Reasons For Treatment Discontinuation Research Articles

Abstract P4-14-20: A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC)

Abstract Background: ONT 380 is a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects. Preclinical studies demonstrate synergism with trastuzumab (T) and chemotherapy, as well as activity in models of HER2+ CNS disease. Based on the potential for increased clinical activity of dual HER2 blockade in the context of a targeted cytotoxic agent, we evaluated the safety, tolerability, and anti-tumor activity of ONT-380 in combination with T-DM1 in patients (pts) with MBC with and without CNS metastases (mets). Methods: 3+3 dose escalation with MTD expansion cohorts in pts with/without CNS mets evaluating ONT-380 (300 or 350 mg PO BID) combined with T-DM1 3.6 mg/kg IV q 21 days. Prior treatment with T and taxane was required; prior lapatinib and asymptomatic brain mets (treated or untreated) were allowed. Assessments included safety, PK, and systemic (RECIST 1.1) and CNS (modified RECIST) tumor response, with brain MRI at baseline and q 6 wks in pts with CNS mets at baseline. DLT was defined as the occurrence of protocol-specified events during the 1st treatment cycle. Results: As of 01 June 2015, 51 pts have been enrolled and have received between 1 and 22 cycles, with safety data available for 43 pts (n=36 at 300 mg BID; n=7 at 350 mg BID). Pts had a median of 2 prior treatments for MBC, including T (n=43); pertuzumab (n=15) and lapatinib (n=7). The MTD for ONT-380 was 300 mg BID with 5/36 pts (14%) with DLT (Gr 3 AST/ALT [n=4]; Gr 2 vomiting/Gr1 diarrhea [n=1]) vs. 3/7 pts (43%) with DLT at 350 mg BID (Gr 3 vomiting [n=1]; Gr 3 hypersensitivity [n=1]; Gr 3 fatigue [n=1]). Overall, the majority of AEs have been Gr 1 or 2. The most common AEs, regardless of relationship, were nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia. Gr 3 AST/ALT elevation has occurred in 7/43 pts (16%), with no events meeting Hy's law, and has been reversible with dose interruption and reduction except in 2 pts found to have progressive liver mets. No Gr 3 diarrhea has occurred at any dose. ONT-380 PK was dose proportional, and no drug-drug interaction was observed with T-DM1. In 33 of 43 pts with data available from at least one follow-up scan to evaluate response, best systemic response regardless of dose was 11 PR, 16 SD, and 6 PD, with clinical benefit rate (CBR= CR, PR, or SD >6 mos) of 19/33 (58%). The most common reason for treatment discontinuation was PD, with 3 pts coming off study for AEs (n=1 each of Gr 3 hypersensitivity, Gr 2 vomiting, Gr 3 AST/ALT). Eight pts to date have been evaluable for CNS response (untreated or progressive CNS mets with ≥1 follow-up MRI), with best CNS response of 1 CNS CR, 2 CNS PR, and 5 CNS SD, with a CNS CBR of 5/8 (63%). All pts with CNS response are still active. Conclusion: Treatment with ONT-380 300 mg BID and T-DM1 3.6 mg/kg has been tolerable. Early evidence of anti-tumor activity has been seen, including clinical benefit in patients with CNS mets. Updated results will be presented. Citation Format: Ferrario C, Hamilton E, Aucoin N, Falkson CI, Khan Q, Krop IE, Welch S, Bedard PL, Conlin A, Chaves J, Vo A, Walker L, Borges V. A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-20.

Abstract P4-13-10: Stomatitis following everolimus (EVE) plus exemestane (EXE) in patients with hormone receptor-positive (HR+), HER2– advanced breast cancer (ABC) in the BALLET trial (CRAD001YIC04)

