Critical Reviews in Oncology/Hematology

Published by Elsevier
Online ISSN: 1040-8428
Publications
Article
Healthy elderly patients with metastatic colorectal cancer may benefit from chemotherapy as much as the younger population. This analysis compares the outcomes of first-line oxaliplatin plus fluoropyrimidines in elderly versus young patients. 348 patients were randomized to capecitabine 1000 mg/(m2 12 h), days 1-14 plus oxaliplatin 130 mg/m2 day 1, every 3 weeks or weekly infusional 5-FU 2250 mg/m2 over 48 h plus bimonthly oxaliplatin 85 mg/m2. We evaluated response rate, time to progression, overall survival and toxicity according to age. ORR for elderly and young patients were 34.9% and 44.7%, respectively (p=0.081). Median TTP did not differ between the two groups: 8.3 months for patients > or =70 years and 9.6 months for those <70 years (p=0.114). Median OS was 16.8 months and 20.5 months for the > or =70 and <70 years groups, respectively (p=0.74). With XELOX, mild paresthesia and an increase in transaminase levels were more frequent for young patients, whereas grade 3/4 diarrhea was higher in those > or =70 years (25% vs. 8%, p=0.005). For FUOX, only paresthesia was significantly lower in patients > or =70 years (53% vs. 71%, p=0.032). Elderly patients with MCRC benefit from first-line oxaliplatin-fluoropyrimidine combinations as much as younger patients, without increased toxicity.
 
Article
From September 2001 to November 2002, 35 patients aged 70-81 (median, 75) years, with measurable metastatic lesions from colorectal carcinoma, were treated with a combination of oxaliplatin (OXA) infused i.v. over 2 h on day 1, and capecitabine, assumed orally twice a day (12-h apart) from day 2 to day 15. An alternated dose escalation for both drugs was planned over the first three cycles for each patient, in the absence of WHO grade > or =2 toxicity on previous cycle: starting doses were 85 mg/m2 for OXA, and 2000 mg/m2 (day) for capecitabine on first cycle; on second cycle, OXA was planned at 100mg/m2, while capecitabine was planned at 2500 mg/(m2 day) on third cycle. Treatment was repeated every 3 weeks until progression, or for a maximum of 12 cycles. A total of 212 cycles were administered, with a median of 6 (range, 1-12) cycles/patient. Dose escalation was performed in 18 (51%) patients for OXA, and in 4 (11%) patients for capecitabine. No grade 4, and 10 (29%) cases of grade 3 toxicity of any type were reported. Abdominal symptoms (pain, nausea, or vomiting) affected 66% of patients, but they were of grade 3 in only 2 (6%) patients. Grade 3 diarrhoea occurred in 3 (9%) patients. Two complete and 12 partial responses (PR) were reported, for an overall response rate of 40% (95% CI, 24-58%). Progression of disease occurred in 23 (66%) patients, and 18 (51%) died. The actuarial median progression-free and survival time were 6.9 and 14.1 months, respectively.
 
Article
Unlabelled: The aim of this study was to determine the impact of patient selection based on age, comorbidity and performance status on the efficacy of platinum-free combination therapy on non-small-cell lung cancer after 65 years of age. We analyzed the overall response rate, the median survival time, the 1-year survival rate, toxicity and quality of life after one to three 6-week cycles of docetaxel 30mg/m(2) weekly and gemcitabine 900mg/m(2) at weeks 1, 2, 4 and 5. Fifty patients (median age 73.7 years) were eligible. The mean number of comorbid conditions per patient was 0.8 [Balducci L. Lung cancer and aging. ASCO 2005. Educational book. p. 587-91; Piquet J, Blanchon F, Grivaux M, et al. Primary bronchial carcinoma in elderly subjects in France. Rev Mal Respir 2003;20:691-9; Jatoi A, Hillman S, Stella P, et al. Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 2005;23:9113-9; Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224-37]. Forty-five patients were assessable: 17 (34%) had an objective response, 18 (36%) had stable disease and 10 progressed (20%). The median survival time was 7 months and the 1-year survival rate 23.5%. The main grade III-IV adverse event was neutropenia (32% of patients). Conclusion: Platinum-free dual-agent chemotherapy gives similar results in patients over 65, selected on the basis of their precise age and comorbidity, to that reported in younger subjects.
 
Article
Few studies have investigated the late (i.e. ≥5 years post-treatment) effects of chemotherapy for non-central nervous system (non-CNS) cancer on the brain. Here we discuss the studies that have investigated the late effects of adjuvant chemotherapy for non-CNS cancer on cognitive function (n=6); brain structure and function (n=5); and incidence of dementia (n=4). The neuropsychological studies showed long-term adverse cognitive problems in chemotherapy-exposed breast cancer survivors. This is in line with results from neuroimaging studies that report long-term brain structural alterations after chemotherapy. The studies exploring the association between chemotherapy and the incidence of dementia were contradictive and showed no clear relationship between the two phenomena. Although several methodological issues limit the validity and interpretation of some of the results of these studies, they suggest that chemotherapy is associated with subtle, yet long-lasting cognitive deficits, possibly related to brain structural and functional differences, but as yet not with an increased risk of dementia.
 
