Search

Multiple sclerosis (MS) is a chronic central nervous system (CNS) autoimmune disease. Studies of cancer risk in MS patients have shown inconsistent findings. A pubmed search of the literature on cancer risk in patients with MS was conducted and found published relative studies. The majority of these studies concluded that there was overall either reduced or no increased risk of developing malignancies between patients with MS compared to the general population. However, several studies suggested that patients with MS may have reduced risk in specific cancers such as of the digestive and respiratory organs, prostate, ovary, or increased risk in breast, brain and bladder tumors. At present it is uncertain if the immunologic profile of MS patients may be related to the increased or reduced frequency of some cancers and warrants further investigation. © 2015 Elsevier Ireland Ltd. 98 29 34

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Major Depressive Disorder (MDD) is common among cancer patients, with prevalence rates up to four-times higher than the general population. Depression confers worse outcomes, including non-adherence to treatment and increased mortality in the oncology setting. Advances in the understanding of neurobiological underpinnings of depression have revealed shared biobehavioral mechanisms may contribute to cancer progression. Moreover, psychosocial stressors in cancer promote: (1) inflammation and oxidative/nitrosative stress; (2) a decreased immunosurveillance; and (3) a dysfunctional activation of the autonomic nervous system and of the hypothalamic–pituitaryadrenal axis. Consequently, the prompt recognition of depression among patients with cancer who may benefit of treatment strategies targeting depressive symptoms, cognitive dysfunction, fatigue and sleep disturbances, is a public health priority. Moreover, behavioral strategies aiming at reducing psychological distress and depressive symptoms, including addressing unhealthy diet and life-style choices, as well as physical inactivity and sleep dysfunction, may represent important strategies not only to treat depression, but also to improve wider cancer-related outcomes. Herein, we provide a comprehensive review of the intertwined biobehavioral pathways linking depression to cancer progression. In addition, the clinical implications of these findings are critically reviewed. © 2016 Elsevier Ltd 52 58 70

Cancer of unknown primary origin (CUP) had a poor prognosis, determined by clinico-histological characteristics, partly due to the lack of insights on its biology. We screened tumour DNA from 87 patients with CUP for CTNNB1 (coding exons 2,3,4,5), MET (coding exon 18), PIK3CA (coding exons 9,20), KRAS (coding exons 1,2), BRAF (coding exon 15) gene mutations by using dd-sequencing and evaluated their impact on prognosis. Mutated gene incidences in the 87 CUP cases were: KRAS 11 (12.6 %), BRAF 5 (5.7 %), PIK3CA 8 (9 %), MET 6 (6.7 %) and CTNNB1 18 (20.7 %). Several mutations in the KRAS gene were not the commonly encountered mutations in other solid tumours. Activating mutations were observed in 10.2 % in KRAS, 4.5 % in BRAF, 6.6 % in PIK3CA, 4.5 % in MET, and 19.5 % in CTNNB1. Activating mutations in PIK3CA coding exon 9 were inversely correlated with MET coding exon 18 activating mutations (p = 0.036). MET activating mutations were prognostic for poor Progression-Free Survival (median PFS 5 vs 9 months, p = 0.009) and Overall Survival (median OS 7 vs 20 months, p = 0.005). The complex profile of either CTNNB1 or MET mutations also had an adverse prognostic significance (median OS 11 vs 21 months, p = 0.015). No other gene mutation exhibited prognostic significance. In multivariate analysis, poor performance status, male gender, visceral disease and adenocarcinoma histology, but not gene mutations, were independently associated with poor patient outcome. CTNNB1 gene mutations are frequent, and along with MET mutations have an adverse prognostic effect in patients with CUP. © 2014, Springer Science+Business Media Dordrecht. 31 7 761 769

The number of cancer patients in Europe is rising and significant advances in basic and applied cancer research are making the provision of optimal care more challenging. The concept of cancer as a systemic, highly heterogeneous and complex disease has increased the awareness that quality cancer care should be provided by a multidisciplinary team (MDT) of highly qualified healthcare professionals. Cancer patients also have the right to benefit from medical progress by receiving optimal treatment from adequately trained and highly skilled medical professionals. Built on the highest standards of professional training and continuing medical education, medical oncology is recognised as an independent medical specialty in many European countries. Medical oncology is a core member of the MDT and offers cancer patients a comprehensive and systemic approach to treatment and care, while ensuring evidence-based, safe and cost-effective use of cancer drugs and preserving the quality of life of cancer patients through the entire 'cancer journey'. Medical oncologists are also engaged in clinical and translational research to promote innovation and new therapies and they contribute to cancer diagnosis, prevention and research, making a difference for patients in a dynamic, stimulating professional environment. Medical oncologists play an important role in shaping the future of healthcare through innovation and are also actively involved at the political level to ensure a maximum contribution of the profession to Society and to tackle future challenges. This position paper summarises the multifarious and vital contributions of medical oncology and medical oncologists to today's and tomorrow's professional cancer care.© The Author 2013.Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 25 1 9 15