Abstract Background Stomatitis is the most common adverse event (AE) associated with mTOR inhibitors, including EVE. In the pivotal BOLERO-2 trial, stomatitis was reported for 59% vs 12% (Gr3, 8% vs <1%) of pts with HR+, HER2– ABC who received EVE + EXE vs EXE alone. Of the limited real world evidence available, the BRAWO trial showed a stomatitis incidence of 39.8% (Gr3, 3.4%) in a similar pt population. Additional data are warranted to better understand the stomatitis incidence and time-course in order to minimize treatment discontinuations. Methods BALLET is a Phase 3b, European, multi-center, open-label, single-arm, expanded-access study that evaluated safety of EVE (10 mg/d) and EXE (25 mg/d) in 2131 postmenopausal women with HR+, HER2– ABC that progressed on prior NSAI treatment. Primary endpoint was safety; secondary endpoint was characterization of grade 3/4 AEs. In this exploratory analysis, we split the pts in two groups based on having experienced at least one all grade stomatitis event in the first 8 wks (cut-off chosen based on reports that 89.4% of stomatitis events occurred within 8 wks of EVE initiation [Rugo, ASCO 2014]) vs none. Results This subgroup analysis included 919 pts with stomatitis (43.1% of the full population). Baseline pt characteristics were comparable to the overall study population, except for more comorbidity (cardiovascular and metabolic disorder) in stomatitis subset. Pts with stomatitis had a longer EVE treatment duration vs pts who didn't (5.8 mo [95%CI, 5.0-6.2] vs 4.7 mo [95%CI, 4.4-5.3]; hazard ratio, 1.121 [95%CI, 0.97-1.28] censored by pts who switched to commercial drug). The relative risk of initial onset of stomatitis at 6 wks was ∼40%; median time to onset was 28 days. Majority of stomatitis events were of grade 1/2 severity (80%); grade 3/4 stomatitis was reported for 20% of pts. Most frequent reasons for treatment discontinuation in pts with stomatitis were reimbursement (37.6%), disease progression (35.0%), and AEs (16.2%). Most frequent AEs which led to treatment discontinuation in these pts were stomatitis in 3.7% (Grade 3/4, 2%), pneumonitis in 2.9% (Grade 3/4, 1.3%) and asthenia in 1.8% (Grade 3/4, 1%). Median EVE relative dose intensity in pts with stomatitis was 0.92. In the stomatitis subset, dose interruptions and reductions were required for 66.7% and 37.6% of pts, respectively; most frequent reasons for dose adjustments were AEs (65.9%) which included stomatitis (46.8%), asthenia (6.3%), and pneumonitis (5.3%). Median time to first dose modification in pts with stomatitis was 30 days; median duration of dose interruptions was 16 days. On-treatment deaths (4.4%) were due to progressive disease (2.1%), AEs (1.7%), and other reasons (0.5%). Conclusions These results confirmed the stomatitis time-course observed previously and that the majority of these events are of low grade. Stomatitis was the most common cause of dose reductions and interruptions due to AEs and was manageable with dose adjustments; there was a positive association between stomatitis and longer treatment duration. Therefore, proactive management, diligent monitoring and appropriate dose modifications, are recommended to keep pts on treatment. Citation Format: Ciruelos EM, Jerusalem G, Generali D, Lang I, Gavila JG, Michelotti A, Tjan-Heijnn VCG, Mariani G, Conte P, Beliera A, Camozzi M, Lorizzo K, Martin M. Stomatitis following everolimus (EVE) plus exemestane (EXE) in patients with hormone receptor-positive (HR+), HER2– advanced breast cancer (ABC) in the BALLET trial (CRAD001YIC04). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-10.

Abstract PD2-01: Randomized phase 3 trial of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor positive, node positive early breast cancer: Final efficacy and safety results of the femara versus anastrozole clinical evaluation (Face) trial

Abstract Background The FACE trial was designed to evaluate the efficacy and safety of adjuvant letrozole (LET) versus anastrozole (ANA) in postmenopausal patients with hormone receptor-positive (HR+), node-positive breast cancer. Materials and methods In this phase 3b, open-label, multicenter trial, postmenopausal women with HR+ and lymph node positive breast cancer were randomized 1:1 to receive either LET (2.5 mg) or ANA (1 mg) daily for 5 years in the adjuvant setting. Randomization was stratified by the number of lymph nodes (1-3 versus 4+) and HER2 status (positive versus negative). Patients with stage IIA, IIB or IIIA invasive cancer were eligible. Treatment continued for 5 years or until disease recurrence. The primary endpoint was disease free survival (DFS) at 5 years. Key secondary endpoints were safety and overall survival (OS). Results Between Dec 2005 and Mar 2008, 4170 patients were randomized to receive LET (n = 2076) or ANA (n = 2094). Baseline characteristics were generally balanced between the two arms. Median age was 62 years; 71.4% of pts had 1-3+ lymph nodes, and 8.7% of cancers were HER2+. Median duration of exposure was 60 months in both arms. With 709 of the protocol-planned 959 DFS events, 5-yr estimated DFS rate was 84.9% for LET vs. 82.9% for ANA (HR = 0.93 [95% CI: 0.80 – 1.07]; p = 0.3150). 5-yr estimated OS rate was 89.9% for LET vs. 89.2% for ANA (HR = 0.98 [95% CI: 0.82 – 1.17]; p = 0.7916). Primary reasons for treatment discontinuation in the LET versus ANA arms were AEs (15.1% vs. 14.3%) and disease progression (9.5% vs. 10.4%). Safety profiles were similar between treatment arms. The most common adverse events (AEs) in the LET versus ANA arms were arthralgia (48.2% vs. 47.9%), hot flushes (32.5% vs. 32.3%) and fatigue (16.8% vs. 16.6%). Suspected drug-related grade 3/4 AEs were reported in 9.5% of patients in the LET arm versus 8.1% of patients in the ANA arm; suspected drug-related AEs leading to discontinuation were reported in 14.0% vs. 12.9% of patients in LET vs. ANA arms, respectively. Preplanned and exploratory subgroup analyses will be presented. Conclusions Treatment with LET did not demonstrate DFS efficacy difference over ANA in postmenopausal patients with HR+, node-positive breast cancer. (Funded by Novartis; ClinicalTrials.gov number NCT00248170). Citation Format: O'Shaughnessy J, Yardley DA, Burris HA, De Boer R, Amadori D, McIntyre K, Ejlertsen B, Gnant M, Jonat W, Pritchard KI, Dowsett M, Hart L, Poggio S, Valagussa P, Salomon H, Wamil B, Smith I. Randomized phase 3 trial of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor positive, node positive early breast cancer: Final efficacy and safety results of the femara versus anastrozole clinical evaluation (Face) trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD2-01.

