The efficacy of tacrolimus and sirolimus in heavily pre-treated unresectable thymic malignancies.

BACKGROUND: Thymomas and thymic carcinomas, although uncommon, constitute a significant proportion of anterior mediastinal tumours. Systemic chemotherapy is the mainstay of treatment for inoperable or recurrent disease, but immunosuppressive therapy may provide an alternative treatment strategy. PATIENTS AND METHODS: We present a series of 18 patients diagnosed with unresectable thymic tumours, of which eight received immunosuppressive therapy following relapse after chemotherapy. RESULTS: Eight individuals were treated with primary immunotherapy after a median of 3.5 lines of chemotherapy (range 2-6 lines), of which 3 had confirmed myasthenia gravis (MG). After 3 months, 2 patients achieved a radiological partial response and 4 had stable disease. The median time to progression measured 6.8 months (CI 1.4-19.3 months). Two of the 4 patients who progressed on tacrolimus and prednisolone received sirolimus. One of these patients has stable disease (SD) at 21 months, and the other has SD at 3 months. CONCLUSIONS: Although previous case reports have related tacrolimus therapy with tumour shrinkage in patients with MG-associated invasive thymomas, these data are the first to demonstrate the efficacy of such immunosuppressive agents in a larger cohort of heavily pre-treated patients with thymic tumours. Our experience adds to the limited anecdotal evidence in the literature, and suggests that immunosuppressive agents represent a valuable additional treatment for thymic tumours.

A phase II study investigating the re-induction of endocrine sensitivity following chemotherapy in androgen-independent prostate cancer.

When chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7-10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P=0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIPC.

GAMEC--a new intensive protocol for untreated poor prognosis and relapsed or refractory germ cell tumours.

There is no consensus as to the management of untreated poor prognosis or relapsed/refractory germ cell tumours. We have studied an intensive cisplatin-based regimen that incorporates high-dose methotrexate (HD MTX) and actinomycin-D and etoposide every 14 days (GAMEC). Sixty-two patients were enrolled in a phase 2 study including 27 who were untreated (IGCCCG, poor prognosis) and 35 with progression despite conventional platinum based chemotherapy. The pharmacokinetics of the drugs were correlated with standard outcome measures. Twenty of the untreated patients were progression free following GAMEC and appropriate surgery, as were 18 individuals in the pretreated group. None of the established prognostic factors for therapy for pretreated patients could identify a poor-prognosis group. Five out of nine late relapses to prior chemotherapy were progression free following GAMEC and appropriate surgery. All patients had at least one episode of febrile neutropenia and there were five (8%) treatment-related deaths. PK values were not predictive of efficacy or toxicity, although the dose intensity in the pretreated group of patients, especially of HD MTX, was significantly correlated with progression-free survival (PFS). GAMEC is a novel intensive regimen for this group of patients producing encouraging responses, although with significant toxicity. For those in whom it fails, further therapy is still possible with durable responses being seen.

A phase II study using a topoisomerase I-based approach in patients with multiply relapsed germ-cell tumours.

BACKGROUND: The outcome of patients with germ-cell tumours (GCTs), who relapse more than once or relapse with a mediastinal primary is poor. We have shown that topoisomerase 1 may be an attractive target in relapsed GCT. We investigated the role of irinotecan, paclitaxel and oxaliplatin (IPO) followed by topotecan-based high-dose therapy in responding patients, in this patient population. PATIENTS AND METHODS: Twenty-eight patients with multiply relapsed gonadal and mediastinal GCT were recruited to this phase 2 study. All patients received IPO chemotherapy and 12 (43%) went on to receive high-dose therapy. The outcome of these patients was assessed using the Kaplan-Meier method with a median progression-free follow-up of 1 year. RESULTS: Twenty patients (71%) responded to the therapy including five complete remissions (18%), 13 (46%) marker-negative partial responses and two (7%) marker-positive partial responses. Nine (32%) patients continue to be progression free, and the median survival for the whole group currently measures 17 months. Out of 12 individuals who received subsequent high-dose therapy consolidation, seven (58%) remain progression free. The commonest grade III/IV toxicity was infection (68%) and there were no IPO-related toxic deaths; there was one death from high-dose therapy. CONCLUSION: Topoisomerase I-based IPO chemotherapy that lacks etoposide is very active in multiply relapsed GCT. This data merit further investigation.

