94, P?<?0.0001). PRIT with 7.4 GBq ¹⁷⁷Lu-IMP288 resulted in low radiation doses to normal tissues (BMD <0.5 Gy, kidney dose <3 Gy). Predicted ¹⁷⁷Lu-IMP288 BMD were in good agreement with the actual measured doses (mean?±?SD difference ?0.0026?±?0.028 mGy/MBq). Hematological toxicity was mild in most patients, with only two (10 %) having grade 3–4 thrombocytopenia. A correlation was found between platelet toxicity and BMD (Spearman’s ρ?=?0.58, P?=?0.008). No nonhematological toxicity was observed.

Conclusion

These results show that individual high activity doses in PRIT in patients with CEA-expressing CRC could be safely administered by predicting the radiation dose to red marrow and kidneys, based on dosimetric analysis of a test dose of TF2 and ¹¹¹In-IMP288.     

Yttrium-90 DOTATOC: first clinical results

In a pilot study, DOTA-d-Phe¹-Tyr³-octreotide (DOTATOC), which can be labelled with the β-emitting radioisotope yttrium-90, has recently been used for the treatment of patients with advanced somatostatin receptor-positive tumours who had no other treatment option. The aim of the present study was to elucidate the therapeutic potential of ⁹⁰Y-DOTATOC in a larger number of patients employing a standardized treatment protocol. Careful attention was paid to any side-effects (renal and/or haematological toxicity). Of 44 patients with advanced somatostatin receptor-positive tumours of different histology, 29 could be included in the study. The 15 patients who were excluded from the study protocol were assigned to our institution for purely compassionate reasons. The 29 patients who were included received four or more single doses of ⁹⁰Y-DOTATOC with ascending activity at intervals of approximately 6 weeks (cumulative dose 6120±1347 MBq/m²) with the aim of performing an intra-patient dose escalation study. In total, 127 single treatments were given. In eight of these 127 single treatments, total doses of ≥3700 MBq were administered. In an effort to prevent renal toxicity, two patients received Hartmann-Hepa 8% solution during all therapy cycles, while 13 patients did so during some but not all therapy cycles; in 14 patients no solution was administered during the therapy cycles. The treatment was monitored by computed tomography and indium-111 DOTATOC scintigraphy. Blood parameters were controlled weekly, while tumour markers and liver enzymes were controlled 6-weekly. Of the 29 patients, 24 patients showed no severe renal or haematological toxicity (toxicity ≤ grade 2 according to the National Cancer Institute grading criteria). These 24 patients received a cumulative dose of ≤7400 MBq/m². Five patients developed renal and/or haematological toxicity. All of these five patients received a cumulative dose of >7400 MBq/m² and had received no Hartmann-Hepa 8% solution during the therapy cycles. Four of the five patients developed renal toxicity; two of these patients showed stable renal insufficiency and two require haemodialysis. Two of the five patients exhibited anaemia (both grade 3) and thrombopenia (grade 2 and 4, respectively). To date, 20 of the 29 patients have shown a disease stabilization, two a partial remission, four a reduction of tumour mass <50% and three a progression of tumour growth. ⁹⁰Y-DOTATOC could be a powerful and promising new therapeutic agent for anti-cancer treatment – at least in terms of an adjuvant starting point of the disease. However, problems with toxicity have to be solved. Evaluation of the effect of amino acid infusions (e.g. Hartmann-Hepa 8% solution) during ⁹⁰Y-DOTATOC treatments with the aim of reducing renal toxicity is ongoing. Received 12 February and in revised form 16 May 1999     

Kinetics and dosimetry of iodine-131-labelled antibody fragments after local administration in patients with rectal cancer

In 11 patients with rectal cancer, a mixture of F(ab)₂ fragments of anti-carcinoembryonic antigen and anti-CA 19.9 labelled with a diagnostic dose of iodine-131 (3–10 MBq) was administered submucosally around the tumour. In this study, the local kinetics in and the dose to the rectal wall, the whole body kinetics and the effective dose equivalent are presented. The early disappearance of the activity from the injection spot was characterized by a T _1/2 of 21 h. Initially, about 50% of the plasma activity was due to free ¹³¹I. After 4 h, the plasma activity was almost completely protein bound (86%). Maximum plasma activity was observed after the 2nd day. From 72 h p.i., the plasma activity decreased with a T _1/2 of 53 h. In the first 24 h, 14% of the injected dose was excreted in the urine and within 4 days about half of the administered activity. The absorbed radiation dose to the rectal wall was estimated to be 0.2 Gy/MBq, presuming a 20 cm³ distribution volume. The dose to the bone marrow was 0.2 mGy/MBq or 0.4 mGy/MBq, assuming a homogeneous tracer distribution or equal blood and bone marrow activity concentrations, respectively. The effective dose equivalent is 1.9 mSv/MBq, mainly determined by the dose to the rectal wall and to a lesser extent by the dose to the remaining body. Postulating comparable kinetics, ¹²³I- or ¹¹¹In- or ^99mTc-labelled fragments would result in 4-25-fold lower effective dose equivalents. We conclude that the theoretical advantages of the local administration of ¹³¹I-labelled antibodies for diagnostic purposes in patients with rectal cancer are not limited by our dosimetric data. Nevertheless, we advocate the use of other radiolabels with more appropriate imaging qualities and probably a lower radiation burden. Offprint requests to: E.J. Derksen