Purpose: We sought to study the microRNA regulation of epithelial mesenchymal transition (EMT), the acquisition of migratory, mesenchymal-like properties of epithelial cells, in cancer of unknown primary (CUP). Patients and methods: We studied the global expression profile of 982 microRNAs by means of microarray technology in 68 CUP cases immunohistochemically characterised as EMT-positive (n = 5 by % of cells or n = 10 by a semiquantitative H-score) or EMT-negative. Results: EMT-suppressive miRNAs such as miR-203 and members of the miR-200 family (miR-200a,b,c and miR-141) presented a 2.45 to 3.64-fold lower expression level in the EMT-positive cases without, however, reaching statistical significance. MiR-205, a squamous tissue-specific marker, was very variable in the data set. Excluding CUP cases with squamous cell histology, miR-205, miR-203 and the miR-200 family exhibited a trend of downregulation in EMT-positive cases. A similar pattern of miRNA expression was detected when the comparison took place between EMT-positive vs EMT-negative cases according to the H-score. Moreover, miR-203, miR-205 and miR-200c were numerically downregulated in those tumours with high expression of the EMT marker N-cadherin. Conclusions: The EMT-suppressive miR-203 and miR-200 family were consistently but non-significantly downregulated in CUP with the EMT phenotype. A larger study is warranted to further explore the role of microRNAs in CUP. © 2013 Federación de Sociedades Españolas de Oncología (FESEO). 16 8 725 731

Background Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed. Methods We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease. Results Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte–associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer. Conclusions Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy. © 2016 Elsevier Ireland Ltd 108 164 174

Non

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. © 2012 Elsevier Ltd. 38 7 834 842

Aim: The association between two polymorphisms of ERCC1 and treatment outcomes after platinum-based chemotherapy in patients with advanced urothelial cancer (UC) was examined. Materials & methods: Genotyping of 19007C>T and 8092C>A polymorphisms was determined by PCR amplification and RFLP in 113 advanced UC patients, treated with platinum-based chemotherapy. Results: Seventy eight patients (69%) were carriers of the 19007T polymorphic allele: 51 (45%) heterozygotes and 27 (24%) homozygotes. Fifty three (47%) patients were carriers of the 8092A polymorphic allele: the frequencies of C/A and A/A genotypes were 37% and 10%, respectively. The T/T genotype was independently associated with prolonged median cancer-specific survival (not-reached vs 14.8 months; p = 0.026). There was no interaction between T/T or any other genotype with the type of platinum derivative (cisplatin/carboplatin). Conclusion: 19007C>T, especially in its homozygotic state, but not 8092C>A polymorphism, could be a useful prognostic marker in advanced UC treated with platinum-based chemotherapy. Original submitted 17 July 2012; Revision submitted 21 September 2012

Purpose: RACGAP1 is a Rac GTPase-activating protein involved in cell growth regulation, cell transformation and metastasis. The aim of the present study was to explore the prognostic and/or predictive significance of RACGAP1 mRNA expression on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients and compare it to that of Ki67 protein expression and to the Nottingham prognostic index (NPI). Methods: A total of 595 high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel. RNA was extracted from 314 formalin-fixed paraffin-embedded primary tumor tissue samples followed by one-step quantitative RT-PCR for assessing RACGAP1 mRNA expression. Results: High RACGAP1 mRNA expression (above the median) was associated with poor DFS (log-rank, p = 0.002) and OS (p < 0.001). High histological grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of RACGAP1. Results of the Cox multivariate regression analysis revealed that high RACGAP1 mRNA expression independently predicted poor overall survival (Wald's p = 0.008). High Ki67 protein expression was also an adverse prognostic factor for death (p = 0.016), while high NPI score values were not. Conclusions: High RACGAP1 mRNA expression, as assessed by qRT-PCR, was found to be of adverse prognostic significance in high-risk early breast cancer patients treated with dose-dense sequential chemotherapy. The utility of RACGAP1 mRNA expression in patient selection for treatment with aggressive chemotherapy regimens should be further explored and validated in larger cohorts. © 2012 Springer-Verlag Berlin Heidelberg. 71 1 245 255

Cancer of unknown primary sites (CUP) is a compilation of various malignant entities-the majority of which behave aggressively and carry poor prognosis. CUP is classified into two different clinicopathological groups: the unfavourable (poor-prognosis) and the favourable (good-prognosis) group. Patients with favourable subsets are treated relevant to the hidden primary tumour chemotherapy regimens and/or radiotherapy. These patients exhibit better responses and prolonged survival. On the other hand, patients of unfavourable subsets are treated with various chemotherapy combinations of platinum- or taxane-containing regimens. Unfortunately, responses and overall survival in this group of CUP patient are not very promising. Several independent prognostic factors have been associated with survival of CUP patients. Since CUP is not an unknown disease, emerging therapeutic innovations are warranted. © The author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 23 SUPPL. 10 x282 x285

In order to describe a novel approach for the clinical study of metastases, we provide here age-specific incidence and survival data for cancer of unknown primary (CUP). Metastases in various organs are found at CUP diagnosis, which have implications for prognosis and we hypothesize similar prognostic implications for metastases found at diagnosis of primary cancers. We identified 33,224 CUP patients from the Swedish Cancer Registry and calculated incidence rates (IRs) for CUP development. Cox proportional hazards regression models were performed to estimate hazard ratios (HRs) for relative survival in CUP patients compared to the general population. In age-group specific analyses, a maximal IR was reached at age 85–89 years, followed by a marked decline to age 90+ (7-fold in men and 3-fold in women). The overall HR for relative survival declined systematically by age. CUP may be applied as an epidemiological age-incidence model for cancer metastases providing evidence in line with autopsy data that the metastatic potential, as shown by the incidence of CUP, appears to weaken markedly at age 85 years, depending on metastatic locations. The relative death rates were highest among young patients, which was probably entirely due to the low death rates in young background population.

