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We are witnessing a silent revolution in the treatment of early stage non-small cell lung cancer (NSCLC), with a series of practice-changing clinical trials enriching the therapeutic perspectives of lung cancer patients with potentially curable disease. The ADAURA study marked the advent of precision medicine and biomarker testing to the early stages setting. The IMPower-010 trial interrupted the negative trend of adjuvant lung cancer immunotherapy, paving the way to the application of immune-checkpoint inhibition in the resected disease. The ITACA trial definitively established no role for tailored adjuvant chemotherapy in NSCLC, while the Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease. Growing evidence is supporting MRD as effective adjuvant prognostic biomarker to stratify disease's recurrence risk after radical interventions and select best candidates to the adjuvant strategies. This work summarizes the recent major breakthroughs in lung cancer adjuvant treatment, and provides a snapshot of the current real-world scenario, discussing the upcoming challenges and opportunities featuring the clinical management of early stage NSCLC patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multifunctional nature of phytochemicals and their chemical diversity has attracted attention to develop leads originated from nature to fight COVID-19. Pharmacological activities of chelerythrine and its congeners have been studied and reported in the literature. This compound simultaneously has two key therapeutic effects for the treatment of COVID-19, antiviral and anti-inflammatory activities. Chelerythrine can prevent hyper-inflammatory immune response through regulating critical signaling pathways involved in SARS-CoV-2 infection, such as alteration in Nrf2, NF-κB, and p38 MAPK activities. In addition, chelerythrine has a strong protein kinase C-α/-β inhibitory activity suitable for cerebral vasospasm prevention and eryptosis reduction, as well as beneficial effects in suppressing pulmonary inflammation and fibrosis. In terms of antiviral activity, chelerythrine can fight with SARS-CoV-2 through various mechanisms, such as direct-acting mechanism, viral RNA-intercalation, and regulation of host-based antiviral targets. Although chelerythrine is toxic in vitro, the in vivo toxicity is significantly reduced due to its structural conversion to alkanolamine. Its multifunctional action makes chelerythrine a prominent compound for the treatment of COVID-19. Considering precautions related to the toxicity at higher doses, it is expected that this compound is useful in combination with proper antivirals to reduce the severity of COVID-19 symptoms.

Purpose: Previous studies have noted increased utilization of perioperative chemotherapy over time. The goal of this study was to determine trends in perioperative chemotherapy use within a contemporary population., Materials and Methods: The National Cancer Database was queried for patients diagnosed with cT2-4N0M0 urothelial muscle invasive bladder cancer from 2011 to 2015 and underwent subsequent radical cystectomy. We retrospectively analyzed factors associated with perioperative chemotherapy and evaluated overall treatment trends in the use of neoadjuvant and adjuvant chemotherapy. Linear regression, logistic regression, Cox regression, and Kaplan-Meier analysis were performed., Results: In total, 7,101 patients met inclusion criteria for analysis. The use of perioperative chemotherapy increased from 46.4% in 2011 to 57.2% in 2015 (p=0.003). Neoadjuvant chemotherapy use increased from 22.9% to 32.3% (p=0.007) over the time period analyzed, while adjuvant chemotherapy use experienced no significant change (23.5% to 24.9%, p=0.182). Logistic regression demonstrated that increased age and Charlson Comorbidity Index were predictors of not receiving chemotherapy (p<0.05), while those with increasing T stage, income above $48,000, and insurance other than Medicaid or Medicare were more likely to receive perioperative chemotherapy (p<0.05). Kaplan-Meier analysis revealed patients receiving neoadjuvant chemotherapy had the best 5-year overall survival at 48.3% compared to adjuvant chemotherapy (42.6%) or no chemotherapy (37.8%) (p<0.001)., Conclusions: The increasing use of perioperative chemotherapy noted in prior studies has continued through 2015. Neoadjuvant chemotherapy appears to drive this increase while adjuvant chemotherapy utilization remains unchanged. Clinical and socioeconomic factors affect utilization of perioperative chemotherapy., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2020.)

