Cancer Treatment Reviews - Articles in Press

Evolving concepts in the management of drug resistant ovarian cancer: Dose dense chemotherapy and the reversal of clinical platinum resistance - Corrected Proof

David J. Pinato, Janet Graham, Hani Gabra, Rohini Sharma — 2012-05-18

Abstract: Despite the initially high response rate to standard front-line debulking surgery followed by platinum-based chemotherapy, the relapse rate in ovarian cancer is high and many patients will recur within 6months of completing platinum based treatment. These patients may still require further chemotherapy despite being considered “platinum resistant”. In this setting, response rates to conventionally scheduled second line platinum and non-platinum agents is low, ranging between 5% and 15%. There is an emerging body of evidence that in this scenario, chemotherapeutic activity can be enhanced using unconventionally scheduled “dose-dense” platinum and non-platinum based regimens with improved response rates of up to 65%. Randomised studies to evaluate the impact of this approach on survival in recurrent, platinum resistant disease are urgently required to confirm the promising phase II findings if there is to be a change in the standard of care of patients with platinum resistant disease. In this review we discuss the evolving strategies to overcome resistance in patients with platinum resistant ovarian cancer with a particular focus on alterations in dose schedule as a means of reversing platinum resistance.

Management of inflammatory breast cancer: Focus on radiotherapy with an evidence-based approach - Corrected Proof

2012-05-07

Summary: Inflammatory breast cancer represents a rare and extremely aggressive subtype of breast cancer. Due to its rarity, prospective studies are a difficult goal to obtain in this field.Nowadays a multimodal approach seems to be the standard approach. Role and timing of surgery, radiotherapy and chemotherapy are still debated issues. In this scenario interest is rising in molecular and target therapies.We performed a review analyzing the management of this unfavorable disease focusing on the role of radiotherapy, with particular emphasis on levels of evidence.

Hypoxia imaging using Positron Emission Tomography in non-small cell lung cancer: Implications for radiotherapy - Corrected Proof

2012-05-07

Abstract: Tumour hypoxia is an important contributor to radioresistance. Thus, increasing the radiation dose to hypoxic areas may result in improved locoregional tumour control. However, this strategy requires accurate detection of the hypoxic sub-volume using PET imaging. Secondly, hypoxia imaging may also provide prognostic information and may be of help to monitor treatment response. Therefore, a systematic review of the scientific literature was carried out on the use of Positron Emission Tomography (PET) to image Tumour hypoxia in non-small cell lung cancer (NSCLC). More specifically, the purpose of this review was (1) to summarize the different hypoxia tracers used, (2) to investigate whether Tumour hypoxia can be detected in NSCLC and finally (3) whether the presence of hypoxia can be used to predict outcome.

Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: A systematic review of randomized controlled trials - Corrected Proof

2012-04-30

Abstract: Trastuzumab, in combination with chemotherapy, is the gold standard in the adjuvant treatment of patients with HER2 positive breast cancer. Limited data are available on the role of adjuvant trastuzumab in the elderly population. We performed a systematic review of prospective randomized trials with available data on the use of adjuvant trastuzumab in patients older than 60years, focusing on both the efficacy and the cardiac safety. Data extrapolated from two prospective trials were included for efficacy and cardiac safety. A significant 47% relative risk reduction was observed in elderly patients receiving trastuzumab compared to chemotherapy alone (pooled Hazard Ratio: 0.53; 95% CI, 0.36–0.77). The pooled proportion of cardiac events in elderly patients treated with trastuzumab was 5% (95% CI, 4–7%). The use of trastuzumab should be considered as a standard of care in the adjuvant therapy of elderly patients with HER-2 positive breast cancer. Acute and chronic medical conditions, nutritional status and level of daily activities should be considered. Uncertainty about cardiac safety in the elderly is a major concern.

Swallowing dysfunction in head and neck cancer patients treated by radiotherapy: Review and recommendations of the supportive task group of the Italian Association of Radiation Oncology - Corrected Proof

2012-04-30

Abstract: Purpose: Dysphagia is a debilitating complication in head and neck cancer patients (HNCPs) that may cause a high mortality rate for aspiration pneumonia. The aims of this paper were to summarize the normal swallowing mechanism focusing on its anatomo-physiology, to review the relevant literature in order to identify the main causes of dysphagia in HNCPs and to develop recommendations to be adopted for radiation oncology patients. The chemotherapy and surgery considerations on this topic were reported in recommendations only when they were supposed to increase the adverse effects of radiotherapy on dysphagia.Materials and methods: The review of literature was focused on studies reporting dysphagia as a pre-treatment evaluation and as cancer and cancer therapy related side-effects, respectively. Relevant literature through the primary literature search and by articles identified in references was considered. The members of the group discussed the results and elaborated recommendations according to the Oxford CRBM levels of evidence and recommendations. The recommendations were revised by external Radiation Oncology, Ear Nose and Throat (ENT), Medical Oncology and Speech Language Pathology (SLP) experts.Results: Recommendations on pre-treatment assessment and on patients submitted to radiotherapy were given. The effects of concurrent therapies (i.e. surgery or chemotherapy) were taken into account.Conclusions: In HNCPs treatment, disease control has to be considered in tandem with functional impact on swallowing function. SLPs should be included in a multidisciplinary approach to head and neck cancer.

The role of high dose chemotherapy and autologous stem-cell transplantation in peripheral T-cell lymphoma: A review of the literature and new perspectives - Corrected Proof

Jean Yared, Amy Kimball — 2012-04-27

Abstract: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin’s lymphoma that carries, except for ALK-positive anaplastic large cell lymphoma, a poor prognosis. Only a third of patients live 5years past diagnosis. The incidence of PTCL has been increasing during the last two decades. In recent years, there was a rising interest in PTCL manifested by the abundance of publications dedicated exclusively to this disease. The international T-cell lymphoma project was formed with an aim of unifying efforts towards a better understanding of the diagnosis and management of this disease. Given the poor outcomes of PTCL patients, high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) have been used in the up-front and salvage settings, with different success rates. However, there are no prospective randomized controlled trials addressing the role of HDT/ASCT in a PTCL-restricted population. This article critically reviews the data available from the retrospective and prospective studies addressing this topic. We will emphasize the favorable prognostic factors of HDT/ASCT such as a solid remission at the time of transplantation, a chemotherapy sensitive disease and a low prognostic index score. As novel agents and new therapeutic strategies are introduced, there is a continued need for prospective randomized trials to define the optimal use of HDT/ASCT in managing PTCL.

Targeted radio-nuclide therapy of skeletal metastases - Corrected Proof

Oliver Sartor, Peter Hoskin, Øyvind S. Bruland — 2012-04-25

Abstract: In this review, we will focus on one particular class of stromal targeted therapy, i.e. the bone seeking radiopharmaceuticals (BSRs), but will also highlight selected issues related to the bone stroma as these concepts are new, rapidly evolving, and clearly linked to the underlying BSR mechanisms of targeting and action. Herein we review clinical BSR-trials of significance with randomized trials at center stage. Furthermore, we cover a new class of BSR in late clinical development based on bone-stromal targeted alpha-particle irradiation. Lastly, we discuss potential advances in combining BSR with bisphosphonates and/or chemotherapy and emphasize the feasibility of repeated dosing.

