Musculoskeletal Events Research Articles

Quality of Life Improvement in Patients Treated with Degarelix versus Leuprorelin for Advanced Prostate Cancer

We used responses to questionnaires included in the CS21 degarelix trial and published mapping algorithms to address the paucity of evidence for health related quality of life in patients with advanced hormone dependent prostate cancer treated with degarelix. We measured health related quality of life in 610 patients enrolled in the CS21 trial using SF-12® and EORTC QLQ-C30. Based on responses to these questionnaires we estimated patient utility using 4 published mapping algorithms. Utility was tested for relationships with aspects of the symptom and side effect burden that may be affected by degarelix treatment, that is prostate specific antigen progression and adverse events. Average utility in patients without prostate specific antigen progression or an adverse event was 0.742, similar to previously published utilities for nonprogressed prostate cancer states. Prostate specific antigen progression was associated with a utility decrement of between 0.062 and 0.134 depending on the mapping algorithm used. Of adverse events considered in our analysis musculoskeletal events were associated with the greatest effects on patient utility with a decrement of between 0.029 and 0.086. The 4 mapping algorithms generated similar utility estimates, although values derived from SF-12 were consistently lower than those derived from EORTC QLQ-C30. Prostate specific antigen progression status and the incidence of treatment and disease related adverse events result in significant decrements to patient health related quality of life. By slowing prostate specific antigen progression degarelix may improve patient utility and the health related quality of life burden.

A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection

Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.

A prospective assessment of musculoskeletal toxicity and loss of grip strength in breast cancer patients receiving adjuvant aromatase inhibitors and tamoxifen, and relation with BMI.

Aromatase inhibitor (AI) therapy for estrogen receptor-positive breast cancer is known to induce or enhance musculoskeletal problems. We have previously reported that loss of grip strength is more pronounced in AI-users with extremes in BMI. We here report results from a larger prospective study. Postmenopausal early breast cancer patients scheduled to start AI or tamoxifen therapy were recruited. A functional assessment grip strength test was performed at baseline, 3, 6, and 12months of therapy. BMI was assessed, and a rheumatologic questionnaire was completed at each visit. 188 patients on an AI and 104 patients on tamoxifen were enrolled. 74% of AI-users reported new/worsened musculoskeletal complaints compared with 37% in the tamoxifen group. This was translated in a larger grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints (p=0.0002). 15% of AI-users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction versus adherent patients (p=0.0107). Young age (p=0.0135), taxane-based chemotherapy (p=0.0223), and baseline VAS score >4 (p=0.0155) were predictors for AI-related musculoskeletal pain. In addition, a quadratic trend of BMI with grip strength change (p=0.0090) and probability of discontinuation was observed (p=0.0424). Musculoskeletal events were a substantial problem in AI-treated patients and an important reason for treatment discontinuation. The decrease in grip strength was larger in AI- than in tamoxifen-users, with a more pronounced change in symptomatic patients. The inverse relationship between BMI extremes and grip strength change was confirmed in this large group of AI-patients.

Efficacy and safety analysis of interferon combined with imatinib in treating chronic myeloid leukemia

Imatinib has been recognized as the frontline therapy drug in chronic myeloid leukemia (CML), however, only limited patients could achieve complete molecular remission (CMR). Recent clinical and basic proofs indicated an improved treatment outcome by the combination of interferon and Imatinib. This study was purposed to evaluated systematically the efficacy and safety of interferon plus Imatinib in patients with CML. Data from relative clinical trials were from clinical trial of gov and Cochrane Collaboration. A comprehensive literature search was performed from data bases such as pubMed and EM. The results indicated that 7 clinical trials and 12 research papers met the criteria enrolled in study, included 697 cases in total. The combination group had higher complete cytogenetic remission (CCgR) rate than imatinib alone at 6 months (58% vs 42%; P = 0.0001) and 12 months (74% vs 68%; P = 0.004). The major molecular remission (MMR) rate was also higher in the combination group at 6 months (58% vs 34%; P = 0.0001) and 12 months (66% vs 47%; P < 0.0001). Furthermore, compared with single drug, the combination group had superior CMR rate at 6 months (13% vs 2%; P = 0.0002) and 12 months (14% vs 5%; P = 0.0009). The major adverse effects of combination therapy were rash, asthenia, edema and musculoskeletal events, and combination therapy was more prone to inducing neutropenia, thrombocytopenia and mild anemia. It is concluded that compared with Imatinib alone, the combination of interferon and Imatinib has better clinical efficacy in treating CML with earlier cytogenetic and molecular remission. It is also a safe therapy in spite of slightly weaker tolerance than single drug therapy.