Five-year survival rates for patients with early-stage non-small cell lung cancer have room for improvement. Adjuvant chemotherapy results in a small but significant increase in overall survival at 5 years. Efforts to improve outcomes by intensifying adjuvant treatment, utilizing cancer-specific vaccines or tyrosine kinase inhibitors in unselected patients, have been unsuccessful. In addition to research with immune checkpoint inhibitors that are addressed in a separate article, ongoing studies to personalize adjuvant therapy either by selecting only patients with evidence of minimal residual disease or targeting tumor driver mutations are promising., Competing Interests: Disclosure Dr H.A. Wakelee: honoraria from Novartis and AstraZeneca; advisory board participation (compensated): AstraZeneca and Xcovery; advisory board (NOT compensated): Merck, Takeda, and Genentech/Roche; research funding to institution: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bayer, BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Xcovery; and travel: AstraZeneca. Dr J.A. Hellyer has no relevant conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In the randomized controlled trial (RCT) EORTC 62931, adjuvant chemotherapy failed to show improvement in relapse-free survival (RFS) or overall survival (OS) for patients with resected high-grade soft tissue sarcoma (STS). We evaluated whether the negative results of this 2012 RCT have influenced multidisciplinary treatment patterns for patients with high-grade STS undergoing resection at seven academic referral centers., Methods: The U.S. Sarcoma Collaborative database was queried to identify patients who underwent curative-intent resection of primary high-grade truncal or extremity STS from 2000 to 2016. Patients with recurrent tumors, metastatic disease, and those receiving neoadjuvant chemotherapy were excluded. Patients were divided by treatment era into early (2000-2011, pre-European Organisation for Research and Treatment of Cancer [EORTC] trial) and late (2012-2016, post-EORTC trial) cohorts for analysis. Rates of adjuvant chemotherapy and clinicopathologic variables were compared between the two cohorts. Univariate and multivariate regression analyses were used to determine factors associated with OS and RFS., Results: 949 patients who met inclusion criteria were identified, with 730 patients in the early cohort and 219 in the late cohort. Adjuvant chemotherapy rates were similar between the early and late cohorts (15.6% versus 14.6%; P = 0.73). Patients within the early and late cohorts demonstrated similar median OS (128 months versus median not reached, P = 0.84) and RFS (107 months versus median not reached, P = 0.94). Receipt of adjuvant chemotherapy was associated with larger tumor size (13.6 versus 8.9 cm, P < 0.001), younger age (53.3 versus 63.7 years, P < 0.001), and receipt of adjuvant radiation (P < 0.001). On multivariate regression analysis, risk factors associated with decreased OS were increasing American Society of Anesthesiologists class (P = 0.02), increasing tumor size (P < 0.001), and margin-positive resection (P = 0.01). Adjuvant chemotherapy was not associated with OS (P = 0.88). Risk factors associated with decreased RFS included increasing tumor size (P < 0.001) and margin-positive resection (P = 0.03); adjuvant chemotherapy was not associated with RFS (P = 0.23)., Conclusions: Rates of adjuvant chemotherapy for resected high-grade truncal or extremity STS have not decreased over time within the U.S. Sarcoma Collaborative, despite RCT data suggesting a lack of efficacy. In this retrospective multi-institutional analysis, adjuvant chemotherapy was not associated with RFS or OS on multivariate analysis, consistent with the results from EORTC 62931. Rates of adjuvant chemotherapy for high-grade STS were low in both cohorts but may be influenced more by selection bias based on clinicopathologic variables such as tumor size, margin status, and patient age than by prospective, randomized data., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The standard treatment for locally advanced gastric cancer differs across the world. In western countries, perioperative chemotherapy or postoperative adjuvant chemoradiotherapy are the preferred treatment options, whereas in Asia, D2 gastrectomy followed by postoperative adjuvant chemotherapy is standard. In Japan, adjuvant chemotherapy with S-1 is the standard treatment for pStage II gastric cancer, whereas adjuvant chemotherapy with a doublet regimen is preferred for pStage III gastric cancer. The efficacy of preoperative neoadjuvant chemotherapy using S-1 plus cisplatin, has been investigated in selected patients with expected poor survival outcomes. To expand the indications for neoadjuvant chemotherapy, a clinical trial investigating the efficacy of preoperative S-1 plus oxaliplatin in patients with cStage III (cT3-4N1-3) gastric cancer (JCOG1509) is ongoing in Japan. The addition of immune checkpoint inhibitors to cytotoxic chemotherapy also seems promising and is being investigated in international randomized clinical trials. Although we have to await the final results of these studies, preoperative neoadjuvant chemotherapy is a promising treatment strategy and likely to become standard treatment for locally advanced gastric cancer in Japan.

Numerous rheumatologic autoimmune diseases, among which rheumatoid arthritis, are chronic inflammatory diseases capable of inducing multiple cumulative articular and extra-articular damage, if not properly treated. Nevertheless, benign conditions may, similarly, exhibit arthritis as their major clinical finding, but with short-term duration instead, and evolve to spontaneous resolution in a few days to weeks, without permanent articular damage. Such distinction- self-limited arthritis with no need of immunosuppressive treatment or chronic arthritis at early stages? -represents one of the greatest challenges in clinical practice, once many metabolic, endocrine, neoplastic, granulomatous, infectious diseases and other autoimmune conditions may mimic rheumatoid arthritis. Indeed, the diagnosis of rheumatoid arthritis at early stages is a crucial step to a more effective mitigation of the disease-related damage. As a prototype of chronic inflammatory autoimmune disease, rheumatoid arthritis has been linked to oxidative stress, a condition in which the pool of reactive oxygen species increases over time, either by their augmented production, the reduction in antioxidant defenses, or the combination of both, ultimately implying compromise in the redox signaling. The exact mechanisms through which oxidative stress may contribute to the initiation and perpetuation of local (in the articular milieu) and systemic inflammation in rheumatoid arthritis, particularly at early stages, still remain to be determined. Furthermore, the role of antioxidants as therapeutic adjuvants in the control of disease activity seems to be overlooked, as a little number of short studies addressing this issue is currently found. Thus, the present review focuses on the binomial rheumatoid arthritis-oxidative stress , bringing insights into their pathophysiological relationships, as well as the implications of potential diagnostic oxidative stress biomarkers and therapeutic interventions directed to the oxidative status in patients with rheumatoid arthritis., Competing Interests: The authors declare that no conflicts of interest exist., (Copyright © 2019 Lucas José Sá da Fonseca et al.)

