Disease Free Survival

PurposeAdjuvant chemotherapy for resected non–small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.Patients and MethodsWithin 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m2intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.ResultsThree hundred-forty-four patients...

Purpose Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. Patients and Methods The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO–European Organisation for Research and Treatment of Cancer (EORTC) classification. Results Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94...

Background: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1-4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors. Patients and methods: A national retrospective study of children 618 years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review. Results: There were 50 patients (31 males; median age at diagnosis of 16.7 months). Twelve patients were >36 months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation. Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5 months (0-32). The median survival time of the entire cohort was 13.5 months (1-117.5 months).

The objective of this study was to assess midterm functional status, wound healing, and in-hospital resource use among a prospective cohort of patients treated in a tertiary hospital, multidisciplinary Center for Limb Preservation. Data were prospectively gathered on all consecutive admissions to the Center for Limb Preservation from July 2013 to October 2014 with follow-up data collection through January 2016. Limbs were staged using the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification scheme at the time of hospital admission. Patients with nonatherosclerotic vascular disorders, acute limb ischemia, and trauma were excluded. The cohort included 128 patients with 157 threatened limbs; 8 limbs with unstageable disease were excluded. Mean age (±standard deviation [SD]) was 66 (±13) years, and median follow-up duration (interquartile range) was 395 (80-635) days. Fifty percent (n = 64/128) of patients were readmitted at least once, ...

DTI-015 (BCNU dissolved in ethanol) utilizes solvent facilitated perfusion (SFP) for intratumoral drug delivery. A phase II clinical trial of DTI-015 and fractionated external beam radiotherapy on newly diagnosed, malignant gliomas investigated early changes in tumour physiology and metabolism, clinical outcome and safety. Pre-and post DTI-015 injection neuro-imaging included computed tomography (CT) cerebral blood flow and volume, glucose and thallium single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Clinical status was determined before and after DTI-015, prior to radiotherapy and 3 monthly thereafter until progression (defined by Macdonald criteria). Primary endpoint was radiographic response. Secondary endpoints were progression free (PFS) and overall survival (OS). Twelve patients were enrolled; eight glioblastoma multiforme (GBM), four anaplastic astrocytoma (AA). Three days after DTI-015 injection, mean tumour blood flow (Paired t-test; P \ 0.001) and blood volume (Paired t-test; P = 0.001) were significantly reduced. There was a significant decrease in glucose utilization (Paired t-test; P \ 0.001) and thallium uptake (Paired ttest; P \ 0.001) at 6 days. Tumour blood volume had a sustained reduction (Paired t-test; P = 0.001) at 26 days after DTI-015. There were two serious adverse events. Two patients with AA achieved a partial response. Median PFS was 39 weeks for AA and 27 weeks for GBM; median OS for GBM was 47 weeks and 132 weeks for AA. The imaging data forms a biological basis for understanding the effects of high dose BCNU delivered intratumorally by SFP, and suggests early effects on tumour vasculature and metabolism.

MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients' choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, P<0.01; new metastases: 7.6 vs 23.1%, P<0.01; deaths: 12.1 vs 31.7%, P<0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P=0.0184) and overall su...

To correlate the clinical features of women presenting with locally advanced breast cancer with event-free survival (EFS) and overall survival (OS) and to evaluate the patterns of relapse. A total of 200 patients presenting consecutively over 9 years with Stage III breast cancer were evaluated for age, socio-economic status (SES), tumour size and grade, number of involved lymph nodes, stage III sub-categories, estrogen and progesterone receptor (ER/PR) status, treatment profiles and responses, and sites of relapse. EFS and OS at 5 and 10 years were calculated. Median age was 45 years. Poorly differentiated tumours were found in 127 patients, while 128 had larger tumours (T3 and T4). Eighty women had extensive nodal involvement (N2 and N3), and 86 had Stage IIIA tumours. Chemotherapy was given to 44 patients before surgery and one of these patients achieved pathological complete response. At 5 and 10 years, EFS was 25% and 7%, and OS was 52% and 31%, respectively. By Cox regression a...

ROSTATE CANCER IS THE MOST common nonskin cancer and the second most common cause of cancer death among men. 1 For the majority of men with incident prostate cancer (approximately 85%), disease is diagnosed at localized (T1-T2) stages, 2 and standard treatment options include surgery, radiation, or conservative management (ie, deferral of treatment until necessitated by disease signs or symptoms). Although not standard or sanctioned by major groups or guidelines, an increasing number of clinicians and patients have turned to primary androgen deprivation therapy (PADT) as an alternative to surgery, radiation, or conservative management, especially among older men. 3,4 For example, in a 1999-2001 survey, PADT had become the second most common treatment approach, after surgery, for localized prostate cancer. 3 Randomized clinical trials support the use of early androgen deprivation therapy (ADT) as an adjunct to surgery or radiation for patients with highrisk cancer. 5-10 In 1 trial, 5,8 early ADT reduced mortality by approximately 50% when used with radiation in highrisk disease (poorly differentiated T1-T2 or T3-T4); whereas, in another trial, 9 See also Patient Page.

