Search

The limited role of bone scanning in the diagnosis of metabolic bone disease might be considerably improved by accurate quantification of skeletal uptake of the radiopharmaceutical. Using a standard shadow-shield whole-body monitor, we have measured whole-body retention (WBR) of Tc-99m HEDP up to 24 hr in 11 patients with renal osteodystrophy (mean WBR 88.6% at 24 hr); in ten patients with Paget's disease (mean 56.9%); in seven patients with osteomalacia (mean 40.7%); in five patients with primary hyperparathyroidism (mean 50.7%); in four patients with osteoporosis (mean 21.2%); and in 12 normals (mean 19.2%). The osteoporotic group could not be differentiated from the normal group, but the other groups were significantly different from the normal group at 24 hr (p less than 0.002), and each individual rest for the 24-hr WBR of Tc-99m HEDP in these groups lay outside our normal range. This test may, therefore, provide a sensitive means of detecting conditions with increased bone turnover. We obtained measurements of plasma activity of Tc-99m HEDP in these patients up to 24 hr, and 4-hr bone to soft-tissue ratios from bonescan images, but little additional information resulted.

Certain easily recognisable features are commonly seen in the bone scans of patients with metabolic bone disorders. Seven such features have been numerically graded by three independent observers in the scans of 100 patients with metabolic bone disease and of 50 control subjects. The total score for each patient is defined as the metabolic index. The mean metabolic index for each group of patients with metabolic bone disease is significantly greater than that for the control group (P less than 0.001).

We have compared bone scintigrams made with Tc-99m-tagged HEDP (1-hydroxyethylidene diphosphonate)and MDP (methylene diphosphonate), the former at 4 hr after injection, the latter at both 2 and 4 hr. In 17 patients with skeletal metastases, there was no significant difference in lesion count or scan quality between the 4-hr images. The tumor-to-bone ratio (T/B) was significantly higher with Tc-HEDP (p less than 0.02). Lesion detection rate and T/B ratios were both lower with Tc-MDP at 2 hr when compared with the 4-hr values for both Tc-HEDP (p less than 0.02, p less than 0.005) and Tc-MDP (p less than 0.02, p less than 0.01). The 4-hr Tc-MDP scan was of significantly higher quality than the 2 hr Tc-MDP scan (p less than 0.01). Although Tc-HEDP produces a higher T/B ratio at 4 hr, the present study does not suggest that either agent is superior in clinical practice.

99Tcm-phosphate bone scans are being increasingly used in the detection of bony metatases. The sensitivity of the bone scan and the non-specific nature of the isotope image, when compared with radiographs, make it important to be aware of the problems and limitations of the technique. This paper describes and illustrates some of the diagnostic problems encountered by the author over the past 3 years.

The 99mTc diphosphonate scan is important in the study of primary breast cancer. The short-term prognosis for scan-positive patients is poor. Serial bone scans provide a safe and reliable prognostic index in patients following mastectomy. By correlating the scan with biochemical tumor markers, a matrix of diagnostic tests may be developed that is capable of identifying high-risk patients who may benefit from systemic therapy.

Zoladex, a sustained-release luteinizing hormone--releasing hormone (LHRH) analogue administered by subcutaneous injection every 28 days, was evaluated at three dose levels in 46 men with untreated advanced prostate cancer. All three Zoladex doses yielded similar endocrinologic effects. After initial transient increases in serum luteinizing hormone, follicle-stimulating hormone, and testosterone concentrations, serum testosterone was suppressed uniformly to castration levels within 22 days. At a median follow-up of 41 weeks, Zoladex had maintained persistent suppression of serum testosterone. Measurements of serum Zoladex levels indicated that release of the drug from the injected depot was sustained over a period of 1 month and that there was no drug accumulation as evaluated over an initial 3-month period. No antibodies to Zoladex were detected. Tumor regression rates and side effects with Zoladex therapy were similar to those reported with daily injections of subcutaneous LHRH therapy. Signs and symptoms consistent with a brief tumor flare after the first injection of the LHRH analogue were noted in eight (17%) of the study entrants. Spinal cord compression was observed in two patients within 1 week from the onset of therapy. Zoladex is considered to be an effective, sustained-release LHRH analogue for the treatment of patients with prostate cancer.

