Cancer Treatment Reviews - Articles in Press

Systematic review and meta-analysis of radiotherapy in various head and neck cancers: Comparing photons, carbon-ions and protons - Corrected Proof

2010-09-03

Abstract: Purpose: To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer.Methods: A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy.Results: In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons.In-silico studies showed a lower dose to the organs at risk, independently of the tumor site.Conclusions: For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy.Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons.

Sunitinib for the treatment of metastatic renal cell carcinoma - Corrected Proof

Stéphane Oudard, Benoit Beuselinck, Jasper Decoene, Peter Albers — 2010-09-03

Abstract: Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor approved multinationally for the first- and second-line treatment of metastatic renal cell carcinoma (mRCC). The recommended dose of sunitinib is 50mg per day for 4weeks followed by 2weeks off-treatment (Schedule 4/2). In a phase III trial in 750 patients with mRCC who had not received prior treatment, sunitinib demonstrated superior efficacy to interferon-α for the first-line treatment of mRCC. Sunitinib doubled progression-free survival compared with interferon-α; furthermore, median OS with sunitinib was greater than 2years. As a result, sunitinib is now considered a reference standard of care for first-line mRCC treatment in patients at favourable or intermediate prognostic risk and is recommended in treatment guidelines. Additionally, results from an expanded-access programme, in a broad, heterogeneous patient population, confirmed the efficacy of sunitinib. Sunitinib has a distinct and predictable profile of adverse events, most of which are manageable with standard medical interventions. Therapy management strategies, including optimisation of dose and treatment duration and adverse event management can help patients achieve optimal efficacy with sunitinib in clinical practice. To further improve outcomes in patients with mRCC, current trials are evaluating sequencing or combination of targeted agents. The use of sunitinib as adjuvant therapy after nephrectomy and as neoadjuvant therapy is also being assessed. This paper provides an in-depth critical review of sunitinib, with particular focus on the data supporting the use of sunitinib for mRCC.

Evolving strategies for the treatment of hepatocellular carcinoma: From clinical-guided to molecularly-taylored therapeutic options - Corrected Proof

2010-08-27

Abstract: Hepatocellular carcinoma (hepatocellular carcinoma, HCC) is the commonest primary liver cancer (80–90%) and represents the leading cause of cancer-related death, after lung and stomach cancer.The process of neoplastic transformation proceeds through the accumulation of mutations in the genes governing cell proliferation and apoptosis.It is currently difficult to determine the natural history of patients with untreated early-stage HCC, since most with early-stage tumor patients undergoes curative therapy. Survival rates at 3years is 65% in patients with Child-Pugh A, and single untreated lesion. This proportion increases to 70% at 5years after radical treatment. In patients included in randomized controlled clinical trials with advanced disease, survival at 1 and 2years is respectively 72% and 50%.Surgery is the only potentially curative treatment for HCC. In carefully selected patients, resection and transplantation in fact, allow a 5years survival from 60% to 70%.Unfortunately most patients in Western countries present with an intermediate or advanced HCC at diagnosis with the consequent inability to use curative treatments. These patients are therefore candidates to palliative therapies that include arterial embolization and chemoembolization and systemic treatments including chemotherapy, immunotherapy and hormonal therapy. Only recently the molecular targeted drug, Sorafenib, has been introduced among the therapeutic options for these patients.

Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: Available evidence and expert opinion on the use of transarterial chemoembolization - Corrected Proof

2010-08-19

Summary: Transarterial chemoembolization (TACE) is considered the gold standard for treating intermediate-stage hepatocellular carcinoma (HCC). However, intermediate-stage HCC includes a heterogeneous population of patients with varying tumour burdens, liver function (Child-Pugh A or B) and disease aetiology. This suggests that not all patients with intermediate-stage HCC will derive similar benefit from TACE, and that some patients may benefit from other treatment options.Results of an extensive literature review into the treatment of unresectable HCC with TACE were combined with our own clinical experience to identify factors that may predict survival after TACE. We also report contraindications to TACE and propose a treatment algorithm for the repetition of TACE. In addition, we have constructed a number of expert opinions that may be used as a guide to help physicians make treatment decisions for their patients with intermediate-stage HCC. The data included in the literature review related almost exclusively to conventional TACE, rather than to TACE with drug-eluting beads. Therefore, the findings and conclusions of the literature review are only applicable to the treatment of HCC with conventional TACE.Treating physicians may want to consider other treatment options for patients with intermediate-stage HCC who are not suitable for or do not respond to TACE. By distinguishing those patients who represent good candidates for TACE from those where little or no benefit might be expected, it may be possible to make better use of current treatment options and improve outcomes for patients.

Luteinising hormone releasing hormone agonists (LH-RHa) in premenopausal early breast cancer patients: Current role and future perspectives - Corrected Proof

Lucia Del Mastro, Alessia Levaggi, Sara Giraudi, Paolo Pronzato — 2010-08-19

Summary: Luteinising hormone releasing hormone agonists (LH-RHa) induce ovarian suppression in premenopausal women that is usually reversible on cessation of therapy. They act by binding to pituitary LH-RH receptors, resulting in down regulation of receptors and subsequent suppression of luteinising hormone and estradiol. LH-RHa are effective in the treatment of advanced breast cancer in premenopausal women but their role as adjuvant treatment of early breast cancer is still controversial. Approximately 60% of tumors in premenopausal women are hormone sensitive and these patients are candidates for hormonal treatment. Tamoxifen for 5years is considered the standard endocrine therapy for all premenopausal women with hormone sensitive breast cancer. There is no definitive evidence of additional benefit associated with the use of LH-RHa administered as an alternative or in addition to tamoxifene. In this review we discuss available data on the role of LH-RHa alone or in combination with tamoxifen; on the role of LH-RHa in combination with aromatase inhibitors; and on the potential role of LH-RHa as a strategy to preserve ovarian function during adjuvant chemotherapy.

