Cancer Treatment Reviews - Articles in Press

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.

Comparison of weekly versus every 3 weeks paclitaxel in the treatment of advanced solid tumors: A meta-analysis - Corrected Proof

Ta-Chen Huang, Toby C. Campbell — 2011-12-12

Abstract: Background: Paclitaxel is commonly given as a 3-h infusion every 3weeks for a variety of malignancies. Several randomized clinical trials comparing weekly paclitaxel with Q3-week (Q3W) have produced mixed results in terms of efficacy and toxicity creating controversy about the ideal dose and schedule.Methods: A literature search using PubMed, Cochrane Library, and Proceedings of the American Society of Clinical oncology from 1995 to 2011 was performed. We included all published and registered RTCs for advanced solid tumors which compared weekly paclitaxel with Q3W. Primary dependent variables – grade 3, 4 neutropenia rates and grade 3 sensory neuropathy rates – were analyzed for all cancer types. Secondary dependent variables – hazard ratios for survival and response rates – were analyzed for each cancer type. Moderators of cancer types, ethnicity, and paclitaxel dose ratio were analyzed for primary dependent variables.Results: Ten trials were included. The summary effects of the meta-analysis revealed less grade 3, 4 neutropenia (odds ratio: 0.49, p=0.0023) and a trend towards less grade 3 sensory neuropathy (odds ratio: 0.54, p=0.092) with weekly paclitaxel compared with Q3W. Moderator analysis by meta-regression revealed that paclitaxel dose ratios have a significantly positive correlation with rates of G3/4 neutropenia and sensory neuropathy. In the five NSCLC (non small cell lung cancer) trials, the summary effect revealed a better response rate with weekly paclitaxel (odds ratio: 1.24, p=0.042).Conclusion: Weekly paclitaxel has a favorable toxicity profile compared to the current standard of Q3W paclitaxel.

EGFR-mutated oncogene-addicted non-small cell lung cancer: Current trends and future prospects - Corrected Proof

Jean-Charles Soria, Tony S. Mok, Federico Cappuzzo, Pasi A. Jänne — 2011-11-28

Abstract: Non-small cell lung cancer (NSCLC) tumours with certain mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase have been termed ‘oncogene addicted’ to reflect their dependence on EGFR-mediated pro-survival signalling and their high susceptibility to apoptosis induced by EGFR tyrosine kinase inhibitors (EGFR–TKIs, e.g. gefitinib and erlotinib). The most common mutations (L858R and exon 19 deletions) predict an improved clinical response to first-line oral EGFR–TKIs compared with standard platinum-based chemotherapy in patients with advanced NSCLC. Moreover, these mutations are also prognostic of a relatively indolent course of disease, regardless of treatment, as compared with classical NSCLC. Treatment strategies for oncogene-addicted NSCLC are therefore distinct from those for non-oncogene addicted NSCLC, and will depend on the specific genetic mutation present.

Epithelial–mesenchymal transition and breast cancer: Role, molecular mechanisms and clinical impact - Corrected Proof

Chiara Foroni, Massimo Broggini, Daniele Generali, Giovanna Damia — 2011-11-28

Abstract: Epithelial–mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. In this process, cells acquire molecular alterations that facilitate dysfunctional cell–cell adhesive interactions and junctions. These processes may promote cancer cell progression and invasion into the surrounding microenvironment. Such transformation has implications in progression of breast carcinoma to metastasis, and increasing evidences support most tumors contain a subpopulation of cells with stem-like and mesenchymal features that is resistant to chemotherapy. This review focuses on the physiological and pathological role of EMT process, its molecular related network, its putative role in the metastatic process and its implications in response/resistance to the current and/or new approaching drugs in the clinical management of breast cancer.

Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis - Corrected Proof

2011-11-28

Abstract: Background: Randomised controlled trials (RCTs) of anti-EGFR monoclonal antibodies (MAb) in patients with advanced colorectal cancer (aCRC) have reported conflicting results.Methods: A systematic review of RCTs comparing standard treatments±anti-EGFR MAbs was conducted. Hazard ratios (HR) for progression-free (PFS) and overall survival (OS) were derived for patients with wild-type (WT) and mutant KRAS. Prespecified analyses were conducted for line of treatment, MAb used, chemotherapy regimen, and choice of fluouropyrimidine. Trials using bevacizumab on both arms were included in a sensitivity analysis.Results: Fourteen eligible RCTs were identified, with results by KRAS status available for ten RCTs. For third line treatment, the effect of anti-EGFR MAbs depended on KRAS status (interaction p<0.00001), with a PFS benefit for patients with WT KRAS only (HR=0.43, 95% CI 0.35–0.52, p<0.00001). For first and second line treatment, the effect also appeared to depend on KRAS status (interaction p=0.0003), again with the PFS benefit only for patients with WT KRAS (HR=0.83, 95% CI 0.76–0.90, p<0.0001). Differences between trial results (heterogeneity p=0.02, I2=62%) were best explained by the fluouropyrimidine used, with PFS benefits confined to trials combining MAbs alongside 5FU-based chemotherapy (HR=0.77, 95% CI 0.70–0.85, p<0.00001). There was no evidence of a PFS benefit when MAbs were given with bevacizumab.Conclusions: For aCRC patients with WT KRAS, there are clear benefits of anti-EGFR MAbs in the third line and in the first and second line, when used alongside infusional 5FU-based regimens. However, there is no benefit for patients with KRAS mutations.

Recommendations for the optimal management of early and advanced urothelial carcinoma - Corrected Proof

2011-11-24

Abstract: The field of urothelial carcinoma has shown considerable advances in terms of diagnosis, staging, and treatment. The increasing knowledge of molecular pathways and genes involved in the occurrence of this tumor has encouraged the search for new, more effective and less toxic therapies, and has prompted the design and development of clinical trials. However, the speed at which results are published makes it difficult for clinicians to cover the vast amount of information available. Moreover, in clinical practice some gaps remain concerning treatment options for patients who have progressed after first-line cisplatin-based combinations, who cannot tolerate cisplatin-based chemotherapy, or who have received platinum-based neoadjuvant or adjuvant therapy, and thus cannot be offered this option on disease progression. The purpose of this review is to issue a series of recommendations on the optimal management of early and advanced urothelial carcinoma based on current evidence and the available updated guidelines.

Radiotherapy versus surgery within multimodality protocols for esophageal cancer – A meta-analysis of the randomized trials - Corrected Proof

Christoph Pöttgen, Martin Stuschke — 2011-11-24

Abstract: During recent years, the curative potential of radiotherapy versus surgery for esophageal cancer was investigated in randomized trials. A PubMED®, Medline®, and Web of Science® search identified six randomized studies comparing definitive (chemo-) radiotherapy with either surgery alone or surgery+/−induction treatment for patients (n=929) with potentially resectable, mainly thoracic squamous cell (810/929pts.) esophageal cancer. In three of the studies (440pts.), resection alone was planned in the surgery arm, in three others induction chemoradiotherapy up to a total dose of 30–46Gy followed by resection was scheduled (489pts.). In the definitive radiation arms (+/−chemotherapy, conservative arm) total radiation doses of 45–71Gy with differing fractionation schedules were planned. Summary hazard ratios for survival, loco-regional control and treatment related mortality were calculated from intent-to-treat data.Overall survival was equivalent between surgery and definitive chemoradiotherapy (hazard ratio (HR) 0.98 [95% CI 0.8–1.2, p=0.84]). There was a trend to more cancer related deaths in the definitive radiation+/−chemotherapy arms (HR 1.19 [0.98–1.44], p=0.07), predominantly due to a higher risk of loco-regional progression (HR 1.54 [1.2–1.98], p=0.0007) but treatment related mortality was lower in the conservative arms (HR 0.16 [0–0.89], p=0.001). Protocol compliance was better in the conservative arms. A high concurrent risk of distant metastases (HR 0.72 [0.52–1.01], p=0.06) worsens the cancer specific survival of the loco-regionally controlled, resected patients with squamous cell cancers. The similar outcome in survival suggests that the safer approach of radiochemotherapy is a reasonable choice especially in comorbid patients with esophageal squamous cell carcinoma.

Breast reconstruction: à la carte not table d’hote - Corrected Proof

Ian S. Fentiman, Jian Farhadi — 2011-11-24

Abstract: NICE guidelines emphasise the need for breast cancer patients undergoing mastectomy to be offered all appropriate options for immediate reconstruction. In the majority of hospitals this is not happening. Patients are being offered the reconstruction technique for which their surgeon has been trained and many never meet an oncoplastic surgeon to discuss the wide range of options that are available. This means that many have sub-optimal reconstructions often using implants that may need to be subsequently replaced and are incompatible with post-operative radiotherapy. Patients will be better served by a few high throughput, high quality centres specialising in tailoring the right reconstruction for the woman who needs a mastectomy rather than the present system of having reconstruction of variable quality available ubiquitously.