Article
Drug resistance remains a major problem in the treatment of cancer patients for both conventional chemotherapeutic and novel biological agents. Intrinsic or acquired resistance can be caused by a range of mechanisms, including increased drug elimination, decreased drug uptake, drug inactivation and alterations of drug targets. Recent data showed that other than by genetic (mutation, amplification) and epigenetic (DNA hypermethylation, histone post-translational modification) changes, drug resistance mechanisms might also be regulated by microRNAs (miRNAs). In this review we provide an overview on the role of miRNAs in anticancer drug resistance, reporting the main studies on alterations in cell survival and/or apoptosis pathways, as well as in drug targets and determinants of drug metabolism, mediated by deregulation of miRNA expression. The current status of pharmacogenetic studies on miRNA and their possible role in cancer stem cell drug resistance are also discussed. Finally, we integrated the preclinical data with clinical evidences, in lung and pancreatic cancers, showing how the study of miRNAs could help to predict resistance of individual tumours to different anticancer drugs, and guide the oncologists in the selection of rationally based tailor-made treatments.
 
Article
Breast and ovarian cancers, like other cancers, occur due to genetic damage. Research aimed to determine the specific genes involved in the development of breast and ovarian cancers will help to understand how normal breast and ovarian epithelial cells escape regulation of proliferation, apoptosis and senescence. It was determined that approximately 10% of ovarian cancers and 20-30% of breast cancers arise in women who have inherited mutations in cancer susceptibility genes such as BRCA1, BRCA2 and other DNA repair genes. The ability to perform genetic testing permits the identification of women at increased risk who can then be offered preventive strategies. The vast majority of ovarian and breast cancers are sporadic, presumably resulting from the accumulation of genetic damage over lifetime. Several genes involved in breast and ovarian carcinogenesis have been identified, most notably the p53 tumor suppressor. The recent availability of expression microarrays has facilitated the simultaneous screening of thousands of genes and this will extend further the understanding of molecular events involved in the dynamic development of ovarian and breast cancers. Then, all this knowledge could be translated into effective screening, surveillance, prevention, and treatment strategies in the future.
 
Article
After 30 years of development, therapy with monoclonal antibodies has started to realize its promise. Clinical use is most widespread in the field of oncology, where half of the agents approved for routine clinical use are employed and a large number of molecules are currently undergoing clinical trials. In the past 2 years alone, three new compounds-the radiolabeled antibody (131)I-tositumomab and two antibodies targeting growth factor receptors (bevacizumab and cetuximab)-have received FDA approval for indications in oncology. This review summarizes the development of this exciting treatment modality over the last three decades, examines the outcome of treatment with these new antibodies and others available for routine clinical use (i.e. rituximab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, (90)Y-ibritumomab tiuxetan) in standard indications and in experimental settings, and gives a brief outlook on possible future developments.
 
Article
Waldenström's macroglobulinemia (WM) is defined as a B-cell lymphoproliferative disorder characterized by lymphoplasmacytic infiltration of the bone marrow associated with a monoclonal IgM component in the serum. Its clinical presentation is marked by diffuse clonal cell expansion, as well as by the physical and chemical properties of the monoclonal component, its autoantibody activity and possible tissue deposition. Initiation of treatment is not determined by the monoclonal IgM level, nor the extent of bone marrow infiltration, but confined to symptomatic patients. Their median overall survival ranges from 5 to 10 years. Poor outcome predictors include advanced age, low hemoglobin levels, low platelet count, high β2-microglobulin and high concentration of the serum monoclonal component. First-line therapeutic approaches include alkylating agents (chlorambucil, melphalan, cyclophosphamide), nucleoside analogs (fludarabine, cladribrine), and rituximab, whether singly or combined. Thalidomide-based regimens and bortezomib have also been assessed, and new agents such as bendamustine and everolimus are being investigated. We review these general features and describe our series of 121 patients with clearly established WM.
 
Article
There is abundant in vitro, animal and epidemiologic evidence to suggest that the Insulin-Like Growth Factor (IGF) family is a multi-component network of molecules which is involved in the regulation of both physiological and pathological growth processes in prostate. The IGF family plays a key role in cellular metabolism, differentiation, proliferation, transformation and apoptosis, during normal development and malignant growth. This family also seem essential in prostate cancer bone metastases, angiogenesis and androgen-independent progression. Therapeutic alternatives in men with progressive prostate cancer after androgen ablation are very limited. More effective therapies are needed for these patients. Pharmacologic interventions targeting the IGF family are being devised. Such strategies include reduction of IGF-I levels (growth hormone-releasing hormone antagonists, somatostatin analogs), reduction of functional IGF-I receptor levels (antisense oligonucleotides, small interfering RNA), inhibition of IGF-IR and its signalling (monoclonal antibodies, small-molecule tyrosine kinase inhibitors) and Insulin-Like Growth Factor Binding Proteins.
 
Article
A vast majority of high-grade gliomas over-express a receptor for interleukin 13 (IL13). This glioma-associated receptor for IL13 is interleukin 4 (IL4)-independent. This is in contrast to the physiological and IL4-shared receptor for the IL13, IL13/4 receptor, which is found on many normal organs. IL13-based Pseudomonas exotoxin (PE)-containing cytotoxic fusion proteins have been shown to be very potent anti-glioma agents. However, native IL13-based cytotoxins interact with both forms of the IL13 receptor. Therefore, mutations in IL13 were made in order to diminish/eliminate IL13's interaction with the shared IL13/4 receptor of normal tissue. These mutations encompassed amino acids located on alpha-helix A and C of IL13. We have engineered double or triple mutants of IL13 linked to various forms of PE. We found that these mutations could be successfully incorporated into IL13 without the loss of the protein's ability to selectively deliver the toxin to glioma cells while reducing their toxicity.
 