Background: Many new antitumor drugs to treat soft tissue sarcoma (STS) were approved in the 2010's, and the need for the management of STS patients by medical oncologists has been increasing. Clinical data about the patterns of treatment of STS patients by medical oncologists in Japan are lacking., Methods: We retrospectively reviewed the clinical records of STS patients who consulted the Department of Medical Oncology at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research between August 2012 and March 2017. The STS patients who received any systemic chemotherapy at the Department of Medical Oncology were enrolled in the analyses. We evaluated the details of the systemic chemotherapies used: treatment regimens, drugs, and treatment settings. We focused on the treatment lines and the prognoses of salvage chemotherapy administered for recurrent and/or metastatic STS patients., Results: Among the 273 patients who consulted the Department of Medical Oncology, 185 patients (68%) received some systemic chemotherapy; 20 patients received chemotherapy as definitive and/or in a perioperative setting, and 171 patients in a salvage setting. The median overall survival of the 171 recurrent and/or metastatic STS patients who received salvage chemotherapy was 14.1 months (95%CI: 10.4-17.8), and the median number of salvage chemotherapy treatment lines throughout their follow-up periods was two lines (range 1-9)., Conclusion: About two-thirds of the STS patients who consulted a medical oncologist underwent chemotherapy. In the recurrent and/or metastatic settings, newly approved drugs such as pazopanib were frequently used, and the prognoses of the STS patients treated by medical oncologists were similar to those reported in recent global clinical trials. For the better management of patients with STS, medical oncologists should contribute to the management as multidisciplinary team members., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Locally advanced muscle-invasive bladder cancer (MIBC) patients who are candidates for radical cystectomy (RC) should receive perioperative chemotherapy (CHT). However, the adherence to CHT guidelines is low. Thus, we tested contemporary CHT use rates and associated cancer-specific mortality (CSM) and overall mortality (OM) rates., Materials and Methods: Within the SEER database (2004-2015), we identified pT3N0/+ MIBC patients, who underwent RC, with or without perioperative CHT. Estimated annual percentage changes (EAPCs) analyses were used. After inverse probability of treatment weighting (IPTW), Kaplan-Meier (KM) analyses and Cox regression models (CRMs) tested the association of CHT on survival in the overall population (n = 3817), as well as after stratification according to stage, gender and age. Landmark analyses tested for immortal time bias., Results: Overall, 44.3% of patients received CHT. Between 2004 and 2015, CHT administration rates increased from 32.1% to 55.6% (EAPC: +6.0%; p < 0.001). In CRMs, CHT was associated with lower CSM (HR 0.73, CI 0.65-0.81) and OM (HR 0.69, CI 0.62-0.76). In sensitivity analyses, CHT was also associated with lower CSM and OM in N0 patients (CSM: HR 0.76, 95% CI 0.65-0.88; OM: HR 0.69, 95% CI 0.60-0.79) and in N+ patients (CSM: HR 0.69, 95% CI 0.59-0.80; OM: HR 0.67, 95% CI 0.58-0.77), as well as according to gender and age. Landmark analyses confirmed the above results., Conclusions: Perioperative CHT was associated with better survival and its rate of use increased in locally-advanced MIBC RC patients. The latter confirm one large observational study and several small prospective studies., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM., Methods: Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS., Results: Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16; P  = 0·318). For the subgroup of 165 patients who received adjuvant FOLFOX successfully (for at least 3 months), the adjusted effect of neoadjuvant chemotherapy was not significant (HR 1·19, 0·74 to 1·90; P  = 0·476). No significant effect of neoadjuvant chemotherapy was observed in multivariable regression analysis., Conclusion: Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Purpose of Review: This article will provide an opinion on adjuvant treatment of stage I-III endometrial cancer based on existing and evolving evidence., Recent Findings: For early-stage (I and II) intermediate risk endometrial cancer, vaginal brachytherapy reduces the risk of locoregional relapse. Recent studies have investigated the use of chemotherapy in early stage, high-risk patient population, but did not demonstrate a survival benefit. As such, chemotherapy is only recommended for selected patients at high risk for distant recurrence. On the other hand, for stage III disease, chemotherapy has a well established role. A landmark trial recently reported confirmed that chemoradiation improves recurrence-free survival compared with radiation alone in stage III endometrial cancer. However, in another randomized phase III trial, chemoradiotherapy was not superior to chemotherapy alone in this group, raising questions as to whether addition of radiation is necessary. Therefore, improved risk stratification using molecular markers in addition to traditional pathological criteria is critically needed to better predict the risk of local and systemic recurrence and to assist therapy decision-making., Summary: Endometrial cancer care is evolving and recent pivotal trials highlight the significance of chemotherapy to the treatment of stage III endometrial cancer and not to the approach for stage I and II cancer. The role of radiation therapy for stage III disease is raised into question.

Drug development in oncology usually establishes efficacy in metastatic disease before advancing a therapy to the adjuvant or neoadjuvant settings. Unfortunately, too often use in adjuvant or neoadjuvant settings fails to improve overall survival. Reasons for the modest benefits include the fact that in many cases surgery cures a majority of patients making it difficult to demonstrate gains. We begin by looking at the history of adjuvant and neoadjuvant therapies and the principles guiding their development. We summarize accepted adjuvant and neoadjuvant therapies in several cancers and tabulate their outcomes. Then, extending our work on the growth and regression rate constants of tumors and the fraction of cells killed we demonstrate that therapies developed in the metastatic setting primarily delay tumor growth rather than kill more cells and argue this is a likely explanation for poor outcomes in adjuvant or neoadjuvant settings. We suggest a rational approach for enhancing success., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Multiple ongoing randomized studies are assessing the impact of omission of chemotherapy (CT) in low-risk node-positive Luminal A breast. The goal of this investigation was to evaluate trends and practice patterns of adjuvant CT use in Luminal A pT1-3N1 breast cancer, along with determining the clinical benefit from adjuvant CT in this patient population., Methods: The National Cancer Data Base was queried (2004-2014) for women with pT1-3N1 luminal A invasive ductal carcinoma receiving adjuvant hormonal therapy (HT). Multivariable logistic regression ascertained factors associated with adjuvant CT administration. Kaplan-Meier analysis evaluated overall survival (OS) between patients treated with CT/HT vs. HT alone, while sub-stratifying patients by age., Results: Of 8548 total patients, 5182 (61%) received CT/HT, while 3366 (39%) received HT alone. A steady rise in omission of adjuvant CT was observed, from 14% (2004-2005) to 41% (2012-2014). A decision not to use CT was more likely in more recent time periods, in older patients, at academic centers, following lumpectomy, and with lower T classification (p < 0.05 for all). CT was associated with higher OS in all patients (p < 0.001) and women ≤50 years old (p = 0.030), but not for ages 51-60 (p = 0.116), 61-70 (p = 0.222), or >70 (p = 0.239)., Conclusions: Using CT for Luminal A N1 breast cancer is decreasing over time, primarily in older patients and at academic centers. Although CT is still associated with an OS advantage in all patients, subgroup analysis demonstrated no OS benefit in women >50 years of age. These results have implications on the ongoing randomized trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Globally, racial and ethnic disparities exist in treatments and outcomes for cancer patients. In Australia, there are few published data related to cancer patients from culturally and linguistically diverse (CALD) backgrounds., Aim: To explore disparities in adjuvant chemotherapy utilisation in cancer patients from CALD groups., Methods: Retrospective analysis of patients who were recommended adjuvant chemotherapy for early stage breast cancer or early stage colorectal cancer between July 2011 and October 2014 was performed. Rates of adjuvant chemotherapy uptake were analysed between those who identified English as their first-preferred language, versus those who did not, as well as between patients who were born in a country where English is the main language (non-CALD), versus those born in a country where English is not the main language (CALD)., Results: Two hundred and eleven patients were identified. One hundred and forty-three (67.7%) patients had early stage breast cancer and 68 (32.2%) patients had early stage colorectal cancer. No difference was detected in the acceptance of adjuvant chemotherapy between non-CALD (80.9%) and CALD patients (81.3%, P = 0.984) or between patients who identified English as their first-preferred language (80.8%) and those who did not (81.8%, P = 0.870). There was no difference in the rate of chemotherapy completion, with 75.6% completion in the non-English-speaking group and 81.1% in the English-speaking group (P = 0.426)., Conclusion: No difference was observed in adjuvant chemotherapy utilisation in patients who identified English as their first-preferred language compared to those who did not, as well as between non-CALD and CALD groups. This is the first study to assess these differences in Australia., (© 2017 Royal Australasian College of Physicians.)

