bluuebunny/crossref_metadata_2025 huggingface dataset:
Response to radiation therapy in solitary fibrous tumor/hemangiopericytoma.
Authors: Baldi Giacomo , Libertini Michela , Stacchiotti Silvia , Marrari Andrea , Palassini Elena , Bertulli Rossella , De Troia Beatrice , Gronchi Alessandro , Sangalli Claudia , Casali Paolo Giovanni
Published: March 2020

10065

Background: To reporton the activity of radiotherapy (RT) in a retrospective series of solitary fibrous tumors (SFT)/hemagiopericytoma (HCP), a rare soft tissue sarcoma subtype whose sensitivity to RT is poorly known. Methods: We retrospectively reviewed all patients with a diagnosis of SFT/HCP whom we saw from 2005 to 2011, focusing on cases treated with RT in neoadjuvant, adjuvant, exclusive, palliative settings. Patients who received concomitant chemotherapy were excluded. We confirmed diagnosis by review in all cases. We evaluated the overall response rate (RR) by RECIST. Results: Nineteen patients were identified (males = 9, females = 10; median age = 61 years, range 39-85; site of primary= 6 meninges, 4 pleura, 3 pelvis, 3 retroperitoneum, 2 limbs, 1 abdominal wall; site of RT= 5 bone and soft tissue, 5 pelvis, 3 soft tissue, 2 meninges, 2 retroperitoneum, 1 abdominal wall, 1 pleura; reason for RT= 3 neoadjuvant, 2 adjuvant, 2 exclusive and 12 palliative setting). Median RT dose was 42 Gy (range 12-60). Seventeen of 19 pts are evaluable for response (2 adjuvant). The RR was: 29% (4 pts) partial response, 65% (12 pts) stable disease (SD), 6% (1 pt) progressive disease (PD). All patients treated with neoadjuvant RT had a RECIST SD as best response to pre-operative treatment with evidence of pathologic response in 2 of 3 cases. Conclusions: Contrary to what is widely thought,this retrospective analysis suggests that SFT/HCP is sensitive to radiation therapy. Prospective studies are needed.
Comparison of BRCA1/2-positive and -negative women diagnosed with metachronous breast and ovarian cancers.
Authors: Brandt Amanda C. , Elsayegh Nisreen , Lin Heather , Gutierrez-Barrera Angelica M. , Lu Karen H. , Arun Banu
Published: March 2020

1546

Background: After a primary breast cancer (BC) or ovarian cancer (OC) diagnosis, women have a risk to develop a second primary cancer, significantly more so in women with a BRCA gene mutation. The objective was to evaluate characteristics of BRCA positive and negative women diagnosed with metachronous BC and OC. Methods: Women with metachronous BC and OC were identified at the University of Texas MD Anderson Cancer Center. BRCA test results, age at diagnosis of both BC and OC, first degree relatives (FDR) with BC and/or OC, total relatives affected, and histopathologic tumor features were obtained from a prospectively maintained research database. Univariate and logistical regression analyses were performed. Results: A total of 64 women with metachronous primary cancers underwent BRCA genetic testing. Of the 45 BRCA positive women, 36 (80%) were diagnosed with BC (mean 40 years) prior to OC and 9 (20%) were diagnosed with OC first (mean 47 years). Of the 19 BRCA negative women, 10 (53%) were diagnosed with BC first (mean 63 years), and 9 (47%) diagnosed with OC first (mean 48 years). Women diagnosed with BC first were more likely to be BRCA positive than women diagnosed with OC first (p=0.03). Patients with a FDR with BC were more likely BRCA positive than women without family history (p=0.0062). Patients with PR negative BR (p=0.0199) or triple negative (TN) BC (p=0.0139) were more likely to test BRCA positive. High grade ovarian carcinomas approached significance (p=0.053) in BRCA positive when compared to BRCA negative cohort. Ethnicity, total number of affected relatives with BC or OC, ER status, Her2 status, and nuclear grade were not statistically significant between the two groups. Conclusions: Women with OC preceding their BC with lack of family history of BC and OC are significantly less likely to test BRCA positive. BC is often the sentinel cancer in women with a BRCA mutation compared to BRCA negative women with metachronous BC and OC. This should be considered during the risk assessment to more accurately estimate the chance of identifying a BRCA mutation in women with metachronous BC and OC.
Retrospective analysis of glioblastoma patients treated with bevacizumab who presented with multifocal disease at diagnosis.
Authors: Hu Jethro Lisien , Nosova Kristin , Nuno Miriam , Yi Anthony , Elramsisy Adam , Mukherjee Debraj , Rudnick Jeremy , Phuphanich Surasak , Bannykh Serguei I. , Yu John , Black Keith L. , Patil Chirag
Published: March 2020