Article
Based on a 15-year old hypothesis, it is believed that an adequate ingestion of folate vitamins decreases, whereas a nutritional depletion of folate increases the risk of colorectal cancer. The present article reviews the efforts to provide biochemical and epidemiological evidence for folate as a chemopreventive agent against colorectal carcinogenesis. BIOLOGICAL EVIDENCE: Tetrahydrofolates govern the intracellular one-carbon metabolism and account for proper DNA biosynthesis and macromolecular modification. Numerous experimental studies traced different molecular pathways and tried to link folate depletion with DNA instability and/or mutagenesis. However, none of the proposed underlying molecular mechanisms appear clearly defined. EPIDEMIOLOGICAL EVIDENCE: Numerous case-control and prospective studies have been conducted on folate and colorectal cancer, which all together miss a clinical bottom line. The recommendation of folate intake to prevent colorectal cancer is therefore not evidence-based.
 
Article
The aim of this study was to assess whether there are differences in treatment strategy and outcome between different age cohorts among men and women with colon cancer. All patients with colon cancer included in the regional quality registry in Uppsala/Orebro and Stockholm between 1996 and December 2004 were analysed (n=11002). Patients were divided into three age categories: < or =65 years, 66-80 years and >80 years. Overall and cancer-specific survival decreased with increasing age for stages II and III colon cancer but was not influenced by gender. Older patients with stage III tumours were less likely to be referred for chemotherapeutic treatment and there was a decrease in cancer-specific survival with increasing age, from 63.7% to 51.0% to 38.4% in the three age groups. Postoperative morbidity and the number of reoperations was significantly higher in men than in women. The present study shows lower cancer-specific survival among older patients than among younger patients. Gender was not a prognostic factor in cancer-specific survival.
 
Article
Retinoids, particularly 13-cis-retinoic acid, have shown great promise against a number of benign, but serious dermatological conditions. In animal models, 13-cis-retinoic acid functions is a potent antipromoter whether a cancer has been initiated by chemical, physical, or viral agents. Additionally, substantial antiproliferative activity of this compound has been demonstrated in vitro in many culture systems. Clinical activity noted against several types of skin malignancies has led to several investigations to determine the anticancer activity of 13-cis-retinoic acid. Response of a variety of preneoplastic and neoplastic lesions of epithelial histology has been demonstrated. The toxicity of 13-cis-retinoic acid largely reflects its tissue distribution with skin and subcutaneous side-effects limiting dose escalation. The pharmacology and pharmacokinetics of 13-cis-retinoic acid has been explored in a number of patients and a long terminal half-life demonstrated. This review will discuss 13-cis-retinoic acid as a good model for a biological response modifier.
 
Article
To determine the prognostic meaning of symptoms in patients with advanced cancer. Medline, Embase, Cochrane and Cinahl databases were systematically explored. The predicting symptoms were also evaluated in the three stages of palliative care: disease-directed palliation, symptom-oriented palliation and palliation in the terminal stage. Out of 3167 papers, forty-four papers satisfied all criteria. Confusion, anorexia, fatigue, cachexia, weight loss, cognitive impairment, drowsiness, dyspnea, dysphagia, dry mouth and depressed mood were associated with survival in ≥50% of the studies evaluating these symptoms. Multivariate analysis showed confusion, anorexia, fatigue, cachexia, weight loss, dyspnea and dysphagia as independent prognostic factors in 30-56% of the studies. In the stage of disease-directed palliation anorexia, cachexia, weight loss, dysphagia and pain and in the stage of symptom-oriented palliation confusion, fatigue, cachexia, weight loss, dyspnea, dysphagia and nausea were shown to be independent predictors of survival in >30% of the studies. Symptoms with independent predictive value are confusion, anorexia, fatigue, cachexia, weight loss, dyspnea and dysphagia. New insights are added by the variance between the three palliative stages.
 
Article
Malnutrition in cancer patients results from multifactorial events and is associated with an alteration of quality of life and a reduced survival. A simple nutritional assessment program and early counselling by a dietitian are essential to guide nutritional support and to alert the physician to the need for enteral (EN) or parenteral nutrition (PN). A daily intake of 20-35 kcal/kg, with a balanced contribution of glucose and lipids, and of 0.2-0.35 g nitrogen/kg is recommended both for EN and PN, with an adequate provision of electrolytes, trace elements and vitamins. EN, always preferable for patients with an intact digestive tract, and PN are both safe and effective methods of administering nutrients. The general results in clinical practice suggest no tumor growth during nutritional support. The indiscriminate use of conventional EN and PN is not indicated in well-nourished cancer patients or in patients with mild malnutrition. EN or PN is not clinically efficacious for patients treated with chemotherapy or radiotherapy, unless there are prolonged periods of GI toxicity, as in the case of bone marrow transplant patients. Severely malnourished cancer patients undergoing major visceral surgery may benefit from perioperative nutritional support, preferably via enteral access. Nutritional support in palliative care should be based on the potential risks and benefits of EN and PN, and on the patient's and family's wishes. Research is currently directed toward the impact of nutritional pharmacology on the clinical outcome of cancer patients. Glutamine-supplemented PN is probably beneficial in bone marrow transplant patients. Immune diets are likely to reduce the rate of infectious complications and the length of hospital stay after GI surgery. Further studies are needed to determine the efficacy of such novel approaches in specific populations of cancer patients, and should also address the question of the overall cost-benefit ratio of nutritional pharmacology, and the effect of nutritional support on length and quality of life.
 
