Purpose: The main goals were to study the safety and tolerability of the α-emitter radium-223 (223Ra) in breast and prostate cancer patients with skeletal metastases. In addition, pain palliation was evaluated. Experimental Design: Fifteen prostate and 10 breast cancer patients enrolled in a phase I trial received a single i.v. injection of 223Ra. Five patients were included at each of the dosages: 46, 93, 163, 213, or 250 kBq/kg and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection. Results: Weekly blood sampling during follow-up revealed mild and reversible myelosuppression with nadir 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1 toxicity was reported. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting was more frequently observed in the highest dosage group. Serum alkaline phosphatase decreased with nadir averages of 29.5% in females and 52.1% in males. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4, and 8 weeks, respectively. 223Ra cleared rapidly from blood and was below 1% of initial level at 24 hours. Gamma camera images indicated, in accordance with pretreatment 99mTc-MDP scans, accumulation of 223Ra in skeletal lesions. Elimination was mainly intestinal. Median survival exceeded 20 months. Conclusions: 223Ra was well tolerated at therapeutically relevant dosages. Phase II studies have therefore been initiated.

Strontium-89 is an established alternative for the alleviation of bone pain in prostate cancer. There are few data evaluating the effect on pain of palliative chemotherapy. The aim of this randomized phase II study was to assess and compare the analgesic efficacy of strontium-89 and chemotherapy (FEM=5-FU, epirubicin, and mitomycin C) in 35 patients with disseminated, hormone-refractory prostate cancer suffering from persisting bone pain despite analgesic treatment. In order to minimize the risk for imbalances regarding the two patient groups, a double-blind randomization was performed. A significant reduction in pain intensity and pain frequency was registered in both patient groups (P < 0.01 in both groups after 3 weeks). Side effects were generally mild in the strontium-89 group and significantly more severe in the FEM group. The effect of FEM on pain is surprising as chemotherapy has generally only limited effect on tumor growth in bone metastases due to prostate cancer. A possible explanation is that FEM has an inhibitory activity on the inflammatory component of metastases.

OBJECTIVE:Subtotal colectomy and ileorectal anastomosis for slow transit constipation has several side-effects. The motor abnormality in some patients may be segmental which could motivate a limited resection of the colon. Therefore a diagnostic tool to identify a segmental colonic motor dysfunction is needed. The aim of this study was to evaluate a scintigraphic method to assess colonic transit with special reference to right- or left-sided delay.METHODS:Twenty-three constipated patients (19 women, mean age 50 years) with slow colonic transit on radio-opaque marker studies and 13 healthy individuals (11 women, mean age 46 years) were studied. All subjects were examined with oral (111)Indium-DTPA scintigraphy. The scintigraphic results for patients and controls were presented as geometric centre of radioactivity and percent activity over time in the right, the left and the recto-sigmoid colon. The inter-observer variation in the interpretation of the scans was also evaluated.RESULTS:There was no difference in transit time between the groups of patients and controls in the right colon whereas the patients had a significant delay in the left colon (P < 0.05). Two patients had a marked delay in the right colon followed by relatively rapid transit in the left colon. The inter-observer correlation was good comparing the right, the left and the recto-sigmoid colon (r = 0.58-0.98, P < 0.01-0.001).CONCLUSION:The results indicate that colonic scintigraphy with oral (111)Indium-DTPA may help to select patients for a left or, in a few cases, a right hemicolectomy for slow transit constipation.

OBJECTIVES Scintigraphy with radiolabelled octreotide (octreoscan) is useful for imaging various neuroendocrine tumours, especially in patients with midgut carcinoids. We were interested in estimating the efficacy of octreoscan for detection of the primary tumour and metastases in patients with bronchial carcinoids.PATIENTS AND METHODS Twenty-eight patients with histologically verified bronchial carcinoids underwent octreoscan and the imaging results were compared to CT regarding soft tissue metastases, and to bone scan and MRI regarding bone metastases. The primary tumour had been removed prior to the octreoscan in 12 patients. Metastatic disease was diagnosed in 22 patients.RESULTS Altogether, 20 patients (71%) had octreoscan-positive tumours, including 2/5 patients with ectopic ACTH secretion resulting in Cushing's syndrome and 8/9 patients with carcinoid syndrome. The primary tumour was octreoscan-positive in 13/16 patients and could be detected on CT in 15/16 patients. CT failed to localize the primary tumour in one octreoscan-positive patient, presenting with ectopic ACTH secretion and Cushing's syndrome. Intrathoracic recurrences/metastases were visualized by octreoscan in 7/9 patients and by CT in 8/9 patients. CT showed liver metastases in 14 patients; nine of these patients (64%) had octreoscan-positive liver metastases. Ten patients had bone metastases; octreoscan was positive in seven and bone scan in nine of these 10.CONCLUSIONS Octreoscan may be used for follow-up and detection of recurrent disease in patients with somatostatin receptor-positive bronchial carcinoids. In our limited patient material, CT however, seems to be better than octreoscan for visualization of the primary tumour as well as liver metastases.

