Don Newling

Progression Delay of Prostate Tumor Skeletal Metastasis Effects by Bisphosphonates

Prostate tumor cell metastasis to the axial skeleton was induced in male Copenhagen rats using the intravenous injection of syngeneic metastatic R3327-MATLyLu tumor cells and concomitant caval vein clamping. The proliferation of tumor cells in the lumbar region was monitored by the progression, within 19 days post tumor cell injection, of hindleg paralysis which appeared in these animals. Histology confirmed the presence of tumor cells within the lumbar spine in 100% of cases displaying hindleg paralysis. Treatment with either of the bisphosphonate drugs, Cl2MDP or APD, suppressed and delayed the development of hind leg paralysis. Bisphosphonate treatment may be expected to delay the onset of axial skeletal metastasis effects in prostate cancer patients.

Long-term therapy with a depot luteinizing hormone-releasing hormone analogue (Zoladex) in patients with advanced prostatic carcinoma.

We treated 191 patients with histologically proved locally advanced stage (T3 or T4) and/or metastatic prostate cancer with a biodegradable depot formulation of a luteinizing hormone-releasing hormone analogue (Zoladex). After an initial increase in serum testosterone in week 1 of therapy a continuous decrease of testosterone to castrate levels was obtained. With a monthly injection of the luteinizing hormone-releasing hormone analogue 4 patients (2 per cent) experienced a transient increase in bone pain, 1 had ureteral obstruction and 1 suffered paraplegia during the first few weeks of therapy. Over-all objective and subjective responses were similar to those obtained by castration or estrogen therapy. The absence of local and systemic (long-term) side effects proves the validity of this approach for patients with advanced prostatic cancer.

Defining an international research agenda for quality of life in men with prostate cancer

While the traditional goal in the management of patients with prostate cancer has been to maximize survival, the recent advent of the medical outcomes movement has underscored the importance of patient‐centered issues, such as health‐related quality of life (HRQOL).

Assessment of hormone refractory prostate cancer

OBJECTIVES To define guidelines for the assessment of treatment in patients with hormone-refractory prostate cancer (HRPC). METHODS In the light of modern research, and taking new treatment options into account, the Committee essays to specify different categories of patients entering clinical trials, and to define response criteria and those endpoints that are relevant in phase III studies and in short-term follow-up. RESULTS HRPC comprises a range of disease states with varying responsiveness to therapy and length of survival. Patients with progression as evaluated by increasing prostate-specific antigen (PSA) values alone have a more favorable prognosis than those presenting with increasing tumor spread. In the assessment of these patients, the modes of previous therapy and the kind of tumor progression must be taken into account. The benefit of treatment of HRPC is often modest. While duration of survival remains the main and ultimate endpoint, the means of measuring short-term responsiveness to therapy are limited. A minority of patients have measurable tumor lesions. Decrease of PSA or other biochemical tumor markers may indicate depression of the tumor activity, but is not always associated with prolongation of survival. A variety of new treatments in HRPC are being investigated. They affect measurable tumor parameters in different ways. CONCLUSIONS When a new agent is to be tested, it is important to measure all possible parameters before deciding which particular ones are appropriate for future investigations of this agent. In symptomatic patients, evaluation of subjective parameters, for example, relief of pain or improvement of performance status, is often the most reliable measure of treatment effect. However, these parameters should be clearly defined.

Mitomycin C versus estramustine in the treatment of hormone resistant metastatic prostate cancer : the final analysis of the European Organization for Research and Treatment of Cancer, genitourinary group prospective randomized phase III study (30865)

A total of 171 patients with progressive metastatic prostate cancer following hormonal therapy was randomized to receive either 560 to 700 mg. estramustine orally per day or 15 mg./m.2 mitomycin C by intravenous infusion every 6 weeks. The patients were recruited during a 2.5-year period, and 70% had undergone more than 1 previous therapy for prostate cancer, with some having received as many as 5 different previous treatments. The overall results were disappointing. The median time to progression was 5 months and 50% of the patients died within 10 months. There was no difference in efficacy between the 2 treatment arms. Toxicity was severe in both arms but appeared earlier in those patients receiving estramustine, leading to a tendency for earlier deterioration in performance status. In this group of heavily pretreated patients there appears to be no justification for the use of either of these agents at the present time.

A Phase II Study of Intravesical Mitomycin C in the Treatment of Superficial Bladder Cancer

Twenty-three patients with histologically proven superficial bladder cancer (Tis, Ta, T1) were treated with intravesical instillations of Mitomycin C at a dose of 20 mg in 20 ml of water 3 times weekly for 21 instillations. Seventeen patients (77%) showed complete disappearance of all known disease and a further 4 showed partial responses. In 8 patients toxic effects developed (thrombocytopaenia 1, chemical cystitis 2, skin rash 3, urinary tract infection 2). All resolved rapidly on stopping the treatment but were severe enough in 5 patients to prevent them from receiving a full course of treatment.