Article
With ageing, function preservation and maintenance of quality of life represent a major goal in an increasing proportion of patients. Life expectancy is a function of age, comorbidity, disability and cancer type and stage. Decision-making involves a delicate balance among all these factors, evaluation of treatment related complications of the overall effects of cancer and cancer treatment on the patients' quality of life. Despite several instruments for the assessment of quality of life being validated, none have been calibrated to the special requirements of the older patients. The structured interview administered by a trained clinician represents a standard approach for geriatric research and even for clinical practice because of the frailty of the older population. The combination of this approach with the self-administered questionnaire appears the most effective way to minimise missing data in collecting information for patients unable to complete the form.
 
Article
The ELDCARE study aims to investigate, at the ecological level, the relationships between socio-economic variables and cancer survival in patients aged 65 years and over. Survival data for patients diagnosed during the period 1985–1989 and followed up to 1994 were provided by 43 European Cancer Registries in 16 countries participating in the EUROCARE 2 project. Relative survival was computed by Hakulinen's methods. Data on socio-economic factors were collected by national statistics offices for the years around 1991. Pearson's correlation was used to study the relationships between cancer survival and socio-economic factors.
 
Article
CD44 is a cell adhesion molecule that was traditionally known as 'homing receptor'. This molecule is known to interact with the ezrin family (ERM family) members and form a complex that plays diverse roles within both normal and abnormal cells, particularly cancer cells. CD44 and ezrin and their respective complex have properties suggesting that they may be important in the process of tumour-endothelium interactions, cell migrations, cell adhesion, tumour progression and metastasis. This article reviews the role of CD44, ezrin family and the CD44/ezrin complex in cancer cells and their clinical impact in patients with cancer.
 
Article
One important regulation of gene expression in eukaryotes occurs at the level of mRNA translation, specifically at the step of translational initiation. Deregulation at this step will cause abnormal gene expression, leading to altered cell growth and possibly cancer. Translational initiation is controlled by multiple eIFs and one of these, eIF3, is the most complex and important factor for regulation of translation. Various subunits of eIF3 have recently been implicated to play important roles in regulating translation of specific mRNAs encoding proteins important for cell growth control. The expression of these eIF3 subunits has also been found altered in various human tumors and their altered expression may cause cancer and/or affect prognosis. Although the importance of translational regulation in cell growth control and oncogenesis is being slowly recognized, more vigorous studies on the role of eIFs in oncogenesis and cancer will likely benefit diagnosis, prognosis, and treatment of human cancers.
 
Article
Early hormone-receptor-positive breast cancer is a chronic relapsing disease that can remain clinically silent for many years. The NCIC-CTG MA.17/BIG 1-97 trial randomized disease-free early breast cancer patients who had received five years of adjuvant tamoxifen to either letrozole or placebo and was the first to demonstrate a benefit with extended endocrine therapy. MA.17/BIG 1-97 was stopped at the first interim analysis because disease free survival was strongly prolonged in the letrozole arm. Subsequent subset analyses and longer follow up have shown that this therapy improved survival across all groups, particularly among women with node-positive disease and those that were pre-menopausal at time of study enrolment. The MA.17/BIG 1-97 study should be considered a paradigm for extended adjuvant endocrine therapy in hormone-receptor-positive early breast cancer.
 
Article
Vascular endothelial cells are ordinarily quiescent in adult humans and divide less than once per decade. When tumors reach a size of about 0.2-2.0mm in diameter, they become hypoxic and limited in size in the absence of angiogenesis. There are about 30 endogenous pro-angiogenic factors and about 30 endogenous anti-angiogenic factors. In order to increase in size, tumors undergo an angiogenic switch where the action of pro-angiogenic factors predominates, resulting in angiogenesis and tumor progression. One mechanism for driving angiogenesis results from the increased production of vascular endothelial growth factor (VEGF) following up-regulation of the hypoxia-inducible transcription factor. The human VEGF family consists of VEGF (VEGF-A), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). The VEGF family of receptors consists of three protein-tyrosine kinases and two non-protein kinase receptors (neuropilin-1 and -2). Owing to the importance of angiogenesis in tumor progression, inhibition of VEGF signaling represents an attractive cancer treatment.
 
Article
As the world population ages, oncologists are increasingly confronted with the problem of comorbidity in cancer patients. This has stemmed an increasing interest into approaching comorbidity in a systematic way, in order to integrate it in treatment decisions. So far, data on the subject have been widely scattered through the medical literature. This article is aimed at reviewing the available data on the interaction of comorbidity and prognosis. This overview should provide an accessible source of references for oncological investigators developing research in the field. Various methods have been used to sum comorbidity. However, a major effort remains to be done to analyze how various diseases combine in influencing prognosis. The main end-point explored so far is mortality, with which comorbidity globally is reliably correlated. A largely open challenge remains to correlate comorbidity with treatment tolerance, and functional and quality of life outcomes, as well as to integrate it in clinical decision-making.
 
