Contrasting effects of an aminobisphosphonate, a potent inhibitor of bone resorption, on lipopolysaccharide-induced production of interleukin-1 and tumour necrosis factor alpha in mice

PURPOSE: To evaluate whether transient androgen deprivation improves outcome in patients irradiated after radical prostatectomy for locally advanced disease, persistent or rising postoperative prostate specific antigen (PSA), or local recurrence. METHODS AND MATERIALS: Records of 105 consecutive patients who were treated with pelvic irradiation after radical retropubic prostatectomy between August 1985 and December 1995 were reviewed. Seventy-four patients received radiation alone (mean follow up: 4.6 years), and 31 received transient androgen blockade with a gonadotropin-releasing hormone agonist (4) androgen receptor blocker (1) or both (24) beginning 2 months prior to irradiation (mean follow-up 3.0 years) for a mean duration of 6 months. Two of these patients were excluded from further analysis because they received hormonal therapy for more than 1 year. Patients received a prostatic fossa dose of 60-70 Gy at 2 Gy per fraction; 48 patients also received pelvic nodal irradiation to a median dose of 50 Gy. Survival, freedom from clinical relapse (FFCR), and freedom from biochemical relapse (FFBR) were evaluated by the Kaplan-Meier method. Biochemical relapse was defined as two consecutive PSA measurements exceeding 0.07 ng/ml. RESULTS: At 5 years after irradiation, actuarial survival for all patients was 92%, FFCR was 77%, and FFBR was 34%. FFBR was significantly better among patients who received transient androgen blockade before and during radiotherapy than among those treated with radiation alone (56 vs. 27% at 5 years, p = 0.004). FFCR was also superior for the combined treatment group (100 vs. 70% at 5 years, p = 0.014). Potential clinical prognostic factors before irradiation did not differ significantly between treatment groups, including tumor stage, summed Gleason histologic score, lymph node status, indication for treatment, and PSA levels before surgery or subsequent treatment. Multivariate analysis revealed that transient androgen deprivation was the only significant predictor for biochemical failure. CONCLUSION: This retrospective study of irradiation after radical prostatectomy suggests that transient androgen blockade and irradiation may improve freedom from early biochemical and clinically evident relapse compared to radiotherapy alone, although more prolonged follow-up will be needed to assess durability of impact upon clinical recurrence and survival rates.     

Postoperative radiation for cervical cancer with pathologic risk factors

PURPOSE: To examine the efficacy of postoperative radiation therapy for early-stage cervical cancer with pathologic risk factors. METHODS AND MATERIALS: We reviewed the charts of 83 patients who received postoperative radiation therapy at our facility from March 1980 to November 1993 for early stage cervix cancer with positive surgical margins, positive pelvic or periaortic lymph nodes, lymphovascular space invasion, deep invasion, or for disease discovered incidently at simple hysterectomy. Twenty-eight patients received low dose rate (LDR) intracavitary radiation with or without external beam pelvic irradiation and 55 patients received external beam pelvic irradiation with high dose rate (HDR) intracavitary implants. Of these 83 patients, 66 were evaluable--20 LDR and 46 HDR patients. All patients received 45-50 Gy external beam irradiation and 20 Gy LDR equivalent intracavitary irradiation prescribed to 0.5 cm below the mucosa. Ninety percent of the LDR group and 92% of the HDR group completed treatment within < 56 days. Treatment-related toxicities were scored according to the GOG toxicity scale. Mean and median follow-up times were 101 months and 111 months (3-172 months) for the LDR group and 42 and 40 months (3-98 months) for the HDR group. RESULTS: The 5-year disease-free survival was 89% for the LDR group and 72% for the HDR group. Local control was observed in 90% (18 out of 20) of the LDR patients and 89% (41 out of 46) of the HDR patients for an overall local control rate of 89.5%. Two of 20 LDR patients (10%) experienced recurrence (two pelvic with distant metastasis). Nine of 46 HDR patients (22%) had recurrence of disease (three pelvic, four distant metastasis, and two pelvic with distant metastasis). In the HDR group, 6 out of 16 (38%) with positive lymph nodes died of disease whereas, 27 out of 30 (90%) of the patients with negative lymph nodes remain free of disease. Three of 20 (15%) LDR patients and 4 out of 46 (9%) HDR patients experienced Grade 2 or 3 late treatment- related complications. No patient in either group had Grade 4 or 5 complications. Pathologic risk factors were analyzed. Lymph node positivity and lymphovascular space invasion were found to be significant (p = 0.01 and p = 0.02). Positive margins, deep invasion, and age were not significant. CONCLUSION: Our results demonstrate the efficacy of postoperative irradiation for cervical cancer with pathologic risk factors. Overall, the local control rate was 89.5% The HDR results demonstrate that this method can be delivered safely and effectively.     

