Cancer Treatment Reviews - Articles in Press

Epidemiology of childhood cancer - Corrected Proof

Peter Kaatsch — 2010-03-15

Abstract: The present contribution reports childhood cancer incidence and survival rates as well as time trends and geographical variation. The report is based on the databases of population-based cancer registries which joined forces in cooperative projects such as Automated Childhood Cancer Information System (ACCIS) and EUROCARE.According to these data, which refer to the International Classification of Childhood Cancer, leukemias, at 34%, brain tumors, at 23%, and lymphomas, at 12%, represent the largest diagnostic groups among the under 15-year-olds. The most frequent single diagnoses are: acute lymphoblastic leukemia, astrocytoma, neuroblastoma, non-Hodgkin lymphoma, and nephroblastoma. There is considerable variation between countries. Incidence rates range from 130 (British Isles) to 160 cases (Scandinavian countries) per million children. Incidence rates have shown an increase over time since the mid of the last century. In Europe, the yearly increase averages 1.1% for the 1978–1997 period and ranges from 0.6% for the leukemias to 1.8% for soft-tissue sarcomas. The probability of survival has risen considerably over the past decades, with the EUROCARE data showing an improvement of the relative risk of death by 8% when comparing the 2000–2002 time span to the 1995–1999 period. Regarding the years 1995–2002, the data show an overall 5-year survival probability of 81% for Europe and similar values for the USA.The data presented here describe the cancer situation with a specific, European focus. They are drawn from population-based cancer registries that ensure excellent data quality, and as a consequence represent the most valid European population-based data existing at present. It is also apparent that not all countries have data available from nationwide childhood cancer registries, a situation which warrants further improvement.

Neuroblastoma: Therapeutic strategies for a clinical enigma - Corrected Proof

Shakeel Modak, Nai-Kong V. Cheung — 2010-03-15

Summary: Neuroblastoma, the most common extracranial pediatric solid tumor remains a clinical enigma with outcomes ranging from cure in >90% of patients with locoregional tumors with little to no cytotoxic therapy, to <30% for those >18months of age at diagnosis with metastatic disease despite aggressive multimodality therapy. Age, stage and amplification of the MYCN oncogene are the most validated prognostic markers. Recent research has shed light on the biology of neuroblastoma allowing more accurate stratification of patients which has permitted reducing or withholding cytotoxic therapy without affecting outcome for low-risk patients. However, for children with high-risk disease, the development of newer therapeutic strategies is necessary. Current surgery and radiotherapy techniques in conjunction with induction chemotherapy have greatly reduced the risk of local relapse. However, refractory or recurrent osteomedullary disease occurs in most patients with high-risk neuroblastoma. Toxicity limits for high-dose chemotherapy appear to have been reached without further clinical benefit. Neuroblastoma is the first pediatric cancer for which monoclonal-antibody-based immunotherapy has been shown to be effective, particularly for metastatic osteomedullary disease. Radioimmunotherapy appears to be a critical component of a recent, successful regimen for treating patients who relapse in the central nervous system, a possible sanctuary site. Efforts are under way to refine and enhance antibody-based immunotherapy and to determine its optimal use. The identification of newer tumor targets and the harnessing of cell-mediated immunotherapy may generate novel therapeutic approaches. It is likely that a combination of therapeutic modalities will be required to improve survival and cure rates.

The role of the ‘innovative therapies for children with cancer’ (ITCC) European consortium - Corrected Proof

2010-03-15

Summary: Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70%. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of treatment can be considerable. The current paradigm for new cancer therapies is to increase our knowledge of the molecular basis of carcinogenesis, followed by the development of cancer-cell specific therapies. Historically, drug development was focused on adult cancers, and the potential efficacy in childhood malignancies was not considered. Recently, a European academic consortium was established, namely ‘innovative therapies for children with cancer’ (ITCC), to address this unmet need. This initiative is focused on the evaluation of novel agents in pediatric cancer pre-clinical models, and early clinical development of promising new drugs. The number of pediatric patients eligible to participate in such trials is limited, and accurate pre-clinical evaluation may provide evidence-based prioritization for clinical development. Until recently, clinical development of new drugs in childhood cancer was restricted by the limited accessibility of such agents. Recent changes in EU legislation oblige pharmaceutical companies to provide pediatric clinical data for all new drugs relevant to children, including anti-cancer drugs. Pediatric consortiums like ITCC have established networks of expertise with the specific aim of evaluating new drugs for the treatment of childhood cancers. Through proper evaluation in collaborative clinical trials we will learn how best to use these new therapeutic approaches and improve the survival rates and reduce toxicity for children with cancer.