Emerging therapies for urothelial cancer - Corrected Proof

2011-11-23

Abstract: Urothelial carcinoma is one of the leading causes of death in Europe and the United States. Despite its chemosensitivity, median overall survival for advanced disease is still nearly 1year. Most second-line chemotherapeutic agents tested have been disappointing. Thus, new treatment strategies are clearly needed. This review focuses on emerging therapies in urothelial carcinoma. Results from recent clinical trials, investigating the activity of new generation cytostatic agents, as well as results from studies assessing the toxicity and efficacy of novel targeted therapies, are discussed. In this setting, anti-epidermal growth factor receptor, angiogenesis, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors account for the majority of phase I and II trials.

Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review - Corrected Proof

2011-11-21

Summary: Epidermal growth factor receptor (EGFR) inhibitors, such as the monoclonal antibodies cetuximab and panitumumab, have proven efficacy in various types of cancer. However, these agents frequently result in skin toxicity, due to the expression of the EGFR in the skin. A correlation between the occurrence of skin toxicity and anti-tumor activity has been suggested in several phase III studies. However, since skin toxicity may impair the quality of life, and severe skin toxicity requires dose reduction or interruption, adequate and timely management of skin toxicity is important to maximize the anti-tumor efficacy of the EGFR inhibitor, as well as maintaining the patient’s quality of life. Due to the small number of randomized controlled trials conducted in the field of EGFR inhibitor-induced skin toxicity so far, it is not possible yet to generate evidence based guidelines on its management. Here, we review and discuss available trials and case studies reporting on the management of EGFR inhibitor-induced skin toxicity.

Diffuse malignant peritoneal mesothelioma – An update on treatment - Corrected Proof

2011-11-21

Abstract: Mesotheliomas are aggressive and lethal neoplasms arising from mesothelial cells lining the pleura, peritoneum, tunica vaginalis testis and pericardium. Malignant peritoneal mesothelioma accounts for about 30% of all mesotheliomas. Asbestos is the main known cause of the disease. Presenting symptoms in these patients include: ascites, abdominal pain, asthenia, weight loss, anorexia, abdominal mass, fever, diarrhea and vomiting. Electron microscopy, immunohistochemistry, computed tomography scan, echotomography, magnetic resonance imaging, positron emission tomography and laparoscopy are used in diagnosis and follow-up. Chemotherapy alone is considered as a palliative treatment for these patients who are not eligible for radical surgery. The most promising non-surgical approach today in the management of peritoneal mesothelioma is the use of the combination chemotherapy regime of an antifolate (pemetrexed and raltitrexed) and a platinum based (cisplatin) agent with a median survival of about 12–14months. Due to peritoneal confinement of malignant mesothelioma and low occurrence of metastasis, a locoregional approach consisting of cytoreductive surgery and perioperative intraperitoneal chemotherapy has been introduced as a curative treatment option over the last decade with an overall 5-year survival rate of 29–63%. In this locoregional approach, surgery can separate the adhesions and remove the bulky tumor, leaving microscopic residual tumors much more susceptible to the killing effect of chemotherapeutic drugs. Here in St. George hospital, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (using cisplatin and doxorubicin) resulted in significant survival advantage. This article describes how the prognosis of the disease has changed over the last decade.

Options on fertility preservation in female cancer patients - Corrected Proof

Kenny A. Rodriguez-Wallberg, Kutluk Oktay — 2011-11-11

Abstract: Infertility following treatment of cancer is a quality of survival’s recognized issue and efforts should be made to help young cancer patients retaining their fertility potential.Options to preserve fertility in female patients include well established methods such as shielding to reduce radiation damage to reproductive organs, fertility-sparing surgery and emergency in vitro fertilization after controlled ovarian stimulation, aiming at freezing embryos. Transfer of frozen/thawed embryos today is a clinical routine in fertility clinics worldwide and it has been used for over 25years. Mature oocytes after ovarian stimulation can also be frozen unfertilized, nevertheless overall pregnancy rates after fertilization of frozen-thawn oocytes are still relatively lower than those with embryo freezing. Remaining fertility preservation options are still in development and include the freezing of immature oocytes aiming at later in vitro maturing and fertilizing them and the cryopreservation of ovarian tissue for future retransplantation or for in vitro growth and maturation of follicles, both still experimental.

