George Pentheroudakis

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

F. A. Peccatori1, H. A. Azim Jr2, R. Orecchia3, H. J. Hoekstra4, N. Pavlidis5, V. Kesic6 & G. Pentheroudakis5, on behalf of the ESMO Guidelines Working Group* Fertility and Procreation Unit, Division of Gynaecologic Oncology, European Institute of Oncology, Milan, Italy; Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Department of Radiotherapy, European Institute of Oncology, Milan, Italy; Department of Surgical Oncology, University Medical Centre Groningen, Groningen, The Netherlands; Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia;

High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up R. Stupp, J.-C. Tonn, M. Brada & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group* Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, and Department of Oncology-Hematology Riveria-Chablais, Vevey, Switzerland; Department of Neurosurgery, Universitatsklinikum Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany; Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, Sutton, UK; Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

R. Stupp1, M. Brada2, M. J. van den Bent3, J.-C. Tonn4 & G. Pentheroudakis5 on behalf of the ESMO Guidelines Working Group* Department of Oncology and Cancer Centre, University Hospital Zurich, Zurich, Switzerland; Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Clatterbridge Cancer Centre, Wirral, UK; Department of Neuro-Oncology, Erasmus MC Cancer Center, Rotterdam, Netherlands; Department of Neurosurgery, Ludwig-Maximilians-University, Munich, Germany; Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece

Prognosis of pregnancy-associated breast cancer: A meta-analysis of 30 studies

BACKGROUND Pregnancy-associated breast cancer (PABC) is relatively rare with considerable controversy regarding its prognosis. PATIENTS & METHODS Two of the authors independently performed a literature search with no date or language restrictions. Eligible studies were control-matched, population-based and hospital-based studies that addressed the outcome of patients diagnosed during pregnancy or 1-year afterwards. The primary and secondary end-points were overall and disease-free survival respectively. Pooling of data was done using the random effect model. RESULTS 30 studies were included in this meta-analysis (3,628 cases and 37,100 controls). PABC patients had a significantly higher risk of death compared to those with non-pregnancy-related breast cancer (pooled hazard ratio (pHR): 1.44; 95% CI [1.27-1.63]). The same results were encountered on restricting the analysis to HRs of multivariate analyses (pHR: 1.40 [1.17-1.67]). A clearer trend of poorer outcome was seen in those diagnosed postpartum (pHR: 1.84; 95% CI [1.28-2.65]) than those diagnosed during pregnancy (pHR: 1.29; 95% CI [0.74-2.24]). DFS analysis showed a significantly higher risk of relapse associated with PABC as well (pHR: 1.60 [1.19-2.16]). CONCLUSION Our results show that PABC is independently associated with poor survival particularly those diagnosed shortly post-partum. This underscores a possible impact of the pregnant breast microenvironment on the biology and consequently the prognosis of these tumors.

Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes

BackgroundMore than half of patients with KRAS-wild type advanced colorectal cancer (CRC) fail anti-EGFR monoclonal antibodies. We studied EGFR-axis messenger RNA (mRNA) expression and RAS, RAF, PIK3CA mutations in order to identify additional biomarkers of cetuximab efficacy.MethodsPreviously genotyped (KRAS, NRAS, BRAF, PIK3CA mutations) formalin-fixed paraffin-embedded tumour biopsies of 226 cetuximab-treated CRC patients (1st to 3rd line therapy) were assessed for mRNA expression of epidermal growth factor receptor (EGFR) and its ligands EGF, Transofrming Growth Factor-a (TGFA), Amphiregulin (AREG) and Epiregulin (EREG) with real time quantitative PCR. Mutations were detected in 72 (31.9%) tumours for KRAS, in 6 (2.65%) for BRAF, in 7 (3.1%) for NRAS and in 37 (16.4%) for PIK3CA.ResultsOnly PIK3CA mutations occasionally coexisted with other gene mutations. In univariate analysis, prognostic significance for survival ( from metastases until death) was seen for BRAF mutations (Hazard Ratio HR 8.1, 95% CI 3.4-19), codon 12-only KRAS mutations (HR 1.62, 95% CI 1.1-2.4), high AREG mRNA expression only in KRAS wild type CRC (HR 0.47, 95% CI 0.3-0.7) and high EREG mRNA expression irrespective of KRAS mutation status (HR 0.45, 95% CI 0.28-0.7). EREG tumoural mRNA expression was significantly associated with a 2.26-fold increased likelihood of objective response to cetuximab therapy (RECIST 1.1). In multivariate analysis, favourable predictive factors were high AREG mRNA in KRAS wild type tumours, high EREG mRNA, low Ephrin A2 receptor mRNA. Cetuximab-treated patients with AREG-low KRAS wild type CRC fared very poorly, their survival being similar to KRAS mutant CRC. Patients with KRAS codon 13 or other non-codon 12 mutations had a median survival (30 months, 95% CI 20–35) similar to that of patients with KRAS wild-type (median survival 29 months, 95% CI 25–35), in contrast to patients with KRAS codon 12 mutations who fared worse (median survival 19 months, 95% CI 15–26).ConclusionsBRAF and codon 12 KRAS mutations predict for adverse outcome of CRC patients receiving cetuximab. AREG mRNA reflects EGFR signalling in KRAS wild type tumours, predicting for cetuximab efficacy when high and failure when low. EREG may have a prognostic role independent of KRAS mutation.

Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis

OBJECTIVES To synthesize the evidence from randomized controlled trials concerning systemic treatment regimens for patients with cancer of unknown primary site (CUP). DATA SOURCES PubMed and the Cochrane Library Central Registry of Controlled Trials. REVIEW METHODS We retrieved all randomized controlled trials comparing at least two arms of different systemic treatment regimens or a systemic regimen to no treatment in patients with CUP, excluding data on favorable subset CUP, whenever these could be separated. Treatments were categorized according to whether they involved platinum, taxane, both, or neither; non-platinum/non-taxane regimens were also categorized in monotherapy and combination regimens. We extracted or estimated the logarithm of the hazard ratio and its variance for death for each randomized comparison. Multiple-treatments meta-analysis with a hierarchical Bayesian model obtained summary hazard ratios with 95% credibility intervals. RESULTS Ten articles were eligible for the meta-analysis. No trials compared systemic treatment to best supportive care and all arms referred to chemotherapy regimens. Overall 683 subjects were randomly assigned and eight randomized comparisons were used for the multiple-treatments meta-analysis of survival (543 patients). Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others, with wide credibility intervals. Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane). CONCLUSION No type of chemotherapy has been solidly proven to prolong survival in patients with CUP. Regimens using either platinum or taxanes or both need further testing.

Malignant melanoma of unknown primary site. To make the long story short. A systematic review of the literature

INTRODUCTION Although more than 90% of melanomas have a cutaneous origin, occasionally it is discovered as a secondary deposit without evident primary site. The aim of this study was to systematically review published literature and analyse data on incidence, presentation, therapeutic interventions, survival and prognostic factors. METHODS We searched MEDLINE, (search terms Melanom*, unknown origin, unknown primary, indolent, occult) and the abstracts from major congresses of the last 4 years and perused the references of the retrieved relevant articles. RESULTS 4348 patients with MUP were reported along with 132,643 patients with Melanoma of Known Primary (MKP). The incidence of MUP was 3.2%. The male to female ratio was 2:1 while the age peak was in the 4th and 5th decades. MUP patients harbouring nodal disease had a median overall survival ranging between 24 and 127 months, 5-year survival rate between 28.6% and 75.6% and 10-year survival rate between 18.8% and 62.9%. MUP patients with visceral disease had median survival times between 3 and 16 months, and 5-year survival rates between 5.9% and 18%. Presence of tumour regression in metastatic sites and low nodal burden were associated with favourable outcome. Potentially curative surgical treatment offered survival advantage in comparison to patients with residual metastatic foci. MUP patients who received adjuvant chemotherapy or radiotherapy paradoxically seemed to fare worse compared to patients observed. CONCLUSIONS This is the first review to bring together the information of 89 years and to analyze all the potential information accumulated. Although a well know entity no consensus is reached in order to describe MUP presentation, management or prognosis.

Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: A systematic literature review

BACKGROUND Gene expression profiling platforms were recently shown to accurately assign cancer of unknown primary (CUP) to a primary tissue of origin, with unknown impact on patient outcome. We examined chemotherapy activity and outcome in CUP trials and in metastatic solid tumour trials in order to screen for a distinct biological behaviour of CUP. PATIENTS AND METHODS An online search for autopsy or molecular platform studies on CUP indolent primaries was followed by identification of phase II or III clinical trials enrolling at least thirty patients with poor-risk CUP from 2002 or later. Chemotherapy activity and patient survival data were narratively compared to data from phase III chemotherapy trials on patients with metastatic breast, lung, pancreatic and colon cancer, to which CUP is most commonly classified by molecular profiling. RESULTS Lung and pancreatic tumours were the primaries most commonly found in CUP autopsy series, whereas microarray platforms assigned CUP to breast, colon in a third and pancreatic, lung primaries in <25% of cases. 14 phase II trials managed 918 CUP patients with platinum-based chemotherapy resulting in objective response rate (ORR) of 32%. Six trials administered anthracycline-containing or gastrointestinal-type chemotherapy in 401 CUP patients, reporting ORR of 22%. The median of quoted median survival times was nine months for platinum and seven for anthracycline or GI-type regimens. Though tumour shrinkage and median survival in CUP patients were similar to those of patients with metastatic lung and pancreatic cancer, they were vastly inferior to response rates of 40-70% and median survival of 15-24 months seen in patients with metastatic breast and bowel cancer. CONCLUSION This systematic review hints that CUP, though accurately classified by molecular methods, may harbour molecular/genetic traits distinct from tumours of known primaries. These should be sought and the impact of molecularly classified primary site-directed therapy on patient outcome prospectively validated in trials.

Anti-angiogenesis in cancer therapy: Hercules and hydra

Solid tumours initiate angiogenesis to support their growth by producing growth factors such as VEGF. Depriving the tumour of the excessive vessels that support its growth became the target for developing anti-angiogenic agents that could provide, in combination with chemotherapy, improved anti-cancer treatment. Naturally most agents targeted VEGF and its signalling cascades. Almost 10 years have lapsed since the first anti-angiogenic drug approved by the FDA in 2004 (a humanized antibody inhibiting VEGF-A) and several other agents followed afterwards. There is sufficient accumulated experience to conclude that the clinical results of anti-angiogenic therapy are very modest resulting in moderate improvement in overall survival. Moreover, the clinical outcome is associated with the development of resistance to the anti-angiogenic agent and the increased risk of invasion and metastasis. The initial expectations are, as yet, unfilled, and the entire concept and strategy of the anti-angiogenic intervention in cancer requires re-evaluation. In the present Mini Review we discuss these issues emphasising the underlying molecular mechanisms.