Intraoperative radiotherapy combined with external beam radiation for prostate cancer without metastasis

Between 1989 and 1996, 35 patients with prostate cancer without metastasis received intraoperative radiotherapy combined with external beam radiation. 10 of 16 stage B patients and all of 19 stage C patients received additional endocrine therapy for the initial treatment. The radiation therapy included 25-30 Gy of intraoperative radiotherapy for prostate and 30 Gy of external beam radiotherapy for small pelvic region. One patient of stage C was dead for cancer and 4 patient were dead for other causes during 15-99 (mean: 41.6) months follow up period. The overall actuarial survival at 5 years by Kaplan-Meier method were 92.3% for stage B and 87.2% for stage C. Although cystitis, proctitis and anal bleeding were observed as the adverse effects of radiotherapy, both acute and chronic symptoms were not critical. In conclusion, intraoperative radiotherapy combined with external beam radiotherapy was revealed as an effective treatment for prostate cancer without metastasis.     

Effect of UFT on treatment of urological cancer--effect of UFT on treatment of invasive bladder cancer and advanced prostate cancer. Ibaraki Urological Cancer Chemotherapy Study Group

A prospective randomized joint study was conducted to evaluate the usefulness of UFT 1) as a postoperative adjuvant therapy in patients with invasive bladder cancer who had undergone curative combination therapy with operation and/or chemotherapy and/or radiation therapy, 2) as an endocrine chemotherapy in patients with newly diagnosed stage C/D prostate cancer, for a period of 3 years from January, 1992. For bladder cancer, of 36 patients with invasive bladder cancer, clinically cured by combination therapy, 20 patients were treated with UFT as an adjuvant chemotherapy over 12 months, and they were compared to 16 patients with no adjuvant therapy. After excluding 10 inappropriate patients, 12 patients in the UFT treatment group and 14 patients with no adjuvant treatment group were observed. For prostate cancer, of 29 patients with clinically stage C/D prostate cancer, 13 were treated with endocrine therapy in combination with UFT, and 16 patients were treated with endocrine therapy alone. After excluding 7 inappropriate patients, 10 patients with endocrine chemotherapy and 12 patients with hormonal therapy were observed. The non-recurrence rate, survival rate and side effects of UFT were evaluated. In the study of bladder cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. In the study of prostate cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. These findings suggest UFT is less useful as an adjuvant therapy for the invasive bladder cancer and as an endocrine chemotherapy for newly diagnosed advanced prostate cancer.     

A prospective randomized trial for treating stages B2 and C prostate cancer: radical surgery or irradiation with neoadjuvant endocrine therapy

A randomized clinical trial of neoadjuvant endocrine therapy followed by either surgery or irradiation and a resumption of endocrine therapy for stages B2 and C prostate cancer has been in progress since 1989. A hundred patients entered the trial between 1989 and 1993, and 95 cases were evaluated. Forty-six patients received surgery and 49 were treated with irradiation. Neoadjuvant endocrine therapy for two months resulted in prostate shrinkage and prostate specific antigen lowering. Except for two patients, one dying of a progression of disease and the other of another concurrent cancer, all are alive with an average follow-up term of 25 (range 3-53) months. The good prognostic results obtained from both treatment groups at present seem to be due in part to the neoadjuvant endocrine therapy; but in order to reach a final conclusion further comparisons need to be made.     

HpSS: a new silver staining method for Helicobacter pylori

Fifty-seven patients with clinically localized prostate cancer were treated by radical prostatectomy or external radiation therapy following pelvic lymphadenectomy. Comparing the outcome of radiotherapy with that of prostatectomy in 42 T2 patients without lymph node metastasis, the 5-year cause-specific survival did not differ between the radical prostatectomy group (n = 31) and radiotherapy group (n = 11). The 5-year disease-free survival of the prostatectomy group, however, was superior to that of radiotherapy group (p = 0.01). To cure patients with T2 prostate cancer, therefore, it is supposed that radical prostatectomy should be performed. To improve the treatment outcome after radiotherapy, stereotactic radiosurgery for prostate cancer has been attempted in our institution. Phantom experiments using a linear accelerator demonstrated a round dose distribution, and high reproducibility of prostate positioning was confirmed by CT when a thermoplastic immobilization device was used to fix the pelvis. In one patient with localized prostate cancer treated by radiosurgery, acute complication has not been recognized during the 5 week follow-up. Radiosurgery may be available to treat clinically localized prostate cancer.     