2080

Background: Glioblastoma patients who present with multifocal disease have an extremely poor prognosis – a recent analysis at our institution demonstrated a median survival of 6 months, versus 11 months for a cohort of unifocal glioblastoma patients matched for age, extent of resection, and KPS. Bevacizumab is frequently used to treat patients with recurrent or progressive glioblastoma. However, its benefit in the setting of multifocal disease is unproven, particularly in light of the concern that antiangiogenic treatment may promote a more invasive, multifocal, and potentially treatment-resistant phenotype. Methods: Between 2004 to 2010, 368 patients were diagnosed with glioblastoma at our institution. We identified 46 patients with multifocal disease on initial presentation, and retrospectively reviewed their clinical course and treatment history. Kaplan-Meier estimates and Wilcoxon tests were used to assess survival distribution. Results: Of the 46 patients with multifocal disease, 12 were treated with bevacizumab (7 upfront and 5 at first recurrence). All 12 bevacizumab-treated patients received external beam radiation therapy, and 11 received temozolomide. In the bevacizumab-treated cohort, median age at the time of surgery was 59 years, and median KPS was 80. For the 34 patients with multifocal disease who did not receive bevacizumab, median age was 69 years, and median KPS was 75. Median survival for the bevacizumab-treated patients was 12.9 months, with 12-month survival of 58.3%. By comparison, median survival for patients with multifocal disease who did not receive bevacizumab was 5.8 months, with 12-month survival of 20.6%. The difference in survival between the two groups was statistically significant, with p-value of 0.045 by the Wilcoxon test. Conclusions: This single-institution retrospective analysis suggests that bevacizumab treatment is associated with a survival benefit for glioblastoma patients who present with multifocal disease. One can infer that the clinical benefit of bevacizumab in this setting outweighs any potential concerns regarding the ability of bevacizumab to promote an invasive, treatment-resistant tumor phenotype.
Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.
Authors: Patnaik Amita , Kang Soonmo Peter , Tolcher Anthony W. , Rasco Drew Warren , Papadopoulos Kyriakos P. , Beeram Muralidhar , Drengler Ronald , Chen Cong , Smith Lon , Perez Crystal , Gergich Kevin , Lehnert Manfred
Published: March 2020

2512

Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]
Technetium-99m sulfur colloid (TSC) as a phenotypic probe for predicting pharmacokinetics (PK) and palmar-plantar erythrodysesthesia (PPE) toxicity of pegylated liposomal doxorubicin (PLD) in patients (pts) with recurrent epithelial ovarian cancer (EOC).
Authors: Giovinazzo Hugh , Kumar Parag , Sheikh Arif , Ivanovic Marija , Walsh Mark Doughty , Caron Whitney Paige , Song Gina , Whitlow Ann B. , Newman Suzanne E. , La-Beck Ninh My , Kowalsky Richard J. , Zamboni Beth A. , Clarke-Pearson Daniel L. , Brewster Wendy R. , Van Le Linda , Bae-Jump Victoria Lin , Gehrig Paola A. , Zamboni William
Published: March 2020