Background: Pregnancy complicated by cancer is relatively rare but, as women in western societies tend to delay childbearing to the third and fourth decade of life, this phenomenon is going to be encountered more often in the future. Material and methods: Review of the literature and description of the different diagnostic and therapeutic approaches which are required to diagnose and treat pregnant mothers with cancer. Results: As in non-pregnant patients, every effort should be made to provide the maximal benefit and best prognosis to the pregnant patient. In most cases, in order to avoid any harm to the fetus, different diagnostic approach should be incorporated and treatment should be tailored to each pregnant woman. Cooperation of multidisciplinary teams, incorporating medical and radiation oncologists, surgeons, obstetricians, neonatologists and experienced nursing staff, is required to provide optimal care for the patient. The benefits from use of surgery, chemotherapy and/or radiotherapy as well as the mother's wishes and beliefs need to be factored into recommendations and treatment planning. Conclusions: With the experience gained, the developments in clinical and radiation oncology and the cooperation of multidisciplinary teams, treatment of cancer during pregnancy with normal fetal outcome is feasible. © 2011 Elsevier Ltd. All rights reserved. 20 4 e175 e185

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Purpose: To study the phenomenon of positive urine cytology in patients with lung cancer in the absence of obvious urothelial metastases. Patients and methods: 150 patients with small (SCLC) and non-small cell lung cancer (NSCLC) of all stages and 3 control groups were prospectively studied. Immunocytochemical study (cytokeratins 7-20, TTF1) in all positive urine specimens and chemokine profile (CXCR4, CCL21) study of the primary tumor in selected positive patients was performed. In experimental study, C57Bl/6 BALB/C mice injected with LLC lung and 4T1 mammary cancer cells were used for the detection of positive urine cytology. Results: 11% of patients with NSCLC, 7% of patients with SCLC and none of the control group had positive urine cytology. In NSCLC, metastatic disease and high tumor burden positively correlated (p = 0.01 and 0.03 respectively) with the phenomenon. In SCLC, correlation with extensive disease and multiple metastatic sites (p = 0.02 and 0.04 respectively) was found. No correlation was found in either group with: age, gender, histology, performance status, line of chemotherapy, previous platinum-based chemotherapy, adrenal metastases, renal function, abnormal urinary sediment, response to chemotherapy and overall survival (p = 0.9). Distinctive chemokine expression was identified in positive patients studied and was not observed in negative patients (×2 p = 0.008). In the experimental study, only the LLC lung cancer cells were detected in the urine cytology of mice. Conclusion: This phenomenon, carrying undefined pathophysiological mechanisms, seems to characterize only patients with metastatic/extensive disease and high tumor burden. Further studies are needed to validate our preliminary chemokine expression results. © 2010 Elsevier Ireland Ltd. 73 1 51 58

Objective: We aimed to assess the course of early non-metastatic colorectal cancer patients' psychological distress and health-related quality of life (HRQOL) and to identify relevant clinical and psychological predictors during a one-year period. Methods: Of the 144 early non-metastatic colorectal cancer patients initially assessed for psychological distress symptoms (SCL-90-R), HRQOL (WHOQOL-BREF), sense of coherence (SOC), defense mechanisms (LSI) and hostility (HDHQ), 84 (58.3%) completed the one-year follow-up. Mean (SD) age was 65.1 (9.8) years and 67.4% were male. Mean (SD) disease duration was 1.7 (2.2) years, with 49.3% being diagnosed within the last six months. In 75.0% the site was at colon and in 25.0% at rectum; 2.1% had stage I, 59.0% stage II and 38.9% stage III disease. Results: Paranoid ideation, psychoticism, interpersonal sensitivity, anxiety and depressive symptoms increased significantly over the one-year period of the study and most of the HRQOL components were significantly decreased over the same period. Men were at greater risk for further developing depressive symptomatology. Low SOC was independent predictor of depression, while hostility independently predicted anxiety, interpersonal sensitivity and psychoticism symptoms. General psychological distress and low SOC were independent predictors of HRQOL, while repression was also an independent predictor of Physical HRQOL. Conclusions: In early non-metastatic colorectal cancer patients, psychological distress symptoms are increased and HRQOL is decreased over one-year period. Symptoms of psychological distress are strong predictors of HRQOL, while personality variables can also predict psychological distress symptoms' increase and HRQOL decrease over time, and this could be relevant to psychological interventions. © 2010 Elsevier Inc. 70 5 411 421

Cancer of unknown primary (CUP) is a common, well-recognized and heterogeneous clinical syndrome. Patients with CUP present with metastatic disease in the absence of an identifiable primary tumour despite a diagnostic work-up. Aetiologically, CUP might either harbor primaries that cannot be detected by the standardized diagnostic investigations or carry distinct genetic and epigenetic aberrations. In this article we try to clarify the clinical and pathological enigma of CUP by answering 20 important questions related to this entity. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 21 SUPPL. 7 vii303 vii307

Introduction: Serous peritoneal papillary carcinoma (SPPC), though managed according to ovarian cancer therapeutic principles, has been variably considered as an ovarian cancer counterpart, a peritoneal malignancy with distinct characteristics or a cancer of unknown primary (CUP). Patients and methods: We systematically reviewed all publications studying molecular pathophysiology, clinical presentation, management and outcome of at least 10 patients with SPPC from 1980 to 2008 in anglophone medical journals and critically analysed the data. Results: Molecular profiling of CUP was performed in eight papers reporting on 211 patients with stage III/IV SPPC by means of immunohistochemistry or PCR-based assays. Twenty-five clinical series, mostly retrospetive, reported management and outcome of 579 patiens with SPPC, in several cases matched to advanced ovarian cancer controls. Though we did not identify statistically significant differences in molecular biology, clinical presentation, management and outcome of SPPC and ovarian cancer cases, some subtle differences emerged: patterns of loss of heterozygosity at several chromosomal loci differed from those seen in ovarian cancer, while the overexpression of the HER2 oncogene was encountered more often. Serous peritoneal tumours affected older patients and were more frequently multifocal or exhibited virulent clonal expansion in metastatic sites. Diffuse micronodular spread formed a high total load of malignancy in omental, peritoneal surfaces, difficult to debulk optimally. Despite effective chemotherapeutic cytoreduction and occasional long-term remissions, SPPC patients survived 2-6 months less than ovarian cancer patients. Conclusions: Patients with SPPC should not be classified in the poor-risk CUP category, in view of the therapeutic and prognostic differences. Still, the assimilation of the SPPC entity by ovarian cancer hindered further research into its genotypic and phenotypic characteristics that may differ from ovarian cancer. Subgroup analyses of large ovarian cancer trials may shed light in this issue. © 2009 Elsevier Ireland Ltd. 75 1 27 42