Article
Thrombosis and disseminated intravascular coagulation (DIC) are common complications in cancer. Patients with malignancy have a prothrombotic state due to the ability of almost all type of cancer cells to activate the coagulation system. However, none of the haemostatic markers of coagulation has any predictive value for the occurrence of the thrombotic events in one individual patient. The pathogenesis of the prothrombotic state in cancer is complex and, probably, multifactorial. Prothrombotic factors in malignancy include the tumour production of procoagulants (i.e., tissue factor (TF) and cancer procoagulant (CP)) and inflammatory cytokines, and the interaction between tumour cells and blood (i.e., monocytes/macrophages, platelets) and endothelial cells. Other mechanisms of thrombus promotion include some general responses of the host to the tumour (i.e., acute phase, inflammation, angiogenesis), decreased levels of inhibitors of coagulation, and impaired fibrinolysis. In addition, the prothrombotic tendency of cancer patients is enhanced by anticancer therapy, such as surgery, chemotherapy, hormone therapy and radiotherapy, by indwelling central venous catheter, and by haemodinamic compromise (i.e., stasis). However, not all of the mechanisms allowing the prothrombotic state of cancer are entirely understood. Therefore, it is presently difficult to rank the relative weight of these multiple interactions on the basis of the well-recognised clinical evidences of enhanced thrombotic episodes in patients with cancer. In this review we attempt to describe the current proposed mechanisms for the pathogenesis of the prothrombotic state in cancer patient. A better understanding of these mechanisms could help clinicians in the developments of more targeted treatment to prevent thromboembolic complications in cancer patient.
 
Article
[18F]-FDG is a glucose analogue labelled with a short-lived positron emitter. During the past decade, it has been proposed to detect in vivo lymphoma lesions with PET, a new non-invasive imaging modality. We aimed at reviewing the current experience with FDG in several clinical settings of lymphoma. Due to the lack of specificity of FDG for lymphoma, histology remains compulsory to establish the diagnosis. Nevertheless, in the case of AIDS, FDG imaging has been proposed to differentiate lymphoma and opportunistic infections in brain lesions. To explore lymphoma extension, FDG-PET highlights more lesions than CT or the clinical examination and results in upstaging 13% of cases. It could also be used for selecting a site for biopsy when the location considered first clinically is difficult to access. Staging lymphoma with FDG-PET also provides baseline images for subsequent evaluation of therapy, which is one of the most promising indications: a negative scan predicts response to therapy and subsequent remission with a predictive value of 89%, and a positive scan either reflects resistance or predicts relapse with a predictive value of 83%. The current achievement of FDG imaging is the early detection of recurrence or of viable tissue in residual masses that remain several months after treatment. Both its sensitivity (84%) and its specificity (95%) overwhelm the values of conventional imaging, mainly CT and gallium-67 scintigraphy. When PET, as a new clinical imaging modality, is not yet widely demanded by clinicians and/or the number of FDG examinations is less than 500 per year, a 'hybrid' gamma-camera or CDET can be an alternative to dedicated PET. For 3 years, we have been using FDG-CDET in the 2D mode without attenuation correction, and obtained the following accuracy in a total of 40 examinations that could be evaluated: 85% for assessment of chemotherapy and 92% to detect recurrences and evaluate residual masses. Our preliminary results also stress the interest in FDG examination in childhood lymphoma, with the same indications as in adults.
 
Article
The control of gene expression by microRNAs influences many cellular processes and has been implicated in the control of many (patho)physiological states. Recently, microRNAs have been detected in serum and plasma, and circulating microRNA profiles have now been associated with a range of different tumour types, diseases such as stroke and heart disease, as well as altered physiological states such as pregnancy. Here we review the disease-specific profiles of circulating microRNAs, and the methodologies used for their detection and quantification. We also discuss possible functions of circulating microRNAs and their potential as non-invasive biomarkers.
 
Article
Background: Liver resection for metastatic colorectal cancer became established without randomized trials. Proponents of surgical resection point out 5-year survival approaching 50% whilst critics question how much of the apparent effect is due to patient selection. Method: A 2006 systematic review of reported outcomes provided the starting point for citation analysis followed by thematic analysis of the texts of the most cited papers. Results: 54 reports from 1988 to 2002 cited 709 unique publications a total of 1714 times. The 15 most cited papers were explored in detail, and showed clear examples of duplicate reporting and overlapping data sets. Textual analysis revealed proposals for a randomized controlled trial, but this was argued to be unethical by others, and no trial was undertaken. Conclusions: This critical review reveals how the case for this surgery was made, and examines the arguments that influenced acceptance and adoption of this surgery.
 
Article
The clinical application of the pure beta emitter (90)Y constitutes a fundamental advancement in non-invasive medicine. Nowadays, mainly three oncological therapies exploit the intrinsic emissive characteristic of (90)Y. Radionuclide therapies include peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumour (NET) treatment, radioimmunotherapy (RIT) in non-Hodgkin's lymphoma (NHL) treatment and transarterial radioembolization therapy (TARET) in unresectable hepatocellular carcinoma (HCC) and liver metastatic colorectal cancer (mCRC) treatment. The last ten years of clinical experience from E-PubMed research have been reviewed and an efficacy correlation between (90)Y-therapies has shown a better objective response rate for RIT (ORR 80±15%; range 53-100) compared to PRRT (ORR 23.5±14%; range 9-50), and TARET (ORR for mCRC, 40±25%; range 19-91, and ORR for HCC, 42±20%; range 20-82). This review reports on the state of the art of the efficacy of (90)Y-therapies from the last decade and discusses new perspectives of therapeutic development.
 