5050

Background: There is significant variability in the PK and PD (efficacy and toxicity) of PLD. Clearance (CL) of PLD has been proposed to occur primarily via uptake by cells of the mononuclear phagocyte system (MPS) mainly located in the liver, spleen, and blood. TSC is a radioactive colloid used clinically for diagnostic and functional imaging of the MPS. Our aim is to evaluate TSC as a phenotypic probe of MPS activity, which may predict PLD PK and PPE toxicity in pts (n=9) with EOC. Methods: Prior to administration of PLD on cycle 1 day 1 (C1D1), TSC was administered at 10 mCi IVP × 1. Dynamic planar and SPECT/CT images of the liver, spleen and hands were acquired using a gamma camera. Blood samples were collected up to 60 min after TSC and analyzed for radioactivity using a gamma counter. On C1D1, PLD was administered at 40 mg/m2 alone or at 30 mg/m2 in combination with carboplatin IV over 1 to 3 h. Serial PK samples were obtained from 0h to 672h post PLD dose. Plasma was processed to measure encapsulated and released doxorubicin (dox) using solid phase separation and HPLC. CL of PLD and TSC were calculated by non-compartmental analysis. The grade of PPE toxicity was determined by NCI CTCAE (v4.03) criteria. Results: Nine patients have undergone TSC imaging and eight patients completed TSC blood PK and PLD plasma PK studies. There was a positive linear relationship between TSC CL and encapsulated dox CL (R2 = 0.61, p=0.02). When patients were subdivided, there was a stronger relationship between TSC CL and encapsulated dox CL (R2 = 0.81, p=0.03) in pts receiving PLD monotherapy. A positive relationship using Spearman’s correlation (ρ=0.84, p=0.006) was also found between maximum grade PPE toxicity developed and estimated AUC of encapsulated dox in hands [(TSC AUCBlood)/(TSC AUCHand)*Encapsulated Dox AUCPlasma]. Conclusions: These results suggest that TSC is a probe for MPS function and PLD PK and PD and may be used to individualize PLD therapy in pts with EOC. In addition, our findings suggest TSC may be able to predict the development of PPE in patients.
The PARADIGM trial: A phase III study comparing sequential therapy (ST) to concurrent chemoradiotherapy (CRT) in locally advanced head and neck cancer (LANHC).
Authors: Haddad Robert I. , Rabinowits Guilherme , Tishler Roy B. , Adkins Douglas , Khuri Fadlo Raja , Clark Joseph , Lorch Jochen H. , Limaye Sewanti Atul , Wirth Lori J. , O'Neill Anne , Riley Sarah , Posner Marshall R.
Published: March 2020

5501

Background: PARADIGM is a multicenter phase III study comparing TPF (docetaxel, cisplatin, and 5-fluorouracil)-based ST (Arm A) to upfront cisplatin CRT (Arm B) in patients (pts) with LAHNC. Pt accrual was terminated in 12/2008 due to slow enrollment with 145 of 300 planned analyzable patients accrued. Safety data was previously presented at the 2010 ASCO annual meeting showing no unusual pattern of toxicities in either arm. Here we present the survival results. Methods: Pts were randomized to receive arm A-ST (as induction chemotherapy (ICT) with TPF x 3) followed by CRT with either weekly carboplatin and once daily radiotherapy, or weekly docetaxel and accelerated boost radiotherapy based on adequate response to ICT; or arm B - accelerated boost CRT with bolus cisplatin x 2. The primary endpoint was survival. With original accrual target of 300 analyzable patients, this study was powered at 80% to detect an improvement in 3-year survival from 55% (arm B) to 70% (arm A). Results: A total of 145 previously untreated pts were enrolled (Arm A: 70; Arm B: 75), of whom 127 were male and 127 were Caucasian. Median age was 55; patients had PS of 0 (97) or 1 (48). Sites of disease were oropharynx: 80, larynx: 24, hypopharynx: 15, and oral cavity: 26. Disease stages were II (1 pt), III (20 pts) and IV (124 pts). After a median follow-up of 49 months, 41 pts have died (20 in arm A and 21 in arm B). Three-year survival was 73% (arm A) and 78% (arm B) (HR1.09; 95% CI 0.59 to 2.03 p=0.77). Three-year progression-free survival was 67% (arm A) and 73% (arm B) (HR 1.2; 95% CI 0.65 to 2.22; p=0.55). Patterns of failure will be presented at the meeting. Conclusions: Althoughthese results suggest no survival differences between CRT and ST for patients with LAHNC, the study was terminated before the planned accrual could be reached. HPV status for the oropharynx cases which represented the majority of patients was not available for stratification; and excellent survival was seen in both arms.
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.
Authors: Gambacorti-Passerini Carlo , Lipton Jeffrey Howard , Tee Goh Yeow , Casado Luis Felipe , Zaritskey Andrey , le Coutre Philipp D. , Duvillie Ladan , Pavlov Dmitri , Countouriotis Athena Maria , Byrne Jennifer
Published: March 2020

