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Prostate Cancer and the Skeleton
R.C.M. Pelger


Supervisor: Prof.Dr. A.A.B. Lycklama à Nijeholt, Prof. Dr. S.E. Papapoulos, Dr. N.A.T. Hamdy
Faculty of Medical Sciences, University of Leiden, 15-Jan-2003

Summary:

Chapter 1 - Prostate cancer is one of the most common malignancies and a leading cause of cancer-related death in men worldwide. In the majority of cases, prostate cancer metastasises to the skeleton, in which case cancer-related bone pain becomes a major cause of morbidity. Androgen ablation is the primary treatment of choice securing regression of skeletal metastases in the majority of cases. Intermittent androgen ablation is an attractive altemative, aimed at minimising side-effects of hormone deprivation hut also potentially delaying hormone-refractoriness. The development of hormone-refractoriness is heralded by a significant increase in morbidity largely because of escalating bone pain caused by the progression of the metastatic process. Skillful use of analgesics is initially successful but eventually fails to control symptoms. Localised metastases are best treated with local radiotherapy, which is rapidly effective. Over the last few years, it has become clear that therapeutic modalities using bone-seeking radionuclides or bisphosphonates have been effective in the palliation of prostate cancer-related bone pain, although not affecting survival. The main limiting factor with the use of radionuclides is bone marrow suppression, a feature of the very late stages of prostate cancer. Bisphosphonates do not carry this disadvantage. Results of large doubleblind placebo-controlled studies should be awaited, however, before advocating the widespread use of these agents in the management of patients with prostate cancer and skeletal metastases.

Chapter 2 - Introduction: We determined whether an early flare in serum alkaline phosphatase activity after orchidectomy was of prognostic value for progression-free survival in patients with advanced prostatic carcinoma.
Materials & methods: A retrospective analysis of a data base from a Dutch multicenter study on prostatic carcinoma was done to determine the prognostic value of a flare in alkaline phosphatase activity after orchidectomy in 112 patients with metastatic (75%) or locally advanced (25%) disease. Cox's proportional hazards models and Kaplan-Meier survival curves were used.
Results: Of the patients 50% had initially increased alkaline phosphatase levels and a flare in activity was demonstrated in 87% 2 to 4 weeks after orchidectomy. The prostate specific antigen nadir (cutoff 4 ng/ml) 6 months after orchidectomy was of significant prognostic value for progression-free survival. A flare in alkaline phosphatase activity after orchidectomy demonstrated an early significant prognostic value for progression-free survival, independent of the serum alkaline phosphatase activity.
Conclusion: The simplicity, ready availability and cost-effectiveness of serum alkaline phosphatase activity as a prognostic index render it attractive to the clinician, particularly early in the course of prostatic carcinoma. Measuring the flare in alkaline phosphatase activity within 1 month of orchidectomy may permit early identification of patients in whom the disease is likely to progress rapidly and who would potentially benefit from aggressive treatment.

Chapter 3 - Introduction: A flare in serum alkaline phosphatase activity post-orchidectomy has been shown to be of negative prognostic value for progression-free survival in patients with prostate cancer. The aim of this study was to investigate whether a flare in serum alkaline phosphatase activity may help identify patients in whom prognosis could be positively influenced by early chemotherapy.
Materials & methods: A retrospective analysis of the database of a Dutch multicenter study was conducted to evaluate the prognostic value of the flare in serum alkaline phosphatase activity postorchidectomy for survival and progression-free survival in 112 patients treated with orchidectomy (previously reported) compared to 121 age- and stage-matched patients additionally treated with estramustine-phosphate as first line therapy.
Results: There was no overall difference in progression-free survival and survival between the two treatment regimen. Subgroup analysis of patients demonstrating a greater than 50% increase in serum alkaline phosphatase activity post-orchidectomy showed, however, a significant increase in progression-free survival in patients additionally treated with estramustine-phosphate.
Conclusion: Our data suggest that the simple measurement of serum alkaline phosphatase activity within four weeks of castration represents a useful adjunct in assessing which patients with prostate cancer undergoing androgen ablation may benefit from additional early chemotherapy.