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC. 21 Suppl 6 vi1 10

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The association of cancer and pregnancy is increasingly encountered nowadays in clinical practice. Due to the relative rarity of the situation, it lacks a systematized approach. Different systemic therapies are used in managing cancer with uncertainty regarding the potential hazards they could pose on the pregnancy and/or the fetus. We have performed a systematic review of literature to identify all reports addressing cancer patients who were exposed to any of the known systemic therapies during the course of the pregnancy. The results were discussed in two parts; part I addresses pregnant patients with solid tumors while part I for those with hematological malignancies. In part I, we identified different solid tumors diagnosed and treated during the course of pregnancy. Breast cancer was the most commonly treated followed by ovarian cancer. Other tumors were treated as well including lung cancer, cervical cancer, sarcoma and melanomas. It is important to acknowledge the intent of therapy (palliative vs. curative) and the patients has to be properly counseled to reach an informed decision. We aim to provide a more robust consensus on how to approach these cases and provide a higher degree of evidence to support the safety of applying certain management strategies over the other.

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. © 2009 Elsevier Ltd. All rights reserved. 35 7 570 573

The diagnostic work-up should include a thorough physical examination, including the pelvis, breasts, lymph nodes, skin and should limit unnecessary exposure to ionizing radiation. Fine needle aspiration, core needle or open excisional biopsies are safe to perform. Chest X-ray and mammography with abdominal shielding and ultrasonic examinations are the cornerstone of a basic staging, supplemented by MRI scans in the second/third trimesters when needed [IV, B]. In view of the theoretical risk of fetal heating/cavitation, first trimester MRI scans should be done sparingly and the potentially teratogenic gadolinium should not be administered [V, D]. Computerized tomography or radioisotope studies should be avoided. Minor staging procedures (spinal tap, bone marrow biopsy, endoscopies) are relatively safe to perform [IV, B].

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

Purpose: To estimate cancer screening coverage among a large sample of Greek individuals. Methods: 7012 adults from 30 Hellenic areas were surveyed. Tests included: faecal occult blood test, sigmoidoscopy, chest X-ray, urine test, testicular examination, trans-rectal ultrasound, full blood count, skin examination, digital rectal examination, PSA, Pap test, mammography, clinical breast examination (CBE), self breast examination and breast ultrasound. Results: Eighty-eight percent of males and 93% of females declared being interested in cancer screening; 37.8% of men and 37.9% of women had had a medical consultation for screening purpose in the previous 2 years. Less than 2% reported having received screening for colorectal cancer or skin malignancies. Screening for cervical cancer, mammography and CBE was reported by 39.6%, 22.8% and 27.9% of females respectively. Twenty percent of males reported screening for prostate cancer. Conclusion: The actual opportunistic screening approach presents important deficiencies with displaced priorities in test performance and a low proportion of individuals undergoing recommended tests. © Feseo 2009. 11 4 228 236

Carcinoma of unknown primary (CUP) is one of the 10 most frequent cancers worldwide. It constitutes 3-5% of all human malignancies. Patients with CUP present with metastases without an established primary site. CUP manifests as an heterogenous group of mainly epithelial cancers recognised by distinct clinicopathological entities. The diagnostic work-up includes extensive histopathology investigations and modern imaging technology. Nevertheless, the primary tumour remains undetected most of the time. Molecular diagnosis with DNA microarrays demonstrates high sensitivity, but its prognostic contribution is still uncertain. Certain clinicopathological CUP entities are considered as favourable sub-sets responding to systemic platinum-based chemotherapy or managed by locoregional treatment. These sub-sets are: the poorly differentiated carcinomas involving the mediastinal-retroperitoneal nodes, peritoneal papillary serous adenocarcinomatosis in females, poorly differentiated neuroendocrine carcinomas, isolated axillary node adenocarcinomas in females or cervical nodal involvement by a squamous cell carcinoma. Patients who belong to the non-favourable sub-sets have a worse prognosis. © 2008 Elsevier Ireland Ltd. All rights reserved. 69 3 271 278

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC > 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10−4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