Opinion Statement: High-risk localized renal cell carcinoma represents a therapeutic challenge with high recurrence rates and poor survival with nephrectomy alone. Multiple agents targeting angiogenic and immunologic pathways have demonstrated remarkable efficacy in the metastatic setting but have failed to replicate similar successes in localized disease. Study results with adjuvant anti-angiogenic therapies may have been compromised by the high incidence of treatment discontinuations or dosage reductions secondary to intolerable side effects. Improving patient selection could play a major role in improving outcomes. Multiple models exist to predict survival but require improved accuracy in identifying recurrence to justify exposing patients to therapies that could significantly impair quality of life. Further understanding of pathological and molecular mechanisms of recurrence is required. Novel tools like gene recurrence scores are emerging to improve prognostication for patient selection. Immunotherapeutic approaches using check point inhibition have the potential to achieve sustained remissions with a significantly improved toxicity profile. Amplifying the immune response with a combination of neoadjuvant and adjuvant therapy to exploit the larger antigenic burden prior to nephrectomy has the biologic potential for making significant improvements in efficacy.

Background: Guidelines support the use of neoadjuvant (NAC) and adjuvant (AC) chemotherapy in muscle-invasive bladder cancer. However, data from North America reported the underutilization of NAC in favor of AC despite the lower level of scientific evidence supporting AC. We aimed to assess current practice patterns of NAC and AC in -Germany., Methods: A 15-question online survey was developed and sent via email newsletters to members of the -German Association of Urology and of the German Society of Residents in Urology in October 2016 to analyze current practice patterns., Results: The survey yielded 141 individual responses from 61 different German urology departments. Eighty-nine (69.0%) and 119 (93.0%) participants were stated to regularly use NAC and AC respectively. The number of participants who were stated to use NAC and AC regularly was not associated with the type of institution (academic vs. nonacademic), number of hospital beds, and number of cystectomies performed annually. Gemcitabine/cisplatin combination chemotherapy was named as the primarily used NAC regimen by 80 (95%) respondents. The median number of administered cycles was 3 for NAC and 4 for AC. In the case of cisplatin ineligibility, combination chemotherapy with gemcitabine/carboplatin was the most common regimen. Respondents stated that chemotherapy was generally administered by urologists (81% for NAC and 85% for AC)., Conclusions: Our survey of current practice shows a high acceptance rate of NAC in Germany, which was independent of the type of institution. Although the scientific level of evidence for AC is lower, it still seems to be more widely accepted than NAC. NAC and AC were generally administered by urologists., (© 2018 S. Karger AG, Basel.)

Purpose: We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care., Materials and Methods: We searched PubMed ® for English language articles published through January 2017 using the keywords "renal cell carcinoma," "kidney cancer," "immunotherapy," "targeted therapy" and "adjuvant therapy." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included., Results: Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon-α and high dose interleukin-2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence-free survival benefit of sorafenib or sunitinib over placebo, while S-TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence-free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit., Conclusions: Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S-TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Surgery had been and remains a mainstay in the treatment of gastric cancer. The Japanese surgical oncologists employed surgery-first approach to treat gastric cancer because of the widespread use of D2 lymph node dissection and the high incidence of oncologically resectable cancer, and early attempts at the multimodality treatment strategy featured surgery followed by postoperative chemotherapy. Although evidence to treat Stage II/III gastric cancer with this strategy is now abundant in the Far East, poor compliance of the post-gastrectomy patients to intense combination chemotherapies has been a limitation associated with this strategy. Evidence in support of neoadjuvant chemotherapy in the West and in various other types of cancer prompted the Japan Clinical Oncology Group (JCOG) researchers to explore this strategy, primarily for a selected population of locally advanced cancer that could either be unresectable by the surgery-first approach or is known to suffer from a poor prognosis; cancers with bulky lymph node metastases or those with a scirrhous phenotype. Encouraged by some promising results from these neoadjuvant trials and taking into account the aforementioned limitations associated with postoperative chemotherapy, the JCOG researchers decided to embark on a phase III trial to explore neoadjuvant chemotherapy among patients with clinically Stage III cancer. This review describes the development of the neoadjuvant strategy for gastric cancer in Japan, mainly by going through a series of clinical trials conducted by the JCOG.

Background: Rectal cancer surgery in Catalonia has been involved in a process of centralisation. We assessed the impact of this health policy strategy on quality of care and clinical results., Methods: We compared patterns of care and clinical outcomes of all rectal cancer patients receiving radical surgery for the first time in public hospitals in two time periods, before (2005 and 2007) and after (2011-2012) centralisation, analysing indicators of care quality according to the regional clinical practice guidelines. Clinical outcomes at two years were also assessed., Results: A total of 3780 patients were included. From 2005 to 2012, the proportion of patients treated surgically for the first time in centres whose annual surgical caseload was more than 11 increased from 84.0% to 90.4%. The rate of locoregional recurrence at two years fell from 4.5 to 3.06/100 person-years (p = 0.005). The crude mortality rate at three months, one and two years was reduced by 55%, 40% and 34% (p < 0.001)., Conclusion: Improvements in quality of care might be associated with the centralisation of surgery and with the selective focus effect derived from the process of auditing. Our results support the continuation of clinical auditing and surveillance of authorised centres., (Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