Chapter 4 - Introduction: We retrospectively studied the significance of age as a prognostic factor for survival and progression-free survival using the database of a previously published study of 412 patients who underwent orchidectomy for locally advanced or metastatic prostate cancer (75% T0-4 M1).
Material & methods: After initial orchidectomy, 205 patients had no further therapeutic intervention whereas 207 patients received additional treatment with estramustine-phosphate (EMP) as first line therapy.
Results: Our findings confirm that age is a significant prognostic factor for survival and progression-free survival in patients with prostate cancer, as well as a predictor of response to chemotherapy. Conclusion: Our data outline the beneficial effect of aggressive treatment strategies in the younger patient but also strongly suggest that aggressive treatment regimens may shorten survival in the older patient (>80 year old). These findings call for caution with the use of aggressive first line treatments in the older patient with prostate cancer.

Chapter 5 - Introduction: Data are scarce on the pathophysiology of disturbances in calcium homeostasis in prostate cancer. To address this question, we studied parameters of bone and mineral metabolism in patients with prostate cancer and Paget's disease of bone.
Material & methods: Parameters of bone and mineral metabolism were studied including intestinal absorption of 45 Calcium in 35 patients with hormone refractory prostate cancer metastatic to the skeleton, in 13 patients with localized PC and in 27 age- and sex-matched controls with active Paget's disease of bone.
Results: None of the patients had hypercalcemia. Hypocalcemia was present in 23% of patients with hormone refractory prostate cancer, 15% with localized prostate cancer and 7% with Paget's disease. Fractional 45 Ca absorption was decreased, however, in 63% of patients with hormone refractory prostate cancer compared to only 15% of patients with localized prostate cancer (p<0.02), and 4% of Paget's patients (p<0.001). There was a significant relationship between fractional 45 Ca absorption and PSA (p<0.001), serum alkaline phosphatase activity (p=0.002), the urinary excretion of calcium and hydroxyproline (p<0.001), hut not serum calcium, 25-hydroxyvitamin D or 1,25dihydroxyvitamin D concentrations.
Conclusion: Our data point to a significant disturbance in intestinal absorption of calcium in more than two-thirds of patients with hormone refractory prostate cancer. This phenomenon appears to be vitamin D-independent and likely to be paraneoplastic, its severity being related to degree of tumor load. These findings hold significant clinical implications in the management of patients with hormone refractory prostate cancer as the increasingly used bisphosphonates for palliation of metastatic bone pain may further compound the already existing disturbance in calcium homeostasis. Due attention should be given to adequate calcium and vitamin D supplementation in the late stages of hormone-refractory prostate cancer metastatic to the skeleton.

Chapter 6 - We report a case of severe symptomatic hypophosphatemic osteomalacia in a 66 year-old patient with hormone-refractory prostate cancer metastatic to the skeleton. A follow-up of 2 years from diagnosis to development of hormone refractoriness and death allowed us to study the natural history of this uncommon disturbance of mineral homeostasis in prostate cancer. Failure of response to conventional therapeutic manipulations and response to antitumor therapy suggest that this group of patients, although carrying a poor prognosis could benefit from aggressive second line therapy. Failure to recognize osteomalacia significantly increases the borden of skeletal complications already prominent in the late stages of prostate cancer.

Chapter 7 - Introduction: Prostate cancer is predominantly associated with osteoblastic bone metastases, bot an increase in bone resorption has been demonstrated consistently, both histological and biochemical. For this reason, bisphosphonates, which effectively suppress bone resorption, have been used in patients with prostate cancer metastatic to the skeleton.
Material & methods: We studied clinical and biochemical responses 5 days and 3 months after administration of the new, potent bisphosphonate, olpadronate, in 28 patients with prostate cancer and bone metastases. All patients received 4 mg of olpadronate intravenously daily for 5 days. No additional treatment was given to the first 12 patients, while treatment was continued with oral olpadronate 200 mg daily in the following 16 patients.
Results: Serum alkaline phosphatase activity was elevated in 93% of the patients and was positively correlated to urinary hydroxyproline excretion (r = 0.81, p < 0.0001), suggesting a coupling between bone formation and resorption. A rapid and significant suppression of bone resorption was observed in all patients after intravenous treatment. This was sustained for 4-6 weeks in all patients, bot reversed thereafter in patients not receiving oral maintenance therapy. No significant changes in serum alkaline phosphatase activity activity were observed in either group during the 3 months of follow-up. At the start of treatment all patients had severe bone pain and 82% and 36% were using NSAIDs and/or opiates, respectively.
Conclusion: Although clinical response was not a primary objective of the study, we observed that intravenous therapy was associated with a decrease in bone pain in 76% of patients and a reduction in the use of analgesics. At 3 months this response was generally sustained only in those patients who were maintained on continuous oral therapy (p < 0.05 compared with the group treated with intravenous olpadronate only). The clinical response thus appeared to parallel the biochemical changes in bone resorption.



 
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