Skeletal metastases

Measurement of serum acid phosphatase activities as an aid in the diagnosis and treatment of advanced prostatic carcinoma is based on the observation by Gutman and Gutman that the activity is elevated by skeletal metastases ( ). Many workers have... 

Babson proposed a-naphthyl phosphate as an essentially specific substrate for the activity of prostatic acid phosphatase in serum (104). However Marshall, Price, and Amador found that this substrate is not specific for the prostatic enzyme because urine of human females contain 50 times more acid a-naphthyl phosphatase than male serum and 50% as much activity as male urine. Platelets have significant activity and the serum activity can increase to abnormal values following clotting. These workers also observed elevated activities in females with skeletal metastases of the breast. In 50 hospitalized male patients who had no evidence of prostatic cancer and 25 hospitalized female patients, the incidence of false positive results was 12%, a magnitude sufficient to preclude meaningful clinical interpretation (105). 

Metastatic spread can occur by local extension, lymphatic drainage, or hematogenous dissemination.17 Lymph node metastases are more common in patients with large, undifferentiated tumors that invade the seminal vesicles. The pelvic and abdominal lymph node groups are the most common sites of lymph node involvement (Fig. 89-1). Skeletal metastases from hematogenous spread are the most common sites of distant... 

A 46-year-old woman with low back pain and osteoporosis took salmon calcitonin subcutaneously 100 U/ day and calcium carbonate orally 1.5 g/day for 7 days before developing nausea and facial flushing (13). Calcitonin was continued for a further 8 days and then stopped. The next day she developed intermittent generalized convulsions. She was subsequently found to have breast cancer with skeletal metastases and hypercalcemia (3.9 mmol/1) without a reduced... 

Carcinoma of the prostate is today one of the three most frequent causes of death from neoplastic disease in men in the United States (G4). The early studies of Gutman and his associates (Gil, G12, R6, S30) established that serum acid phosphatase activity was elevated very frequently in patients with metastatic carcinoma of the prostate. It is of interest to consider briefly the uncertainties inherent in the development of this relationship. Skeletal metastases, if sufficiently large, are of course detectable by roentgenographic examination, but smaller ones may not be, and metastases to soft tissues may likewise be undetectable. For example, in 15 cases of metastazing carcinoma reported by Gutman... 

In 1956, Fishman et al. (F2) summed up their experience with a series of 91 cases of proven cancer of the prostate and a total of 1198 patients with other diseases. Of these 91 cases, 32, or 35%, had elevated total serum acid phosphatase activities. This incidence was much lower than that, 85%, reported by Sullivan et al. (S30) in 1942 or the value of 89% reported by Herbert (H5) in 1946 for patients with carcinoma of the prostate and skeletal metastases. These investigators had used the method of Gutman and Gutman (GIO, G14), which was essentially the same method as that employed by Fishman and Lerner (FI) and gave the same ranges of normal values (Table 6). The possibility existed that treated cases had normal total serum phosphatase activities and thus weighted the overall incidence toward a low value. However, the data of Fishman et al. (F2) show that the incidence of total serum acid phosphatase activities in treated cases was 20/52, or 38%, even higher than the incidence 12/39, or 31%, in the untreated cases. 

Table 10 shows the distribution of serum acid phosphatase activities in neoplastic disease other than prostatic cancer. The incidences of elevations were 19% in patients with skeletal metastases 2% in pa-... 

G12. Gutman, A. B., Gutman, E. B., and Robinson, J. N., Determination of serum acid phosphatase activity in differentiating skeletal metastases secondary to prostatic carcinoma from Paget s disease of bone. Amer. J. Cancer 38, 103-108 (1940). 

Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, De Souza P, Zheng M, UrbanowitzG, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors a randomized, phase iii, double-blind, placebo-controlled trial. Cancer 2004 100 2613-2621. 

BodyJJ, Diel IJ,Tripathy D, Bergstrom B. Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer phase III trial results. Eur J Cancer Care (Engl) 2006 15 299-302. 

Strontium 89 chloride is used for relief of bone pain for patients with skeletal metastases. Because it is toxic to nor-ool bone, the benefits and risks of its use must be assessed. 

Serum alkaline phosphatase estimations are less reliable in the detection of skeletal metastases than are bone scintigrams (03). More than 30% of patients with positive bone scans have normal serum alkaline phosphatase activities (C35). Patients with skeletal metastases from prostatic carcinoma have higher mean serum alkaline phosphatase values than do patients with skeletal metastases derived from other sites (S17), particularly when hypocalcemia is also present (R5). It has been suggested (L21) that prostatic metastases cause oncogenic osteomalacia but serum alkaline phosphatase measurements do not distinguish patients with this complication from those without (L21). The use of serum alkaline phosphatase measurements in carcinoma of the breast is discussed in Section 10.1. 

Hyperphosphatasemia in patients with breast carcinoma usually denotes the presence of hepatic or skeletal metastases (C32, C35, Gl). Nathanson and Fishman (Nl) claimed that, in at least some patients with breast carcinoma, hyperphosphatasemia was due to the ectopic production of alkaline phosphatase by the tumor. Measurements of serum alkaline phosphatase values are of little use in monitoring the effects of endocrine ablation and other therapeutic agents (D14, Gl). 

White et al. (W19) studied the correlation between hyperphosphatasemia and the presence of hepatic and skeletal metastases in patients with breast carcinoma. Elevated serum alkaline phosphatase values were present in almost every patient with a positive liver scan but in only 64 % of patients with positive bone scans. Hyperphosphatasemia was associated with a significantly shortened median survival (W19). 