Adjuvant systemic chemotherapy and hormonal therapy. Effect on local recurrence in the conservatively treated breast cancer patient

BACKGROUND: The purpose of this study is to determine the impact of adjuvant systemic chemotherapy and adjuvant hormonal therapy on local relapse in the conservatively treated breast. MATERIALS AND METHODS: Before December 1989, 548 patients underwent lumpectomy with axillary dissection followed by radiation therapy to the intact breast. Adjuvant systemic therapy was administered as clinically indicated. The majority of patients with pathologically involved lymph nodes received adjuvant systemic therapy, whereas those with pathologically negative lymph nodes received no adjuvant systemic therapy. The majority of patients received a course of radiation therapy either concomitant with or before systemic therapy. In only nine cases was radiation therapy delayed more than 16 weeks after surgery. RESULTS: As of June 1992, the 548 patients had a median follow-up of 6.4 years. In univariate and multivariate Cox regression analysis, patient age and adjuvant systemic chemotherapy were statistically significant independent prognostic factors relating to breast relapse. Those patients who received adjuvant systemic chemotherapy had a lower breast relapse than those who did not. Among patients who received tamoxifen, there was a statistically insignificant trend toward a lower relapse rate compared with those who did not receive tamoxifen. CONCLUSIONS: It appears from this retrospective analysis that patients who received adjuvant systemic therapy, either concomitantly or after their course of radiation therapy, had a lower relapse rate in the conservatively treated breast than those patients who received no adjuvant systemic therapy.     

Irradiation of clinically uninvolved cervical lymph nodes

Of 402 patients with cancers of the oral cavity, oropharynx, and supraglottic larynx treated at Stanford between 1957 and 1972, 164 had clinically uninvolved cervical lymph nodes prior to the initiation of radiation therapy. Lymph node metastases developed later in 38 per cent of patients with primary oral cavity carcinomas who were treated with interstitial radium implants alone. No late cervical lymph node involvement was found in those patients who received high dose external irradiation to at least the primary site and first echelon lymph nodes. Lymph node failures were ultimately noted in 20 of the 140 patients (14 per cent), who received partial or complete neck irradiation, but 18 of these occurred in patients with uncontrolled primary lesions, suggesting that re-seeding of cervical lymph nodes had taken place rather than failure of the initial irradiation to control subclinical metastases. Our present policy is to treat the primary lesion and adjacent lymph nodes with high dose megavoltage techniques, combined with interstitial irradiation if possible. Bilateral supplemental inferior neck radiation ports are added for patients with advanced primary neoplasms and for those with clinically involved cervical lymph nodes. All other patients undergoing radiation therapy for stage T1 primary lesions and clinically negative necks also receive ipsilateral low neck irradiation. In addition, cervical lymph nodes are electively irradiated when the primary lesion has been resected. When these policies are adopted, the incidence of cervical lymph node failures is extremely low in patients whose primary sites remain controlled, and morbidity from the cervical radiation fields is negligible.     