IMPORTANCE Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. OBJECTIVE To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. DESIGN, SETTING, AND PARTICIPANTS A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. INTERVENTIONS Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m 2 , weekly intramuscular) plus best supportive care (BSC) or BSC alone. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti-ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18 F-fluorodeoxyglucose positron-emission tomography. RESULTS Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. CONCLUSIONS AND RELEVANCE In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01279967

The purpose of this study was to assess prognostic factors, treatment outcomes and patterns of relapse in patients with early stage (T1-2 N0) squamous cell carcinoma of oral tongue treated primarily by surgery. The medical records of all patients with early stage (T1-2 N0) oral tongue cancer, radically treated at King Faisal Specialist Hospital and Research Center between January 1980 and December 1997, were reviewed. Eighty-®ve patients were identi®ed for analysis, 38 male and 47 female. With a median follow-up for surviving patients of 64 months, 5-year actuarial overall, disease-speci®c (DSS), and relapse-free survival (RFS) were 71, 75, and 63%, respectively. Univariate analysis for DSS showed survival advantage for patients with tumor thickness (TT) of 410 mm (P=0.0002) and distance from resection margin (DFRM) of >5 mm (P=0.005). The eect of TT of 410 mm was maintained (P=0.001) on multivariate analysis. Higher RFS was observed with TT of 410 mm (P=0.0002), DFRM of >5 mm (P=0.0002) and DFRM of >10 mm (P=0.007). On multivariate analysis higher RFS was also found for TT 410 mm (P=0.01) and DFRM >5 mm (P=0.01). Salvage of local tongue recurrence was higher than neck node failure, with 5-year DSS of 71 and 19%, respectively (P=0.007). Time interval for recurrence showed no signi®cant impact on outcome. In T1-2 N0 oral tongue cancer, TT, and DFRM are signi®cant prognostic factors for both local control and survival. Neck node recurrence is associated with poor prognosis and low salvage rate.

Context: Approximately 15-25% of men who undergo radical prostatectomy for localized prostate cancer (PCa) will experience recurrence of their cancer; men with poorly differentiated cancer, non-organ-confined disease, and positive surgical margins are at the highest risk.

The goal of this study is to study and report the clinical outcomes and patterns of failure after intensitymodulated radiotherapy (IMRT) for T4 nasopharyngeal carcinoma (NPC). A total of 70 patients treated with IMRT between 2004 and 2009 were eligible for study inclusion. According to the staging system of 2010 AJCC, all the primary tumors were attributed to T4 stage, while the distribution of disease by N stage was N0 in 2, N1 in 23, N2 in 39, N3a in 1, and N3b in 5. The location and extent of locoregional failures were transferred to the pretreatment planning computed tomography for dosimetry analysis. The median follow-up period was 26.8 (range, 4-78) months. The overall 2-year local failure-free survival, regional failure-free survival, distant failure-free survival, and overall survival rate was 82.1%, 92.3%, 73.8%, and 82.5%, respectively. Thirty-three patients had developed treatment failure. Of the 33 patients, 11, 2, and 15 had developed local failure, regional failure, and distant metastasis, respectively, 2 had developed locoregional failure, 1 had developed distant metastasis and failure at the primary, and 2 had developed distant metastasis and failure at the primary and nodal site. Eight of the locoregional failures were marginal. The results of treating T4 NPC with IMRT were excellent. Advanced T4 disease remained difficult to treat. One possible strategy is to lessen the dose constraint criteria of selected neurologic structures. Distant metastasis remains the most difficult treatment challenge for patients with T4 NPC at present, and more effective systemic chemotherapy should be explored.