Characteristics of clients using a community-based drug treatment service (‘CAPS-AD’) in Brazil: An exploratory study

BackgroundSubstance use is common in Brazil. In order to improve availability of substance misuse care services, over 400 Psycho-Social Care Centres for Alcohol and Drugs (CAPS-AD) – providing community-based care – have been established following mental health care reform (2001). Information on CAPS-AD clients and outcomes is limited. The present study examined select characteristics of local CAPS-AD clients. MethodsN=143 adult CAPS-AD clients in Ceilândia (suburb of Brasília, Federal District) participated in a 1-week ‘snapshot’ assessment of service users (February 2015). Following consent, descriptive data were collected by a brief, anonymous interviewer-administered questionnaire that included socio-demographic, drug use, treatment history and needs/barriers information. ResultsParticipants were predominantly male; middle-aged; unemployed; married; with middle-school education; primary problem drugs indicated were alcohol and cocaine/crack; half had prior treatment histories and indicated that treatment was externally motivated; 60% reported ways to improve treatment and possible reasons for treatment discontinuation; in multi-variate analyses, the latter was associated with employment and education status (both p<.05). ConclusionCAPS-AD services appear to have increased low-barrier substance misuse treatment availability in Brazil, as well as attract individuals new to the treatment system. Various potential barriers to continuing in treatment should be addressed and more research on CAPS-AD clients and outcomes is needed.

Everolimus and sunitinib as first- and second-line treatments of patients with metastatic papillary renal cell carcinoma (pRCC): A retrospective study of the GETUG (Groupe Français d’Etude des Tumeurs Uro-Génitales).

505 Background: pRCC accounts for 15% of all renal cancers. Two French prospective phase II trials demonstrated efficacy of both Sun and Eve in first-line treatment of metastatic disease (RAPTOR (NCT00688753) and SUPAP (NCT00541008)). Most patients (pts) usually receive the alternate drug at progression. We report the first series of drug sequencing in pRCCs. Methods: We updated clinical data of metastatic pts with pathologically documented pRCC, who were treated in firs line or more with Sun or Eve, from 2/06 to 6/15, in 24 GETUG centers. Results: 196 pts (166 men, 30 women), median aged of 61 years, with histological subtypes (HST) I (28 pts), II (122 pts) or unclassified (46 pts), were treated for metastatic pRCC in 1st-line: group 1 Su 50 mg daily 4/6 weeks (n=158 pts) ; group 2 Eve 10 mg daily (n=38 pts). 76 pts were included in the RAPTOR or SUPAP studies. The median follow-up was 59.5 months. We found no difference between the 2 groups in terms of patients’ characteristics, clinical benefit in first-line (CR+PR+SD) (71% vs 72%; p=0.95) or progression-free survival (PFS) (PFS-1: 5.7 vs 4.6 months; p=0.152). Reasons for treatment discontinuation were tumor progression (74% vs 70%) or toxicity (26 vs 30%) (p=0.58). 134 pts received the alternative drug in second-line (group 1: Eve; group 2: Sun) with similar clinical benefit (64% vs 58%; p=0.69) and median PFS (PFS-2: 3.5 vs 3.0 months p=0.98). Overall survival (OS) did not differ between the two groups (16.4 vs 17.6 months; p=0.58). Age, Karnofsky performance status &lt; 80 (KPS-80), HST, platelet (Plts) and absolute neutrophil counts (ANC), hemoglobin and calcium levels, time from diagnosis to metastases (TTM) were studied as prognostic variables. In multivariable analysis, only Plts and KPS-80 had prognostic impact on EFS-1, whereas ANC, KPS-80 and TTM were prognostic for OS. We found a trend in favor of HST I vs non I, with no statistical difference in terms of PFS or OS. Conclusions: In this large retrospective series of metastatic pRCC pts, Sun and Eve had good compliance and similar efficacy in terms of first-, second-line PFS and overall survival.