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.
Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma.
Authors: Weber Jeffrey S. , Flaherty Keith T. , Infante Jeffrey R. , Falchook Gerald Steven , Kefford Richard , Daud Adil , Hamid Omid , Gonzalez Rene , Kudchadkar Ragini Reiney , Lawrence Donald P. , Burris Howard A. , Long Georgina V. , Algazi Alain Patrick , Lewis Karl D , Kim Kevin B. , Puzanov Igor , Sun Peng , Little Shonda M , Patel Kiran , Sosman Jeffrey Alan
Published: March 2020

8510

Background: In preclinical models, the BRAFi/MEKi combination has demonstrated enhanced activity against BRAF-mutant cancer cells compared with either drug alone, delayed emergence of BRAFi resistance, and prevented BRAFi-related proliferative skin lesions. A 3-part study investigating the dabrafenib/trametinib combination was conducted in patients (pts) with V600 BRAF mutant solid tumors. Interim data from the study were previously reported (Infante, ASCO 2011); updated safety and efficacy data are presented. Methods: In Part 2, 125 pts with V600 BRAF mutant solid tumors enrolled, including 77 melanoma pts with no prior BRAFi, and measurable disease according to RECIST 1.1. Pts were treated on 4 escalating dose levels of dabrafenib/trametinib (mg BID/mg QD): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 77 melanoma pts with no prior BRAFi and safety data for all 125 Part 2 pts are reported. Results: Among 77 melanoma pts, median age was 52 years, 61% male, 57% ECOG PS of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 CR, 39 PR, 29 SD and, 3 PD. Confirmed response rate for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% (n=25), and 54% (n=24). Median PFS (months) for each dose level, respectively, was: 8.7, 8.3, 5.5; PFS is not mature for 150/2. Overall PFS was 7.4 (95% CI: 5.5-9.2). Among the 125 pts, there were 2 grade (G) 5 adverse events (AEs), pneumonia and hyponatraemia. The most common G3/4 AEs were pyrexia (n=6, 5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ G2 occurred in 17 (14%) pts. Cutaneous squamous cell carcinoma occurred in 3 (2%) pts and actinic keratoses in 2 (2%). Conclusions: The combination of dabrafenib/trametinib has an acceptable safety profile, with a lower incidence of MEKi-related rash and BRAFi-induced hyperproliferative skin lesions compared with the single agents. The clinical activity of dabrafenib/trametinib observed in pts with V600 BRAF mutant metastatic melanoma is encouraging and will be investigated further in a phase III trial.
Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations.
Authors: Ascierto Paolo Antonio , Berking Carola , Agarwala Sanjiv S , Schadendorf Dirk , Van Herpen Carla , Queirolo Paola , Blank Christian U. , Hauschild Axel , Beck J. Thaddeus , Zubel Angela , Niazi Faiz , Wandel Simon , Dummer Reinhard
Published: March 2020