Topotecan for relapsed small cell lung cancer: A systematic review and economic evaluation - Corrected Proof

2010-08-16

Summary: Background: Topotecan is a relatively new drug for use as a second-line treatment in patients with relapsed small cell lung cancer (SCLC). We performed a systematic review and economic evaluation of topotecan, and consider it here in relation to the NICE end of life criteria.Methods: Seventeen bibliographic databases (including Cochrane library, Medline and Embase) were searched from 1990 to February 2009, and experts and manufacturers were consulted, to identify relevant randomised controlled trials (RCTs) which were selected according to prospectively defined criteria. An economic evaluation was undertaken to assess cost effectiveness compared with best supportive care (BSC) in the UK.Results: Five RCTs were included. The clinical evidence indicates a statistically significant benefit of oral topotecan plus BSC compared to BSC alone for overall survival. Intravenous topotecan was similar in efficacy to both oral topotecan and CAV (cyclophosphamide, doxorubicin and vincristine). In the survival model, oral topotecan plus BSC was associated with an average gain in life expectancy of approximately 4months, resulting in a gain of 0.183 quality-adjusted life years (QALYs). At an incremental cost of approximately £6200 the incremental cost effectiveness ratio (ICER) is £33,851 per QALY gained.Conclusions: Compared with BSC alone, oral topotecan for patients with relapsed SCLC was associated with improved health outcomes but at increased cost. The ICER is at the upper extreme of the range conventionally regarded as cost effective from an NHS decision making perspective. However, this treatment may fall under supplementary guidance for life extending, end of life treatments.

Advances in the systemic treatment of pancreatic neuroendocrine tumors - Corrected Proof

Suayib Yalcin — 2010-08-12

Abstract: Constituting about 1–2% of all tumors of the pancreas, pancreatic neuroendocrine tumors (PNETs) are a subgroup of gastroenetropancreatic neuroendocrine tumors (GEP-NETs) with distinct tumor genetics, biology, and clinicopathological features. Surgical resection is amenable only in a minority of the cases so systemic therapies are considered in most of them. The goals of medical treatment are to control the associated symptoms and signs of the specific tumors and to shrink the tumor mass. Somatostatin analogues can, not only decrease the secretion of peptides and inhibit their functions but also stop tumor growth. Other medical options for limiting tumor growth include interferon, systemic chemotherapy, and targeted therapies including, angiogenesis inhibitors, epidermal growth factor inhibitors, and mTOR inhibitors. Newer agents are tested and the treatment options expected to increase in the near future. Meanwhile optimal use of the available therapeutic strategies is critical.

Use of molecular markers for predicting therapy response in cancer patients - Corrected Proof

Michael J. Duffy, Norma O’Donovan, John Crown — 2010-08-04

Abstract: Predictive markers are factors that are associated with upfront response or resistance to a particular therapy. Predictive markers are important in oncology as tumors of the same tissue of origin vary widely in their response to most available systemic therapies. Currently recommended oncological predictive markers include both estrogen and progesterone receptors for identifying patients with breast cancers likely to benefit from hormone therapy, HER-2 for the identification of breast cancer patients likely to benefit from trastuzumab, specific K-RAS mutations for the identification of patients with advanced colorectal cancer unlikely to benefit from either cetuximab or panitumumab and specific EGFR mutations for selecting patients with advanced non-small-cell lung cancer for treatment with tyrosine kinase inhibitors such as gefitinib and erlotinib. The availability of predictive markers should increase drug efficacy and decrease toxicity, thus leading to a more personalized approach to cancer treatment.

Cancer of unknown primary patients with midline nodal distribution: Midway between poor and favourable prognosis? - Corrected Proof

George Pentheroudakis, Aikaterini Stoyianni, Nicholas Pavlidis — 2010-08-02

Abstract: Background: Midline nodal cancer of unknown primary (CUP) has varying definitions and an unclear natural history compared to that of extragonadal germ cell cancer (EGCC) and neuroendocrine tumors.Methods: We systematically reviewed all published series of patients with midline nodal CUP using three distinct definitions and presented our own retrospective cohort.Results: Sixty four fit patients (median age 64) with poorly differentiated carcinoma or adenocarcinoma in midline nodal areas were treated from 1998 to 2008 at our center. Only two patients had elevated serum germ cell markers. Forty-eight percentage of patients responded to platinum-based chemotherapy (CR 11%). The median survival was 12months (2-year survival 18%). Good PS (Hazard Ratio HR 0.287, p=0.058) and administration of platinum (HR 0.340, p=0.08) predicted for more favourable outcome. A subgroup of 15 male patients selected with stricter criteria had a CR rate of 33% and median survival of 18months (2-year survival 24%). We identified 10 series of midline nodal CUP patients defined with discordant criteria. Despite high response rates (35–65%) to platinum chemotherapy, the median survival clustered around 12months. Predictive factors for superior survival were low tumor bulk, patient fitness, female gender, carcinomatous histology, and absence of visceral metastases. There were differences between midline nodal CUP patients and EGCC as well as neuroendocrine tumors (age, tumor markers, response to therapy, long-term survival).Conclusions: Midline nodal CUP patients are poorly defined, fare less well than EGCC or neuroendocrine cancer and probably constitute a heterogeneous entity with a minority harbouring atypical germ cell cancer.

Malignant pheochromocytomas and paragangliomas – The importance of a multidisciplinary approach - Corrected Proof

2010-08-02

Abstract: Approximately 10% of the pheochromocytomas and 20% of the paragangliomas are malignant with poor survival. As the biological behaviour of these tumours cannot be predicted with certainty from pathology the diagnosis of malignancy is difficult. Genetic testing is gaining impact as mutations in the tumour suppressor gene Von Hippel-Lindau and the mitochondrial succinate dehydrogenase enzyme complex subunit B (SDHB) are associated with malignancy. Excess release of catecholamines is characteristic for pheochromocytomas. High levels of chromogranin A, that is co-stored and co-secreted with catecholamines, may indicate tumour mass and malignancy and can be used to monitor response and relapse. The secretory and non-secretory tumours can be visualised with functional (specific and non-specific) imaging as SPECT and PET using 123I-MIBG, somatostatin analogues, 18F-DOPA, and 18F-FDG. These modalities are recommended in patients with extra-adrenal and suspected metastatic/malignant disease, in case of distorted post-operative anatomy, and when suspected recurrence. The sensitivities of 123I-MIBG scintigraphy or 18F-DOPA PET are relatively low in SDHB mutated tumours, but high using 18F-FDG. Specific PET imaging with somatostatin analogues generally has high sensitivity in malignant disease. There are no curative therapeutic options for malignant, metastatic pheochromocytomas/paragangliomas, wherefore consolidation of quality of life is essential. Adjuvant radionuclide treatment with beta-emitting isotopes coupled to MIBG or somatostatin analogues have shown response in approximately 30%. Chemotherapy is restricted to patients not accessible for surgery and resistant to radionuclide therapy. Novel targeted therapies, which mainly through a cytostatic effect interfere with specific targeted molecules needed for carcinogenesis and tumour growth show encouraging results.

