Mahila Ferrari

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

Abstract. 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.

Pre-Targeted Locoregional Radioimmunotherapy with 90Y-biotin in Glioma Patients: Phase I Study and Preliminary Therapeutic Results

The aim of this study was to determine the maximum-tolerated dose, of a pre-targeting three-step (3-S) method employing 90Y-biotin in the locoregional radioimmunotherapy (RIT) of recurrent high grade glioma, and to investigate the antitumor efficacy of this new treatment. Twenty-four patients with recurrent glioma underwent second surgical debulking and implantation of a catheter into the surgical resection cavity (SRC), in order to introduce the radioimmunotherapeutic agents [biotinylated monoclonal antibody (MoAb), avidin and 90Y-biotin]. Eight patients with anaplastic astrocytoma (AA) and 16 patients with glioblastoma (GBM) were injected with biotinylated anti-tenascin MoAb (2 mg), then with avidin (10 mg; 24 h later) and finally 90Y-biotin (18 h later). Each patient received two of these treatments 8-10 weeks apart. The injected activity ranged from 0.555 to 1.110 GBq (15-30 mCi). Dosage was escalated by 0.185 GBq (5 mCi) in four consecutive groups. The treatment was well tolerated without acute side effects up to 0.740 GBq (20 mCi). The maximum tolerated activity was 1.110 GBq (30 mCi) limited by neurological toxicity. None of the patients developed hematologic toxicity. In three patients infection occurred around the catheter. The average absorbed dose to the normal brain was minimal compared with that received at the SRC interface. At first control (after 2 months), partial (PR) and minor (MR) responses were observed in three GBM (1 PR; 2 MR) and three AA patients (1 PR; 2 MR) with an overall objective response rate of 25%. Stable disease (SD) was achieved in seven GBM and five AA patients (50%). There was disease progression in six GBM patients (25%), but in none of the AA patients. At the dosage of 0.7-0.9 GBq per cycle, locoregional 3-S-RIT was safe and produced an objective response in 25% of patients. Based on these encouraging results, phase II studies employing 3-S-RIT soon after first debulking are justified.

Radiation protection in radioguided surgery of breast cancer

The protocols for sentinel lymph node biopsy and radioguided occult lesion localization could potentially be of great value in the management of breast cancer patients. Both involve the injection of a 99Tcm-labelled radiopharmaceutical close to or into the lesion, localization of the sentinel lymph node or occult lesion by scintigraphy, and surgical removal with the aid of a hand-held gamma-ray detector. We present dosimetric data on patients and hospital personnel involved in these procedures. For evaluation of radiation protection, we measured the absorbed dose and air kerma rate. Activity levels in excised tissues and surgical instruments were also determined. For patients, the mean absorbed dose to the abdomen was 0.45 mGy, which is low compared to doses received from other diagnostic examinations. For surgeons after 100 operations, the mean absorbed dose to the hands was 0.45 mGy and the mean effective dose 0.09 mSv. Absorbed doses to all hospital personnel involved in the procedures were very low compared to recommended annual limits stipulated by the International Commission on Radiological Protection. We conclude that these procedures, performed according to protocols laid down by the European Institute of Oncology, Milan, are safe from the point of view of radiological protection and that only routine precautions are necessary.

Quantitative Analysis of 90Y Bremsstrahlung SPECT-CT Images for Application to 3D Patient-Specific Dosimetry

AIM The aim of this study was to evaluate the accuracy of the activity quantification of single-photon emission computed tomography/computed tomography (SPECT-CT) (90)Y-Bremsstrahlung images and to validate the S-voxel method. METHODS An anthropomorphic torso phantom with radioactive inserts ((90)Y) was acquired by SPECT-CT. Constant calibration factors (cps/MBq) for the quantification were evaluated, considering different volume, shape, position inside the phantom, activity concentration and background, and distance from detectors. S-voxel values (EGSnrc) were implemented in MATLAB R0086 USA software. Dose comparisons between S-voxel and the conventional Medical Internal Radiation Dose method were repeated in a group of 11 patients administered with (90)Y-DOTATATE. RESULTS Using the appropriate calibration factors to recover the volume variability, the error about the measurement repeatability and the activity variation was within 4%. The variability of activity quantification, depending on the position in the phantom, detector distance, and background, was <10%, <5%, and <10%, respectively. The absorbed-dose values calculated by OLINDA were in agreement with the mean dose values obtained by the S-voxel method (difference, <10%). CONCLUSIONS The results confirm that, with the hybrid SPECT-CT system, quantitative analysis of SPECT (90)Y-Bremsstrahlung images and the generation of three-dimensional dose distributions are feasible. The improved analysis of Bremsstrahlung images could have a notable clinical impact, allowing to address the dosimetric verification to patients during the course of therapy.