8511

Background: BRAF and NRAS mutations occur in 50-60% and 15-20% of cutaneous melanomas, respectively. MEK162, a selective inhibitor of the kinases MEK1 and MEK2, has shown pre-clinical activity in BRAF and NRAS mutant (mt) melanoma models. This open label, phase II study assessed the antitumor activity of MEK162 in patients (pts) with BRAFV600 and NRAS mt advanced cutaneous melanoma. Methods: MEK162 was administered orally at a starting dose of 45 mg twice daily. Treatment was until unacceptable toxicity, disease progression (PD) or investigator or patient refusal. Tumor response was assessed by CT imaging every 8 weeks (RECIST 1.0) until PD. Results: As of 16 Sept 2011, the full analysis and safety populations comprised 66 pts: 42 BRAF mt and 24 NRAS mt. Median age 58.0 years; 57.6% male; 72.7% WHO performance status 0. All NRAS pts and all but 2 BRAF (1 each stage IIIB and IIIC) pts had stage IV disease, and 87.5% of NRAS pts and 66.7% of BRAF pts had received prior therapy at study entry. Median time from 1st diagnosis to 1st dose of drug was 40.4 months. Median time on study was 10.4 and 8.5 weeks for the BRAF and NRAS arms. Relative dose intensities of 80–<100% were received by 71.4% and 70.8% of pts, respectively. Among 29 BRAF mt and 13 NRAS mt pts evaluable for efficacy, 1 confirmed and 6 unconfirmed partial responses (PRs) and 9 pts with stable disease (SD) were recorded in the BRAF arm and 2 confirmed PRs, 1 unconfirmed PR and 4 pts with SD recorded in the NRAS arm. Common treatment–related adverse events (AEs), all grades (Gs) and all pts, were rash (40.9%), diarrhea (33.3%), acneiform dermatitis (27.3%), creatine phosphokinase (CK) elevation (25.8%), fatigue (18.2%) and peripheral edema (21.2%). Central serous retinopathy-like retinal events (G 1/2 only) were reported in 8 (12.1%) pts (6 G1, 2 G2). All retinal events were reversible. G3/4 AEs in >1pt were diarrhea (4.5%) and CK elevation (15.2%). 5 pts discontinued due to toxicity. 34 pts are ongoing with more responses under current review. Conclusions: MEK162 showed clinical activity and good tolerability in pts with BRAF and NRAS mt advanced melanoma. This is the 1st targeted therapy to show activity in pts with NRAS mt melanoma.
A phase II single arm study of pazopanib and paclitaxel as first-line treatment for unresectable stage III and stage IV melanoma: Interim analysis.
Authors: Fruehauf John P. , Alger Beverly , Parmakhtiar Basmina , Jakowatz James G. , Bettis Claudette , Chuang Tony , Ein-Gal Shlomit Y.
Published: March 2020

8524

Background: Metastatic melanoma lacks effective therapy. Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 20 eligible patients have been enrolled with 17 evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST criteria were used to define treatment response. Results: For the 17 evaluable patients treated to date the following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall RR (CR+PR) was 40%. Total disease control rate was 80% (PR+SD). The most common AEs/lab abnormalities were nausea (71%), hypertension (57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included hypertension (28%), transaminitis (21%) and neutropenia (14%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 5 patients and for paclitaxel in one patient. Conclusions: Planned interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients.
Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms and fatigue in women with breast cancer starting adjuvant letrozole: The VITAL trial.
Authors: Khan Qamar J. , Kimler Bruce F. , Reddy Pavan S. , Sharma Priyanka , Klemp Jennifer R. , Fabian Carol J.
Published: March 2020

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=<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.
Evaluation of food effect on pharmacokinetics (PK) of GDC-0449 (G) in advanced solid tumor patients.
Authors: Sharma Manish , Kang Soonmo Peter , Karrison Theodore , Wu Kehua , Turcich Michelle , Geary David , Takebe Naoko , Graham Richard A. , Maitland Michael L. , Schilsky Richard L. , Ratain Mark J. , Cohen Ezra E. W.
Published: March 2020