Generation of superoxide anion and induction of superoxide dismutase and peroxidase in bean leaves infected with pathogenic fungi

PURPOSE: The purpose of this study was to review management strategies with respect to systemic therapy, radiation therapy treatment techniques, and patient outcome (local regional control, distant metastases, and overall survival) in patients undergoing conservative surgery and radiation therapy (CS + RT) who had four or more lymph nodes involved at the time of original diagnosis. METHODS AND MATERIALS: Of 1040 patients undergoing CS + RT at our institution prior to December 1989, 579 patients underwent axillary lymph node dissection. Of those patients undergoing axillary lymph node dissection, 167 had positive nodes and 51 of these patients had four or more positive lymph nodes involved and serve as the patient population base for this study. All patients received radiation therapy to the intact breast using tangential fields with subsequent electron beam boost to the tumor bed to a total median dose of 64 Gy. The majority of patients received regional nodal irradiation as follows: 40 patients received RT to the supraclavicular region without axilla to a median dose of 46 Gy, 10 patients received radiation to the supraclavicular region and axilla to a median dose of 46 Gy. Thirty of the 51 patients received a separate internal mammary port with a mixed beam of photons and electrons. One patient received radiation to the tangents alone without regional nodal irradiation. Adjuvant systemic therapy was used in 49 of the 51 patients (96%) with 27 patients receiving chemotherapy alone, 14 patients receiving cytotoxic chemotherapy and tamoxifen, and 8 patients receiving tamoxifen alone. RESULTS: As of December 1994, with a minimum evaluable follow-up of 5 years and a median follow-up of 9.29 years, there have been 18 distant relapses, 2 nodal relapses, and 5 breast relapses. Actuarial statistics reveal a 10-year distant metastases-free rate of 65%, 10-year nodal recurrence-free rate of 96%, and a 10-year breast recurrence-free rate of 82%. All five patients who sustained a breast relapse were successfully salvaged with mastectomy. Both patients with nodal relapses (one supraclavicular and one axillary/supraclavicular) failed within the irradiated volume. Of the 40 patients treated to the supraclavicular fossa (omitting complete axillary radiation), none failed in the dissected axilla. With a median follow-up of nearly 10 years, 29 of the 51 patients (57%) remain alive without evidence of disease, 15 (29%) have died with disease, 2 (4%) remain alive with disease, and 5 (10%) have died without evidence of disease. Overall actuarial 10-year survival for these 51 patients is 58%. CONCLUSIONS: We conclude that in patients found to have four or more positive lymph nodes at the time of axillary lymph node dissection, conservative surgery followed by radiation therapy to the intact breast with appropriate adjuvant systemic therapy results in a reasonable long-term survival with a high rate of local regional control. Omission of axillary radiation in this subset of patients appears appropriate because there were no axillary failures among the 41 dissected but unirradiated axillae.     

Does pelvic irradiation play a role in the management of prostate cancer?

The optimal management of patients with lymph node-positive prostate cancer remains controversial. The role of pelvic irradiation in patients at high risk for nodal involvement continues to be debated. Studies of prostate irradiation with and without inclusion of the pelvic lymph nodes show poor outcomes for node-positive patients, supporting the concept that many of these patients have systemic disease at presentation. Although no randomized trial has examined the role of pelvic irradiation in pathologically node-positive patients, available data fail to reveal any significant benefit of this approach over prostate-alone irradiation. More promising therapeutic approaches involve the combination of local therapy and sustained hormonal therapy. Series comparing prophylactic irradiation of the pelvis and prostate to irradiation of the prostate alone have shown no clear benefit of pelvic irradiation. Pelvic irradiation may play a role in the treatment of early-stage or occult nodal disease, although this has yet to be examined. Until prospective, randomized trials demonstrate the efficacy of pelvic irradiation in the management of prostate cancer, its use cannot be routinely recommended. Data support the use of lymphadenectomy in high-risk patients to identify those with positive nodes, since these patients require androgen withdrawal therapy.     

