Comparative effectiveness of pulmonary scintigraphy and radiography in detecting toxic side-effects of Bleomycin treatment (author's transl)]

Pulmonary toxic effects subsequent to intravenous injections of bleomycin in cancer therapy have well been demonstrated. In order to prevent the acute pathological pulmonary manifestations of the treatment, it is necessary that the patient be submitted to repeated controls of the lungs. As yet, the efficiency of the current diagnostic procedures for detecting the lesions dues to bleomycin injections is not clearly demonstrated. The authors present the results of a comparative study on the effectiveness of radiological and scintigraphic examination of the lung in detecting toxic side-effects of bleomycin. Both procedures were used repeatedly on rabbits, before, during and after the bleomycin treatment. The findings are discussed on the basis of the macroscopic and histological examination of the lungs. The results demonstrate that pulmonary scintigraphy with radioactive macroaggregates is more sensitive than radiography in detecting the early lesions of the lungs after bleomycin treatment.     

Radiolabeled antitumor agents

Bleomycin serves as a useful prototype for a study of the various properties required in a radiopharmaceutical for tumor imaging. Both in vitro and in vivo results using bleomycin labeled with a large number of different radionuclides have now been reported. In general, it has not been possible to predict in vivo biologic behavior solely from in vitro data.For example, 57Co-bleomycin and 111In-bleomycin both have identical patterns in several different chromatographic systems and do not break down with prolonged storage in saline, exposure to heat, or other cations. However, when the labeled bleomycin is exposed to serum transferrin (and to other as yet unidentified ligands in the body) a difference in stability becomes obvious. The stability and biologic activity of 57Co-bleomycin in humans demonstrate the validity of metal chelation as a labeling technique for this specific molecule, and also suggests that other stable chelates will have useful applications. Although 57Co-bleomycin has the most desirable biologic characteristics of all the chelates of bleomycin, the extremely long physical half-life of 57Co of 270 days creates a significant contamination problem in the hospital. Because of this, the use of 57Co-bleomycin is limited to a few specialized centers. All users have emphasized the need for a better radionuclide to produce a labeled bleomycin with the same or superior biologic characteristics to 57Co-bleomycin. Unfortunately, the elements forming the most stable chelates with bleomycin (copper, zinc, cobalt, and nickel) do not have radionuclides with suitable physical characteristics for scanning. Copper-67 may become available in the future from high-energy linear accelerators. However, even if it were available, copper will probably not have as good chemical properties as cobalt.     

Bleomycin lung toxicity detected by technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy

In this study we investigated bleomycin-induced pulmonary toxicity in patients with germ-cell tumour by means of technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy. Twenty untreated patients who had no clinical or radiological evidence of pulmonary disease received four courses of etoposide, cisplatin and bleomycin chemotherapy. Aerosol lung scintigraphy and pulmonary function tests were performed in all patients before bleomycin treatment and after administration of 180 and 360 mg bleomycin. On the basis of the scintigrams the percentage decline in activity per minute (Kep) was evaluated, which represented an accurate parameter of lung membrane permeability. Pretreatment Kep values (0.891 ±0.286) were significantly lower than those obtained following 180 and 360 mg bleomycin treatment (1.176±0.336 and 1.389±0.477, respectively; P<0.0005). The Kep values obtained with 180 and 360 mg bleomycin treatments were also significantly different (P<0.005). In contrast, no significant change was observed in the results of pulmonary function tests. Our results demonstrate that evaluation of the pulmonary clearance of ^99mTc-DTPA represents a useful means of monitoring the functional status of the lung epithelial membrane during bleomycin treatment. Further prospective studies are needed to assess the relationship between increase in permeability and development of lung toxicity in order to decide which patients should discontinue bleomycin therapy. Correspondence to: O. Ugur     

The place of 57Co-bleomycin scanning in the evaluation of tumors.

The clinical records and imaging studies of 140 patients who had 57Co-bleomycin scans were reviewed. In 53% of the patients with known tumor at the time of examination, all clinically demonstrable lesions picked up cobalt. The success rate was particularly high in carcinoma of the lung (15 of 17) and gastrointestinal tract (12 of 17). The major role of cobalt bleomycin seems to be as an early screening test for metastases in patients with carcinoma of the lung, gastrointestinal tract, and uterus. The scan is most useful in demonstrating spread to the brain, liver, and adrenals.     