Radioembolization of Hepatic Lesions from a Radiobiology and Dosimetric Perspective

Radioembolization (RE) of liver cancer with 90Y-microspheres has been applied in the last two decades with notable responses and acceptable toxicity. Two types of microspheres are available, glass and resin, the main difference being the activity/sphere. Generally, administered activities are established by empirical methods and differ for the two types. Treatment planning based on dosimetry is a prerogative of few centers, but has notably gained interest, with evidence of predictive power of dosimetry on toxicity, lesion response, and overall survival (OS). Radiobiological correlations between absorbed doses and toxicity to organs at risk, and tumor response, have been obtained in many clinical studies. Dosimetry methods have evolved from the macroscopic approach at the organ level to voxel analysis, providing absorbed dose spatial distributions and dose–volume histograms (DVH). The well-known effects of the external beam radiation therapy (EBRT), such as the volume effect, underlying disease influence, cumulative damage in parallel organs, and different tolerability of re-treatment, have been observed also in RE, identifying in EBRT a foremost reference to compare with. The radiobiological models – normal tissue complication probability and tumor control probability – and/or the style (DVH concepts) used in EBRT are introduced in RE. Moreover, attention has been paid to the intrinsic different activity distribution of resin and glass spheres at the microscopic scale, with dosimetric and radiobiological consequences. Dedicated studies and mathematical models have developed this issue and explain some clinical evidences, e.g., the shift of dose to higher toxicity thresholds using glass as compared to resin spheres. This paper offers a comprehensive review of the literature incident to dosimetry and radiobiological issues in RE, with the aim to summarize the results and to identify the most useful methods and information that should accompany future studies.

Lymphatic mapping to tailor selective lymphadenectomy in cN0 tongue carcinoma: beyond the sentinel node concept.

PurposeCervical lymph node status is the most important pathological determinant of prognosis and decision making in head and neck squamous cell carcinoma (SCC). The aim of this study was to demonstrate that lymphoscintigraphy (LS) can supply a complete map of the lymphatic drainage before surgery, allowing planning of the type of intervention and serving to guide lymphadenectomy.MethodsThe study population comprised 14 patients with T2–4 SCCs of the tongue and clinically negative lymph nodes in the neck (cN0) who were scheduled to undergo tumour resection and selective level I–IV neck dissection extended to level V. LS was performed in all patients following the injection of 99mTc-colloidal sulphide in three aliquots around the primary lesion. Dynamic, static and tomographic images of the head and neck were acquired. The operative specimens were subjected to lymphoscintigraphic evaluation. Preoperative and postoperative imaging results were compared with the pathological findings. All nodes were examined using haematoxylin-eosin staining.ResultsPreoperative LS was successful in all patients. Preferential pathways of lymphatic drainage were identified: level II of the neck was the most common lymphatic drainage pattern, followed by levels IV and III. Contralateral drainage occurred in 11 patients and in two of them metastatic nodes were found on the contralateral side. Metastases were observed only in radioactive lymph nodes.ConclusionLS is able to supply a complete map of the lymphatic drainage before surgery, making it possible to tailor selective neck dissection to each individual patient based on the results of preoperative mapping, thereby sparing healthy lymphatic tissue and reducing surgery-related morbidity.

High-Dose Radioimmunotherapy with 90Y-Ibritumomab Tiuxetan: Comparative Dosimetric Study for Tailored Treatment