Recurrent pericarditis due to mesalamine hypersensitivity: a pediatric case report and review of the literature

BACKGROUND: Uterine papillary serous carcinoma (UPSC) is an uncommon, aggressive type of endometrial cancer associated with an advanced stage at initial presentation, rapid progression of disease, and poor prognosis. METHODS: Twenty-three patients with UPSC were included in this study. History, treatment, follow-up, and 5-year overall survival probability (5-yr OS%) were evaluated. RESULTS: All women underwent total hysterectomy and bilateral salpingo-oophorectomy. Positive lymph nodes were found in 10 of 17 patients who underwent pelvic lymphadenectomy. Eight patients had FIGO Stage I/II, whereas 15 patients showed Stage III or IV tumors. After surgery 5 women underwent radiotherapy, 5 chemotherapy, and 8 both radiotherapy and chemotherapy. Chemotherapy consisted of cisplatin/carboplatin plus cyclophosphamide. Adjuvant irradiation consisted of vault and external beam irradiation. The median duration of follow-up was 39.4 months (25th and 75th percentiles; 26. 1, 68.1). The median overall survival was 43.3 months (12.9, 75th percentile not reached). Three of 10 patients who received only chemotherapy or radiotherapy are alive, whereas 7/8 patients who received a combination of both are alive with no evidence of disease at the time of reporting. The 5-yr OS% was 80% in those who received radio- and chemotherapy and only 30% in those who were treated with radiotherapy alone (log rank = 0.05). CONCLUSION: These results stress the need to study and evaluate the usefulness of combined chemo- and radiation therapy in patients with uterine serous papillary cancer.     

Induction androgen deprivation plus prostatectomy for stage T3 disease: failure to achieve prostate-specific antigen-based freedom from disease status in a phase II trial

OBJECTIVES: There is interest in treating prostate cancer with induction androgen deprivation prior to radical prostatectomy. Data on long-term prostate-specific antigen (PSA)-based survival analyses among patients treated with neoadjuvant hormonal therapy (NHT) and prostatectomy are limited. In 1991 we instituted a pilot study for T3 disease based on endorectal coil magnetic resonance imaging (eMRI), mandatory negative laparoscopic nodal dissection prior to hormonal manipulation, and prostatectomy followed by pathologic and PSA-based outcome determinations. METHODS: Of 26 patients, 21 had negative laparoscopic lymphadenectomy followed by 4 months of NHT (leuprolide +/- flutamide) prior to radical prostatectomy. eMRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3-month intervals. Prostatectomy specimens were evaluated by 3-mm whole-mount step sections. RESULTS: Prior to prostatectomy, biochemical response was documented in all patients and downsizing was observed by eMRI in 57%. Pathologic downstaging to a lower stage (T2c or lower) was achieved in 48%. However, the actuarial 3-year freedom from biochemical relapse rate was only 24%. CONCLUSIONS: Using laparoscopy to exclude node-positive patients and 4 months of NHT appears to result in pathologic and initial biochemical evidence of regression. These factors have not translated into improved freedom from biochemical relapse among patients with Stage T3 disease treated with NHT and prostatectomy. Recent data strongly suggest a beneficial effect in patients with clinical T2 disease treated with NHT and radical prostatectomy. The NGT and radical prostatectomy approach appeared to offer no clear advantage when compared with PSA-based benchmarks achieved with conformal irradiation or NHT followed by external beam treatment among patients with clinical T3 disease.     

A pivotal role for glutamate in the pathogenesis of schizophrenia, and its cognitive dysfunction