Progress in the surgical treatment of malignant liver tumors in children - Corrected Proof

Jean-Bernard Otte — 2010-03-15

Summary: During the last decade, important progress has been made in the surgical treatment of malignant liver tumors in children. For hepatoblastoma, there is a general consensus for combining surgical resection with neoadjuvant (and adjuvant) chemotherapy. Long-term disease-free survival of around 85–90% can be achieved for resectable HB involving no more than three sections of the liver (PRETEXT I–III). For unresectable HB without extrahepatic invasion (PRETEXT IV with involvement of all four sections and some cases of PRETEXT III with invasion of, or close contact with major venous structures), similar results can be obtained with total hepatectomy and liver transplantation.For hepatocellular carcinoma, most often without underlying liver disease in children of the western world, results of resection with partial hepatectomy remain dismal, due to a high rate of recurrence. In contrast, remarkable survival rates have been obtained during the last decade with liver transplantation. There is no argument, either biological or based on evidence, that the selection of pediatric candidates for transplantation should be based on the same criteria as in adult patients (the Milan criteria).Optimization of results require to concentrate children with a malignant liver tumors in specialized, multidisciplinary pediatric centers with expertise in chemotherapy and in both major liver resections and transplantation.Enrolling these children in prospective trials should be encouraged, as well as prospective registration of transplanted patients in PLUTO (Pediatric Liver Unresectable Tumor Observatory-http://Pluto.cineca.org) in order to clarify issues unresolved by retrospective studies.

Molecular biology of breast cancer stem cells: Potential clinical applications - Corrected Proof

2010-03-15

Summary: Breast cancer stem cells (CSC) have been postulated recently as responsible for failure of breast cancer treatment. The purpose of this study is to review breast CSCs molecular biology with respect to their mechanism of resistance to conventional therapy, and to develop treatment strategies that may improve survival of breast cancer patients. A literature search has identified in vitro and in vivo studies of breast CSCs. Breast CSCs overexpress breast cancer resistance protein (BCRP) which allows cancer cells to transport actively chemotherapy agents out of the cells. Radioresistance is modulated through activation of Wnt signaling pathway and overexpression of genes coding for glutathione. Lapatinib can selectively target HER-2 positive breast CSCs and improves disease-free survival in these patients. Metformin may target basal type breast CSCs. Parthenolide and oncolytic viruses are promising targeting agents for breast CSCs. Future clinical trials for breast cancer should include anti-cancer stem cells targeting agents in addition to conventional chemotherapy. Hypofractionation radiotherapy may be indicated for residual disease post chemotherapy.

Dasatinib: A potent SRC inhibitor in clinical development for the treatment of solid tumors - Corrected Proof

John Araujo, Christopher Logothetis — 2010-03-12

Abstract: SRC is a tyrosine kinase that plays a role in oncogenic, invasive and bone-metastatic processes. It has therefore been prioritized as a candidate therapeutic target in patients with solid tumors. Several SRC inhibitors are now in development, of which dasatinib has been most explored. Preclinical studies in a wide variety of solid tumor cell lines, including prostate, breast and glioma, have shown that that dasatinib acts as a cytostatic agent, inhibiting the processes of cell proliferation, invasion and metastasis. Dasatinib also inhibits the activity of osteoclasts, which have a major role in the development of metastatic bone lesions. Dasatinib has additive or synergistic activity in combination with a number of other agents, including cytotoxic agents and targeted therapies, providing a rationale for combination treatment in a clinical setting. Emerging clinical data with dasatinib support experimental observations, with preliminary phase 1 and 2 data demonstrating activity, both as a single agent and as combination therapy, in a range of solid tumors. Future clinical trials will further assess the clinical value of SRC inhibition with dasatinib.

Aetiology of childhood leukaemia - Corrected Proof

Tim Eden — 2010-03-11

Summary: The acute leukaemias account for about 30% of all malignancy seen in childhood across the Western world. A peak incidence of precursor B cell ALL has emerged as socio-economic conditions have improved in countries worldwide. From twin studies and the use of neonatal blood spots it has been possible to back track the first initiating genetic events within critical haemopoietic cells to foetal development in utero for most precursor B cell ALL and some cases of AML. These events may occur as part of normal foetal development. Whether other factors (environmental or constitutional) are involved to increase the chance of these first genetic changes happening is unclear. For some leukaemias (e.g. infant MLL positive ALL) the first event appears adequate to create a malignant clone but for the majority of ALL and AML further ‘genetic’ changes are required, probably postnatal. Many environmental factors have been proposed as causative for leukaemia but only ionising irradiation and certain chemicals, e.g. benzene and cytotoxics (alkylators and topoisomerase II inhibitors) have been confirmed and then principally for acute myeloid leukaemia. It appears increasingly likely that delayed, dysregulated responses to ‘common’ infectious agents play a major part in the conversion of pre-leukaemic clones into overt precursor B cell ALL, the most common form of childhood leukaemia. Constitutional polymorphic alleleic variants in immune response genes (especially the HLA Class II proteins) and cytokines may play a role in determining the type of immune response.High penetrance germ-line mutations are involved in only about 5% of childhood leukaemias (more in AML than ALL). There is little evidence to support any role of viral transformation in causation, unlike in animals. Other environmental factors for which some evidence exists include non-ionising electromagnetic radiation and electric fields, although their mode of action in leukaemogenesis remains unclear. There is no single cause for childhood leukaemia and for most individuals a combination of factors appears to be necessary; all involving gene–environment interactions. To date few clear preventative measures have emerged, except the complete avoidance of first trimester X-rays in pregnancy; a healthy diet with adequate oral folic acid intake both preconception and early in pregnancy; and the early exposure of children to other children outside the home to facilitate stimulation and maturation of the natural immune system. Here then are clear echoes of the “hygiene hypothesis” regarding the initiation of allergies, autoimmune disease and type I diabetes mellitus in children and young people.

