Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001).

BACKGROUND: Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease. METHODS: Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m(-2) day 1, cisplatin 60 mg m(-2) day 1, 5-flurouracil 750 mg m(-2) per day days 1-5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival. RESULTS: 10/26 evaluable patients (38.5%, 95% CI: 20.2-59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event. CONCLUSION: Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.

Do all patients with bilateral testis cancer have a hereditary predisposition?

An international study has demonstrated that patients with bilateral testicular cancer are significantly more likely to have brothers with testis cancer than those with unilateral disease. This, together with other evidence, implies that patients with bilateral disease are likely to carry a predisposing genotype. But is it the great majority of them which is thus predisposed? We show that if as few as half of these patients have the predisposing genotype, its penetrance would have to be 80%, causing 38% of resulting cases to be bilateral. Evidence from the International Testis Cancer Linkage Consortium shows that the proportion of familial cases with bilateral disease is much lower. It is likely that at least the majority of cases of bilateral testis cancer arise as a result of a predisposing genotype.

A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder.

PURPOSE: We conducted a multicenter randomized trial in the United Kingdom to determine the efficacy of radical radiotherapy in reducing the incidence of progression of pT1G3 transitional cell carcinoma of the bladder to muscle invasive disease and subsequent disease fatality. MATERIALS AND METHODS: Patients with a new diagnosis of pT1G3 NXM0 transitional cell carcinoma with unifocal disease and no carcinoma in situ (group 1), or with multifocal disease and/or carcinoma in situ (group 2) were eligible for the trial. Patients in group 1 were randomized between observation and radiotherapy to the bladder, and in group 2 between intravesical therapy and radiotherapy. RESULTS: From September 1991 to February 2003 a total of 210 patients from 37 centers in the United Kingdom were entered into the study. There were 77 patients in group 1 and 133 patients in group 2, and 6 patients were excluded from analysis because they were found to have pT2 disease by the reference pathologist. No evidence of an advantage with radiotherapy was found in terms of progression-free interval (hazard ratio 1.07; 95% CI 0.65, 1.74; p = 0.785), progression-free survival (hazard ratio 1.35; 95% CI 0.92, 1.98; p = 0.133) or overall survival (hazard ratio 1.32; 95% CI 0.86, 2.04; p = 0.193). CONCLUSIONS: To our knowledge this is the largest randomized trial performed in patients with pT1G3 disease for which 210 patients were recruited during 11 years. There is no evidence that radiotherapy is better than more conservative treatment. The prognosis of this group of patients appears to be poor irrespective of treatment and new treatment strategies need to be investigated.

A second look at the pT1 G3 bladder tumour.

People with pT1 G3 bladder cancer are at high risk of tumour progression and death. Induction and maintenance intravesical Bacillus Calmette-Guerin (BCG) has been proven to reduce tumour progression in superficial bladder cancer at moderate risk of progression. By extrapolation, this treatment is often now given for pT1 G3 bladder cancer. Phase II studies published over the past 10 years on the use of adjuvant intravesical BCG following transurethral resection (TUR) of the tumour(s) suggest an important effect on the number of patients progressing. The data are mixed, however. A randomised study of the use of adjuvant radiotherapy in pT1 G3 bladder cancer has shown that it is not of benefit and that, overall, the progression rate remains high. Early cystectomy for high-risk cases is not commonly used, and its results are often disappointing, presumably a consequence of negative selection. Identification of patients at extra high risk of progression is desirable. Tumour size, the co-existence of carcinoma in situ and early tumour recurrence may be prognostic indicators, but the data are at present insufficient.

Adjuvant bleomycin, vincristine and cisplatin (BOP) for high-risk stage I non-seminomatous germ cell tumours: a prospective trial (MRC TE17).

