Intermittent hormone therapy and its place in the contemporary endocrine treatment of prostate cancer.

Castration results in dangerous and disabling side effects. Deferred hormone therapy has been shown to be associated with decreased survival. Intermittent hormone therapy (IHT) was attempted initially to reduce morbidity of treating metastatic prostate cancer with stilboestrol. Preclinical work using castrate mice with hormone sensitive prostate tumours demonstrated that pulses of testosterone delayed the onset of androgen independent growth and PSA production in these mice. This led to development of clinical treatment protocols for use in phase II trials by a number of centres in a variety of clinical scenarios. These phase II trials demonstrated apparent safety of this approach, prompting several large scale RCTs. Thus far no difference in survival has been demonstrated between IHT and continuous hormone therapy despite large numbers and prolonged follow-up. Quality of life has been proven to improve with stopping hormone therapy. A recent meta-analysis and multivariate analysis of phase II studies provides a unique opportunity to identify features of the various published IHT protocols which engender treatment success and allow the following recommendations to be made which may guide the clinician in devising their own IHT protocol. A PSA nadir below 1 ng/ml has been shown to be the best determinant of when it is safe to stop treatment. It can be achieved after as little as three months in patients with local disease. Patients with metastatic disease should be treated for at least eight months. Restarting treatment when the PSA rises to 15 ng/ml prolongs survival. MAB or LHRH monotherapy should be the standard of care in all patients with possible exception of recurrent disease after radiotherapy or prostatectomy where anti-androgen monotherapy may be appropriate. Initial PSA and the level of the PSA nadir achieved enable definition of prostate cancer patients in whom this approach may define a subgroup of local disease patients in whom it may be safe to avoid radical therapy. Preclinical and clinical data from a phase II trial demonstrating that addition of finasteride prolongs the off treatment period and provide the impetus for a randomized controlled trial (RCT) to prove this.

Long-term follow-up of testicular cancer patients shows no predisposition to osteoporosis.

UNLABELLED: Most patients with testis cancer are cured with treatment. However, the incidence of osteoporosis after prolonged follow-up is unknown. This study investigates the incidence of osteoporosis in 39 testis cancer patients with follow-up from 5 to 28 years. There was no increased incidence of osteoporosis. These initial data are reassuring but require further investigation. INTRODUCTION: The majority of patients with testis cancer are cured with either a unilateral orchidectomy alone or orchidectomy and chemotherapy. However, the long-term incidence of osteoporosis following treatment for testicular cancer has not been established. METHOD: This was a single-centre cross-sectional study, where bone mineral density (BMD) measurements were performed in male patients who were previously treated for testicular cancer. BMD measurements were made by dual-energy X-ray scanning (DXA) using a HOLOGIC imaging bone densitometer. The World Health Organisation criteria were used to define osteoporosis and osteopenia. Blood samples were taken from each patient at the time of the DXA scan. Statistical analyses were performed in STATA10. RESULTS: Neither orchidectomy alone nor orchidectomy and chemotherapy together predisposed to osteoporosis [p value = 0.4 (95%CI -0.1-0.8) and p value = 0.2 (95%CI -0.2-0.7), respectively]. Analysis also showed no evidence of an association between cases of osteopenia and length of follow-up (assessed by logistic regression). CONCLUSION: This work found no association between treatment for testis cancer and the development of osteoporosis. Screening the whole population of testis cancer survivors for osteoporosis in the long term is not necessary; however, targeting specific patients with risk factors may be warranted.

Pitfalls in the diagnosis of prostatic cancer: retrospective review of 1791 cases with clinical outcome.

AIMS: To assess the possible reasons for error in the diagnosis of prostatic cancer with available follow-up data. METHOD AND RESULTS: A cohort of 1791 cases of prostatic cancer diagnosed in the UK between 1990 and 1996 was examined. All cases were clinically localized at presentation, treated by non-curative methods and detailed follow-up was available. A panel of genitourinary pathologists reviewed the pathology of all cases. One hundred and thirty-three (7.5%) of cases were reassigned to a non-malignant diagnosis. Where possible, reasons for the initial diagnosis were given. These included severe atrophy, inflammatory induced atypia, sclerosing adenosis, atypical adenomatous hyperplasia and basal cell hyperplasia. Follow-up of these patients showed an extremely low death rate from prostatic cancer: lower than that for the Gleason combined score of five or less tumours diagnosed in this series. CONCLUSIONS: Many morphological entities potentially mimic prostatic cancer and may be responsible for misdiagnosis in routine specimens. Continuing education in prostatic morphology and immunohistochemistry may have helped reduce this error rate.

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.

Molecular characterisation of the t(1;15)(p22;q22) translocation in the prostate cancer cell line LNCaP.

