The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer

PURPOSE: Hormone refractory prostate cancer is dominated by osseous metastases leading to bone pain and pathological fractures. We assessed the clinical efficacy of bisphosphonate in the management of symptomatic skeletal metastases due to prostate cancer. MATERIALS AND METHODS: A total of 85 patients with painful osseous metastases due to hormone refractory prostate cancer were treated with clodronate in an open prospective nonrandomized clinical study. Clodronate was started as an intravenous phase for 8 days at a dose of 300 mg. daily followed by an oral maintenance phase of 1,600 mg. daily. The primary study end point was decreased pain without an increase in analgesic medication for at least 2 consecutive measurements. Secondary end points were decreased analgesics, an improved Karnofsky index and mobility as well as the duration of bisphosphonate action. Decreased pain was documented by a 10-point visual analog scale and consumption of analgesics was documented in a diary. RESULTS: A palliative response with a significant decrease in mean pain score from 7.9 (range 6 to 10) to 2.5 (range 0 to 4) (p <0.001) was achieved in 64 of the 85 patients (75%), 19 (22%) were completely pain-free without further need of analgesics and 45 significantly decreased the daily consumption of analgesics. The mean duration of bisphosphonate action was 9 weeks (range 4 to 22) and mean survival was 12 weeks (range 6 to 22). Improvement in bone pain was paralleled by an improvement in the mean Karnofsky index of 45% (range 30% to 60%) to 70% (range 50% to 80%) at the end of the treatment period. CONCLUSIONS: Bisphosphonate treatment of painful osseous metastases due to hormone refractory prostate cancer results in a significant pain decrease and a significant decrease in the daily consumption of analgesics in 75% of patients. Each characteristic is paralleled by an increase in the Karnofsky index, mainly due to better mobility. Bisphosphonate should have a definite role in the palliative management of symptomatic hormone refractory prostate cancer.     

Prognostic significance of the time of developing motor deficits before radiation therapy in metastatic spinal cord compression: one-year results of a prospective trial

Purpose: To investigate prospectively the prognostic value of the time of developing motor deficits before radiation therapy (RT) for post-treatment functional outcome in metastatic spinal cord compression.

Methods and Materials: From November 1998 until October 1999, 57 patients were included. Two subgroups were formed according to the time of developing motor deficits before RT: 1–14 days (n = 29) and > 14 days (n = 28). Therapeutic effect on motor function was evaluated by an 8-point scale directly, 6, 12, and 24 weeks after RT. Patients with rapid deterioration of motor function within 48 h before RT (n = 14) were evaluated separately.

Results: Directly after RT, 26/28 patients (93%) of the group developing motor deficits > 14 days showed improvement of motor function, in comparison to 3/29 patients (10%) of the group 1–14 days (p < 0.001). Deterioration rates were 0% (> 14 days) and 45% (1–14 days). In patients with rapid deterioration of motor function within 48 h before RT, prognosis was poor (improvement 0%, no change 43%, deterioration 57%). Results were comparable 6, 12, and 24 weeks after RT.

Conclusion: A slower development of motor deficits before RT predicts a better post-treatment functional outcome. In patients with rapid deterioration of motor function within 48 h before RT, prognosis was extraordinarily poor. These results support the findings of our preceding retrospective analysis.     

Effect of therapy on the lymphoid cell distribution in the venous blood of breast cancer patients]

Rosetting properties (E, EAh, EAox, EAC rosettes) and presence of surface immunoglobulins (SIg) were examined on peripheral blood lymphocytes from 30 breast cancer patients immediately prior to therapy and 4 weeks thereafter. Therapy consisted of limited radical surgery followed by combined X-ray and telecobalt radiotherapy. The results were compared to patients who had received the same treatment 1 year ago (n = 13), 2 years ago (n = 13) and 3 to 10 years ago (n = 20). All irradiated patients exhibited a considerable leuko- and lymphopenia with a particular decrease of E and EAh rosettes, and a concommittant relative increase of EAox and EAC rosettes. SIg positive cells showed no significantly different percentages before and after therapy although in absolute counts they were similarly reduced as the other subpopulations after radiotherapy. The possible prognostic influence of radiation induced lymphopenia is discussed without coming to clear conclusions.     