Treatment of clinically localized prostatic cancer--endocrine therapy

We assessed the actuarial survival of 28 patients with localized prostate cancer who were treated with endocrine therapy in comparison with that of 19 patients who had radical prostatectomy between 1972 and 1995. There were no significant differences among the cause-specific curves and clinical disease-free survival of patients treated with endocrine therapy and radical prostatectomy but the all-cause survival curves favored the surgery group. The results of endocrine therapy alone were unsatisfactory for the patients with high grade tumors. In conclusion, the patients with localized prostate cancer at high risk of death from other complications are reasonable candidates for endocrine therapy.     

Treatment of metastatic prostate cancer: certainty and doubts

HIGH MORTALITY: Despite progress in early diagnosis, mainly due to prostate specific antigen (PSA) assay, metastasic cancer of the prostate remains an important health problem; more than 40,000 men died from prostate cancer in 1996 in the USA. More than 50 years after the hormone sensitivity of prostate cancer, antiandrogen therapy remains the cornerstone of treatment protocols. Although this is only a palliative therapy, it does delay disease progression for several years before the tumor inevitably escapes from hormone control. STAGE D1 DISEASE: In patients with microscopic nodal metastases (stage D1) it is classical to propose early or delayed hormone therapy which gives a 5-year survival rate in the 77-85% range. Certain teams also associate radical treatment (radical prostatectomy or pelvic prostate radiotherapy) with the hormone therapy, basically with the aim of better local control despite the lack of proven gain in survival rate. STAGE D2 DISEASE: Medical or surgical castration is the gold standard when the disease reaches stage D2. Specific treatments for urinary, neurological or bone complications may also be associated. Median survival is approximately 3 years. ASYMPTOMATIC PATIENTS: There remains a certain controversy about the best time to initiate treatment. Some advocate treatment immediately upon diagnosis while others propose delaying treatment until the onset of symptoms. There is a trend towards early treatment, but the beneficial effect in terms of survival and quality of life has not been proven. STAGE D3 DISEASE: When the tumor escapes hormone control (stage D3) mean survival is less than one year. Castration should be maintained and antiandrogens, which may have been given initially in combination with castration to achieve total androgen blockade, should be withdrawn (antiandrogen withdrawal syndrome) before assessing the need for second intention hormonal or other treatment. Such second intention regimens usually have a temporary and symptomatic effect. Their indication depends on side effects which may have a deleterious effect on quality of life. Symptomatic treatment plays a predominant role at this stage, combining analgesics, external or metabolic radiotherapy for bone pain, transurethral excision and/or urinary tract derivations for neurological or urological complications, and psychological care which requires the combined efforts of the radiotherapist, oncologist, urologist, and general practitioner.     

Science behind total androgen blockade: from gene to combination therapy

Probably the most important finding in the endocrine therapy of prostate cancer is that the testicles and adrenals contribute approximately equal amounts of dihydrotestosterone (DHT), the active androgen that stimulates normal and cancerous prostatic cell growth and function. Structure of the cDNAs and genes encoding most of the enzymes responsible for the transformation of the adrenal precursor dehydroepiandrosterone (DHEA) into DHT have recently been elucidated, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase, and 5 alpha-reductase. With the action of these enzymes, DHT is then made locally in the prostate from circulating DHEA of adrenal origin. Given such an important role of the adrenals, it is essential to use a pure antiandrogen for maximal blockade of the interaction of DHT with the androgen receptor while the testicles are blocked by orchiectomy or treatment with a luteinizing hormone-releasing hormone (LHRH) super-agonist. This combination therapy was first developed to treat advanced prostate cancer. The multicenter clinical data recently obtained confirm our original data and demonstrate the major importance of the intracrine or in situ formation of androgens in the human prostate from the inactive adrenal steroid precursors. Combination therapy thus permits, for the first time, to prolong life in advanced prostate cancer and, most importantly, offers the possibility of a major improvement in the efficacy of a curative therapy, namely, radical prostatectomy in early stage disease.     