Referral of elderly cancer patients to specialists: Action proposals for general practitioners - Corrected Proof

Fleur Delva, Pierre Soubeyran, Muriel Rainfray, Simone Mathoulin-Pélissier — 2012-04-25

Abstract: Background: Many studies have identified advanced age as a barrier to accessing specialized oncological care.Objectives: To identify elements from the literature influencing general practitioners (GPs) in their decisions to refer elderly patients with cancer to oncology teams, and propose focused actions to improve referral processes.Methods: Eligible articles published up to July 2010 identifying factors associated with referral decisions for elderly cancer patients were selected. A quality assessment of each article was performed. All factors identified were considered for possible interventions classified by the Effective Practice and Organisation of Care (EPOC) taxonomy and development of recommendations for referral of elderly patients.Results: Thirty eligible articles were found with only 18 articles specifically exploring factors influencing physicians in the referral of their patients with cancer. Twelve focused on delay to treatment and only two uniquely on elderly patients. Patient age was the main factor associated with referral decisions, but this factor can influence GP’s differently depending on the type of cancer. The small size of these studies, heterogeneity of study populations, and diversity of outcome measures used meant that compilation of guidelines based on high-quality evidence was not possible. However, organizational factors hindering decisions to refer are identified and highlighted as crucial for inclusion in intervention programs, specifically to reach GPs in smaller locations or with less experience in collaborating with specialists. For patient-related factors, professional and organizational interventions are necessary, aimed at both GPs and patients to update knowledge of the non-linear relationship between chronological age and a patient’s ability to tolerate treatment.Conclusions: First and foremost, this article highlights the scarcity of literature specific to elderly patients with cancer. It also identifies the public health need for better knowledge of the factors for referral of elderly patients. Focussed action proposals are presented to improve knowledge and consequently, optimize the referral process.

Comparative clinical benefits of systemic adjuvant therapy for paradigm solid tumors - Corrected Proof

2012-04-23

Abstract: Adjuvant therapy employing cytotoxic chemotherapy, molecularly targeted agents, immunologic, and hormonal agents has shown a significant impact upon a variety of solid tumors. The principles that guide adjuvant therapy differ among various tumor types and specific modalities, but generally indicate a greater impact of therapy in the postsurgical setting of micrometastatic disease, for which adjuvant therapy is commonly pursued, vs. the setting of gross unresectable disease. This review of adjuvant therapies in current use for five major solid tumors highlights the rationale for current effective adjuvant therapy, and draws comparisons between the adjuvant regimens that have found application in solid tumors.

Prostate-specific antigen kinetics as a surrogate endpoint in clinical trials of metastatic castration-resistant prostate cancer: A review - Corrected Proof

G. Colloca — 2012-04-16

Abstract: Prostate cancer is the most common cancer in men. Overall survival is considered the best endpoint for clinical trials, but it is difficult to use in phase-2 studies.Although the reduction of PSA after cytotoxic chemotherapy has been identified as a valid surrogate for overall survival, it has not proven reliable for the evaluation of many biologics. Moreover, the PSA progression-free survival at 3months was validated only for cytotoxic drugs, and the various measures of progression/delay have not been confirmed by large studies. Ultimately, outside of overall survival, no measure has been validated as a surrogate endpoint after treatment with targeted therapies and vaccine therapy.The PSA levels have a great variability and, theoretically, the use of measures of cell kinetics and PSA may be the most reliable approach to estimate the behavior of metastatic disease. Some measures of PSA kinetics have been well developed in the clinical castration-resistant prostate cancer, the PSA doubling time and the growth rate constant. The studies about the kinetics of PSA measures are reviewed and discussed.To date, studies that consider the measures of PSA kinetics as surrogate endpoints are still very few. However in the near future, the drug evaluation can not proceed separately, with distinct endpoints between cytotoxic and non-cytotoxic agents. Therefore, extensive analysis and validation of measures of kinetics derived from PSA, and candidates for a role for surrogate endpoint, will be needed in phase-3 studies, in order to test their effectiveness in different disease scenarios.

Therapeutic approaches to myeloma bone disease: An evolving story - Corrected Proof

Vito Longo, Oronzo Brunetti, Stella D’Oronzo, Franco Dammacco, Franco Silvestris — 2012-04-11

Abstract: Bone disease is a major morbidity factor in patients with multiple myeloma and significantly affects their overall survival. A complex interplay between malignant plasma cells and other marrow cells results in the generation of a microenvironment capable of enhancing both tumor growth and bone destruction. Bisphosphonates have consistently reduced the incidence of skeletal-related events in patients with multiple myeloma and other osteotropic tumors as well. However, their use is burdened with side-effects, including the risks of osteonecrosis of the jaw and kidney failure, suggesting that they should be discontinued after prolonged administration. New molecular targets of cell cross-talk in myeloma bone marrow are therefore under intensive investigation and new drugs are being explored in preclinical and clinical studies of myeloma bone disease. Compounds targeting osteoclast activation pathways, such as receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin, B-cell activating factor, mitogen-activated protein kinase and macrophage inflammatory protein-1α/chemokine receptor for macrophage inflammatory protein-1α axes, or soluble agents that improve osteoblast differentiation by modulating specific inhibitors such as Dickkopf-1 and transforming growth factor-β, as well as novel approaches of cytotherapy represent a new generation of promising drugs for the treatment of myeloma bone disease.

Mesenchymal stem cell signaling in cancer progression - Corrected Proof

Anja Torsvik, Rolf Bjerkvig — 2012-04-11

Abstract: Mesenchymal (multipotent) stem/stromal cells (MSCs) may affect cancer progression through a number of secreted factors triggering activation of various cell signaling pathways. Depending on receptor status, phosphatase and tensin homolog (PTEN) status, or Wnt activation in the cancer cells, the signals may either result in increased growth and metastasis or lead to inhibition of growth with increased cell death. Thus, MSCs can play a dual role in cancer progression depending on the cellular context wherein they reside. The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway has a central role in regulating tumor growth, and several MSC secreted factors stimulate activation of this pathway. A comprehensive understanding of the signals regulating MSC–tumor cross-talk is highly important for the development of MSCs as potential therapeutic vehicles. Thus, the presented review focuses on factors released by MSCs and on the dual role they may have on various stages of tumorigenesis.

Antiresorptive treatment options and bone health in cancer patients—safety profiles and clinical considerations - Corrected Proof

Peyman Hadji, Matti Aapro, Luis Costa, Michael Gnant — 2012-04-06

Abstract: Antiresorptive therapies are the standard of care for maintaining bone health in patients with advanced cancers involving bone. In the absence of antiresorptive therapies, many patients with bone metastases from solid tumors will experience potentially debilitating skeletal-related events. Furthermore, older age is associated with decreased bone integrity both in female and male patients and also with increased risk for malignancies, such as breast and prostate cancer, which have a high risk of metastasis to bone. Although antiresorptive therapies are generally well tolerated, there have been reports of associated serious adverse events. Hypocalcemia, osteonecrosis of the jaw, renal events, and acute-phase reactions have been reported in patients with cancer receiving all types of antiresorptive therapies. Because the clinical indications of antiresorptive agents continue to expand, and new options are becoming available, it is important for clinicians to recognize adverse events so that they may be prevented or properly treated and managed. Moreover, the risk–benefit profiles of those agents must be considered on a per-patient basis.