Pharmacologic Options for Intestinal Rehabilitation in Patients With Short Bowel Syndrome

A primary goal of intestinal rehabilitation programs is to facilitate intestinal adaptation. Adult patients with short bowel syndrome (SBS) who are dependent on parenteral nutrition and/or intravenous fluid (PN/IV) support have 2 hormonal pharmacologic treatment options available that may promote intestinal growth: a glucagon-like peptide 2 analog (teduglutide) and recombinant human growth hormone (somatropin). In two phase III clinical trials (N=169), 24 weeks of teduglutide administered to outpatients with SBS resulted in significant decreases in PN/IV volume requirements of 2.5-4.4 L/wk. In an extension study of one of these trials, patients with SBS who completed 30 months of teduglutide experienced a mean PN/IV reduction of 7.6 L/wk from baseline. Furthermore, some patients achieved independence from PN/IV support. The most common adverse events associated with teduglutide treatment in clinical trials were gastrointestinal symptoms, including abdominal distension, abdominal pain, and nausea. This safety profile is consistent with the associated underlying diseases leading to SBS or the known mechanism of action of teduglutide. A single phase III study (N=41) evaluated the safety and efficacy of a 4-week inpatient course of somatropin in combination with a glutamine-supplemented diet for adults with SBS. Somatropin treatment significantly reduced parenteral support requirements by 1.1 L/d in these patients. The most common adverse events were peripheral edema and musculoskeletal events. Large-scale, long-term follow-up studies of somatropin for SBS have not been conducted. Although treatment for patients with SBS must be individualized, teduglutide and somatropin are positive extensions to existing fluid and nutrient management strategies.

A169: Cumulative Long‐Term Safety, Efficacy and Patient‐Reported Outcomes in Children With Juvenile Idiopathic Arthritis Treated With Intravenous Abatacept: Up to 7 Years of Treatment

Background/Purpose: The long-term efficacy and safety of intravenous abatacept in patients (pts) with juvenile idiopathic arthritis (JIA) have been reported previously from the Phase III AWAKEN trial ([1, 2]). Here, we report efficacy, safety and pt-reported outcomes from the open-label, long-term extension (LTE) of AWAKEN, with up to 7 years of follow-up. Methods: Pts entered the LTE if they were JIA ACR 30 non-responders (NR) at the end of the 4-month lead-in period (abatacept only), or if they received abatacept or placebo (pbo) in the 6-month double-blind (DB) period. The Child Health Questionnaire was used to evaluate health-related quality of life (HRQoL); physical (PhS) and psychosocial (PsS) summary and pain scores were analyzed. Pain was assessed by parent global assessment using a 100 mm visual analog scale. Efficacy and HRQoL evaluations are reported up to Day 1765 (~ Year 5.5). Safety is presented for the cumulative period (lead-in, DB and LTE), for all pts who received abatacept during the LTE. Results: Of the 153 pts entering the LTE (58 from DB abatacept group, 59 from DB pbo group, 36 NR), 69 completed the trial (29 abatacept, 27 pbo, 13 NR). For pts treated in the LTE, mean (range) exposure to abatacept was 53.6 (5.6–85.6) months. During the LTE, incidence rates of AEs and serious AEs per 100 pt-years were 209.1 and 5.6. Thirty pts (19.6%) had serious AEs; most were unrelated and were musculoskeletal (8.5%) or infectious events (6.5%). No malignancy was reported. There was one death (accidental; unrelated). At Day 169, JIA ACR 50 and 70 response rates were 79.3% and 55.2% in the abatacept group, and 52.5% and 30.5% in the pbo group; 31.0% and 10.2% of pts in the abatacept and pbo groups, respectively, had inactive disease. By Day 1765, JIA ACR 50 and 70 response rates were 93.9% and 78.8% in the abatacept group, and 80.0% and 63.3% in the pbo group; 51.5% and 33.3% had inactive disease. In the NR group, 69.2% and 53.8% of pts achieved JIA ACR 50 and 70 responses at Day 1765, and 30.8% had inactive disease. In pts who entered the LTE, mean baseline PhS scores were below the range for healthy children (abatacept 30.2, pbo 31.0, NR 29.5). At Day 169, 38.3% of pts had reached a PhS score >50 ((1). By the end of the LTE, 43.5% of pts had reached a PhS score >50. At baseline, mean PsS scores for those who entered the LTE were slightly lower than the mean for healthy children (abatacept 43.5, pbo 44.2, NR 47.0). At Day 169, 54.9% of pts had a PsS score >50 (1). By Day 1765, 58.1% of pts had reached a PsS score >50. At baseline, the mean pain score was 42.9. By Day 169, 13.9% of pts were considered pain free (pain score = 0); this was maintained over the LTE (1). Table 1. NR(%) n=36 DB abatacept (%) n=58 DB pbo (%) n=59 Total (%) n=153 Day 169 (start of LTE) PhS >50 20.0 46.2 41.2 38.3 PsS >50 50.0 57.7 54.9 54.9 Pain free 0 20.4 15.7 13.9 Day 1765 (end of LTE) PhS >50 33.3 55.6 34.8 43.5 PsS >50 58.3 55.6 60.9 58.1 Pain free 0 17.9 16.0 13.1 Conclusion: Long-term treatment with abatacept for up to 7 years was associated with consistent safety, and sustained clinical efficacy and quality-of-life benefits in patients with JIA who remained on therapy.