Article
(19)Fluorine magnetic resonance spectroscopy ((19)F MRS) offers unique possibilities for monitoring the pharmacokinetics of fluoropyrimidines in vivo in tumors and normal tissue in a non-invasive way, both in animals and in patients. This method may therefore be useful for predicting response to fluoropyrimidine-based therapy with or without the effects of modulating agents, and this may be of value for the individualization of anticancer therapy and the strategic development of new anticancer drugs. (19)F MRS has been very valuable in elucidating the basic aspects of fluoropyrimidine metabolism, especially in animal studies. Studies in humans have indicated its clinical potential, but widespread application has been hampered by the relatively low detection sensitivity of the method. The recent introduction of clinical MR scanners with magnetic fields above 1.5 T may stimulate increased clinical use of (19)F MRS.
 
Article
Understanding the mechanisms of carcinogenesis and progression of gynecological tumors is important as these insights might lead to improved diagnostic tools for the pathologist, improved prediction of prognosis, response to therapy, and eventually better biology-based disease management, thereby improving prognosis and quality of life for the individual patient. Hypoxia is an important event in carcinogenesis because it renders a more aggressive phenotype with increased invasiveness and proliferation, formation of metastases and poorer survival. Although selecting patients with hypoxic tumors may therefore be clinically important, there is no consensus as to the method best suited for routine assessment of hypoxia. One of the potential tumor hypoxia markers is hypoxia inducible factor 1 (HIF-1). HIF-1 is the key cellular survival protein under hypoxia, and is associated with tumor progression and metastasis in various solid tumors. In this review, we show that in gynecological cancers, HIF-1A is emerging as an important factor in carcinogenesis, and that overexpression of HIF-1A and its target genes CA9 and SLC2A1 seems associated with shorter progression free- and overall survival. Since hypoxia and HIF-1A expression are associated with treatment failure, targeting HIF-1A could be an attractive therapeutic strategy with the potential for disrupting multiple pathways crucial for tumor growth. Currently, HIF-1A inhibitors are being studied in clinical trials in recurrent ovarian- and cervical cancer, and trials in other gynecological cancers are expected.
 
Article
The insulin-like growth factor (IGF) system is comprised of receptors, ligands (IGF-I and IGF-II), and a family of binding proteins (IGFBPs). It plays an important role in growth and development and in the maintenance of normal homeostasis. We present a review of the current laboratory and epidemiologic evidence that suggests an important role of the IGF system in colorectal carcinogenesis. Due to the complexity of this system, we have focused the review on the role of the IGF-1 receptor and its ligands in colorectal carcinogenesis and the strategies to block this pathway as a potential anti-cancer therapy.
 
Article
We performed a sensitivity and meta-regression analysis, cumulating all randomized trials exploring the benefit of afatinib, erlotinib and gefitinib versus chemotherapy in advanced EGFR mutant NSCLC, to investigate the potential role of additional clinico-pathological predictors of TKIs efficacy. With regard to progression-free survival (PFS), a significant interaction according to ethnicity (Asian versus Caucasian versus mixed) and to trial design (retrospective versus prospective EGFR analysis), was found; a trend toward significance with regard to type of drug (gefitinib versus erlotinib versus afatinib) was determined. No statistically significant differences in survival were observed. With regard to response, a significant interaction according to ethnicity, trial design and type of drug, was found. These data, together with a deeper characterization of the molecular background sustaining the oncogenic process, may contribute to create a clinico-pathologic predictive model, aimed to improve the magnitude of benefit expected from the use of targeted agents.
 
Article
Over 70% of the total incidence of cancer recorded in Europe in 1996 was in the elderly population (> or =60 years). Despite such high statistics, elderly cancer patients have often been denied the treatment that younger patients routinely receive. The response of elderly cancer patients to full-dose chemotherapy treatment in several neoplasms is similar to that of younger patients, demonstrating that age should not be a barrier to the administration of potentially curative or palliative chemotherapy. In order to provide optimal treatment to elderly cancer patients, management guidelines are recommended which take into account various factors, such as the physical well-being of the patient, the type of malignancy and any conditions that may hamper compliance with chemotherapy. The evidence-based guidelines of the National Comprehensive Cancer Network (NCCN) in the US recommend that the safest and most effective treatment of cancer in older individuals may be achieved by proper patient selection based on comprehensive geriatric assessment, dose adjustment of renally excreted drugs, prophylactic use of haematopoietic growth factors in patients treated with chemotherapy of dose-intensity comparable to cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) and maintenance of haemoglobin levels > or =12 g/l. The objective of this article is to report the conclusions of the meeting of the International Society of Geriatric Oncology (SIOG) in September 2001, including the need for geriatric assessment to tailor the management of patients to their personal circumstances and general health and the importance of evidence-based guidelines for the management of elderly cancer patients cannot be over-estimated.
 
Article
In recent years, strategy in cancer therapy in general, and breast cancer in particular, has been the use of maximum tolerated doses of toxic non-specific agents as well as the investigation of a range of new agents that specifically target tumor-related molecules, in a variety of biological pathways. The trial of chemotherapy (CT) versus chemotherapy+trastuzumab (Herceptin) in HER-2-overexpressing metastatic breast cancer (MBC) was one of the first to use a biological agent in combination with chemotherapy with success and, together with some trials of taxanes in anthracycline-resistance patients one of the few to demonstrate an overall survival (OS) advantage in MBC. Five main molecular pathways are of particular interest in terms of new drug development in breast cancer: the estrogen receptor (ER) pathway, the tyrosine kinase signal transduction pathway, the cell cycle regulation pathway, the apoptosis pathway and the angiogenesis pathway. This review will focus on new agents, cytotoxic, hormonal and molecular-targeted, which are in advanced clinical stages of development for the treatment of MBC.
 