Comparison of the gamma camera bone scan and radiological survey in 190 patients with breast cancer has confirmed the superiority of the bone scan in the positive diagnosis of skeletal metastases. In 47 patients with known (X-ray positive) bony metastases the scan was positive in all but 2, and in 24 (50 per cent) the scan showed more lesions than the X-ray had indicated. In 60 patients with a clinical suspicion of bone metastases but negative X-rays, the scan was positive in 29 (48 per cent). Eighty-three patients with primary breast cancer were studied at the time of initial presentation. All had a normal radiographic skeletal survey but 24 (27 per cent) had scan evidence of occult metastases. It is concluded that a bone scan is indicated in all patients with breast cancer where skeletal metastases are suspected. Repeated bone scans may introduce new therapeutic possibilities, by providing an earlier objective index of progression of metastatic disease and also by providing a quantitative method of assessing the response to therapy.

Malignancy-associated hypercalcemia is a common and recalcitrant problem. Current modes of therapy are often ineffective or prohibitively toxic. Clodronate disodium is a diphosphonate capable of inhibiting bone resorption resulting in a hypocalcemic effect. In this randomized, placebo-controlled study, we investigated the effect of hydration only (Rx-1) vs the effect of hydration plus either intravenously administered clodronate disodium, 4 mg/kg of body weight per day for three days (Rx-2) or intravenously administered clodronate disodium, 12 mg/kg of body weight given once only (Rx-3). By the third day of observation, Rx-2 produced a significant 2.8 mg/dL (0.70 mmol/L) reduction in serum calcium levels, whereas Rx-1 and Rx-3 did not produce a significant hypocalcemic effect when compared with baseline values. There were no toxicities observed. Intravenously administered clodronate appears to be an excellent agent for the acute treatment of malignancy-associated hypercalcemia.

A comparison of 2 h and 4 h bone scan images obtained with technetium labelled H.E.D.P. in ten patients demonstrated no increase in lesion detection rate between the 2 h and 4 h scans. The 2 h bone scans were of sufficient quality to permit identification of tumours in all cases.

Hypophosphatemia and osteomalacia have been described in patients with metastatic prostate cancer. The mechanism of hypophosphatemia in prostate cancer is not known. A decrease in serum phosphate levels was observed in 16 of 18 patients with metastatic prostate cancer treated with high-dose diethylstilbestrol diphosphate. To determine if the fall in serum phosphate was indeed due to diethylstilbestrol diphosphate, the data from several similar groups of patients treated with chemotherapy and combined chemohormonal therapy that included diethylstilbestrol diphosphate were re-examined. Fifty-eight patients were treated with doxorubicin, doxorubicin plus cis-platinum, doxorubicin plus diethylstilbestrol diphosphate, or diethylstilbestrol diphosphate alone. A significant decrease in serum phosphate levels was seen only in patients treated with diethylstilbestrol diphosphate. Hypophosphatemia and possibly osteomalacia in metastatic prostate cancer may be related to estrogen therapy.

The low incidence of measurable or evaluable metastases in patients with prostatic cancer makes evaluation of response difficult. This is particularly true in patients with bone metastases only. With a digital model it is possible to measure quantitatively from the radioisotope bone scan the total area of skeletal involvement by metastatic tumor. Definitions of response in bone have been derived from this model. These response criteria have been compared to response in acid phosphatase determinations and clinical status in a study of 44 patients with advanced prostatic cancer treated with estramustine phosphate. Based on serial quantitative bone scans, serial measurements of acid phosphatase levels and repeat clinical evaluations a system is proposed for defining response to systemic therapy that is applicable to the majority of patients with metastatic prostatic cancer.