Disease Control Outcomes from Analysis of Pooled Individual Patient Data from Five Comparative Randomised Clinical Trials of Degarelix Versus Luteinising Hormone-releasing Hormone Agonists

BackgroundStudies comparing the gonadotropin-releasing hormone antagonist, degarelix, with luteinising hormone-releasing hormone (LHRH) agonists indicate differences in outcomes. ObjectiveTo assess differences in efficacy and safety outcomes in a pooled analysis of trials comparing degarelix with LHRH agonists. Design, setting, and participantsData were pooled from five prospective, phase 3 or 3b randomised trials (n=1925) of degarelix and leuprolide or goserelin in men requiring androgen deprivation therapy for the treatment of prostate cancer. Patients received either 3 mo (n=467) or 12 mo (n=1458) of treatment. InterventionMen were randomised to receive degarelix (n=1266), leuprolide (n=201), or goserelin (n=458). Outcome measurements and statistical analysisUnadjusted Kaplan-Meier analyses were supported by the Cox proportional hazards model, adjusted for disease-related baseline factors, to estimate hazard ratios (HRs) of efficacy and safety outcomes. The Fisher exact test compared crude incidences of adverse events. Results and limitationsProstate-specific antigen (PSA) progression-free survival (PFS) was improved in the degarelix group (HR: 0.71; p=0.017). For patients with baseline PSA levels >20 ng/ml, the HR for PSA PFS was 0.74 (p=0.052). Overall survival (OS) was higher in the degarelix group (HR: 0.47; p=0.023). OS was particularly improved with degarelix in patients with baseline testosterone levels >2 ng/ml (HR: 0.36; p=0.006). In terms of disease-related adverse events, there were, overall, fewer joint-related signs and symptoms, musculoskeletal events, and urinary tract events in the degarelix group. ConclusionsThese data indicate clinical benefits with degarelix, including a significant improvement in PSA PFS and OS, as well as reduced incidence of joint, musculoskeletal, and urinary tract adverse events, compared with LHRH agonists.

Abstract S3-01: Breast cancer prevention using anastrozole in postmenopausal women at high risk