OBJECTIVE Surgical excision is the mainstay treatment for resectable low-grade intramedullary spinal cord tumors (IMSCTs) in the pediatric age group. Chemotherapy and radiation treatments are generally reserved for progressive or recurrent disease. Given the indolent nature of low-grade tumors and the potential side effects of these approaches, their long-term treatment benefits are unclear. The aim of the study was to determine long-term disease outcomes and the therapeutic roles of surgery and adjuvant therapies in pediatric patients with low-grade IMSCTs over an extended follow-up period. METHODS Case records for all pediatric patients (< 21 years of age) with a histopathological diagnosis of low-grade IMSCT were selected over a period from January 1975 to January 2010. Outcome variables including McCormick functional grade, overall survival (OS), and progression-free survival (PFS) were analyzed with respect to demographic and treatment variables. RESULTS Case records of 37 patients with low-grade IMSCTs were identified, with a mean follow-up duration of 12.3 ± 1.4 years (range 0.5-37.2 years). Low-grade astrocytomas were the most prevalent histological subtype (n = 22, 59%). Gross-total resection (GTR) was achieved in 38% of patients (n = 14). Fusion surgery was required in 62% of patients with pre- or postoperative deformity (10 of 16). On presentation, functional improvement was observed in 87% and 46% of patients in McCormick Grades I and II, respectively, and in 100%, 100%, and 75% in Grades III, IV, and V, respectively. Kaplan-Meier PFS rates were 63% at 5 years, 57% at 10 years, and 44% at 20 years. OS rates were 92% at 5 years, 80% at 10 years, and 65% at 20 years. On multivariate analysis, shunt placement (hazard ratio [HR] 0.33, p = 0.01) correlated with disease progression. There was a trend toward improved 5-year PFS in patients who received adjuvant chemotherapy and radiation therapy (RT; 55%) compared with those who did not (36%). Patients who underwent subtotal resection (STR) were most likely to undergo adjuvant therapy (HR 7.86, p = 0.02). CONCLUSIONS This extended follow-up duration in patients with low-grade IMSCTs beyond the first decade indicates favorable long-term OS up to 65% at 20 years. GTR improved PFS and was well tolerated with sustained functional improvement in the majority of patients. Adjuvant chemotherapy and RT improved PFS in patients who underwent STR. These results emphasize the role of resection as the primary treatment approach, with adjuvant therapy reserved for patients at risk for disease progression and those with residual tumor burden.

Objective: The aim of this study was to evaluate the use of neoadjuvant chemotherapy (NACT) and primary debulking surgery (PDS) before and after results from a randomized trial were published and showed non-inferiority between NACT and PDS in the management of advanced-stage ovarian carcinoma., Methods: We evaluated consecutive patients with advanced-stage ovarian cancer treated at our institution from 1/1/08-5/1/13, which encompassed 32 months before and 32 months after the randomized trial results were published. We included all newly diagnosed patients with high-grade histology and stage III/IV disease. Associations between the use of NACT and clinical variables over time were evaluated., Results: Our study included 586 patients. Median age was 62 years (range, 30-90); 406 patients (69%) had stage III disease, and 570 (97%) had disease of serous histology. Twenty-six percent (154/586) were treated with NACT and 74% (432/586) with PDS. NACT use increased significantly from 22% (56/256) before 2010 (at which point the results of the randomized trial were published) to 30% (98/330) after 2010 (p=0.037). Although patients who underwent PDS were more likely to experience grade 3/4 surgical complications than those who underwent NACT, those selected for PDS had a median OS of 71.7 months (CI, 59.8-not reached) compared with 42.9 months (CI 37.1-56.3) for those selected for NACT., Conclusions: In this single-institution analysis, the best survival outcomes were observed in patients who were deemed eligible for PDS followed by platinum-based chemotherapy. Selection criteria for NACT require further definition and should take institutional surgical strategy into account., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Most literature describing surgery for colorectal cancer (CRC) liver metastases (LM) comes from high volume centres. Here, we report management and outcomes achieved in routine clinical practice., Methods: All cases of CRC in Ontario who underwent resection of LM in 1994-2009 were identified using the population-based Ontario Cancer Registry. Electronic treatment records identified chemotherapy delivery. Temporal trends are described for 3 periods: 1994-1999, 2000-2004, 2005-2009. We describe volume of resected CRCLM as a ratio of incident cases per CRCLM resection. Overall (OS) and cancer-specific survival (CSS) are measured from time of LM resection., Results: 2717 patients underwent resection of CRCLM. Between 1994 and 2009 there was a 78% increase in case volume; from one resection for every 48 incident cases to one resection for every 27 incident cases, p < 0.001. Use of peri-operative chemotherapy increased over study periods from 44% (306/700), to 52% (429/830), to 65% (777/1187, p < 0.001). Chemotherapy utilization rates varied across geographic regions (range 43%-69%, p < 0.001). Post-operative mortality rates at 30 and 90 days were 2.5% and 4.3% respectively. Five year OS during the study periods was 36% (95% CI 32-39%), 40% (95% CI 36-43%), and 46% (95% CI 43-49%) (p < 0.001); CSS was 38% (95% CI 35-42%), 42% (95% CI 38-45%), 49% (95% CI 44-53%) (p < 0.001). The temporal improvement in OS/CSS persisted on adjusted analyses., Conclusions: Outcomes of patients with resected CRCLM in routine practice is comparable to those reported from high volume centres. Survival improved over the study period despite a greater proportion of patients with CRC undergoing liver resection., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Ependymomas are a heterogeneous group of neuroepithelial tumors of children and adults. In pediatric cases, the standard of care has long consisted of neurosurgical resection to the greatest extent acceptable followed by adjuvant involved field irradiation. Complete macroscopic surgical resection has remained the only consistent clinical variable known to improve survival. Adjuvant chemotherapy has yet to predictably affect outcome, possibly due to the molecular heterogeneity of histologically similar tumors. The administration of chemotherapy subsequently remains limited to clinical trials. However, recent comprehensive genomic, transcriptomic, and epigenetic interrogations of ependymomas have uncovered unique molecular characteristics and subtypes that correlated with clinical features such as age, neuroanatomical location, and prognosis. These findings represent a potential paradigm shift and provide a biologic rationale for targeted therapeutic strategies and risk-adapted administration of conventional treatment modalities. In this review, we focus on intracranial WHO grade II and III ependymoma of children and discuss conventional management strategies, followed by recent biologic findings and novel therapeutics currently under investigation.

The morbidity and mortality of lung cancer rank the first place among all the malignant tumor. According to the histopathological characteristics, lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer. Only 20% patients diagnosed with NSCLC have the chance for surgery while their 5-yr overall survival is about 30%-60%. The therapeutic outcome of surgery alone is not satisfying. Adjuvant chemotherapy after surgical resection in stage II-IIIa lung cancer showed efficacy in many randomized clinical trials, but its role in stage I disease remains controversial. The choice of appropriate chemotherapy candidates, the selection of chemotherapy regimens and the research progress on biomarker are mainly discussed in this review.