Managing progressive disease in patients with GIST: Factors to consider besides acquired secondary tyrosine kinase inhibitor resistance - Corrected Proof

Shreyaskumar Patel — 2011-10-31

Abstract: The use of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Currently, imatinib mesylate is the standard first-line treatment for unresectable and/or metastatic GIST, extending recurrence-free and overall survival for many patients. Nonetheless, eventual progression during imatinib therapy is prevalent, and the development of treatment paradigms for managing GIST progression is of importance. Sunitinib malate has been approved as a second-line treatment for unresectable and/or metastatic GIST and is an option for patients who are intolerant to imatinib or experience disease progression due to acquired resistance, otherwise referred to as secondary resistance. In many cases, however, there may be other causes for GIST progression besides secondary resistance, and consideration of these factors is necessary before switching to second-line treatment. This review presents a treatment strategy for GIST patients who have progressed after initial imatinib responsiveness and addresses necessary considerations that include instances of false progression, insufficient TKI plasma levels, and patient non-adherence. In situations where true progression has occurred, patients may benefit from imatinib dose escalation. Surgery also provides a viable option for patients with stable disease or limited progression, and may prevent and/or delay the development of resistant clones by reducing tumor burden. Switching to second-line therapy with sunitinib should be considered for imatinib-intolerant or -resistant GIST patients.

Endothelial vascular toxicity from chemotherapeutic agents: Preclinical evidence and clinical implications - Corrected Proof

2011-10-10

Abstract: In cancer biology angiogenesis plays a vital role in tumour growth and its subsequent metastatic potential. By targeting the angiogenic process, a new treatment strategy was added in the clinician’s therapeutic armamentarium. On the other hand, numerous classic cytotoxic agents are currently considered as potential angiogenesis inhibitors, although they were not originally developed as such, representing the so-called “accidental” anti-angiogenic drugs. The discovery of these new properties of classic cytotoxic agents led to the re-evaluation of their effect on vascular cells, rendering thus the endothelium an appealing target for therapeutic intervention, either with chemotherapy alone or with combination of cytotoxics with molecular angiogenesis inhibitors. Moreover, current evidence supports that chemotherapy-induced endothelial dysfunction constitutes an integrating predictive marker of future cardiovascular events and correlates well with traditional cardiovascular risk factors. It has therefore been suggested that evaluation of endothelial function may be useful in identifying asymptomatic subjects at high risk for cardiovascular events as well as for risk stratification of patients with established cardiovascular disease. Integration of the assessment of endothelial function in the clinical setting will thus enable effective intervention strategies to prevent or minimize the impact of these late adverse effects and design accurate follow-up protocols focused on cardiovascular complications. In the current review we provide a comprehensive overview of the effects of cytotoxic chemotherapeutic agents on endothelial function and the clinical implications of chemotherapy-associated endothelial toxicity in patients with cancer.

Direct and indirect anticancer activity of bisphosphonates: A brief review of published literature - Corrected Proof

Michael Gnant, Philippe Clézardin — 2011-10-10

Abstract: The bone marrow microenvironment provides a site for cancer cells to evade systemic anticancer therapy. Dormant tumor micrometastases are believed to be the source of disease persistence and relapse; however, the exact characteristics of cancer stem cells vs. cancer cells with limited metastatic potential have yet to be elucidated. Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss. Altering the bone marrow microenvironment to make it less conducive to cancer cell survival is now emerging as an important means to prevent cancer recurrence. This review aims to distill the diverse literature and provide a brief overview of the numerous preclinical and early clinical studies of bisphosphonates demonstrating a variety of direct and indirect anticancer activities that affect both the tumor cell (the “seed”) and surrounding microenvironment (the “soil”). Recently, zoledronic acid was found to improve disease-free survival and overall survival in some adjuvant breast cancer settings and prolonged survival in patients with multiple myeloma and other advanced cancers. In the prostate cancer setting, antiresorptive therapy was reported to delay the development of overt bone metastases. Ongoing studies will provide further insight regarding the anticancer potential of bisphosphonates and other antiresorptive agents.

New treatment options for patients with metastatic castration-resistant prostate cancer - Corrected Proof

Celestia S. Higano — 2011-09-26

Abstract: Chemotherapy for men with metastatic castration-resistant prostate cancer (CRPC) conferred no survival advantage until 2004 when docetaxel was shown to improve survival when compared with mitoxantrone, which was approved for palliation of symptomatic disease in 1996. Since then, clinical trials have concentrated on three main populations of patients with metastatic CRPC: those who are chemotherapy naïve and are asymptomatic or minimally symptomatic, those who need docetaxel therapy, and those who have received docetaxel previously and/or those with symptomatic disease. Over the last year, four Phase III therapeutic trials have met their primary endpoint of improved overall survival: sipuleucel-T in the pre-chemotherapy setting, cabazitaxel and abiraterone in the post-docetaxel setting, and radium-223 for those with symptomatic bone metastases who have received or are not suitable to receive docetaxel. In addition to these therapeutic trials, a Phase III head-to-head trial of denosumab compared to zoledronic acid showed that denosumab was superior to zoledronic acid in delaying or preventing skeletal related events. As a result, the treatment paradigm for metastatic CRPC is changing rapidly. This paper reviews the data from these five completed Phase III trials and places these new agents, as well as those in ongoing Phase III trials, in the context of the old treatment paradigm for metastatic CRPC and discusses some of the challenges ahead for determining optimal timing and sequencing of treatments for metastatic CRPC.