Abstract Background: Third generation aromatase inhibitors are the most effective endocrine treatment for hormone receptor positive breast cancer in postmenopausal women. Here, we assess the efficacy of anastrozole in postmenopausal women who do not have breast cancer, but are at high risk of developing the disease. Methods: A multi-centre randomised placebo-controlled trial of 1mg/day oral anastrozole vs. matching placebo for five years was conducted in 3864 postmenopausal women at increased risk of breast cancer. The primary endpoint was the incidence of breast cancer (including ductal carcinoma in-situ (DCIS) and differences were assessed by the proportional hazards model. Detailed information on adverse events was collected. Results: After a median follow up of 5.03 years, 125 breast cancers were recorded. A 53% reduction (95% CI (32-68%), P&amp;lt;0.0001) was seen in the anastrozole arm. Significant reductions were seen for all invasive (50%), oestrogen receptor positive invasive (58%) and in situ tumours (70%). Fractures were non-significantly higher (8.5% vs. 7.7%, P = 0.3) and musculoskeletal events were significantly higher in the anastrozole arm (1226 vs. 1124, RR = 1.10 (1.05-1.16)) but were very common in both arms (63.9% vs. 57.8%). Vasomotor symptoms were also increased with anastrozole (RR = 1.15 (1.08-1.22)). Cancers at other sites were significantly decreased (40 vs. 70, RR = 0.58 (0.39-0.85)). Deaths from breast cancer and other causes were similar in both arms. Conclusions: Anastrozole is an effective agent for reducing breast cancer incidence in postmenopausal women at high risk. Anastrozole was well tolerated and side effects associated with oestrogen deprivation were only slightly higher than for placebo. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-01.

Breast cancer chemoprevention: little progress in practice?

Breast cancer chemoprevention: little progress in practice?

Ocorrências de lesões musculoesqueléticas em pilotos de caça da Base Aérea de Anápolis

Studies with fighter pilots demonstrate that these professionals, undeniably, have been submitted to musculoskeletal discomfort. In order to investigate the influence of the air activity in their lives this study aimed to identify possible musculoskeletal events that affect the fighter pilots at the 1st Air Defense Group (1st ADG).The data was collected individually in the auditorium of the 1st ADG, after the explanation of the purpose of the study, between March 8 and April 8. It was used an adapted version of the Nordic musculoskeletal questionnaire. The survey assessed 20 pilots of the Squadron, using the descriptive statistical analysis for data interpretation and the results showed an incidence in the lumbar spine (low back) as the main discomfort reported by the pilots of the 1st ADG, followed by the cervical spine (neck). Low back pain was also predominant in studies carried out by Brazilian and foreign researchers with pilots of various aviation, and addressed the influence of +Gz force and posture while seated in the cockpit during training missions, as contributing factors for low back pain as well. It is concluded that the most frequent occurrences are related to the lumbar and cervical region.

A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer.

4010 Background: PEGPH20 is a PEGylated version of human recombinant hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetically-engineered murine model of PDA, PEGPH20 + gemcitabine (Gem) significantly prolonged survival compared to Gem alone. In Ph1 PEGPH20 monotherapy studies, the MTD was 3.0 μg/kg. The most common AEs were musculoskeletal events (MSEs). Methods: This was a dose-escalation study to find the recommended Phase 2 dose (RP2D) of PEGPH20 in combination with Gem in patients (pts) with Stage IV previously untreated pancreatic cancer. Pts received PEGPH20 at 1, 1.6, or 3 μg/kg IV twice a week for Wks 1-4, weekly for Wks 5-7, then 1 wk rest. Dose escalation was based on safety. Gem was given at 1000 mg/m2 IV once a week for Wks 1-7, then 1 wk rest. Thereafter, PEGPH20 + Gem were given once a week for 3 wks in 4-wk cycles. Dexamethasone was given pre and post PEGPH20 doses. Results: Of the 28 pts enrolled, the majority had a Karnofsky performance status of 80%, and 85%/19%/26% of pts had liver/lung/visceral metastases. The median age was 58 yrs. Four pts received PEGPH20 at 1 μg/kg, 4 at 1.6 μg/kg, and 20 at 3 μg/kg. The RP2D was 3 μg/kg. Treatment duration ranged from 1-274 days; 5 pts remain on study. Treatment was generally well tolerated. Ten pts had 1 Gem dose reduction, 2 pts had 1 PEGPH20 dose reduction (3 to 1.6 µg/kg), but no pt had a DLT. The most common PEGPH20-related AEs were MSEs (25% Gr1; 18% Gr2) and fatigue (21% Gr1; 11% Gr2). Objective response was assessed by an independent central radiologist using RECIST 1.1. Of the 21 pts evaluable for efficacy, 7 had partial response (PR) for an overall response rate (ORR) of 33%, and 9 had stable disease for ≥ 2 mo. Tumor biopsies from 12 pts were evaluable for HA staining. HA was high in 9 and low in 3. Of the 9 with high HA staining, 5 had PR (56% ORR); HA data were not available for the other 2 PR pts. PK results show dose-dependent exposure consistent with data from PEGPH20 monotherapy studies. Conclusions: PEGPH20 in combination with Gem is generally well tolerated in advanced pancreatic cancer and shows promising efficacy, especially in pts with high intratumoral HA content. Clinical trial information: NCT01453153.

