Evidence Of Disease Progression Research Articles

Effects of gemcitabine and stereotactic body radiotherapy on quality of life in locally advanced pancreatic cancer.

278 Background: Existing literature on the impact of radiation therapy for locally advanced pancreatic cancer (LAPC) on quality of life (QoL) is limited and is specific to standard chemoradiation. We prospectively investigated patient-reported QoL after treatment with fractionated stereotactic body radiation therapy (SBRT). Methods: Forty-nine patients with LAPC treated were prospectively enrolled in a clinical trial at 3 institutions. Participants received a total of 33 Gy in 6.6 Gy daily fractions using SBRT either upfront (N=5) or after a single induction cycle of gemcitabine (N=44), followed by post-SBRT gemcitabine until evidence of disease progression. Two validated questionnaires, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and pancreatic cancer-specific QLQ-PAN26, were administered to patients prior to SBRT and at 4-weeks and 3 to 4-months following SBRT. Results: QoL questionnaires were available for 43 patients (88%) in the clinical trial at enrollment, of which 38 (88%) and 22 (51%) also had data at 4-weeks and 3 to 4-months following SBRT, respectively. There was no significant change in global QoL scores from enrollment at 4-weeks (p=0.682) and 4-months (p>0.999) following SBRT. Patients demonstrated a significant improvement in pancreatic pain (p=0.001), body image (p=0.007) and jaundice (p=0.001) scores from the pre-SBRT values at 4 weeks following SBRT. The initial 4-week results were similar when restricted to those patients with both 4-week and 4-month QoL data (p=0.020) and jaundice (p=0.004); however, these symptoms had returned to enrollment levels by the 4-month follow-up. An improvement in body image (p=0.016) and decline in role functioning (p=0.002) were observed in patients with 4-month follow-up QoL questionnaires. Conclusions: LAPC patients undergoing SBRT experience no impairment in global QoL and have short-term improvements in symptoms commonly bothersome to this population including pancreatic pain, body image, and jaundice. Patients also experience a delay in impaired role functioning several months after treatment. These results warrant further investigation of SBRT for LAPC. Clinical trial information: NCT01146054.

Management of Stage 4S Composite Neuroblastoma With a MYCN-amplified Nodule

MYCN amplification in neuroblastoma is usually associated with a poor prognosis. Very few cases of heterogenous MYCN amplification have been previously reported, and the clinical significance of heterogeneity is unclear. We report a neonate with an adrenal stage 4S neuroblastoma with a small focus of MYCN-amplified cells within a nonamplified background. After adrenalectomy, the patient has been observed without use of chemotherapy and has no evidence of disease progression.

Liposome-encapsulated doxorubicin citrate (Myocet) for treatment of recurrent epithelial ovarian cancer

The aim of this study was to assess the clinical activity and toxicity of liposome-encapsulated doxorubicin citrate (Myocet) in a retrospective multicenter cohort of epithelial ovarian, primary peritoneal, and tubal cancer patients. Records of patients with recurrent epithelial ovarian, primary peritoneal, and tubal cancer treated with liposome-encapsulated doxorubicin citrate (60 mg/m on day 1 of a 21-day cycle) after failure of more than one previous regimen were reviewed. Fifty-three patients were evaluated for efficacy and toxicity. The median age of the patients was 59 (range 39-73). The median follow-up was 6 months (range 1-17). One patient (1.9%) showed a complete response and 13 patients (24.5%) showed a partial response, yielding an overall response rate of 26.4% (14/53 patients). Clinical benefit was achieved in 36 patients (67.9%). The median progression-free survival (PFS) for the entire study population was 4.0 months (range 1.0-14.8). The median PFS for platinum-sensitive and platinum-resistant patients was 4.0 months (ranges 1.0-14.8 and 1.0-9.4, respectively; P=0.652). The median overall survival from the start of liposome-encapsulated doxorubicin citrate was 10.0 months. Multivariate survival analysis showed no association between the liposome-encapsulated doxorubicin citrate line of treatment or platinum sensitivity to PFS in age and BRCA status-adjusted models. Only 11.3% of patients experienced grade 3-4 hematologic toxicities, 80% grade-2 alopecia, and 50% grade-1-2 fatigue. No other grade-4 toxicities, no significant cardiac events, or hand and foot syndromes were reported. Liposome-encapsulated doxorubicin citrate was well tolerated, with a good response and high clinical benefit rate. Further evaluation in a larger prospective cohort is warranted.