Where can biology of childhood ALL be attacked by new compounds? - Corrected Proof

Jean Pierre Bourquin, Shai Izraeli — 2010-03-11

Summary: Although the majority of children with acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy, the challenge remains to salvage patients with resistant disease and to reduce treatment related toxicity. To meet this challenge, it will be essential to incorporate new agents targeting the biological Achilles Heels of this cancer more rapidly into currently available treatment regimen. Here we review the principles of current ALL therapy, recent advances in understanding ALL biology and discuss a selection of promising areas for drug development that may take advantage of the underlying leukemia biology. We focus particularly on strategies to interfere with common effector mechanisms that can be trigged by different individual oncogenic lesions and on new agents from drug development programs in adult oncology, as such agents will come with better chances for sustainable commercial development.

Targets for cancer therapy in childhood sarcomas - Corrected Proof

Marco Wachtel, Beat W. Schäfer — 2010-03-11

Summary: Development of chemotherapeutic treatment modalities resulted in a dramatic increase in the survival of children with many types of cancer. Still, in case of some pediatric cancer entities including rhabdomyosarcoma, osteosarcoma and Ewing’s sarcoma, survival of patients remains dismal and novel treatment approaches are urgently needed. Therefore, based on the concept of targeted therapy, numerous potential targets for the treatment of these cancers have been evaluated pre-clinically or in some cases even clinically during the last decade. This review gives an overview over many different potential therapeutic targets for treatment of these childhood sarcomas, including receptor tyrosine kinases, intracellular signaling molecules, cell cycle and apoptosis regulators, proteasome, hsp90, histone deacetylases, angiogenesis regulators and sarcoma specific fusion proteins. The large number of potential therapeutic targets suggests that improved comparability of pre-clinical models might be necessary to prioritize the most effective ones for future clinical trials.

Surgical modalities in the treatment of bone sarcoma in children - Corrected Proof

Rafiq Abed, Robert Grimer — 2010-03-11

Summary: Primary malignant bone tumours are rare but are one of the most common malignancies in adolescents. The optimum management of a child with a bone tumour is at a specialist treatment centre by a multidisciplinary team experienced in the diagnosis, chemotherapy and surgical management of these conditions. Most tumours are treated with chemotherapy followed by surgery. The surgical aim is to completely resect the tumour whilst ideally preserving the limb and maintaining function. The perfect limb salvage operation that restores normal function with no long term morbidity is rarely possible and most operations will restore function with potential long term complications. The variety of techniques possible for limb salvage includes the use of prostheses, allografts, reimplantation of sterilised bone or use of vascularised bone. Extendible prostheses are now common place and can maintain limb length following tumour resection even in the young child. Assessing outcomes is notoriously difficult but various measures are starting to allow comparisons of long term outcomes for this group of patients.

Male breast cancer - Corrected Proof

2010-03-02

Summary: Male breast cancer accounts for around 1% of all breast cancer cases, but the incidence has increased over the past 25years. The rarity of this entity precludes prospective randomized clinical trials. Although breast carcinoma in both genders share certain characteristics, notable differences have emerged. Familial cases usually have BRCA2 rather than BRCA1 mutations. Klinefelter syndrome is the strongest risk factor for developing male breast carcinoma. Men tend to be diagnosed at an older age than women. Presentation is usually a painless lump, but is often late, with more than 40% of individuals having stage III or IV disease. When survival is adjusted for age at diagnosis and stage of disease, outcomes for male and female patients with breast cancer is similar. Surgery is usually mastectomy with axillary clearance or sentinel node biopsy. Because 90% of tumors are hormonal receptor positive, tamoxifen is standard adjuvant therapy. Indications for radiotherapy and chemotherapy are similar to female breast cancer. For metastatic disease, hormonal therapy is the main treatment, but chemotherapy can also provide palliation.

The contribution of the Epstein-Barr virus to the pathogenesis of childhood lymphomas - Corrected Proof

2010-03-02

Summary: The Epstein-Barr virus (EBV) is a lymphotropic herpes virus with oncogenetic properties which can lead to the development of lymphomas such as Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), or post-transplant lymphoma. This review discusses our current understanding of lymphomagenesis in relation to EBV and the potential for targeted therapies.

Is there a role for a specialized follow-up clinic for survivors of pediatric cancer? - Corrected Proof

Pinki K. Prasad, Travis Bowles, Debra L. Friedman — 2010-03-02

Abstract: Due to advances in chemotherapy and supportive care, greater than 70% of patients with childhood cancer will survive 5years. However, there are long-term physiological and psychological sequelae of these treatments that may not manifest until pediatric survivors are into adulthood. Various studies done in the long-term pediatric survivors have noted that they are at increased risk for poor health and for chronic health problems. One complicating factor in treating these patients for their health problems is that many childhood cancer survivors are unaware of their past medical history and what their past cancer treatment entailed. There are also a number of barriers to medical care in survivors of childhood cancer which include inadequate insurance coverage for many and lack of knowledge of long-term effects physicians. As pediatric cancer survivors age they usually transition to community physicians. This paper proposes different models for follow-up clinics for survivors of pediatric cancers so childhood cancer survivors are not be subjected to cost ineffective or excessive evaluations but rather medical screening tests that are risk and guidelines that are set forth by experts.