Adjuvant BEP (bleomycin, etoposide, cisplatin) is effective treatment for high-risk clinical stage I (HRCS1) non-seminomatous germ cell tumours (NSGCT), but the known toxicities of etoposide, and the expansion of the HR group to any patient with vascular invasion (50% of patients), led the Medical Research Council to pilot the BOP regimen. Patients received two courses of BOP 14 days apart: cisplatin 50 mg m(-2) days 1 and 2, vincristine 1.4 mg m(-2) (max. 2 mg) days 2 and 8, bleomycin 30,000 IU days 2 and 8. Primary outcome was relapse rate; quality of life, fertility, hearing and lung function were assessed pre- and post-treatment. In all, 100 patients were required. A total of 115 eligible patients were registered, all received two courses of chemotherapy. Median follow-up is 70 months; two relapses have occurred and the 5-year relapse-free rate is 98.3% (95% confidence interval (CI) 95.5%, 99.9%). As assessed by clinicians during treatment, complete (reversible) alopecia was present in 20% of patients; World Health Organization (WHO) grade 1/2 neurotoxicity was present in 41%/5% of patients during treatment and 22%/1% at 6 months. However, 12% of patients reported 'quite a bit' or 'very much' pain/numbness/tingling in hands/feet 2 years after chemotherapy. Mature follow-up confirms high efficacy for two courses of cisplatin-based adjuvant chemotherapy in HRCS1 NSGCT. Substituting vincristine for etoposide decreases alopecia, but gives a low incidence of significant neuropathy. There are no clearcut advantages to 2 x BOP over 2 x BEP, except for patients who wish to maximise the chance of avoiding significant alopecia.

Epirubicin carboplatin and 5-fluorouracil (ECarboF) chemotherapy in metastatic hormone refractory prostate cancer.

The aim of this study was to examine the efficacy and toxicity of the epirubicin, carboplatin and 5-fluorouracil (ECarboF) regime in patients aged 70 or less with metastatic prostate cancer resistant to LHRH analogues. The majority of patients had previously received steroids as part of their systemic management and had progressive disease on steroids. In total, 80 patients were treated over a 6-year period, with objective response rates (PSA or radiological) of 45% and median time to relapse of 9.5 months. Median survival of the group was 9.2 months. In all, 32% of patients were alive at 12 months. Grade 3/4 neutropenia occurred in 34% of patients with an 8.7% rate of neutropenic sepsis. Grade 3/4 nonhaematological toxicity occurred in 28% of patients. For a substantial minority of patients with hormone refractory prostate cancer, combination chemotherapy can induce remission of significant duration. While similar responses have been documented for systemic cytotoxic-steroid combinations, the responses in this study are likely to reflect the activity of cytotoxic drugs alone.

Paclitaxel-containing high-dose chemotherapy for relapsed or refractory testicular germ cell tumours.

High-dose regimes containing etoposide, carboplatin and an oxazaphospharine can salvage 30-40% of patients with relapsed or refractory male germ cell tumours (GCTs). The additional benefit of paclitaxel in such high-dose therapy has not been tested. Between March 1995 and November 2002, 36 male GCT patients were treated with Carbop-EC-T (paclitaxel 75 mg x m(-2), etoposide 450 mg x m(-2), carboplatin AUC 10 on days -7, -5 and -3 and cyclophosphamide 60 mg x kg(-1) on days -5 and -3) followed by peripheral blood stem cell infusion (day 0). The 1-year overall survival rate for all patients is 67% (median follow-up 29 months). For the 24 patients with cisplatin-sensitive disease, the 1-year overall and event-free survivals are 88 and 64%, respectively. For those with cisplatin refractory or absolutely refractory disease, the 1-year overall survival is 25%. In all, 12 patients relapsed at a median duration of 5 months, 11 of whom have died. There were also six treatment-related deaths, five associated with pneumonitis. Pulmonary toxicity has been reported with paclitaxel in other high-dose regimes. Since altering our protocol so that paclitaxel is infused over 24 h with steroid prophylaxis, only one of 18 patients (13 testicular GCTs and five other tumour types) has had a treatment-related death. Our results suggest that Carbop-EC-T may enable a greater proportion of patients with relapsed and refractory GCTs to enter long-term remission.