The majority of patients with carcinoma of the lung have normal serum alkaline phosphatase values (G6). Hyperphosphatasemia in this disorder may be due to hepatic or skeletal metastases or, rarely, to the synthesis of alkaline phosphatase by the tumor (Cll, S73). Pulmonary osteoarthropathy with hyperphosphatasemia has been described (C6a, H5). 

The majority of patients with radiologically demonstrable skeletal metastases have elevated serum alkaline phosphatase values (G14, 03). Patients with skeletal metastases demonstrable only by bone scintiscans usually have normal serum alkaline phosphatase values (B24, 03). 

Galasko, C. S., Skeletal metastases and mammary cancer. Ann. R. Coll. Surg. Engl. 50, 3-28 (1972). 

Patients presenting with skeletal metastases often have primary carcinomas in the lung, breast, kidney, or urogenital region, and imaging studies have been particularly useful in elucidating the primary tumor. 

Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective smdy of a diagnostic strat. J Bone Joint Surg Am. 1993 75 1276-1281. 

Sodium phosphate P 32 is a radiopharmaceutical. Phosphorus is necessary to the metabolic and proliferative activity of cells. Radioactive phosphorus concentrates to a very high degree in rapidly proliferating tissue. Sodium phosphate P 32 decays by beta emission with a physical half-life of 14.3 days. The mean energy of the sodium phosphate P 32 beta particle is 695 keV. It is indicated in the treatment of polycythemia vera, chronic myelocytic leukemia, and chronic lymphocytic leukemia and skeletal metastases. 

Strontium-89, a radioisotope, is used in the relief of metastatic bone pain. Strontium-89 chloride is a radiopharmaceutical. Following IV injection, soluble strontium compounds behave like their calcium analogs, clearing rapidly from blood and selectively locahzing in bone mineral. Uptake of strontium by bone occurs preferentially in sites of active osteogenesis. It selectively irradiates sites of primary metastatic bone involvement with minimal effect on soft tissues distant from bone lesions. It is indicated for painful skeletal metastases. 

Figure 104.6 (a) Skeletal metastases (arrows) from follioular thyroid oaroinoma on initial postoperative soan. (b) Positive post-treatment images 1 week after therapy. 

Eustace S, Tello R, DeCarvalho V, Carey J, Wroblicka JT, Melhem ER, Yucel EK (1997) A comparison of whole-body turboSTIR MR imaging and planar " Tc-methy-lene diphosphonate scintigraphy in the examination of patients with suspected skeletal metastases. AJR Am J Roentgenol 169 1655-1661... 

Basil. T. K.. Raven. R. W.. Dickerson, J. W. T.. artd Williams. D. C. Leucocyte ascorbic acid and urinary hydroxyprolir>e levels in patients bearing breast cancer with skeletal metastases. Eur. J. Cancer, 70 507-511,1974. 

Recurrent cervical cancer is associated with bone metastases (Fig. 7.39) in 15%-29% of patients at autopsy [ too, 103]. Typical locations are the bony pelvis as well as the lumbar and other vertebral bodies. Bone metastases in the ribs and extremities are less common. Skeletal metastases typically have an osteolytic character and originate from locally advanced or recurrent tumor in the pelvic sidewall or arise through retrograde tumor spread in patients with para-aor-tic lymph node metastasis [104]. Hematogenous dissemination to the skeleton occurs late. MRl with unenhanced and contrast-enhanced fat-saturated Tl-weighted sequences depicts bone metastases as hyperintense lesions in the low-intensity bone marrow with a high sensitivity. CT primarily shows the extent of osseous destruction. 

There are presently a large number of physidan-sponsored clinical trials in progress using the Oak Ridge National Laboratory (ORNL) alumina-based W/ Re generator system. Re-labeled HEDP (Palmedo et al. 2000 Savio, et al. 2001) and DMSA (Blower et al. 2000) have proven to be effective agents for the palliative rehef of bone pain from skeletal metastases in patients with prostatic carcinoma, and may represent a more cost-effective alternative to... 

Embolization Embolization of skeletal neoplasms was initially performed as an adjunct to surgical resection for hypervascular tumors to decrease operative blood loss (Chuang et aL 1981a Dick et al. 1979). Subsequently, this technique was adapted for palliation of pain caused by skeletal metastases (Feldman et al. 1975). At MDACC, most of the giant cell tumors in a group of 21 patients with these neoplasms were located in the sacrum, Oium, and thoracolumbar spine and had not responded to other forms of therapy. 

Embolization Transarterial embolization produces a reduction in surgical blood loss and allows more extensive surgical procedures to be done. Embolization has also been used for the palliation of pain caused by skeletal metastases (Fig. 9.19) (Reuter et al. 1992). Our efforts have been mostly concentrated on hypervascular metastases such as those from renal and thyroid carcinomas. Metastases from renal cell carcinoma like the primary neoplasm are hypervascular in 65%-85% of cases. The incidence of skeletal metastases is 30%-45% for patients with renal cell or thyroid carcinoma (Monteil et al. 1985 Rowe et al. 1984 Weber 1982). The 5- and 10-year survival rates for this patient population is 65% and 18%, respectively (Marcocci et al. 1989), compared with an 80%-95% 10-year survival in the absence of bone metastases (Schlumberger 1998). 

Among the many pharmaceutical drugs there are some which can be analyzed directly by ion chromatography. A known and important example is clodronate, the disodium salt of dichloromethylenebisphosphonic acid, which is registered for use in the effective management of hypercalcaemia and bone pain associated with skeletal metastases in patients with multiple myeloma or carcinoma of the breast. 

---