Background: According to Barcelona Clinic Liver Cancer classification transarterial chemoembolization is indicated in patients with Hepatocellular Carcinoma in the intermediate stage. Drug-eluting microspheres can absorb and release the chemotherapeutic agent slowly for 14 days after its intra-arterial administration. This type of transarterial chemoembolization approach appears to provide at least equivalent effectiveness with less toxicity. Methods: This is a prospective, single-center study, which evaluated 21 patients with intermediate and advanced hepatocellular carcinoma who underwent transarterial chemoembolization with drug-eluting microspheres. The follow up period was 2 years. Inclusion criteria was Child-Pugh A or B liver disease patients, intermediate or advanced hepatocellular carcinoma and performance status equal or below 2. Transarterial chemoembolization with drug-eluting microspheres was performed at 2-month intervals during the first two sessions. The third and subsequent sessions were performed according to the image findings on follow-up, on a "demand schedule". Tumor response and time to progression were evaluated along the two-year follow up period. Results: Of the 21 patients 90% presented with liver cirrhosis, 62% had Barcelona Clinic Liver Cancer stage B and 38% had Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma. Average tumor size was 6.9 cm. The average number of Transarterial chemoembolization with drug-eluting microspheres procedures was 3 with a total of 64 sessions. The predominant toxicity was mild. Liver function was not significantly affected in most patients. Two deaths occurred within 90 days after Transarterial chemoembolization with drug-eluting microspheres (ischemic hepatitis and hydropic decompensation). Technical success was achieved in 63 of 64 procedures. The mean hospital stay was 1.5 days. The progression free and overall survival at 1 and 2 years were 73.0% and 37.1%, 73.7% and 41.6%, respectively. Conclusion: Transarterial chemoembolization with drug-eluting microspheres is able to deliver significant tumor response and progression free survival rate with acceptable toxicity. Larger studies are needed to identify exactly which subset of advanced hepatocellular patients may benefit from this treatment.

Commonly used adjuvant systemic therapies harbor high rates of severe short-term and long-term side effects but are often justified to patients because of curative intent in early-stage breast cancer. One of the oldest and least toxic adjuvant regimens, CMF (oral cyclophosphamide given with intravenous methotrexate and 5-fluourouracil), has been largely abandoned because of the perception that it underperforms for survival outcomes compared with modern regimens containing anthracycline and/or taxanes. To address this misperception, we performed a review of all consecutive breast cancer patients at the Seattle Cancer Care Alliance over the past decade who received 6 months of adjuvant CMF as their sole chemotherapy regimen and determined rates for relapse-free survival (RFS), overall survival (OS), and major organ toxicity. From January 2003 to August 2013, 248 patients (median age of 52 years at the start of chemotherapy) met criteria for inclusion in this series and had a median fo...

570 patients with osteosarcoma of the extremities were treated with ®ve dierent protocols of neoadjuvant chemotherapy at Rizzoli Institute between 1983 and 1995. Surgery consisted of limb salvage in 83% rotation plasty in 5% and amputation in 12%. The 5-year event-free survival (EFS) was 60% which varied according to the protocol followed, ranging from 47.6% to 66.4%. 234 patients relapsed. The pattern of relapse was analysed. The mean relapse time was 23.8 months (range: 2±96). The ®rst site of systemic relapse was the lung in 88% (32% of these had less than three pulmonary metastases and 68% three or more), bone in 9%, lung and bone in 2% and other sites in 3%. The relapse time and the number of pulmonary metastases were strictly correlated with the ecacy of the protocol of chemotherapy used. Patients treated with the three protocols that gave a 5-year EFS of more than 60% relapsed later and had fewer pulmonary lesions than patients treated with the two protocols that gave a 5-year EFS of 47.6% and 52.5%. The rate of local recurrence was relatively low (6%). This was not correlated with the protocol or the type of surgery used: limb salvage (6.4%), rotation plasty or amputation (4.1%). However, the rate of local recurrence was very high (21.9%) in the few patients (7%) that had less than wide surgical margins. We conclude that for patients with osteosarcoma of the extremities treated with neoadjuvant chemotherapy: (a) the pattern of systemic relapse changes according to the ecacy of the protocol of chemotherapy used. This should be always considered when evaluating the preliminary results of new studies as well as in de®ning the time of follow-up; (b) limb salvage procedures are safe and do not jeopardise the outcome of the patient, provided that wide surgical margins are achieved.

BACKGROUND: Traditionally, survival estimates have been reported solely as survival from the time of surgery, but future survival probability likely changes based on the survival time already accumulated after therapy-otherwise known as conditional survival (CS). We sought to assess the comparative performance of various colorectal liver metastasis prognostic scoring systems, as well as to investigate the CS of patients who underwent resection of colorectal liver metastasis. STUDY DESIGN: Between 1982 and 2008, 949 patients who underwent colorectal liver metastasis resection were identified from an international multi-institutional database. Various prognostic scoring systems were evaluated using Cox proportional hazards models and calculated concordance index (c). CS estimates were calculated as CS ϭ S (xϩ5) /S (x). RESULTS: Overall survival after liver resection was 65% at 3 years and 45% at 5 years, with a median survival of 52 months. All of the prognostic scoring systems had poor-to-moderate prognostic discriminatory ability (Fong c ϭ 0.57, Nordlinger c ϭ 0.56, Memorial Sloan-Kettering Cancer Center nomogram c ϭ 0.58). Using CS, the probability of surviving an additional 5 years, given that the patient had already survived 1, 3, or 5 years, was 41%, 40%, or 50%, respectively. The inadequate performance of the prognostic scoring systems was explained by the fact that as survival from liver resection increased from 0 to 5 years, the 5-year observed CS improved substantially for patients who were initially predicted to have poor survival at the time of surgery. CONCLUSIONS: Colorectal liver metastasis prognostic scoring systems have fair-to-moderate performance. CS can provide more accurate prognostic information for patients and physicians after colorectal liver metastasis resection and should be incorporated into the quantification of survival.