Adjuvant radiotherapy after radical prostatectomy: Evidence and analysis - Corrected Proof

Ann Raldow, Daniel A. Hamstra, Sung N. Kim, James B. Yu — 2010-07-28

Abstract: Although surgery provides excellent control for localized prostate cancer, pathologic examination of more than one-third of specimens will reveal positive surgical margins, seminal vesicle invasion, and/or extracapsular extension, thus putting these patients at increased risk of cancer recurrence. “Adjuvant” radiotherapy (ART) refers to treatment of patients with an undetectable PSA that is delivered after surgery (usually less than 12–16weeks from the time of surgery). Currently, there are no standardized guidelines for the use of ART and the bulk of patients are solely monitored for signs of recurrence after prostatectomy. In this article, we review the evidence for ART from three randomized clinical trials. Although radiation therapy in the adjuvant setting has generally been well tolerated, we also examine the complication data associated with treatment. In addition, we discuss the technical aspects of treatment, including dose escalation and treatment target volume. The ability to increase dose and limit target volume would likely result in higher cure rates and decreased side effects, thus ensuring a better clinical outcome and increasing quality of life. Finally, we discuss the cost-effectiveness of ART, in the context of other medical interventions.

Controversies in the management of adjuvant breast cancer with taxanes: Review of the current literature - Corrected Proof

2010-07-26

Summary: Taxanes offer clear benefits in adjuvant chemotherapy for early breast cancer. This review examines evidence to date on the clinical effectiveness and cost-effectiveness of their use in the adjuvant treatment of women with early breast cancer, based on three meta-analyses, one systematic review, five clinical practice guidelines and 16 randomized clinical trials. Against the background of a major increase in the use of docetaxel rather than paclitaxel in our setting over the past few years, implying a major increase in costs, we examined whether this higher use of docetaxel is supported by the available evidence. In this wide study, we found no evidence that regimens containing docetaxel yield greater benefits than those including paclitaxel. From an effectiveness standpoint, the change from paclitaxel to docetaxel in our setting is not justified.

Current and future adjuvant immunotherapies for melanoma: Blockade of cytotoxic T-lymphocyte antigen-4 as a novel approach - Corrected Proof

Sanjiv S. Agarwala, Steven J. O’Day — 2010-07-20

Abstract: The current treatment for melanoma with nodal involvement, but without distant metastasis, is surgical excision and lymph node dissection followed by adjuvant therapy. A number of systemic regimens have been evaluated for melanoma patients with a medium or high risk of disease recurrence following surgery. The only agent approved for the adjuvant therapy of melanoma is high-dose interferon (IFN)-α2b, which prolongs relapse-free survival, but its effects on overall survival remain controversial. Its use is also accompanied by significant toxicity. Thus, despite its approval, high-dose IFN-α2b is not always used for the adjuvant therapy of melanoma, particularly in countries other than the United States. Studies aimed at identifying subgroups of patients that have the greatest benefit-to-risk ratio with this regimen are ongoing. Several vaccines have been studied in the adjuvant setting for melanoma, but none has shown superiority to IFN-containing regimens. The GMK ganglioside vaccine, for instance, has actually been shown to be inferior to high-dose IFN-α2b. Therefore, a therapeutic regimen which improves overall survival with a favorable safety profile would be a major advance in the adjuvant therapy of melanoma. One approach that is currently being investigated is the potentiation of antitumour immune responses through blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4). Here, we provide an overview of the current unmet needs in the adjuvant therapy of melanoma and evaluate the potential of CTLA-4 blockade as a future therapeutic option in this setting.

Which factors should be taken into account in perimenopausal women with early breast cancer who may become eligible for an aromatase inhibitor? Recommendations of an expert panel - Corrected Proof

2010-07-01

Summary: Menopausal status is a major consideration in adjuvant breast cancer therapy. The variable onset and duration of the menopausal transition and the poor predictive value of bleeding patterns and hormone levels mean many women fall naturally into a “perimenopausal” category. Women becoming amenorrhoeic during cytotoxic or endocrine treatment are also of uncertain status since ovarian function may resume even in older patients after several months without menses. The recent St. Gallen panel acknowledged that aromatase inhibitors (AIs) should form part of standard endocrine therapy for postmenopausal women with receptor-positive tumours. Among perimenopausal women at sufficiently high risk of recurrence, there may also be a case for adjuvant AIs either up-front or after tamoxifen. Such treatment should be initiated only after careful consideration of the patient’s age, menstrual history and the effects of tamoxifen (which may make hormone levels an unreliable guide to ovarian function). In treatment-naïve women whose postmenopausal status cannot be confirmed by reliable, serial hormone measurements, treatment should start with tamoxifen. Serial monitoring of hormone levels may enable an AI to be started if postmenopausal status is confirmed. In women with treatment-induced amenorrhoea, any decision to start an AI requires baseline hormone levels consistent with postmenopausal status; and continuation of treatment requires that hormone levels remain postmenopausal during regular monitoring.

5-Azacytidine in myelodysplastic syndromes: A clinical practice guideline - Corrected Proof

2010-06-30

Summary: Background: Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoiesis that results in peripheral blood cytopenias and a marked propensity to progress to acute myelogenous leukemia. With 40,000–76,000 new cases per year in the USA, MDS is the commonest of the hematological malignancies and represents a significant burden of morbidity and premature death. Although supportive or palliative measures such as blood transfusion have long been the mainstay of management of MDS, disease-modifying medical therapies have recently become available. The most extensively characterized of these is 5-azacytidine (5-Aza); however, no consensus exists on how this agent should be deployed in MDS.Methods: An overarching search of the literature identified 7019 citations investigating the treatment or management of MDS. Of those, six clinical articles of prospective phase 2–3 study design or meta-analyses were selected for inclusion in a systematic review of the evidence.Conclusions: The Canadian Consortium on Evidence-Based Care in MDS recommends 5-Aza as first line therapy in all MDS patients with IPSS high-intermediate and high risk scores including WHO-defined AML (20–30% blasts) who cannot proceed immediately to allogeneic stem cell transplant.5-Aza is not recommended as first line therapy with MDS patients with IPSS Low and Low-intermediate risk scores as there is no evidence that it alters the natural history of the disease nor is superior to standard therapy.The MDS consortium does not recommend combining 5-Aza with other agents at this time outside the context of a clinical trial.