Taxane resistance in breast cancer: Mechanisms, predictive biomarkers and circumvention strategies - Corrected Proof

S. Murray, E. Briasoulis, H. Linardou, D. Bafaloukos, C. Papadimitriou — 2012-04-02

Abstract: Background: Taxanes are established in the treatment of metastatic beast cancer (MBC) and early breast cancer (EBC) as potent chemotherapy agents. However, their therapeutic usefulness is limited by de-novo refractoriness or acquired resistance, which are common drawbacks to most anti-cancer cytotoxics. Considering that the taxanes will remain principle chemotherapeutic agents for the treatment of breast cancer, we reviewed known mechanisms of resistance in with an outlook of optimizing their clinical use.Methods: We searched the PubMed and MEDLINE databases for articles (from inception through to 9th January 2012; last search 10/01/2012) and journals known to publish information relevant to taxane chemotherapy. We imposed no language restrictions. Search terms included: cancer, breast cancer, response, resistance, taxane, paclitaxel, docetaxel, taxol. Due to the possibility of alternative mechanisms of resistance all combination chemotherapy treated data sets were removed from our overview.Results: Over-expression of the MDR-1 gene product Pgp was extensively studied in vitro in association with taxane resistance, but data are conflicting. Similarly, the target components microtubules, which are thought to mediate refractoriness through alterations of the expression pattern of tubulins or microtubule associated proteins and the expression of alternative tubulin isoforms, failed to confirm such associations. Little consensus has been generated for reported associations between taxane-sensitivity and mutated p53, or taxane-resistance and overexpression of Bcl-2, Bcl-xL or NFkB. In contrary sufficient in vitro data support an association of spindle assembly checkpoint (SAC) defects with resistance. Clinical data have been limited and inconsistent, which relate to the variety of methods used, lack of standardization of cut-offs for quantitation, differences in clinical endpoints measured and in methods of tissue collection preparation and storage, and study/patient heterogeneity. The most prominent finding is that pharmaceutical down-regulation of HER-2 appears to reverse the taxane resistance.Conclusions: Currently no valid practical biomarkers exist that can predict resistance to the taxanes in breast cancer supporting the principle of individualized cancer therapy. The incorporation of several biomarker analyses into prospectively designed studies in this setting are needed.

Cancer stem cells: In the line of fire - Corrected Proof

Malcolm R. Alison, Wey-Ran Lin, Susan M.L. Lim, Linda J. Nicholson — 2012-04-02

Abstract: Most tumours appear to contain a sub-population (s) of self-renewing and expanding stem cells known as cancer stem cells (CSCs). The CSC model proposes that CSCs are at the apex of a hierarchically organized cell population, somewhat akin to normal tissue organization. Selection pressures may also facilitate the stochastic clonal expansion of sub-sets of cancer cells that may co-exist with CSCs and their progeny, moreover the trait of stemness may be more fluid than hitherto expected, and cells may switch between the stem and non-stem cell state. A large body of evidence points to the fact that CSCs are particularly resistant to radiotherapy and chemotherapy. In this review we discuss the basis of such resistance that highlights the roles of ABC transporters, aldehyde dehydrogenase (ALDH) activity, intracellular signalling pathways, the DNA damage response, hypoxia and proliferative quiescence as being significant determinants. In the light of such observations, we outline strategies for the successful eradication of CSCs, including targeting the self-renewal controlling pathways (Wnt, Notch and Hedgehog), ALDH activity and ABC transporters, blocking epithelial mesenchymal transition (EMT), differentiation therapy and niche targeting.

Metastatic pancreatic neuroendocrine tumors (pNET): Placing current findings into perspective - Corrected Proof

Alexandria T. Phan — 2012-03-29

Abstract: Progress during the past 3 decades in the treatment of advanced neuroendocrine tumors (NET) has been slow, despite a substantial increase in the incidence of NET at all primary sites and stages of disease. In the United States, the annual incidence of pancreatic NET (pNET) was estimated as 0.32 per 100,000 people in 2004. Until recently, there were few available therapies for the treatment of patients with advanced pNET. Nonetheless, substantial strides have been made within the past several years. In 2011, 2 new systemic therapies (everolimus and sunitinib) were approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced pNET, based on recently published results from 2 phase III studies. Additions to the pNET treatment arsenal significantly expanded options for clinicians who treat these patients. However, important differences between the key clinical studies existed, preventing optimal direct comparison of the study results. Therefore, the clinical implications of these study results continue to be debated. The following commentary briefly summarizes the background of NET and provides an overview of available options, highlighting the important findings of the 2 pivotal studies. In this review, the data supporting the use of everolimus and sunitinib in advanced pNET are reviewed, and the incorporation of these targeted therapies into a pNET treatment algorithm is further discussed.

An overview of neoadjuvant chemotherapy in the multimodality treatment of malignant pleural mesothelioma - Corrected Proof

G. Pasello, G.L. Ceresoli, A. Favaretto — 2012-03-29

Abstract: Malignant Pleural Mesothelioma (MPM) is an aggressive tumour with poor prognosis and increasing incidence in industrialized countries because of the previous widespread exposure to asbestos fibres and to the long lag period from time of exposure and the diagnosis of the disease.MPM shows high refractoriety to systemic treatment, single-modality treatment was generally ineffective and did not achieve higher results than supportive care.The incidence of local and distant recurrences after surgery remains high and that was the reason for many centres to perform combined treatments. In the attempt of reducing the incidence of local recurrences, a multimodality approach with surgery followed by adjuvant radiotherapy was explored. Extrapleural pneumonectomy (EPP) allows higher doses of radiotherapy to the whole hemithorax by avoiding pulmonary toxicity and the results of this approach is a significant reduction of loco-regional relapses; although, extrathoracic metastasis represent a major problem in the management of the disease because of the impact on overall survival. The success with surgical resection after neoadjuvant chemotherapy in stage IIIA lung cancer has been the impetus for several groups to apply this strategy in MPM aiming at reducing the incidence of distant relapse after surgery.Platinum-based chemotherapy plus gemcitabine or pemetrexed for 3–4 cycles followed by surgery and postoperative high-dose radiotherapy showed the best results in terms of overall and progression free survival.This review will focus on the main clinical studies and overview the results of different chemotherapy regimens in the neoadjuvant treatment of MPM.

Assessment of quality of life in advanced non-small-cell lung cancer: An overview of recent randomized trials - Corrected Proof

Everardo D. Saad, Krzysztof Adamowicz, Artur Katz, Jacek Jassem — 2012-03-26

Abstract: Background: Health-related quality of life (HRQOL) parameters are often used as secondary endpoints in advanced non-small-cell lung cancer (NSCLC). We assessed the frequency and correlates of both usage and gain in HRQOL endpoints in NSCLC phase III trials.Methods: We searched PubMed for phase III trials on systemic anticancer therapies for NSCLC published between 1/98 and 12/09 in 13 leading journals.Results: The search yielded 122 trials that enrolled a total of 56,031 patients in 273 trial arms. HRQOL was reportedly used as an endpoint in 72 trials (59%). HRQOL parameters were used as primary or co-primary endpoints in nine trials, whereas overall survival (OS) was the primary endpoint or one of the co-primary endpoints in 90 trials. There was no temporal trend for usage of HRQOL parameters as endpoints. Formal statistical comparisons involving HRQOL were reported in 68/72 cases, and a significant difference was found in 37/68 trials (54.4%), 24 of which favored the experimental arm. In many cases, such differences were restricted to specific symptoms or even favored more than one regimen according to symptoms analyzed. We found no significant association between gain in HRQOL and gain in OS or any other trial feature.Conclusions: HRQOL has been assessed formally in nearly 60% of contemporary phase III trials in advanced NSCLC, and a significant gain in HRQOL has been found in almost one-half of cases. It is questionable, however, whether HRQOL results may help select between treatments with no differential impact on OS.