Aggressive surgery has been suggested for improving local tumor control in patients with retroperitoneal sarcoma (RS). This study aimed at investigating local disease-free and overall survival after complete surgery, in patients with RS. Retrospective data of patients submitted to complete surgery for RS were extracted from a prospectively-maintained database. Forty-three out of 78 patients (55%) presented with primary RS. Infiltrated organs were resected in 42 patients (54%). Patients presenting with recurrent (hazard ratio (HR)=5.57, p=0.002) and high-grade (HR 3.47, p=0.041) tumors were at higher risk of local recurrence. Microscopically-involved tumor resection margins (HR=3.47, p=0.04) and recurrent tumor at presentation (HR=2.49, p=0.008) were independent predictors of poor survival. Patients presenting with primary RS had longer local disease-free survival and overall survival than those with recurrent tumor after complete surgery. Complete surgery remains the standard-of-car...

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncolo...

Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer. 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m(2)/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate. The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from...

Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real--time PK.Results: Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m(2) Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m(2); n = 1) or grade 4 thrombocytopenia (470 mg/m(2); n = 2). Most common treatment-related adverse events (AE)...

Based on promising preclinical data, we conducted a single arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined  as complete/partial response (CR/PR) or stable disease (SD) ≥24 weeks, in HER2(mut) non-amplified metastatic breast cancer (MBC).  Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2(mut) detection.  <p>Experimental Methods:  Tumor tissue positive for HER2(mut) was required for eligibility.  Neratinib was administered 240mg daily with prophylactic loperamide.  ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2(mut)). </p> <p>Results:  2.4% (9/381) tumors sequenced centrally harbored HER2(mut) (lobular 7.8% vs ductal 1.6%; p=0.026).  Thirteen additional HER2(mut) cases were identified locally.  21 of these 22 HER2(mut) cases were estrogen receptor positive.  Sixteen patients (median age 58 [31-74] years and 3 [2-...

Prostate cancer is the most common cancer in North American men. Currently available prognostic factors inadequately predict which cancers will be aggressive and which will lead an indolent course. This study was aimed at investigating the role of matrix metalloproteinase (MMP)-2 in prostate cancer disease-free survival. We correlated MMP-2 expression by malignant prostatic epithelium and stromal cells with prostate cancer disease-free survival in 187 stage pT3NxM0 prostate carcinomas using immunohistochemistry. MMP-2 was expressed by cancer cells in 131 cases (70.0%) and by stromal cells in 142 cases (75.9%). MMP-2 expression by stromal cells was not associated with progression (P = 0.7270). However, in multivariate analyses, adjusting for the Gleason score, tumor-node-metastasis stage, and initial serum prostate-specific antigen, MMP-2 expression by >50% of malignant epithelial cells was associated with decreased disease-free survival (hazard ratio, 4.267; P = 0.0012). Increase...

Background: The aim of this study is to investigate the effect of tumor characteristics and parameters of treatment response in predicting biochemical disease-free survival (BFS) for patients with intermediate or high risk prostate cancer treated by combined definitive external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT). Methods: Between June 1995 and January 2015, 375 patients with localized prostate cancer and a National Comprehensive Cancer Network (NCCN) intermediate or high risk categories were treated by definitive EBRT and ADT. Median duration of androgen blockade was 10 months (range: 3-36 months); Median radiation dose was 72 Gy (Range: 70-78 Gy). Median follow-up time was 5.8 years (range: 0.8-16.39 years). The main study endpoint was biochemical disease free survival (BFS). Results: Forty seven patients (12.5%) developed biochemical recurrence (BCR) during the observation period. Monovariate analysis identified baseline PSA (bPSA) (p = 0.024), T-stage (p = 0.001), Gleason's score (GS) (p = 0.042), radiation dose (p = 0.045), PSA pre-radiation therapy (p = 0.048), and nadir PSA (nPSA), (p < 0.001) as significant variables affecting BCR. The receiver operating characteristic (ROC) curve identified a nPSA of 0.06 ng/ml as optimal cutoff value significantly predicting the patients' risk of BCR (p < 0.001). Multivariate cox regression analysis revealed T-stage, GS, and nPSA as independent variable affecting BFS, while bPSA, age, and radiation dose were not. Conclusion: Nadir PSA at 0.06 is a strong independent predictor of BFS in patients with intermediate or high risk prostate cancer treated by definitive EBRT and ADT.