Chlorambucil and lomustine (CL56) in absolute hormone refractory prostate cancer: re-induction of endocrine sensitivity an unexpected finding.

The management of androgen independent prostate cancer is increasingly disputed. Diethylstilbestrol and steroids have useful second-line activity in its management. The value of chemotherapy still remains contentious. This paper reports a phase 2 study of two orally active chemotherapy drugs in patients who are absolutely hormone refractory having failed primary androgen blockade and combined oestrogens and corticosteroids. In total, 37 patients who were biochemically castrate with absolute hormone refractory prostate cancer and performance status of 0-3 were enrolled. Therapy consisted of chlorambucil 1 mg kg(-1) given as 6 mg a day until the total dose was reached and lomustine 2 mg kg(-1) given every 56 days (CL56). During this time all hormone therapy was stopped. One patient normalised his PSA with a further two having a greater than 50% decline leading to an objective response rate of 10%. The median time to progression was 3.6 months with an overall survival of 7.1 months. The median survival of this group of patients from first becoming androgen independent was 23.5 months. Eight of 17 (47%) patients who were subsequently re-challenged with hormonal therapy following failure of chemotherapy had a further PSA reduction, three (17%) of which were >50%. The median progression-free interval for the eight patients was 4 months. In conclusion, CL56 has a low objective response rate in the management of absolute hormone refractory prostate cancer. Toxicity was mild. Re-induction of hormone sensitivity following failure of chemotherapy was an unexpected finding that requires further study.

Long-term outcomes in patients with prostate cancer managed with intermittent androgen suppression.

OBJECTIVES: To assess the long-term outcomes of patients with prostate cancer managed with intermittent androgen suppression (IAS) following their enrollment in an open, non-randomised feasibility study initiated 10 years ago. PATIENTS AND METHODS: Patients with prostate cancer who developed marked side effects following androgen deprivation were considered for entry into the study. All patients were required to have been managed with androgen deprivation for a minimum of 9 months and to have achieved PSA remissions to levels <4 ng/ml or falls to greater than 90% of pre-treatment levels. Patients remained off treatment until PSA values rose to >20 ng/ml or individuals became symptomatic--at which stage a 9-month cycle of androgen suppression was repeated. Such on-off cycling continued until hormone-resistant disease developed and patients proceeded (off trial) to second-line therapies. RESULTS: 75 patients were recruited to the study following an initial referral with treatment-related side effects specifically associated with androgen deprivation. 86% of these remain alive at a median of 134 months (11 years) since initial histological diagnosis. Survival times and times to hormone resistance (from first cycle hormone deprivation) have also been calculated. Overall there is a median survival time of 95 months (8 years) from initial (first-cycle) androgen deprivation in those presenting with localised or locally advanced disease and a median survival time of 87 months (7 years) for those presenting with metastatic disease. There exists a median of 83 months to hormone resistance in the localised and locally advanced group and a median of 50 months in those presenting with metastatic disease. We have calculated a 100% 5-year actuarial survival rate for those presenting with localised or locally advanced disease (from time of first cycle hormone ablation) and a 70% 5-year actuarial survival rate for those presenting with metastatic. CONCLUSIONS: Long-term outcome figures and actuarial survival rates presented here provide further support for a pulsed or intermittent approach to androgen ablation in patients with prostate cancer. In addition, they serve as valuable extended outcome data for patients managed in this way. Likewise, data presented here suggests that apparent survival advantages appear related, at least in part, to a delay in the onset of androgen resistance and that such a management approach is both safe and effective in those presenting with both metastatic disease as well as those with more localised pathology.

IPM chemotherapy in cytokine refractory renal cell cancer.