e13106

Background: GDC-0449 (Vismodegib, Genentech), an orally bioavailable small-molecule SMO (Smoothened) inhibitor, was recently approved for advanced basal cell carcinoma (BCC) and is being evaluated in other solid tumors. This study sought to determine whether there is a significant effect of food on the PK of G. Methods: In part I, patients (pts) were randomized 1:1 to fasting overnight (FO) or a high fat meal (HF) before a single dose of G 150 mg. The study was later amended to 1:1:2 randomization to FO, HF or a low fat meal (LF). Plasma concentrations of G were determined by a validated liquid chromatography-tandem mass spectrometry assay. PK endpoints were observed Cmax, observed Tmax, and AUC (0-24 and 0-168 hours). In part II, pts randomized to FO or HF in part I took G 150 mg/day in a fasting state, while pts randomized to LF took G 150 mg/day in a fed state. PK endpoints after two weeks were steady state (ss) Cmax, ss Tmax, and ss AUC (0-24 hours). 60 pts enrolled 10/09-11/11, of which 43 were evaluable for PK: 18 FO; 14 HF; 11 LF. Pt characteristics: Female 53%; median age 59; PS 0: 62%, 1: 38%. Tumor types: 43% colorectal; 17% pancreatic; 40% other. Results: PK data were log-transformed for analysis. AUC (0-168 hours) after a single dose was higher in HF than in FO pts (p = 0.049); ratio of geometric means = 1.46 (90% CI = 1.07-1.99). There was a trend toward higher Cmax after a single dose in HF than in FO pts (p = 0.071); ratio of geometric means = 1.39 (90% CI = 1.03-1.88). There were no significant differences between groups for single dose AUC (0-24 hours) and Tmax. There were no significant differences between fasting and fed groups for ss Cmax, ss Tmax, or ss AUC (0-24 hours). The frequencies of drug-related Grade ≥ 3 toxicities were similar in the fasting and fed groups. There were no objective responses; 11 pts (18%) had stable disease for a median duration of 16 weeks and a maximum of 104 weeks (BCC). Conclusions: A high fat meal increases plasma exposure to a single dose of G, but there are no significant PK or safety differences between fasting and fed groups at ss. GDC-0449 can be taken with or without food for daily dosing. This study design is an efficient way to evaluate the effect of food on oral anti-cancer drugs. Supported by NCI grant 5U01-CA69852-12.
Medical treatment consensus in unresectable midgut gastrointestinal neuroendocrine tumors.
Authors: Strosberg Jonathan R. , Fisher George A. , Benson Al B. , Malin Jennifer L. , Anthony Lowell Brian , Arslan Bulent , Gibbs John F. , Greeno Edward , Iyer Renuka V. , Kim M. K. , Maples W. , Philip Philip Agop , Wolin Edward M. , Cherepanov Dasha , Broder Michael S.
Published: March 2020

e14610

Background: Neuroendocrine tumors (NETs) comprise mostly carcinoid or pancreatic NETs and are rare with symptoms that may be difficult to control. Current treatment guidelines lack some specificity. We summarize an expert panel consensus on medical treatment of well-differentiated unresectable midgut NETs. Methods: Consensus statements were developed via RAND/UCLA Delphi process, which involved a diverse group of physician experts (e.g., by specialty, geography, practice) developing comprehensive clinical patient scenarios and rating the scenarios on the appropriateness of various medical therapies before and after a face-to-face meeting. Experts and moderator were blinded to funding source. Scenarios were rated on a 1-9 scale and were labeled as appropriate, inappropriate, or uncertain. Scenarios with >2 ratings in 1-3 and >2 in 7-9 range were considered to have disagreement and were not assigned an appropriateness rating. Results: Panelists (age: 38-63 years) were from the northeast, midwest, south, and west regions. Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean 15.5 years (range: 6-33). Panelists rated 202 scenarios. The proportion for which there was disagreement decreased from 11.7% (23 scenarios) before the meeting to 4.5% (9) after. Post-meeting, 49% (99 scenarios) were rated inappropriate, 29.7% (60) were uncertain, and 16.8% (34) were appropriate. Consensus statements from the scenarios included: 1) it is appropriate to use somatostatin analogs (SA) as 1st-line therapy in all patients, 2) it is appropriate to increase the dose/frequency of octreotide-LAR as 2nd-line therapy in patients with uncontrolled symptoms up to 60 mg every 4 weeks or up to 40 mg every 3 or 4 weeks for refractory carcinoid syndrome. Other treatment options may also be appropriate in 2nd-line. Conclusions: Treatment consensus obtained in this study is concordant with NCCN recommendations. The Delphi process allowed quantification of ratings in a systematic and reliable way while improving consensus in a group of physicians on the appropriateness of medical therapies in midgut NETs.
Gender as a factor associated with poor compliance in the treatment of metastatic renal cell carcinoma with VEGF-targeted therapy in Japanese patients.
Authors: Uemura Motohide , Tsujimura Akira , Kawashima Atsunari , Arai Yasuyuki , Tanigawa Go , Nin Mikio , Yasunaga Yutaka , Yoshioka Toshiaki , Nomura Hironori , Mukai Masatoshi , Fukuda Satoko , Oka Daizo , Nishimura Kenji , Yoshida Takahiro , Satou Mototaka , Hatano Koji , Nakai Yasutomo , Takayama Hitoshi , Nishimura Kazuo , Nonomura Norio
Published: March 2020