The comparative values of bone marrow aspirate and trephine for obtaining bone scan-targeted metastases from hormone-refractory prostate cancer.

Samples of metastatic prostate cancer to bone are difficult to obtain. The aim of this study was to compare the results of bone marrow aspirate and trephine biopsy for obtaining metastatic hormone-refractory prostate cancer (HRPC) samples using previous diagnostic planar 99(m)Tc-HDP bone scans to guide the procedure. All samples taken were for the purposes of research and molecular studies on HRPC. Twenty patients with HRPC had bone marrow aspirate and trephines taken from lesions in the posterior superior iliac spine or sacro-iliac region when shown on diagnostic 99(m)Tc-HDP bone scans. Three patients also underwent plain X-ray, 18F-positron emission tomography bone scan, pelvic MRI scan and 99(m)Tc nanocolloid bone marrow scans. These images were used to assess if the extra imaging information provided, such as three-dimensional localisation of the bone metastases, was of value for target bone metastases. Cancer cells were obtained in 15/20 (75%) cases in which a trephine biopsy was attempted and 0/20 of cases in which a bone marrow aspiration was attempted. The additional information provided by the range of other imaging investigations was of little benefit in obtaining tumour samples, but did suggest why negative biopsies were obtained in some cases after targeting with planar bone scans. We recommend the use of bone marrow trephine biopsy alone, guided by previous diagnostic 99(m)Tc planar bone scan as a practical method to obtain prostate cancer cells from bone metastases.

Survival prospects after screen-detection of prostate cancer.

OBJECTIVE: To ascertain more realistic survival values for screen-detected prostate cancer than those in current use which are derived from conventionally presenting, usually symptomatic, populations. MATERIALS AND METHODS: Survival data for conventionally detected cases were derived from the Surveillance, Epidemiology and End Results database for men diagnosed in the years 1983-1988. The incidence of screen-detected prostate cancer by age and grade was taken from published data. RESULTS: For a cohort of men, initially 55 years old, screen-detected cases were estimated to outnumber by 2-3-fold, depending on age, those detected by conventional means. By assuming various survival characteristics for the screen-detected cases the mean lead time was estimated to be 9 years. Because screen-detected cases usually have clinically localized disease they are commonly advised on survival times derived from conventionally detected cases. Applying these survival times over-predicts the number of deaths by factors of at least 3.4, 1.9 and 1.5 at 65, 75 and 85 years old, respectively. CONCLUSIONS: Screening detects prostate cancer a mean of 9 years before clinical presentation. The prognosis of screen-detected prostate cancer is considerably better than that of conventionally presenting localized disease. The advice given to patients with early prostate cancer should take account of this.

Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer.

The aim of this study was to examine the prevalence of androgen receptor (AR) amplification in metastases to bone and other sites in patients with hormone-refractory prostate cancer (HRPC) and to compare these findings with those in pretreatment primary tumour samples from the same patients. Tissue from 24 patients with HRPC was available for study, together with 13 primary tumour specimens. AR gene amplification and copy number for X-chromosome were assessed by fluorescence in situ hybridization (FISH) using a SpectrumOrange-labelled probe at locus Xq11-13 for the AR gene and a SpectrumGreen-labelled alpha-satellite probe for the X-chromosome (Vysis, UK, Ltd.). A minimum of 20 nuclei were scored in each of three tumour areas by two independent observers. Samples from 18/24 patients with HRPC (12 bone marrow biopsies, three local tumour recurrences, and three lymph nodes) and nine primary tumour specimens were adequate for FISH analysis. Results were expressed as a mean ratio of AR gene copy number : mean X-chromosome number, with a ratio of greater than 1.5 defined as amplification. AR gene amplification was seen in 9/18 (50%) cases of HRPC and in none of the primary (untreated) tumour specimens (p = 0.0048, Fisher's exact test). For the 12 bone marrow samples, AR gene amplification occurred in 5/12 (38%) cases. Elevated copy number for chromosome X occurred in 3/18 (17%) HRPC and 4/9 (44%) matched primary tumours. This study shows for the first time that AR gene amplification can be demonstrated by FISH in bone metastases from HRPC patients. Because bone marrow biopsies can be obtained from most patients with HRPC, the findings provide a rational basis for the routine selection of patients who may respond more favourably to second-line anti-androgen therapy.