Background: A large number of trials have assessed various chemotherapy regimens for the treatment of advanced cervical cancer, but there is uncertainty about the magnitude of survival benefits. Methods: We searched (last update January 2006) for trials in women with locally advanced or disseminated cervical cancer that compared neo-adjuvant or concurrent chemotherapy plus radiotherapy versus radiotherapy alone; or different chemotherapy regimens among themselves (with or without background radiotherapy in both arms). Sixty-five trials were identified with survival data on 11,180 women. Results for survival were combined with fixed and random effects models and between-study heterogeneity was estimated. Separate results were obtained for different regimens, cycle length, and type of chemotherapy (neo-adjuvant, concurrent, without radiotherapy). Results: Twenty two comparisons had survival data on 3837 women randomized to receive chemotherapy plus radiotherapy versus radiotherapy alone; the summary relative hazard for mortality was 0.95, 95% CI, 0.83-1.08. Modest between-study heterogeneity (I2 = 38%) seemed to be due to contradictory results in early trials; trials published in the last decade had a summary relative hazard 0.89 (95% CI, 0.78-1.02) and no between-study heterogeneity (I2 = 0%). Results were similar for neo-adjuvant chemotherapy and for concurrent chemo-radiotherapy. Cisplatin or cisplatin-based combinations had no significant benefit overall, but a potential benefit was seen with short-length cycles (≤14 days) and a marginally significant harm with longer-length cycles (summary relative hazards 0.80, 95% CI, 0.66-0.99 and 1.18, 95% CI, 1.02-1.38, respectively). The summary relative hazard was 1.02, (95% CI, 0.84-1.24) for trials using neo-adjuvant chemotherapy and 0.85 (95% CI, 0.73-1.00) for trials using concurrent chemotherapy. Conclusions: Evidence on chemotherapy in women with advanced cervical cancer is not encouraging for major survival benefits. However, small benefits have been observed in some trials, especially with short-length cycles of cisplatin-based regimens and concurrent chemotherapy and radiotherapy. © 2006. 33 1 24 38

Background: Sleep disturbances are common in cancer patients, but little is known about the complex interplay between the background psychological profile, coping with health stressors capacities and psychological distress in the formation of sleep difficulties in colorectal cancer. Aims: To study the course and to identify psychological predictors of sleep difficulties in early non-metastatic colorectal cancer patients over a one-year period. Methods: In this 1-year prospective study, we assessed in 84 early non-metastatic colorectal cancer patients the association of psychological distress (SCL-90-R), sense of coherence (SOC-29), and defense styles (Defense Style Questionnaire) with sleep difficulties (SCL-90-R) in multiple regression models. Eighty-two patients with breast cancer and 50 patients with cancer of unknown primary site served as disease controls, and 84 matched for age and sex alleged healthy individuals served as healthy controls. Results: Colorectal cancer patients presented more sleep difficulties compared to healthy participants but fewer than patients with breast cancer and cancer of unknown primary site. Colorectal cancer patients’ trouble falling asleep (p = 0.033) and wakening up early in the morning (p < 0.001) deteriorated over time. Sleep that was restless or disturbed was independently associated with low SOC (p = 0.046) and maladaptive defenses (p = 0.008). Anxiety symptoms (p < 0.001) predicted deterioration in trouble falling asleep, while depressive symptoms (p = 0.022) and self-sacrificing defense style (p = 0.049) predicted deterioration in wakening up early in the morning. Conclusions: Psychological parameters and coping with health stressors capacities are independently associated with sleep difficulties in colorectal cancer patients, indicating the need for psychological interventions aiming at improving adjustment to the disease. © 2015, Springer Science+Business Media New York. 61 1 273 282

Although modern social structure and medical advances have led to the increasing number of women childbearing in older age, cancer remains a rare diagnosis during pregnancy. There is little given information throughout the literature concerning gestation associated with the coexistence of gastrointestinal stromal tumor (GIST). In this review, we present 12 reported cases of GIST during pregnancy and we discuss the maternal and fetal outcome, as well as the therapeutic plan that was followed in each situation. From the collected data, 8 out of 12 cases had an uneventful outcome of their fetus. In 11 out of 12 cases surgical excision of the tumor was the treatment of choice, while seven women were treated with imatinib. Two of them were already on imatinib therapy during conception due to preexisting GIST diagnosis. Surgery remains the gold standard for the treatment of local or resectable GIST, while published data concerning the use of imatinib during pregnancy indicate that teratogenicity or fetal loss might be induced, especially if given during the first trimester of pregnancy. GIST during gestational period is a rare tumor in which a multidisciplinary approach should be designed, taking always into consideration that it has a favorable outcome on targeted treatment. © 2015, Federación de Sociedades Españolas de Oncología (FESEO). 17 10 757 762

Cancer of Unknown Primary (CUP) comprises a heterogeneous disease group with diagnosis of metastatic malignancy in the absence of an identifiable primary site after diagnostic work up. CUP may either resemble a specific primary tumor site sharing common clinicopathological characteristics and prognosis, or present as a distinct disease entity with undifferentiated pathological features, usually bearing dismal prognosis. Diagnosis and management have traditionally been based on clinicopathological characteristics and therapeutic strategies have been mainly empirical. In the last decade, the advent of massive gene sequencing and the advances in genomic technologies have shed light on the genomic landscape of CUP. Several gene panel tests are currently commercially available and are used in an effort to correlate the genomic characteristics of a specific CUP tumor to those of a known primary tumor, guiding thus therapeutic management. Nevertheless, these efforts are hampered by the rarity of CUP and the inability to validate the results of such tests due to the paucity of randomized clinical trials. In the current work, we provide an overview of CUP with emphasis on the impact of the genome sequencing technologies on diagnosis and management of these tumors. We also discuss potential implications of genomics for the future treatment of CUP and address the challenges of the implementation of these therapeutic strategies in routine clinical practice. © 2015 Elsevier Ltd. 41 7 598 604