RESULTS: Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% ± 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated ...

Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger MCL patients from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%) were significantly associated with inferior outcomes (together with MIPI, MIPI-c, Blastoid morphology and Ki67&gt;30%); however, in multivariate analyses only TP53 mutations (HR=6.2, p&lt;0.0001) retained prognostic impact for overall survival (OS), while TP53 mutations (HR=6.9, p&lt;0.0001) and MIPI-c high-risk (HR=2.6, p=0.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome with a median OS of 1.8 years and 50...

Background Bevacizumab plus fl uoropyrimidine-based chemotherapy is standard treatment for fi rst-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard fi rst-line bevacizumab-based treatment. Methods In an open-label, phase 3 study in 220 centres in Austria,

Background Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the fi rst-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is eff ective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as fi rst-line treatment for patients with indolent and mantle-cell lymphomas. Methods We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratifi ed by histological lymphoma subtype, then randomly assigned according to a prespecifi ed randomisation list to receive either intravenous bendamustine (90 mg/m² on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1•4 mg/m² on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m² on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. Findings 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was signifi cantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69•5 months [26•1 to not yet reached] vs 31•2 months [15•2-65•7]; hazard ratio 0•58, 95% CI 0•44-0•74; p<0•0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0•0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0•0001), infections (96 [37%] vs 127 [50%]); p=0•0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0•0001), and stomatitis (16 [6%] vs 47 [19%]; p<0•0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0•024). Interpretation In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred fi rst-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic eff ects.

Add to CiteULike Add to Complore Add to Connotea Add to Del.icio.us Add to Digg Add to Facebook Add to Reddit Add to Technorati Add to Twitter What&#x27;s this? ... From the Odette Cancer Centre and Sunnybrook Health Sciences Centre; Princess Margaret Hospital, Toronto; London ...

Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz fre...

PURPOSE: Follow-up should identify metachronous colonic neoplasms and precancers, suture line recurrences, and isolated liver or pulmonary metastases. For some sites of failure the surgical re-resection and multimodal approaches increase disease-flee survival and quality of life. The aim of our study was to evaluate the role of the different follow-up plans and the carcinoembryonic antigen directed second-look surgery. METHODS: One hundred-sixty patients radically resected for Dukes B or C colorectal cancer were evaluated by a follow-up plan (plasma carcinoembryonic antigen every 2 months; echography every 6 months; chest x-ray every 12 months; and colonscopy at 1 year and then every 3-5 years). RESULTS: Eighty-nine recurrences were detected (55.6 percent). In 72 recurrences plasma carcinoembryonic antigen elevation was present. Eight carcinoembryonic antigen directed second-look surgeries were performed: in four patients surgical evidence of recurrence was found (two isolated liver metastases were radically resected); two patients with no surgical evidence of recurrence developed a surrenalic isolated metastases and pelvic and hepatic recurrences; two patients had a five-year diseasefree survival. In the 17 symptomatic patients with no carcinoembryonic antigen elevation diffuse disease was present, not resectable for cure. Four solitary liver metastases, one metachronous colonic neoplasm, and one suture line recurrence presented a five-year survival. CONCLUSIONS: The authors emphasize that carcinoembryonic antigen-directed second-look surgery is not acceptable for elevated costs. Intensive follow-up plans are superfious, while the monitoring of the carcinoembryonic antigen and instrumental restaging as an indicator of solitary liver metastases and mucosal lesions are very useful.

Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lun...

✓ It has previously been reported in a single-institution trial that progression-free survival of children with medulloblastoma treated with radiotherapy and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), cisplatin, and vincristine chemotherapy during and after radiotherapy was better than the outcome in children treated with radiotherapy alone. To better characterize long-term outcome and duration of disease control, this treatment approach was used for 10 years and expanded to three institutions. Sixty-three children with posterior fossa medulloblastomas were treated with craniospinal local-boost radiotherapy and adjuvant chemotherapy with vincristine weekly during radiotherapy followed by eight 6-week cycles of cisplatin, CCNU, and vincristine. To be eligible for study entry, patients had to be older than 18 months of age at diagnosis and have a subtotal resection, evidence of metastatic disease, and/or brainstem involvement. Patients younger than 5 years of age and without...