The role of the in situ local inflammatory response in predicting recurrence and survival in patients with primary operable colorectal cancer - Corrected Proof

C.S.D. Roxburgh, D.C. McMillan — 2011-09-26

Abstract: Colorectal cancer progression and survival is dependent on complex interactions between the tumour and the host. The pronounced local inflammatory response in and around the tumour is thought to represent the in situ host anti-tumour immune response. Since early reports, 40years ago, there has been a continuing interest in establishing the cellular composition of immune cell infiltrates and their relationship with survival in colorectal cancer. In this review, we comprehensively examine the evidence for the local inflammatory cell reaction/in situ immune response in predicting outcome in primary operable colorectal cancer and make recommendations as to how such information may be incorporated into routine clinical assessment.Generally, an increasing number/density of immune cells in and around the tumour is associated with improved outcome in over 100 studies. Whilst the prognostic value of a generalized lymphocytic infiltrate or non-specific peritumoural inflammatory response is strongly related to survival based on 40 different studies, it is also apparent that most individual immune cell types relate to recurrence and cancer specific survival. The evidence is particularly robust for tumour infiltrating T lymphocytes and their subsets (CD3+, CD8+, CD45RO+, FOXP3+) in addition to tumour associated macrophages, dendritic cells and neutrophils. Taken together, the evidence suggests both adaptive and innate anti-tumour immune responses play key roles in determining cancer progression.In order to establish routine clinical utility there is a need to rationalise this prognostic information, published over a 40years period, into a standardized assessment of tumour inflammatory cell infiltrate. Such standardization may also guide development of novel therapeutic interventions.

Clinical and future applications of high intensity focused ultrasound in cancer - Corrected Proof

Osama Al-Bataineh, Jürgen Jenne, Peter Huber — 2011-09-19

Abstract: High intensity focused ultrasound (HIFU) or focused ultrasound (FUS) is a promising modality to treat tumors in a complete, non invasive fashion where online image guidance and therapy control can be achieved by magnetic resonance imaging (MRI) or diagnostic ultrasound (US). In the last 10 years, the feasibility and the safety of HIFU have been tested in a growing number of clinical studies on several benign and malignant tumors of the prostate, breast, uterine, liver, kidney, pancreas, bone, and brain. For certain indications this new treatment principle is on its verge to become a serious alternative or adjunct to the standard treatment options of surgery, radiotherapy, gene therapy and chemotherapy in oncology. In addition to the now clinically available thermal ablation, in the future, focused ultrasound at much lower intensities may have the potential to become a major instrument to mediate drug and gene delivery for localized cancer treatment. We introduce the technology of MRI guided and ultrasound guided HIFU and present a critical overview of the clinical applications and results along with a discussion of future HIFU developments.

Pharmacogenetics of anti-estrogen treatment of breast cancer - Corrected Proof

Marzia Del Re, Angela Michelucci, Paolo Simi, Romano Danesi — 2011-09-15

Abstract: A major effort is underway to select genetic polymorphisms potentially relevant to the clinical efficacy and safety of endocrine treatment of breast cancer. Genetic factors of the host that affect the metabolism of tamoxifen, a widely used drug for the adjuvant treatment of breast cancer, have received particular attention. Cytochrome P450 isoform 2D6 (CYP2D6) is a key step in the metabolism of tamoxifen to its active moiety endoxifen. Women with functionally deficient genetic variants of CYP2D6 who are given drugs that inhibit CYP2D6 are exposed to low endoxifen plasma levels and may enjoy reduced benefits from tamoxifen treatment. Therefore, CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; unfortunately, the data are not uniformly concordant, and definitive evidence that would suggest the routine analysis of CYP2D6 before commencing tamoxifen treatment is not yet available. Recent research has focused on the role UDP-glucuronosyltransferases, a family of metabolizing enzymes that play an important role in the metabolic clearance of tamoxifen and of the aromatase inhibitors as well, and how interindividual differences in these enzymes may play a role in the clinical outcome upon administration of anti-estrogen treatment. In conclusion, whether a pharmacogenetic profile should be obtained prior to initiating tamoxifen therapy is currently a matter of debate, although summing up all the scientific evidence available on this issue it appears that the genetic screening would be an useful support for clinical decision making in selected patients.