Medsafe reports corticosteroid-induced musculoskeletal events

Medsafe reports corticosteroid-induced musculoskeletal events

A randomized pilot study of tenofovir/emtricitabine (TDF/FTC) + boosted atazanavir (ATV/r) vs. raltegravir (RAL BID) + ATV/r vs. RAL BID + ATV BID

Patients virologically suppressed on TDF/FTC + ATV/r may require alternative regimens that maintain suppression while addressing some drug‐related side effects. We explored two alternative regimens that replace RTV and/or TDF/FTC. This open‐label exploratory pilot trial enrolled 43 patients on TDF/FTC + ATV/r. Subjects were randomized to one of three arms. Arm 1 (n=15) replaced TDF/FTC with RAL 400 mg BID while continuing ATV/r. Arm 2 (n=14) made two changes: TDF/FTC was stopped and RAL BID was used instead; ritonavir was stopped and ATV 300 mg BID was used. Arm CTL (n=14) continued the baseline (BL) regimen. The week 48 final endpoint is summarized. The primary endpoint was maintaining virologic suppression (&lt;40 c/mL); secondary endpoints compared safety measures. Overall mean age was 46, with 74% Caucasian, 21% black race and 12% female; similar characteristics noted across arms. Through week 48, all but two patients maintained virologic suppression; both virologic failures (&gt;200 c/mL on two consecutive tests) were on arm 2; both reported adherence problems and no resistance mutations were detected. Overall CD4 counts were 534/mm3 at BL and 555/mm3 at week 48. There was a significant CD4 cell count difference favoring CTL (+52/mm3) vs. arm 2 (−14/mm3), p=0.03. No significant differences across arms were noted in lipid fractions or other lab tests. There were no clinically significant EKG changes across arms. Among AEs of interest through week 48, there were more neurologic AEs on arm 1 (n=7) and 2 (n=6) vs. CTL (n=1), and more musculoskeletal events noted on arm 2 (n=7) vs. arm 1 (n=3) and CTL (n=1). Quality of life was measured with a self‐assessment Likert scale. Scores were similar across arms despite the BID dosing in two arms. Self‐reported adherence using 3‐day recall was&gt;95% in all three arms at both baseline and week 48. In this randomized pilot study, two of the three arms maintained virologic suppression in all subjects; there were two virologic rebounds in arm 2. No resistance mutations were detected in either, and adherence issues were noted for both subjects. We also noted that the CD4 cell change was significantly less on arm 2, and there were more neurologic and musculoskeletal AEs on arm 2 vs. CTL. In this study, the use of ATV/r with either TDF/FTC or RAL was successful over 48 weeks, but unboosted BID ATV 300 mg+BID RAL 400 mg as an alternative in virologically suppressed patients should be used with caution.

Suicide attempt with an overdose of imatinib

Imatinib is approved for the treatment of chronic myelogenous leukaemia (CML) as well as gastrointestinal stromal tumour (GIST), both of which show dysregulated imatinib-sensitive tyrosine kinase activity. Imatinib is rapidly absorbed after oral administration (bioavailability 86%) and is mainly metabolized by the CYP3A4 and CYP3A5 isoenzymes of the liver [1]. Although the drug is usually well-tolerated, grade 1–2 adverse effects, such as musculoskeletal events, are frequently observed [2–4]. In a phase I clinical trial in patients with CML, the minimum therapeutic dose of imatinib required to obtain an optimal therapeutic response was determined to be 300 mg day−1. However, the maximum tolerated dose has not yet been defined. In addition, there have been few case reports of imatinib overdose [5]. We herein report the results of a pharmacokinetic analysis in a patient with CML who took 2000 mg of imatinib as a single dose together with brotizolam and triazolam in an attempt to commit suicide.

Targeting hyaluronan (HA) in tumor stroma: A phase I study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of pegylated hyaluronidase (PEGPH20) in patients with solid tumors.