Although chromosome translocations are well-documented recurrent events in hematological malignancies and soft tissue sarcomas, their significance in carcinomas is less clear. We report here the molecular characterization of the reciprocal translocation t(1;15)(p22;q22) in the prostate carcinoma cell line, LNCaP. The chromosome 1 breakpoint was localized to a single BAC clone, RP11-290M5, by sequential FISH analysis of clones selected from the NCBI chromosome 1 map. This was further refined to a 580-bp region by Southern blot analysis. A 2.85-kb fragment spanning the der(1) breakpoint was amplified by long-range inverse PCR. The breakpoint on chromosome 1 was shown to lie between the CYR61 and the DDAH1 genes with the der(1) junctional sequence linking the CYR61 gene to the TSPAN3 (TM4SF8) gene on chromosome 15. Confirmatory PCR and FISH mapping of the der(15) showed loss of chromosome material proximal to the breakpoint on chromosome 15, containing the PSTPIP1 and RCN2 genes. On the available evidence we conclude that this translocation does not result in an in-frame gene fusion. Comparative expressed sequence hybridization (CESH) and comparative genomic hybridization (CGH) analysis, showed relative down-regulation of gene expression surrounding the breakpoint, but no gross change in genomic copy number. Real-time quantitative RT-PCR for genes around the breakpoint supported the CESH data. Therefore, here we may have revealed a gene down-regulation mechanism associated with a chromosome translocation, either through small deletion at the breakpoint or through another means of chromosome domain related gene regulation.

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

Does human papillomavirus play a role in the development of bladder transitional cell carcinoma? A comparison of PCR and immunohistochemical analysis.

AIM: To investigate the role of human papillomavirus (HPV) in the development of bladder transitional cell carcinoma (TCC). METHODS: Seventy eight paraffin wax embedded TCC samples were tested for the presence of HPV by two methods. First, immunohistochemistry was carried out using a polyclonal antibody capable of detecting the capsid protein of all known papillomaviruses. The second method was a consensus GP5+/6+ primer mediated polymerase chain reaction (PCR) technique, with the products analysed by both agarose gel electrophoresis and an enzyme immunoassay using type specific oligonucleotide probes for 10 different mucosal genotypes. To exclude false negative results because of the poor quality of DNA extracted from paraffin wax embedded samples, the series was extended to include 20 further blocks for which the corresponding snap frozen unfixed tissue was available. RESULTS: The two methods produced contrasting results, with 47 of the 78 samples positive for HPV antigen and none positive for HPV DNA. HPV DNA was not detected in the 20 additional paraffin wax embedded TCCs or in the 20 paired unfixed samples. In contrast, HPV DNA was amplified by PCR from all six of the paraffin wax embedded cervical carcinoma and anogenital wart control samples. CONCLUSION: The disparity between the two sets of results is probably caused by false positives resulting from the non-specificity of the polyclonal antibody used for immunohistochemistry. These results suggest that HPV is unlikely to play an aetiological role in the development of bladder TCC.

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.

The frequency of intratubular embryonal carcinoma: implications for the pathogenesis of germ cell tumours.

AIMS: To define the frequency and distribution of intratubular embryonal carcinoma (IEC) in an attempt to shed light on the pathogenesis of non-seminomatous germ cell tumours (NSGCTs). Intratubular germ cell neoplasia of unclassified type (IGCNU) is common in NSGCT; however, IEC is rarely described. METHODS AND RESULTS: Sixty-two germ cell tumours were reviewed. Immunochemistry for CD30, placental alkaline phosphatase (PLAP) and c-kit was performed. The distribution, immunohistochemistry and morphology of the intratubular neoplasia were noted. All cases showed widespread IGCNU with PLAP and c-kit staining. CD30 showed strong focal intratubular positivity in 20/31 NSGCTs, 1/29 seminomas and 1/4 mixed seminomas/NSGCTs. In 17 of these cases, the CD30+ tubules were not easily identified as IEC on routine stains. These tubules were scanty in number and c-kit was negative, though some showed patchy PLAP staining. The cells within these tubules differed morphologically from IGCNU. CONCLUSIONS: IEC defined by CD30 positivity is not always easily identified on haematoxylin and eosin staining. We suggest that IEC is a common intermediate step between IGCNU and NSGCTs. The patchy and focal distribution of IEC suggests it may evolve quickly to invasive disease.

Detection of genetic alterations in primary bladder carcinoma with dual-color and multiplex fluorescence in situ hybridization.

Cytogenetic studies of bladder cancer have shown several nonrandom aberrations. Numerical aberrations of both sex chromosomes were investigated in 32 primary bladder tumors with bicolor fluorescence in situ hybridization (FISH). Loss of chromosome Y and overrepresentation of chromosome X were observed in subgroups of male patients. Chromosome X was represented normally in female patients. Two of the above primary bladder tumors, a transitional cell carcinoma (TCC) and an adenocarcinoma, were further analyzed with both multiplex FISH (24-color M-FISH) and G-banding. Both cases exhibited 1) common breakpoints on 5q11 approximately q12 and 15q24; 2) involvement of the pericentromeric area of chromosome 13; 3) structural abnormalities of chromosomes 8 and 17, with loss of material on the short arm; 4) structural abnormalities involving chromosome 11; and 5) loss of chromosome Y. The TCC case also exhibited structural abnormalities of chromosome 9, resulting in loss of 9q. The combined G-banding and M-FISH findings could help reveal regions potentially involved in bladder tumorigenesis.