Cytokines, chemokines and leukotrienes profile and signature analysis in HTLV-1 infection as an evidence of disease progression

Cytokines, chemokines and leukotrienes profile and signature analysis in HTLV-1 infection as an evidence of disease progression Ana LB Starling, Denise U Goncalves, Vanessa Peruhype-Magalhaes, Jordana Coelho-dos-Reis, Jose R Lambertucci, Ludimila Labanca, Silvio R Souza Pereira, Marina L Martins, Joao G Ribas, Andrea Teixeira-Carvalho, Bruno C Trindade, Lucia H Faccioli, Anna BF Carneiro-Proietti, Olindo A Martins-Filho

Randomized Phase III Study of Erlotinib Versus Observation in Patients With No Evidence of Disease Progression After First-Line Platin-Based Chemotherapy for Ovarian Carcinoma: A European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup Study

This trial evaluated the efficacy of maintenance erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, after first-line chemotherapy. Eligible patients had high-risk International Federation of Gynecology and Obstetrics stage I or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first-line platinum-based chemotherapy (CT) and showed no signs of progression at the end of CT. Patients were randomly assigned to maintenance erlotinib 150 mg orally daily for 2 years or to observation. EGFR immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutation analyses were performed in 318 patients. Between October 2005 and February 2008, 835 patients were randomly assigned (median follow-up, 51 months). Twenty-six percent of the patients stopped erlotinib as a result of adverse effects (of these, 67% were due to rash). For erlotinib and observation, respectively, the median progression-free survival was 12.7 and 12.4 months (hazard ratio [HR], 1.05; 95% CI, 0.90 to 1.23), and the median overall survival was 50.8 and 59.1 months (HR, 0.99; 95% CI, 0.81 to 1.20 months), respectively. No subgroup could be identified with improved effect of erlotinib, based on IHC or FISH for EGFR, or mutations in genes related to the EGFR pathway, or on rash during erlotinib therapy. However, patients with a positive FISH EGFR score had a worse overall survival (46.1 months) than those with a negative score (67.0 months; HR, 1.56; 95% CI, 1.01 to 2.40; P = .044). Global health/quality-of-life scores showed a significant difference during the first year (P = .0102) in favor of the observation arm. Maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival.

Indatuximab Ravtansine (BT062) In Combination With Lenalidomide and Low-Dose Dexamethasone In Patients With Relapsed and/Or Refractory Multiple Myeloma: Clinical Activity In Len/Dex-Refractory Patients

BackgroundBT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprising the anti-CD138 chimerized MAb (nBT062) and the maytansinoid DM4 as cytotoxic agent. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to target cell death. CD138 (Syndecan-1) is highly overexpressed on various solid tumors and in hematological malignancies, and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. Data from two studies investigating BT062 as single agent demonstrated an acceptable tolerability profile and evidence of clinical activity in patients with heavily pretreated relapsed and/or refractory MM (1, 2). Preclinical studies showed enhanced anti-MM activity when BT062 was combined with lenalidomide and dexamethasone (Len/Dex). Based on these data, a Phase I/IIa study in MM was initiated to evaluate the safety and efficacy of BT062 in combination with Len/Dex. ObjectivesTo determine the dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the recommended phase II dose (RPTD), pharmacokinetics (PK), and anti-MM activity of increasing doses of BT062 (days 1, 8, and 15, every 4 weeks) in combination with Len (25 mg, daily on days 1-21) and low dose Dex (40 mg on days 1, 8, 15, and 22) in patients with relapsed and/or refractory MM. MethodsThis is a prospective, open label, dose-escalation, multicenter Phase I/IIa study. The Phase I part includes dose escalation, and the Phase IIa the expansion of the MTD or RPTD cohort. Patients aged ≥18 years with relapsed and/or refractory MM who have failed at least one prior therapy were eligible to participate. Prior treatment with Len and/or Dex was allowed. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for additional treatment cycles. Patients were enrolled in cohorts of at least 3 at each dose level; DLT in the first cycle triggered cohort expansion. Toxicities were assessed by CTCAE v4 and clinical response was assessed according to International Myeloma Working Group criteria. ResultsAs of July 2013, a total of 15 patients have received BT062 at dose levels of 80 mg/m2 (N=3), 100 mg/m2 (N=6) or 120 mg/m2 (N=6). Two patients at the highest dose level discontinued study due to toxicity (DLT), another patient withdrew consent. The other 12 patients remain on treatment; median duration 144 days (range 8–385). The median number of prior therapies was 4 (range 1–11), 87% of patients had prior Len exposure, and 50% were Len/Dex refractory. The maximum administered dose (MAD) has been reached at 120 mg/m2, with mucosal inflammation (CTC grade 3) as DLT in one, and anemia (CTC grade 3) in a second of the 6 patients treated at this dose level. About 85% of reported Adverse Events (AE) were of CTC grade 1 or 2. The most common reported AEs were fatigue, hypokalemia, and diarrhea. Amongst the 9 patients currently evaluable for efficacy, responses were observed across all dose levels with a overall response rate (ORR) of 78%; including 1 patient with complete response (120 mg/m2), 1 patient with very good partial response (80 mg/m2), and 5 patients with partial response (80 and 100 mg/m2). Two other patients achieved disease stabilization, resulting in a clinical benefit in 100% of the evaluated patients. Interestingly, partial response was observed in 3 patients refractory to prior treatment with Len/Dex. The MTD has been defined as 100 mg/m2 and is currently expanded to further evaluate the safety and efficacy of BT062 at the RPTD. ConclusionPreliminary data from this ongoing study indicate that BT062 is well tolerated in combination with Len/Dex at dose levels that induce responses in patients with relapsed and/or refractory multiple myeloma, including Len/Dex-refractory patients. Updated results on safety and efficacy will be presented.

Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle Cell Lymphoma: Multi-Center Phase II Study Of Lenalidomide Plus Rituximab

BackgroundInitial treatment for mantle cell lymphoma (MCL) is not standardized. Current conventional upfront chemoimmunotherapies are generally not curative and can be deferred in some patients. This presents an opportunity to evaluate novel therapeutic approaches in the first line setting. Lenalidomide, an immunomodulatory compound which targets both the tumor cells directly and the tumor microenvironment, has shown clinical efficacy either alone or in combination with rituximab in relapsed MCL. We report findings of the first study of a chemotherapy-free approach as initial treatment for MCL, using lenalidomide and rituximab as a combination biologic doublet. MethodsThe study protocol includes both an induction phase and a maintenance phase. During the induction phase, lenalidomide is administered at 20 mg daily on days 1-21 of a 28-day cycle for a total of 12 cycles, with dose escalation to 25 mg daily if tolerated. Standard dose rituximab is administered weekly x 4 during cycle 1, then once every other cycle, for a total of 9 doses. During the maintenance phase which starts with cycle 13, lenalidomide is administered at 15 mg daily on days 1-21 of a 28-day cycle, with rituximab maintenance once every other cycle until progression of disease. The primary objective was to evaluate overall response rate (ORR). Secondary objectives included safety analysis, progression-free survival, overall survival, and QOL assessment. Based on a Simon two-stage design comparing an ORR of ≥60% with treatment to an unacceptable ORR of ≤40% (alpha=10%, power=80%), 15 or more overall responses out of 28 enrolled patients were required to declare the treatment effective and worthy of further testing. ResultsFrom 7/2011 to 2/2013, 31 subjects with previously untreated MCL were enrolled at 4 centers, and the study met its accrual. At study entry, median age was 65 years (range 42-86), and the M:F ratio was 3:1. All patients had stage III/IV disease, 12 (39%) had elevated LDH, and 27 (87%) had bone marrow involvement. MIPI scores were evenly distributed between low-, intermediate-, and high-risk (36%, 32%, and 32% respectively). Ki67 index was <30% in 23 (74%) subjects. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (39%), thrombocytopenia (13%) and anemia (7%). Grade 3-4 non-hematologic toxicities included rash (23%), tumor flare (7%) and serum sickness associated with rituximab (7%). Grade 1-2 infections included URI (29%), UTI (10%), pneumonia (10%) and sinusitis (7%). One incidence each of DVT and PE were observed and resolved with treatment. As of July 2013 at a median follow-up of 12 months (range 5-23 months), 27 (87%) patients remain on study without evidence of disease progression, including 18 who have completed induction and now in the maintenance phase. Four patients went off study – one withdrew consent, two had progression of disease, and one could not tolerate tumor flare associated side effects. Thirty patients are evaluable for efficacy with at least one response assessment. The preliminary ORR for evaluable patients is 77% (95% CI = 57% to 89%) with 40% CR/CRu (95% CI = 23% to 59%), and may further improve with additional follow-up on continued treatment. Median time to objective response was 2.8 months, with CR typically confirmed between 6-12 months. Four patients (13%) have stable disease with ongoing clinical benefit at 5+, 6+, 12+ and 13+ months. Median progression-free survival and duration of response have not been reached. Neither MIPI score nor Ki67 index correlated with response. All patients have maintained or improved quality of life parameters during treatment by FACT-Lym analysis. ConclusionsThis study provides the first demonstration that a chemotherapy-free, combination biologic approach is feasible as initial therapy for mantle cell lymphoma. Lenalidomide up to 25 mg daily given 21 out of 28 days can be safely combined with rituximab as frontline therapy for MCL. Preliminary efficacy data on response rates are encouraging. More precise assessment of response rate and durability will require more follow-up with additional subjects. However, these data justify further evaluation of the lenalidomide + rituximab regimen both alone and as a platform for the integration of novel agents in combination approaches in MCL both in the upfront and relapsed settings. Disclosures:Ruan:Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in the frontline treatment of mantle cell lymphoma. Martin:Seattle Genetics: Consultancy, Speakers Bureau; Millennium: Research Funding; Genentech: Speakers Bureau; Celgene: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Schuster:Celgene: Research Funding. Smith:Micromet: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy; Genentech: Consultancy; Onyx: Consultancy. Furman:Celgene: Research Funding. Coleman:Celgene: Consultancy. Leonard:Celgene: Consultancy; Genentech: Consultancy.