PURPOSE: To compare the outcome for patients with squamous cell carcinoma of cervical lymph nodes metastatic from an unknown primary site who were irradiated to both sides of the neck and potential mucosal sites with opposed photon beams, and for those irradiated to the ipsilateral side of the neck alone with an electron beam. METHODS AND MATERIALS: Fifty-two patients with squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site were irradiated by two different methods. Thirty-six were irradiated with a bilateral technique (BT), i.e., to both sides of the neck, including the naso-oro-hypopharyngeal mucosa, and 16 were irradiated with an electron beam (EB) to the ipsilateral side of the neck alone. Twenty patients of the BT group and 11 of the EB group had cervical lymph node dissections, and the remaining 21 patients had lymph node biopsies, prior to radiotherapy. RESULTS: Tumor control in the ipsilateral side of the neck did not differ for either radiation technique, but was significantly higher after lymph node dissection than after biopsy (90 vs. 48%; p = 0.0004). Control of subclinical metastases in the contralateral cervical lymph nodes was higher for patients irradiated with BT than for patients irradiated with EB (86 vs. 56%; p = 0.03). The occult primary was later discovered in 8% of the patients in the BT group and 44% of the EB group (p = 0.0005). The disease-free survival rate at 5 years for patients who had lymph node dissection prior to irradiation was 61%, and was 37% for those who had biopsy (p = 0.05). Only 20% of patients who subsequently developed an occult primary were salvaged and survived for 5 years after salvage treatment. CONCLUSION: Bilateral neck and mucosal irradiation is superior to ipsilateral neck irradiation in preventing contralateral cervical lymph node metastases and the subsequent appearance of an occult primary cancer. Both techniques combined with cervical lymph node dissection were equally effective in controlling the ipsilateral neck disease.     

Contemporary hormonal management of advanced prostate cancer

The traditional definition of "advanced" prostate cancer includes only patients with widespread osteoblastic or soft-tissue metastases (clinical or pathologic stage T any N any M1; or stage D2). Current evidence indicates that this definition should be broadened. Because many patients with T3 disease or local lymph node metastases progress to distant metastases, the concept of advanced prostate cancer should also include stages C and D1 (T3, T4, and any T N1). Furthermore, based on pretreatment prostate-specific antigen (PSA) levels, many men treated for clinically localized disease will progress rapidly and, depending on their age and general health, should be included in the advanced-disease category. Also, using prognostic marker modeling with PSA, tumor grade, and other factors, recurrences can be predicted even earlier in many cases. This may be particularly significant in light of recent clinical data indicating that early androgen ablation therapy delays disease progression and improves survival in patients with advanced (M0 or M1) disease. The luteinizing hormone-releasing hormone (LHRH) agonists have become the preferred method of androgen ablation in patients with advanced prostate cancer. Use of an LHRH agonist, alone or combined with an antiandrogen, is more acceptable to many patients than orchiectomy and lacks the potential cardiotoxicity associated with estrogens. Combined hormonal therapy remains controversial but may provide a modest survival benefit, especially in men with minimal metastatic disease. Intermittent hormonal therapy has great appeal, particularly because of the potentially deleterious effects of long-term hormonal therapy; however, its efficacy has yet to be proven.     

Impaired reactivity of rat aorta to phenylephrine and KCl after prolonged hypoxia: role of the endothelium

PURPOSE: The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS: Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION: This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.     

External beam radiation therapy as an agent in the aetiology of carcinoma of the bile duct: a report on two patients

Two cases of biliary duct carcinoma occurring in patients who had received prophylactic abdominal irradiation 17 years previously are described. Although external beam radiation has been implicated in the aetiology of many malignancies, there is only one previous report of it being associated with carcinoma of the bile duct. All patients receiving external beam irradiation for curable malignancies require long term follow-up so that treatment induced malignancies may be detected.     

Current studies of combined radiotherapy-hormone therapy in localized and locally advanced prostatic cancers

In locally advanced prostate cancer three clinical randomized trials have shown that external irradiation combined with LHRH analogue with or without antiandrogen improved survival: disease-free survival, local recurrence-free survival, metastasis-free survival (P < 0.001). EORTC trial 22863 alone has shown a significant improvement of overall survival (P = 0.001), with an LHRH analogue (goserilin acetate, zoladex) started the first day of irradiation and followed every 4 weeks for 3 years; for RTOG trial 85-31 the same LHRH analogue started during the last week of irradiation and given until relapse increases survival of patients with poor differentiated tumours with gleason score ranging from 8 to 10 (P = 0.03). In locally confined prostate carcinoma randomized trials are ongoing to assess the impact of conventional irradiation or three dimensional conformal radiotherapy with or without adjuvant hormonotherapy.     