Long-term follow-up of Anglian Germ Cell Cancer Group surveillance versus patients with Stage 1 nonseminoma treated with adjuvant chemotherapy.

OBJECTIVES: To study survival and late events after adjuvant chemotherapy in Stage 1 nonseminoma. METHODS: From 1978 to 1986, all patients had surveillance. From 1986, adjuvant chemotherapy (initially a 3-day regimen of etoposide, bleomycin, and cisplatin, but, more recently, bleomycin, Oncovin, and cisplatin) was offered to patients at a high risk of relapse (greater than 30%). RESULTS: A total of 382 patients with Stage 1 nonseminoma treated between 1978 and 2000 were reviewed. Of the 234 patients treated by surveillance, 71 (30%) had relapses (5 after 2 years), 6 died (2.6%) of germ cell cancer, and 3 developed second primary testicular cancer. Of the 148 men treated with adjuvant chemotherapy, 6 (4%) had relapses and 2 (1.4%) died of chemoresistant cancer. After one course of etoposide, bleomycin, and cisplatin, 3 (6.5%) of 46 developed a relapse; after two courses, 1 (3.6%) of 28 did so; and after bleomycin, Oncovin, and cisplatin every 10 days x2, 2 (2.7%) of 74 patients did so. Of the high-risk patients who were offered adjuvant treatment, 24% declined. As a consequence, the relapse rate of the surveillance patients only fell from 36% to 27% after the introduction of adjuvant therapy, although for the total cohort treated in the adjuvant era, the relapse rate was 16%. CONCLUSIONS: Adjuvant chemotherapy is more effective than retroperitoneal lymph node dissection for reducing the relapse risk in high-risk Stage 1 nonseminoma. However, given the uncertainty about the incidence of postchemotherapy late events, surveillance and retroperitoneal lymph node dissection remain justified alternatives. With positron emission tomography and laparoscopy showing increasing promise in these cases, quality-of-life studies and greater patient involvement in treatment selection are needed.

Testis conserving chemotherapy in germ cell cancer: its potential to increase understanding of the biology and treatment of carcinoma-in-situ.

Prompted by recognition of the potential of chemotherapy to increase the success of testis conserving surgery in patients with germ cell cancer, background and outcome data are reviewed and their contribution to the ongoing debate about how germ cell cancer develops discussed. The review is based on three previous studies of: a) time trends in tumour size in 578 personal series of all stages of testis cancer treated since 1978; b) impact of chemotherapy on actuarial risk of tumours in contralateral testis examined on 1221 patients treated in trials through the Anglian Germ Cell Cancer Consortium; and c) testes conservation attempted using chemotherapy in 78 patients. Since 1978 tumour size has decreased from 4.8 to 3.0 cms while cure has gone from 77 to 97%. There was no overall long term reduction in second cancers beyond 10 years in stage 1 patients after orchidectomy alone compared to stage 1 or metastatic disease patients receiving chemotherapy though the incidence was non significantly lower up to 10 years particularly in those patients receiving etoposide based combination. Testis conservation was initially successful in 28 of 78 (36%). An additional 25 (32%) had no viable cancer in orchidectomy specimen. In the 28 primary tumours cured by chemotherapy there was a 26% late relapse rate between 5 and 10 years (all cured by orchidectomy) compared to less than 5% in those cured with established metastases. In conclusion, testis conservation with chemotherapy is safe and feasible, though relapse is too frequent for routine service use. Confirmation of the high frequency of late relapse by others has raised the question whether these recurrences are due to post pubertal events reinducing CIS in intrauterine oestrogen primed germ cells and highlights the potential of testes conservation studies to better understand germ cell cancer development.

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.

Post-biopsy rise in serum PSA. A potential tool for the dynamic evaluation of prostate cancer/prostatic intraepithelial neoplasia (PIN).

OBJECTIVES: The biochemical response of prostatic cells to needle core biopsies is known to manifest as a rise in serum PSA. The aim of this study is to evaluate the PSA response to mechanical trauma in prostate cancer patients, when compared to benign controls. MATERIALS AND METHODS: 50 consecutive patients undergoing transrectal ultrasound guided prostatic needle biopsies had their total serum PSA measured thirty minutes after the procedure. Change from the baseline PSA was estimated and correlated to histology. RESULTS: Data was analysed in 48 patients (mean age 68 years; range 55-87 years). Histology showed benign, cancer and PIN results in 24, 19 and 5 patients respectively. The highest rise in post biopsy PSA was observed in the PIN group. A significant difference in the rise in serum PSA was noted between controls and the cancer group. CONCLUSION: Post biopsy PSA response differs significantly between benign and malignant prostatic tissue. PIN causes an excessive in PSA values on mechanical stimulation. This small study indicates that the biopsy model may help us to assess the dynamics of prostate cancer.