UNLABELLED The somatostatin analog diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide labeled with 111In has been applied extensively for diagnosis of neuroendocrine tumors using SPECT or planar scintigraphy. However, the spatial resolution of planar scintigraphy and SPECT prohibits imaging of small tumors, and the quantification accuracy of both methods is limited. METHODS We developed a method to prepare the positron-emitting radiopharmaceutical 110mIn-DTPA-D-Phe1-octreotide based on a commercially available kit. Phantom studies were done to investigate and compare the performance of 110mIn PET and 111In SPECT. A clinical imaging study using 110mIn-DTPA-D-Phe1-octreotide and PET was done to investigate the application of this radiopharmaceutical. RESULTS An almost 3-fold better resolution and much better quantitative capabilities were found for 110mIn PET than for 111In SPECT. The clinical imaging study demonstrated the potential use of 110mIn-octreotide in PET to image tumors and quantify radioactivity uptake in humans using (110m)In-DTPA-D-Phe1-octreotide. CONCLUSION PET with 110mIn-DTPA-D-Phe1-octreotide greatly improved detection of small tumors and offers a possibility of more accurate quantification of tumor uptake than can be obtained with 111In-DTPA-D-Phe1-octreotide and SPECT.

Somatostatin analogs and α-interferon induce good responses as single drugs in the treatment of endocrine pancreatic tumors. We examined the efficacy and tolerability of the combination of α-interferon and somatostatin analogs in 16 patients with metastatic endocrine pancreatic tumors. All patients except one had received prior treatment and were in a progressive state. Doses of α-interferon and somatostatin analogs were individually titrated. The α-interferon doses varied between 9 and 25 million units per week and were combined with 100–1500 µg of octreotide or 6000 µg of lanreotide daily. Radiological response was seen in 3 of 16 (19%) patients (median duration 23 mo). Biochemical response was seen in 10 of 16 (62.5%) patients (median duration 22 mo). All three patients previously progressing on both α-interferon and somatostatin analog as single drugs achieved a stabilization of the disease when treated with the combination (median duration 10 mo). Seven of eight (88%) patients previously progressing on α-interferon treatment benefited from the combination with biochemical partial response or stabilization. All six patients previously progressing during somatostatin analog treatment achieved biochemical partial response or stabilization. More than 80% of patients who progressed during previous treatment with either drug benefited from the combined treatment, which also was well tolerated. Thus, a combination of α-interferon and somatostatin analogs may be considered for patients previously progressing on treatment with α-interferon or somatostatin analogs. However, in this study, the value of sequential treatment has not been evaluated.

Somatostatin receptors (SRS, five subtypes) are expressed in a variety of human tumors, including most tumors of neuroendocrine origin, breast tumors, certain brain tumors, renal cell tumors, lymphomas, and prostate cancer. Somatostatin (SMS) triggers cytostatic and cytotoxic effects and has a general inhibitory effect on secretion mediated through its interaction with SRS. That is the basis for its use in the treatment of SRS‐positive tumors. Radiolabeled SMS analogs can also be used for systemic radiotherapy and for diagnostic investigations.

BACKGROUND:In a previous study we reported on a new approach describing intravesical instillation of charged dextran in patients with superficial bladder carcinoma. The cationic derivative showed a strong tumor-selective accumulation. To develop this approach, the present study investigates the cytotoxic effect of cationic dextran derivatives on two urinary bladder cancer cell lines (J82 and 5637).METHODS:The dextran conjugates were prepared by periodate activation and subsequent coupling by reductive amination. A fluorimetric cytotoxicity assay (FMCA) was used for the cytotoxicity assay. The tumor cells were seeded into 96-well microtiter plates and different cationic dextran derivatives were added and incubated for 72 hours.RESULTS:The results showed that cationic epirubicin-dextran had a clear inhibitory effect on the growth in both cell lines (40-95% growth inhibition). The corresponding values for epirubicin (the reference) was 90-100% inhibition. Interestingly, cationic dextran had, by itself, a growth inhibitory effect. This cytotoxic effect could be strongly enhanced to be almost equal to the reference by changing the cationic sidegroup to aminohexane. Dextran alone showed no effect.CONCLUSION:The finding that cationic dextran by itself can be made cytotoxic, together with its capacity to accumulate in superficial bladder cancer, suggests possibilities for new therapeutic constructs. Cationic dextran with different cationic side-groups and in combination with cytotoxic drugs will be studied further. The cytotoxic mechanism needs to be elucidated.