Can lung cancer stem cells be targeted for therapies? - Corrected Proof

Xiaodan Wu, Hong Chen, Xiangdong Wang — 2012-03-21

Abstract: Lung cancer is the leading cause of cancer death, with a poor prognosis. Lung cancer stem cells (CSCs) are proposed as one of therapeutic targets for lung cancer. It is important to understand the exact role of lung CSC subpopulations in tumor initiation, recurrence, drug resistance and metastasis and explore biomarkers, signaling pathways and differentiation regulation specific to lung CSCs. Numerous measures targeting lung CSCs, e.g. genomics, proteomics and bioinformatics, have been used to investigate molecular mechanisms, eradicate cancer cells, and improve patient outcome. The present review overviewed the biological functions, biomarkers, signal pathways, differentiation regulation, genomics and proteomics, targeting roles of lung CSCs and related information on other CSCs as references. There are still a number of challenges to translate the research and understanding of lung CSCs to clinical applications and therapies, identify lung CSCs-specific and dynamic network biomarkers, study lung CSCs isolated from human samples, and clarify the source of lung CSCs. It is necessary to design effective therapies to target CSC biomarkers and signaling pathways, reverse drug resistance and induce differentiation of lung CSCs. Thus, lung CSCs as one of therapeutic target candidates for lung cancer need global forces and databases to integrate the genes, proteins, receptors, signal pathways and functions with clinical informatics and phenotypes together.

Cancer treatment-induced bone loss in premenopausal women: A need for therapeutic intervention? - Corrected Proof

2012-03-19

Abstract: Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <−2.0 or Z-score ⩽−1.0 and/or a 5–10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements.

A network meta-analysis of therapies for previously untreated chronic lymphocytic leukemia - Corrected Proof

2012-03-14

Abstract: Background: Several therapy options are available for symptomatic, treatment-naïve chronic lymphocytic leukemia (CLL). Many of these therapies have been compared against chlorambucil, but have not been directly compared against each other. There is currently no agreed upon standard therapeutic regimen for treatment-naïve CLL.Methods: We performed a systematic literature review to identify randomized controlled trials (RCTs) published prior to November 2011 of therapies for previously untreated CLL. We conducted a network meta-analysis using fixed and random effect statistical models to estimate differences between shape and scale parameters of progression-free survival (PFS) curves for each competing therapy. We used the parameter estimates and a Weibull distribution to project mean PFS for each therapy option.Results: Five RCTs were included in our comparison network. Overall, patients were younger (59–65years), had good performance status based on the Eastern Cooperative Oncology Group scale (ECOG 0-1), and earlier stage disease (Rai 0–II or Binet A or B). The combination regimen fludarabine with cyclophosphamide and rituximab (FCR) was estimated to yield mean PFS of 76months (95% CrI: 60, 91), FC 60months (46, 73), fludarabine 38months (27, 49), alemtuzumab 24months (15, 32), and chlorambucil 23months (15, 32).Conclusion: Our results suggest that FCR has relatively higher potential of preventing disease progression in younger, healthier, treatment-naïve CLL patients and should be considered an optimal initial treatment strategy for this patient population. However, because estimates are based on model simulation, additional studies of FCR are necessary to clinically validate its therapeutic potential.

Seed, soil and secreted hormones: Potential interactions of breast cancer cells with their endocrine/paracrine microenvironment and implications for treatment with bisphosphonates - Corrected Proof

C. Wilson, I. Holen, R.E. Coleman — 2012-03-07

Abstract: The process of formation of metastasis is undoubtedly inefficient, with the majority of disseminated tumour cells perishing in their metastatic environment. Their ability to survive is determined by their intrinsic abilities, with emerging evidence of the importance of cancer stem cells possessing self propagating potential, but also the interaction with the premetastatic niche, which may either help or hinder their formation into micrometastasis, thus influencing recurrence and survival in breast cancer patients. Use of the bone targeted agents bisphosphonates in the adjuvant setting has been extensively studied in large clinical trials, and demonstrated an interesting interplay with the endocrine microenvironment, with postmenopausal women or premenopausal women receiving ovarian suppression therapy gaining a survival advantage compared to pre/perimenopausal women. The interaction between the endocrine hormones and the paracrine TGFβ growth factors may provide an explanation for the differences seen according to ovarian function in the response to bisphosphonates. In this review the evidence of interplay between ovarian endocrine hormones, TGFβ paracrine growth factors and bisphosphonates will be presented, and subsequent influence on breast cancer cells in the bone pre-metastatic niche hypothesised.

The impact of pharmacogenetics on radiation therapy outcome in cancer patients. A focus on DNA damage response genes - Corrected Proof

2012-03-05

Abstract: More than half of cancer patients are treated by radiation therapy, with a wide inter-patient variability in tumour response. Recent advances have been made in understanding molecular mechanisms that govern the behaviour of tumour cells and tissues exposed to ionizing radiation. Accumulating data suggest an important role of DNA damage response genes, including DNA repair (especially double-strand breaks), apoptosis and cell-cycle control genes. It has been hypothesized that frequent germinal polymorphisms, most often single-nucleotide polymorphisms, in DNA damage response genes may impact tumour response and clinical outcome for patients receiving a radiotherapy-based treatment. We reviewed literature covering the relationships between candidate gene polymorphisms in DNA damage response and the efficacy of a radiation-based treatment. Although several methodological limitations may preclude a definitive conclusion, single nucleotide polymorphisms of several candidate genes such as ERCC- or XRCC-family genes seem to be potential predictive biomarkers of radiotherapy efficacy, even though not strictly involved in radiotherapy-induced double-strand breaks repair. In order to improve the relevance of clinical results, and our interpretation of them, we draw a parallel between clinical findings and available preclinical data on polymorphism functionality. Clinical findings require validation in larger replication studies and open the prospect of future clinical trials.

Letter to the editors: Essentials for an updated epidemiology of laryngeal carcinoma - Corrected Proof

Gino Marioni — 2012-03-05

I read with interest the recent review by Thomas and co-workers, who investigated the role of open laryngectomy for laryngeal squamous cell carcinoma, which is controversial nowadays in view of the improvements in transoral laser microsurgery, radiotherapy and chemotherapy (and their combinations).

Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer - Corrected Proof

Ivan Diaz-Padilla, Ignacio Duran, Blaise A. Clarke, Amit M. Oza — 2012-03-01

Abstract: Advanced recurrent gynecological malignancies have a poor prognosis despite systemic treatment, which is usually cytotoxic chemotherapy. Responses are generally short-lived and more effective treatments are needed. Rationally designed molecularly targeted therapy is an emerging and important option in this setting. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway with a critical role in controlling cancer cellular growth, metabolism and cell cycle progression. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including ovarian, endometrial and cervical cancer. Early clinical studies of first-generation mTOR inhibitors have shown promising clinical activity in endometrial cancer. However, the molecular basis of sensitivity and resistance to these agents remains largely unknown. In this review, we will update the clinical and biological data underlying the development of first generation mTOR inhibitors in the treatment of gynecological tumors. The role of potential new combination regimens with mTOR inhibitors in gynecological cancers will also be discussed.