The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors - Corrected Proof

Giorgio V. Scagliotti, Silvia Novello — 2011-09-12

Abstract: The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have become increasingly recognized as having a driving role in the development of malignancy, and consequently IGF-1R has become a potential target for cancer therapy. Several inhibitors of IGF-1R are in clinical development for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). These IGF-1R-targeted agents include monoclonal antibodies such as cixutumumab (IMC-A12), AMG-479, AVE1642, BIIB022, dalotuzumab (MK-0646), and robatumumab (Sch717454), the ligand neutralizing antibody Medi-573, and the small molecule inhibitors BMS-754807, linsitinib (OSI-906), XL228, and AXL1717. Two phase III trials of the anti-IGF-1R monoclonal antibody, figitumumab (CP-751,871), were discontinued in 2010 as it was considered unlikely either trial would meet their primary endpoints. In light of disappointing clinical data with figitumumab and other targeted agents, it is likely that the use of molecular markers will become important in predicting response to treatment. This review outlines the role of IGF-1R signaling in solid tumors with a particular focus on NSCLC, and provides an overview of clinical data.

Biologic therapies in the metastatic colorectal cancer treatment continuum – Applying current evidence to clinical practice - Corrected Proof

Marc Peeters, Timothy Price — 2011-09-07

Abstract: More therapeutic options are now available than ever before for patients with metastatic colorectal cancer (mCRC) and, as such, treatment decisions have become more complex. A multidisciplinary approach is, therefore, required to effectively manage these patients. In the past few years, many trials have reported on the value of combining biological agents, such as those targeting vascular endothelial growth factor A and epidermal growth factor receptors, with chemotherapy. However, despite the plethora of information now available, the optimal treatment strategy for patients with mCRC remains unclear. Indeed, the propensity of investigators to conduct clinical trials utilising a variety of chemotherapy backbones combined with the increased complexity of retrospectively incorporating analyses of genetic mutation status (e.g. KRAS and BRAF) have led to conflicting results for seemingly similar endpoints, particularly overall survival. As a result, guidelines that have been developed, whilst having some similarities, have distinct differences in terms of suggested therapeutic combinations. Therefore, here, we review and distil the currently available data reported from phase III trials of biologic agents in the first-, second- and third-line mCRC settings.

Docetaxel combined with targeted therapies in metastatic breast cancer - Corrected Proof

Javier Cortes, Henri Roché — 2011-08-29

Abstract: The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation.

Chemoprevention for breast cancer - Corrected Proof

I. Bozovic-Spasojevic, E. Azambuja, Worta McCaskill-Stevens, P. Dinh, F. Cardoso — 2011-08-19

Abstract: Despite the progress that has been made in breast cancer diagnosis and treatment, this disease is still a major health problem, being the most frequently diagnosed cancer and the first leading cause of cancer death among women both in developed and economically developing countries. In some developed countries incidence rate start to decrease from the end of last millennium and this can be explained, at least in part, by the decrease in hormone replacement therapy use by post-menopausal women.Chemoprevention has the potential to be an approach of utmost importance to reduce cancer burden at least among high-risk populations. Tamoxifen and raloxifene are both indicated for the prevention of breast cancer in women at high risk for the development of the disease, although raloxifene may have a more favorable adverse-effect profile, causing fewer uterine cancers and thromboembolic events. Aromatase inhibitors will most probably become an additional prevention treatment option in the near future, in view of the promising results observed in adjuvant trials and the interesting results of the very recently published first chemoprevention trial using an aromatase inhibitor. Despite impressive results in most clinical trials performed to date, chemoprevention is still not widely used. Urgently needed are better molecular risk models to accurately identify high-risk subjects, new agents with a better risk/benefit ratio and validated biomarkers.

Electrochemotherapy of chest wall breast cancer recurrence - Corrected Proof

Gregor Sersa, Tanja Cufer, Snezna Marija Paulin, Maja Cemazar, Marko Snoj — 2011-08-19