Possibilities of new therapeutic strategies in brain tumors - Corrected Proof

Eric Bouffet, Uri Tabori, Annie Huang, Ute Bartels — 2010-02-26

Summary: Advances in the management of pediatric brain tumors have been less successful than in other areas of pediatric oncology. This gap in outcome is essentially related to specific aspects of these tumors in this age group such as the fact that the surrounding brain is still developing, vital structures limit aggressive attempts at removing infiltrating lesions, drug penetration into the central nervous system is often poor and short and long term toxicities of some treatments to the surrounding brain are significant. This review describes new therapeutic strategies and their impact in the pediatric neuro-oncology practice. Although the number of new active antineoplastic agents has been limited during the last decade, significant improvements in the chemotherapeutic management of pediatric brain tumors have been observed. These relate to the optimization of chemotherapy protocols, the development of new schedules of administration such as metronomic schedules, sequential high dose chemotherapy, concomitant administration of chemotherapy and radiation, or the introduction of intrathecal or intraventricular chemotherapy in specific protocols. Technological advances in radiotherapy allow delivering optimal doses to the target volume while decreasing the volume of normal surrounding tissue receiving radiation. As a consequence, conformal radiation therapy currently plays a major role in the management of several pediatric brain tumors, including in infants where radiation has been traditionally avoided. The role of molecularly targeted agents is still unclear and a number of phase I and II trials are ongoing to better define the future of these new therapies in pediatric brain tumors.

Langerhans cell histiocytosis: Current concepts and treatments - Corrected Proof

Oussama Abla, R. Maarten Egeler, Sheila Weitzman — 2010-02-26

Abstract: Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of cells with the phenotype of activated Langerhans cells. The diagnosis of LCH is often delayed or missed. Many questions about LCH remain to be answered, including whether it is caused by a malignancy or by immune dysregulation. Data from the early 1990s showed that LCH consisted of an accumulation of monoclonal LCH cells, suggesting a neoplastic disorder. However, further investigations with current sophisticated techniques have not shown consistent genomic aberrations. Recent data which suggests a role for an IL-17A dependant pathway of dendritic cell fusion in LCH remains to be proven. The most recent data taken together swing the pendulum towards an immunologic aberration.The clinical course of LCH is highly variable, ranging from a self-healing solitary bone lesion to widely disseminated life-threatening disease. Patients with multisystem (MS) disease with organ dysfunction, particularly those refractory to front line therapy, and those with multiple reactivations of disease associated with significant permanent sequelae represent the greatest challenge. Early switch of refractory patients to salvage therapies has contributed to the improvement in survival of MS-LCH patients. Due to the rarity of LCH in children and adults, patients must be enrolled on multi-national clinical trials, whenever possible, to advance our knowledge of the optimal therapeutic strategies and long-term outcomes.

New developments in arc radiation therapy: A review - Corrected Proof

David A. Palma, Wilko F.A.R. Verbakel, Karl Otto, Suresh Senan — 2010-02-24

Abstract: Arc therapies have gained widespread clinical interest in radiation oncology over the past decade. Arc therapies have several potential advantages over standard techniques such as intensity-modulated radiation therapy, with implications for patients, administrators, and oncologists. This review focuses on the rationale for arc therapy, descriptions of the modern arc techniques that are currently clinically available, and highlights some distinguishing features of arc therapies, such as dose distributions, treatment times, and imaging capabilities. Arc therapies are exciting examples of progress in radiotherapy through technological innovation, aimed at ultimately improving the therapeutic ratio for patients receiving radiation.

Patient-reported outcomes after cytotoxic chemotherapy in metastatic castration-resistant prostate cancer: A systematic review - Corrected Proof

Giuseppe Colloca, Antonella Venturino, Franco Checcaglini — 2010-02-24

Summary: Background: In the clinical setting of metastatic castration-resistant prostate cancer the aim of treatment is palliation. Palliation can refer to symptom management or non-curative treatments. Patient-reported outcome is any outcome based on data provided by patients. The aim of this paper is to perform a systematic review of clinical trials including a patient-reported outcome assessment in patients treated with cytotoxic chemotherapy, and to compare their results by traditional medical and patient-reported outcomes assessment.Methods: In November 2009 a literature search for published studies was undertaken. Selected phase-3 studies were primarily evaluated on the quality of patient-reported outcomes reporting and assessment methodology.Findings: Health-related quality of life assessment was the most common endpoint, pain control the second one. Results of patient-reported and traditional endpoints analysis are resumed, as well as methodology assessment and quality of patient-reported outcomes reporting. Frequently, methodologic limitations affect patient-reported outcomes assessment in clinical trials, either data analysis, particularly not reporting individual scores of health-related quality of life questionnaires, statistical corrections, limited efforts to avoid missing data, or lacking report of duration of palliative response.Conclusions: Results of trials can differ if different outcomes, medical or patient-reported, are considered in the analysis. Cytotoxic chemotherapy of metastatic castration-resistant prostate cancer is a challenging issue. A survival benefit is reported only for docetaxel, but this treatment is not always feasible. In all patients, initiation of chemotherapy should be based on patient’s preferences within discussion of individual risk and benefit, particularly in patients with extensive asymptomatic and symptomatic metastases.