Patterns of subregional mesiotemporal disease progression in temporal lobe epilepsy

Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus. In this study, we tracked progressive structural changes in the hippocampus, amygdala, and entorhinal cortex in drug-resistant temporal lobe epilepsy at a subregional level. Furthermore, we evaluated the relation between disease progression and surgical outcome. We combined cross-sectional modeling of disease duration in a large cohort of patients (n = 134) and longitudinal analysis in a subset that delayed surgery (n = 31). To track subregional pathology, we applied surface-shape analysis techniques on manual mesiotemporal labels. Longitudinal and cross-sectional designs showed consistent patterns of progressive atrophy in hippocampal CA1, anterolateral entorhinal, and the amygdalar laterobasal group bilaterally. These regions also exhibited more marked age-related volume loss in patients compared with controls. We found a faster progression of hippocampal atrophy in patients with a seizure frequency ≥6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse. We observed progressive atrophy in hippocampal, amygdalar, and entorhinal subregions that frequently display neuronal loss on histology. The bilateral character of cumulative atrophy highlights the importance of early surgery. In patients who nevertheless delay this procedure, serial scanning may provide markers of surgical outcome.

Modeling grade progression in an active surveillance study

Prostate cancer grade, assessed with the Gleason score, describes how abnormal the tumor tissue and cells appear, and it is an important prognostic indicator of disease progression. Whether prostate tumors change grade is a question that has implications for screening and treatment. Empirical data on tumor grade over time have become available from men biopsied regularly as part of active surveillance (AS). However, biopsy (BX) grade is subject to misclassification. In this article, we develop a model that allows for estimation of the time of grade change while accounting for the misclassification error from BX grade. We use misclassification rates from studies of prostate cancer BXs followed by radical prostatectomy. Estimation of the transition times from true low-grade to high-grade disease is conducted within a Bayesian framework. We apply our model to serial observations on BX grade among 627 cases enrolled in a cohort of AS patients at Johns Hopkins University who were biopsied annually and referred to treatment if there was any evidence of disease progression on BX. We consider different prior distributions for the time to true grade progression. The estimated likelihood of grade progression within 10 years of study entry ranges from 12% to 24% depending on the prior. We conclude that knowledge of rates of grade misclassification allows for determination of true grade progression rates among men with serial BXs on AS. Although our results are sensitive to prior specifications, they indicate that in a nontrivial fraction of the patient population, tumor grade can progress.

