Radiotherapy for regionally localized hormone refractory prostate cancer

PURPOSE: Patients with regionally localized hormone refractory adenocarcinoma of the prostate are often referred for radiotherapy to relieve local symptoms, prevent further local progression, or prevent impending urinary tract obstruction. However, the merits of radiotherapy for this patient population have not been documented. In this retrospective series, the results of 29 such patients treated at our institution between 1987-1992 are reviewed. METHODS AND MATERIALS: Prior to androgen ablation, the majority of these patients (79%) had Stage D0 or D1 disease. After androgen ablation, radiotherapy was given to 16 (55%) for progressive symptoms (mostly urinary obstructive), 11 (38%) for palpable local progression in the absence of symptoms, and 2 for a rising prostate specific antigen (PSA) profile without palpable disease. None of the patients had distant metastasis at the time of radiotherapy. The median dose to the prostate was 66 Gy and the median follow-up after radiotherapy was 43 months. RESULTS: Following local-regional radiotherapy, the actuarial rate of local failure at 4 years was only 39%. However, 80% had disease progression or a rising PSA in this time period. The actuarial survival at 4 years following radiotherapy was 39%. Univariate analyses of potential prognostic factors revealed that preandrogen ablation Gleason score, preradiotherapy PSA, and preradiotherapy prostatic acid phosphatase (PAP) were predictive of patient outcome. Most importantly, doses above 60 Gy to the prostate at standard fractionation were associated with symptom-free local control in 90% of patients at 3 years. The majority of the patients were treated using limited fields (n = 20). CONCLUSIONS: The regionally localized hormone refractory prostate cancer patients described benefited from high dose, continuous course, local radiotherapy in that excellent local control rates were obtained for an extended period. Because the majority of these patients fail with distant metastasis within 4 years, this treatment represents an aggressive approach to palliation that is justified by the maintenance of freedom from local symptoms.     

Regression of prostatic cancer metastasis by high doses of diethylstilbestrol diphosphate

Diethylstilbestrol diphosphate (DES-P) has shown effective symptomatic relief in patients with metastatic carcinoma of the prostate. Although there is little known about its role in soft tissue metastasis, our experience in 3 patients with advanced carcinoma of the prostate infiltrating the trigone and ureterovesical junction revealed significant improvement of hydronephrosis. All patients failed to respond to conventional doses of stilbestrol. Diethylstilbestrol diphosphate is recommended in the treatment of advanced carcinoma of the prostate with soft tissue metastasis. It is safe and effective, and the tumor responses outweigh the side effects of the drug. The mechanism of action of this compound is discussed.     

High-dose intravenous steroid pulse therapy in thyroid-associated ophthalmopathy

MIcrospheres containing diclofenac sodium (DS) were prepared using carboxymethylcellulose (CMC) as the main support material (1.0, 2.0, 3.0% (w/v)) and aluminum chloride as the crosslinker. Drug to polymer ratios of 1:1, 1:2 and 1:4 were used to obtain a range of microspheres. The microspheres were then coated with an enteric coating material, Eudragit S-100, efficiency, % yield value, particle sizes an in-vitro dissolution behaviour were investigated. The surface of the enteric coated microspheres seemed to be all covered with Eudragit S-100 from scanning electron microscopy observation. It was also observed that increasing the CMC concentration led to an increase in the encapsulation efficiency, % yield value and particle size and decreased the release rate. Eudragit S-100 coating did not significantly alter the size but the release rate was significantly lower even when the lower concentration solution was used.     

Management of hormone refractory prostate cancer: current standards and future prospects

PURPOSE: Recent advances in the biology and treatment of hormone refractory prostate cancer are reviewed. MATERIALS AND METHODS: A MEDLINE literature search of secondary hormonal therapy and chemotherapy for hormone refractory prostate cancer was performed. Recent advances in the biology of hormone refractory prostate cancer, changes in the measurement of response to therapy, and testing of new drugs and combinations of drugs were reviewed. RESULTS: Historically the treatment of hormone refractory prostate cancer has been disappointing. Useful parameters to monitor clinical response have been lacking but perhaps more importantly a scarcity of apparently active drugs has contributed to these results. Recently several developments have improved the outlook for treatment of hormone refractory prostate cancer. Recognition of antiandrogen withdrawal responses has had important ramifications for clinical trial interpretation and patient care. Secondary hormonal therapies, such as alternative antiandrogens and anti-adrenal agents, are well tolerated and can provide significant clinical benefits. Combining prostate specific antigen values with quality of life and measurable disease responses has made clinical trial end points more objective and more clinically relevant for the patient. Furthermore, a better understanding of the biology of hormone refractory prostate cancer, refinements in measuring response to treatment and availability of agents with proved palliative capabilities and/or generating greater than 50% response have all lead to improvements in treatment management. In 2 randomized studies mitoxantrone in combination with steroids has demonstrated significant palliative benefit compared with steroids alone. In phase II studies more than half of patients respond to estramustine combinations with vinblastine, etoposide or paclitaxel. Other novel combinations and new drugs currently are being tested. CONCLUSIONS: Recent advances suggest that available therapies for hormone refractory prostate cancer can have a meaningful impact on the disease. Improving treatment of hormone refractory prostate cancer remains an area of active investigation.     