Use of Balloon Catheters for Ureteral Occlusion in Urinary Leakage

Purpose: Urinary fistula after treatment for cancer constitutes a therapeutic dilemma, especially in patients who have had various other treatments. We report on 7 patients with urinary leakage, treated conservatively with ureteric occlusion by way of percutaneous transrenal balloon catheters.Materials and Methods: The indication for ureteral occlusion was persisting urinary leakage despite diversion by nephrostomy and drainage with atransurethral catheter. All patients had had previous treatment because of pelvic malignancy. Small Foley balloon catheters and angioplasty catheters were used. These devices were inserted percutaneously in an antegrade fashion. Results: In all but 2 of the patients the leakage ceased with the aid of these devices. Insufficient ureteral occlusion necessitated unilateral uretero–cutaneostomy in 1 patient. In another patient a vesico vaginal fistula was closed surgically. The maximum duration of occlusion was 169 (mean 94, range 45–169) days, without any evidence of ureteric pressure necrosis. Despite good overall results many adjustments and replacements of catheters were necessary because of recurrent urinary leakage caused by inadequate obstruction and/or leakage of the occluding catheters.Conclusions: We conclude that long–term ureteral occlusion with percutaneous transrenal balloon catheters appears to be safe and does not result in pressure necrosis. Using this approach, urinary fistula can heal in some patients without the need for open surgery.

Radionuclide therapy for prostate cancer lumbar metastasis prolongs symptom-free survival in a rat model.

OBJECTIVES The present study was initiated to explore the effects of hydroxyethylidene diphosphonate labeled with rhenium 186(186Re-HEDP) treatment on the progression of lumbar skeletal metastasis in an animal model and to correlate the eventual treatment efficacy with the radioisotope tissue distribution. METHODS The effect of 186Re-HEDP on the progression of lumbar metastasis from prostate cancer was investigated in the Copenhagen rat model. Metastatic prostate tumor deposits were induced in male rats by tail vein injection of R3327-MATLyLu prostate tumor cells under concomitant clamping of the inferior caval vein. The development of clinical symptoms such as onset of hind leg paralysis and urinary bladder swelling was monitored and related to the presence of tumor cells within histologic sections of L-5 and L-6 vertebrae. RESULTS The 186Re-HEDP administration, given either 1 day or 8 days after surgical induction of lumbar metastasis, could significantly increase the symptom-free survival of the animals. These results were confirmed by a significant decrease in the presence of histologically detectable tumor tissue. Biodistribution studies demonstrated the uptake of the major part of the radioisotope within bone tissue. Uptake of radioactivity within the lumbar vertebrae on a microscopic scale, as shown by phosphor screen autoradiography, was concentrated in areas of bone formation and turnover. Signs of radiotoxicity, such as bone marrow replacement by fat cells and the absence of megakaryocytes, were observed. CONCLUSIONS The results show that radionuclide treatment using 186Re-HEDP is a potentially efficacious treatment option in prostate cancer disseminated to the skeleton. The optimal treatment dose should be determined carefully and aimed at acceptable levels of myelotoxicity.

Early versus late androgen deprivation therapy in metastatic disease.

Patients presenting with metastatic prostatic cancer can be categorized into 3 groups. At present, most patients seen with metastases are those identified as having lymph-node disease when being assessed for curative therapy. The second group consists of patients with a high level of prostate-specific antigen, without symptoms, who are found incidentally to have asymptomatic bone metastases or metastases in soft tissue. The third group, who previously comprised about half of patients presenting with metastatic prostate cancer, are those presenting with painful metastases. There can be little doubt that most urologists will treat the second and third group of patients with hormone therapy at the outset. The question is whether the mere presence of lymph-node metastases or painless bony or soft tissue metastases justifies the side effects of long-term hormone therapy. A number of studies have shown a benefit in progression-free survival in the treatment of patients with lymph-node disease. Only 1 study has shown an advantage in overall survival. All studies of hormone therapy in asymptomatic and symptomatic metastatic disease have shown that serious complications of the disease can be avoided by offering hormonal therapy when the diagnosis is established. With the new generation of antiandrogens, differentiation therapies, and possibly alpha-reductase inhibitors, hormone therapy causes many fewer side effects than in the past and can be tolerated for longer periods of time. An aim of early hormonal therapy and its justification is a possible improvement in the quality of life of patients with metastatic prostate carcinoma, whose quantity of life cannot be lengthened.