Controlling angiogenesis in breast cancer: A systematic review of anti-angiogenic trials - Corrected Proof

2012-02-27

Abstract: Purpose: Angiogenesis is critical for tumor growth and a promising therapeutic target. This review will summarize and analyze data from clinical trials of anti-angiogenic agents in the treatment of breast cancer (BC).Design: A systematic search of PubMed and conference databases was performed to identify reports of randomized clinical trials investigating specific anti-angiogenic agents in the treatment of BC.Results and discussion: Phase III trials in advanced BC have demonstrated a reduction in the risk of disease progression (22–52%), improved response rates and net improvements in progression-free survival of 1.2 to 5.5months, but no significant improvements in overall survival with the addition of bevacizumab to chemotherapy. Results of phase III trials in early breast cancer have been inconsistent. Bevacizumab-containing regimens have also been associated with higher overall adverse event rates compared to chemotherapy alone. Phase III trials of the tyrosine kinase inhibitor sunitinib were negative, while randomized phase II trials of sorafenib and pazopanib have improved some outcomes when combined with chemotherapy or targeted therapy compared to controls. In addition to expected vascular class safety signals, tyrosine kinase inhibitors show “off-target” side effects. Ongoing clinical trials evaluating combinatorial strategies based on biological synergies and translational studies identifying biological predictors of response will be crucial to establish meaningful clinical benefits in selected BC populations.Conclusion: Most trials of anti-angiogenic agents in BC have reported improved response rate and progression-free survival but no increase in overall survival compared to chemotherapy alone. Optimizing the therapeutic indices of these agents is a focus of ongoing research and will be critical to their future development.

Antiresorptive therapies in oncology and their effects on cancer progression - Corrected Proof

Nigel Bundred — 2012-02-27

Abstract: Bone health is an emerging concern in the early breast cancer setting. Current adjuvant therapies, especially hormonal therapies in premenopausal patients (e.g. goserelin) and aromatase inhibitors in postmenopausal patients, have been associated with substantial decreases in bone mineral density that may place patients at risk for fractures. Bisphosphonates—and the recently approved anti-RANKL antibody, denosumab—have both demonstrated activity for the treatment of postmenopausal osteoporosis and cancer treatment-induced bone loss (CTIBL) in breast cancer patients, although neither has received widespread approval specifically for CTIBL. However, some bisphosphonates, especially the nitrogen-containing bisphosphonate zoledronic acid, have also demonstrated clinically meaningful anticancer effects in patients receiving adjuvant hormonal therapy for breast cancer and in other oncology settings. The effects of denosumab on cancer disease outcomes in the adjuvant setting remain to be established. This discrepancy has created a dilemma in terms of how to evaluate the complete benefit:risk profile of bone-health management options in the adjuvant breast cancer setting. This review summarises the current data on the course of cancer in clinical trials of the antiresorptive agents and provides important insight into the relative anticancer potential of the various therapies.

A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension - Corrected Proof

Paul Cavuoto, Michael F. Fenech — 2012-02-20

Abstract: Methionine is an essential amino acid with many key roles in mammalian metabolism such as protein synthesis, methylation of DNA and polyamine synthesis. Restriction of methionine may be an important strategy in cancer growth control particularly in cancers that exhibit dependence on methionine for survival and proliferation. Methionine dependence in cancer may be due to one or a combination of deletions, polymorphisms or alterations in expression of genes in the methionine de novo and salvage pathways. Cancer cells with these defects are unable to regenerate methionine via these pathways. Defects in the metabolism of folate may also contribute to the methionine dependence phenotype in cancer. Selective killing of methionine dependent cancer cells in co-culture with normal cells has been demonstrated using culture media deficient in methionine. Several animal studies utilizing a methionine restricted diet have reported inhibition of cancer growth and extension of a healthy life-span. In humans, vegan diets, which can be low in methionine, may prove to be a useful nutritional strategy in cancer growth control. The development of methioninase which depletes circulating levels of methionine may be another useful strategy in limiting cancer growth. The application of nutritional methionine restriction and methioninase in combination with chemotherapeutic regimens is the current focus of clinical studies.

Inhibitor of Apoptosis (IAP) proteins as therapeutic targets for radiosensitization of human cancers - Corrected Proof

Simone Fulda — 2012-02-20

Summary: Radiotherapy initiates a variety of signaling events in cancer cells that eventually lead to cell death in case the DNA damage cannot be repaired. However, the signal transduction pathways that mediate cell death in response to radiation-inflicted DNA damage are frequently disturbed in human cancers, contributing to radioresistance. For example, aberrant activation of antiapoptotic programs such as high expression of Inhibitor of Apoptosis (IAP) proteins has been shown to interfere with the efficacy of radiotherapy. Since IAP proteins have been linked to radioresistance in several malignancies, therapeutic targeting of IAP proteins may open new perspectives to overcome radioresistance. Therefore, molecular targeting of IAP proteins may provide novel opportunities to reactivate cell death pathways that mediate radiation-induced cytotoxicity. A number of strategies have been developed in recent years to antagonize IAP proteins for the treatment of cancers. Some of these approaches have already been translated into a clinical application. While IAP protein-targeting agents are currently being evaluated in early clinical trials alone or in combination with conventional chemotherapy, they have not yet been tested in combination with radiation therapy. Therefore, it is a timely subject to discuss the opportunities of antagonizing IAP proteins for radiosensitization. Preclinical studies demonstrating the potential of this concept in relevant in vitro and in vivo models underscore that this combination approach warrants further clinical investigation. Thus, combination protocols using IAP antagonists together with radiotherapy may pave the avenue to more effective radiation-based treatment options for cancer patients.

Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma - Corrected Proof

Alain Ravaud, Marine Gross-Goupil — 2012-02-13

Abstract: Targeted agents have substantially improved patient outcomes in metastatic renal cell carcinoma (mRCC) and have now replaced cytokines as standard of care. Despite the clinical benefits observed, resistance to targeted agents has been shown to develop after a median of 5–11months of treatment. Furthermore, a small subset of patients does not experience any clinical benefit from targeted therapy. Two general modes of resistance have been proposed: intrinsic (pre-existing) and evasive (adaptive). Evasive resistance is thought to be the mechanism involved when patients progress after initial clinical benefit. It has been suggested that upregulation of alternative pro-angiogenic factors and/or downregulation of angiostatic factors may be involved. Several strategies have been shown to enable clinical benefit in patients who have experienced disease progression during prior therapy. These strategies include: adjusting the dose of the drug, combination therapy or switching to an alternative agent, with or without a different mechanism of action. Improvements in our understanding of the mechanisms of resistance associated with targeted agents and refinement of management strategies may help to improve patient outcomes further. In this article, we review the available evidence supporting mechanisms of resistance to targeted agents in mRCC, with a focus on tyrosine kinase inhibitors, and consider the potential management strategies which may allow further clinical benefit to be achieved.

The ethnic divide in breast reconstruction: A review of the current literature and directions for future research - Corrected Proof

Jonas A. Nelson, Priscilla Nelson, Julia Tchou, Joseph M. Serletti, Liza C. Wu — 2012-02-10

Abstract: Ethnic disparities exist in many areas of breast cancer treatment. When a mastectomy is necessary, the next discussion in the overall surgical management often focuses on breast reconstruction. This review will examine breast reconstruction trends within different ethnic groups and will briefly discuss underlying factors influencing current disparities. The literature available on differences in breast reconstruction loosely fits into two general categories: (1) the decision making process for reconstruction and (2) the receipt, timing and type of breast reconstruction. This review will seek to highlight several areas for possible intervention as well as areas where further research is needed.