Labelled bleomycin as a tumour-localizing agent. II. The effect of dose loading of the different forms of 57Cobalt-bleomycin A2, B2, and pepleomycin on the tissue distribution and tumour uptake in tumour-bearing rats

The different forms of 57cobalt-bleomycin (57C0-blm) A2 and B2 as well as 57Co-pepleomycin (57Co-pep), were investigated in tumour-localizing properties of both forms of 57Co-blm are identical if 57Co-blm is injected as a bleomycin solution without carrier cobalt. Differences between the biological behaviour of the various cobalt complexes (which differ in ligand arrangement) were found if these complexes were injected together with inactive cobalt bleomycin complexes of the same form. In this case Co-blm B2 form I and Co-pep form I localize better than Co-blm b2 form II and Co-pep form II respectively. Such a decrease in uptake by the tumour, compared with form I, was not observed for Co-blm A2-II.     

The evaluation of 123I-MIBG scintigraphy in medullary thyroid carcinoma (MTC)

The diagnostic value of 123-I-MIBG (meta-iodobenzylguanidine) scintigraphy was investigated in six patients with recurrence and/or metastatic spread of a medullary thyroid carcinoma. In no case was there MIBG storage in tumor tissue. Thus, our results show that MIBG scintigraphy is not suitable as a screening method either in the primary diagnostics or the follow-up of medullary thyroid carcinoma. If, however, inoperable metastases have been detected by other diagnostic methods, MIBG scintigraphy is indicated in order to test a potential therapeutic application in these patients. In the imaging diagnostics and follow-up of medullary thyroid carcinoma, the examination with 99mTc(V)-DMSA (technetium-99m-dimercaptosuccinate) is markedly superior to MIBG scintigraphy. High-resolution cervical sonography is of major importance in the hands of an experienced examiner.     

Pulmonary epithelial permeability in patients treated with bleomycin containing chemotherapy detected by technetium-99m diethylene triamine penta-acetic acid aerosol (99mTc-DTPA) scintigraphy

Purpose

To evaluate pulmonary epithelial permeability using^99mTc-DTPA scintigraphy in patients treated with bleomycin-containing regimens.

Material and Methods

Twelve nonsmoking chemotherapy-naive patients with no clinical or radiological evidence of pulmonary disease and treated with bleomycin-containing chemotherapy were tested with^99mTc-DTPA scintigraphy before the first cycle and every 3 weeks until the third month after the end of chemotherapy (total cumulative dose of bleomycin 347.9 mg).

Results

Pretreatment values (T1/2 74.93 minutes) of^99mTc-DTPA scintigraphy were significantly higher than those obtained after the total dose of bleomycin (T1/2 51.00 minutes) (p < 0.001). This difference was more important in the later evaluations especially, on the third week and third month measures after discontinuing treatment (p < 0.001). All the tests of Within-Subjects Effects were significant (p < 0.001). Comparing pretreatment and post-treatment scintigraphies the mean T1/2^99mTc-DTPA values decreased as the bleomycin dose increased.

Conclusion

We conclude that cumulative bleomycin doses are related to increased pulmonary epithelial permeability at a dose of 256.5 mg. However, whether this is related to clinical toxicity is uncertain and large, multi-center prospective studies are needed.     

Current role of bone scan with phosphonates in the follow-up of breast cancer

A number of studies have demonstrated that bone scintigraphy has high sensitivity and efficacy in the early detection of bone metastases from several tumours, including breast cancer. Bone scintigraphy is the most definitive tool for diagnosing and monitoring metastatic spread of breast cancer. However, in the past decade there has been a wide debate on its impact on survival time, morbidity and quality of life. Worldwide economic restrictions and these studies have led to the adoption of an almost minimalist policy for breast cancer follow-up using evidence-based guidelines. The recommended breast cancer surveillance testing includes only a few procedures (history, physical and breast self-examination, patient education on symptoms, pelvic examination). The routine use of additional tests, such as blood cell count, tumour markers, liver ultrasonography, bone scan and chest X-rays, is not recommended. Accordingly, scintigraphy should be reserved for a limited number of patients. On the other hand, early diagnosis of bone involvement may reduce the risk of skeletal related events, thus leading to a significant improvement in quality of life. Furthermore, new drugs (e.g. bisphosphonates) can now delay the onset of bone metastasis and reduce the number of patients who experience skeletal complications. In conclusion, the evidence of the clinical usefulness of bone scintigraphy (to allow early planning of new treatments in advanced disease) has to be re-evaluated, possibly by large randomised prospective trials.     