Mu-Ghayeb: a culture-specific response to bereavement in Oman

BACKGROUND: Preoperative endocrine therapy has been suggested to improve surgical radicality and/or patient prognosis in prostate cancer. METHODS: Patients with clinical stage A2, B, and C prostate cancer were randomized to either group I (n = 113) or group II (n = 111). Group I patients were to receive preoperative endocrine therapy consisting of leuprolide and chlormadinone for 3 months, followed by radical prostatectomy with lymph node dissection. Group II patients were to undergo the surgery before endocrine therapy. RESULTS: Group I patients showed a remarkable decrease in prostate-specific antigen (PSA) (mean +/- SE: 41.8 +/- 8.6 ng/mL to 2.7 +/- 0.7 ng/mL) and prostate volume (29.8 +/- 1.7 mL to 21.2 +/- 1.6 mL) during the preoperative therapy. Histopathologic analysis showed a significant difference in the rates of down-staging (19.1% in group I versus 3.3% in group II), positive surgical margins (63.8% versus 81.3%) and positive lymph node metastasis (20.7% versus 36.5%). No significant difference was detected in operating features. Subgroup analyses indicated that beneficial effects were correlated positively with degree of histologic differentiation and negatively with the basal PSA level. CONCLUSIONS: Preoperative endocrine therapy reduced local extension of prostate cancer, and the effects depended on histologic differentiation and PSA level. Long-term follow-up data are needed to determine the effects on the patient prognosis.     

Incidence and clinical significance of false-negative sextant prostate biopsies

PURPOSE: Since most patients do not undergo repeat sextant prostate biopsies after a biopsy is positive for prostate cancer, the true incidence of false-negative biopsies is not well defined. We assess the incidence and clinical significance of false-negative sextant prostate biopsies in patients undergoing radical prostatectomy. MATERIALS AND METHODS: A total of 118 patients with biopsy proved prostate cancer underwent repeat sextant prostate biopsy before enrollment in a prospective randomized trial of radical prostatectomy with or without neoadjuvant hormonal therapy. Clinical parameters were assessed to determine potential sources of bias. Pathological parameters and prostate specific antigen relapse-free survival rates were compared to determine the clinical significance of false-negative biopsies. RESULTS: Of the 118 patients 27 (23%) had a negative repeat sextant biopsy. Except for initial clinical stage, no differences were noted in the clinical or pathological parameters, or prostate specific antigen relapse rates in patients with negative versus positive repeat biopsies. CONCLUSIONS: Our findings suggest that this 23% incidence of false-negative biopsies represents significant cancer. This relatively high incidence is important to consider in treatment modalities in which prostate biopsy may be performed to determine response to therapy.     

Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.     

Predictors of survival for prostate carcinoma patients treated with salvage radical prostatectomy after radiation therapy

BACKGROUND: Salvage radical prostatectomy is a treatment option for patients with recurrent cancer following radiation therapy. This study was conducted to identify predictors of survival for patients treated with salvage radical prostatectomy. METHODS: The authors studied 86 prostate carcinoma patients who underwent salvage radical prostatectomy for locally persistent or recurrent prostate carcinoma at Mayo Clinic between 1967 and 1996. The mean interval from radiation therapy to biopsy-proven recurrence was 3.7 years (range, 6 months to 17 years). Patient age at surgery ranged from 51 to 78 years (median, 66 years). The mean follow-up after surgery was 5.8 years (range, 1.0-15.2 years). Cox proportional hazards models were used to identify clinical and pathologic factors associated with distant metastasis free survival and cancer specific survival. RESULTS: Actuarial distant metastasis free survival, cancer specific survival, and overall survival were 83%, 91%, and 85% at 5 years and 69%, 64%, and 54% at 10 years, respectively. In multivariate analysis, radical prostatectomy Gleason score and DNA ploidy were independent predictors of distant metastasis free survival and cancer specific survival. CONCLUSIONS: Postirradiation Gleason score and DNA ploidy were highly predictive of the clinical outcomes of patients treated by salvage radical prostatectomy after radiation therapy.     

Taxotere in various solid tumors]

One of the delicate problems in a cancer treatment is the acquisition of a tolerance for a medicine. Antiandrogen treatment is valid in treatment of prostate cancer, but the disease develops into hormone-refractory prostate cancer after a uniformity period. The molecular mechanisms of recurrence and endocrine therapy failure in prostate cancer have remained unclear. In this paper we discuss the hormone-refractory prostate cancer that has been reported by many investigators.     

