A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK).

BACKGROUND: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS: Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS: Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS: Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV: NCT00942877.

Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience.

BACKGROUND: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ∼15%, with adjuvant treatment this risk is reduced to ∼4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS: A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve × 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5-year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse.

Clinical outcomes following neoadjuvant cisplatin-based chemotherapy for bladder cancer in elderly compared with younger patients.

Bladder cancer is a disease of the elderly. Older patients might potentially be undertreated due to assumptions about benefit versus risk. Our objective was to determine outcomes in older patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC). We hypothesised that appropriately selected elderly patients (≥70 years) with MIBC could have similar clinical outcomes, and be safely treated, with standard neoadjuvant chemotherapy prior to definitive cystectomy or radiotherapy. We utilised a single institution case series analysis of patients with T2-4a N0 M0 transitional cell carcinoma of the bladder treated with cisplatin-based neoadjuvant chemotherapy between 2005 and 2011. Eighty-three patients were eligible. Median age was 68 (range 48-80), 33 patients (40%) were ≥70 years. Overall survival at 3 years was 65.8% (≥70) and 63.2% (<70) (P = 0.653), relapse-free survival at 3 years was 61.6% and 54.8% respectively (P = 0.471). The rates going forward to definitive local therapy (87.9% ≥ 70 and 84.0% < 70) and the pathological complete response rate (31.3% ≥ 70 and 40% < 70) were similar. Disease relapse rate was also similar (63.6% ≥ 70 vs. 60% < 70, P = 0.906). Elderly patients with good functional status and limited comorbidities diagnosed with MIBC receiving standard neoadjuvant chemotherapy followed by cystectomy or radiotherapy can have similar clinical outcomes as their younger counterparts. Prospective studies evaluating the optimum curative management in this elderly population are warranted.

Serum total hCGß level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract.

BACKGROUND: Serum total human chorionic gonadotrophin ß subunit (hCGß) level might have prognostic value in urothelial transitional cell carcinoma (TCC) but has not been investigated for independence from other prognostic variables. METHODS: We utilised a clinical database of patients receiving chemotherapy between 2005 and 2011 for urothelial TCC and an independent cohort of radical cystectomy patients for validation purposes. Prognostic variables were tested by univariate Kaplan-Meier analyses and log-rank tests. Statistically significant variables were then assessed by multivariate Cox regression. Total hCGß level was dichotomised at < vs ≥2 IU l(-1). RESULTS: A total of 235 chemotherapy patients were eligible. For neoadjuvant chemotherapy, established prognostic factors including low ECOG performance status, normal haemoglobin, lower T stage and suitability for cisplatin-based chemotherapy were associated with favourable survival in univariate analyses. In addition, low hCGß level was favourable when assessed either before (median survival not reached vs 1.86 years, P=0.001) or on completion of chemotherapy (4.27 vs 0.42 years, P=0.000002). This was confirmed in multivariate analyses and in patients receiving first- and second-line palliative chemotherapy, and in a radical cystectomy validation set. CONCLUSIONS: Serum total hCGß level is an independent prognostic factor in patients receiving chemotherapy for urothelial TCC in both curative and palliative settings.

Relevant risk of carboplatin underdosing in cancer patients with normal renal function using estimated GFR: lessons from a stage I seminoma cohort.