The role of imaging in Graves' disease: a cost-effectiveness analysis

According to many guidelines, scintigraphy remains the first suggested diagnostic procedure in hyperthyroid patients in spite of the widespread availability of ultrasounds. The aim of this study was to evaluate the cost-effectiveness of sonography versus scintigraphy in the management of Graves's disease, and to assess ultrasound features suggesting cancer in detecting thyroid nodules. Among 1470 hyperthyroid patients evaluated in our department from 2002 to 2005, 426 (29%) had Graves' disease: echographic and scintigraphic features were not suggestive of GD in 20/426 (4.8%) and 11/426 (2.6%) patients, respectively (p=0.763), even if one of the two procedures was almost always diagnostic. Ultrasound identified 68/426 (16%) patients with a concomitant solid lesion, while scintigraphy detected only 9/426 (2.1%) "cold" nodules (p<0.001). Thyroid cancer was diagnosed in 30/68 (47.7%) patients. Malignancy presented at ultrasound investigation blurred margins (26.7% versus 15.8%), microcalcifications (33.3% versus 28.9%) and an anteroposterior and transverse diameter ratio>or=1 (73.3% versus 71.1%); more frequently than benign nodules, but this was not statistically significant. The total cost to obtain a diagnosis by ultrasound was euro14645.34 (euro13312.5 for echography+euro1332.84 for scintigraphy in the 29 patients "negative" at echographic evaluation for GD) versus euro19922.71 by scintigraphy (euro19578.96 for scan+euro343.75 for ultrasounds in the 11 patients "negative" at scintigraphy). Our data show no difference in terms of diagnosis between sonography and scintigraphy. Indeed, scintigraphy was less sensitive in detecting nodules (often of malignant nature) than ultrasound, and, moreover, with a consequent increase of the direct cost of nodule management when scintigraphy is the first line procedure. In conclusion, according to our results, we suggest that ultrasounds with color-Doppler evaluation should be performed as first step in all hyperthyroid patients, and that scintigraphic examination should be limited only to the uncommon cases, where physician's observation, laboratory assays and/or ultrasounds are not diagnostic.     

Detection of lung cancer with 55Co-bleomycin using a positron camera. A comparison with 57Co-bleomycin and 55Co-bleomycin single photon scintigraphy

57-Co-bleomycin is useful in the detection and staging of lung cancer, but the long half-life of 57Co (270 days) has discouraged its widespread acceptance. We investigated the shorter living positron emitting 55Co (half-life 18.2 h) as a level for bleomycin. In eleven patients with proven lung cancer scintigraphy with 55Co-bleomycin, using a positron camera, demonstrated the tumor in ten cases. Tumor to lung ratios were calculated. The results were superior to those obtained with 55Co-bleomycin single photon imaging but inferior to those obtained with 57Co-bleomycin scintigraphy.     

The prospect of incidental detection of unsuspected skeletal tuberculosis by bone scintigraphy should not be overlooked