Second-line chemotherapy for small-Cell Lung Cancer (SCLC) - Corrected Proof

Young Hak Kim, Michiaki Mishima — 2010-06-28

Abstract: Although small-cell lung cancer (SCLC) generally shows an excellent response to initial chemotherapy, most patients finally relapse and salvage chemotherapy is considered. Usually, the response to salvage chemotherapy significantly differs between sensitive and refractory relapse. Sensitive relapse is relatively chemosensitive and re-challenge with the same drugs as used in the initial chemotherapy has been used historically, while refractory relapse is extremely chemo-resistant and its prognosis has been abysmal. To date, a number of clinical trials have been carried out for relapsed SCLC; however, the number of randomized trials is quite limited. At present, topotecan is the only drug approved by the US Food and Drug Administration for relapsed SCLC, and is considered the standard second-line chemotherapy in many countries. More recently, amrubicin has also shown more favorable antitumor activity, and is the most promising at present. Unfortunately, targeted agents have failed to demonstrate effectiveness for SCLC. Better understanding of the molecular mechanisms is clearly needed.

Hairy-cell leukemia variant: Recent view on diagnosis, biology and treatment - Corrected Proof

Tadeusz Robak — 2010-06-17

Abstract: Hairy-cell leukemia variant (HCl-V) is a district clinico-pathological entity with intermediate features between classical HCl (HCl-C) and B-cell prolymphocytic leukemia. HCl-V is now included in the World Health Organization (WHO) classification as a provisional entity. It is an uncommon disorder accounting for approximately 0.4% of chronic lymphoid malignancies and 10% of all HCl cases. In contrast to HCl-C, HCl-V is a more aggressive disease and according to the new WHO classification it is no longer considered to be biologically related to HCl-C. Patients with HCl-V have an elevated white blood count, easy-to-aspirate bone marrow and weak reactivity to tartrate – resistant acid phosphatase (TRAP). Immunophenotypically, HCl-V cells are positive for CD103 and CD11c and negative for CD25. The HCl-V cells express also the B-cell antigens, CD19, CD20 and CD22. The HCl-V patients have frequently an unmutated Ig gene configuration. Currently, the principles of therapy for this rare disease derive from uncontrolled single institutional studies, or even single case reports. In contrast to HCl-C, the HCl-V response to purine nucleoside analogs (PNA) is limited to partial responses in approximately 50% of patients. However, complete responses were observed in patients treated with rituximab and anti-CD22 immunotoxins. In Japan, a distinct subtype of HCl known as HCl-Japanese variant (HCl-JV) has been identified. As with HCl-V, patients with HCl-JV have leukocytosis, weak TRAP activity in leukemic cells, and lack of CD25 antigen. In this review, the biology, diagnostic criteria, and current therapeutic options in HCl-V and HCl-JV are presented.

Anticancer oral therapy: Emerging related issues - Corrected Proof

2010-06-07

Abstract: The use of oral anticancer drugs has shown a steady increase. Most patients prefer anticancer oral therapy to intravenous treatment primarily for the convenience of a home-based therapy, although they require that the efficacy of oral therapy must be equivalent and toxicity not superior than those expected with the intravenous treatment. A better patient compliance, drug tolerability, convenience and possible better efficacy for oral therapy as compared to intravenous emerge as the major reasons to use oral anticancer agents among oncologists. Inter- and intra-individual pharmacokinetic variations in the bioavailability of oral anticancer drugs may be more relevant than for intravenous agents. Compliance is particularly important for oral therapy because it determines the dose-intensity of the treatment and ultimately treatment efficacy and toxicity. Patient stands as the most important determinant of compliance. Possible measures for an active and safe administration of oral therapy include a careful preliminary medical evaluation and selection of patients based on possible barriers to an adequate compliance, pharmacologic issues, patient-focused education, an improvement of the accessibility to healthcare service, as well as the development of home-care nursing symptom-focused interventions. Current evidences show similar quality of life profile between oral and intravenous treatments, although anticancer oral therapy seems to be more convenient in terms of administration and reduced time lost for work or other activities. Regarding cost-effectiveness, current evidences are in favor of oral therapy, mainly due to reduced need of visits and/or day in hospital for the administration of the drug and/or the management of adverse events.

The safety and effectiveness of endoscopic and non-endoscopic approaches to the management of early esophageal cancer: A systematic review - Corrected Proof

Paul McCann, Tania Stafinski, Clarence Wong, Devidas Menon — 2010-06-07

Summary: Introduction: Traditionally, management of early cancer (stages 0–IIA) has comprised esophagectomy, either alone or in combination with chemotherapy and/or radiotherapy. Recent efforts to improve outcomes and minimize side-effects have focussed on minimally invasive, endoscopic treatments that remove lesions while sparing healthy tissue. This review assesses their safety and efficacy/effectiveness relative to traditional, non-endoscopic treatments for early esophageal cancer.Methods: A systematic review of peer-reviewed studies was performed using Cochrane guidelines. Bibliographic databases searched to identify relevant English language studies published in the last 3 years included: PubMed (i.e., MEDLINE and additional sources), EMBASE, CINAHL, The Cochrane Library, the UK Centre for Reviews and Dissemination (NHS EED, DARE and HTA) databases, EconLit and Web of Science. Web sites of professional associations, relevant cancer organizations, clinical practice guidelines, and clinical trials were also searched. Two independent reviewers selected, critically appraised, and extracted information from studies.Results: The review included 75 studies spanning 3124 patients and 10 forms of treatment. Most studies were of short term duration and non-comparative. Adverse events reported across studies of endoscopic techniques were similar and less significant compared to those in the studies of non-endoscopic techniques. Complete response rates were slightly lower for photodynamic therapy (PDT) relative to the other endoscopic techniques, possibly due to differences in patient populations across studies. No studies compared overall or cause-specific survival in patients who received endoscopic treatments vs. those who received non-endoscopic treatments.Discussion: Based on findings from this review, there is no single “best practice” approach to the treatment of early esophageal cancer.