High-dose rate iridium192 afterloading therapy in combination with external beam irradiation for localized prostate cancer

The number of donors aged 60 years and over has increased. This study examined discard rates and transplant outcomes in organs recovered from older donors. Data were obtained using a standard tool for donors aged 60 years and older during 1993 and 1994 and included demographics, medical history, use of vasopressors, renal/liver function studies, organ disposition, biopsy findings, and recipient organ function. Of 58 kidneys recovered, 24 were transplanted, 26 were used for research, and 8 were discarded. Of 14 livers recovered, 11 were transplanted, 1 was used for research, and 2 were discarded. Sixty-three percent of kidney recipients had immediate function; 79% at 30 days. Nine liver recipients had immediate function; 6 at 30 days, with 1 graft lost. Results show that kidneys and livers can be transplanted from older donors with positive outcomes. Factors such as medical history, use of vasopressors, and organ function studies may help predict organ disposition and function.     

High-dose dexamethasone therapy for a 14-month-old boy with refractory idiopathic thrombocytopenic purpura

A 14-month-old boy with refractory idiopathic thrombocytopenic purpura (ITP), who was successfully treated with pulsed high-dose oral dexamethasone therapy is reported. The platelet count increased after six scheduled courses of treatment (10 mg/day x 4 days, six courses). Twenty-four months later, the platelet count remained over 10.0 x 10(4)/microL. No obvious side effects were observed during or after the therapy. This treatment could be taken into consideration not only for adults but also for young children with refractory ITP. It is effective, safe, easy to administer, patient comfort is taken into consideration, and hospitalization duration and costs are minimized.     

Recent advance in luteinizing hormone-releasing hormone analogue therapy in management of prostate cancer

Luteinizing hormone-releasing hormone (LHRH) analogue therapy is one of the most widely used hormonal therapy for prostate cancer. LHRH analogue is effective and safety therapy for prostate cancer, when appropriate consideration is given to the disease flare. Recently, new long acting 3-month LHRH analogue depot has been developed and showed the therapeutic equivalence to the 1-month depot. In basic research, the expression of LHRH and its receptor has been demonstrated in some kinds of hormone depend cancer including prostate cancer. Although precise role of LHRH system in those cancers remains unclear, these findings suggests the presence of an autocrine system based on LHRH. More understanding of LHRH system might provide new treatment approaches to those cancer.     

Prospects for gene therapy in human prostate cancer

Prostate cancer is the most common neoplasm in men and a significant cause of mortality in affected patients. Despite significant advances, current methods of treatment are effective only in the absence of metastatic disease. Gene therapy offers a renewed hope of using the differential characteristics of normal and malignant tissue in constructing treatment strategies. Several clinical trials in prostate cancer gene therapy are currently under way, using immunomodulatory genes, anti-oncogenes, tumor suppressor genes and suicide genes. A continued understanding of the etiological mechanisms involved in the establishment and progression of prostate cancer, along with advances in gene therapy technology, should make gene therapy for prostate cancer therapeutically valuable in the future.     

Clinical application for gene therapy in prostate cancer

We report a patient with peripheral neuropathy caused by cisplatin for the treatment of testicular tumor. Routine studies of nerve conduction and somatosensory evoked potentials demonstrated large myelinated fiber neuropathy suggesting ganglioneuronopathy. We also performed a CO2 laser evoked potential study, and found that small myelinated fibers, which are related to pain sensation, were well preserved in this patient.     

Usefulness of initial chemoendocrine therapy for advanced prostate cancer

The 5 year cancer specific survival rate of advanced prostate cancer, especially in metastatic cancer is less than 40%. Recently, maximum androgen blockade showed some beneficial effects in cases of minor disease but no additional usefulness in major cases. The treatment modality referred to as initial chemoendocrine, used to treat prostate cancer, seems to be a reasonable method because prostate cancer cells contain heterogeneity. This procedure means that the endocrine treatment is best suited to treat hormone sensitive cells, whereas chemotherapy is more appropriately used as a firstline therapy for hormone insensitive cells. We reported that the initial chemoendocrine method showed superiority in the 5 year cancer specific survival category than in the endocrine therapy analyzing non-randomized trials. From that stage on we reviewed the beneficial point of the treatment, and are now trying randomized control studies.     

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.     