BACKGROUND: The potential roles of bone scintigraphy in the evaluation of tuberculosis are not well-defined. It is commonly considered that skeletal tuberculosis occurs only after pulmonary tuberculosis. Bone scintigraphy was not known to be an effective imaging modality in the evaluation of skeletal tuberculosis, especially in those without known systemic tuberculosis. PURPOSE: To assess the prospect of bone scintigraphy in the detection of skeletal tuberculosis in patients who came to the department of nuclear medicine to evaluate back pain. METHODS: Patient records and the images of 1817 cases of consecutive bone scintigraphy performed for the evaluation of unknown causes of back pain were retrospectively reviewed. The imaging findings were compared with the status of tuberculosis before and after scintigraphy. RESULTS: Sixteen patients had skeletal tuberculosis confirmed by histopathological examination. Six patients had solitary while 10 had multifocal skeletal lesions. Before bone scintigraphy, 2 patients were suspected but not confirmed to have pulmonary tuberculosis, 4 were suspected to have skeletal tuberculosis by other modalities while the remaining 10 patients were not suspected to have tuberculosis in any part of the body. Following bone scintigraphy, among those 10 patients who were unsuspected of having tuberculosis, further tests demonstrated that 3 had pulmonary tuberculosis in addition to skeletal tuberculosis and 1 had cervical tuberculous lymphadenitis. In total, among those 16 patients with confirmed skeletal tuberculosis, only 6 had concurrent extraskeletal tuberculosis while 10 patients had their tuberculosis limited to the skeletal system. CONCLUSIONS: Our results indicate that pulmonary or systemic tuberculosis is not a prerequisite for skeletal tuberculosis. Skeletal tuberculosis should be among the differential diagnoses when there is a positive bone scan in patients without a malignancy in an endemic region.     

201Tl imaging for differentiating between malignant and benign neck masses

The aim of this study was to assess the ability of 201Tl scintigraphy to differentiate between malignant and benign neck masses. Fifty-eight patients with neck masses, whose diagnoses were confirmed by histological examination, were examined. The sensitivity, specificity and accuracy of 201Tl scintigraphy were 80%, 96% and 88% respectively; when salivary gland masses were excluded, these values were 87%, 95% and 91% respectively. Our results suggest that 201Tl scintigraphy is highly reliable in determining the malignancy of neck masses, especially when salivary gland masses are excluded.     

Complementary roles of CT and 131I-MIBG scintigraphy in diagnosing pheochromocytoma

Recently 131I-MIBG (metaiodobenzylguanidine), an adrenergic tissue-localizing radiopharmaceutical, has been used for diagnosis of pheochromocytoma. In a retrospective study of 32 patients with pathologically proved primary, metastatic, or recurrent pheochromocytoma, the roles of 131I-MIBG scintigraphy and computed tomography (CT) in pheochromocytoma detection were compared. The two methods were equally accurate in the identification of primary and recurrent pheochromocytoma. 131I-MIBG scanning was more accurate as the initial examination in patients with extraadrenal tumors. In patients with metastatic disease, scintigraphy was preferable to CT because of its nontomographic nature, which permitted imaging of the entire body. Although a positive MIBG scan is diagnostic of pheochromocytoma, CT of extraadrenal tumors (particularly in the chest) has been very useful in planning appropriate surgical intervention. Furthermore, the roles of 131I-MIBG scintigraphy and CT in the detection of pheochromocytoma are complementary because each method has certain limitations.     

The role of technetium-99m sestamibi single photon emission tomography in the follow-up of malignant melanoma and the detection of lymph node metastases

In the follow-up of patients with malignant melanoma treated by surgical resection of the cutaneous tumour, it is important to achieve early detection of possible lymph node metastasis. In many cases, clinical examination alone will not be sufficient. In our study, single-photon emission tomography (SPET) with technetium-99m sestamibi (MIBI) was used in the assessment of 30 patients with previously resected malignant melanoma when the clinical examination raised the suspicion of lymph node metastasis. Using MIBI, 16 out of 17 lymph node metastases were detected and confirmed by histology. No false-positive results were obtained during this prospective study. It is concluded that MIBI scintigraphy may be useful in the early detection of lymph node metastases of malignant melanomas. If our preliminary results are confirmed, early detection of lymph node metastasis of previously resected malignant melanoma by ^99mTc-MIBI scintigraphy may have a significant impact on the management of these patients. Received 1 May and in revised form 13 August 1997     

Bone scintigraphy for the staging of lymphogranulomatosis?