Dietary constituents of broccoli and other cruciferous vegetables: Implications for prevention and therapy of cancer - Corrected Proof

Ingrid Herr, Markus W. Büchler — 2010-02-22

Summary: Over the past several decades, research on the action of bioactive constituents of plants has focused predominantly on their cancer-preventive properties. Today it can be explained why the consumption of fruits and vegetables may lead to a reduced frequency of certain cancer entities and why certain foods have therapeutic effects. Secondary plant products and especially glucosinolates from vegetables of the cruciferae family are supposed to have anti-carcinogenic potential. The present article gives an overview about secondary plant products in general and focuses to mechanisms of preventive and therapeutic effects of cruciferae, particular the brassica family and their famous member broccoli. Also, this article summarizes our knowledge of safety, tolerance and metabolism of glucosinolates and their therapeutic active degradation products isothiocyanates in animals and clinical studies.

Advanced gastric cancer – Slow but steady progress - Corrected Proof

Derek G. Power, David P. Kelsen, Manish A. Shah — 2010-02-22

Summary: Progress in gastric cancer has been slow, but steady. Historically, patients commonly presented with significant disease related co-morbidity and received treatment of marginal benefit but unfortunately associated with significant toxicity. Today there is no universally accepted reference standard chemotherapy for this disease. However, there is reason for optimism. Meta-analyses of randomized trials have shown a benefit for first-line combination chemotherapy. Current three drug chemotherapy regimens remain toxic, though perhaps less so than previously, and can result in a small but significant survival advantage in carefully chosen patients. Incremental improvements have been observed in both treatment-related toxicity and survival after first-line therapy. More patients are candidates for chemotherapy beyond progression with first-line therapy and response rates with second-line regimens are similar to those seen in other solid tumor malignancies. Although there is no randomized data to support its use second-line treatment should be considered in appropriate patients. Even before the integration of targeted therapies in the treatment of gastric cancer, it was evident that survival for more than 2 years is possible in a subset of patients and large retrospective studies have highlighted clinicopathologic factors associated with improved survival. Presently, with the addition of targeted therapy, especially anti-angiogenic and anti-Her2 therapy, and a better understanding of the biology of the disease, perhaps a sense of optimism should indeed suppress the nihilism commonly associated with this disease.

Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma - Corrected Proof

Manuela Schmidinger, Joaquim Bellmunt — 2010-02-17

Summary: The plethora of novel agents recently approved for the management of metastatic renal cell carcinoma (RCC) has changed the therapeutic landscape in this disease. The plethora of targets some of these agents inhibit can result in a wide range of side effects. While these novel therapies can be viewed as inhibitors of angiogenesis that directly or indirectly target the vascular endothelial growth factor (VEGF) pathway, their individual mechanisms of action (MoA) are key to defining their side-effect profiles. Direct VEGF inhibition with the anti-VEGF monoclonal antibody bevacizumab, is primarily associated with side effects related to the precise inhibition of VEGF, such as proteinuria, hypertension and minor bleeding events. In contrast, non-VEGF-related side effects are observed with agents inhibiting multiple receptor tyrosine kinases (sunitinib, sorafenib, axitinib and pazopanib) and mammalian target of rapamycin inhibitors (temsirolimus and everolimus); these include diarrhoea, skin rash, stomatitis, hand–foot skin reaction, hypothyroidism, and haematological and metabolic abnormalities. This review discusses the MoA of these novel therapies and how a greater understanding of MoA may help to predict the range and type of side effects, develop combinations of agents with acceptable tolerability, enable a more rational approach to patient selection, and allow the development of effective side-effect management strategies.

Adjuvant aromatase inhibitor therapy: Outcomes and safety - Corrected Proof

Wolfgang Janni, Philip Hepp — 2010-02-04

Summary: Adjuvant therapy with the third-generation aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane has largely replaced the use of tamoxifen (TAM) as standard adjuvant endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer. Treatment strategies investigated in large, randomized, well-controlled clinical studies include the use of an AI as an upfront replacement for TAM, as an alternative to continued treatment with TAM, and in the extended adjuvant setting after at least 5years of TAM. The efficacy of AIs over TAM has been demonstrated, particularly in terms of improving disease-free survival (DFS), and reductions in early distant metastasis with AIs may ultimately translate into improved overall survival. As AI therapy offers prolonged DFS, safety is an important concern over the long term. The AIs are better tolerated than TAM in terms of troublesome gynecologic adverse events such as vaginal bleeding and discharge, as well as life-threatening complications such as venous thromboembolic events and endometrial cancer. On the other hand, AI therapy has been associated with losses in bone density and a potential effect on lipids and cardiovascular risk. In trials comparing AIs with TAM, only limited conclusions can be made because of the putative cardioprotective, lipid-lowering, and bone-sparing effects of TAM. Studies comparing AIs with placebo, and/or in healthy women, may be more useful in understanding the long-term safety of adjuvant AI therapy. Results of ongoing safety analyses within some of the large AI trials should provide further insight into the long-term tolerability of AI therapy in the adjuvant setting.

Esophagogastric cancer: Targeted agents - Corrected Proof

Geoffrey Y. Ku, David H. Ilson — 2010-02-01

Summary: Because of the poor prognosis for patients with locally advanced and metastatic esophageal, gastroesophageal junction and gastric cancers, increasing attention has focused on the integration of targeted agents into current therapies. The molecular targets of these agents include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or its receptor, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle. In this review article, we briefly discuss pre-clinical data and the rationale for targeting these pathways and summarize the results of clinical trials to-date, including completed and ongoing phase III evaluations.