e15065

Background: Sorafenib and Sunitinib are multikinase inhibitors used as first -or second-line treatment of metastaic renal cell carcinoma (mRCC). In a multi-institutional study with Japanese patients, we found that good compliance(one month relative dose intensity ≥50% in Sorafenib (Eur J Can 2011) and continuing therapy for more than one course in Sunitinib) was the most important factor in improving progression free survival (PFS) time. Because PFS has been reported to be a predictor of overall survival(OS) (Heng et al. Cancer 2011), we hypothesized that good compliance with these drugs was the most important factor contributing to positive outcomes. Here, we analyzed the clinical results in our series and determined the factors most closely associated with poor compliance of VEGF-targeted therapy. Methods: We retrospectively analyzed a database comprising 143 patients treated by Sorafenib and 69 patients by Sunitinib as both first- and second-line therapy for mRCC. Cohorts were defined by gender, eGFR, Eastern Cooperative Oncology Group Performance Status (ECOG PS), T stage, prior nephrectomy, lactate dehydrogenase level, anemia, hypercalcemia, initial oral dose, and compliance. We used the Cox regression model and logistic regression analysis to calculate the hazard ratio (HR) for univariate and multivariate analysis. Results: Median PFS and OS were 9.0 months and 30.3 months, respectively. Median PFS time of the patients with good compliance (9.1months, 95%CI; 7.1-11.0) was much better than that of the patients with poor compliance (3.0 months, 95%CI; 2.5-3.5) (p<0.001), although there was no significant difference in median OS time. In multivariate analysis, good compliance together with PS and anemia became the prognostic factor to predict superior PFS. In clinical items, female (HR; 3.513, 95%CI 1.567-7.871, p=0.002), poor ECOG PS (p=0.022) and renal impairment (p=0.026) were significantly associated with poor compliance in multivariate analysis. Conclusions: We need to improve drug compliance of femalepatients and patients with poor ECOG PS and renal impairment receiving sorafenib or sunitinib for the treatment of mRCC.
Severe zoledronic acid (ZOL)-associated hypophosphatemia and prognosis in patients with castration-resistant prostate cancer (CRPC).
Authors: Warr Julia , Yam David , VanDraanen Leah , Goodall Shannon , Giotis Angie , Pasetka Mark , Isogai Pierre K , Mamedov Alexandre , DeAngelis Carlo , Emmenegger Urban
Published: March 2020