Cáncer cérvicouterino, reporte de tres años en una unidad médica de atención ambulatoria

Objective: to determine the epidemiological characteristics of cervical cancer during a three-year period in a medical ambulatory care unit (macu) of the General Hospital of the zone 15 in Reynosa, Tamaulipas. Methods: the information was gathered in the care unit database, from March to October 2012. This base contained a follow-up of 1 663 women who diagnosed dysplasia and, uterine and cervical cancer; in addition, it was provided monitoring care and treatment for 8 489 women. Results: 59.1% were probable cases and in 40.9% dysplasia and cancer were confirmed. The most affected group was that of women between 25 and 44 years old. 17.74% was estimated as a percentage of abandonment of treatment and 54.7% of correlation between cytological and histopathological. Conclusions: as this is a descriptive study, it only allowed us to know the frequency but not the reason for abandoning the treatment. It would be necessary to conduct a follow-up study to determine the reasons for discontinuation of treatment.

Use and satisfaction of complementary and alternative medicine among diabetic patients in a tertiary care hospital

Background: Diabetes is a chronic disorder which requires long-term treatment. Non- adherence to treatment is a major factor responsible for morbidities and mortalities associated with diabetes. Complementary and alternative medicine (CAM) use has been one of the reasons for discontinuation of treatment. This study was conducted to assess the extent to which CAM and non-CAM users adhere to medical treatment. Methods: 200 patients attending the diabetic clinic over a period of 2 months participated in the study. After obtaining written informed consent, they were administered a CAM use and satisfaction questionnaire (TSQM) based on effectiveness, no side-effects, convenience and global satisfaction. Results: Out of 200 participants, 29% (58) used CAM. Naturopathy was the most commonly followed type of CAM (60 %; 35). Residing in the rural areas (OR-3.7), Socio- economic status above poverty line (OR- 9), diabetics with co- morbidities (OR- 6) and microvascular complications (OR-6) and using insulin (OR-3) was found to be the predictors of CAM use. However, the incidence of hypoglycemic episodes was 52 times higher among CAM users. (91%; 52) of the CAM users did not reveal the use to their physicians, out of which (70%; 40) did not disclose due to the fear of discouragement by the doctor. CAM was found to be better in all aspects of patient satisfaction like effectiveness, no- side-effects and global satisfaction than conventional medicine while conventional medicine users scored it to be more convenient to use than CAM. Conclusions: Doctors should enquire diabetics regarding CAM use since the voluntary disclosure is very less. Keeping lines of communication open for any discussions regarding pros and cons of CAM. Increasing patient awareness about potential drug interactions, when CAM is practised along with conventional medicine.

Utilization of Subcutaneous Methotrexate in Rheumatoid Arthritis Patients After Failure or Intolerance to Oral Methotrexate: A Multicenter Cohort Study.

IntroductionLow-dose weekly methotrexate (MTX) is the mainstay in the therapy of rheumatoid arthritis (RA). It can be given via oral, intramuscular or subcutaneous (SC) route. This study sought to determine the real-world pattern of treatment with SC MTX in Portuguese adult patients with active RA.MethodsUtilization of Metoject® in Rheumatoid Arthritis (UMAR) was a non-interventional, cohort multicenter study with retrospective data collection. Eligible patients had active RA, at least 18 years of age, and started SC MTX treatment in 2009 or 2010 after failure or intolerance to oral MTX. Data were collected from patient’s clinical records. Both non-parametric and parametric survival methods were used to obtain a detailed understanding of SC MTX treatment duration.ResultFifty patients were included, of which only 9 discontinued SC MTX during the study follow-up period. The probability of discontinuation after 1, 2, and 3 years of treatment of SC MTX treatment is expected to be 6.10%, 8.50%, and 23.20%, respectively. The extrapolated median duration of SC MTX using an exponential model was 106.4 months/8.87 years. Mean dose of SC MTX was 18.36 mg. The reasons for treatment discontinuation were occurrence of adverse events in six patients and lack of efficacy in three.ConclusionThe long treatment duration of SC MTX highlights its excellent tolerability compared to oral MTX, especially concerning the frequent adverse gastrointestinal events of MTX. Furthermore, long MTX treatment duration provides the opportunity to postpone or even avoid expensive therapies with biologics. The results obtained from the UMAR study provide important information for the utilization and public financing of SC MTX in Portugal.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0276-3) contains supplementary material, which is available to authorized users.

UDP-glucuronosyltransferase 1A1*6 and *28 polymorphisms as indicators of initial dose level of irinotecan to reduce risk of neutropenia in patients receiving FOLFIRI for colorectal cancer.