Congenital tumors of the central nervous system (CNS) are often arbitrarily divided into "definitely congenital" (present or producing symptoms at birth), "probably congenital" (present or producing symptoms within the first week of life), and "possibly congenital" (present or producing symptoms within the first 6 months of life). They represent less than 2% of all childhood brain tumors. The clinical features of newborns include an enlarged head circumference, associated hydrocephalus, and asymmetric skull growth. At birth, a large head or a tense fontanel is the presenting sign in up to 85% of patients. Neurological symptoms as initial symptoms are comparatively rare. The prenatal diagnosis of congenital CNS tumors, while based on ultrasonography, has significantly benefited from the introduction of prenatal magnetic resonance imaging studies. Teratomas constitute about one third to one half of these tumors and are the most common neonatal brain tumor. They are often immature because of primitive neural elements and, rarely, a component of mixed malignant germ cell tumors. Other tumors include astrocytomas, choroid plexus papilloma, primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, and medulloblastomas. Less common histologies include craniopharyngiomas and ependymomas. There is a strong predilection for supratentorial locations, different from tumors of infants and children. Differential diagnoses include spontaneous intracranial hemorrhage that can occur in the presence of coagulation factor deficiency or underlying vascular malformations, and congenital brain malformations, especially giant heterotopia. The prognosis for patients with congenital tumors is generally poor, usually because of the massive size of the tumor. However, tumors can be resected successfully if they are small and favorably located. The most favorable outcomes are achieved with choroid plexus tumors, where aggressive surgical treatment leads to disease-free survival.

In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high-grade B-cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0AE03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression-free and overall survival.

The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells &gt;1.0 G/l and neutrophils &gt;0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P&lt;0.0001, each), and further reduced by 2 days (P&lt;0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P&lt;0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusion...

One of the mainstays of treatment for locally advanced head and neck squamous cell carcinoma is surgery. However, for post-operative patients with high-risk factors for recurrence, surgery alone is insufficient and improving survival requires adjuvant treatment after surgery. Unlike with most other malignancies, the standard adjuvant treatment for post-operative head and neck cancer patients with high-risk factors for recurrence is radiotherapy concurrent with chemotherapy. This review article focuses on the history and future perspectives of adjuvant treatment for post-operative head and neck squamous cell carcinoma.

Background: The prognostic significance of intraperitoneal tumour cells (IPCs) in colorectal cancer is not clear. This study aimed to determine whether detection of IPCs could be used a prognostic marker for selecting patients at high risk of recurrence. Methods: The study included 226 patients with colorectal cancer who underwent elective resection. Clinical variables, including the presence of IPCs, were analysed for their prognostic significance. Results: Thirty-three patients (14•6 per cent) were positive for IPCs. Univariable analysis indicated that the presence of IPCs was a significant prognostic factor in patients with stage III colorectal cancer; the 5-year disease-specific survival rate was 14 per cent in IPC-positive patients versus 79 per cent in those without IPCs (P < 0•001). Multivariable analysis showed that IPC positivity was the most robust prognostic factor in stage III disease (hazard ratio 2•2; P = 0•003), whereas nodal category (N1 or N2) showed no significant association with prognosis. In addition, IPCs were associated with haematogenous recurrence (P = 0•004) rather than peritoneal or local recurrence (P = 0•077) in patients with stage III disease. Conclusion: The presence of IPCs is a significant prognostic factor in patients with stage III colorectal cancer.

Background The epidermal growth factor receptor (EGFR) signaling pathway is crucial for regulating tumorigenesis and cell survival and may be important in the development and progression of non-small cell lung cancer (NSCLC). We examined the impact of EGFR-tyrosine kinase inhibitors (TKIs) on progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with and without EGFR mutations. Methods Randomized trials that compared EGFR-TKIs monotherapy or combination EGFR-TKIs-chemotherapy with chemotherapy or placebo were included. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of EGFR-TKIs for the EGFR mutationpositive (EGFRmut +) and EGFR mutation-negative (EGFRmut-) subgroups were calculated with the fixed-effects inverse variance weighted method. All statistical tests were two-sided. Results We included 23 eligible trials (13 front-line, 7 second-line, 3 maintenance; n = 14 570). EGFR mutation status was known in 31% of patients. EGFR-TKIs treatment prolonged PFS in EGFRmut + patients, and EGFR mutation was predictive of PFS in all settings: The front-line hazard ratio for EGFRmut + was 0.43 (95% confidence interval [CI] = 0.38 to 0.49; P < .001), and the front-line hazard ratio for EGFRmutwas 1.06 (95% CI = 0.94 to 1.19; P = .35; P interaction < .001). The second-line hazard ratio for EGFRmut + was 0.34 (95% CI = 0.20 to 0.60; P < .001), and the second-line hazard ratio for EGFRmutwas 1.23 (95% CI = 1.05 to 1.46; P = .01; P interaction < .001). The maintenance hazard ratio for EGFRmut + was 0.15 (95% CI = 0.08 to 0.27; P < .001), and the maintenance hazard ratio for EGFRmutwas 0.81 (95% CI = 0.68 to 0.97; P = .02; P interaction < .001). EGFR-TKIs treatment had no impact on OS for EGFRmut + and EGFRmutpatients. Conclusions EGFR-TKIs therapy statistically significantly delays disease progression in EGFRmut + patients but has no demonstrable impact on OS. EGFR mutation is a predictive biomarker of PFS benefit with EGFR-TKIs treatment in all settings. These findings support EGFR mutation assessment before initiation of treatment. EGFR-TKIs should be considered as front-line therapy in EGFRmut + advanced NSCLC patients.