Cancer of unknown primary of the head and neck is a challenging entity for the oncologist. The role of human papilloma virus/p16 in carcinogenesis and in prognosis is well established in certain HNSCC especially in that of the oropharynx. In the case of occult primary of the head and neck the role of HPV/p16 positivity is not well defined regarding prognosis and localization of the primary. An independent review of PubMed and ScienceDirect database was performed up to May 2014 using combinations of terms such as "occult primary of the head and neck", "CUP of the head and neck" "metastatic cervical squamous cell carcinoma of unknown primary", "HPV" and "HPV and head and neck cancer". Literature review shows a strong association between HPV/p16 positivity and primary location in the oropharynx in patients with CUP of the head and neck as well as a better clinical outcome. HPV positivity and p16 overexpression could be used as surrogate markers in the search of the primary site of patients with CUP of the head and neck therefore maybe guiding treatment decisions. © 2014 Elsevier Ltd. All rights reserved. 51 2 119 123

K. Fizazi1, F. A. Greco2, N. Pavlidis3, G. Daugaard4, K. Oien5 & G. Pentheroudakis3, on behalf of the ESMO Guidelines Committee* Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Tennessee Oncology, Centennial Medical Center, Nashville, USA; Department of Medical Oncology, University of Ioannina, Ioannina, Greece; Department of Oncology 5073, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; University of Glasgow, Institute of Cancer Sciences, Glasgow, UK

Guidelines should provide recommendations on the optimal management of a patient in specific clinical circumstances based on the scientific evidence. ESMO, as Europe's leading society in medical oncology produces a range of guideline products in order to assist the cancer specialist towards implementation of quality cancer care, as well as in order to provide information to patients establishing standards for up-to-date optimal management. The ESMO 'guideline products' include the Clinical Practice Guidelines, the complementing Consensus Conferences on focused clinical scenarios, as well as memory tools such as print and e-Pocket Guidelines and Patient Guides. In this manuscript, methodology, design and characteristics of the ESMO guideline products are explained and discussed by their strengths and weaknesses, opportunities and threats in order to stimulate reflections on room for improvement and future strategy. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 26 v1 v7

Background: Cancer in pregnancy is a rare disease with breast cancer, cervical cancer, melanoma and Hodgkin's disease to be the most commonly diagnosed malignancies during gestation. Cancer of unknown primary (CUP) is a wellrecognized clinical disorder where the primary site can not be identified after a standard diagnostic approach. CUP in pregnancy has rarely been described. Materials and Methods: We searched MEDLINE and contacted cancer Centers in Europe, United States and Australia where patients with CUP or pregnant patients with cancer were diagnosed and treated. Results: Since 1976 we identified 18 pregnant women with CUP in a median gestational age of 34 weeks. Most of these patients were diagnosed with poorly-differentiated histology, had poor response to systemic treatment and a median maternal survival of 8 months. Seventy-two percent of mothers have died, while 80% of the newborns were alive and healthy. Almost one fourth of placentas examined showed metastatic disease. Conclusion: CUP during pregnancy is a very rare coexistence, usually has an aggressive disease with poor response to chemotherapy and a dismal prognosis. Both obstetricians and oncologists should be aware of this rare condition. 35 1 575 580

While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to stepwisely test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers ., While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers.

The aim of this study is to investigate the feasibility and determine the pharmacokinetics of low-dose paclitaxel in cancer patients with severe hepatic dysfunction. This was a prospective study. Patients with liver metastases who had either transaminase serum levels higher than 10 times the upper normal limit or bilirubin serum levels higher than 5 times the upper normal limit were eligible. All patients underwent pharmacokinetic evaluation during the first course of treatment. Pharmacokinetics in severe hepatic dysfunction patients were compared with data from a reference group of patients with normal hepatic function who participated in a phase I study. Nine severe hepatic dysfunction patients were treated with paclitaxel 70 mg/m administered as a 1-h infusion every 2 weeks. They received a median three treatment courses (range 1-9) without clinically relevant toxicity. The area under the concentration-time curve of paclitaxel was markedly higher in severe hepatic dysfunction patients when compared with the normal hepatic function control group treated with the same dose (98% increase, P0.1) concentration threshold in the severe hepatic dysfunction patients who received paclitaxel 70 mg/m approximated pharmacokinetics of paclitaxel in patients with normal liver function who received 130 mg/m. Maximum plasma concentration (Cmax) did not differ between the two groups. In conclusion, paclitaxel 70 mg/m was safely delivered every 2 weeks in patients with severe hepatic dysfunction and resulted in adequate plasma concentrations. Paclitaxel at this dosage can be taken as an option for severe hepatic dysfunction patients who are expected to get clinical benefits from taxanes. Anticancer Drugs

Introduction: Despite unique tumor epidemiology and a higher cancer incidence compared to pediatric patients, adolescents and young adults have not been receiving specialized, multidisciplinary, centralized care. In an effort to emphasize this need, we present outcome and toxicity data from a reference centre. Methods: Cohort of 150 patients aged 15-30 treated for malignant tumors of lymphoid and solid organs from 1986 to 2002. Results: Patients aged 15-19 commonly had lymphomas, germ cell tumors and pediatric sarcomas, whereas those aged 20-30 experienced germ cell tumors, lymphomas, melanomas and epithelial tumors more often. Overall 5- and 10-year survival was 80%, whereas 5-year and 10-year time to treatment failure was 68% and 43.5% respectively. 24% of patients experienced persistent, late treatment-related toxicities that interfered with their normal lifestyle. Conclusion: Despite the need for specialized care, psychosocial support and enrollment in clinical trials, youngsters have not been recognized as a patient group with distinct needs. Development of «Juvenile» oncology is required. © FESEO 2006. 8 6 444 449