BackgroundIrinotecan (CPT-11)-induced neutropenia is associated with UDP-glucuronosyltransferase (UGT) 1A1*6 and *28 polymorphisms. This prospective study investigated whether using these polymorphisms to adjust the initial dose of CPT-11 as part of FOLFIRI treatment in colorectal cancer patients might improve safety.MethodsAll data were collected by a physician. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia, reasons for treatment discontinuation, and time-to-treatment failure were evaluated. Multivariate analysis was used to assess the risk of neutropenia.ResultsA total of 795 patients were divided into wild-type (*1/*1) (50.1 %), heterozygous (*28/*1, *6/*1) (41.1 %), and homozygous (*28/*28, *6/*6, *28/*6) (8.which are associated with a decrease in the8 %) groups, in which the median starting dose of CPT-11 was 143.0, 143.0, and 115.0 mg/m2, respectively. First-cycle grade ≥3 neutropenia occurred in 17.3, 25.4, and 28.6 % of these patients, respectively. Multivariate analysis revealed that the incidence of grade ≥3 neutropenia was significantly greater in the heterozygous and homozygous groups than in the wild-type group [odds ratio (OR) 1.67; 95 % confidence interval (CI) 1.16–2.42; p = 0.0060, and OR 2.22; 95 % CI 1.22–4.02; p = 0.0088, respectively]. Age (OR 1.77; 95 % CI 1.24–2.53; p = 0.0017), coelomic fluid (OR 1.84; 95 % CI 1.05–3.25; p = 0.0343), and non-reduction in starting dose (OR 1.53; 95 % CI 1.08–2.18; p = 0.0176) were also identified as significant risk factors.ConclusionThe risk of neutropenia was higher in the heterozygous and homozygous groups at initiation of CPT-11 treatment. This suggests that when a reduction in dose is required in patients harboring two variant alleles, the decrease should be approximately 20 %.

Factors associated with radiation therapy incompletion for patients with early-stage breast cancer.

The purpose of the study was to examine factors associated with adjuvant radiation treatment (RT) incompletion for women with breast cancer within a large national cancer database. We identified 394,334 women diagnosed with stage I-III breast cancer during 2004-2012 in the national cancer database who initiated adjuvant external beam adjuvant RT and examined the proportion of women not completing treatment. We used multivariable logistic regression to examine patient, clinical, and facility factors associated with RT incompletion for those who had breast-conserving surgery (BCS), defined as<15 fractions and<3990 centiGray [cGy] (accounting for adoption of hypofractionation), and mastectomy (PMRT, defined as<5000cGy and<25 fractions), separately. We also examined RT incompletion after BCS using more traditional definitions of<25 fractions and<4500cGy for diagnosis years≤2010. Among the 319,003 women who underwent BCS and the 75,331 women who underwent mastectomy and initiated RT, 98.4 and 97.8% completed radiation, respectively. In adjusted analyses, older age was associated with RT incompletion (odds ratio [O.R.] for age≥80=2.53 for BCS-treated, 95% confidence interval [CI] 2.19-2.92; O.R. for PMRT incompletion=2.33, 95% CI 1.84-2.96; both versus age<50). In addition, those with≥2 comorbidities and lower-risk disease had higher odds of RT incompletion. After defining RT completion using more traditional definitions, 94.0% completed treatment. Reassuringly, we found a very low proportion of patients not completing RT, though we observed a higher likelihood for treatment incompletion in some sub-groups, most notably older women. Further studies should focus on reasons for treatment discontinuation in populations at risk for suboptimal treatment.

SAFETY OF LAMOTRIGINE IN PAEDIATRICS: A SYSTEMIC REVIEW

BackgroundLamotrigine has been increasingly used for the treatment of paediatric epilepsy. It is the most commonly prescribed new generation antiepileptic drug in the UK.ObjectivesTo identify adverse drug reactions associated with lamotrigine in children, compare the safety profile with other antiepileptic drugs and identify all clinical studies and case reports involving lamotrigine safety in children.MethodsDatabases EMBASE (1974-November 2013), Medline (1946-November 2013), PubMed and the Cochrane library for randomised controlled trials were searched for original research or reports in which paediatric patients received at least a single dose of lamotrigine for the treatment of epilepsy, with safety as an outcome measure.ResultsA total of 76 articles involving 2,184 paediatric patients were identified. There were 1,952 adverse events (AEs) reported. Fifty two of these AEs were from 49 case reports. Rash was most commonly reported, with a risk of 8.96 per 100 patients. Other common AEs included headache, fever, somnolence, vomiting, seizure aggravation, dizziness, cough, aggression, ataxia and insomnia. There were significantly higher risks of dizziness [RR 4.57, 95% CI: 1.88–11.12, p&lt;0.001], abdominal pain [RR: 2.53, 95% CI: 1.12–5.70, p=0.03] and nausea [RR: 5.94, 95% CI: 1.59–22.13, p=0.008] with lamotrigine than placebo. When compared with valproic acid, the risk of somnolence and vomiting was significantly lower for lamotrigine [RR: 0.35, 95% CI: 0.13–0.89, p=0.04] and [RR: 0.20, 95% CI: 0.04–0.89, p=0.03]. Discontinuation due to an adverse drug reaction was recorded in 72 children (3.2% of all treated patients). Rash was the most common reason, with 58% of treatment discontinuation attributed to different forms of rash.ConclusionRash is the most common adverse reaction of lamotrigine, seen in around 9% of patients, and it is the most common reason for treatment discontinuation.