Introduction: Besides clinicopathological parameters, molecular markers can be very important, and further characterize colorectal carcinomas into chromosomally unstable, microsatellite instable and “CqG-island methylator phenotype” groups. Aim: To study the frequency of microsatellite instability using immunohistochemical evaluation of MLH1, MSH2, MSH6 and PMS2 proteins in colorectal carcinoma. Method: 122 colorectal carcinomas as well as in 69 paired liver metastases were evaluated. Additionally, prognostic and predictive potential of mismatch repair status was tested. Results: Microsatellite instable phenotype was identified in 11.5% (14/122) of the tumours. There were no differences regarding staining intensity of tumour regions. Mismatch repair status was discordant in primaries vs. metastases in 20.2%. There was no difference in progression free- and overall survival according to mismatch repair status. The mismatch repair status was not predictive for survival within systemic...

Background'. Docetaxel (DTX) has been shown to be a very active drug in both breast cancer (BC) and non-small-cell lung cancer (NSCLC). Irinotecan (CPT-11) is also active in NSCLC, and has shown promising antitumor activity in pretreated BC. Purpose: To define the MTDs of these two drugs given together every other week with the use of filgrastim support in pretreated BC and NSCLC patients. Patients and methods: Patients (aged 18-70 years, performance status < 2) with advanced NSCLC or BC who had received at least one prior chemotherapy regimen were candidates for this phase I study. The starting DTX and CPT-11 doses were 2 60 mg/m and 80 rag/m-. Doses were alternately escalated at each step by 10 mg/m 2 for both drugs. Filgrastim 300 gg/day was given subcutaneously from days 4 through 7 of each cycle. Results: From April 2000, 41 patients were included in the trial (27 BC, 14 NSCLC). All BC patients had received epirubicin plus paclitaxel (with or without cisplatin) as first-line treatment. Of the 14 NSCLC patients, 12 had received cisplatin-based first-line therapy, and 8 patients had been pretreated with paclitaxel. The dose escalation proceeded through five dose levels up to DTX and CPT-11 doses of 80 mg/m ~-and 100 mg/m 2, respectively. Overall, ten patients showed dose-limiting toxicity during the first cycle, diarrhea in seven and neutropenia in the remaining three. Considering all 218 cycles delivered, grade 3 or 4 neutropenia occurred in 14 patients (34%), with only one episode of neutropenic fever, while severe diarrhea was observed in 9 patients (23%). A total of 21 objective

Background: Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer. However, its efficacy is limited by intrinsic and acquired resistance. Here the potential of S100β as a biomarker and inhibition of its signaling network as a therapeutic strategy in endocrine treated patients was investigated. Methods: The expression of S100β in tissue and serum was assessed by immunohistochemistry and an enzymelinked immunosorbent assay, respectively. The S100β signaling network was investigated in cell line models of endocrine resistance by western blot, PCR, immunoprecipitation, and chromatin-immunoprecipitation. Endocrine resistant xenografts and tumor explants from patients with resistant tumors were treated with endocrine therapy in the presence and absence of the p-Src kinase inhibitor, dasatinib. Results: Tissue and serum levels of S100β were found to predict poor disease-free survival in endocrine-treated patients (n = 509, HR 2.32, 95% CI is 1.58-3.40, p < 0.0001 and n = 187, HR 4.009, 95% CI is 1.66-9.68, p = 0.002, respectively). Moreover, elevated levels of serum S100β detected during routine surveillance over the patient treatment period significantly associated with subsequent clinically confirmed disease recurrence (p = 0.019). In vivo studies demonstrated that endocrine treatment induced transcriptional regulation of S100β which was successfully disrupted with tyrosine kinase inhibition. In endocrine resistant xenografts and tumor explants from patients with endocrine resistant breast cancer, combined endocrine and dasatinib treatment reduced tumor proliferation and down-regulated S100β protein expression in comparison to endocrine treatment alone. Conclusions: S100β has potential as a new surveillance tool for patients with ER-positive breast cancer to monitor ongoing response to endocrine therapy. Moreover, endocrine resistant breast cancer patients with elevated S100β may benefit from combined endocrine and tyrosine-kinase inhibitor treatment. Trial registration: ClinicalTrials.gov, NCT01840293). Registered on 23 April 2013. Retrospectively registered.