New therapies in HER2-positive breast cancer: A major step towards a cure of the disease? - Corrected Proof

Ahmad Awada, Ivana Bozovic-Spasojevic, Louis Chow — 2012-02-06

Summary: Overexpression of the human epidermal growth factor receptor 2 (HER2) predicts a poor prognosis in metastatic breast cancer. While the introduction of HER2-targeted therapies, such as the monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib, has significantly improved outcomes in HER2+ breast cancer compared with previously available therapies, use of these targeted therapies is often limited by the development of drug resistance and tolerability issues. These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways. Recently, several agents have demonstrated promising activity in HER2+ metastatic breast cancer, either as monotherapy or in combination therapy, including the tyrosine-kinase inhibitors neratinib (HKI-272) and afatinib (BIBW-2992) and the anti-HER2 monoclonal antibodies pertuzumab and trastuzumab-DM1 (T-DM1). Agents that target other molecular pathways, such as the vascular endothelial growth factor receptor, mammalian target of rapamycin, PI3-kinases, insulin-like growth factor (IGFR), HSP-90, and other kinases also have potential, in combination with anti-HER2 and/or other systemic therapies, to be active in this subtype of breast cancer. Innovative clinical studies are required in well-characterized patient populations to define the true clinical value of these emerging new approaches.

Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: Optimizing patient benefit - Corrected Proof

Stéphane Oudard, Reza-Thierry Elaidi — 2012-01-30

Abstract: Multiple targeted agents are now available for the treatment of patients with metastatic renal cell carcinoma (mRCC). Although targeted agents offer improvements over previous treatments and significantly prolong progression-free survival, most patients eventually experience disease progression. For these patients, sequential treatment with multiple lines of therapy may afford sustained clinical benefit. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) are recommended as first-line therapy for most patients with mRCC. Current clinical practice guidelines uniformly recommend treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus after initial VEGFr-TKI failure. Recent results of the AXIS phase 3 trial demonstrated improved efficacy with second-line axitinib compared with sorafenib in patients who progressed on a variety of first-line therapies, including the VEGFr-TKI sunitinib. Available clinical evidence, individual patient profile, and toxicity concerns should be carefully evaluated when deciding whether to administer an mTOR inhibitor or a second VEGFr-TKI after progression on a first-line VEGFr-TKI. In patients who progress on a VEGFr-TKI and an mTOR inhibitor, retrospective analyses indicate that treatment with a second VEGFr-TKI in the third-line setting provides additional clinical benefit. Recent results from a prospective phase 1/2 trial indicate that third-line therapy with the investigational TKI, dovitinib, may have promising efficacy in patients who progress on a VEGFr-TKI and an mTOR inhibitor; a phase 3 trial of dovitinib versus sorafenib in this patient population is ongoing. This review discusses and evaluates current clinical evidence for sequential therapy with targeted agents in patients with mRCC.

Treatment of elderly patients with glioblastoma: From clinical evidence to molecular highlights - Corrected Proof

2012-01-30

Abstract: Elderly patients with glioblastoma are characterized by a high rate of associated morbidities, and a poor prognosis. Therefore, they have been excluded from most prospective clinical trials. However, the poorer outcome retrospectively reported in these patients might be also related to that those are less likely to receive the appropriate treatment than their younger counterparts. We reviewed the literature with regard to the optimal therapeutic management of this particular population, with focus on molecular perspectives for improving patients’ selection. Clinical data have demonstrated that open craniotomy with resection of the tumor was superior to biopsy only in elderly patients with good Karnofsky Performance Status (KPS) score. Then, postoperative radiotherapy (RT) improves survival without impairing functional status or neurocognitive functions, compared with best supportive care only following resection. Despite promising preliminary data, the addition of concomitant temozolomide to RT has not been validated in patients more than 70-years old. In case of additional poor prognostic factors or after biopsy only, there is no definitive demonstration that RT, chemotherapy, or both could improve outcome. Incorporation of more sensitive predictive and/or prognostic molecular factors could help physicians in patients’ selection. Further prospective trials should incorporate age-dependent molecular specificities in their design, and better focus on particular subgroup of patients exhibiting specific molecular alterations.

A preclinical and clinical review of aflibercept for the management of cancer - Corrected Proof

Andrew Gaya, Vivien Tse — 2012-01-24

Abstract: Aflibercept, also known as vascular endothelial growth factor (VEGF)–Trap, is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting not only all forms of VEGF-A, but also VEGF-B and placental growth factor. It inhibits VEGF-induced angiogenesis in preclinical models. In tumor models, aflibercept is associated with the reduction of tumor vasculature and size, and the inhibition of ascites formation. Clinical studies are investigating the use of aflibercept alone and in combination with other antineoplastic therapies for the treatment of various cancers. Phase I and II studies have provided proof of principle, and support the continuing clinical investigation of aflibercept. Results from the phase III study, VITAL, of aflibercept in the second-line setting in patients with advanced non-small cell lung cancer [NCT00532155] demonstrated efficacy in progression-free survival and overall objective response rate, but overall survival was not significantly improved. A full report awaits publication. The Phase III VANILLA trial in metastatic pancreatic cancer [NCT00574275] showed no improvement in overall survival. Most recently, the phase III VELOUR study [NCT00561470] of aflibercept plus FOLFIRI compared with placebo plus FOLFIRI in patients with metastatic colorectal cancer following failure of an oxaliplatin regimen showed significant improvements in overall survival, progression-free survival, and response rate and the complete results have been submitted to a peer-reviewed journal. This review summarizes preclinical and clinical data for aflibercept and discusses future directions and clinical trials for this agent.

Uveal melanoma - Corrected Proof

Francesco Spagnolo, Graziano Caltabiano, Paola Queirolo — 2012-01-24

Abstract: Uveal melanoma, which arises from melanocytes residing in the stroma, is the most common primary intraocular tumor in adults. Up to 50% of patients with primary uveal melanoma will ultimately develop distant metastasis, the liver being involved in up to 90% of individuals and the median survival reported to be 4–5months.The current treatment of metastatic uveal melanoma is limited by the lack of effective systemic therapy. The intrinsic resistance of uveal melanoma to conventional systemic chemotherapy has led researchers to evaluate new approaches. Molecular biology and a better knowledge of cancer cells allowed the development of target therapies: these refer to drugs designed to interact with a specific molecular pathway known to have a critical role in tumor growth or progression. Several drugs, such as bevacizumab, imatinib and MEK-inhibitors, are currently under investigation as single agents or in combination with chemotherapeutic drugs for the treatment of metastatic uveal melanoma. Finally, ipilimumab, which targets the immune compartment, was reported to increase overall survival in cutaneous melanoma patients, with preliminary evidence of similar activity in ocular melanoma.

State-of-the-art classification and multimodality treatment of malignant thymoma - Corrected Proof

2012-01-16

Abstract: Thymomas are the most common tumors of the anterior mediastinum. Classification, treatment options and understanding of the pathophysiology of thymoma have changed over the past years. It is hoped that novel therapeutic strategies will lead to a survival benefit in these patients. It has turned out that patients with thymoma are best treated with multimodality therapy. In this review, a pathologist, an immunologist, a surgeon, a radiotherapist, a pneumologist and oncologists discuss the current status of classification and strategies for the treatment of thymoma patients.

