Platinum-Based Chemotherapy 'Rechallenge' in Advanced Non-ovarian Solid Malignancies.

Platinum-based chemotherapy forms the backbone of treatment for many solid cancers. However, resistance inevitably develops in those with advanced disease. Platinum rechallenge is a well-established concept in the management of ovarian cancer, small cell lung cancer and germ cell tumours. In other solid malignancies there is a lack of quality evidence to support platinum rechallenge, yet it is a widely adopted strategy. Often, patients are within the last year of life, making questions of efficacy, treatment-related toxicity and quality of life critical factors for treatment recommendations. In this overview we appraise the available evidence for platinum rechallenge and strategies being developed to attempt resensitisation of tumours to platinum-based chemotherapy.

EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees†.

BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. SETTING: Online Delphi survey and consensus conference. PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.

Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: a Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC).

Background: Cisplatin-based combination chemotherapy is the standard treatment of advanced urinary tract cancer (aUTC), but 50% of patients are ineligible for cisplatin according to recently published criteria. We used a multinational database to study patterns of chemotherapy utilization in patients with aUTC and determine their impact on survival. Patients and methods: This was a retrospective study of patients with: UTC (bladder, renal pelvis, ureter or urethra); advanced disease (stages T4b and/or N+ and/or M+); urothelial, squamous or adenocarcinoma histology. Primary objective was overall survival (OS). Eligibility-for-cisplatin was defined by Eastern Cooperative Oncology Group performance status ≤ 1, creatinine clearance ≥ 60 ml/min, no hearing loss, no neuropathy and no heart failure. Cox regression multivariate analyses were used to establish independent associations of cisplatin versus noncisplatin-based chemotherapy on OS. Results: 1794 patients treated between 2000 and 2013 at 29 centers were analyzed. Median follow-up was 29.1 months. About 1333 patients (74%) received first-line chemotherapy: the use of first-line chemotherapy was associated with longer OS: [hazard ratio (HR): 1.91, 95% confidence interval (CI): 1.67-2.20]. Type of first-line chemotherapy received was: cisplatin-based 669 (50%), carboplatin-based 399 (30%) and other 265 (20%). Cisplatin use was an independent favorable prognostic factor (HR: 1.54, 95% CI: 1.35-1.77). This benefit was independent of baseline characteristics or comorbidities but was associated with eligibility-for-cisplatin: eligible patients treated with cisplatin lived longer than those who were not (HR: 1.74, 95% CI: 1.36-2.21), while such benefit was not observed among ineligible patients. About 26% of patients who did not receive cisplatin were eligible for this agent. Median OS of ineligible patients was poor irrespective of the chemotherapy used. Conclusions: The importance of applying published criteria of eligibility-for-cisplatin was confirmed in a multinational, real-world setting in aUTC. The reasons for deviations from these criteria set targets to improve adherence. Effective therapies for cisplatin-ineligible patients are needed.

Chemotherapy at First Diagnosis of Advanced Prostate Cancer - Revolution or Evolution? Findings from a British Uro-oncology Group UK Survey to Evaluate Oncologists' Views on First-line Docetaxel in Combination with Androgen Deprivation Therapy in Castrate-sensitive Metastatic and High-risk/Locally Advanced Prostate Cancer.

AIMS: There have been three randomised trials investigating docetaxel in combination with androgen deprivation therapy as first-line therapy for hormone-sensitive metastatic and locally advanced/high-risk prostate cancer. The largest of these studies, UK STAMPEDE trial, recently presented in June 2015. The aim of this survey was to evaluate if oncologists' practice has changed as a result of these studies, or if their practice is likely to change in different clinical settings in the future. MATERIALS AND METHODS: The British Uro-oncology Group issued a semi-structured online questionnaire to its membership of 160 specialist urological oncologists practising in the UK. Links to the abstracts of GETUG-AFU-15, E3805 CHAARTED and STAMPEDE were attached with the survey for respondents to review before completing the survey. RESULTS: In total, 111 participants completed the survey; 87% stated that STAMPEDE will influence their clinical practice in the future. Almost all (96%) would offer docetaxel with androgen deprivation therapy to men presenting with high volume metastatic prostate cancer. Fewer oncologists would offer this treatment to men with low volume metastatic prostate cancer, locally advanced or relapsed disease. Various patient- and disease-related factors were considered in decision making, as well as resource implications. CONCLUSIONS: This survey reports oncologists' attitudes towards a major change in practice in the standard of care for men with newly diagnosed advanced prostate cancer in the UK. The survey highlighted the complexities surrounding the clinical implementation of the data from these studies, including changes in referral pathways, with the early involvement of oncologists in such patients' care, increases in workloads for oncologists and chemotherapy units and the need for national approval for re-imbursement of these treatments.