Immunoepidemiology of Dracunculus medinensis infections I. Antibody responses in relation to infection status

OBJECTIVES: The sites of recurrent carcinoma of the prostate were localized with radiolabeled monoclonal antibody, and these sites were correlated with the response of patients treated with pelvic radiation after prostatectomy. METHODS: Radionuclide scans were performed with indium 111-labeled CYT-356, a monoclonal antibody that binds to prostate epithelial cells, in 48 men diagnosed with recurrent carcinoma detected by prostate-specific antigen (PSA) screening after radical retropubic prostatectomy. RESULTS: In 48 patients with recurrent carcinoma detected by PSA screening following radical retropubic prostatectomy, 73% had monoclonal antibody activity beyond the prostatic fossa, and only 3 patients (6%) had activity in the prostatic fossa alone; 65% had monoclonal antibody activity in pelvic lymph nodes despite the fact that lymph node dissections were pathologically negative at the time of prostatectomy in 90% of the patients; and 23% of patients had monoclonal antibody activity in abdominal and extrapelvic retroperitoneal nodes. Of 48 patients, 13 underwent external beam radiation therapy after monoclonal antibody scans. Six patients had scans showing activity beyond the field of radiation, and radiation therapy failed in 4 of these patients. Seven patients had scans with no activity beyond the field of radiation therapy, and radiation therapy failed in only 2 of these patients. CONCLUSIONS: The scans frequently show monoclonal antibody uptake in pelvic, abdominal, and extrapelvic retroperitoneal sites beyond the region of limited obturator node dissections and may account for the understaging and subsequent failure of radical prostatectomy in some patients. The monoclonal antibody scan seems to be a good predictor of which patients will respond to radiation therapy after radical prostatectomy, but because these patients often have nodal activity beyond the radiated field, this initial response may not be curative.     

Effectiveness of RF capacitive hyperthermia combined with radiotherapy for stages III and IV oro-hypopharyngeal cancers: a non-randomized comparison between thermoradiotherapy and radiotherapy

Seventy-two patients with Stages III and IV (TNM, UICC, 1987) squamous-cell carcinoma of the oropharynx and hypopharynx (oro-hypopharyngeal cancer) were treated with external irradiation, or irradiation plus 13.56 MHz radiofrequency (RF) capacitive hyperthermia from 1989 to 1995. This study compared initial response, histological effect and 5-year survival rate of thermoradiotherapy (TRT) group with those of radiotherapy alone (RT) group. In the TRT group, 15 patients were treated definitively, and 18 patients preoperatively. In the RT group, 15 patients were treated definitively, and 24 patients preoperatively. With definitive irradiation, the complete response rate of the primary lesions was 73% in the TRT group and 27% in the RT group (p = 0.009) and the complete response rate of the metastatic lymph nodes was 80% in the TRT group and 27% in the RT group (p = 0.005). With preoperative irradiation, the pathological CR (No residual cancerous cells) rate of the primary lesions was 56% in the TRT group and 8% in the RT group (p = 0.01), and the pathological CR rate of the lymph nodes was 72% in the TRT group and 21% in the RT group (p = 0.001). The 5-year survival rates with definitive irradiation were 47.6% in the TRT group and 18.7% in the RT group (p = 0.025). Thus TRT was more effective than RT for advanced oro-hypopharyngeal cancer.     