Adjuvant immunotherapy for non-small cell lung cancer - Corrected Proof

Zachary C.G. Tucker, Benjamin A. Laguna, Edmund Moon, Sunil Singhal — 2012-01-09

Abstract: Non-small cell lung cancer (NSCLC) is the biggest cancer killer in the United States and worldwide. In 2011, there are estimated to be 221,130 new cases of lung cancer in the United States. Over a million people will die of lung cancer worldwide this year alone. When possible, surgery to remove the tumor is the best treatment strategy for patients with NSCLC. However, even with adjuvant (postoperative) chemotherapy and radiation, more than 40% of patients will develop recurrences locally or systemically and ultimately succumb to their disease. Thus, there is an urgent need for developing superior approaches to treat patients who undergo surgery for NSCLC to eliminate residual disease that is likely responsible for these recurrences. Our group and others have been interested in using immunotherapy to augment the efficacy of current treatment strategies. Immunotherapy is very effective against minimal disease burden and small deposits of tumor cells that are accessible by the circulating immune cells. Therefore, this strategy may be ideally suited as an adjunct to surgery to seek and destroy microscopic tumor deposits that remain after surgery. This review describes the mechanistic underpinnings of immunotherapy and how it is currently being used to target residual disease and prevent postoperative recurrences after pulmonary resection in NSCLC.

Impact of bortezomib on bone health in myeloma: A review of current evidence - Corrected Proof

Maurizio Zangari, Evangelos Terpos, Fenghuang Zhan, Guido Tricot — 2012-01-09

Abstract: Bone disease is a key feature in multiple myeloma (MM) and can have a substantial impact on patient morbidity and quality-of-life. The pathogenesis of lytic bone disease in MM is complex and associated with increased osteoclast activity and impaired osteoblast function. Lytic lesions rarely heal in MM; however, the proteasome inhibitor bortezomib has been linked to increased bone formation and osteoblastic activity. Various clinical studies have reported a positive effect of bortezomib on bone health, including fewer bone disease-related MM progression events, increases in bone volume, and improvements in osteolytic lesions. Alkaline phosphatase (total and bone isoenzyme), a marker of bone formation, is increased during bortezomib treatment; the degree of increase may be associated with treatment response. Bortezomib is associated with a reduction in Dickkopf-1, an inhibitor of osteoblast function. Increases of other bone-formation markers and decreases of bone-resorption markers, have also been observed. These clinical effects are supported by preclinical data suggesting bortezomib is associated with an increase in bone formation and osteoblast numbers/activity, arising from direct effects of bortezomib and proteasome inhibition. As reviewed here, a growing body of evidence indicates that bortezomib exerts a positive effect on bone metabolism in MM and has a bone anabolic effect.

Phenotyping drug disposition in oncology - Corrected Proof

Frans L. Opdam, Hans Gelderblom, Henk-Jan Guchelaar — 2012-01-06

Abstract: Efficacy and toxicity of anticancer agents are highly variable between patients and variation in drug disposition is thought to be an important determinant. Genetics, physiology, and environment all are underlying factors contributing to this variation. Phenotyping drug metabolizing enzymes and drug transporters by using in vivo probes is a method that can be used to individualize drug therapy. This review discusses drug disposition of anticancer agents and the potential of phenotyping probes for phase I, II metabolic enzymes, and drug transporters in oncology.

Systemic treatment of advanced pancreatic cancer - Corrected Proof

Volker Heinemann, Michael Haas, Stefan Boeck — 2012-01-06

Abstract: Pancreatic cancer belongs to the most malignant gastrointestinal cancers and, in its advanced stage, remains a deadly disease for nearly all affected patients. Treatment of metastatic adenocarcinoma of the pancreas not only involves chemotherapy and targeted therapy, but also requires attention to accompanying comorbidities as well as frequently intensive supportive treatment and psychosocial support. Gemcitabine-based combinations with fluoropyrimidines and platin analogs have essentially failed to provide a substantial prolongation of survival and may constitute a treatment option only in patients with a good performance status. Among targeted therapies, only the EGFR tyrosine kinase inhibitor erlotinib has shown activity which is marginal in the overall population, but clinically relevant in patients developing skin rash. New avenues of polychemotherapy are presently explored since the gemcitabine-free FOLFIRINOX-regimen (infusional 5-fluorouracil/folinic acid plus irinotecan and oxaliplatin) was shown to be markedly superior to gemcitabine in selected good-performance patients. Pancreatic cancer is notably characterized as a hypovascular tumor rich in desmoplastic stromal tissue. An innovative approach to treatment therefore focuses on peritumoral fibroblasts and aims to induce a depletion of the stroma either by inhibition of the hedgehog pathway or by targeting SPARC (secreted protein acidic and rich in cysteine) via application of albumin-bound paclitaxel.

Optimizing radioimmunoconjugate delivery in the treatment of solid tumor - Corrected Proof

Chen-Yu Huang, Mohammad H. Pourgholami, Barry J. Allen — 2012-01-06

Abstract: Radioimmunotherapy (RIT) is a therapeutic modality which delivers alpha, beta or Auger emitters directly to targeted cancer cells. It has the advantage of regressing tumors while reducing non-targeted toxicities with the help of the targeting antibody. RIT applications relate to hematologic malignancies and now extend to solid tumors. Therapeutic efficacy of solid tumor RIT was limited by the inadequate penetration of radioimmunoconjugate (RIC). This paper reviews the properties of tumor vasculature abnormalities, the mechanisms of RIC penetration into solid tumors and strategies to enhance RIC delivery to facilitate RIT in reaching its full potential as a systemic cancer therapy.

Targeted (and chemotherapeutic) agents as maintenance treatment in patients with metastatic non-small-cell lung cancer: Current status and future challenges - Corrected Proof

Athanasios G. Pallis, Kostas Syrigos — 2012-01-04

Abstract: Maintenance treatment has been intensively investigated in the field of advanced/metastatic non-small lung cancer in order to improve outcomes in this devastating disease. Two different approaches have been evaluated; the so-called continuation maintenance when the maintenance agent was part of initial therapy and is continued in the absence of disease progression (“maintained”) or switch maintenance when a third agent is initiated after a defined number of cycles chemotherapy in the absence of disease progression. Several phase III trials with both chemotherapeutic and targeted agents have demonstrated either PFS prolongation (continuation maintenance) or both PFS and OS benefit (switch maintenance). Currently, erlotinib and pemetrexed are registered as maintenance treatment in patients with NSCLC not progressing after four cycles of standard platinum-based doublet chemotherapy. However, the development of maintenance treatment has raised a series of questions such as the role of treatment-free intervals, the timing of second-line treatment, selection of patients for maintenance treatment and selection of the most proper agent, and trial design issues such as optimal end-points. The purpose of this paper is to present and discuss the current trials investigating the main treatment paradigms and argue on the above mentioned questions.

Profiling clinical cancer research across the Atlantic: A review of research and its characteristics presented at ASCO and ESMO Congresses during the last decade - Corrected Proof

2012-01-03

Abstract: Introduction: The comparison of clinical cancer research characteristics across the Atlantic and their evolution over time have not been studied to date.Methods: We collected oral presentations on breast, lung and colorectal cancer at ASCO (n=506) and ESMO (n=239) Congresses in years 2000–2010.Results: EU-originated research constituted 52% of all ASCO presentations while US-research 26.7% of ESMO Congress presentations. Industry sponsorship was reported in 24.8% of ASCO vs. 31.8% of ESMO Congress trials. ASCO-presented trials were larger with longer follow-up periods but were blinded less often. ESMO-presented trials used Event-Free Survival (EFS, 38.1%) and Surrogate (18.4%) primary endpoints and reported positive primary endpoints (65%) more often than ASCO-presented trials. Interim analysis resulted in discontinuation of a trial more often at ASCO Congress (8.3% vs. 3.2%). ASCO Congress-presented research was more often published (69.2% vs. 59.8% at ESMO) at higher impact factor journals. Strong trends over the decade were seen for more frequent industry sponsorship, blinded design, larger sample size, early interim discontinuation, use of EFS endpoints and biomarker evaluation.Conclusions: Cancer clinical research is a complex scientific activity with common global but also distinct characteristics at the two sides of the Atlantic.