BACKGROUND: Seminoma stage I is the most frequent testis cancer and single-dose carboplatin (AUC7) is an effective and widely used adjuvant treatment. Underdosing of carboplatin by 10% has been shown to almost double the rate of relapse and hence correct dosing based on accurate GFR measurement is crucial. The gold standard of GFR measurement with a radiolabelled isotope is expensive and not readily available. In many institutions, it is replaced by GFR estimation with the Cockcroft-Gault formula, which might lead to significant carboplatin underdosing and potentially inferior clinical outcome. METHODS: Retrospective analysis of all patients with stage I seminoma treated with adjuvant carboplatin between 1999 and 2012. All patients had serum creatinine measured and underwent GFR measurement with a radioisotope ((51)Cr EDTA or (99m)Tc DTPA), which was compared with seven standard GFR estimation formulae (Cockcroft-Gault, CKD-EPI, Jelliffe, Martin, Mayo, MDRD, Wright) and a flat dosing strategy. Bias, precision, rates of under- and overdosing of GFR estimates were compared with measured GFR. Bland-Altman plots were done. RESULTS: A total of 426 consecutive Caucasian male patients were included: median age 39 years (range 19-60 years), median measured GFR 118 ml/min (51-209), median administered carboplatin dose 1000 mg (532-1638). In comparison to isotopic GFR measurement, a relevant proportion of patients would have received ≤ 90% of carboplatin dose through the use of GFR estimation formulae: 4% using Mayo, 9% Martin, 18% Cockcroft-Gault, 24% Wright, 63% Jelliffe, 49% MDRD and 41% using CKD-EPI. The flat dosing strategy, Wright and Cockcroft-Gault formulae, showed the smallest bias with mean percentage error of +1.9, +0.4 and +2.1, respectively. CONCLUSIONS: Using Cockcroft-Gault or any other formula for GFR estimation leads to underdosing of adjuvant carboplatin in a relevant number of patients with Seminoma stage I and should not be regarded as standard of care.

An unusual differential diagnosis of penile warts: metastases from rectal carcinoma.

Patients with penile lesions, such as virally induced papillomata, frequently present to genitourinary medicine clinics and general practitioners. Their diagnosis is usually based on clinical observation and biopsy is not generally undertaken. Penile lesions may rarely have a more sinister aetiology and represent metastatic spread from solid tumours arising at distant sites. Penile metastases arise most frequently from genitourinary cancers (prostate, bladder and kidney), but may also arise from tumours of the large bowel; other primary sites are extremely uncommon. We report the case of a patient presenting with penile metastases from rectal carcinoma arising during third-line chemotherapy for metastatic disease.

The combination of raltitrexed (Tomudex) and mitomycin-C in the treatment of advanced colorectal cancer--a phase II study.

AIMS: To investigate the combination of raltitrexed and mitomycin-C as first-line chemotherapy treatment in patients with advanced colorectal cancer. MATERIALS AND METHODS: A phase II study. RESULTS: In total, 22 patients were treated with a combination of raltitrexed 3 mg/m2 every 3 weeks and mitomycin-C 7 mg/m2 every 6 weeks for up to 24 weeks. The study was closed early for safety reasons as there were three unexpected treatment-related deaths. The overall response rate was 20%, and a further 40% achieved stable disease. The median time to progression was 3.9 months and the median overall survival time was 11.6 months. CONCLUSION: Owing to the potential for increased toxicity, the combination of raltitrexed and mitomycin-C cannot be recommended as first-line treatment in patients with advanced colorectal cancer.

Experience of first- and subsequent-line systemic therapy in the treatment of non-small cell lung cancer.

INTRODUCTION: The treatment of advanced non-small cell cancer (NSCLC) has changed with multiple new treatment algorithms proposed based on histological and molecular subtyping but low mutation rates will ensure the dominance of cytotoxic chemotherapy. Accordingly, we undertook a detailed review of our practice delivering multiple lines of systemic therapy. METHOD: We undertook a retrospective review of consecutive patients presenting with advanced (stage IIIb/IV) NSCLC treated with systemic therapy at two UK hospitals during a 2-year period, January 2007 to December 2008. RESULTS: A total of 130 patients were identified, treated with predominantly carboplatin/gemcitabine (20 initially radically). Fifty of 110 patients (45%) treated with first-line systemic therapy subsequently received second-line therapy, of which 10 patients received third-line and two patients fourth-line therapy. Sixty three of 110 first-line patients (58%) achieved clinical benefit, 19 out of 50 (38%) in the second-line, 6 out of 10 (60%) in third-line but both patients progressed at fourth-line. Median overall survival for 110 patients was 10 months (95% confidence interval [CI] 8.6-11.4); but 16 months (95% CI 14-17.9) in those receiving multiple lines. Median survival from the first cycle of last-line treatment to death in the multiple therapy lines was 5 months (95% CI 2.6-7.3) and the majority of patients spent more time off treatment. CONCLUSION: Overall our outcomes are consistent with published data and show good survival times can be achieved. The future of advanced NSCLC is in selecting the best treatment approach on a histological and genotypic basis.