[111In]-DTPA-D-Phe1-octreotide (OctreoScan®, Mallinkrodt) is widely used for detection of neuroendocrine tumors and has lately been proposed for radionuclide therapy. We found, using HPLC and a GF-250 column (Zorbax®, Hewlett Packard), that OctreoScan® can be separated in two radiolabeled components of about equal amount. The analytical conditions for a quantitative isolation indicate that the two-peptide components of OctreoScan®have different lipophilicity. The isolated components are stable and do not transform into each other at room temperature during 6 hours (shelf-life of OctreoScan®).

UNLABELLED:Treatment with tumor-targeting substances is currently being evaluated in clinical trials. For patients with neuroendocrine tumors expressing somatostatin receptors, the 111In-labeled somatostatin analog [diethylenetriaminepentaacetic acid (DTPA)-DPhe1]-octreotide has been used with promising results. To further investigate the clinical effect of the injected conjugate, we analyzed the cellular distribution of 111In by ultrastructural autoradiography.METHODS:Seven patients with somatostatin receptor-expressing midgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, fixed, and processed for electron microscopy. A thin layer of film emulsion was applied on sections and after the exposure film was developed. The cellular distribution of silver precipitations indicating the presence of isotope was evaluated.RESULTS:Cell surface receptor binding and internalization of [111In-DTPA-D-Phe1]-octreotide in the tumor cells was easily revealed by silver precipitations in the film. Multiple silver grains were seen at the plasma membrane, in the cytoplasmic area among secretory granules and vesicular compartments, and in the perinuclear area. Silver grains were also regularly located in the nucleus. For all patients, the silver precipitation patterns from 111In decay were identical in all examined cells from removed tumors, and in most cells 111In could be seen in the nucleus. The specificity of the silver reaction products is supported by the observation that enterocytes in intestinal tissue specimens from near the tumor did not show any silver grains and no background labeling was seen in the plastic.CONCLUSION:After internalization through the somatostatin receptor system, 111In is translocated to the perinuclear area and into the nucleus. Whether the nuclide is still conjugated to the intact somatostatin analog or to part of it cannot be evaluated in this study. Despite the short irradiation range of 111In, the nuclear localization can explain its clinical effectiveness. The results from this study suggest that [111In-DTPA-D-Phe1]-octreotide may act as a powerful tumor cell-targeting substance.

Purpose: To make a review of the literature of (89)strontium-chloride and a retrospective study of time to palliative intended external irradiation, number of portals and overall-survival after (89)strontium-chloride therapy. Results. In total 93 patients were treated 116 times with (89)strontium. The patients with prostatic carcinoma received 91% of all (89)strontium therapies. Median over-all survival was 10 months after injection. In those cases when (89)strontium was given before palliative radiotherapy, the average of total number of local fields was significantly lower (1.1 versus 4.1) compared to those cases where local fields preceded (89)strontium therapy. However (89)new external irradiation after (89)strontium injection time to was equal between these groups (3.8 versus 2.9 months). Conclusion: A review of literature conclude that (89)strontium is effective for the reduction of pain originating from osteoblastic metastases. It also reduce the need for external radiotherapy and therefore is cost-effective. However, (89)strontium is more effective in an early phase of the metastatic disease and preferably as an adjuvance to external radiotherapy.

PURPOSE:The aim of this study was to theoretically investigate how the radiation dose to cell nuclei depends on the subcellular position of (131)I. The influence of the size of the cells and crossfire irradiation in clusters of cells was also studied. METHODS AND MATERIAL:Using data describing the dose rate around a point source of (131)I, we calculated the dose distributions inside and around cell models of different sizes. The assumed positions of (131)I were on the cellular or nuclear membrane, in the cytoplasm, in the nucleus, or spread in the whole cell. The mean doses to the nucleus of the targeted cell and to the nuclei of its neighbors were calculated using the dose distributions. RESULTS:The dose distributions inside a single targeted cell showed very different distribution profiles depending on the subcellular position of the (131)I. Targeting the nucleus instead of the cellular membrane could increase the dose to the nucleus 10-fold. Crossfire irradiation can be the major contributor to the nuclear dose in clusters of more than six cells. CONCLUSIONS:Dosimetry without microscopic considerations is inadequate for targeted radionuclide therapy of disseminated or clustering tumor cells exposed to (131)I. Therapeutic doses could be achieved, even in single cells, when (131)I was positioned near, or inside the cell nucleus, or when the clusters were large enough.