High-dose 90Y-ibritumomab tiuxetan therapy and associated autologous stem cell transplantation (ASCT) were applied after dosimetry. This paper reports dosimetric findings for 3 different methods, including image corrections and actual organ mass corrections. Our first goal was to identify the most reliable and feasible dosimetric method to be adopted in high-dose therapy with 90Y-ibritumomab tiuxetan. The second goal was to verify the safety of the prescribed activity and the best timing of stem cell reinfusion. Methods: Twenty-two patients with refractory non-Hodgkins lymphoma were enrolled into 3 activity groups escalating to 55.5 MBq/kg. A somewhat arbitrary cutoff of 20 Gy to organs (except red marrow) was defined as a safe limit for patient recruitment. ASCT was considered of low risk when the dose to reinfused stem cells was less than 50 mGy. 111In-Ibritumomab tiuxetan (185 MBq) was administered for dosimetry. Blood samples were collected up to 130 h after injection to derive individual blood clearance rates and red marrow doses. Five whole-body images were acquired up to 7 d after injection. A transmission scan and a low-dose CT scan were also acquired. The conjugate-view technique was used, and images were corrected for background, scatter, and attenuation. Absorbed doses were calculated using the OLINDA/EXM software, adjusting doses for individual organ masses. The biodistribution data were analyzed for dosimetry by the conjugate-view technique using 3 methods. Method A was a patient-specific method applying background, scatter, and attenuation correction, with absorbed doses calculated using the OLINDA/EXM software and doses adjusted for individual organ masses and individually estimated blood volumes. Method B was a reference method using the organ masses of the reference man and woman phantoms. Method C was a simplified method using standard blood and red marrow volumes and no corrections. Results: The medians and ranges (in parentheses) for dose estimates (mGy/MBq) according to method A were 1.7 (0.3–3.5) for lungs, 2.8 (1.8–10.6) for liver, 1.7 (0.6–3.8) for kidneys, 1.9 (0.8–5.0) for spleen, 0.8 (0.4–1.0) for red marrow, and 2.8 (1.3–4.7) for testes. None of patients had to postpone ASCT. Absorbed doses from method B differed from method A by up to 100% for liver, 80% for kidneys, 335% for spleen, and 80% for blood because of differences between standard and actual masses. Compared with method A, method C led to dose overestimates of up to 4-fold for lungs, 2-fold for liver, 5-fold for kidneys, 7-fold for spleen, 2-fold for red marrow, and 2-fold for testes. Conclusion: Patient-specific dosimetry with image correction and mass adjustment is recommended in high-dose 90Y-ibritumomab tiuxetan therapy, for which liver is the dose-limiting organ. Overly simplified dosimetry may provide inaccurate information on the dose to critical organs, the recommended values of administered activity, and the timing of ASCT.

A multiple points method for 4D CT image sorting

PURPOSE Artifacts affect 4D CT images due to breathing irregularities or incorrect breathing phase identification. The purpose of this study is the reduction of artifacts in sorted 4D CT images. The assumption is that the use of multiple respiratory related signals may reduce uncertainties and increase robustness in breathing phase identification. METHODS Multiple respiratory related signals were provided by infrared 3D localization of a configuration of markers placed on the thoracoabdominal surface. Multidimensional K-means clustering was used for retrospective 4D CT image sorting, which was based on multiple marker variables, in order to identify clusters representing different breathing phases. The proposed technique was tested on computational simulations, phantom experimental acquisitions, and clinical data coming from two patients. Computational simulations provided a controlled and noise-free condition for testing the clustering technique on regular and irregular breathing signals, including baseline drift, time variant amplitude, time variant frequency, and end-expiration plateau. Specific attention was given to cluster initialization. Phantom experiments involved two moving phantoms fitted with multiple markers. Phantoms underwent 4D CT acquisition while performing controlled rigid motion patterns and featuring end-expiration plateau. Breathing cycle period and plateau duration were controlled by means of weights leaned upon the phantom during repeated 4D CT scans. The implemented sorting technique was applied to clinical 4D CT scans acquired on two patients and results were compared to conventional sorting methods. RESULTS For computational simulations and phantom studies, the performance of the multidimensional clustering technique was evaluated by measuring the repeatability in identifying the breathing phase among adjacent couch positions and the uniformity in sampling the breathing cycle. When breathing irregularities were present, the clustering technique consistently improved breathing phase identification with respect to conventional sorting methods based on monodimensional signals. In patient studies, a qualitative comparison was performed between corresponding breathing phases of 4D CT images obtained by conventional sorting methods and by the described clustering technique. Artifact reduction was clearly observable on both data set especially in the lower lung region. CONCLUSIONS The implemented multiple point method demonstrated the ability to reduce artifacts in 4D CT imaging. Further optimization and development are needed to make the most of the availability of multiple respiratory related variables and to extend the method to 4D CT-PET hybrid scan.

High activity 90Y-ibritumomab tiuxetan (Zevalin®) with peripheral blood progenitor cells support in patients with refractory/resistant B-cell non-Hodgkin lymphomas

Radioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B‐cell non‐Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y‐ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed – 30 MBq/kg (0·8 mCi/kg), 45 MBq/kg (1·2 mCi/kg) and 56 MBq/kg (1·5 mCi/kg) – and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin® administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non‐haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high‐activity Zevalin® with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high‐dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy.

Radioimmunotherapy of brain tumor

Abstract Despite years of intensive research, the prognosis of high-grade gliomas (HGG) remains poor, as these tumors are highly resistant to currently available therapies. Therefore, there is a need for the development of new therapeutic strategies, such as the use of monoclonal antibodies (MoAbs) in association with radioisotopes, in order to achieve better responses and prognosis. This article describes our experience in radioimmunotherapy (RIT) with MoAbs and tumor pre-targeting with the avidin-biotin system, either in systemic or locoregional administrations. This therapy offers the exciting prospect of increasing the specificity of tumor cell irradiation with radioisotopes. We suggest that RIT, both systemic and locoregional, should be used as part of a combined modality approach: in combination with surgery, radiotherapy and chemotherapy.