Microsatellite instability (MSI) and aneuploidy are inversely related phenomena. We tested whether ploidy status influences the clinical impact of MSI in endometrioid endometrial cancer (EEC). We analyzed 167 EECs for MSI and ploidy. Tumors were classified in three categories according to MSI and ploidy status. Associations with clinicopathological and molecular variables, survival, and treatment response were assessed. All MSI tumors (23%) were scored as diploid, and 14% of microsatellite stable (MSS) tumors presented aneuploidy. MSI tumors associated with older age at diagnosis, non-obesity, high histological grade, and advanced surgical stage. MSS-aneuploid tumors also associated with higher grade and advanced stage. In multivariate survival analysis MSI did not influence disease-free survival (DFS) or cancer-specific survival (CSS). However, when just diploid tumors were considered for the analysis, MSI significantly contributed to worse DFS and CSS, and the same was observed fo...

Fractionated doses have been advocated to prevent chemoperitonitis after intraperitoneal infusion of mitoxantrone. Patients with peritoneal carcinomatosis of various origin underwent surgery, including intestinal resections, with minimal residual disease. Peritoneal mitoxantrone in 1000 ml/m 2 saline was planned on the first post-operative day in groups of four patients (5 mg/m 2 for 3 and 5 days, 7.5 mg/m 2 for 3 and 4 days, 10 mg/m 2 for 2-4 days, if possible). Due to dose-limiting myelosuppression, only one and three patients received the 7.5-mg 4-day and 10-mg 3-day regimens, respectively. A total of 20 patients were consequently treated. Neither major complications nor severe pain were observed. Pharmacokinetics were completed on the 1st day in five 5-mg and five 10-mg patients, on the 5th day in three 5-mg patients, and on the 3rd day in one 10-mg patient. On the 1st day, mean peritoneal peak concentrations of mitoxantrone resulted 1.45±0.56 (range 0.48-1.9) and 1.9±0.85 (range 1.27-3.13) g/ml in the 5-mg and 10-mg patients, respectively. Mean dialysate/plasma exposure (AUC) ratio was 115. Even in patients with sutures, early post-operative fractionated intraperitoneal mitoxantrone appears feasible and safe, with a high local advantage, for up to 5 days of treatment and a maximum tolerated total dose of 20-25 mg/m 2 .

Background Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the effi cacy and safety of substituting fl uorouracil with the oral prodrug capecitabine. Methods This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemo radiotherapy with fl uorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m² days 1-14, repeated day 22), followed by chemoradiotherapy (50•4 Gy plus capecitabine 1650 mg/m² days 1-38), then three cycles of capecitabine. Patients in the fl uorouracil group received two cycles of bolus fl uorouracil (500 mg/m² days 1-5, repeated day 29), followed by chemoradiotherapy (50•4 Gy plus infusional fl uorouracil 225 mg/m² daily), then two cycles of bolus fl uorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemo radiotherapy (50•4 Gy plus capecitabine 1650 mg/m² daily) followed by radical surgery and fi ve cycles of capecitabine (2500 mg/m² per day for 14 days) and patients in the fl uorouracil group received chemo radiotherapy (50•4 Gy plus infusional fl uorouracil 1000 mg/m² days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fl uorouracil (500 mg/m² for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratifi cation by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12•5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993. Findings Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fl uorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fl uorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0•0004; post-hoc test for superiority p=0•05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fl uorouracil group (p=0•07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fl uorouracil group, p=0•67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0•04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fl uorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [<1%] grade 3-4 vs ten [5%], one [<1%] grade 3-4) than did those in the fl uorouracil group, whereas leucopenia was more frequent with fl uorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4). Interpretation Capecitabine could replace fl uorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.

Treatment of myeloma has benefited from the introduction of more effective and better tolerated agents, improvements in supportive care, better understanding of disease biology, revision of diagnostic criteria, and new sensitive and specific tools for disease prognostication and management. Assessment of minimal residual disease (MRD) in response to therapy is one of these tools, as longer progression-free survival (PFS) is seen consistently among patients who have achieved MRD negativity. Current therapies lead to unprecedented frequency and depth of response, and next generation flow and sequencing methods to measure MRD in bone marrow are in use and being developed with sensitivities in the range of 10(-5)‒10(-6) cells. These technologies may be combined with functional imaging to detect MRD outside of bone marrow. Moreover, immune profiling methods are being developed to better understand the immune environment in myeloma and response to immunomodulatory agents, while methods fo...