Therapeutic options in advanced cancer of the prostate

Drug therapy modalities in locally advanced and metastatic carcinoma of the prostate are primarily palliative. Therefore, the goal of systemic therapy is prevention or palliation of complications, such as pain, obstructive symptoms and bleeding. Thus far, there seems to be no survival benefit from hormonal treatment. The first step is always withdrawal of male sex hormones by means of orchiectomy or administration of LH-RH analogues, 70 to 80% of the patients respond favorably. Orchiectomy and LH-RH analogues are considered equal with regard to effectiveness and side effects, however, in the latter case an antiandrogen must be administered during the two weeks prior to start of treatment to prevent the flare-up phenomenon. Estrogens are rarely used anymore, because they can cause cardiovascular complications. In asymptomatic patients, the question remains to be answered if androgen withdrawal should be performed immediately at the time of diagnosis or delayed in case of possible symptoms. Antiandrogen agents block directly the androgen receptors in the prostatic cell. However, monotherapy with antiandrogens is not yet an established procedure. Instead, since 5% of circulating androgens are of adrenal origin, antiandrogens are combined with either orchiectomy or LH-RH analogues for total androgen suppression. The benefit of such a combined androgen suppression could not be proven conclusively and might be minimal at best. Novel modalities of hormonal therapy like intermittent androgen suppression are currently being investigated. In most cases, tumor progression after hormonal therapy is due to hormone-refractory cell lines. Cytotoxic chemotherapy is largely ineffective in treating prostatic cancer. Commonly used chemotherapeutic substances lead to temporary remission in 10 to 20% of the patients at most. External beam irradiation or Strontium-89 therapy are useful in palliation of painful bone metastases.     

Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study

PURPOSE: We compare the combination of orchiectomy and radiotherapy to radiotherapy alone as treatment for pelvic confined prostate cancer, that is T1-4, pN0-3, M0 (TNM classification). MATERIALS AND METHODS: In this prospective study 91 patients with clinically localized prostate cancer were, after surgical lymph node staging, randomized to receive definitive external beam radiotherapy (46) or combined orchiectomy and radiotherapy (45). Patients treated with radiotherapy alone had androgen ablation at clinical disease progression. The effects on progression-free, disease specific and overall survival rates were calculated. RESULTS: After a median followup of 9.3 years (range 6.0 to 11.4) clinical progression was seen in 61% of the radiotherapy only patients (group 1) and in 31% of the combined treatment patients (group 2) (p = 0.005). The mortality was 61 and 38% (p = 0.02), and cause specific mortality was 44 and 27%, respectively (p = 0.06), in groups 1 and 2. The differences in favor of combined treatment were mainly caused by lymph node positive tumors. For node negative tumors there was no significant difference in survival rates. CONCLUSIONS: The progression-free, disease specific and overall survival rates for patients with prostate cancer and pelvic lymph node involvement are significantly better after combined androgen ablation and radiotherapy than after radiotherapy alone. These results strongly suggest that early androgen deprivation is better than deferred endocrine treatment for these patients.     

Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer

CONTEXT: Interstitial radiation (implant) therapy is used to treat clinically localized adenocarcinoma of the prostate, but how it compares with other treatments is not known. OBJECTIVE: To estimate control of prostate-specific antigen (PSA) after radical prostatectomy (RP), external beam radiation (RT), or implant with or without neoadjuvant androgen deprivation therapy in patients with clinically localized prostate cancer. DESIGN: Retrospective cohort study of outcome data compared using Cox regression multivariable analyses. SETTING AND PATIENTS: A total of 1872 men treated between January 1989 and October 1997 with an RP (n = 888) or implant with or without neoadjuvant androgen deprivation therapy (n = 218) at the Hospital of the University of Pennsylvania, Philadelphia, or RT (n = 766) at the Joint Center for Radiation Therapy, Boston, Mass, were enrolled. MAIN OUTCOME MEASURE: Actuarial freedom from PSA failure (defined as PSA outcome). RESULTS: The relative risk (RR) of PSA failure in low-risk patients (stage T1c, T2a and PSA level < or =10 ng/mL and Gleason score < or =6) treated using RT, implant plus androgen deprivation therapy, or implant therapy was 1.1 (95% confidence interval [CI], 0.5-2.7), 0.5 (95% CI, 0.1-1.9), and 1.1 (95% CI, 0.3-3.6), respectively, compared with those patients treated with RP. The RRs of PSA failure in the intermediate-risk patients (stage T2b or Gleason score of 7 or PSA level >10 and < or =20 ng/mL) and high-risk patients (stage T2c or PSA level >20 ng/mL or Gleason score > or =8) treated with implant compared with RP were 3.1 (95% CI, 1.5-6.1) and 3.0 (95% CI, 1.8-5.0), respectively. The addition of androgen deprivation to implant therapy did not improve PSA outcome in high-risk patients but resulted in a PSA outcome that was not statistically different compared with the results obtained using RP or RT in intermediate-risk patients. These results were unchanged when patients were stratified using the traditional rankings of biopsy Gleason scores of 2 through 4 vs 5 through 6 vs 7 vs 8 through 10. CONCLUSIONS: Low-risk patients had estimates of 5-year PSA outcome after treatment with RP, RT, or implant with or without neoadjuvant androgen deprivation that were not statistically different, whereas intermediate- and high-risk patients treated with RP or RT did better then those treated by implant. Prospective randomized trials are needed to verify these findings.     