The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by Tumor-Vascular Disrupting Agents - Corrected Proof

Dietmar W. Siemann — 2010-06-07

Abstract: The vasculature of solid tumors is fundamentally different from that of normal vasculature and offers a unique target for anti-cancer therapy. Direct vascular-targeting with Tumor-Vascular Disrupting Agents (Tumor-VDAs) is distinctly different from anti-angiogenic strategies, and offers a complementary approach to standard therapies. Tumor-VDAs therefore have significant potential when combined with chemotherapy, radiotherapy, and angiogenesis-inhibiting agents. Preclinical studies with the different Tumor-VDA classes have demonstrated key tumor-selective anti-vascular and anti-tumor effects.

Gene expression profiling for diagnosis and therapy in acute leukaemia and other haematologic malignancies - Corrected Proof

Ulrike Bacher, Alexander Kohlmann, Torsten Haferlach — 2010-06-07

Abstract: A decade ago, gene expression profiling (GEP) was successfully introduced in haematological research. Considering the heterogeneity of haematological malignancies, the growing arsenal of compounds, allowing targeted therapy, e.g. in myelodysplastic syndromes (MDS) or chronic myeloid leukaemia (CML), and the more differentiated indication to allogeneic stem cell transplantation, routine diagnostic procedures would highly benefit from an introduction of this novel methodology: by now, the majority of genetically defined leukaemia subtypes has been accurately reproduced on the basis of distinct gene expression patterns by various independent research groups. Moreover, classification of histomorphologically overlapping lymphoma subentities (e.g. Burkitt lymphoma and diffuse large B-cell lymphoma, DLBCL), was considerably improved by GEP. Beyond that, differential gene expression has provided the basis for assays being able to predict prognosis of individual patients as well as the response to specific treatment approaches, e.g. to lenalidomide in MDS. In a high proportion of Philadelphia positive acute lymphoblastic leukaemia (ALL) patients, prognostically adverse deletions of the IKZF1 gene coding for a specific transcription factor were identified with GEP analysis, which revealed new insights in the clinical variability of this disorder. Given these advantages of GEP, the introduction of this methodology in current diagnostic algorithms of haematological malignancies should further be validated in clinical studies.

Personalized treatment of early-stage breast cancer: Present concepts and future directions - Corrected Proof

Nadia Harbeck, Marwa Salem, Ulrike Nitz, Oleg Gluz, Cornelia Liedtke — 2010-05-31

Abstract: Breast cancer is the most common malignancy in women. Effective loco-regional as well as systemic treatment options have rendered breast cancer a curable disease for the vast majority of early-stage patients. Considering tumor biology and clinical outcomes, breast cancer is a very heterogeneous disease. With the recent understanding of distinct molecular sub-types, the era of “one size fits all” therapy concepts has passed and a new era of personalized therapy concepts has started. This review will focus on recent advances in personalized treatment of early-stage breast cancer, with a particular interest in tumor biology-guided treatment decisions. It will also highlight how carefully molecular tests need to be methodologically and clinically validated before they can be applied for clinical decision making.

Practical management of tyrosine kinase inhibitor-associated side effects in GIST - Corrected Proof

Heikki Joensuu, Jonathan C. Trent, Peter Reichardt — 2010-05-31

Summary: Patients diagnosed with advanced gastrointestinal stromal tumor (GIST) are currently treated with oral tyrosine kinase inhibitors (TKIs). Imatinib mesylate is the standard first-line treatment, and sunitinib malate is administered second-line for patients who are intolerant or progress on imatinib. Imatinib has recently been approved for adjuvant treatment of GIST patients who have a significant risk for relapse. In both the metastatic and adjuvant settings, patients may be on these TKIs for many years. Low plasma imatinib levels have been reported to be associated with a short median time to progression of advanced GIST, stressing the importance of maintaining optimal drug levels. We summarize management of the most frequent and clinically significant adverse effects of imatinib and sunitinib in the treatment of GIST in the context of current guidelines, published literature, and the experience of three large GIST referral centers. The adverse events reviewed include nausea and vomiting, diarrhea, skin rash, musculoskeletal complaints, fatigue, hemorrhage, edema, hand–foot skin reaction, skin and hair discoloration, mucositis, hypertension, cardiac toxicity, hypothyroidism, liver transaminase changes, and hematological toxicity of imatinib and sunitinib. Potential drug–drug interactions with each respective agent are also discussed. With prudent use of supportive care measures, many side effects can be managed without dose reduction or interruption of treatment. On the other hand, individualized tailoring of the dose is often required to manage severe toxicity, such as painful hand–foot skin reactions, fatigue, hepatotoxicity, or cardiac toxicity. Management of many TKI-related adverse effects require further evaluation in prospective clinical trials.

Cowden syndrome - Corrected Proof

A. Farooq, L.J. Walker, J. Bowling, R.A. Audisio — 2010-05-26

Summary: Cowden syndrome (CS) is a rare inherited condition characterised by multiple hamartomas in a variety of tissues from all three embryonic layers. It is a cancer predisposition syndrome with an increased risk of developing malignancy in many tissues but especially breast, thyroid and endometrium. It is inherited in an autosomal dominant manner with ∼80% of patients having a germ-line mutation of the PTEN tumour suppressor gene. Presenting signs and symptoms are highly non-specific. Nevertheless clinicians should be able to recognise this syndrome so that patients may be screened for cancerous growths and afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. We present a review of this unusual but important condition with particular emphasis on the diagnostic criteria, clinical features, genetics, management and surveillance.

Altered fractionation in radiotherapy: From radiobiological rationale to therapeutic gain - Corrected Proof

Loredana G. Marcu — 2010-05-24

Summary: The implementation of altered fractionation schedules in clinical practice came as a need to improve loco-regional control and survival in those cancer patient groups which did not respond satisfactorily to conventionally fractionated radiotherapy. The current review aims to present the radiobiological rationale behind various non-conventional treatment schedules including the encountered challenges, through a compilation of clinical studies/trials and their contribution towards therapeutic gain.