Cisplatin neurotoxicity in the treatment of metastatic germ cell tumour: time course and prognosis.

In order to ascertain the incidence and prognosis of cisplatin-induced neurotoxicity in testis cancer patients undergoing combination chemotherapy, 29 patients with metastatic disease were studied prospectively. Assessments included enquiry into neurological symptoms, measurement of sural nerve sensory action potential and conduction velocity, and vibration threshold in the left big toe. At the end of chemotherapy (3 to 4 cycles) only 3 out of 26 (11%) patients had paraesthesiae, but 3 months later the proportion rose to 65%. Resolution occurred in the majority over the ensuing 12 months so that only 17% had persistent symptoms. None of the 11 patients treated with 3 cycles of chemotherapy had persisting symptoms. Vibration thresholds showed a significant deterioration during chemotherapy (P = 0.032), further deterioration in the 3 months following chemotherapy (P = 0.009) and significant improvement between 3 and 12 months after chemotherapy (P = 0.038). Sural nerve sensory action potentials and conduction velocities were unhelpful.

The role of the histopathologist in the management of testicular germ cell tumour in adults.

In the last 20--30 years the availability of effective chemotherapy and more accurate clinical staging has greatly improved the prognosis for patients with testicular germ cell tumours. Initially, such treatment appeared to diminish the role of histopathology to the distinction between seminoma and nonseminomatous germ cell tumour (NSGCT) in the primary specimen. However, histopathology has evolved as a prognostic tool indicating the risk of relapse in various defined clinical contexts thereby facilitating therapeutic decisions. The clinical emphasis has been on quality of life and reduction of therapy both in terms of the number of patients treated and the number of chemotherapy courses given to each patient. The treatment of adult testicular germ cell tumours may differ between countries but protocols are established. Therefore it is appropriate to discuss the role of histopathology during this era of relative therapeutic stability.

First report of an isolated jejunal seminoma: presentation with melaena and iron deficiency anaemia.

We present the case history of a man with isolated seminoma in the jejunum and abnormal testes but no provable malignant testicular disease. Treatment with cisplatin-based chemotherapy led to complete resolution of the jejunal seminoma. The rarity of seminoma involving the small bowel is highlighted. A literature search did not reveal other similar cases of isolated seminoma affecting the jejunum. The possible origins of this tumour are discussed.

A medical research council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. MRC Testicular Tumour Working Party.

The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m(2)to be corrected for glomerular filtration rate outside the range 81-120 ml min(-1)and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60-82%) in patients allocated C and 81% (71-90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was - 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32-1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75-92%) in those allocated C, and 89% (81-96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35-2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies.

A randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced transitional cell carcinoma: results and a report on prognostic factors in a Medical Research Council study. MRC Advanced Bladder Cancer Working Party.