Radiation therapy with neoadjuvant hormonal therapy for prostate cancer confined to pelvis

Neoadjuvant endocrine treatment prior to radical prostatectomy for prostate cancer confined to pelvis has of some value to prevent progression although there are many controversies. In order to improve the prognosis of locally advanced prostate cancer (stage B2 and C), definitive radiotherapy with neoadjuvant endocrine therapy has been investigated. Endocrine therapy reduces the volume of prostate, thus reduces the amount of side effect via reducing the area of irradiated normal tissue. Effect of radiation and that of endocrine therapy to induce apoptosis might be synergistic. The result is favorable although the follow-up period is too short. Further studies are needed to make conclusion.     

Prostate-specific antigen in the diagnosis of organ-confined treatable prostate carcinoma

Prostate cancer is now the most common cancer and the second most common cause of death from cancer among men. Several studies have shown a frequency of autopsy-detected cancer of 40% in men over 50 years of age. In contrast, the lifetime probability of prostate cancer being diagnosed clinically is only 8%. Thus histologically documented prostate cancer only becomes clinically relevant if the tumors are > 0.5 cm3 and the life expectancy exceeds 10 years. Therapy with curative intention is only possible for organ confined disease. Because disease specific survival is about 80-90% after 10 years for conservative treatment of organ confined disease, early detection of prostate cancer is useful for patients with a life expectancy > 10 years. Organ confined prostate cancer is usually asymptomatic. The use of prostate specific antigen (PSA) combined with digital rectal examination (DRE) results in a 2-3 fold increase in prostatic carcinoma detection rate, especially of organ confined disease, by PSA. In men with a minimally elevated PSA-value of 4-10 ng/ml (Hybritech Assays), 25% will have a prostatic carcinoma regardless of the finding of the DRE, which would have reached clinical significance in the follow-up. The indication for biopsy should be established at an early date. There is no support for the common opinion that early detection programs detect clinically unimportant cancers. 95% of tumor volumes are > 0.5 cm3. Furthermore only 3-5% of subjects show prostate cancer in detection programs though 8% will develop clinical symptoms of prostate cancer during their lifetime. This difference is a reason for longitudinal programs with PSA and DRE control once a year, as proposed by the American Cancer Society and the American and Canadian Urological Association, in contrast to other health care organizations, which would wait with general screening until data from prospective randomized trials with beneficial effects of screening are available. To introduce prostate cancer therapy with curative intention for symptomatic patients as well, the cancer should be detected below a PSA level of 10 ng/ml. Insufficient specificity of PSA (2-4 patients have to undergo biopsies to detect one cancer patient) is still an unsolved problem.     

Clinical studies on the prognostic factors in prostate cancer

To evaluate the prognostic factors and the outcome of treatment, a retrospective study was done on 141 patients with prostate cancer who were newly diagnosed at Kitano Hospital between January 1985 and November 1996. In recent years, the number of patients and the ratio of low stage cancer have increased. The overall 5-year crude survival rate was 49.9%. The 5-year crude survival rate for clinical stage A, B, C and D was 67%, 70%, 62% and 30% respectively. The overall 5-year disease-specific survival rate was 65.6%. The 5-year disease-specific survival rate for clinical stage A, B, C and D was 100%, 89%, 72% and 42%, respectively. By univariate analysis, clinical stage, Gleason score, prostate specific antigen (PSA) level, and patient age were prognostic factors for disease-specific survival of prostate cancer. According to Cox's regression analysis by the stepwise forward regression method, clinical stage and Gleason score were selected as more valuable prognostic factors than PSA level, patient age, comorbidity, and initial treatment. In Gleason score 2 to 8, the prognosis became significantly worse as clinical stage advanced, but in Gleason score 9 and 10 the prognosis was poor regardless of clinical stage.     

Hormone ablation therapy as neoadjuvant treatment to radical prostatectomy

Two hundred consecutive patients with presumed localized prostate cancer had radical prostatectomy alone (n = 119) or were treated for an average period of 3 months with combination therapy using the antiandrogen flutamide and one luteinizing hormone-releasing hormone (LHRH) agonist (Lupron or Zoladex). The positive margins decreased from 35.3% in the group undergoing prostatectomy alone to 11.5% in the group of men who received combination therapy before radical prostatectomy. In 41 apical tumors, the incidence of positive margins decreased from 50% in the control group to 18.6% in the combination therapy group. In stage C disease, the incidence of positive tumor showed a tendency to decrease with the extended duration of endocrine treatment with a rate of 37.5% after 3 months and 16.7% after 6 months. Whether the decreased incidence of positive surgical margins will all translate into prolonged survival remains to be verified by long-term follow-up of these patients. However, the initial results obtained in the present study are very encouraging.