Long-term Effectiveness of Antiepileptic Drug Monotherapy in Partial Epileptic Patients: A 7-year Study in an Epilepsy Center in China.

Background:It is important to choose an appropriate antiepileptic drug (AED) to manage partial epilepsy. Traditional AEDs, such as carbamazepine (CBZ) and valproate (VPA), have been proven to have good therapeutic effects. However, in recent years, a variety of new AEDs have increasingly been used as first-line treatments for partial epilepsy. As the studies regarding the effectiveness of new drugs and comparisons between new AEDs and traditional AEDs are few, it is determined that these are areas in need of further research. Accordingly, this study investigated the long-term effectiveness of six AEDs used as monotherapy in patients with partial epilepsy.Methods:This is a retrospective, long-term observational study. Patients with partial epilepsy who received monotherapy with one of six AEDs, namely, CBZ, VPA, topiramate (TPM), oxcarbazepine (OXC), lamotrigine (LTG), or levetiracetam (LEV), were identified and followed up from May 2007 to October 2014, and time to first seizure after treatment, 12-month remission rate, retention rate, reasons for treatment discontinuation, and adverse effects were evaluated.Results:A total of 789 patients were enrolled. The median time of follow-up was 56.95 months. CBZ exhibited the best time to first seizure, with a median time to first seizure of 36.06 months (95% confidential interval: 30.64–44.07). CBZ exhibited the highest 12-month remission rate (85.55%), which was significantly higher than those of TPM (69.38%, P = 0.006), LTG (70.79%, P = 0.001), LEV (72.54%, P = 0.005), and VPA (73.33%, P = 0.002). CBZ, OXC, and LEV had the best retention rate, followed by LTG, TPM, and VPA. Overall, adverse effects occurred in 45.87% of patients, and the most common adverse effects were memory problems (8.09%), rashes (7.76%), abnormal hepatic function (6.24%), and drowsiness (6.24%).Conclusion:This study demonstrated that CBZ, OXC, and LEV are relatively effective in managing focal epilepsy as measured by time to first seizure, 12-month remission rate, and retention rate.

Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon.

BackgroundIn the treatment of multiple sclerosis, a change of therapy is considered after treatment failure or adverse events. Although disease modifying drugs’ (DMD) efficacy and side effects have been fully analysed in clinical trials, the effects of previous therapy use are less well studied. We aimed to study medication persistence with glatiramer acetate in treatment-naive patients and in patients previously treated with interferon.MethodsA retrospective study of relapsing-remitting multiple sclerosis patients treated with glatiramer acetate in an MS Unit of a Spanish University Hospital (January 2004 – September 2013). Treatment time on glatiramer acetate was studied. Reasons for treatment discontinuation were considered as follows: lack of efficacy, serious adverse event, injection-related side effect, pregnancy and lost to follow-up. Use of prior DMD was registered and analysed. Homogeneity of groups was analysed using Fisher's and Mann-Whitney’s tests. The Kaplan Meier method and Cox regression model were used to estimate time to and risk of treatment discontinuation.ResultsIn total, 155 relapsing-remitting multiple sclerosis patients were treated with glatiramer acetate: 100 treatment-naive patients and 55 treated previously with interferon. At the end of the study, 76 patients (49.0 %) continued on glatiramer acetate (with an average treatment time (ATT) of 50.4 months, s.d.32.8) and 50 patients (32.3 %) had switched therapy: 27 patients (17.4 %) for inefficacy (ATT 29.2 months, s.d.17.5), 20 patients (12.9 %) for injection site reactions (ATT 16.5 months, s.d.20.3) and 3 patients (1.9 %) after serious adverse events (ATT 15.7 months, s.d.15.1). ATT in our cohort was 39 months (s.d.30.0), median follow-up 34 months. Six months after glatiramer acetate initiation, probability of persisting on GA was 91.4 %, 82.5 % after 12 months and 72.5 % after 2 years. The risk of glatiramer acetate treatment discontinuation was 2.8 [1.7 – 4.8] times greater for treatment-naive patients than for patients treated previously with interferon and this was hardly modified after adjusting for sex and age.ConclusionsGlatiramer acetate was safe and useful with low rates of serious adverse events and low rates of break-through disease. Injection intolerance proved a major limitation to glatiramer acetate use. Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.