Localized adenocarcinoma of the esophagogastric junction – Is there a standard of care? - Corrected Proof

D.G. Power, J.V. Reynolds — 2010-02-01

Summary: Adenocarcinoma of the esophagogastric junction (AEG) is the most rapidly increasing tumour in the Western world. Most patients present with locally advanced resectable disease and treatment can be curative. However, no accepted standard treatment exists. Cancer specialists frequently differ on optimum treatment strategies. Areas of debate include the aetiology of AEG, TNM staging, type and extent of resection, relative benefits of preoperative chemotherapy versus preoperative chemoradiation (CRT) versus post-operative CRT, use of early PET scan, and integration of targeted therapy. Randomized trials are weakened by underpowered numbers for AEG tumours, and by methodologic flaws. R0 resection and pathologic complete responses (pCR) predict long-term survival, and most treatment strategies target this as a proxy measure of improved outcome. Some preoperative chemotherapy trials show a benefit but the numbers of true AEG tumours in these studies is unclear. The MAGIC study was powered for gastric cancer only, with just 27% of patients having AEG. Compared with chemotherapy alone, preoperative CRT trials show higher rates of pCR. A large randomized study, with significant toxicity, has shown long-term benefit with adjuvant CRT after resection of gastric cancer (20% AEG). An international consensus on the true definition and optimum management of AEG is required. Molecular and imaging biomarkers will play a vital role in future trials. Trimodality therapy is likely to be optimum with surgery shifted to later in the treatment pathway. Rectal cancer provides an analogous paradigm in this regard. As systemic disease is the primary cause of mortality chemosensitivity should be determined early.

Bevacizumab as a treatment option in advanced renal cell carcinoma: An analysis and interpretation of clinical trial data - Corrected Proof

David F. McDermott, Daniel J. George — 2010-01-29

Summary: The availability of molecularly targeted agents has improved outcomes for patients with renal cell carcinoma (RCC), a disease long considered refractory to systemic therapy. The hypervascularity observed in RCC tumors, which is driven by the inactivation of the von Hippel–Lindau gene, provided a rationale for targeting angiogenesis, in particular vascular endothelial growth factor (VEGF). Bevacizumab, a potent and specific anti-VEGF monoclonal antibody, has demonstrated significant clinical benefits when used in combination with interferon-alfa (IFN-α) for the treatment of metastatic RCC in two randomized phase III trials. The use of bevacizumab with IFN-α received approval in Europe for the first-line treatment of patients with advanced or metastatic RCC, and more recently this combination was approved for use in patients with mRCC in the United States. Bevacizumab with IFN-α has also been recommended by the National Comprehensive Cancer Network for first-line therapy of relapsed or metastatic unresectable RCC with predominantly clear cell histology. Two phase II studies suggest that bevacizumab has single-agent activity, which is characterized by encouraging progression-free survival rates and evidence of tumor regressions in patients with advanced or metastatic RCC. Here we review these trials along with recent and ongoing studies that explore the combination of bevacizumab with other targeted agents, its optimal sequencing with tyrosine kinase inhibitors, and its combination with low-dose IFN-α. Collectively, these studies allow the role of bevacizumab-based therapy to be defined in the context of a new and evolving algorithm for the treatment of patients with advanced RCC.

17q12-21 – The pursuit of targeted therapy in breast cancer - Corrected Proof

R.W. Glynn, N. Miller, M.J. Kerin — 2010-01-25

Summary: Purpose: Identification of HER2/neu, and the subsequent development of targeted therapy for patients who over-express it, has revolutionized their management. Research has since focused on the area of chromosome 17 in which HER2/neu is located in order to identify other genes in the vicinity. The aims of this review are, firstly, to discuss current thinking in relation to the role of these genes in the pathogenesis of breast cancer and, secondly, to examine how this evidence may be assimilated such that new forms of targeted therapy can be developed.Experimental design: This review discusses the evidence in relation to 4 genes located at the HER2/neu amplicon, namely TOP2A, GRB7, STARD3 and RARA.Results: TOP2A has aroused particular interest as over-expression of its protein has been shown to correlate, both with amplification of HER2/neu, and with response to anthracycline-based chemotherapeutic agents in breast cancer. GRB7 is included on Oncotype DXtm, and has recently been implicated in gastric and oesophageal cancer. STARD3 and RARA also hold clinical relevance, the former having been shown to function in steroidogenesis and therefore implicated in hormone-receptor-positive breast cancer. Finally, RARA may be the key to unlocking the problem of resistance to all-trans retinoic acid (ATRA) in breast cancer sufferers; this treatment has previously been demonstrated to induce remission in over 80% of patients with acute promyelocytic leukaemia (APML).Conclusion: These genes hold potential as therapeutic targets, and warrant further investigation as we move towards our goal of individually tailored therapeutic strategies in breast cancer.