Risk-reducing laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for low-grade appendiceal mucinous neoplasm: early outcomes and technique

Low-grade appendiceal mucinous neoplasm (LAMN) is a precursor lesion of pseudomyxoma peritonei, which, if treated suboptimally, may later disseminate throughout the abdominal cavity. We previously demonstrated the role of cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) to reduce the dissemination risk. Here we describe the feasibility and safety of minimal access cytoreductive surgery (MACRS) and HIPEC as an alternative to the open approach. We evaluated patients with LAMNs at risk of dissemination (known as LAMN II) who were referred to a national treatment centre between 2010 and 2012 and comparison is made between this group and patients undergoing open CRS and HIPEC for the same pathology over the same time period. Of the 39 patients with LAMN II, 10 patients were treated by MACRS and HIPEC and 7 were treated by an open approach. Among the MACRS procedures, there were no conversions to open surgery; median procedure length, median length of stay, and complication rates were similar between groups and there were no 30-day deaths. After 3- and 11-months median follow-up respectively, no patients have evidence of disease progression. The present series demonstrates that MACRS and HIPEC is a feasible and safe alternative to the open procedure with the advantage of smaller abdominal wounds and comparable morbidity and inpatient stay. Longer follow-up is needed to assess the impact on disease progression.

Phase II study of cilengitide in the treatment of refractory or relapsed high-grade gliomas in children: A report from the Children's Oncology Group

Cilengitide, an αv integrin antagonist, has demonstrated activity in recurrent adult glioblastoma (GBM). The Children's Oncology Group ACNS0621 study thus evaluated whether cilengitide is active as a single agent in the treatment of children with refractory high-grade glioma (HGG). Secondary objectives were to investigate the pharmacokinetics and pharmacogenomics of cilengitide in this population. Cilengitide (1800 mg/m(2)/dose intravenous) was administered twice weekly until evidence of disease progression or unacceptable toxicity. Thirty patients (age range, 1.1-20.3 years) were enrolled, of whom 24 were evaluable for the primary response end point. Toxicity was infrequent and mild, with the exception of one episode of grade 2 pain possibly related to cilengitide. Two intratumoral hemorrhages were reported, but only one (grade 2) was deemed to be possibly related to cilengitide and was in the context of disease progression. One patient with GBM received cilengitide for 20 months and remains alive with continuous stable disease. There were no other responders, with median time to tumor progression of 28 days (range, 11-114 days). Twenty-one of the 24 evaluable patients died, with a median time from enrollment to death of 172 days (range, 28-325 days). The 3 patients alive at the time of this report had a follow-up time of 37, 223, and 1068 days, respectively. We conclude that cilengitide is not effective as a single agent for refractory pediatric HGG. However, further study evaluating combination therapy with cilengitide is warranted before a role for cilengitide in the treatment of pediatric HGG can be excluded.

Xanthoma of the Sphenoid Sinus: A Rare Presentation

Objectives:1) Present what is to the best of our knowledge the first reported case of a patient with a sphenoid sinus xanthoma. 2) Discuss the details of the clinical presentation, histopathological and radiological findings, and management of this patient.Methods:Medical charts and the scientific literature were reviewed.Results:A 36‐year‐old female patient with family history of hyperlipidemia presented with a 1‐year history of sporadic epistaxis and an episode of severe headache 2 months prior to evaluation. The rest of her medical history and physical examination were unremarkable. Computed tomography (CT) scan and magnetic resonance images revealed a soft tissue lesion occupying and infiltrating the posterolateral aspect of an expanded sphenoid sinus on the left side. Patient underwent endoscopic sinus surgery in December 2011 with intraoperative findings of a yellow‐tan, friable soft tissue filling the left sphenoid sinus. Biopsy was taken for which histologic and immunohistochemical analysis revealed proliferating foamy histiocytes consistent with xanthoma cells. As of her last follow‐up examination (9 months post‐op), the patient has remained asymptomatic without evidence of disease progression on nasal endoscopy or CT scan.Conclusions:Very few cases of xanthomas arising in the paranasal sinuses have been described in the literature. Those that have been described have only occurred in the maxillary sinus. We present the case of a 36‐year‐old woman with family history of herlipidemia with a left sphenoid sinus xanthoma. This is to our knowledge the first case of such a lesion reported in the English literature.