Article
The incidence of cancer increases with age in humans and in laboratory animals alike. There are different patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by several mechanisms: (1) tissue accumulation of cells in late stages of carcinogenesis; (2) alterations in homeostasis, in particular, alterations in immune and endocrine system and (3) telomere instability linking aging and increased cancer risk. Increased susceptibility to the effects of tumor promoters is found both in aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Available evidence supporting the relevance of replicative senescence of human cells and telomere biology to human cancer seems quite strong, however, the evidence linking cellular senescence to human aging is controversial and required additional studies. Data on the acceleration of aging by carcinogenic agents as well as on increased cancer risk in patients with premature aging are critically discussed. In genetically modified mouse models (transgenic, knockout or mutant) characterized by the aging delay, the incidence of tumors usually similar to those in controls, whereas the latent period of tumor development is increased. Practically all models of accelerated of aging in genetically modified animals show the increase in the incidence and the reduction in the latency of tumors. Strategies for cancer prevention must include not only measures to minimize exposure to exogenous carcinogenic agents, but also measures to normalize the age-related alterations in internal milieu. Life-span prolonging drugs (geroprotectors) may either postpone population aging and increase of tumor latency or decrease the mortality in long-living individuals in populations and inhibit carcinogenesis. At least some geroprotectors may increase the survival of a short-living individuals in populations but increase the incidence of malignancy.
 
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In light of recent reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include an intravenous bisphosphonate, Novartis convened an international advisory board of experts in the fields of oral surgery and pathology, medical oncology, metabolic bone disease, and orthopedics to review existing data and provide updated recommendations on the clinical diagnosis, prevention, and management of ONJ in the oncology setting. Recommendations were developed to help guide healthcare professionals in early diagnosis and patient management. It is recommended that patients be encouraged to receive a dental examination prior to initiating bisphosphonate therapy and, if possible, complete any necessary dental procedures (e.g., tooth extraction) prior to initiating bisphosphonate therapy. Patients should receive regular dental visits during bisphosphonate therapy. Patients should be encouraged to practice good oral hygiene and minimize possible jaw trauma. If possible, patients should avoid dental surgery during treatment with bisphosphonates. If exposed bone is observed or reported in the oral cavity at any time (suspected ONJ), refer the patient to a dental professional immediately.
 
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Venous thromboembolism (VTE) is a major therapeutic issue in cancer patients. Advances in this field and heterogeneities in clinical practices prompted us to establish guidelines in the management of VTE in cancer patients according to the SOR (Standards, Options and Recommendations) methodology. A literature review of the studies published on this topic between 1999 and 2007 was performed. The guidelines were developed from the analysis of 38 out of 418 publications selected. They were peer-reviewed by 65 independent experts. The treatment of VTE in patients with cancer, including those with intracranial malignancies, should be based on low-molecular-weight heparins administered at therapeutic doses for at least 3 months. In the event of recurrent VTE, pulmonary embolism with hemodynamic failure or contra-indication to anticoagulant treatment, the indications and usages of vena cava filters and thrombolytic drugs should be the same as in non-cancer patients.
 
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Angiogenesis regulation is one of the newest fronts in the fight against cancer. Anti-angiogenic therapy is based on inhibiting factors required to solicit vessel formation thus cutting-off the tumor's supply of nutriments and oxygen. Initial vascular response is followed by formation of necrosis. Volumetric regression occurs more tardively. Effective monitoring of this new therapeutic approach thus requires imaging techniques that can detect early microvascular changes. A number of clinical studies provide evidence that contrast-enhanced ultrasound (CEUS) can provide early indication of tumor response to anti-angiogenic therapy. More sophisticated imaging and analysis techniques for CEUS and contrast agents targeted for adhesion to anti-angiogenic markers have also demonstrated promise in animal model studies. This review underlines the relevance of CEUS for anti-angiogenic therapy monitoring by summarizing the current clinical results, emerging CEUS techniques and preclinical data.
 
Article
Secondary tumours (ST) represent a major concern in survivors of Hodgkin's disease (HD). Breast cancer (BC) is the most frequent ST among young treated women. One hundred and eighty-nine women treated for HD by radiotherapy (RT) and/or chemotherapy (CT) subsequently developed 214 BCs. Median age at HD diagnosis was 25 years (34% were less than 20). Median interval between HD and BC was 18.6 years, with a 42-year median age at first BC. According to the TNM classification, there were 30 (14%) T0 (non palbable lesions), 86 (40%) T1, 56 (26%) T2, 13 (6%) T3T4 and 29 (14%) Tx. There were 25 (13.2%) contralateral BC. 160 (75%) and 15 (7%) tumours were infiltrating ductal and lobular carcinomas, 7 (3.3%) were other subtypes and 27 (22%) DCIS. The rate of axillary nodal involvement was 32%. Among 203 operated tumours, 79 (39%) were treated by breast conserving surgery (BCS), with RT in 56 (71%) cases. CT and hormonal treatment were delivered in 51% and 45% of the patients. With a 50-month median follow-up, local recurrence occurred in 12% of the tumours (9% after mastectomy, 21% after lumpectomy alone and 13.7% after lumpectomy with RT). Metastasis occurred in 47 (26%) patients. The risk factors were pN+, pT, high SBR grade and young age (< 50 years). The ten-year overall and specific survival rates were 53% and 63.5%, respectively. The ten-year specific survival rates were 79% for pT0T1T2, 48% for pT3T4 (p = 0.0002) and 79% for pN0 versus 38.5% for pN+ (p = 0.00026). Among 67 deaths, 43 (73%) were due to BC. Patients and physicians should be aware that BC is the most frequent secondary tumour in young women treated for HD. The new RT modalities (lower doses and involved fields) may decrease the risk in the future. However, these women require a careful monitoring as from 8 to 10 years after HD treatment, combining mammography, ultrasound and MRI according to several ongoing studies. BC with whole breast irradiation is feasible in some selected cases.
 
