Cancer Treatment Reviews - Articles in Press

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.

Targeted therapeutic approaches for hormone-refractory prostate cancer - Corrected Proof

Flora Stavridi, Eleni M. Karapanagiotou, Kostas N. Syrigos — 2010-01-27

Summary: Prostate cancer is one of the leading causes of cancer related death in men, and remains incurable in the metastatic setting. Despite the initial response to androgen deprivation, the disease gradually progresses to a hormone-refractory state due to cumulative genetic alterations in tumour cells or the microenvironment. Docetaxel represents the first chemotherapeutic agent with a small survival benefit for metastatic hormone-refractory prostate cancer (HRPC). In an attempt to improve survival benefit, several novel drugs targeting specific pathways involved in cell signaling, proliferation, angiogenesis, apoptosis and immune modulation are currently under investigation either as single agents or in combination with cytotoxic drugs. Clinical trials evaluate the inhibition of prostate cancer cells growth by targeting the nuclear receptor of vitamin D alongside cytotoxic therapy. Angiogenesis inhibitors as well as epidermal growth factor receptor blockage are also under clinical investigation in several combinations. Immunomodulatory agents and autologous dendritic cells or allogenic whole cell vaccines have progressed up to phase III trials. New drugs targeting bone microenvironment or apoptotic and proliferation pathways may enhance antitumour activity of chemotherapy in HRCP. Given the complexity of mechanisms underlying prostate cancer progression, future therapeutic strategies should rely on multidisciplinary approaches, thus exploiting newer molecular targets in concert with immunotherapy and cytotoxic chemotherapy. Here, we review the latest clinical evidence regarding the use of novel agents in HRPC.

Management of prostate cancer recurrence after definitive radiation therapy - Corrected Proof

Christian Boukaram, Jean-Michel Hannoun-Levi — 2010-01-25

Summary: The management of prostate cancer (PC) recurrence after definitive radiation therapy (RT) is shifting and there is no consensus regarding the optimal strategy. The major challenge is determining the anatomical site of relapse. In case of biochemical relapse (BR), androgen deprivation therapy (ADT) is a non-curative option commonly used, while patients with a local PC recurrence could be managed through a curative intent. Based on a Pubmed data search, this manuscript focused on the management of post-RT local PC recurrences. In case of BR (nadir+2ng/ml), classical imaging work-up is not contributive for PSA levels <10ng/ml while new imaging investigations (diffusion MRI, 11C-choline PET) are more sensitive to detect local and distant recurrences at lower PSA levels. Positive prostate biopsies are the only method for confirming local recurrence, although this technique presents limitations. Primary PC presentation as well as PSA-related features (interval to failure, PSA kinetic) and patient features (life expectancy, urinary, sexual status) are important to consider. Results of curative salvage options (radical prostatectomy, cryotherapy, brachytherapy and high-intensity focused ultrasound-HIFU) are analyzed and discussed. Each of these therapies appears feasible and has its own set of experience and toxicity profile. Other therapeutic options (photodynamic therapy, ADT, observation) are discussed. Longer follow-up and mature series are needed to evaluate the optimal strategy and prospective trials are warranted. Each clinical situation should be discussed in a multidisciplinary setting. Different options should be explained to the patient and decision should be taken after balancing treatment outcomes with life expectancy.

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.

Exploiting cellular pathways to develop new treatment strategies for AML - Corrected Proof

Amir T. Fathi, Steven Grant, Judith E. Karp — 2010-01-07

Summary: The standard approaches to the treatment of acute myeloid leukemia (AML) have been predominantly based on cytarabine and anthracyclines. Yet, the outcomes associated with AML continue to be poor, especially for those patients who are older or carry higher-risk disease. In recent years, extensive research has led to the development and study of novel agents which target AML by diverse and varied mechanisms. Among these are targeted therapeutics such as kinase inhibitors and oligonucleotide constructs. These aim to suppress the production or activity of proteins, such as FLT3 and BCL2, among others, and thus disrupt related signaling cascades essential for leukemogenesis and proliferation. In addition, other agents like flavopiridol appear to target the myeloid blast by various mechanisms including suppression of cyclin-dependent kinases and interference with nucleotide synthesis. Another class of novel therapies includes inhibitors of histone deacetylase, which cause growth arrest and apoptosis through histone acetylation and resultant conformational changes. Clinical trials are now studying these and other agents alone and in combination with traditional cytotoxic therapies, with some encouraging results. In this review, we aim to provide a summary of the preclinical and clinical investigations of selected promising agents currently under study.