2579 Background: HA, a glycosaminoglycan, accumulates in ~25% of solid tumors and is associated with poor prognosis. Tumors that accumulate HA develop high interstitial fluid pressure (IFP) and become resistant to chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA and increased efficacy of chemotherapy. Methods: This ongoing phase 1 study was designed to assess safety, tolerability, PK, PD, and the maximum tolerated dose (MTD) of PEGPH20 as a single agent in patients with treatment-refractory solid tumors. IV PEGPH20 was administered in a twice weekly or a once weekly dosing schedule with oral dexamethasone (dex) pre-and post dose. Biomarkers included tumor histochemistry to detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET. Results: Fifteen patients have been enrolled into the study. Dose administration ranged from 0.5 µg/kg to 5 µg/kg. Musculoskeletal events (MSEs) were the most common and dose limiting toxicities. To date, up to 3 µg/kg twice weekly IV infusions of PEGPH20 were well tolerated with manageable Grade 1 MSEs in most patients. MTD has not been reached. Plasma concentrations of PEGPH20 showed dose proportional exposure with a terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor biopsies from 2 colon patients demonstrated 23-60% reduction in tumor HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 in one patient each. Doses of ≤3 µg/kg were tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels &gt; 3 µg/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in dose-dependent systemic exposure and is tolerated with concomitant dex treatment. HA catabolites in plasma demonstrated the in vivo enzymatic activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI and FDG-PET images confirmed PD activity. Increased tumor perfusion by PEGPH20 may enhance drug delivery to tumor. Combination studies of PEGPH20 with cytotoxic chemotherapy are planned.

BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) after 30 months of follow-up.

6512 Background: The BELA study compared the efficacy and safety of BOS (dual Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502 pts with newly diagnosed CP CML were randomized to BOS 500 mg/d (n = 250) or IM 400 mg/d (n = 252) and stratified by Sokal risk group and geographic region. Efficacy analyses included all randomized pts (ITT); safety analyses included all treated pts (BOS, n = 248; IM, n = 251). Data described below are for ≥24 mo of follow-up; updated data for ≥30 mo of follow-up will be presented. Results: Median treatment duration was 27.5 mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving treatment. The primary reason for BOS discontinuation was a treatment-emergent adverse event (TEAE; 24% vs 7% with IM); the primary reason for IM discontinuation was disease progression (13% vs 4% with BOS). Cumulative complete cytogenetic response (CCyR) rates by 24 mo were 79% for BOS and 80% for IM. Cumulative major molecular response (MMR) rates by 24 mo were 59% for BOS and 49% for IM (P = 0.019), including 16% and 12% of pts with complete molecular response (4.0-log sensitivity). On-treatment transformation to accelerated/blast phase occurred in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7 BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML progression); 24-mo Kaplan-Meier overall survival estimates were 97% (BOS) and 95% (IM). BOS was associated with higher incidences of gastrointestinal events than IM (diarrhea [70% vs 25%], vomiting [32% vs 16%]; primarily transient), but lower incidences of edema (13% vs 40%) and musculoskeletal events (cramps [4% vs 22%], bone pain [4% vs 10%]). Grade ≥3 TEAEs in ≥2% of BOS or IM pts were diarrhea (12% vs 1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade ≥3 lab abnormalities (≥15% of pts) with BOS and IM were neutropenia (10% vs 24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase (23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS was effective for newly diagnosed CP CML and had a distinct toxicity profile. With continued follow-up both on-treatment transformation to accelerated/blast phase and overall survival continue to favor BOS versus IM.

Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole: The VITAL trial.