Lapatinib and HER2 status: Results of a meta-analysis of randomized phase III trials in metastatic breast cancer - Corrected Proof

Eitan Amir, Alberto Ocaña, Bostjan Seruga, Orit Freedman, Mark Clemons — 2010-01-25

Summary: Background: In vitro studies have shown that lapatinib is most active in HER2 over-expressing tumors, but also has activity in cell lines over-expressing HER1. Consequently, clinical testing of lapatinib has been carried out in both HER2-positive and HER2-negative patients. Here we evaluate the clinical efficacy of lapatinib in HER2-positive and HER2-negative patients.Methods: A published data meta-analysis of randomized trials that evaluated the efficacy of combining lapatinib with chemo- or endocrine therapy in patients with metastatic breast cancer was undertaken. Hazard ratios (HR) were extracted for progression free survival (PFS) and overall survival, while odds ratios were extracted for disease stabilization, serious adverse events (SAEs) and need for discontinuation. Pooled estimates were computed using inverse-variance and random-effect modeling.Results: Three randomized controlled trials with a total of 2264 patients met the inclusion criteria. Meta-analysis demonstrated the HR for PFS with lapatinib was 0.69 in patients with HER2-positive disease, while there was no improvement in PFS (HR=0.98, 95% CI 0.80–1.19) for treatment of HER2-negative breast cancer. Similarly, overall survival was improved in HER2-positive patients (HR 0.76, 95% CI 0.60–0.96), but not in HER2-negative patients (HR 0.89, 95% CI 0.65–1.21). Patients on lapatinib were 64% more likely to develop a SAE and 2.3 times more likely to discontinue therapy due to toxicity.Conclusion: Clinical benefit from treatment with lapatinib is limited to patients with HER2-positive breast cancer. Outside of the clinical trial setting, lapatinib should not be administered to women with HER2-negative disease because it causes increased toxicity without improving disease outcome.

Late complications of chemotherapy in testicular cancer - Corrected Proof

Kyriaki Pliarchopoulou, Dimitrios Pectasides — 2010-01-21

Summary: Cisplatin-based treatment has significantly increased survival in testicular cancer patients. Therefore, there has been enough interest for the late toxic effects of chemotherapy which affect the quality of life of the cancer survivors. These toxic effects may either persist or present long after the end of chemotherapy and involve the impairment of renal function, neurotoxicity, pulmonary toxicity and vascular disease. Also, a major issue experienced by a large number of patients is infertility, which has been improved due to modified surgical techniques, reduced treatment intensity, the use of sperm cryopreservation and methods of assisted reproduction. Physicians should also be aware of the risk of secondary malignancy development. Therefore, close follow-up of the testicular cancer survivors as well as, focus on minimizing treatment complications through improvement of treatment strategies are warranted.

Is age a negative prognostic factor for the treatment of advanced/metastatic non-small-cell lung cancer? - Corrected Proof

A.G. Pallis, C. Gridelli — 2010-01-21

Summary: As a result of an increasing life expectancy, the incidence of non-small-cell lung cancer (NSCLC) in the older population is rising. As a consequence oncologists and their older patients commonly face the dilemma of whether or not to give/receive treatment for NSCLC. The current evidence supports the safety and efficacy of treatment for NSCLC cancer in fit older patients and demonstrates that treatment outcome can be similar to that of their younger counterparts and that chronological age per se is not a negative prognostic factor. However, it should be noted that these data are derived from retrospective studies which are likely to suffer from selection bias. Prospective data support the use of third generation single-agent (vinorelbine, gemcitabine, docetaxel) as first-line treatment for older NSCLC patients. Although cisplatin-based doublets represent the cornerstone of chemotherapy treatment for advanced/metastatic NSCLC their role in the treatment of older patients needs to be further elucidated. Despite a growing body of data, further work is still needed to establish optimal strategies to care for this special population and prospective specific trials for older NSCLC patients are clearly needed.

Intravesical therapy for superficial bladder cancer: A systematic review of randomised trials and meta-analyses - Corrected Proof

Mike D. Shelley, Malcolm D. Mason, Howard Kynaston — 2010-01-15

Summary: Background: In 2002 there were estimated to be 357,000 new cases of bladder cancer worldwide and 145,000 deaths making bladder cancer the 9th most common malignancy globally. At diagnosis, 60–80% of tumours are superficial and endoscopic resection is the initial treatment for this disease. In patients with low, medium or high risk disease, about 20%, 40% and 90%, respectively, will develop tumour recurrence. To delay or prevent recurrence, intravesical therapy is routinely used. Commonly used intravesical agents include immunotherapy with BCG and chemotherapy with cytotoxics such as Mitomycin C, Adriamycin, Epirubicin and Gemcitabine. However, controversy exists as to which agent and schedule should be used.Methods: An overarching search of the literature was used to identify relevant studies to assess the clinical benefit of intravesical therapy and provide clinical guidance in a comprehensive systematic review of randomised trials and meta-analyses of intravesical therapy for superficial bladder cancer. Findings and interpretation the search identified over 80 randomised trials and 11 meta-analyses. The extensive evidence suggests that an immediate post-operative instillation of a chemotherapeutic agent, such as Mitomycin C or Epirubicin, is effective in reducing tumour recurrence. In intermediate or high risk patients, further intravesical induction and maintenance therapy with BCG is recommended.Intravesical chemotherapy with either Mitomycin C or Epirubicin would be an option for those patients failing or who are unsuitable for BCG therapy. Intravesical BCG is superior to chemotherapy in terms of complete response and disease-free survival. However, there is no conclusive evidence that one agent is superior in terms of overall survival.