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.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

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.

Epigenetic therapy: histone acetylation, DNA methylation and anti-cancer drug discovery.

Histone proteins are subject to a diverse range of post-translational modifications which, along with DNA methylation, play a major role in controlling gene expression, cell division, survival and differentiation. Alterations in these chromatin modifications are thought to contribute to important human diseases including cancer. Inhibition of the enzymes that introduce and remove these chromatin modifications is proving an effective approach to cancer therapy and inhibitors of histone deacetylases and DNA methyltransferases have been approved for use in haematological malignancies. Here we provide a background to the biology of chromatin modifications and review some of the evidence validating histone deacetylases and DNA methyltransferases as targets for anti-cancer drug discovery. We then focus on two of the key issues in this field; the identification of novel inhibitors to overcome shortcomings of first generation agents and the potential role of histone deacetylase and DNA methyltransferase inhibitors in combination therapies for oncology. Finally, we highlight some of the challenges that will need to addressed to further progress the development of epigenetic-based therapies for cancer.

Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential?

Histone deacetylase inhibitors have progressed rapidly from the laboratory to clinical testing. This review highlights the promising data for their combination with a wide range of established and novel anticancer agents and discusses the mechanisms that underpin these interactions.

Primary diffuse large B-cell lymphoma of the breast: prognostic factors and outcomes of a study by the International Extranodal Lymphoma Study Group.

BACKGROUND: Primary diffuse large B-cell lymphoma (DLBCL) of breast is rare. We aimed to define clinical features, prognostic factors, patterns of failure, and treatment outcomes. PATIENTS AND METHODS: A retrospective international study of 204 eligible patients presenting to the International Extranodal Lymphoma Study Group-affiliated institutions from 1980 to 2003. RESULTS: Median age was 64 years, with 95% of patients presenting with unilateral disease. Median overall survival (OS) was 8.0 years, and median progression-free survival 5.5 years. In multifactor analysis, favourable International Prognostic Index score, anthracycline-containing chemotherapy, and radiotherapy (RT) were significantly associated with longer OS (each P < or = 0.03). There was no benefit from mastectomy, as opposed to biopsy or lumpectomy only. At a median follow-up time of 5.5 years, 37% of patients had progressed--16% in the same or contralateral breast, 5% in the central nervous system, and 14% in other extranodal sites. CONCLUSIONS: The combination of limited surgery, anthracycline-containing chemotherapy, and involved-field RT produced the best outcome in the pre-rituximab era. A prospective trial on the basis of these results should be pursued to confirm these observations and to determine whether the impact of rituximab on the patterns of relapse and outcome parallels that of DLBCL presenting at other sites.

Brain as sanctuary site of relapse in germ cell cancer patients previously treated with chemotherapy.

BACKGROUND: Post chemotherapy isolated relapse to the brain of germ cell cancer is potentially curable. PATIENTS AND METHODS: We reviewed the experience of germ cell cancer with cerebral metastases at the CRC Wessex Medical Oncology Unit in Southampton. Patients were classified according to their presentation (initial diagnosis, solitary relapse or widespread). Treatment and outcome of these patients is presented and compared with previous series. RESULTS: Of 1049 patients treated for metastatic germ cell cancer, 15 were diagnosed with cerebral metastases. Six patients had cerebral sanctuary site relapse, and underwent resection and cranial irradiation. Four of these are continuously disease free after treatment at 2, 67, 96, and 145 months from therapy, another is receiving chemotherapy for limited systemic relapse and the sixth has relapsed and died. Three further patients relapsed with cerebral disease in the presence of active disease elsewhere and each progressed and died. The final six patients had cerebral disease at presentation of whom five have progressed and died. CONCLUSIONS: Isolated cerebral metastases occurring after successful systemic chemotherapy for germ cell cancer are curable. An aggressive salvage approach with surgery followed by radiotherapy is indicated.

Lipid metabolite peaks in pattern recognition analysis of tumour in vivo MR spectra.

The ability to classify spectra of tumours according to their stage and type will be essential if magnetic resonance spectroscopy (MRS) is to be used as an aid in the diagnosis of cancer. MRS data are normally classified on the basis of selected peak measurements but these may be difficult to extract automatically. We present two alternative methods of feature extraction which we used to discriminate between spectra from tumours and normal tissues. Discrimination could be achieved either using features from the whole spectrum, or from a selected region containing the peaks from the phospholipid precursors in the phosphomonoester region.