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Although the incidence of gastric cancer has been decreasing in the United States, it remains a leading cause of cancer death in the world, only lung cancer causes more deaths worldwide. The combination of relatively low prevalence, lack of pathognomonic symptoms, and lack of defined risk factors are associated with a delay in diagnosis leading to a dismal prognosis. For localized disease, surgery remains a cornerstone of treatment but much controversy remains regarding optimal peri-operative therapy. For advanced disease, several new agents and new combination chemotherapies have offered encouraging results. This paper seeks to review the major topics surrounding gastric cancer and cover the results of recently reported and ongoing trials.
 
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High-risk prostate cancer is a heterogeneous group that includes patients with clinically locally advanced stage disease at diagnosis. Unlike overt locally advanced disease, prediction of risk in clinically localized disease at an individual patient level, is not always easy or accurate with present knowledge. Gleason score, pretreatment prostate specific antigen (PSA), and stage (capsular invasion, seminal vesicle and nodal involvement) are the universally recognized criteria used to define risk. Overall, this group of patients have a greater than 50% risk of relapse. Historically, local treatment modalities with radical prostatectomy or radiation therapy constituted the mainstay of therapy in the majority of localized prostate cancer patients. However, the primary cause of failure and disease mortality stems from the development of systemic metastases. As we continue to witness stage migration towards earlier stage disease (presumably PSA related) and mortality reduction, devising better strategies for cure is a must. Recently completed randomized trials indicate a benefit from the use of hormonal therapy in patients with locally advanced prostate cancer treated with radiation therapy or node positive patients, post radical prostatectomy. While hormone-based combined modality trials have consistently shown improvements in local and systemic disease control, only two of these demonstrated improvements in overall survival. The palliative benefit of chemotherapy in hormone refractory disease and the promising response rates with newer agents has evoked interest in the use of chemotherapy in high-risk prostate cancer in the adjuvant and neoadjuvant settings. Several phase II and III trials are ongoing. Novel avenues of therapy such as tyrosine kinase inhibitors, gene therapy and angiogenesis inhibitors incorporated in a multimodality treatment strategy are likely to impact the course of this disease in the future.
 
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The difficult separation of clinical graft-versus-tumor (GVT) effects from graft-versus-host disease (GVHD) reflects their shared biology. Experimental approaches to mediate GVT effects while limiting GVHD include: (1) allograft T cell depletion followed by immune enhancement; (2) modulation of T cell dose or T cell subset composition; (3) donor lymphocyte infusion; (4) reduced-intensity host preparation; (5) modulation of Th1/Th2 and Tc1/Tc2 cell balance; (6) cytokine therapy or neutralization; (7) T regulatory cell therapy; (8) co-stimulatory pathway modulation; (9) chemokine pathway modulation; (10) induction of antigen-specific T cells; (11) alloreactive NK cell therapy; and (12) targeted pharmaceutical inhibition of proteosome, mammalian target of rapamycin, and histone deacetylase pathways. Clearly, a multitude of approaches exist that hold promise for separating GVT effects from GVHD. Future success in this endeavor will require a strong commitment towards translational research and continued advances in cell, vaccine, cytokine, monoclonal antibody, and targeted molecular therapy.
 
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B acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy. Although patient cure has reached an excellent rate, a minority of cases relapse and need novel therapies. IL-12, IL-23 and IL-27 belong to the IL-12 superfamily and exert immunological and anti-tumor functions. The latter can be mediated by activation of immune responses or by the direct activity on cancer cells. Recently, the role of IL-12, IL-23 and IL-27 in the control of pediatric B-ALL has been unveiled. Here, we discuss in a translational perspective the role of IL-12 family cytokines in pediatric B-ALL, highlighting similarities and differences in their mechanisms of action.
 
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Effective immunosuppression is an essential pre-requisite for successful organ transplantation and improvements in outcome after transplantation have to a large extent been dependent on developments in immunosuppressive therapy. Here we provide an overview of the different immunosuppressive agents currently used in solid organ transplantation. A historical perspective on the development of immunosuppression for organ transplantation is followed by a review of the individual agents, with a focus on their mechanism of action and efficacy. Steroids, anti-proliferative agents (azathioprine and mycophenolate), calcineurin inhibitors (cyclosporine and tacrolimus) and TOR inhibitors (sirolimus and everolimus) are discussed along with both polyclonal and monoclonal antibody preparations. Many of the key clinical trials that underpin current clinical usage of these agents are described and side-effects of the different agents are highlighted. Finally, a number of newer agents still in various stages of clinical development are briefly considered.
 
Top-cited authors
Nicola Normanno
  • Istituto Nazionale Tumori "Fondazione Pascale"
Ralf Brandt
  • vivoPharm Global
Martine Extermann
  • Moffitt Cancer Center
Silvio Monfardini
  • Fondazione Don Carlo Gnocchi
Olaf Ahlers
  • Charité Universitätsmedizin Berlin