Inhibition of fluid transport in the isolated gall bladder of the guinea pig by isoprenaline,theophylline and cyclic adenosine 3′,5′-monophosphate

Summary The isolated gall bladder of guinea pigs was used to study the effects of isoprenaline and orciprenaline on fluid transport. Both drugs in the range 10^–8 M to 10^–4 M inhibited fluid transport 20–50 min after application, when applied to the serosal side. The maximum inhibition observed was 49±3.9% by a concentration of 10^–5 M. After this inhibitory phase the transport rate returned to control values. Doubling the concentration did not evoke a new inhibitory response, but washing gall bladders with fresh Ringer's solution restored the sensitivity to isoprenaline. Isoprenaline was ineffective when added to the mucosal side. Propranolol but not practolol, prevented the action of isoprenaline. Theophylline inhibited fluid transport in the range 10^–3 M to 10^–2 M. Cyclic adenosine 3,5-monophosphate (cyclic AMP) 3.3×10^–3 M decreased fluid transport only when added to the serosal side. In contrast to isoprenaline, both theophylline and cyclic AMP caused a prolonged decrease in fluid transport. The results are in accordance with the assumption that the inhibition of fluid transport in the gall bladder by -sympathomimetic drugs may be caused by an increase of the intracellular cyclic AMP level.Part of this work was presented at the 14th meeting of the Deutsche Pharmakologische Gesellschaft in Mainz, 1973.This work was supported by a grant from the Deutsche Forschungsgemeinschaft given to the Sonderforschungsbereich 160, Eigenschaften biologischer Membranen, Projekt T.     

Treatment options for hormone-refractory prostate cancer

Surgical or medical androgen deprivation therapy in its multiple variants represents the standard therapeutic approach in the management of metastatic prostate cancer resulting in a primary response rate of about 90%. However, about 90% of the men treated will develop PSA progression within 3-4 years resulting in androgen-independent and later on hormone-refractory prostate cancer. Management of AIPCA and HRPCA still represents a therapeutic challenge despite the development of new and effective treatment options. PSA progression following primary ADT defines an androgen-refractory but still hormone-sensitive PCA which might respond to secondary hormonal manipulations such as antiandrogen withdrawal, addition of nonsteroidal antiandrogens, and administration of estrogens, ketoconazole and hydrocortisone, and somatostatin analogues. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of two prospective, randomized clinical phase III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA and pain response, and represents the treatment of choice in the management of HRPCA.Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal-related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain as has been demonstrated for ibandronate and zoledronate. The current article critically reflects on the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer. The development, rationale, and results of systemic chemotherapy are discussed critically and a therapeutic algorithm is demonstrated.     

Correlation between right ventricular indices and clinical improvement in epoprostenol treated pulmonary hypertension patients

The aim of this study was to evaluate which parameter of right ventricular (RV) echocardiographic best mirrors the clinical status of patients with pulmonary arterial hypertension. Patients with pulmonary arterial hypertension on epoprostenol therapy were identified via hospital registry. Twenty patients, (16 females, 4 males) were included in the study, 9 with primary pulmonary hypertension and 11 with other diseases. Echocardiograms before therapy and at 22.7 (+/-9.3) months into therapy were compared. The right ventricular myocardial performance index (RVMPI) was measured as the sum of the isometric contraction time and the isometric relaxation time divided by right ventricular ejection time. Other measures included peak tricuspid regurgitation jet velocity (TRV), pulmonary artery systolic pressure (PASP), pulmonary valve velocity time integral (PVVTI), PASP/PVVTI (as an index of total pulmonary resistance) and symptoms by New York Heart Association (NYHA) functional class. Echo parameters of right ventricular function were analyzed in patients, before and during therapy. There was significant improvement of NYHA class in patients following epoprostenol therapy (P < 0.0001). Peak tricuspid regurgitant jet velocity (pre 4.2 +/- 0.6 m/sec, post 3.8 +/- 0.7 m/sec, P = 0.02) and PASP/PVVTI (pre 6.7 +/- 3.3 mmHg/m per second, post 4.8 +/- 2.2 mmHg/m per second, P < 0.0001) were significantly improved during treatment. RVMPI did not improve (pre 0.6 +/- 0.3, post 0.6 +/- 0.3, P = 0.54). Changes in NYHA class did not correlate with changes in RVMPI (P = 0.33) or changes in PASP/PVVTI (P = 0.58). Despite significant improvements in TRV, PASP/PVVTI, and NYHA class, there was no significant change in RVMPI on epoprostenol therapy. Changes in right ventricular indices were not correlated with changes in NYHA class.