Twenty-five patients with metastatic prostate cancer were treated with a combination of Adriamycin 50 mg/m2 and cis-platinum (CDDP) 50 mg/m2 every three weeks. Response was evaluated using radioisotope bone scan, serum acid phosphatase levels, and clinical status. Response rates of 6% bone, 21% acid phosphatase, and 24% clinical status were noted. Major toxicity was gastrointestinal (due to CDDP). Treatment was well tolerated even in patients with extensive bone metastases and prior irradiation. Using the response criteria described here, patients with metastatic prostate cancer without measurable soft tissue disease are eligible for Phase II and III study.

Normocalcemic patients with cancer who had been successfully treated for an episode of hypercalcemia were enrolled in a randomized, multisite, double-blind, placebo-controlled trial designed to determine the efficacy of maintenance oral etidronate in preventing the recurrence of moderate to severe hypercalcemia (serum calcium level, greater than 11.5 mg/dL [greater than 2.87 mmol/L]). Ten (40%) of 25 etidronate-treated patients and 17 (46%) of 37 placebo-treated patients had recurrence of hypercalcemia within 150 days. Although patients taking etidronate had a longer time to the development of hypercalcemia (median, 55 days vs 28 days), this was not significantly different from the control group. The high attrition rate in this trial from hypercalcemia and other malignancy-related causes represents a major difficulty in conducting studies with agents that may require prolonged administration before producing a therapeutic effect.

Seventy-five women with clinical stage I or stage II carcinoma of the breast have had radionuclide bone scans at the time of presentation and at 6-monthly intervals during a mean follow-up period of 39 months. Patients with evidence of metastases on bone scan, either at the time of presentation or during follow-up, had significantly higher mortality and morbidity rates than those with persistently negative scans. Whatever the clinical stage, breast cancer patients with a positive bone scan have a very poor short term prognosis and local therapy to the breast is inadequate. A plan is outlined which incorporates the patient's bone scan status into the decision to introduce endocrine therapy or chemotherapy.

Four patients with adrenal cortical carcinoma were treated with standard doses of o,p'-DDD. Plasma levels of o,p'-DDD and its metabolites o,p'-DDA and o,p'-DDE were measured. o,p'-DDD was measurable for up to 8 months after stopping therapy, and trace levels of metabolites were detectable at 18 months. Although 2 of 3 patients with measurable disease had objective tumor response and one patient achieved a complete response, severe drug toxicity occurred in all patients and signs of adrenal insufficiency occurred in three. Low dose therapy with o,p'-DDD is suggested, together with full gluco and mineralocorticoid replacement. Measurement of o,p'-DDD and its metabolites in plasma may prove clinically useful in developing effective but less toxic dosage schedules.

Combined chemohormonal therapy of metastatic prostate cancer has not been previously evaluated in patients failing primary hormones (estrogens and/or orchiectomy). The combination of Adriamycin and high-dose diethylstilbestrol diphosphate (Stilphostrol) was studied in 19 heavily pretreated patients, to document toxicity and patient acceptability. Major toxicity was myelosuppression, cardiac failure and venous thrombosis. Clinical improvement was noted in 10/16 (63%) of evaluable patients. Patients with pre-existing cardiac disease or venous thrombosis are not suitable for this therapy.

Fifty-nine evaluable patients with stage III bronchogenic carcinoma, participating in a randomized clinical trial evaluating the effect of adjuvant immunotherapy with levamisole or BCG in the treatment of clinically advanced lung cancer, were studied for their immunocompetence by in vitro and in vivo assays. Immunological tests consisted of measurements of natural killer (NK) cell and killer (K) cell cytotoxicity, skin testing reactivity to recall antigens, absolute lymphocyte count, and serum immunoglobulin (Ig) levels. Pretherapy K cell cytotoxic levels, skin test reactivity to trichophyton antigen, and increased IgA levels were predictive of the overall clinical course. Despite non-specific immunotherapy, progressive decline of NK and K cell cytotoxicity occurred during the course of the disease. These findings, however, were of limited clinical value. Initial performance status and disease extent significantly influenced time to progression and survival. Little further prognostic information was obtained from the immunological tests over those provided by clinical performance status and disease extent. No statistically significant differences were found in either time to progression or survival between controls and patients receiving either levamisole or BCG.