Efficacy and safety profile of long‐term exposure to lenalidomide in patients with recurrent multiple myeloma

Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len/Dex. A total of 50 patients with RRMM who were treated with long-term Len for ≥ 2 years from 2 Intergroupe Francophone du Myélome (IFM) centers (Lille and Nancy) were included in the current study. The median age of the patients was 58 years, with 30% of the patients aged >65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len/Dex for ≥ 3 years. The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for ≥ 3 years. With a median follow-up of 4 years, 19 (38%) patients had stopped treatment with Len/Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to <3 years and for ≥ 3 years (P=025). The safety profile was manageable, similar to that of Len when administered for a shorter period of time; 16% of patients had grade 3 to 4 neutropenia, 6% had thrombopenia, 6% had anemia, and 20% experienced thromboembolic events, all of venous type. The annual incidence rate of second primary malignancy was 1.96% in the current series. The results of the current study confirmed that the Len/Dex combination is feasible for long-term use in patients with RRMM, with a significant benefit noted in terms of time to disease progression for prolonged treatment with Len/Dex.

Icrucumab, a fully human monoclonal antibody against the vascular endothelial growth factor receptor-1, in the treatment of patients with advanced solid malignancies: a Phase 1 study

IMC-18F1 (icrucumab), a human monoclonal antibody against vascular endothelial growth factor receptor-1 (VEGFR-1), potently inhibits ligand-dependent phosphorylation of VEGFR-1 and downstream signaling, making icrucumab an attractive candidate for antitumor activity. The primary objective was to determine the safety profile and maximum tolerated dose of icrucumab in patients with advanced solid tumors that were previously unresponsive to standard therapy or for which no standard therapy was available. In this open-label, dose-escalation, Phase 1 study, patients received icrucumab intravenously weekly at 2, 3, 6, and 12 mg/kg (Cohorts 1-4), every other week (q2w) at 15 mg/kg (Cohort 5), or every third week at 20 mg/kg (Cohort 6). Patients received icrucumab until evidence of progressive disease or other withdrawal criteria were met. Twenty-six patients received icrucumab. The most common adverse events were fatigue, nausea, peripheral edema, anemia, dyspnea, and vomiting. No dose-limiting toxicities (DLTs) were observed in Cohorts 1-5. Two DLTs were observed in Cohort 6 (anemia and hyponatremia), and enrollment was stopped. No patient demonstrated an immunogenic response. Overall, icrucumab exhibited nonlinear pharmacokinetics at doses >6 mg/kg. Six patients (23.1 %) achieved stable disease with median duration of 11.1 weeks (range = 10.3-18.7 weeks); tumor types were thyroid, melanoma, colorectal (3 patients), and small-cell lung cancers. Icrucumab was safely administered weekly at doses of 2-12 mg/kg and q2w at a dose of 15 mg/kg with no DLTs. Based on achievement of stable disease, icrucumab has potential for antitumor activity against advanced solid tumors.

A Multicenter Phase 1 Study of EMD 525797 (DI17E6), a Novel Humanized Monoclonal Antibody Targeting αv Integrins, in Progressive Castration-resistant Prostate Cancer with Bone Metastases After Chemotherapy

BackgroundEMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the αv subunit of human integrins. Blocking αv integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis. ObjectiveEvaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments. Design, setting, and participantsA phase 1 open-label study in 26 patients (four European centers). Eligible patients (≥18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate-specific antigen (PSA) values. InterventionPatients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500mg every 2 wk). Outcome measurements and statistical analysisTreatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used. Results and limitationsPatients were treated for a mean of 16.8 ± 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for ≥18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials. ConclusionsNo DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500mg every 3 wk were chosen. Trial registrationNCT00958477 (EMR 62242-002).

Defining cardiac adaptations and safety of endurance training in patients with m.3243A&gt;G-related mitochondrial disease

BackgroundCardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown.Methods and resultsBefore and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p < 0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p < 0.01). Peak arterial–venous oxygen difference (p < 0.05), oxygen uptake (VO2) and power were decreased in patients (both p < 0.01) with no significant difference in cardiac power output. All patients remained stable and completed ≥ 80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p < 0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post-exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p < 0.05).ConclusionPatients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis.