Biomarkers in the development of anti-angiogenic therapies for ovarian cancer - Corrected Proof

Fharat A. Raja, Jane M. Hook, Jonathan A. Ledermann — 2011-12-30

Abstract: The treatment of ovarian cancer remains challenging as the majority of patients will relapse and die from their disease despite successful first-line treatment. New treatment strategies are needed and recently there has been an explosion of new agents being tested in ovarian cancer. Most of these are directed against molecularly defined pathways and a significant proportion target angiogenesis, an important process in the growth of ovarian cancer. We review the role of angiogenesis in the pathophysiology of ovarian cancer and discuss the development of the most promising anti-angiogenic drugs in this disease, including the first large phase III trials with bevacizumab which have demonstrated a disease-modifying role in ovarian cancer. Other studies with this drug and other inhibitors of the angiogenic pathways are underway in the first-line and recurrent disease settings. The financial cost of these agents, increased toxicity and requirement for prolonged therapy necessitates the urgent need to identify and validate biomarkers to guide the use of these drugs in the future. There are over 200 candidate biomarkers being studied in ovarian cancer. However, currently there are no validated biomarkers to predict response or progression of disease. In this review we present a selection of biomarkers that are under investigation and discuss their benefits and limitations.

Targeted agents in non-small cell lung cancer (NSCLC): Clinical developments and rationale for the combination with thoracic radiotherapy - Corrected Proof

Pek Keng Koh, Corinne Faivre-Finn, Fiona H. Blackhall, Dirk De Ruysscher — 2011-12-26

Abstract: In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions.

Cancer stem cells hypothesis and stem cells in head and neck cancers - Corrected Proof

Giuditta Mannelli, Oreste Gallo — 2011-12-26

Summary: There is increasing evidence that the growth and spread of cancer is driven by a small subpopulation of cancer cells, defined as cancer stem cells (CSCs). Recent data indicate that the initiation, growth, recurrence and metastasis of cancers are related to the behavior of a small population of malignant cells with properties of stem cells, and information about them are potentially helpful in identifying the target for the tumor’s therapeutic elimination. The presence of subpopulation cells with phenotypic and behavioral characteristics corresponding to both normal epithelial stem cells and to cells capable of initiating tumors has been also reported in head and neck squamous cell carcinomas (HNSCCs).

Molecular biology in breast cancer: Intrinsic subtypes and signaling pathways - Corrected Proof

Pilar Eroles, Ana Bosch, J. Alejandro Pérez-Fidalgo, Ana Lluch — 2011-12-19

Abstract: The last decade has brought a breakthrough in the knowledge of the biology of breast cancer. The technological development, and in particular the high throughput technologies, have allowed researchers to inquire more deeply into the nature of the disease through the comparative study of large numbers of samples. The classification of breast cancer by traditional parameters has been joined by rankings based on gene expression. Among the most popular platforms are MammaPrint®, Oncotype DX® the wound-response model, the rate of two genes model, the genomic grade index and the intrinsic subtype model. The latter one provides the amplest biological information and allows for the classification of breast cancer into six intrinsic subtypes: luminal A, luminal B, HER2-enriched, basal-like, normal breast and claudin-low. These new classifications are not yet fully applicable to clinical practice not only because they have not been standardized, but also because they entail a substantial economic outlay. Nevertheless, they have provided valuable information on tumor biology that has led to a better understanding of the signaling pathways governing the processes of formation, maintenance and expansion of the tumors. Researchers now know more about the HER2, estrogen receptor, IGF1R, PI3K/AKT, mTOR, AMPK and angiogenesis pathways which has allowed for the development of new targeted therapeutics now being tested in ongoing clinical trials.In general, one can say that the last decade has changed the way researchers understand, classify and study breast cancer, and it has reshaped the way doctors diagnose and treat this disease. In addition, it has undoubtedly changed the search for alternative therapies by integrating molecular studies and the selection of study populations based on their molecular markers into clinical trials. The present review summarizes the advances that have allowed researchers to both better classify the disease, as well as explore some of the most important signaling pathways.

Tissue confirmation of disease recurrence in breast cancer patients: Pooled analysis of multi-centre, multi-disciplinary prospective studies - Corrected Proof

2011-12-19

Abstract: Background: Treatment decisions in recurrent breast cancer are usually based on the estrogen (ER), progesterone (PgR) and HER2 receptor status of the primary tumour. Retrospective studies suggest that discordance between receptor expression of primary and recurrent breast cancer exists.Methods: A pooled analysis of individual patient data from two large prospective studies comprising biopsy of recurrent lesions obtained from consenting patients was undertaken. Tissue was analyzed for ER, PgR by immunohistochemistry and HER2 by FISH. Receptor status of recurrent disease was compared with that of the primary tumour. Recruiting clinicians assessed whether or not receptor discordance affected subsequent systemic treatment.Results: Two hundred and eighty-nine patients underwent biopsy. Recurrent biopsy specimens were obtained from locoregional recurrence in 48.1% and from distant metastases in 51.9%. Distant sites included skin/soft tissue (25.0%), bone/bone marrow (19.2%) and liver (15.8%). Benign disease or second primary cancer was observed in 7.6% of biopsies. Discordance in ER, PgR or HER2 between confirmed primary and recurrent breast cancer was 12.6%, 31.2% and 5.5%, respectively (all p<0.001). Biopsy results altered management in 14.2% of patients undergoing biopsy (95% confidence intervals 10.4–18.8%, p⩽0.0001). The duration between primary and recurrent disease, the site of recurrence and the receptor profile of the primary tumour did not affect discordance rates.Conclusions: There is substantial discordance in receptor status between primary and recurrent breast cancer. The number needed to biopsy in order to alter treatment was 7.1. Patients with recurrent breast cancer should have tissue confirmation of receptor status of recurrent disease.

Treatment of hepatocellular carcinoma (HCC) by intra-arterial infusion of radio-emitter compounds: Trans-arterial radio-embolisation of HCC - Corrected Proof

2011-12-15

Abstract: Traditional radiotherapy is only effective in treating hepatocellular cancer (HCC) in doses above 50Gy, but this is above the recommended liver radiation exposure of about 35Gy, which is an important limitation making this treatment unsuitable for routine clinical practice. Trans-arterial radio-embolisation (TARE), consists of delivery of compounds linked to radio-emitter particles which end up in hepatic end-arterioles or show affinity for the neoplasm itself, allowing localised delivery of doses beyond 120Gy. These are well tolerated in patients treated with this type of internal radiation therapy.TARE for HCC is used for palliative treatment of advanced disease which cannot be treated in other ways, or for tumour down-staging before liver transplantation, or as adjuvant therapy for surgically resected HCC.Tumour response after TARE is between 25% and 60% if assessed by using RECIST criteria, and 80% by EASL criteria.In this review we outline the advantages and limitations of radio-emitter therapy including 131-I, 90-Y and 188-Re. We include several observational, and all comparative studies using these compounds. In particular we compare TARE to trans-arterial chemo-embolisation and other intra-arterial techniques.