Overexpression of the epidermal growth factor receptor (EGFR) has been reported in bladder cancer and is a potential target for therapy with radionuclides. In this study, we investigated the binding of EGF-dextran-(99m)Tc to the EGFR. The aim of this study was to determine if intravesically administered EGF-dextran conjungate selectively accumulated in the tumor tissue and to correlate the uptake to tumor characteristics.Eight patients received the conjugate intravesically for about 30 min followed by bladder irrigation and then transurethral resection. Radioactivity of the biopsy specimens from normal urothelium and tumor areas was measured in a gamma counter.Five patients received EGF-dextran-(99m)Tc, three received dextran-(99m)Tc and one received only (99m)Tc. The 5 patients who received the complete conjugate had a mean ratio of radioactivity between tumor and normal urothelium of 664:1 (range: 2.4-1,710). The dextran-(99m)Tc showed a slightly increased ratio and (99m)Tc did not bind at all.The results are encouraging and further studies are warranted to investigate if EGF-dextran could be effective as intravesical therapy, either conjugated with cystostatic drugs or labeled with suitable radionuclides.

BACKGROUND Prostatic cancer is the leading cause of death in Swedish men. Approximately 50% have disseminated disease at diagnosis. Radiolabelled antibodies could possibly be a treatment modality for disseminated prostatic cancer, so that in this study the expression of the human milk fat globulin 1 (HMFG1) antigen in prostate cancer was examined. MATERIALS AND METHODS An immunohistochemistry technique with a murine monoclonal antibody was used, as well as the human prostate cancer cell line DU-145, which expresses this cell surface antigen. TUR specimens from patients with prostate cancer were also examined. RESULTS Eighteen out of 22 (82%) patients exhibited an HMFG1-positive tumour. An inhomogenity in the immunostaining could occasionally be seen, with smaller apparently negative areas. The immunolocalisation properties of the antibody were investigated using a radiolabelled antibody injection into nude mice bearing heterotransplants of the DU-145 cell line. The highest accumulation of the antibody was seen in the tumour tissue and the liver. CONCLUSION The results obtained form a basis for further investigations with the goal of using the antibodies for staging and therapy for prostate cancer.

Radioactive tumor targeting agents are highly interesting and for treatment of neuroendocrine tumors expressing somatostatin receptors, radiolabeled somatostatin analogues (including [111In-DTPA-D-Phe1]-octreotide) has been tried in a small number of patients with encouraging results. To increase our knowledge about the in vivo processing of administered [111In-DTPA-D-Phe1]-octreotide we have examined tumor and normal tissue material from a patient with a midgut carcinoid tumor. By ultrastructural autoradiography, silver grains indicating the presence of [111In-DTPA-D-Phe1]-octreotide could be identified within tumor cells, both in the primary tumor and in the mesenteric metastases. Silver grains were also found in leukocytes and in blood vessels. However, normal enterocytes did not show any specific radioligand uptake. This study indicates that the binding and endocytosis of [111In-DTPA-D-Phe1]-octreotide is a specific process that takes place in cells expressing somatostatin receptors. However, the importance of the number of somatostatin receptors and subtypes expressed will have to be further studied.

Positron emission tomography (PET) is a medical imaging tool with high resolution and good quantitative properties, which makes it suitable for in vivo quantification of radioimmunotargeting agents. Most radionuclides used in radioimmunotherapy have positron-emitting analogues, which can be used for PET imaging, and this opens the possibility of performing dosimetry with PET. These isotopes, however, often emit gamma radiation and high-energy positrons in their decay, influencing the imaging properties of PET. Spatial resolution, reconstructed background and line source recovery for a number of non-pure positron emitters were investigated and compared with the imaging properties of 18F. PET imaging properties did not degrade severely for these non-pure positron emitters, but caution has to be applied when doing quantitative measurements. To assess the possibility of conducting PET studies during therapy, by combining, for example, a small amount of 124I with 131I, the influence of the presence of large amounts of gamma radiation on PET count rate characteristics was studied. The results of these studies were related to the necessary amounts of radioactivity needed for treatment of post-operative remains of glioma. The results indicate that the count rate capabilities of 2D PET permit PET studies for dose evaluation during radioimmunotherapy.