Objective: Uterine leiomyosarcoma (LMS) is a relatively rare malignancy that is associated with a poor prognosis. The rarity of LMS has led to a lack of consensus regarding appropriate treatment. The goal of this study was to identify the role that chemotherapy and radiotherapy have played in the treatment of uterine LMS in the United States as well as the effectiveness of adjuvant treatment., Materials/methods: We used the SEER (Surveillance, Epidemiology, and End Results)-Medicare database to gather information on uterine LMS patients older than the age of 66 years diagnosed between 1992 and 2009. Basic demographic and clinical characteristics were collected. A logistic regression model analysis was performed to determine predictors of treatment. Cox proportional hazards models were used to identify clinical parameters and treatment strategies associated with survival differences., Results: Our final study group included 230 patients. We found that the rate of use of chemotherapy and radiotherapy in the treatment of patients with uterine LMS increased over the period investigated. However, we identified no significant survival advantage associated with either mode of therapy. The strongest predictor of survival was stage at diagnosis. The logistic regression model analysis revealed that age at diagnosis, treatment year, stage, and underlying health status were all independent predictors of chemotherapy. Age at diagnosis was also a predictor of radiation therapy., Conclusions: The increasing rates of chemotherapy and radiotherapy use in this population seem to be unfounded given the lack of survival benefit. Further investigation into alternative treatment regimens is merited. The prognostic significance of stage at diagnosis indicates the importance of improving early detection of uterine LMS.

Treatment of early stage ovarian cancer remains controversial despite advances in chemotherapeutic options. Over the past 30 years, molecular and clinicopathologic studies accelerated and treatment of ovarian cancer has undoubtedly improved although there is a debate as to whether this impacts outcome or not. More recently, the introduction of targeted therapy started a new era. Probably it is because early stage disease comprises a small portion of the epithelial ovarian cancer, studies have mostly ignored this group and still there is no clear consensus regarding systemic treatment of early-stage lesions. However this group of patients has the best chance of cure. In this review, we focus on current developments in the treatment of early stage ovarian cancer and query the options.

Background: Multiple prospective, randomized trials have demonstrated that the addition of adjuvant therapy after surgical resection of pancreatic cancer improves survival compared to surgery alone. However, the optimal type of adjuvant therapy, chemotherapy alone, or chemotherapy combined with chemoradiation therapy remains controversial. Our aim was to examine the treatment trends for surgically resectable (stages I and II) pancreatic cancer in the USA using the National Cancer Database., Methods: The National Cancer Database (NCDB) is a national oncology outcomes database for over 1,500 Commission on Cancer accredited cancer programs. Patients diagnosed with stage I-II pancreatic adenocarcinoma between 2003 and 2010 were selected from the NCDB Hospital Comparison Benchmark Reports. Attention was paid to the initial treatment regimen, such as surgery alone, surgery plus chemotherapy, or surgery plus chemoradiation. In addition, data on hospital setting (teaching hospitals vs. community hospitals) were collected and analyzed. The Cochran-Armitage test for trend was used to assess changes in treatment over time., Results: Fifty-nine thousand ninety-four patients with stage I-II pancreatic adenocarcinoma were included in the analysis. Between 2003 and 2010, the use of surgery alone as first course treatment of stage II disease decreased significantly at both teaching hospitals and community hospitals among patients who underwent surgery (P < 0.0001 for both cases). In the same period, the use of chemotherapy in addition to surgery as treatment of stage I and II disease increased at least twofold at both hospital settings (P < 0.0001 for all cases). Treatment with surgery plus chemoradiation decreased significantly for both stages in both hospital settings (P < 0.0001 for all cases). Nonsurgical treatment for stage II disease was surprisingly high and significantly increased over time (P < 0.001 for both hospital types), ranging from approximately 30-37 % at teaching hospitals and 39-47 % at community hospitals., Conclusion: Data from the NCDB from 2003 to 2010 illustrate changes in the adjuvant treatment of pancreatic cancer. The use of chemotherapy alone as adjuvant therapy increased whereas the use of multimodality therapy decreased. In addition, there remains an alarmingly high rate of nonsurgical therapy for stage I and II disease.

Adjuvant chemotherapy aims to eradicate micrometastatic tumor cells before and after curative surgery. Many Phase III trials have been conducted to study the efficacy of postoperative adjuvant chemotherapy; however, most trials have failed to show any survival benefit because of their low statistical power and/or poor patient compliance. Since 2000, two pivotal Phase III trials, the ACTS-GC and the CLASSIC, have demonstrated the efficacy of postoperative adjuvant chemotherapy following D2 gastrectomy. Although treatment with S-1 for 1 year or combination therapy with capecitabine and oxaliplatin for 6 months is effective, more intensive chemotherapy is necessary to further improve the survival rates. In Europe, two Phase III trials, the MAGIC and the FNCLCC/FFCD, have produced results that strongly suggest that neoadjuvant chemotherapy is beneficial. The advantages of neoadjuvant chemotherapy include a high rate of R0 resection, tumor regression, high compliance and the avoidance of unnecessary surgery. The disadvantage of neoadjuvant chemotherapy is over-diagnosis. In Japan, the Japan Clinical Oncology Group has conducted several clinical trials using neoadjuvant chemotherapy to target extensive nodal disease and/or scirrhous carcinomas. The optimal courses and regimens of neoadjuvant chemotherapy should, therefore, be clarified in the future.

Objective: Advances in multimodality therapy have led to increased survival for patients with metastatic colorectal cancer, but the impact on patients undergoing resection for colorectal liver metastases is unclear. The purpose of this study was to evaluate patterns of treatment for resectable colorectal liver metastases in the USA over the last two decades., Methods: Using the Surveillance, Epidemiology, and End Results-Medicare database, 1,926 patients who underwent hepatic resection for colorectal liver metastasis between 1991 and 2007 were included and divided into two cohorts: period 1 (1991-2000) and period 2 (2001-2007). Demographic data, treatment patterns, and outcomes of the two periods were compared by univariate methods. Multivariable regression models were constructed to predict the use of perioperative chemotherapy, postoperative complications, and 90-day mortality following liver resection., Results: The overall use of perioperative chemotherapy was 33 % and did not differ between periods, but shifted from postoperative to preoperative over time. By multivariable analysis, older age, black race, stage III primary cancer, and metachronous disease were predictive of lesser likelihood of chemotherapy use. The use of preoperative chemotherapy was not associated with any increase in perioperative morbidity or mortality., Conclusions: Despite increased survival and widespread recommendations for the use of multimodality therapy, the overall resection rate and use of perioperative chemotherapy for resectable colorectal liver metastases remain underutilized and have not increased over time. Efforts to investigate barriers to the widespread use of multimodality therapy for these patients are warranted.