The aim of this retrospective study was to illustrate the clinicopathologic data and the treatment results in patients with primary gastrointestinal tract non-Hodgkin's lymphoma (GI NHL). Among 810 patients with NHL, 128 cases (15.8%) were diagnosed as primary GI tract NHL. There were 79 males and 49 females with median age of 62 years. The most common primary site was the stomach (68%). Overall, 67.2% of the patients were in stages I - II, and 32.8% in stages III - IV. Simultaneous involvement of the GI tract and other extranodal sites was observed in 26 patients (20%). Extranodal marginal zone B-cell lymphoma (MZBL) (i.e., low-grade lymphoma of mucosa-associated lymphoid tissue type) accounted for 48.4% of lymphomas. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBL]) accounted for 44.5%. Eighty-three patients (67.5%) achieved complete response (CR), either by surgery (43/43 patients, 17 with DLBL and 25 with MZBL) or by primary chemotherapy (40/64 patients, 22 with DLBL and 17 with MZBL). Sixty-two patients remain in CR; 33/43 after surgical resection (13/17 with DLBL and 20/25 patients with MZBL), and 29/40 after only chemotherapy (18/22 with DLBL and 10/17 with MZBL). The major prognostic factor for outcome in the present study was the stage of the disease. Patients with localized lymphoma (stage I and II) had significantly longer DFS and OS (DFS and OS at 3-year: 83% and 87%, respectively) than patients with extended disease (stage III and IV) (DFS and OS at 3-year: 46% and 60%, respectively) (P < 0.0001). The International Prognostic Index (IPI) for patients with aggressive lymphomas was prognostic only for DFS (79% for low-risk patients [IPI score 0 - 1] vs 49% for higher risk groups [IPI score >1] at 3-year, P = 0.0131). Leuk Lymphoma

The aim of the study was to investigate angiogenesis in patients with advanced-stage ovarian carcinoma. We used paraffin-embedded tumor tissues from 33 patients diagnosed with FIGO III ovarian cancer who had optimal surgery and received platinum-based chemotherapy. The tissue expression of CD34, vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1) was assessed immunohistochemically. CD34 stained hot spot areas were used to evaluate tumor microvessel density (MVD). VEGF and TSP-1 were assessed by semiquantitative methods. The studied molecules were investigated for relationship with standard clinicopathologic parameters. MVD count was high: median value of 39, range 12–143 microvessels/mm2. VEGF was present in all cases and stained strong in 91%. Stroma staining for TSP-1 was weak in 79% of the cases, strong in 6%, and absent in five (15%). We did not find correlations between the three studied markers and histologic type or tumor grade. MVD score did not relate to VEGF or TSP-1. We only observed a trend toward a longer survival in patients with tumors expressing high TSP-1 (60 vs. 36 months, P= 0.1). Proangiogenetic factor VEGF is highly expressed in advanced-stage ovarian carcinomas. The findings of this study may offer support for considering VEGF-targeted therapeutics in ovarian cancer treatment research.

AIM: The irinotecan-cisplatin combination has emerged as a new standard for the treatment of advanced-stage small-cell lung cancer (AS-SCLC). To move forward we developed a 3-day regimen of cisplatin, etoposide and irinotecan. METHODS: Successive cohorts of AS-SCLC patients were treated with irinotecan administered as a single 1-h infusion in combination with fixed doses of cisplatin (20 mg/m(2)) and etoposide (75 mg/m(2)), both given for three consecutive days (ECI regimen). Irinotecan dose was escalated from 60 mg/m(2) by 40-mg/m(2) increments. At mid-step between the maximum tolerated dose (MTD) and the previous dose level, patients were randomized for the day of administration of irinotecan (day 1 vs day 3). RESULTS: A total of 36 AS-SCLC patients received 166 courses of treatment at four dose levels. The MTD of irinotecan was 140 mg/m(2) (three dose-limiting toxicities, DLTs), and the recommended optimal dose (ROD) 120 mg/m(2) (two DLTs). DLTs were febrile neutropenia and grade 3 diarrhea. Other toxicities were mild. No difference in toxicity was seen between the two time schedules. A 77% (95% CI 63.25-90.75%) response rate was recorded among 31 evaluable patients and the median survival was 12 months. CONCLUSIONS: The ECI regimen was well tolerated and showed considerable activity in patients with AS-SCLC. Phase II/III evaluation is ongoing. Cancer Chemother Pharmacol

Leptomeningeal carcinomatosis is defined as malignant infiltration of the pia matter and arachnoid membrane. Leukaemias and lymphomas, lung, breast cancer and melanoma are the primary tumours commonly associated with leptomeningeal carcinomatosis. Diagnosis is based on compatible symptoms and signs, cytological evidence of malignancy in the cerebrospinal fluid, and neuroimaging studies. Treatment is largely palliative (median survival 2 - 4 months). Patients with lympomatous or leukaemic meningitis, chemosensitive tumours such as breast cancer, low tumour burden, minimal neurological deficits, good performance status and controllable systemic disease survive longer with occasional long-term responses. Available treatment options include focal radiation therapy to CNS sites of bulky, symptomatic or obstructive meningeal deposits, intrathecal cytotoxic therapy and systemic chemotherapy. No evidence of superiority of intrathecal treatment compared with best palliative care (including radiation therapy and systemic treatment) is available from clinical trials. Novel treatment approaches include intrathecal liposomal Ara-C, the development of new cytotoxic compounds, signal transduction inhibitors and monoclonal antibodies for intrathecal or systemic use. Until data from multi-centre randomised trials are available, rationalisation of therapy should be done by stratifying patients to prognostic groups. High-risk patients will only survive for a few weeks and are better managed with supportive measures, whereas low-risk patients justify vigorous cerebrospinal fluid-directed treatment combined with radiation therapy and systemic chemotherapy. © 2005 Ashley Publications Ltd. 6 7 1115 1125