The importance of bone scintigraphy for the classification of stages of lymphogranulomatosis is judged differently, the indications in literature are not unanimous. The high sensitivity of this method is uncontested, but it is said to be not very reliable in the exclusion of a bone manifestation because of its low specificness. Bone scintigraphy demonstrates a disturbance in bone metabolism; in clinical examination this has to be checked by X-ray view in order to exclude not tumor-induced reasons for the increased or decreased concentration. In a prospective study we have investigated if this combined radiologic approach allows to use scintigraphy in the classification of stages. Four out of 23 patients in stage I showed a tumor-suspicious scintigram which was confirmed by X-ray examination within 1 1/2 years in two patients. One quarter of 133 patients in stage II and III had a pathologic scintigram. In 34 out of 36 patients who could be followed up, this was confirmed later on by an X-ray finding in the same site. 15 out of 36 patients in stage III with initially normal scintigram showed a conversion to a tumor-suspicious scan during the later course of the disease. The tumor-suspicious scintigraphy found at the time of classification of stages has been confirmed later on by X-ray examination in 91% of our series. So, scintigraphy may be considered to be valuable for the classification of stages. Furthermore the conformity of tumor-suspicious scintigram and bone marrow biopsy was investigated. Whereas in 62% of patients with M+ a bone manifestation could be demonstrated by scintigraphy, only 46% of patients with scintigraphic 0+ showed a histologic manifestation in bone marrow. Consequently, bone scintigraphy cannot be used to demonstrate or to exclude a manifestation in bone marrow. As the metabolism is modified by therapy in case of a demonstrated bone manifestation, scintigraphy should be a sensitive parameter in these cases, too, for an early indication of response to cytostatic treatment. The scintigram became normal in 46 patients coming to a complete remission; eight out of nine patients the scintigraphic findings of whom became worse were non-responders. Five out of twelve patients with unchanged scintigram came to a remission. A normalizing scintigram indicates a response to therapy, whereas a deterioration suggests a non-response. Bone scintigraphy can also be used to judge the success of a cytostatic therapy.     

Labelled bleomycin as a tumour-localizing agent II. The effect of dose loading of the different forms of 57Cobalt-bleomycin A2, B2, and pepleomycin on the tissue distribution and tumour uptake in tumour-bearing rats

The different forms of ⁵⁷cobalt-bleomycin (⁵⁷Co-blm) A₂ and B₂ as well as ⁵⁷Co-pepleomycin (⁵⁷Co-pep), were investigated in tumour-bearing rats in relation to the dose given. It appeared that the tumour-localizing properties of both forms of ⁵⁷Co-blm are identical if ⁵⁷Co-blm is injected as a bleomycin solution without carrier cobalt.Differences between the biological behaviour of the various cobalt complexes (which differ in ligand arrangement) were found if these complexes were injected together with inactive cobalt bleomycin complexes of the same form. In this case Co-blm B₂ form I and Co-pep form I localize better than Co-blm B₂ form II and Co-pep form II respectively. Such a decrease in uptake by the tumour, compared with form I, was not observed for Co-blm A₂-II.For part I, see Vos et al. 1979     

Clinical relevance of gallium-67 scintigraphy in lymphoma before and after therapy

The clinical impact of gallium-67 scintigraphy before and after therapy for lymphoma remains controversial. The aims of this study were: (1) to compare the staging of lymphoma by 67Ga scintigraphy only with staging by clinical examination and conventional imaging (CI), and (2) to analyse the clinical relevance of both 67Ga imaging and CI after treatment. From March 1995 to November 1998, 86 67Ga scintigraphy studies were performed in 62 patients with Hodgkin's disease (n=52) or non-Hodgkin's lymphoma (n=10). 67Ga scintigraphy was performed at diagnosis (n=44) or after therapy (n=42) using 185-220 MBq 67Ga citrate and planar and single-photon emission tomography (SPET) studies. Treatment comprised radiotherapy, chemotherapy or combined modalities. CI included plain chest radiography, computed tomography (CT) of the chest and abdomen/pelvis, ultrasound of the abdomen, lymphography, bone marrow biopsy and, when necessary, magnetic resonance imaging (MRI) and bone scintigraphy. For individual suspected sites of disease before treatment, complete agreement between clinical examination and CI on the one hand and 67Ga scintigraphy on the other hand was observed in 25/44 patients (57%; 95% confidence interval 41%-72%). Clinical examination and CI showed more sites than did 67Ga scintigraphy in 12/44 patients (27%) and 67Ga imaging demonstrated more sites than CI in 6/44 patients (11%). The clinical stage of the disease as assessed using 67Ga scintigraphy only was in agreement with that using all diagnostic procedures in 34/44 patients (77%; 95% confidence interval 62%-89%). Compared with CI staging, 67Ga scintigraphy downstaged seven patients (16%) and upstaged three (7%). 67Ga scintigraphy downstaged mainly because of the limited value of the technique below the diaphragm and upstaged owing to the good sensitivity in the lung. After therapy, both CI and 67Ga scintigraphy were normal in 11 patients. All but one of these patients were in complete remission after a median follow-up of 31 months. In contrast, radiological residual mass was observed in 31/42 patients. 67Ga imaging was normal in 22/31 (71%); 17 of these 22 patients, including nine with a large residual mass (> or =2 cm), were in complete remission after a median follow-up of 32 months, while four suffered relapses 8-45 months later. The cause of death remained unknown in one patient. 67Ga scintigraphy showed abnormal uptake in 9 of the 31 patients with a large residual mass. Active disease was demonstrated in eight patients and one patient was in complete remission 30 months thereafter. Our data show that 67Ga imaging cannot replace CI in initial staging but can demonstrate additional individual sites of disease in more than 10% of patients and can lead to clinical upstaging with potential prognostic and therapeutic consequences. After therapy, 67Ga scintigraphy has a clinical impact when radiological abnormalities persist because it can either avoid unnecessary complementary treatment or confirm the need to change treatment modalities.     