Abstract: Chest wall breast cancer recurrence after mastectomy is a disease difficult to treat. Its incidence varies between 5% and 30% in different subset of patients. When possible, radical surgical therapy represents the main treatment approach, however when the disease progresses and/or treatments are not successful, ulceration, bleeding, lymphedema and psychological distress of progressive disease significantly decrease the quality of the remaining life of a patient. When surgical excision of chest wall recurrence is not possible, other local treatments such as radiotherapy, radiotherapy with hyperthermia, topical chemotherapy and electrochemotherapy might be taken into account. Electrochemotherapy provides safe, efficient and non-invasive locoregional treatment approach for chest wall breast cancer recurrence. Several clinical studies have demonstrated high efficacy and a good safety profile of electrochemotherapy applied in single or multiple consecutive sessions, till clinical response was reached. Electrochemotherapy can be performed either with cisplatin injected intratumorally or with bleomycin given intratumorally or intravenously. Furthermore, it can be effectively used in heavily pre-treated areas, after surgery, radiotherapy or systemic chemotherapy. These are the advantages that might demand its use especially in patients with pre-treated extensive disease and in frail elderly patients. With development of the technology electrochemotherapy could even be suggested as a primary local therapy in patients not suitable for surgical removal of the primary tumor.

A role for maintenance therapy in managing sarcoma - Corrected Proof

Isabelle Ray-Coquard, Axel Le Cesne — 2011-08-16

Summary: Despite the use of recommended chemotherapy regimens, patients with metastatic sarcomas have a poor prognosis. To date, the median overall survival for metastatic disease remains less than 18months. First-line treatment of most metastatic sarcomas consists of chemotherapy with or without surgical excision of residual disease, followed by “watchful waiting” until disease progression or recurrence. According to the current treatment paradigm, recommended by United States and European clinical guidelines, chemotherapy is administered for a fixed number of cycles, and then a watchful waiting approach is taken once a best response is achieved. Single-agent doxorubicin remains the standard for treatment of most soft-tissue sarcomas (STS), as combination and dose-intense regimens have largely failed to improve survival. Combination chemotherapy is the standard treatment approach for osteosarcoma and Ewing’s sarcoma, but outcomes are poor for patients with recurrent disease. In order to improve outcomes (in particular, progression-free survival [PFS] and overall survival [OS]), strategies shown to be effective in other solid malignancies, such as maintenance therapy and long-term treatment with targeted therapy, are being investigated in patients with advanced sarcomas. One potential promising approach is the use of mammalian target of rapamycin (mTOR) inhibitors for maintenance therapy. One such mTOR inhibitor, ridaforolimus (AP23573, MK-8669), is currently being evaluated in patients with advanced bone and STS in the ongoing Sarcoma mUlti-Center Clinical Evaluation of the Efficacy of riDaforolimus (SUCCEED) trial.

Physician’s guide to the clinical management of adverse events on nilotinib therapy for the treatment of CML - Corrected Proof

2011-08-16

Abstract: Nilotinib is a rationally designed tyrosine kinase inhibitor with improved specificity and binding affinity for BCR-ABL compared with imatinib. Nilotinib is approved in patients with imatinib-resistant and -intolerant Philadelphia chromosome-positive chronic myeloid leukemia (CML), as well as in patients with newly diagnosed CML. Nilotinib is generally well tolerated, with mild and manageable side effects, and is associated with some adverse events that require management to insure patient adherence to therapy and optimal treatment outcomes. The objectives of this article are to review the clinical management of the most frequent of these adverse events and to guide physicians in helping their patients maintain adherence and achieve optimal outcomes with nilotinib therapy.

Cyto-reductive Surgery combined with Hyperthermic Intra-Peritoneal Chemotherapy for Peritoneal Surface Malignancies: Current treatment and results - Corrected Proof

Antonio Sommariva, Pierluigi Pilati, Carlo Riccardo Rossi — 2011-08-02

Abstract: Cyto-reductive Surgery (CS) combined with Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) as loco-regional treatment of Peritoneal Surface Malignancies (PSM) has increasingly gained acceptance in clinical practice. This review summarizes the more relevant studies on this topic. Indications, pre-operative work-up, technical aspects, outcome and future directions of this combined approach in the treatment of Peritoneal Surface Malignancies are discussed here and proposed in an informative and didactic manner.

Assessment of quality of life in advanced breast cancer. An overview of randomized phase III trials - Corrected Proof

Krzysztof Adamowicz, Jacek Jassem, Artur Katz, Everardo D. Saad — 2011-08-02

Abstract: Background: Health-related quality of life (HRQOL) parameters are often used as end points in phase III trials in advanced breast cancer. The frequency and correlates of significant gains in HRQOL have not been assessed.Methods: To evaluate the contemporary role for HRQOL assessment in advanced breast cancer, we searched PubMed for the main and companion papers reporting the results of phase III trials on systemic antineoplastic therapies published between 1/98 and 7/09 in 11 leading journals.Results: The search yielded 87 trials that enrolled a total of 33,669 patients. HRQOL was mentioned/reported in the main paper in 34 trials, reported in a companion paper in one (a total of 35/87=40%), and mentioned in the abstract of the main paper in 19/34 cases (56%). There was no temporal trend for reporting on HRQOL in the two 6-year periods. Although formal statistical comparisons were reported in 31/35 cases (89%), a significant difference was found in only 4/31 (13%) trials, always favoring the experimental arm. Given the small number of studies with a significant HRQOL finding, we could not assess correlates of gain in HRQOL.Conclusions: HRQOL is one of the key indicators of treatment benefit in advanced breast cancer, but contemporary systemic therapies in this setting do not appear to affect HRQOL differentially.