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.

An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome - Corrected Proof

Tariq I. Mughal, A. Ahsan Ejaz, John R. Foringer, Bertrand Coiffier — 2009-12-25

Summary: Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder that occurs when tumor cells undergo rapid decomposition spontaneously or in response to cytoreductive therapy. Delayed recognition of the metabolic imbalances caused by the massive release of tumor cell contents may result in clinical complications such as acute kidney injury, seizures, and cardiac arrhythmias. Prevention, the key principle in TLS management, relies on the identification of patients at risk for developing TLS during chemotherapy or because of disease progression. TLS-related risk factors pertain to tumor type (particularly hematologic malignancies), specific tumor characteristics (e.g. bulky tumor, high cellular proliferation rate, sensitivity to cytoreductive therapy), and other host-related factors. A comprehensive grading system proposed by Cairo and Bishop classifies TLS syndromes into laboratory or clinical TLS, thus facilitating TLS prevention and management. The mainstays of TLS management include monitoring of electrolyte abnormalities, vigorous hydration, prophylactic antihyperuricemic therapy with allopurinol, and rasburicase treatment of patients at high TLS risk or with established hyperuricemia. Urine alkalinization and use of diuretics remain controversial clinical practices. In this review, we describe the incidence of, risk factors for, and diagnostic characteristics of TLS and summarize strategies for the prevention and management of TLS-associated metabolic abnormalities, particularly hyperuricemia. We specifically highlight recently published TLS management guidelines, which focus on the prevention of TLS and hyperuricemia based on a patient’s level of risk, and the important role of nephrologists in the prevention and treatment of one of the most serious complications of TLS, acute kidney injury.

Approach to radiation therapy in hepatocellular carcinoma - Corrected Proof

2009-12-25

Summary: Hepatocellular carcinoma (HCC), the 5th most common cancer and the third most common cause of cancer-related death in the world with an estimated incidence of proximately 1 million new cases annually, has becoming a major global health problem in the world. A variety of treatment modalities, including resection, liver transplantation, transarterial chemoembolization (TACE), local ablative therapy and radiation therapy (RT) have been reported. Although partial hepatectomy and liver transplantation may offer the best chance of cure, only 15% of the patients have the chance to be treated by surgery when diagnosed. The effectiveness of systemic chemotherapy for HCC has been minimal, and local ablative therapy may offer comparable survival in patients with small HCC and preserve liver function. Recently, with developments in radiotherapy techniques, radiotherapy has been shown to play potential roles in a wide spectrum of HCC and to become more important so that it is necessary to evaluate the effect of radiotherapy in treatment of HCC. This paper is aiming mainly at the current radiation therapy strategies and their current advances, the optimal radiation therapy strategies will complement the current treatments and improve the treatment efficiency.

Forkhead box M1 transcription factor: A novel target for cancer therapy - Corrected Proof

2009-12-21

Summary: FoxM1 signaling has been reported to be associated with carcinogenesis. Therefore, the FoxM1 may represent a novel therapeutic target, and thus the development of agents that will target FoxM1 is likely to have significant therapeutic impact on human cancer. This review describes the mechanisms of signal transduction associated with FoxM1 and provides emerging evidence in support of its role in the carcinogenesis. Further, we summarize data on several FoxM1 inhibitors especially “chemopreventive agents” and these agents could be useful for targeted inactivation of FoxM1, which indeed could become a novel approach for the prevention and/or treatment of human cancer.

Treatment of the pregnant mother with cancer: A systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part II: Hematological tumors - Corrected Proof

Hatem A. Azim, Nicholas Pavlidis, Fedro A. Peccatori — 2009-12-17

Summary: Managing pregnant patients with hematological tumors pose even more conflicts compared to solid tumors. Unlike the majority of solid tumors, hematological malignancies are potentially curable; hence it is important to deliver the best treatment options available, which sometimes could be too aggressive to deliver during pregnancy.In part II, we report the results of women with hematological malignancies treated with systemic therapies during the course of pregnancy. Lymphoma, acute leukemia and chronic myeloid leukemia were the most commonly treated.We discuss the safety of the different regimens reported and propose alternatives to standardized approaches in case they pose significant risk to the pregnancy and/or the fetus.