Renal cell carcinoma (RCC) is notoriously chemoresistant. Current management of metastatic disease usually includes immunological agents of which the most clearly evaluated is alpha interferon. Following the failure of such agents no clear second-line therapy exists. The use of a novel combination of cisplatin, irinotecan and mitomycin may offer some palliative benefit in this situation. Thirty-three patients with cytokine refractory RCC and documented progression and documented active progressive disease with performance status 0-3 were enrolled. Therapy consisted of cisplatin 40 mg m(-2) on day 1 and day 15, irinotecan 100 mg m(-2) on day 1 and day 15, and mitomycin 6 mg m(-2) on day 1 of a 28-day cycle. The results showed that one patient (3%) had a partial response, eight (24%) had minor responses and nine (27%) had stable disease, overall 61% had symptomatic responses. Quality-of-life (QOL) assessment did not change significantly during therapy. Seventy-one percent of those who had primary refractory disease to cytokine therapy subsequently responded to IPM. The median progression-free interval was 4.8 months in this cohort on chemotherapy, compared to 3.9 months with their previous cytokine treatment. In conclusion, IPM produced symptomatic relief for a majority of patients with cytokine refractory RCC without any deterioration in QOL. Disease stabilisation on radiological assessment and symptomatic improvement were associated with prolonged survival. A degree of non-crossresistance to cytokine therapy was seen. IPM may be considered in patients with renal cancer following failure of cytokines.

Multidisciplinary team working in urological cancer: one CNS's role.

The 'cancer journey' for a patient with urological cancer can be complicated, with many different specialists involved and many treatment options. The uro-oncology clinical nurse specialist's role in one multidisciplinary team is to provide support, information and a link between all the staff involved in the patient's care.

Stilboestrol plus adrenal suppression as salvage treatment for patients failing treatment with luteinizing hormone-releasing hormone analogues and orchidectomy.

OBJECTIVE: To investigate the efficacy of low-dose stilboestrol (SB) with hydrocortisone in patients with advanced prostate cancer refractory to androgen suppression. PATIENTS AND METHODS: Thirty-four consecutive patients (median age 70 years, range 51-83) with metastatic disease who progressed on hormone therapy, as shown by recurrent/worsening symptoms and an increase in prostate-specific antigen (PSA) level, were recruited and discontinued hormonal treatment before starting SB. Patients received SB (1 mg/day) combined with hydrocortisone (40 mg/day). In an attempt to reduce the incidence of thrombo-embolic events, aspirin (75 mg/day) was also added. RESULTS: Stilboestrol was the second-line treatment in 19 patients and the third or fourth in 15. The median (range) duration of treatment with SB was 5 (0.5-21) months and the median follow-up 7.5 months, with 18 patients still alive and 14 still on treatment. Of 29 symptomatic patients, 24 had symptomatic improvement and five had no clear benefit; the median duration of benefit was 6 (2-21) months. The PSA level decreased by 0-50% in six patients, by 50-90% in 13 and by > 90% in eight, while there was symptomatic improvement in these three categories in five, 11 and seven patients, respectively. The median times to PSA nadir and progression were 4 and 6 months, respectively. Some thrombo-embolic events and fluid retention occurred but overall the treatment was well tolerated. CONCLUSION: Low-dose SB with hydrocortisone is effective in refractory prostate cancer, although there is some toxicity. Randomized studies against hydrocortisone or SB alone are needed to establish the cost/benefit ratio of this combination.

Potential of intermittent hormone therapy for M+ and M0 prostate cancer patients.