Skeletal metastasis in renal cell carcinoma: Current and future management options - Corrected Proof

Steven L. Wood, Janet E. Brown — 2011-08-01

Abstract: Metastasis to the skeleton is common in advanced renal cancer and leads to debilitating skeletal complications including severe pain, increased fracture rate and spinal cord compression. The incidence of renal cell carcinoma is increasing by around 2% per year and recent advances in targeted anti-angiogenic therapy for advanced disease are expected to lead to longer survival times. The clinical management of metastatic bone disease in renal cell carcinoma therefore merits greater focus than hitherto. Bone metastases arising from renal cancer are highly osteolytic and particularly destructive. Fortunately, the continuing development of anti-resorptive drugs is revolutionising the medical management of metastatic bone disease across many tumour types and making a major impact on quality of life. The bisphosphonate zoledronic acid is now licensed for use in advanced renal cell carcinoma and appears to yield a greater benefit in terms of reduction in skeletal related events than in bone metastases arising from other tumour types. Drugs which are directed at specific targets in the bone metastasis pathway are in development, including denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappa B ligand, which has recently been licensed in the United States for use in renal cell carcinoma, with European licensing expected soon. This review examines the increasing options for treatment of metastatic bone disease in renal cell carcinoma, with a focus on drug-based advances and progress in the development of existing and new biomarkers to support clinical management.

Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: A systematic review - Corrected Proof

2011-07-21

Abstract: Background: Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein thrombosis and pulmonary embolism in women <50years given tamoxifen for breast cancer prevention.Methods: We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20mg per day) with placebo for five years in high-risk women <50years. The absolute risk and relative risk (RR) for each outcome were estimated.Results: The RR for endometrial cancer in women <50years given tamoxifen is 1.19 (95% CI, 0.53–2.65; p=0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23–4.31; p=0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38–2.67; p=0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55–2.43; p=0.6).Interpretation: The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention.

Problems involved in the clinical trials for non-small cell lung carcinoma - Corrected Proof

Nagahiro Saijo — 2011-07-20

Abstract: Along with changes in smoking habits, non-small cell lung carcinoma (NSCLC) has come to account for about 90% of all cases of lung cancer. For the treatment of NSCLC, cytocidal antineoplastic drugs such as pemetrexed and molecular-targeted drugs such as gefitinib, erlotinib, and bevacizumab have been approved globally and used as a part of the standard treatment. The importance of better patient selection based on the optimum indication of these drugs is attracting much attention. Additionally, timing for the use of these drugs also seems to be an important issue. The present review presents a critical discussion about the following issues based on the results of clinical studies: (1) whether or not the assessment of the EGFR mutation status in NSCLC patients is indispensable; (2) whether gefitinib and erlotinib have different effects; (3) the need to sub-classify NSCLC by histologic type; (4) significance of maintenance therapy for NSCLC; and (5) whether platinum-doublet chemotherapy plus bevacizumab is a standard treatment for non-squamous cell carcinoma.

Open conservation partial laryngectomy for laryngeal cancer: A systematic review of English language literature - Corrected Proof

2011-07-18

Abstract: Background: Different modalities of treatment in early laryngeal cancer lead to equivalent oncological outcomes. Hence this systematic review was undertaken to synthesise the key oncological outcomes following primary open partial laryngectomy for laryngeal cancer.Methods: A systematic review of the English literature with statistical pooling of outcomes, the main outcome measure being local control at 24months.Results: A total of 53 articles satisfied inclusion criteria and were included in the review. The pooled local control rate at 24months from 5061 patients was 89.8% (95% CI 88.3–91.2), pooled overall survival was 79.7% (n=3967; 95% CI 76.5–782.8) and pooled mean disease free survival was 84.8% (n=2344; 95% CI 80.6–88.7). The pooled mean operative mortality, laryngectomy for function, tracheostomy decannulation and permanent gastrostomy rates were 0.7%, 1.7%, 96.3%, and 2.0%, respectively.Conclusions: Open conservation laryngectomy is a good option in selected primary laryngeal cancers with excellent oncological outcomes.