Combination chemotherapy with cis-platinum and ifosfamide for hormone unresponsive prostate cancer

PURPOSE: There is no effective therapy against hormone refractory prostate cancer. This led us to evaluate the effectiveness and toxicity of cis-platinum (CDDP) and ifosfamide (IFM) combination chemotherapy in the patients with hormone-unresponsive carcinoma of the prostate. METHODS: Patients with hormone-unresponsive prostate cancer were scheduled to receive CDDP 70 mg/m2 intravenously on day 1 and IFM 1.2 g/m2/day intravenously on day 1 through day 5 of 28-day cycle. RESULTS: Twenty seven patients with hormone unresponsive prostate cancer were enrolled onto this trial. Of these patients, seven (26%) demonstrated a partial objective response (PR), and ten (37%) a stable disease (ST). The response duration of PR cases lasted from 6 to 49 months with a median of 16 months and the response duration of PR + ST cases lasted from 3 to 36 months with a median of 10 months. Subjective improvement was obtained in 11 patients (41%). Survival duration of all cases were 4 to 89 months with a median of 23 months and probabilities of survival at 3 years and 5 years were 36% and 24%, respectively. The toxicity of this treatment was mostly mild to moderate, anemia (96%), leukocytopenia (89%), anorexia (81%), alopecia (67%), thrombocytopenia (44%), hematuria (38%), renal dysfunction (19%) and liver dysfunction (7%) were noticed. Severe toxicity was observed in two cases, one acute renal failure and one endotoxin shock. CONCLUSION: We conclude that CDDP and IFM combination chemotherapy was active regimen for hormone unresponsive prostate cancer.     

The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acetate

BACKGROUND: Although many physicians measure serum prostate specific antigen (PSA) during the follow-up of patients with hormone refractory prostate carcinoma (HRPC), little has been done to formalize the determination of how these serial values of PSA impact on prognosis. To understand HRPC fully, make decisions about choices of treatment as well as about clinical research on treatments for HRPC patients, and design appropriate measures of PSA response, it seems that first it would be necessary to understand how these serial measures of PSA relate to survival. The purpose of this study was to determine how repeated measurements of PSA impact on the probability of imminent death for patients with HRPC. METHODS: One hundred forty-eight men with HRPC were enrolled in Cancer and Leukemia Group B Study 9181, in which they were treated with either a low dose (160 mg/day) or a high dose (640 mg/day) of megestrol acetate (MA). Because preliminary data analysis indicated that these treatments had no effect on survival, the authors pooled the data to analyze the overall dynamics of PSA and survival during the follow-up period. The authors attempted to correlate initial and monthly PSA measurements, which were mandated by the study protocol, with the probability of death at any time during follow-up. For statistical analysis, the Cox proportional hazards model and the general linear model were used. In addition to the level of PSA, the authors used the relative velocity of PSA, which was defined as (dy/dt)/y, with "y" symbolizing serum PSA and "t" symbolizing time. RESULTS: Both log(PSA) and the average relative velocity of PSA (rva) were significantly correlated with survival time (P=0.0001 and P=0.0008, respectively), and the analysis performed with the Cox proportional hazards model yielded the following formula for a PSA hazard score: PSA hazard score =0.251*(log(PSA) - mean log(PSA)) + 24.5*(rva - mean rva) This hazard score tended to be higher for patients who were about to die. For example, there was a close correlation between the hazard score and the probability of death as the next observed event. Furthermore, the hazard score provided a dynamic measure of how PSA was affected by treatment. CONCLUSIONS: The average relative velocity of PSA has been identified by the authors as a new measure of the dynamics of PSA in HRPC. It can be determined from sequential values of PSA. This average, together with the log(PSA), are significantly related to the probability of imminent death.     

Application and limitation of neoadjuvant hormonal therapy for prostate cancer

Of 156 patients, 111 (clinical stage T1a-b; 21, T1c; 17, T2a-b; 36, T2c; 27, T3; 10) immediately underwent radical prostatectomy (surgery group), and 45 (clinical stage T1a-b; 8, T1c; 4, T2a-b; 10, T2c; 9, T3; 14) received neoadjuvant hormonal therapy (NHT group). NHT offered probability of increasing organ-confined cancer(OCC; pathological stage pT2 or lower N0M0) in the following group, which contains (a) patients who had moderately differentiated adenocarcinoma in the biopsy specimen and T2b or lower diseases, and (b) those who had well differentiated adenocarcinoma, T2c diseases and PSA levels of 10 ng/ml or higher, referred to as "OCC suitable criteria". Of 156 patients, 51 (33%) met OCC suitable criteria. In those cases, the proportion of OCC in NHT group was significantly higher than that in surgery group (11/12 (92%) vs. 16/39 (41%), p = 0.002). NHT is useful for increasing OCC in patients who meet OCC suitable criteria.     

High-dose therapy with cytostatic agents as primary treatment of advanced breast cancer

Thousands of women with breast cancer have received high dose chemotherapy prior to the results from controlled clinical trials being known. As one of these patients the author reviews and discusses the results of the first randomised study from South Africa. High dose therapy with autologous stem cell support was compared with conventional chemotherapy in 90 young women with metastatic aggressive breast cancer. Though survival was short in both groups the disease free survival was doubled in the high dose group. A significant increase was found in response rate, duration of response and survival. Data from America show the cost effectiveness of this treatment to be comparable to that of other life-saving therapies. A comparison is made with the absolute and relative survival benefit of simvastatin treatment. A Norwegian White Paper on high dose therapy does not include advanced breast cancer in the planned trial protocols. It is argued that future health planning should give high priority to the treatment of advanced breast cancer in young women.