Metastasis and bone loss: Advancing treatment and prevention - Corrected Proof

2010-05-18

Abstract: Tumor metastasis to the skeleton affects over 400,000 individuals in the United States annually, more than any other site of metastasis, including significant proportions of patients with breast, prostate, lung and other solid tumors. Research on the bone microenvironment and its role in metastasis suggests a complex role in tumor growth. Parallel preclinical and clinical investigations into the role of adjuvant bone-targeted agents in preventing metastasis and avoiding cancer therapy-induced bone loss have recently reported exciting and intriguing results. A multidisciplinary consensus conference convened to review recent progress in basic and clinical research, assess gaps in current knowledge and prioritize recommendations to advance research over the next 5years. The program addressed three topics: advancing understanding of metastasis prevention in the context of bone pathophysiology; developing therapeutic approaches to prevent metastasis and defining strategies to prevent cancer therapy-induced bone loss. Several priorities were identified: (1) further investigate the effects of bone-targeted therapies on tumor and immune cell interactions within the bone microenvironment; (2) utilize and further develop preclinical models to study combination therapies; (3) conduct clinical studies of bone-targeted therapies with radiation and chemotherapy across a range of solid tumors; (4) develop biomarkers to identify patients most likely to benefit from bone-targeted therapies; (5) educate physicians on bone loss and fracture risk; (6) define optimal endpoints and new measures of efficacy for future clinical trials; and (7) define the optimum type, dose and schedule of adjuvant bone-targeted therapy.

Current perspectives of treatment of ductal carcinoma in situ - Corrected Proof

2010-05-12

Summary: DCIS is a genetically diverse group of diseases with different prognosis. The similarities between DCIS and ductal infiltrating carcinoma (DIC) suggest that the key step in tumorigenesis is the transformation from high grade ductal hyperplasia to DCIS. The prognostic factors of DCIS include anatomo-pathologic factors, age and molecular factors. The key questions for DCIS management include: which patients are more likely to present an invasive failure; in which an excision is sufficient and who can be spared from radiation therapy. The role of post operative radiation therapy to reduce by 50–60% ipsilateral invasive and non-invasive local failure has been established in four randomized clinical trials. The question whether radiation therapy can be avoided in some patients remains controversial. Treatment with tamoxifen should be recommended to patients with estrogen receptor positive tumors who have been treated with conservative surgery. However, data from randomized trials suggest that addition of tamoxifen to locoregional treatment decreases the recurrence rate of invasive cancer as well as contralateral tumors. Sentinel lymph node biopsy is recommended for patients with clinically palpable, large DCIS in which the risk of microinvasion is high as well as in extensive DCIS requiring mastectomy. Mammography continues to be the best method to detect DCIS. Newer digital mammography improves the detection of microcalcifications. Current ultrasound can detect associated invasive cancer. MRI is also useful in DCIS. Combined with mammography, MRI increases the diagnoses of DCIS. Current trend includes the use of radiology guided-vacuum assisted-large bore needles that allow obtaining larger amounts of tissue, improving diagnostic yield.

Timing of first-line cancer treatments – Early versus late – A systematic review of phase III randomized trials - Corrected Proof

A.R. Mhaskar, G. Quinn, S. Vadaparampil, B. Djulbegovic, C.K. Gwede, A. Kumar — 2010-05-05

Summary: Purpose: To conduct a systematic review and meta-analysis of all phase III randomized controlled trials comparing efficacy of early versus late first-line or initial treatments for cancer.Methods: A comprehensive literature search of MEDLINE and Cochrane library databases was performed (1966–2008). Data was extracted and pooled as per the methods recommended by the Cochrane Collaboration.Results: Of the 570 identified studies, 10 (3811 patients) met inclusion criteria: three each in prostate cancer and multiple myeloma (MM), two in chronic lymphocytic leukemia (CLL), and one each in lung cancer, and follicular lymphoma. The analyses showed no survival benefit with early treatment except in prostate cancer (hazard ratio [HR]=1.23, 95% CI 1.11–1.37 p<0.001). There was no survival difference in MM (HR=0.92, 95% CI 0.56–1.52 p=0.74), CLL (HR=0.76, 95% CI 0.56–1.04 p=0.09), lung cancer (HR=0.95, 95% CI 0.72–1.24 p=0.71), or follicular lymphoma (HR=1, 95% CI 0.55–1.83 p=0.99). No statistically significant difference in response rate between early and late treatment was detected in any cancer type.Conclusions: Data shows that delaying cancer treatments does not necessarily compromise therapeutic outcomes except possibly in locally advanced prostate cancer. These findings provide a unique window to oncologists and patients to address time-sensitive issues if desired by patients.

Unravelling the biology of human papillomavirus (HPV) related tumours to enhance their radiosensitivity - Corrected Proof

Marie-Catherine Vozenin, Hannah-Kate Lord, Dana Hartl, Eric Deutsch — 2010-04-23

Summary: HPV infection is associated with most squamous cell carcinomas (SCC) of the uterine cervix and many head and neck SCC. While recent understanding of the mechanisms of HPV-induced carcinogenesis has lead to the development of prophylactic vaccines, the principal modality of treatment is radiotherapy and despite concurrent chemotherapy, outcomes remain suboptimal. Improving the radiotherapeutic index thus remains an important challenge as well as defining predictive assays for treatment outcome of HPV-related tumours. Therefore elucidating the influence of the HPV virus on tumour radiosensitivity is of major interest due to the prevalence of HPV-related tumours worldwide and due to evidence that head and neck HPV-tumours have markedly different clinical outcomes compared to non-HPV-related tumours. This difference may allow for different treatment strategies to be developed. The present review aims to summarize the current understanding of radiosensitivity and HPV-related tumour biology in order to subsequently develop new approaches to enhance the therapeutic index. This review also emphasizes the relevance of E6 and E7 oncoproteins to tumour cell response to radiotherapy suggesting that specific targeted approaches such as concomitant modulation of additional pathways using targeted therapies should offer new therapeutic avenues.

DNA mismatch repair and the DNA damage response to ionizing radiation: Making sense of apparently conflicting data - Corrected Proof

2010-04-22

Summary: The DNA mismatch repair (MMR) pathway detects and repairs DNA replication errors. While DNA MMR-proficiency is known to play a key role in the sensitivity to a number of DNA damaging agents, its role in the cytotoxicity of ionizing radiation (IR) is less well characterized. Available literature to date is conflicting regarding the influence of MMR status on radiosensitivity, and this has arisen as a subject of controversy in the field. The aim of this paper is to provide the first comprehensive overview of the experimental data linking MMR proteins and the DNA damage response to IR. A PubMed search was conducted using the key words “DNA mismatch repair” and “ionizing radiation”. Relevant articles and their references were reviewed for their association between DNA MMR and IR. Recent data suggest that radiation dose and the type of DNA damage induced may dictate the involvement of the MMR system in the cellular response to IR. In particular, the literature supports a role for the MMR system in DNA damage recognition, cell cycle arrest, DNA repair and apoptosis. In this review we discuss our current understanding of the impact of MMR status on the cellular response to radiation in mammalian cells gained from past and present studies and attempt to provide an explanation for how MMR may determine the response to radiation.

Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers - Corrected Proof

2010-04-21

Summary: Approximately two million fractions of radiotherapy are administered in the UK every year, as part of adjuvant, radical or palliative cancer treatment. For many tumour types, radiotherapy is routinely combined with concomitant chemotherapy as part of adjuvant or radical treatment. In addition, new agents have been developed in recent years and tested in phase 1, 2 and 3 trials concomitantly with radiotherapy or chemoradiotherapy. One such class of drugs, the poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in conjunction with radiotherapy in several cancer cell lines. Pre-clinical data suggest that PARP inhibitors may potentiate the effects of radiotherapy in several tumour types, namely lung, colorectal, head and neck, glioma, cervix and prostate cancers. In vitro, PARP inhibitors are radiosensitisers in various cell lines with enhancement ratios of up to 1.7. In vivo, non-toxic doses of PARP inhibitors have been shown to increase radiation-induced growth delay of xenograft tumours in mice. Clinical trials to assess the toxicity and potential benefit of combining radiotherapy with PARP inhibition are now needed.

Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited - Corrected Proof

Abhinav Deol, Lawrence G. Lum — 2010-04-12

Summary: Background: Treatment of relapsed hematological malignancies after an allogeneic peripheral blood stem cell transplant (SCT) is challenging. Donor lymphocyte infusion (DLI) from the stem cell donor is an attractive clinical option to salvage this group of patients.Methods: We reviewed the important studies looking at donor lymphocyte infusion as a therapy for the treatment of hematological disorders that are either refractory to or have relapsed after allogeneic SCT.Results: The response to DLI is dependent upon type of disease, dose of infused lymphocytes, and the development of graft vs. host disease (GvHD). The best response rates are seen in patients with chronic myeloid leukemia (CML) followed by patients with lymphomas, multiple myeloma and acute leukemias, respectively. The responses in patients with CML are durable whereas durable responses in other diseases are rare.Conclusions: Given the development of new drugs to treat some hematological diseases, DLI has taken a backseat. New modalities to target the infused cells to the tumor and new approaches to reduce GvHD that will augment the graft vs. leukemia/lymphoma (GvL) effect and decrease the injury to normal host tissues need to be developed. Understanding the factors and mechanisms that differentiate the GvL effect from GvHD will help in the development of newer treatment modalities.

Targeting DNA repair in breast cancer: A clinical and translational update - Corrected Proof

Eitan Amir, Bostjan Seruga, Rosario Serrano, Alberto Ocana — 2010-04-12

Summary: DNA-repair mechanisms play an important role in the maintenance of DNA integrity and protection against DNA damage. Deregulation of these mechanisms is associated with the development of cancer as is seen in breast tumours with mutations in genes like BRCA1 and BRCA2. Recent biologic findings suggest that in tumours in which one DNA repair pathway is deficient, concomitant inhibition of other repair pathways could have potential synergistic activity. Pharmacological inhibition of Poly (ADP-ribose) polymerase (PARP), a key element of the base excision repair pathway, can have synthetic lethality in tumours with deficient homologous recombination. These findings have paved the way for the clinical development of PARP inhibitors in breast tumours especially in patients with germline mutations in the BRCA1 and/or BRCA2, a population known to have deficient homologous recombination. Patients with sporadic breast cancer, especially those with a basal-like profile may also develop cancer which is deficient in DNA repair and may be susceptible to PARP inhibition. In this review we will update the clinical and biological data underlying the development of drugs targeting DNA repair with a focus on breast cancer.

Molecular predictive and prognostic markers in colon cancer - Corrected Proof

Thomas Winder, Heinz-Josef Lenz — 2010-04-05

Summary: Colorectal cancer remains one of the major cancer related death despite progress in the cytotoxic treatment of colorectal cancer (CRC) over the past decade. The introduction of targeted agents has improved the progression free and overall survival of metastatic disease. However, 40–50% of patients do not experience beneficial effects and it remains a challenge to select patients likely to respond to therapy. Several new molecular predictive and prognostic markers have been identified and are now being translated into routine clinical practice. K-Ras mutation is the first established molecular marker with a lack of response in K-Ras mutated patients treated with an epidermal growth factor receptor (EGFR)-targeted therapy. The validation of predictive and prognostic markers will result in more successful and less toxic therapeutic regimens for cancer patients. This review aims to summarize the most important currently available predictive and prognostic molecular markers in colorectal cancer.

Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM×anti-CD3) as a targeted cancer immunotherapy - Corrected Proof

Diane Seimetz, Horst Lindhofer, Carsten Bokemeyer — 2010-03-29

Summary: Catumaxomab is a trifunctional antibody (trAb) characterized by its unique ability to bind three different cell types: tumor cells, T-cells, and accessory cells. It has two different antigen-binding specificities: one for epithelial cell adhesion molecule (EpCAM) on tumor cells and one for the CD3 antigen on T-cells. Catumaxomab also binds to type I, IIa, and III Fcγ receptors (FcγR) on accessory cells, e.g. macrophages, dendritic cells, and natural killer cells, via its intact Fc region. Its anti-tumor activity results from T-cell-mediated lysis, antibody-dependent cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory cells. Importantly, no additional activation of immune cells is necessary for effective tumor eradication by catumaxomab, which represents a self-supporting system. Catumaxomab’s efficacy and safety have been demonstrated in a pivotal phase II/III study and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions on days 0, 3, 7, and 10 at doses of 10, 20, 50, and 150μg, respectively. Catumaxomab has been approved in the European Union since April 2009 for the i.p. treatment of malignant ascites (MA) in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible. Catumaxomab is the first trAb and the first drug worldwide to be approved specifically for the treatment of MA. It is in clinical trials in a number of other indications including ovarian and gastric cancer. Alternative routes of administration are also under evaluation to further exploit the therapeutic potential of catumaxomab in EpCAM-positive carcinomas.