Follow-up of differentiated thyroid cancer: comparison of multiple diagnostic tests

The radioablation of thyroid remnants improves the prognosis of differentiated thyroid cancer. In our prospective study an activity of 3.7 GBq 131I failed to completely ablate the remnants in 46 out of 101 patients, but a 3-year follow-up period was uneventful. One other patient had a recurrence early after thyroidectomy. In view of possible stunning effects of 131I it might be advantageous to visualize such remnants by imaging modalities which do not emit beta-particles. Our data have revealed that neither magnetic resonance imaging (MRI), nor ultrasonography (US), nor 99Tcm-sestamibi scintigraphy, nor positron emission tomography could detect or reliably exclude minimal remnants. Such remnants did not produce thyroglobulin (Tg). A 123I and 131I uptake of> 10% after thyroidectomy was associated with about a 90% probability of persistent remnants. On the other hand, MRI was helpful in the patient group (n = 32) with Tg>4ng x ml(-1) at the second whole-body scintigraphy (TSH>30 mU x l(-1)) for planning the management of lymph node metastases (n = 15 patients): 12 patients had subsequent surgery and three patients radioiodine therapy. We recommend that MRI be used early in follow-up care when Tg is elevated. The decision of whether or not to treat persistent thyroid remnants should not be made on the basis of MRI, US or nonspecific scintigraphic methods. Complete ablation did not appear to have any clinical benefit in our study group.     

Diverse findings in cranial CT and scintigraphy in space occupying lesions (author's transl)

Incongruent statements in CT and scintigraphy may disturb therapy planning. Many years of scintigraphy have presented here an established method. Cranial CT was performed here with 2000 persons in one year. Parallel CT and scintigraphy was performed in about 350 cases. There were some cases with positive findings in CT and negative in scintigraphy and vice versa. These cases will be compared with the definite diagnosis, we will discuss the different findings and the relevance of both methods as a diagnostic aid for the neurosurgeon and therapeutic radiologist.     

Thyroid scintigraphy for the detection of radiation-induced thyroid cancer

Thyroid scintigraphy with Tc-99m pertechnetate was performed in 249 patients who received radiation therapy for abnormalities in the head or neck in order to determine the role of this examination in the detection of abnormal nodules arising from cancer. These patients received a mean total dose of about 10.1 Gy. The mean follow-up period was 39 years. All patients underwent physical examination without prior knowledge of the scintigram. Scintigrams were evaluated without prior knowledge of the physical examination. In 158 cases, both the physical examination and scintigraphy were negative. In 64 cases, both examinations were positive. In ten patients, the physical examination was positive and scintigraphy was negative and vice versa in 17 patients. Of 249 patients, 28 ultimately underwent thyroid surgery; a total of four had carcinoma. A cost-benefit relationship as to routine scintigraphy as a screening procedure is presented. If patients are first screened by palpation, a number of abnormal nodules will be missed. In addition, a considerable number with positive palpation would probably undergo surgery unnecessarily. From a clinical and financial point of view, it is believed that scintigraphy is the examination of choice for screening for radiation-induced thyroid malignancies.