Hipofraccionamento no Carcinoma Localmente Avançado da Mama: Esquema “Flash”

Breast cancer is a major cause of death in our country. The Department of Radiation Oncology of Portuguese Institute of Oncology in Coimbra are using a scheme of hypofraccionation called "Flash" as a treatment option for elderly patients or low performance status, with locally advanced breast cancer, or with stage IIb or IV, as a neoadjuvante or palliative aim. Evaluation of the therapeutic response, for the group of patients selected, who did the hypofractionated schemed, in a retrospective study. Between January 2006 and December 2008, a total of 83 patients diagnosed with locally advanced breast cancer or with stage IIb or IV, were subjected to breast "Flash". The radiation dose prescribed was 13Gy in 2 fractions in 3 days (in 23 patients - 27.7%) and 26 Gy in 4 fractions in 5 weeks (60 patients - 72.3%), with 4MV photons, in the sick breast. Global survival was evaluated using the Kaplan-Meier method. Statistical analysis was performed by applying the version 17.0 of SPSS and statistical tests were evaluated at a significance level of 5%. 80 patients (96.4%) who have made breast "Flash" were female, aged between 59 and 93 years and performance status (Karnosfky scale) between 90 and 50%. In 72 patients (86.7%) the histology was invasive ductal carcinoma. Surgery was held in 53% of patients (44) after breast "Flash", the radical modified mastectomy was the most common surgical technique. The diagnosis of bone metastasis was made in 10 patients (12%), while the global survival rate was 68.7% (57 patients). 10 patients (12%) died because disease progression or persistence. In 50.6% (42 patients) there was no evidence of disease progression and 3.6% (3 patients) showed clinical improvement. The "Breast Flash" is a safe treatment modality, in terms of secondary effects, and a valid therapeutic option for elderly patients or low performance status, with the diagnosis of locally advanced cancer or stage IIb or IV, as neoadjuvante, adjuvant or palliative aim. There is a little risk of relapse or progression in patients with good conditions, so the global survival rate is greater in these cases. There is a little iatrogenesis associated with this type of treatment; just one patient had grade III radiodermatitis.

Real-world symptom burden and early treatment discontinuation in first-line metastatic breast cancer (MBC).

9619 Background: Treatment options in 1st line metastatic breast cancer (MBC) vary and may include chemotherapy, targeted, and hormone therapy. Some patients (pts) do not complete therapy as planned, perhaps due to treatment related toxicities. The current study examined the association of symptom burden with early treatment discontinuation (ETD) of 1st line therapy of MBC in real-world settings. Methods: Data were abstracted from medical records of pts at 9 community oncology practices. Eligible pts had stage IV breast cancer with start of 1st line therapy on 1/2004 to 6/2012, were ≥ 18 years, and had ≥ 1 Patient Care Monitor (PCM) survey during 1st line. The PCM is an 86-item survey of cancer-related symptoms collected as part of routine clinical care. Age, race, HER2 status, hormone status, oral and infused agents, dates of diagnosis, treatment, progression, and death were recorded. ETD was defined by direct indication of early stopping in the medical record, or by treatment duration ≤ 6 weeks without evidence of disease progression. Cox regression of ETD with time varying covariates was used to examine the impact of 23 separate symptoms as well as an overall composite symptom burden score based on pt responses on each symptom. Results: 797 pts were included, with mean age of 58.4 years, 62.1% White; with 340 on Chemotherapy (CT), 349 on CT + Targeted therapy (T) and 108 on Hormone therapy only (H). Overall, ETD occurred in 95 (11.9%) pts, with rates highest among CT (15.3%), followed by T (10.0%) and H (7.4%). Cox regression showed that 21 of 23 symptoms each increased the risk of ETD. In the composite symptom burden score (median 7.1; range 0 - 21) analysis, overall symptom burden was found to be significant (HR = 1.124, p &lt; 0.0001), indicating a 12.4% increased risk of ETD with each additional symptom. Pts with 10+ symptom score had a significantly increased risk of ETD (HR = 3.09, p &lt; 0.0001) compared to pts with &lt; 5 symptom score. Pts with 15+ symptom score had the highest risk of ETD (HR = 5.75, p &lt; 0.0001). Conclusions: Pts treated with CT for 1st line MBC had the highest rate of ETD. The likelihood of ETD increased as the number of symptoms increased. Future research is needed to evaluate ETD on pt outcomes, including overall survival.

Methotrexate, rituximab, and temozolomide in CNS lymphoma: The Mayo Clinic experience.