Can chemotherapy concomitantly delivered with radiotherapy improve survival of patients with resectable rectal cancer? A meta-analysis of literature data - Corrected Proof

2010-03-24

Summary: Background: There is clear evidence from two systematic reviews that radiotherapy (RT) reduces the risk of local recurrence in patients with resectable rectal cancer, though the data on survival are still equivocal.Objective: To assess the effects of chemotherapy combined concomitantly with radiotherapy (CRT) on the increase of overall survival, and on the prevention of local recurrence and distant metastases.Data sources: Computerized bibliographic searches of MEDLINE and CANCERLIT (1970–2008) were supplemented with hand searches of reference lists.Study selection: Studies were included if they were randomized controlled trials (RCTs) comparing preoperative or postoperative CRT to preoperative or postoperative RT alone, and if they included patients with resectable, histologically-proven, rectal adenocarcinoma without metastases. Thirteen RCTs, seven of preoperative CRT vs. preoperative RT (2787 patients), four of postoperative CRT vs. postoperative RT (726 patients) and two of postoperative CRT vs. preoperative RT (1400 patients), were analyzed.Data extraction: Data on population, intervention, and outcomes were extracted from each RCT, in accordance with the intention-to-treat method, by three independent observers, and combined using the DerSimonian method and Laird method.Results: Preoperative CRT compared to preoperative RT alone significantly reduces the 5-year local recurrence rate (RR 1.05; 95%CI 1.01–1.10). No increase was observed in 5-year overall survival rate (RR 0.94; 95%CI 0.94–1.09), and in the occurrence of distant metastases (RR 0.97; 95%CI 0.93–1.02). Instead, postoperative CRT did not reduce local recurrence (RR 0.96; 95%CI 0.80–1.16), distant metastases (RR 1.11; 95%CI 0.94–1.31) and overall mortality (RR 1.09; 95%CI 0.83–1.41). By pooling data on postoperative CRT vs. preoperative RT a significant reduction of local recurrence was found for the preoperative approach (RR 0.93; 95%CI 0.90–0.96), though no difference was found in distant metastases rates and overall survival. Finally, the risk of mortality related to toxic events was significantly higher when adding chemotherapy to radiotherapy (RR 2.86; 95%CI 0.99–8.26).Conclusions: In patients with resectable rectal cancer, CRT does not increase overall survival, despite the fact that preoperative CRT significantly reduces the risk of the local recurrence. No reduction in the distant metastases rate was found. Toxicity-related mortality is significantly increased by the concomitant approach, emphasizing the need for safer treatment combinations.

Timing of adjuvant systemic therapy and radiotherapy after breast-conserving surgery and mastectomy - Corrected Proof

2010-03-22

Abstract: In the last two decades, systemic adjuvant treatment for breast cancer, in association with radiotherapy, has been shown to prolong disease-free survival and overall survival in patients with operable breast tumors. So far, the optimal sequence of systemic therapy and radiotherapy for breast cancer patients after conservative surgery or mastectomy is unclear. Several retrospective analyses showed a possible detrimental effect on local regional recurrence rates when radiation therapy is delayed after chemotherapy. On the other hand, delaying chemotherapy after radiotherapy may increase the risk of distant failure and affect the survival. Concurrent administration of targeted treatment (e.g. non-anthracycline/taxane containing chemotherapy, trastuzumab, endocrine therapy) with radiotherapy is considered a valid option. A “tailored” approach on sequencing of chemotherapy and radiotherapy which takes into account various variables, such as histological and biological features of the tumor, as well as the patient status and the treatment modality is required in order to optimize the delivery of adjuvant treatments. This review focuses on the effects of timing of chemotherapy–radiotherapy and risks of relapse, in terms of locoregional and distant recurrence in patients with operable breast cancer.

The cost-effectiveness of particle therapy in non-small cell lung cancer: Exploring decision uncertainty and areas for future research - Corrected Proof

2010-03-19

Summary: Purpose: To review and synthesize all available evidence in order to explore the cost-effectiveness of particle therapy (carbon-ions, protons) compared to the best current treatments for non-small-cell lung cancer (NSCLC), and the value of additional research. The present study focuses on stage I NSCLC, as no data is available for more advanced stages.Methods: A probabilistic decision-analytic Markov model was constructed to synthesize all available evidence. Comparative treatments were carbon-ions, protons, conventional radiotherapy (CRT) and stereotactic radiotherapy (SBRT) for inoperable stage I NSCLC; and carbon-ions and SBRT for operable stage I NSCLC. The expected value of perfect information (EVPI) was calculated to support research decisions.Results: For inoperable stage I NSCLC, carbon-ion therapy costed €67.257 per quality-adjusted-life-year gained compared to SBRT. Both treatments dominated protons and CRT. Considerable uncertainty surrounded these results, resulting in a high EVPI. For operable stage I NSCLC SBRT dominated carbon-ion therapy.Conclusions: Due to the considerable uncertainty in stage I NSCLC, and the lack of data on more advanced stages, it is recommended not to adopt particle therapy as standard treatment in NSCLC yet. More evidence is needed to reduce the decision uncertainty and to support evidence-based treatment decisions. It might be worthwhile to invest in a particle facility for clinical research. Future research should also weigh the investment risk, value of information and costs of delay.

Gene-expression profiles, tumor microenvironment, and cancer stem cells in breast cancer: Latest advances towards an integrated approach - Corrected Proof

2010-03-18

Summary: During the past decade, several high throughput analytical methods for gene-expression profiling have been developed. DNA microarrays and multiplex RT-PCR have been applied in the field of breast-cancer research to establish new molecular taxonomic classifications, or a selected group of genes able to predict the prognosis of the patients and/or their response to chemotherapy. This technology provides an opportunity to refine the anti-neoplastic treatment and avoid the currently observed under- and over-treatment of breast-cancer patients. In parallel, high throughput technologies for gene-expression analysis have been applied to research on cancer stem cells (CSCs) and the tumor microenvironment, offering a wider vision of the molecular processes that influence carcinogenic events, disease development, and the response to the treatment of breast-cancer patients. In this report, we briefly revisit the most relevant genomic studies on breast-cancer prognosis and prediction to introduce the latest advances in tumor dormancy, its implications in the clinical outcome of disease-free patients and its connection with CSCs biology and microenvironment influence in the metastatic process. Finally, we have discussed the contribution of the results of these studies to the design of new experimental strategies oriented towards personalized medicine.

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

2010-03-15

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

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

John Araujo, Christopher Logothetis — 2010-03-12

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

Male breast cancer - Corrected Proof

2010-03-02

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

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

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

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