Increasingly animal and clinical studies suggest that intermittent therapy may improve the duration of hormone dependence in patients with prostate cancer. However there remains uncertainty as to optimal duration of treatment and level of prostate-specific antigen (PSA) before treatment is restarted. The aim of this study was to identify risk factors that predict duration of therapy in prostate cancer patients receiving intermittent hormone therapy. Any patients who had achieved PSA complete remission after hormone therapy for metastatic or locally advanced prostate cancer were included in the study. Fifty patients entered on intermittent hormone therapy after achieving a PSA complete remission. In all, 57% of patients remained off treatment at 12 months and the median time for restarting further hormone therapy was 14 months. At 1 y, 95% of patients retreated are progression free and overall 92% are alive at 3 y. There was some evidence that there was a slower progression to require treatment in older M0 patients and those who had been on treatment for more than 9 months. Although M0 patients receiving radiation concurrently after initial hormone down staging had a slower recurrence rate, 53% of M0 patients treated with hormone alone remained off hormones for more than one year. Clearly selection cannot be excluded as a cause for this good survival. However as overall survival in this study is at least as good as that of patients with M0 disease on hormone therapy in the immediate arm of the MRC immediate vs deferred therapy study, there is a case to extend examination of this approach to a randomized trial. This might also include patients failing to achieve PSA complete remission in order to examine the issue of whether continued androgen withdrawal is required in the terminal treatment phase of hormone-resistant patients to keep the hormone sensitive clone under control. Prostate Cancer and Prostatic Diseases (2000) 3, 286-289

Radiofrequency heat-treatment to the prostate for bladder outlet obstruction associated with benign prostatic hyperplasia: a 4-year outcome study.

OBJECTIVES: To evaluate the long-term effect on symptom relief and voiding performance of prostatic radiofrequency thermal treatment for bladder outlet obstruction (BOO) associated with benign prostatic enlargement (BPE). PATIENTS AND METHODS: During 1991-1994, 151 patients (mean age 76 years, range 49-91) with symptomatic BOO associated with BPE (i.e. reduced urinary flow rate and persistent residual urine) but with no clinical evidence of carcinoma of the prostate, were treated using the Thermex II (Direx, Israel) intraurethral radiofrequency (RF) prostatic thermal treatment system. This treatment rates the intraurethral temperature to 48 degrees C for 3 h in a single session under local anaesthesia. The patients were followed using symptom scores and uroflowmetry for 24-48 months after treatment. RESULTS: At 1 year, 70% had a good outcome, but by 3 years this had fallen to 40% and at 4 years to 22%. An increase in mean urinary flow rate, from 9 to 12 mL/s, was sustained throughout the follow-up. There was a reduction in mean residual urine from 83 to 51 mL at 6 months, but this increased to 70 mL by 3 years (not significant). The voiding pressure, which declined at 6-12 months, increased again to near pre-treatment values at 1-2 years. CONCLUSIONS: In patients with symptomatic BPE, prostatic thermal treatment with RF relieves symptoms in 60% for at least 2-3 years. In selected cases it is a useful form of management, as it can be performed as a day-case with minimal risk. Changes in standard objective variables were small but statistically significant for at least one year. The study highlights the importance of waiting for late results from clinical trials.

Urethral anaesthesia with topical bupivacaine. A role for a longer-acting agent.

OBJECTIVE: To assess the efficacy and toxicity of bupivacaine as a topical urethral anaesthetic. PATIENTS AND METHODS: This prospective two-part study comprised a pilot study of 10 men (mean age 73 years, range 39-86), to determine the toxicology, pharmocokinetics and suitable preparation of bupivacaine gel, and a study of 40 men (mean age 76 years, range 59-92) to compare the efficacy of bupivacaine with lignocaine gel. All patients were undergoing treatment for benign prostatic hyperplasia by transurethral radiofrequency heating using the Direx Thermex II system. RESULTS: There were no major adverse events. Bupivacaine provided good topical anaesthesia with a mean duration of 141 min, compared with 29 min for lignocaine. Serum samples taken from patients showed that the drug was absorbed slowly, and with a dose of 50 mg there was a wide margin between serum drug concentrations and toxic levels. CONCLUSION: Bupivacaine is safe and effective as a topical anaesthetic agent in the urethra in circumstances where prolonged duration of action is desirable. For lower urinary tract procedures 20-22 mL of anaesthetic gel is required, giving 2-3 h of analgesia/anaesthesia with no significant toxicity or adverse effect. The application of longer-acting anaesthetic agents need not be only during surgical intervention, but might usefully be extended post-operatively to provide early management of pain.