Late relapse of metastatic non-seminomatous testicular germ cell tumours.

Although the majority of men presenting with non-seminomatous germ cell tumours (NSGCT) are cured, late relapse (occurring more than 2 years after obtaining a complete response to treatment) is increasingly recognized. The typical patterns of disease spread have been well-documented, but the findings at late relapse are more variable and less well-described. We discuss the phenomenon of late relapse, the characteristics of teratoma differentiated (TD), and the issue of long-term imaging surveillance of patients with NSGCT. The potential sites of late relapse of NSGCT and the associated spectrum of imaging appearances are illustrated.

Orchidectomy after chemotherapy for patients with metastatic testicular germ cell cancer.

OBJECTIVE: To evaluate the contribution of routine orchidectomy in the management of patients who present with advanced, metastatic, testicular germ cell cancer and who are treated with initial chemotherapy. PATIENTS AND METHODS: Sixty consecutive patients presenting with metastatic testicular germ cell cancer and treated with initial chemotherapy followed by orchidectomy were identified. The results from a clinical and pathological review of these patients are presented. The pathological findings at orchidectomy were compared with the pathological findings from metastatic masses resected after chemotherapy, and are reviewed with the clinical outcome. RESULTS: Of the 60 orchidectomy specimens after chemotherapy, 24 (40%) contained significant histological abnormalities comprising residual invasive germ cell cancer, intratubular germ cell neoplasia and/or mature teratoma. The remaining 36 (60%) orchidectomy specimens contained fibrous scarring with or with no necrosis. Six (10%) orchidectomy specimens contained residual invasive germ cell cancer, three nonseminomatous germ cell cancer (NSGCT) and three seminoma. The patients with residual invasive NSGCT present within the testis had evidence of residual invasive NSGCT within extragonadal masses resected after chemotherapy; all three have relapsed and died from chemorefractory progressive disease. CONCLUSION: Orchidectomy after chemotherapy is recommended in all patients undergoing primary chemotherapy, as a significant proportion (40%) are left with histological abnormalities that predispose to subsequent relapse. Persistence of invasive NSGCT at the site of the primary tumour after chemotherapy is associated with persistence of invasive disease at other metastatic sites and is a poor prognostic finding.

Routine computerised tomographic scans of the thorax in surveillance of stage I testicular non-seminomatous germ-cell cancer--a necessary risk?

BACKGROUND: The standard management approach to stage I testicular non-seminomatous germ-cell tumours (NSGCT) in the UK is a surveillance programme with adjuvant bleomycin, etoposide, cisplatin (BEP) chemotherapy being offered to individuals with high risk disease. Conventionally, computed tomography (CT) scanning of the thorax has formed part of the surveillance programme. This paper evaluates the contribution of routine thoracic CT imaging in the management of this disease. PATIENTS AND METHODS: We retrospectively reviewed the case notes of 168 patients with stage I NSGCT referred to the Wessex Medical Oncology Unit over a period of 13 years (1986-1998). These patients entered onto a surveillance programme that included serial chest X-ray follow up rather than thoracic CT. RESULTS: Forty-two out of 168 patients (25%) evaluated suffered relapse during the follow up period. Eight of 42 patients (19%) relapsed with intrathoracic disease. Seven out of eight of these patients (87.5%) had at least one other indicator of disease recurrence (elevated serum marker, abnormal abdominal CT). One of 42 patients (2.4%) relapsed with isolated intrathoracic disease with no other indicator of relapse. All patients with intrathoracic relapse had evidence of disease on chest X-ray. Of the 42 relapsing patients, 93% could be categorised as having good prognosis metastatic disease. Seven per cent relapsed with intermediate or poor prognostic disease; relapse in these patients would not have been detected earlier with the inclusion of routine thoracic CT. Only one patient has died giving a cure rate of 98% for relapsing patients. CONCLUSIONS: The elimination of chest CT did not compromise outcome but significantly reduced radiation exposure thereby minimising the risk of radiation-induced secondary malignancy. Continued review of surveillance programmes is essential if we are to optimise management of this disease.