9000 Background: Musculoskeletal (MS) pain and fatigue are common in women on adjuvant Aromatase Inhibitors (AIs) and lead to reduced compliance. Pilot studies suggest a positive impact of vit D on MS pain and disability from AIs. We conducted a bi-institutional, double blind, placebo controlled randomized trial to study the impact of 30,000 I.U of vit D3 in preventing worsening of MS pain and fatigue in women starting letrozole. Methods: Women with stage I-III breast cancer starting adjuvant AI and a 25(OH)D level of 40 ng/ml or less were eligible. Women with prior renal stones or hypercalcemia were excluded. All subjects received letrozole, plus standard dose vitD3 (600 IU) and calcium (1200 mg) daily, all provided by the study. Women were randomly assigned to 30,000 IU of oral vitD3 wkly (vitD arm) or matched placebos (PL arm) for 24 weeks. The following were assessed at baseline, 12 wks, and 24 wks (end of study): 1) 25OHD levels, 2) symptoms tools (BFI – Brief Fatigue Inventory, HAQII - Health Assessment Questionnaire II, Qualitative Joint Pain (none, mild, moderate, severe), BPI – Brief Pain Inventory) and 3) hand grip strength with a dynamometer. Results: 160 women (80/arm) were enrolled from 4/09 to 7/10. There were no differences between the two arms in demographics/tumor characteristics. Median age was 61, median BMI was 29.8 kg/m2. 43% had adjuvant chemotherapy. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 wks and 31 at 24 wks in the PL arm and 22, 53 and 57 in vitD arm. One patient in the PL arm developed mild hypercalcemia. There were no SAEs. 147 subjects were evaluable for efficacy. 3 subjects, all in the PL arm discontinued early due to a MS adverse event. At wk 24, a higher proportion of women in PL (51%) vs vitD arm (37%) had a protocol defined MS event (worsening of joint pain, disability from joint pain or discontinuation of Letrozole due to MS symptoms) (p=0.069). A significantly higher proportion of women in PL (72%) vs vitD arm (42%) had an adverse QOL event (worsening of pain, disability or fatigue) (p=&lt;0.001). Conclusions: 30,000 IU/week of vitamin D3 is safe and results in decreased adverse QOL events from adjuvant aromatase inhibitors in women with breast cancer.

Targeting hyaluronan (HA) in tumor stroma: Interim safety and translational evaluation of pegylated hyaluronidase (PEGPH20) in patients (pts) with advanced solid tumors—A focus on gastrointestinal malignancies.

249 Background: HA, a glycosaminoglycan in the tumor matrix, accumulates in 20-30% of solid tumors and ≥28%, ≥42% and ≥87% of colon, gastric and pancreatic ductal adenocarcinoma (PDA) tumors, respectively. Tumors that accumulate HA can develop high interstitial fluid pressure (IFP) and are resistant to chemotherapy. HA in human PDA is associated with disease progression and poor prognosis. In animal models, PEGPH20 reduced tumor-associated HA, tumor IFP and tumor growth, and increased efficacy of chemotherapy. Pharmacodynamic (PD) activity of PEGPH20 is being evaluated in Phase 1 (Ph1) trials. Methods: Two Ph1 studies in pts with advanced solid tumors refractory to prior therapy examined the safety, tolerability, PK, PD and MTD of single-agent IV PEGPH20. Dosing in Study 1 was 2x/wk and then reduced to q21d and in Study 2 is 1-2x/wk x 4wks and 1x/wk thereafter with dexamethasone pre-medication regimen. Biomarkers evaluated: Histochemistry to detect depletion of tumor HA, serum HA catabolites, Dynamic Contrast Enhanced (DCE)-MRI and FDG-PET. Results: In Study 1, the first 3 pts demonstrated musculoskeletal events (MSE; 2 pts dosed with 50 µg/kg 2x/wk, severe; 1 pt dosed with 0.5µg/kg 2x/wk, moderate) not predicted from GLP safety studies. The frequency of drug administration was reduced to q21d and the next 10 pts tolerated ≤1.5 µg/kg. In Study 2, dexamethasone pre-medication regimen was evaluated while dosing at 1-2x/wk. Nine pts were dosed ≤5.0 µg/kg. Doses ≤3.0 µg/kg administered 2x/wk were tolerated with intermittent Grade 1-2 MSE. Activity of PEGPH20 was reflected by increased HA serum catabolites. Pre- and post-dose biopsies from 2 colon pts demonstrated a 23-60% reduction in tumor HA after 4 wks of PEGPH20 dosing. DCE-MRI of PDA and FDG-PET of lung metastases increased tumor perfusion (Ktrans) and decreased metabolic activity 8 and 24hrs post-PEGPH20 dose and was still apparent after 4 wks of treatment with PEGPH20. Conclusions: Ongoing Ph1 studies have shown in vivo activity of PEGPH20 through HA plasma catabolites, tumor HA depletion, DCE-MRI and FDG-PET.

Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2–3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study

Aromatase inhibitors are more effective than is tamoxifen in prevention of breast-cancer recurrence, but at the expense of increased musculoskeletal side-effects, such as carpal tunnel syndrome. The aim of this study was to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with the steroidal aromatase inhibitor exemestane or with tamoxifen after 2-3 years of tamoxifen. In the Intergroup Exemestane Study, postmenopausal women treated for early invasive breast cancer who remained disease free and on treatment after 2-3 years of tamoxifen were randomised to switch to exemestane or to continue tamoxifen for the remainder of the 5-year period of endocrine treatment. The primary endpoint for this retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome. The relation between musculoskeletal symptoms reported by 6 months from randomisation and survival from 9 months onwards was assessed by Cox proportional hazards models. The trial is registered, number ISRCTN11883920. It has completed accrual and follow-up is continuing for enrolled participants. After a median follow-up of 91·0 months (IQR 83·0-99·2), carpal tunnel syndrome had been reported for 66 (2·8%) of 2319 patients in the exemestane group compared with 13 (0·6%) of 2338 in the tamoxifen group (odds ratio [OR] 5·23, 99% CI 2·39-11·49; p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (66 [2·8%] vs seven [0·3%], adjusted OR 9·90, 99% CI 3·52-27·82; p<0·0001). There was no significant difference between groups in events in the post-treatment period (ten with exemestane [0·4%] vs seven with tamoxifen [0·3%]; p=0·46). More patients in the exemestane group (1082 of 2319 patients, 46·7%) had musculoskeletal symptoms than in the tamoxifen group (901 of 2338, 38·5%; OR 1·48, 99% CI 1·32-1·67, p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (984 [42·4%] vs 776 [33·2%], adjusted OR 1·59, 99% CI 1·32-1·91; p<0·0001), with this difference persisting to some extent in the post-treatment period (449 [19·4%] vs 390 [16·7%]; p=0·017). Of 73 on-treatment cases of carpal tunnel syndrome, 58 (79·5%) completed questionnaires were available. 27 patients (46·6%) had bilateral carpal tunnel syndrome and 31 (53·4%) had unilateral disease; 40 (69·0%) underwent surgical release. The disorder greatly affected daily-life activities in 21 (36·2%) cases. Occurrence of musculoskeletal symptoms, including carpal tunnel syndrome, was associated with improved disease-free survival in unadjusted analysis (p=0·023), but not with overall survival (p=0·36). However, after adjustment for possible confounding factors, musculoskeletal symptoms were not associated with disease-free survival (hazard ratio [HR] 0·96, 95% CI 0·82-1·14, p=0·67) or overall survival (HR 1·02, 95% CI 0·84-1·25, p=0·82). Occurrence of carpal tunnel syndrome is higher in patients with breast cancer given exemestane than in those treated with tamoxifen, and surgical release might be necessary in most cases. Development of musculoskeletal symptoms in the first 6 months of treatment is not an independent biomarker of improved disease outcome. Further investigation is warranted into the relation between treatment-emergent musculoskeletal symptoms and clinical outcome in patients with breast cancer receiving hormonal therapy. Pfizer.

Musculoskeletal events associated with the management of endocrine-responsive breast cancer

Musculoskeletal symptoms have been reported in patients treated with third generation aromatase inhibitors (AIs) and with blockers of hypothalamic–pituitary gonadal axis. AIs act by suppressing postmenopausal estrogen biosynthesis through inhibition of the enzyme aromatase, which is responsible for the conversion of androgens to estrogens in many tissues. Maximal estrogen and/or androgen deprivation is beneficial for cancer growth suppression but could be associated with side effects such as accelerated bone loss and osteoporotic fractures which are extensively reported. Musculoskeletal events, another group of adverse events, have been studied to a lesser extent and are usually commonly reported as arthralgia and myalgia. Furthermore, the pathogenesis and anatomical findings of musculoskeletal symptoms have not been adequately elucidated. In this communication, we review recent information related to musculoskeletal symptoms in breast cancer and speculate on possible explanations for musculoskeletal pain related to hormone deprivation. We outline treatment options for control of arthralgia and myalgia due to hormonal therapy. More knowledge about the etiology and management of musculoskeletal adverse effects breast cancer during endocrine therapy is needed because discontinuation of the treatment due to intolerant symptomatology may result in disruption of the treatment schedule.