Basic principles and initial results of adjuvant hormone therapy and irradiation of prostatic carcinoma

Radiotherapy is an effective treatment for localized prostate cancer. A dose response relationship has been demonstrated for both local tumor control and complications. Reducing the volume of normal tissue treated may allow dose escalation without an increase in RT induced side effects. Androgen blockade before RT could, by reducing tumor volume, increase local control, disease-free (DFS) and overall survival in patients (pts) with prostatic adenocarcinoma. A total of 79 patients with T2-T4 prostate cancer have been treated initially with LHRH agonists and cyproterone acetate followed by radical irradiation between 1988 and 1993. The first cohort of 22 patients were monitored intensively by transrectal ultrasound and computed tomography. For each patient conformal photon beam radiotherapy and conventional treatment plans were produced and dose volume histograms compared for total volume, rectal volume, and bladder volume. Overall mean reduction of prostate volume was about 50%, and radiotherapy target volume was reduced by 37%. 53 further patients without clinical evidence of regional or distant metastases were given 3 months preradiotherapeutic hormonal cytoreduction with a short course of cyproterone acetate and LHRH. PSA level fell rapidly in most patients and after 3 months treatment the median PSA level was 1 ng/ml and 83% had PSA level 10 ng/ml. At 18 months PSA levels continued to be < 2 ng/ml in 70% of the patients. Combined modality treatment with the neoadjuvant or adjuvant androgen deprivation and conformal therapy show considerable promise as novel methods to improve the therapeutic ratio. This treatment approach may be used to explore the possibility of dose escalation in prostate cancer to enhance local control, and therapeutic randomised studies are underway to test these approaches.     

Hormonal treatment before radical prostatectomy: a 3-year followup

PURPOSE: Hormonal treatment administered before radical prostatectomy has been shown to decrease the rate of positive surgical margins. We determine whether preoperative hormonal treatment has any impact on the subsequent failure rate. MATERIALS AND METHODS: We prospectively evaluated 122 patients with stages T1bNxM0 to T3aNxM0, grades 1 to 3 prostate cancer, including 64 randomly assigned to immediate radical retropubic prostatectomy and 58 randomly assigned to radical retropubic prostatectomy preceded by 3 months of pretreatment with a gonadotropin-releasing hormone agonist. We performed intention to treat analysis on the data with failure defined as lymph node involvement, serum prostate specific antigen greater than 0.5 ng./ml., or the need for postoperative hormonal or radiation adjuvant treatment. RESULTS: The positive margin rate was 23.6 versus 45.5% in the pretreatment plus prostatectomy versus prostatectomy only groups (p = 0.016). There were 20 failures (34.5%) in the pretreatment plus prostatectomy subgroup and 26 (40.6%) in the prostatectomy only group (p = 0.48). A negative surgical margin was associated with a significantly lower risk of progression than a positive surgical margin (20.8 versus 50.0%, p = 0.0016), and progression was delayed by approximately 1 year after hormonal pretreatment. However, at a median followup of 38 months there was no difference in progression-free survival (p = 0.57). CONCLUSIONS: Although hormonal pretreatment significantly decreased the positive margin rate, it did not result in any difference in progression-free survival when followup exceeded 3 years. Thus, our current results do not support the routine administration of hormonal treatment before radical prostatectomy.