Transitional cell carcinomas may arise at any site within the urinary tract and are a source of considerable morbidity and mortality. In particular, patients with metastatic disease have a poor prognosis, with less than 5% alive at 5 years. A multicentre randomized trial comparing methotrexate and vinblastine (MV) with cisplatin, methotrexate and vinblastine (CMV) in advanced or metastatic transitional cell carcinoma was conducted in the UK. From April 1991 to June 1995, 214 patients were entered by 16 centres, 108 randomized to CMV and 106 to MV. A total of 204 patients have died. The hazard ratio (relative risk of dying) was 0.68 (95% CI 0.51-0.90, P-value = 0.0065) in favour of CMV. This translates to an absolute improvement in 1-year survival of 13%, 16% in MV and 29% in CMV. The median survival for CMV and MV was 7 months and 4.5 months respectively. Two hundred and eight patients objectively progressed or died. The hazard ratio was 0.55 (95% CI 0.41-0.73, P-value = 0.0001) in favour of CMV. Two hundred and nine patients symptomatically progressed or died. The hazard ratio was 0.48 (95% CI 0.36-0.64, P-value = 0.0001) in favour of CMV. The most important pretreatment factors influencing overall survival were WHO performance status and extent of disease. These two factors were used to derive a prognostic index which could be used to categorize patients into three prognostic groups. We conclude that the addition of cisplatin to methotrexate and vinblastine should be considered in patients with transitional cell carcinoma, taking into account the increased toxicity.

Intratubular germ cell neoplasia of the contralateral testis in testicular cancer: defining a high risk group.

PURPOSE: We define a group of testis cancer patients who are at high risk for carcinoma in situ of the contralateral testis and, therefore, a second germ cell tumor. MATERIALS AND METHODS: The histology was reviewed in 186 testis cancer patients who underwent contralateral testicular biopsy either because of a history of testicular maldescent or an atrophic contralateral testis (defined as a volume of 12 ml. or less). Testicular volume, semen analysis, serum gonadotropin levels, serum testosterone and estradiol levels were assessed in the majority of patients. RESULTS: Univariate analyses identified contralateral testicular atrophy, low sperm density, young age at presentation and low Johnsen score as factors associated with increased risk of a positive biopsy. A history of maldescent in the absence of atrophy was associated with carcinoma in situ prevalence of only 4%. Multivariate analysis identified only testicular atrophy and age at presentation as independent determinants of a positive biopsy. Testis cancer patients with a small contralateral testis had a 20% and those presenting at age 30 years or younger had a 34% prevalence, respectively, of carcinoma in situ on contralateral testis biopsy (95% confidence interval 20 and 46%, respectively). CONCLUSIONS: Testis cancer patients with an atrophic contralateral testis who present before the age of 31 years are at high risk for carcinoma in situ of the contralateral testis and, therefore, a second germ cell tumor. It is estimated that this group comprises 6% of all testis cancer patients. We predict that a policy of performing contralateral testicular biopsy will produce positive results for carcinoma in situ in a third of these patients and will detect contralateral carcinoma in situ in approximately 40% of all testis cancer patients.

Prognostic factors for patients with advanced seminoma treated with platinum-based chemotherapy.

Prognostic factors for 3-year progression-free survival (PFS) were defined in 286 patients with advanced seminoma treated with cisplatin-based chemotherapy at 10 European oncology units (no prior treatment: 236; prior radiotherapy: 50). Previously irradiated patients displayed a 69% PFS as compared to 87% in those presenting with advanced seminoma at the time of diagnosis (P = 0.009). In the univariate analysis, the extent and site of disease before chemotherapy and the level of serum LDH (< 2.0 versus > or = 2.0 x upper limit of normal) correlated with PFS in previously non-irradiated patients, but not in patients with prior radiotherapy. The multivariate analysis was, therefore, restricted to previously non-irradiated patients. The presence of non-pulmonary visceral metastases and a serum LDH level of > or = 2 x normal (N) proved to be independent prognostic factors. Based on these variables, two prognostic models were constructed and validated in an external data set of 166 comparable patients. For clinical use, Model 2 is recommended. The good-prognosis group comprises non-irradiated patients with stage II seminoma and any LDH level at presentation, or stage III and IV patients (with lung metastases only) whose serum LDH level is < 2 x N. These patients display a 94% 3-year PFS. The poor prognosis group includes all other patients with a 56% PFS. With this prognostic model, individualisation of the therapeutic approach may be considered in patients with advanced seminoma and a high risk of chemotherapy-related toxicity.