2058 Background: We present a tertiary center experience with high-dose methotrexate, rituximab and temozolomide (MRT) chemotherapy in both primary and secondary CNS lymphoma. Methods: A retrospective analysis was performed for a total of 27 patients (20 male, 7 female) who underwent treatment at Mayo Clinic, Rochester between November 2010 and October 2012. The median age was 63 years (range 23-73). Of these, 12 patients were diagnosed with primary CNS lymphoma, while 15 patients had secondary CNS lymphoma. All patients received at least 1 cycle of MRT. The most common histological subtype was diffuse large cell lymphoma (23 of 27 patients). Other histological subtypes were high grade lymphoma (2 patients), Burkitt’s lymphoma (1 patient) and Mantle cell lymphoma (1 patient). Results: Of 26 patients, who underwent imaging studies for response assessment after MRT, 14 patients achieved complete response (CR), 4 patients achieved partial response (PR), 2 patients had stable disease, while 6 patients had evidence of disease progression. Overall, the median number of chemotherapy cycles with MRT was 3 (range 1-6). For patients, who achieved CR, the median number of MRT cycles was 4 (range 2-6). MRT was well tolerated. Of 27 patients, who underwent their entire treatment at Mayo Clinic, grade 3 or higher treatment related toxicity were noted to be as follows – neutropenia (9/27), thrombocytopenia (4/27), anemia (7/29), and transaminitis (10/27). 16 of 27 patients proceeded to high dose chemotherapy and autologous stem cell transplant. Out of 16 patients, 14 received BCNU/Thiotepa as conditioning regimen, while 2 patients underwent BEAM conditioning. All 16 patients who underwent transplantation remain in CR at this time. Of the remaining 11 patients, 4 are being planned for autologous transplantation, 2 received and responded to salvage chemotherapy, while 5 patients died of progressive disease. Conclusions: Overall, the MRT regimen was well tolerated. Overall response rate was noted to be 67% (18 of 27 patients) and achieved CR in 54% patients (14 of 26 patients). Patients who underwent autologous stem cell transplantation as consolidation therapy continue to do well at a median followup of 12.5 months (range 2-20 months).

Everolimus for Korean patients with metastatic renal cell carcinoma who have failed initial treatment of a vascular endothelial growth factor (VEGF): Tyrosine kinase inhibitor (TKI).

e15516 Background: To assess the efficacy, prognostic factor, and safety of everolimus for Korean patients with metastatic renal cell carcinoma (mRCC) who have failed treatment with vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Correlation between everolimus associated adeverse events (AEs) and clinical outcome was also analyzed. Methods: Clinical data was collected from all patients with mRCC treated with second-line or more everolimus, patients who has not underwent follow up evaluation after 2 weeks without evidence of disease progression were excluded due to lack of safety evaluation. Results: Totally 100 patients met the inclusion criteria, the median follow-up duration from the time of everolimus initiation was 10.2 months (range, 0.9 – 30.9). The median progression free survival (PFS) of everolimus was 4.4 months, and the overall survival (OS) was 9.1 months. Heng’s criteria was an independent prognostic factor for OS. [Hazzard ratio (HR) (favouralbe risk group vs. poor risk group) = 0.12, P=0.014; HR (intermediate vs. poor) = 0.40, P=0.005] Response to initial VEGF-TKI was also independent prognostic factor for both PFS and OS. [PFS : HR (progression group vs. disease control group) = 3.17, P=0.002; and OS : HR =4.75, P&lt;0.001] Grade 3 or more AEs with everolimus were anemia (15%), hyperglycemia (8%), pneumonitis (7%), and stomatitis (6%). Of note, incidence of pneumonitis was similar (28 cases, 29%) to that of western, 12 patients permanently discontinued. Existence of hyperglycemia and anemia independently correlated with favorable PFS, [HR (Hyperglycemia group vs. non-hyperglycemia group) = 0.58, P =0.056; HR (Anemia group vs. non-anemia group) = 0.51, P=0.021]. Conclusions: Our results suggest that everolimus was effective also in Korean patients. Types and incidences of AEs after everolimus in Korean were mostly similar to western, while they were more severe and permanent discontinuation occurred, especially in pneurmonitis. Thus, Korean mRCC patients who were treated with everolimus should be carefully assessed for AEs to achieve uninterrupted full-dose therapy.