SRC kinase inhibition: Targeting bone metastases and tumor growth in prostate and breast cancer - Corrected Proof

Fred Saad, Allan Lipton — 2009-12-16

Summary: Prostate and breast cancer cells preferentially metastasize to bone, whereupon a complex interaction between metastatic tumor cells, osteoclasts, and osteoblasts results in the development of bone lesions that cause significant pain and patient morbidity. For patients with bone lesions, the goals of treatment are to decrease tumor growth, prevent further metastases, and inhibit tumor-associated bone pathology. Preclinical data suggest that SRC, a nonreceptor tyrosine kinase, is an important signaling molecule during the processes of osteoclast-mediated bone resorption, tumor growth, and metastasis, and that SRC has a role in hormone receptor signaling and resistance. As such, SRC represents a logical target for the treatment of advanced metastatic prostate or breast cancer. SRC-targeting agents, including dasatinib, saracatinib, and bosutinib, are currently in clinical development for patients with solid tumors. Preliminary data from phase 1/2 trials, including tumor responses and bone-specific activity in patients with prostate or breast cancer, demonstrate that SRC inhibitors have potential in the clinical setting. Data arising from ongoing and future clinical trials will confirm whether SRC inhibitors provide clinical benefits for patients with advanced disease.

Treatment of the pregnant mother with cancer: A systematic review on the use of cytotoxic, endocrine, targeted agents and immunotherapy during pregnancy. Part I: Solid tumors - Corrected Proof

Hatem A. Azim, Fedro A. Peccatori, Nicholas Pavlidis — 2009-12-16

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

Exercise and cancer rehabilitation: A systematic review - Corrected Proof

Rosalind R. Spence, Kristiann C. Heesch, Wendy J. Brown — 2009-12-07

Summary: Introduction: Cancer is increasingly being viewed as a chronic illness requiring long-term management, and there is a growing need for evidence-based rehabilitation interventions for cancer survivors. Previous reviews have evaluated the benefits of exercise interventions for patients undergoing cancer treatment and long-term survivors, but none have investigated the role of exercise during cancer rehabilitation, the period immediately following cancer treatment completion. This systematic review summarises the literature on the health effects of exercise during cancer rehabilitation and evaluates the methodological rigour of studies in this area to date.Methods: Relevant studies were identified through a systematic search of PubMed and Embase to April 2009. Data on study design, recruitment strategy, participants, exercise intervention, adherence rates, and outcomes were extracted. Methodological rigour was assessed using a structured rating system.Results: Ten studies were included. Breast cancer patients were the predominate patient group represented. Most interventions were aerobic or resistance-training exercise programmes, and exercise type, frequency, duration and intensity varied across studies. Improvements in physical functioning, strength, physical activity levels, quality of life, fatigue, immune function, haemoglobin concentrations, potential markers of recurrence, and body composition were reported. However, all studies were limited by incomplete reporting and methodological limitations.Conclusions: Although the methodological limitations of studies in this new field must be acknowledged, initial evidence indicates that exercise is feasible and may provide physiological and psychological benefits for cancer survivors during the rehabilitation period. Future studies with rigorous study designs are now required to advance the field.

The choice of the antigen in the dendritic cell-based vaccine therapy for prostate cancer - Corrected Proof

Lina Matera — 2009-12-02

Summary: Tumor antigens (TA) are promising candidates for targeted treatment of prostate cancer (PCa). Critical issues in the preparation of dendritic cell (DC)-based TA vaccines are the DC maturation state and the appropriateness of the TA. Prostate-specific antigen (PSA) and prostate acide pshosphatase (PAP) presented by DC have produced encouraging results and PAP-loaded DCs are at late-stage development for PCa patients. TAs indispensable for tumor survival and propagation are now emerging as first choice TAs for future vaccines. The increased expression and enzymatic activity of prostate specific membrane antigen (PSMA) and prostate stem cell antigen (PSCA) by aggressive prostate tumors is indicative of a unique, selective advantage on the part of cells expressing them. Human telomerase reverse transcriptase (hTERT) and survivin are both involved in tumor cell survival and considered universal TAs. The T cell epitope potential of peptides derived from these TAs has been defined by computer-assisted prediction programs and has been tested in vitro and in vivo in terms of their ability to recruit cytotoxic T lymphocytes (CTL) and to be recognised as CTL targets. Results, reviewed here, show that anti-tumor immunity can be induced in vivo by DC loaded with both whole TAs and TA peptides. The promising, but still limited clinical success suggests further exploration of this immune therapy in the more appropriate setting of minimal disease. In advanced stages, vaccine can still be effective when combined with systemic or local cytoreductive therapies, which may overcome antigen specific tolerance and subvert the tumor immunosuppressive environment.