Background: Interest in the use of preoperative systemic treatment in the management of breast cancer has increased because such neoadjuvant therapy appears to reduce the extent of local surgery required. We compared the clinical end points of patients with breast cancer treated preoperatively with systemic therapy (neoadjuvant therapy) and of those treated postoperatively with the same regimen (adjuvant therapy) in a meta-analysis of randomized trials. Methods: We evaluated nine randomized studies, including a total of 3946 patients with breast cancer, that compared neoadjuvant therapy with adjuvant therapy regardless of what additional surgery and/or radiation treatment was used. Fixed and random effects methods were used to combine data. Primary outcomes were death, disease progression, distant disease recurrence, and loco-regional disease recurrence. Secondary outcomes were local response and conservative local treatment. All statistical tests were two-sided. Results: We found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms associated with death (summary risk ratio [RR] = 1.00, 95% confidence interval [CI] = 0.90 to 1.12), disease progression (summary RR = 0.99, 95% CI = 0.91 to 1.07), or distant disease recurrence (summary RR = 0.94, 95% CI = 0.83 to 1.06). However, neoadjuvant therapy was statistically significantly associated with an increased risk of loco-regional disease recurrences (RR = 1.22, 95% CI = 1.04 to 1.43), compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant, than the adjuvant, arm received radiation therapy without surgery (RR = 1.53, 95% CI = 1.11 to 2.10). Across trials, we observed heterogeneity in the rates of complete clinical response (range = 7%-65%; P for heterogeneity of

Despite unique tumour epidemiology, a higher cancer incidence and modest survival improvement compared to paediatric patients, adolescents and young adults aged 15-30 have not been considered as a separate, 'special' group of patients in the frame of medical oncology. In an effort to emphasise this need, we review the particular characteristics of diagnosed tumours, a aetiologic associations, nosologic classification, management, outcome and late toxic effects. Adolescents and young adults are in need of specialised care for intensive treatment of curable malignancies, skilled nursing care, interaction with peers, family and physicians as well as continuous psychosocial support. Enrolment in clinical research trials and close follow-up via the development of a cooperative infrastructure are imperative for the optimisation of management and avoidance of late effects. Similar to geriatric and paediatric oncology, we call for the intensification of treatment, support and research multidisciplinary efforts in order to better fulfil the pressing demands of this patient group. © 2005 European Society for Medical Oncology. 16 2 181 188

Background. Although the TNM system is useful in predicting survival in resected colorectal cancer, heterogeneity within the same stages regarding prognosis exists. We are presenting a pooled analysis of prognostic factors from two randomized studies of adjuvant treatment conducted by the Hellenic Cooperative Oncology Group. Patients and Methods. Patients with stage II or III colon (n = 279) or rectal (n = 220) cancer were included in this analysis. Following surgery, patients received: 5-fluorouracil/leucovorin (5-FU/LV) (n = 135), 5-FU/LV and interferon Alfa-2a (IFNA-2a) (n = 138), 5-FU/LV and pelvic chemoradiotherapy (n = 106), and pelvic chemoradiotherapy alone (n = 108). Results. Median follow up was 92 mo. The number of involved lymph nodes (LNs), tumor differentiation, and the presence of regional implants were independent prognostic factors for both OS and TTP, while nerve invasion was only significant for TTP. Patients were stratified into three prognostic groups (low-risk: no LNs and grade 1/2; high-risk: > 3 LNs and grade 3/4; intermediate-risk: remaining patients) with distinct differences in 5-yr survival (84.7% vs 57.6% vs 32.4%) and 5-yr TTP (81.2% vs 54.5% vs 28.6%). Conclusion. The combination of clinicopathological prognostic factors can be more informative than the traditional TNM staging system. Such stratification may be necessary in randomized trials and could be useful in deciding the most appropriate adjuvant treatment strategies. © Copyright 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 36 1 29 38

Purpose: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. Experimental Design: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. Results: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. Conclusions: The schedule B daily cisplatin-topotecan × 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Purpose: To investigate the pharmacokinetics of polyethylene glycol-coated liposomal doxorubicin (PLD, Caelyx) when given as a single agent and in combination with the taxanes paclitaxel or docetaxel in humans. Methods: The plasma kinetics of PLD were studied in 19 cancer patients treated with PLD every 4 weeks combined with either paclitaxel (on a weekly basis in seven and as a single infusion in three patients) or docetaxel (weekly in seven and as a single infusion in two). Plasma concentrations of PLD were quantified in two sets of samples per patient to compare the same pharmacokinetic parameters in each subject when treated with single-agent PLD and again with the combination. Total doxorubicin concentrations in plasma were quantified by HPLC. Pharmacokinetics were evaluated by noncompartmental analysis and the data obtained were compared for differences by a matched-pairs nonparametric test. Results: Coadministration of paclitaxel produced a median/mean 54/80% increase in PLD AUCinf (95% confidence interval 23% to 136%, P=0.002). The observed increase was consistent among all subjects. PLD clearance was also decelerated in the presence of paclitaxel (P=0.013) while other pharmacokinetic parameters were affected modestly. A small increase in the AUC of PLD was observed in the docetaxel/PLD arm (mean increase 12%, P=0.039) while PLD clearance decreased marginally and other pharmacokinetic parameters remained unaffected. AUC extrapolated to infinity was below 8% in both arms. Conclusions: This study showed the presence of a pharmacokinetic interaction that led to higher plasma concentrations of PLD when combined with paclitaxel and to a minor extent when combined with docetaxel. This pharmacokinetic information may be of value when planning combination therapies of PLD with taxanes. © Springer-Verlag 2004. 53 5 452 457