Comparison of efficacy and safety of tacrolimus and methotrexate in combination with abatacept in patients with rheumatoid arthritis; a retrospective observational study in the TBC Registry

Objectives. Tacrolimus (TAC) and abatacept (ABT) inhibit T-cells via different mechanisms and, in combination, may be effective against rheumatoid arthritis. However, they may also disrupt normal immune functions. We compared the efficacy and safety of ABT administered to patients in combination with TAC, methotrexate (MTX), or other drugs. Methods. This was a retrospective multicenter study conducted to compare the efficacy and safety of ABT in 211 patients: the drug was administered together with TAC (ABT+ TAC group; 22 patients), MTX (ABT+ MTX group; 102 patients), or patients treated without concomitant MTX or TAC (ABT mono group; 87 patients). The disease activity, treatment continuation rate, and reason for discontinuation of treatment were investigated. Results. The retention rate at Week 24 was similar in the three groups. There were no cases of discontinuation related to the appearance of adverse events in the ABT+ TAC group. At Week 24, according to the European League Against Rheumatism response criteria, the “good” response rates were 33.3%, 13.4%, and 13.4% in the ABT+ TAC, ABT+ MTX, and ABT mono groups, respectively. Statistically significant decreases in various disease activity scores/indices were observed in all the groups as early as Week 4. Conclusions. Although the sample size was small, the results of this retrospective study suggest that the ABT+ TAC combination therapy has at least comparable safety and efficacy to those of the ABT+ MTX combination, and that it can thus be a useful option for patients who cannot take MTX.

Reasons for Treatment Discontinuation and Switch in Patients with Epilepsy: A Retrospective Observational Study in a US Population (P7.010)

Reasons for Treatment Discontinuation and Switch in Patients with Epilepsy: A Retrospective Observational Study in a US Population (P7.010)

Baseline demographics of the randomized, placebo-controlled, double-blind, phase III RADIANT-4 study of everolimus in nonfunctional gastrointestinal (GI) or lung neuroendocrine tumors (NET).

276 Background: NET are malignant tumors arising from neuroendocrine cells throughout the body. Everolimus (EVE), a mammalian target of rapamycin inhibitor, is approved for the treatment of advanced, well-differentiated pancreatic NET. There is an unmet medical need in GI and lung NET; targeted therapies, such as everolimus, are of particular interest. Methods: Patients with advanced nonfunctional NET of GI or lung origin with progressive disease (PD) within the past 6 months were randomized (2:1) to EVE 10 mg/d or placebo, both with best supportive care. Concomitant use of somatostatin analogue (SSA) was not allowed during the study, except for control of emergent carcinoid symptoms not manageable by standard therapy. Patients were stratified based on tumor sites, prior SSA exposure, and WHO performance status (PS) at baseline. Primary endpoint was progression-free survival (PFS) as assessed by central radiology review using modified RECIST 1.0 criteria. Primary analysis is planned after ~176 PFS events. Crossover to open label EVE after progression would not be allowed prior to the primary analysis. Overall survival was the key secondary endpoint. Results: Recruitment is completed. Of 388 patients screened, 302 were randomized (planned, 285). Median age was 63 years, 53% were females, and majority of them (76.2%) were white. The most common tumor sites were lung (29.8%), ileum (23.5%), and rectum (13.2%). WHO PS was 0 in 219 (72.5%) patients and 1 in 82 (27.2%) patients; 52% had received SSA prior to study entry. As of Sep 16, 2013, 173 (57.3%) patients remain on treatment, 127 (42.1%) discontinued treatment and 2 (0.7%) were not treated. PD (24.2%) and adverse events (10.6%) were the most common reasons for treatment discontinuation. Results of primary analysis are expected by early 2015. Conclusions: RADIANT-4 is the first phase III study to assess the efficacy and safety of EVE in patients with nonfunctional NET of GI or lung origin. Non-crossover design and prospective stratification of the population based on known prognostic factors should minimize confounding in the estimation of the treatment effect. Clinical trial information: NCT01524783.

Abstract 13907: Statin-Induced Myopathy is Mediated by Isoprenoid Depletion and is Independent of Serum Cholesterol Levels

Statin use is associated with muscle-related side-effects (ie, MRSE) in ~10-20% patients and is the most common reason for discontinuation of treatment. Moreover, high-risk patients who have inadequately controlled LDL-C as a result of statin intolerance present a significant public health problem. A study to assess the role of cholesterol and/or isoprenoid intermediates of the cholesterol biosynthetic pathway in statin-induced myopathy was conducted in female rats treated with cerivastatin for 14 days. Cerivastatin treatment of rats fed standard diet induced myopathy in type II muscle fibers, but not in type I muscle fibers. Cholesterol supplementation in the diet of cerivastatin treated rats increased circulating cholesterol levels, but failed to prevent myopathy, suggesting that statin-mediated myopathy was independent of the cholesterol lowering effects of statins. Conversely, mevalonate supplementation of the diet abrogated cerivastatin induced myopathy evidenced by either microscopy or sensitive biomarkers of muscle injury including AST, CK, sTnI, FABP3, and urinary myoglobin. These data suggest that statin-induced myopathy involves a cholesterol biosynthetic intermediate upstream of cholesterol and downstream of mevalonate. Most animals with myopathy had increased expression of genes involved in stress (UCP1, NRF2), inflammation (Alox5ap), and autophagy/mitophagy (GABARAP), and decreases in genes involved in energy production (GATM, ATP5b, ATP5f1) or mitochondrial biogenesis (PGC-1α). These data suggest that sensitive muscle fibers may have deficits in mitochondrial biogenesis in the presence of increased autophagy/mitophagy that result in an energy crisis. In addition, many of these genes have also been reported to be changed in human statin myopathy, suggesting a similarity in mechanisms between rats and humans. In conclusion, cerivastatin-induced myopathy in rats involves a step upstream of cholesterol in isoprenoid intermediary metabolism that likely results in an energy crisis. These data suggest that lowering of cholesterol by mechanisms other than HMG CoA inhibition-associated isoprenoid intermediate depletion would not be expected to result in myopathy.