There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000-2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in- and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early-stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early-stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab- and taxane-containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab-containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab-containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines., (© 2013 Wiley Periodicals, Inc.)

The direct thrombin inhibitor bivalirudin has gained popularity in cardiovascular medicine over the past decade because, in comparison with unfractionated heparin, it guarantees a predictable dose-related degree of anticoagulation with a low immunogenic profile and, possibly, with reduced rates of major bleeding complications. In the past bivalirudin has been frequently employed in the management of patients with heparin-induced thrombocytopenia. The REPLACE-2, ACUITY and ISAR-REACT4 studies demonstrated bivalirudin non-inferiority in comparison with unfractionated heparin in terms of ischemic end-points with a reduction of the bleeding rate also in patients acute coronary syndrome without ST elevation. Finally the results of the HORIZONS-AMI study positioned this drug as a first choice anticoagulant during percutaneous coronary interventions in patients with ST-elevation myocardial infarction. In fact the bivalirudin alone regimen, compared to unfractionated heparin plus GP2b3a inhibitors, decreased in-hospital bleeding rates and short and long term mortality. Given the body of clinical evidence, bivalirudin is likely to contend to GP2b3a inhibitors the leading place among the proposed anticoagulation strategies in the setting of acute coronary syndromes. The duration of the bivalirudin infusion after PCI and the optimal oral antiplatelet regimen associated to bivalirudin are important issues to be solved in future randomized controlled studies.

Despite advances with adjuvant endocrine treatment for hormone receptor-positive tumors and with trastuzumab for HER2-positive disease, overall, over 50% of women with early-stage breast cancer experience recurrence and die of the disease. Biomarkers for tailoring systemic adjuvant treatment to responder patients are needed. The multigene assays, 21-gene recurrence score (Oncotype DX [Genomic Health, CA, USA]) and 70-gene signature (MammaPrint [Agendia, CA, USA]), and the isolated tumor cells in sentinel lymph node(s) represent the latest advances for improving adjuvant chemotherapy decisions. This article evaluates how these new markers, added to current standard factors (age, tumor size, grade, hormone receptor status and HER2 status), could improve early breast cancer treatment decisions. Moreover, emerging evidence from the latest large-scale studies using next-generation DNA-sequencing technology reveals a high heterogeneity and complexity of breast cancer. This assessment now shapes a new research strategy towards completion of a breast cancer causal (driver) mutations catalog and understanding complex genetic interactions and signaling pathway networks. Despite multiple challenges, advances in cancer genomes and systems biology approaches promise the future development of robust biomarkers.

A third of breast cancer diagnoses are made in women aged 70 years or over. Historically, older women have been regarded as presenting with tumors that are low grade and hormone sensitive and that are likely to have a good prognosis. However, in those older women whose tumors overexpress the HER2 oncogene, the prognosis is likely to be worse. Under these circumstances, due consideration should be given to adjuvant systemic therapy, including chemotherapy and targeted treatments, in order to minimize risks of disease recurrence. In this article we discuss the evidence base for the role of adjuvant systemic therapy in older women with HER2-positive early breast cancer.

Patients with breast cancer who achieve a complete pathologic response (pCR) after preoperative (neoadjuvant) chemotherapy have an improved prognosis compared to those with residual disease; pCR being a good surrogate of long-term survival and cure from breast cancer. Despite their relative chemosensitivity, less than 25% of all patients with HER2/neu negative (0-2+), and hormone receptors (HR) negative tumors, so-called "Triple Negative" breast cancer (TNBC) treated with standard preoperative chemotherapy achieve pCR. Among patients with residual disease (no pCR) following neoadjuvant chemotherapy, patients with TNBC have the worst prognosis and overall survival. These patients lack the benefit of subsequent targeted therapy. Many studies have addressed improving the efficacy of neoadjuvant chemotherapy by including different cytotoxic agents, biologic modifiers, regimens, and schedules. Up to now, apart from trastuzumab for HRE2/neu+ tumors, none of the targeted agents can be considered a standard therapeutic option for primary systemic treatment. We hereby review the current literature on neoadjuvant chemotherapy for breast cancer, emphasizing treatment of TNBC. We also discuss potentially new therapeutic strategies that target this high risk group.

Adjuvant systemic treatment for breast cancer has evolved resulting in improved outcomes. A relevant question is whether these advances have changed the pattern of distant relapse. Women diagnosed with stage I-III breast cancer were divided into three time cohorts according to changes in adjuvant therapy; A: 1989-1991-CMF chemotherapy in premenopausal and tamoxifen for postmenopausal women; B: 1992-1997-anthracycline chemotherapy and tamoxifen for pre/postmenopausal women; C: 1998-2001-broader use of anthracyclines. The primary endpoint was 5-year cumulative incidence of bone metastasis (BM) as first site of metastasis (FSOM) versus non-bone metastasis (NBM). The ratios NBM/BM in each period were calculated. The eligibility criteria were met by 21,415 cases; Cohorts A: 1989-1991 (n = 3,915), B: 1992-1997 (n = 9,229) and C: 1998-2001 (n = 8,271). Between 1989 and 2001, the percentage of patients receiving adjuvant chemotherapy increased from 23.1 to 34.4%. A decline in cumulative 5-year incidence rates for BM and NBM as FSOM was seen comparing cohort A to C, P < 0.0001. The ratio NBM/BM was significantly increased from 1.53 in the early cohort to 2.00 in the later one, P = 0.0083. The most prominent increase (84%) was in the ER-negative group, chemotherapy treated, P = 0.0272. A significant decline in 5-year cumulative incidence of metastases and an increase in the proportion of NBM as first site of metastasis were observed between earlier and later cohorts. This may reflect the need for more successful adjuvant treatment options for aggressive breast cancer subtypes which are more likely to present with early spread to visceral organs. Understanding patterns of relapse may help design new adjuvant strategies.