Ingestion of selenium and other antioxidants during prostate cancer radiotherapy: A good thing? - Corrected Proof

A. Tabassum, R.G. Bristow, V. Venkateswaran — 2010-01-15

Summary: Radiation and many chemotherapy agents work to kill cells by inducing free radicals that damage DNA and proteins. Antioxidants such as vitamin E, β carotene, lycopene, and selenium have been associated with a reduction in cancer risk when ingested by prostate cancer patients. Selenium is a promising agent currently being evaluated as a prostate cancer prevention agent. Selenium is an essential trace element and is involved in antioxidant protection and the redox-regulation in humans. Several adverse effects of radiotherapy and chemotherapy in cancer patients have been linked to oxidative cell processes in the human body. Selenium supplementation may protect healthy tissues and reduce the side effects of treatment. Despite two decades of research into this question, no clear answer has appeared. Therefore, understanding the mechanism(s) by which dietary nutrients exert their effects in prostate carcinogenesis, may lead to the exploitation of new chemoprevention agents. A large body of epidemiological evidence, including observational, trials, and randomized controlled clinical trials, support the proposition that selenium may prevent prostate cancer in humans. These clinical studies are supported by in vitro and in vivo data using prostate cancer models. This systematic review provides the first evidence that antioxidant supplementation during chemotherapy holds potential for reducing dose-limiting toxicities. The pre-clinical and clinical evidence as to whether ingestion of supplemental selenium, in addition to radiotherapy/chemotherapy is beneficial, detrimental or neutral towards patient outcome is also discussed.

Triple-negative breast cancer: Molecular features, pathogenesis, treatment and current lines of research - Corrected Proof

Ana Bosch, Pilar Eroles, Rosa Zaragoza, Juan R. Viña, Ana Lluch — 2010-01-11

Summary: Breast cancer is a heterogeneous disease with different morphologies, molecular profiles, clinical behaviour and response to therapy. The triple negative is a particular type of breast cancer defined by absence of oestrogen and progesterone receptor expression as well as absence of ERBB2 amplification. It is characterized by its biological aggressiveness, worse prognosis and lack of a therapeutic target in contrast with hormonal receptor positive and ERBB2+ breast cancers. Given these characteristics, triple-negative breast cancer is a challenge in today’s clinical practice.A new breast cancer classification emerged recently in the scientific scene based in gene expression profiles. The new subgroups (luminal, ERBB2, normal breast and basal-like) have distinct gene expression patterns and phenotypical characteristics. Triple-negative breast cancer shares phenotypical features with basal-like breast cancer, which is in turn the most aggressive and with worse outcome. Since microarray gene-expression assays are only used in the research setting, clinicians use the triple-negative definition as a surrogate of basal-like breast cancer.The aim of this review, that focuses on triple-negative breast cancer, is to summarize the most relevant knowledge on this particular type of cancer in terms of molecular features, pathogenesis, clinical characteristics, current treatments and the new therapeutic options that include the use of platinum compounds, EGFR antagonists, antiangiogenics and PARP inhibitors. Advances in research are promising and new types of active drugs will become a reality in the near future, making possible a better outcome for this subgroup of breast cancer patients.

Human AP endonuclease 1 (APE1): From mechanistic insights to druggable target in cancer - Corrected Proof

Rachel Abbotts, Srinivasan Madhusudan — 2010-01-07

Abstract: DNA base excision repair (BER) is critically involved in the processing of DNA base damage induced by alkylating agents. Pharmacological inhibition of BER (using PARP inhibitors), either alone or in combination with chemotherapy has recently shown promise in clinical trials. Human apurinic/apyrimidinic endonuclease 1(APE1) is an essential BER protein that is involved in the processing of potentially cytotoxic abasic sites that are obligatory intermediates in BER. Here we provide a summary of the basic mechanistic role of APE1 in DNA repair and redox regulation and highlight preclinical and clinical data that confirm APE1 as a valid anticancer drug target. Development of small molecule inhibitors of APE1 is an area of intense research and current evidence using APE1 inhibitors has demonstrated potentiation of cytotoxicity of alkylating agents in preclinical models implying translational applications in cancer patients.

Combined treatment with cytoprotective agents and radiotherapy - Corrected Proof

Piotr Winczura, Jacek Jassem — 2009-12-31

Abstract: Radiotherapy is associated with several toxicities affecting healthy tissues. One of the strategies aimed at decreasing radiation toxicity is the use of radioprotective agents, such as amifostine and palifermin, or factors stimulating hemopoetic stem cells (colony stimulating factors, CSFs): granulocyte-CSF, granulocyte macrophage-CSF and recombinant erythropoetins. The potential beneficial effect of these substances demonstrated in preclinical in vitro and in vivo studies led to numerous clinical trials. This review addresses the current experience on the use of cytoprotective agents in combination with radiotherapy, with particular focus on the safety of these approaches. Despite a relatively large body of literature data, the role of cytoprotective agents combined with radiotherapy remains controversial. Overall, their use in this application is still limited due to modest radioprotective effect for normal tissues, potential risk of tumor protection and increased treatment toxicity. The use of erythropoetins in combination with radiotherapy should generally be discouraged, whereas the safe and effective application of other agents warrants further investigations.