Prospective, observational real-life study on eligibility for and outcomes of antiviral treatment with peginterferon α plus ribavirin in chronic hepatitis C

BackgroundWe aimed to investigate eligibility, reasons for treatment discontinuation and characteristics of chronic hepatitis C patients with treatment failure to peginterferon/ribavirin in clinical practice. Methods1128 chronic hepatitis C patients, from 45 Italian Hepatology centres, were enrolled in this phase-4, prospective, observational study from January 2009 to February 2010. Results687/1118 patients (61.4%) were eligible for antiviral treatment, of which 598 (87.0%) agreed with the physician's decision. Outcome information was available in 500/598 patients, among whom 348 (69.6%) completed treatment. Treatment was discontinued in 152 patients due to: lack of response (28.9%), personal reasons (29.6%), adverse events (38.2%), and decompensation (1.3%). Sustained virological response was obtained in 263/500 (52.6%), 71 (14.2%) relapsed and 61 (12.2%) were non-responders. Treatment outcome was not available in 105 (21%): lost while receiving treatment (33.3%), lost during follow-up (25.7%), withdrawn for adverse events (19.1%) or for administrative reasons (21.9%). ConclusionIn clinical practice, only 61% of chronic hepatitis C patients are considered eligible for peginterferon/ribavirin. Of these, 13% refuse treatment. Approximately 30% do not complete the scheduled treatment and, despite this, the sustained virological response rate is similar to that of randomized-controlled trials. In the era of new antiviral combinations, these findings have important implications for assessing eligibility and estimating drop-out rates.

Evidence and Clinical Relevance of Tumor Flare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma

BackgroundSeveral tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a tumor flare (TF) but its clinical relevance is still questionable. ObjectiveThis analysis investigates the occurrence of tumor flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC. Design, setting, and participantsPatients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2. Outcome measurements and statistical analysisOverall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 – GR1). Cox proportional hazards regression was used to assess the prognostic role. Results and limitationsSixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] –0.07 to 0.53) and 0.70cm/mo (IQR 0.21–1.46), respectively (p=0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08–1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001–1.225; p=0.048). ConclusionsThis study reports clinical evidence that TKI discontinuation results in acceleration of tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients. Patient summaryIn this report, we looked at the outcomes for patients affected by metastatic kidney tumors who discontinued treatment with antiangiogenic agents. We found that tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in tumor growth rate, which is related to patient survival.

O2-5-2 - Experience with Regorafenib Treatment for Metastatic Colorectal Cancer at Aichi Cancer Center

Background: Regorafenib, an oral small-molecule inhibitor of multikinases, was found to significantly improve overall survival (OS) of metastatic colorectal cancer patients (pts) with disease progression after standard therapies. In Japan, regorafenib has been used since May 2013. We evaluated the efficacy and toxicity of regorafenib and determined pts for whom regorafenib discontinued after a short treatment period, the reasons, and treatment for such pts.Methods: We performed a retrospective analysis of pts treated at our institution from May to December 2013 using medical charts. Thirty pts with disease progression after standard therapies who underwent regorafenib treatment were analyzed.Results: In all 30 pts, the median age was 62.5 years, and PS0/1/2 was 7/21/2. The efficacy of regorafenib was non-PD/PD/NE in 8/7/15. The median number of treatment cycles was 1.5. In the 1st cycle, 24 pts had interrupted treatment, 14 pts discontinued treatment, and only 4 pts had dose reduction before discontinuation. The reasons for treatment discontinuation in the 1st cycle were adverse events (AEs) in 8 pts and disease progression in 5 pts. AEs leading to discontinuation in the 1st cycle were anorexia, fatigue, rash, fever, and liver dysfunction. OS was 3.3 months, and time to treatment failure (TTF) was 1.2 months. In all pts, major AEs were hand foot syndrome (HFS) (63%), fatigue (60%), fever (43%), anorexia (40%), hoarseness (40%), hypertension (30%), and diarrhea (30%). Grade 3 and 4 AEs were HFS (30%), hypertension (13%), and liver dysfunction (10%). In univariate analysis, metastatic site, liver metastasis, and LDH, ALP, and AST levels influenced TTF. The median TTF of the group with dose reduction and without dose reduction was 2.7 and 0.5 months, respectively. Conclusion: Regorafenib treatment should be carefully performed, and when these patients show AEs, regorafenib should be interrupted, and dose reduction should be attempted before discontinuation.