Evaluation of response to systemic therapy in metastatic prostate cancer is often difficult because of the infrequency of nonbony indicator lesions. The authors previously described a set of response criteria for Phase II and III studies which can be applied in patients with only bony disease. They have retrospectively evaluated response to Adriamycin (doxorubicin) and (5-fluorouracil) 5-FU in 38 patients with measurable soft tissue and visceral disease, using their response criteria for acid phosphatase and clinical status and standard definitions of response. No correlation was attempted for bone disease. Agreement between the results obtained with each system was good. Using this system of evaluating response, patients with metastatic prostate cancer with bone-dominant disease are eligible for Phase II and III studies.

Plasma aldosterone levels were measured in 50 patients with confirmed liver metastases from various histologically proved primary tumors. None of these patients had electrolyte abnormalities or history of benign liver disease, congestive heart failure, hypertension, or renal disease. Patients with edema, ascites, or both had significantly greater elevation of plasma aldosterone levels compared to nonedematous patients; these patients also demonstrated a substantial degree of hepatic dysfunction as evidenced by lower serum albumin levels and higher bilirubin and alkaline phosphatase levels. This study provides a rational basis for the use of the specific aldosterone inhibitor spironolactone in the treatment of patients with advanced metastatic liver disease and edematous states.

Twenty patients with locally advanced and/or metastatic transitional cell cancer of the urinary tract were treated with cyclophosphamide 500 mg/m2, Adriamycin (doxorubicin) 40 mg/m2 and cis-platinum (CDDP) 40 mg/m2 given every three weeks for 2 cycles, alternating with methotrexate 40 mg/m2 weekly for six weeks (CAP-M). Five of thirteen (38%) evaluable patients responded, with a significant prolongation of survival. Toxicity in 18 evaluable patients was mild to moderate. Methotrexate can be combined with CAP with significant reduction in dosage of cyclophosphamide, Adriamycin and CDDP and reduced toxicity, without major loss of efficacy. The precise role of methotrexate in combination chemotherapy of bladder cancer remains to be defined.

Twenty-one patients with adrenocortical carcinoma (ACC) diagnosed at three hospitals over a ten-year period were reviewed for clinical and pathologic features that might have therapeutic implications. Depending upon the extent of cellular pleomorphism, ACC could be defined as anaplastic or differentiated. Anaplastic ACC occurred more often in male patients, produced more frequent cutaneous metastases (P = 0.01), and was associated with a lack of clinical or laboratory evidence of hormone production (P = 0.01). In contrast, differentiated ACC usually occurred in women and produced clinical or laboratory evidence of hormonal excess. Median survival time of patients with anaplastic ACC was only five months, while median survival time of those with differentiated ACC was 40 months (P = 0.005). Patients with differentiated ACC survived for long periods, even with metastatic disease. Three of 5 such patients had objective responses to o,p'-DDD (Mitotane) therapy. The histopathology of ACC is an important prognostic factor and should be considered in the design of future therapeutic trials.

The usefulness of plasma ribonuclease assays was studied in (i) patients with possible protein deficiency, (ii) patients with myelomatosis, (iii) patients with carcinoma of the breast. In each group, the major factor associated with elevation of plasma ribonuclease was impairment of renal function. The assay was therefore of little value in the assessment of patients with myelomatosis or carcinoma of the breast. However, in the patients with possible protein deficiency and normal renal function, an elevation of plasma ribonuclease is, in general, associated with a decrease in serum albumin, transferrin and cholinesterase. Plasma ribonuclease may therefore be a useful parameter in the assessment of protein nutritional status.

The in vitro properties of lyophilized 99mTc stannous diphosphonate bone-scanning agent have been studied with particular reference to those properties which are of relevance to its routine clinical use. The results of quantitative studies in patients with bony tumors indicate that reliable reproducible bone scans will be obtained despite the variations in technetium presentation, labelling and injection procedures which may be anticipated in any department of nuclear medicine.