The emergence of molecularly targeted agents in oncology has not only revolutionized the care of cancer patients, but also changed the daily practice of medical oncologists. Molecularly targeted agents indeed often differ from traditional cytotoxic agents by their administration schedules and routes, their toxicity profiles, and/or the assessment of their antitumor activity. In addition, the observation that molecularly targeted agents sometimes have limited antitumor activity as single agents has led clinical investigators to combine molecularly targeted agents together or with cytotoxic agents. We review here the current challenges for the early clinical development of anticancer agents in the era of molecularly targeted agents. We focus on the choice of end points in phase I oncology clinical trials, as well as on the choice of dose escalation methods with an emphasis on available dose escalation methods for molecularly targeted agents and for combination trials.

Treatment options for patients with breast cancer have progressively improved over the past 40 years, from an era of no chemotherapy to the introduction of taxanes, hormonal therapy, and biologic therapy. These advances have resulted in substantial, 15%-20% improvements in clinical outcomes. However, progress has yet to be made to improve the prognosis in many breast cancer patients, and research is currently under way to test new tools, or new applications of older tools, to advance breast cancer management. Chemotherapy clearly remains a cornerstone of adjuvant breast cancer treatment, because breast cancer can be very sensitive to the currently available agents. Meanwhile, the era of a one-size-fits-all approach to breast cancer management is over, and the maximum potential of chemotherapy should now be reached by targeting specific populations. Effective biomarkers are therefore needed to optimize chemotherapy, define more selective populations, and clearly tailor treatment. This paper discusses recent data, including new trials that are more fully incorporating current knowledge with respect to molecular markers and the underlying biology of breast cancer.

Background: Although >70% of younger women with nonmetastatic breast cancer (BC) received adjuvant chemotherapy, only approximately 15% to 20% of elderly women with BC received chemotherapy. The decision to treat may be associated with nonmedical factors, such as patient, physician, or practice characteristics. In the current study, the association between oncologist characteristics and the receipt of chemotherapy in elderly women with BC was evaluated., Methods: Women aged >65 years who were diagnosed with American Joint Committee on Cancer stages I to III BC between 1991 and 2002 were identified in the Surveillance, Epidemiology, and End Results-Medicare database. The Physician Unique Identification Number was linked to the American Medical Association Masterfile to obtain information on oncologists. Investigated was the association between demographic, tumor, and oncologist-related factors and the receipt of chemotherapy, using Generalized Estimating Equations to control for clustering. Patients were defined as low risk (estrogen/progesterone receptor positive, stage I/II disease) and high risk (estrogen/progesterone receptor-negative, stage II/III disease)., Results: Of 42,544 women identified, 8714 (20%) were treated with adjuvant chemotherapy. In a hierarchical analysis, women who underwent chemotherapy were more likely be treated by oncologists primarily employed in a private practice (odds ratio [OR], 1.40; 95% confidence interval [95% CI], 1.23-1.59) and who graduated after 1975 (OR, 1.12; 95% CI, 1.01-1.26) and were less likely to have an oncologist trained in the United States (OR, 0.83; 95% CI, 0.74-0.93). The association between a private practice setting and the receipt of chemotherapy was found to be similar for patients at high risk (OR, 1.55) and low risk (OR, 1.35) for cancer recurrence., Conclusions: Elderly women with BC treated by oncologists who were employed in a private practice were more likely to receive chemotherapy. Efforts to determine whether these associations reflected experience, practice setting, insurance type, or other economic incentives are warranted.

Colon cancer is the second cause of death for cancer worldwide. In most cases it is diagnosed when it is still localized to the intestinal wall or in regional lymphnodes. Post-operative systemic therapy with 5-fluorouracil and folinic acid in combination with Oxaliplatin is the standard option for patients with radically resected stage III disease. In stage II, the value of a post-operative treatment remains controversial, but the identification of prognostic factors, histopathological and molecular, may allow the selection of patients who can benefit from adjuvant treatment. The inclusion of molecular targeted agents in combination regimens with cytotoxics, already proven effective in advanced disease, is the main field of development in the most recent protocols of adjuvant therapy.

Surgery is still the treatment of choice in patients with resectable oesophageal cancer. However, recent randomised controlled trials suggest beneficial effects of adjuvant or neoadjuvant treatment modalities on progression-free and overall survival compared to surgery alone. Neoadjuvant chemoradiotherapy in combination with surgery is most effective in squamous cell carcinomas. Increased perioperative morbidity and mortality should be minimised by surgery in a high-volume centre. In adenocarcinomas of the gastro-oesophageal junction neoadjuvant chemotherapy shows beneficial effects compared to surgery alone. A transhiatal resection should be preferred in distal oesophageal cancer compared to a transthoracic oesophageal resection if the patient is in poor condition. In all other cases a transthoracic resection remains the procedure of choice. Chemoradiotherapy alone is an alternative to surgery in high-risk patients with squamous cell carcinomas of the oesophagus. Therefore the treatment of patients with oesophageal cancer should always include an individualised, multimodal approach including surgery, chemotherapy, and radiotherapy.

Women with hormone receptor-positive breast cancer have traditionally been treated with 5 years of adjuvant tamoxifen to reduce their risk of subsequent recurrent disease. Among those who experience subsequent disease recurrence, the majority do so after 5 years, suggesting that longer durations of endocrine therapy might be beneficial. Two options tested include longer tamoxifen and, in postmenopausal women, a switch to an aromatase inhibitor (AI). In the National Cancer Institute of Canada Cooperative Trials Group MA.17 trial, we tested the AI letrozole given to postmenopausal women for 5 years after tamoxifen as extended adjuvant therapy because of its efficacy in patients with advanced breast cancer in progression on previous tamoxifen. The first interim analysis (median, 2.4 patient years) showed substantial benefits from letrozole, and all patients were unblinded and offered the option of letrozole. Despite two thirds of the patients crossing over to letrozole, an intent-to-treat analysis at 54 months' follow-up continued to demonstrate the strong beneficial effect of extended adjuvant letrozole. Furthermore, significant benefit was demonstrated among patients who had been randomized to placebo but elected to take letrozole after a prolonged washout from previous tamoxifen (late extended adjuvant therapy). A trial examining the merits of > 5 years of treatment with an AI, MA.17R, is ongoing, as are a number of other trials of duration of therapy. This article reviews results from MA.17 and the design of these trials of duration.