e15180

Background: ZOL therapy is associated with severe (i.e., grade ≥ 3) hypocalcemia and hypophosphatemia in a subset of patients with metastatic CRPC. However, as opposed to the distinct clinical picture of hypocalcemia, the symptoms of hypophosphatemia are less pathognomonic. Furthermore, serum phosphate abnormalities are not regularly reported. Methods: To characterize the rate and clinical impact of severe hypophosphatemia in CRPC patients undergoing ZOL therapy, we identified CRPC patients receiving at least 3 doses of ZOL at our Centre between 01/2004 and 03/2011. Patient demographics, disease characteristics and laboratory parameters were extracted using the Oncology Symptom Control and Information Resource database, and by means of manual chart review. Results: 12 of 90 evaluable patients developed grade ≥ 3 hypophosphatemia (nadir) after 364±299 days (mean±SD) following the first dose of ZOL. While only one patient presented with concomitant severe hypocalcemia, the hypophosphatemia nadir coincided with rising PSA readings in 9 out of 11 informative patients. Severe ZOL-associated hypophosphatemia identified patients with worse outcome (median overall survival from time of CRPC diagnosis to death 685 days) compared to patients without documented hypophosphatemia (907 days, HR 0.52, p=0.049; n=42), or patients with grade 1-2 hypophosphatemia (1035 days, HR 0.44, p=0.016; n=36). Otherwise, the prognostic nomogram developed by Armstrong et al appears not to capture the poor prognosis of patients with severe ZOL-associated hypophosphatemia. Conclusions: Grade 3-4 hypophosphatemia occurs in about 15% of CRPC patients undergoing ZOL therapy and is associated with worse prognosis when compared to patients with absent or mild hypophosphatemia. The latter is usually transient and likely related to increased parathyroid hormone levels due to calcium decreases as a consequence of bisphosphonate therapy. On the other hand, the distinct clinical behavior of CRPC presenting with ZOL-associated severe hypophosphatemia suggests that secreted tumor-associated factors such as fibroblast growth factor 23 may contribute to this phenomenon.
ST03: A randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with operable gastric, oesophagogastric junction (OGJ) or lower oesophageal adenocarcinoma.
Authors: Smyth Elizabeth C , Langley Ruth E , Stenning Sally P , Stevenson Laura , Allum William H. , Grabsch Heike , Alderson Derek , Riddell Angela M , Crosby Thomas , Mason Robert , Griffin Michael , Mansoor Wasat , Evans Linda , Middleton Gary William , Seymour Matthew T. , Falk Stephen , Smith David , Sumpter Katherine Anne , Blazeby Jane M , Cunningham David
Published: March 2020

TPS4143

Background: Perioperative ECX chemotherapy is a standard of care for localised gastric/OGJ/lower oesophageal adenocarcinoma (Cunningham NEJM 2006). B is a monoclonal antibody targeting VEGF-A, and in combination with chemotherapy results in improved response rates (RR) and progression free survival in advanced gastric cancer (Ohtsu JCO 2011). The aim of ST03 is to assess the safety and feasibility (stage I, first 200 pts) and efficacy (stage II) of the addition of B to perioperative ECX chemotherapy. Methods: ST03 is a multicentre, open-label, phase II/III randomised trial ongoing at 92 UK centres; sites in Germany will open in 2012. Eligibility criteria are histologically proven, untreated, resectable, lower oesophageal, OGJ or gastric adenocarcinoma; age ≥18 years; WHO PS 0-1; and adequate cardiac ejection fraction (EF). Exclusion criteria are TIA/CVA or MI ≤1 year; uncontrolled hypertension; ≥Grade II NYHA heart failure; recent gastrointestinal inflammatory conditions or major surgery/trauma/open biopsy <28d of study entry. Pts receive 3 pre- and 3 postoperative ECX (epirubicin 50 mg/m2 iv D1, cisplatin 60 mg/m2 iv D1 and capecitabine 1250mg/m2/D1-21) +/- B 7.5mg/kg D1 q3wk during chemotherapy, then 6 Bev q3wk (investigational arm). Surgery is pre-specified and laparoscopic procedures allowed only after quality assurance review. All specimens undergo central pathology review; blood and tissue collection for translational correlates is ongoing. The primary outcome measures for Stage I (safety results including cardiac EF) have been reported (Okines ASCO 2011). The stage II primary outcome measure is overall survival. Secondary outcome measures are RR, resection rate, disease free survival, toxicity, and QoL. An MRI substudy is open, a PET substudy is planned. 558 of ~950 pts required have been recruited, accrual expected to complete in 2013. An embedded pilot study within ST03 randomising HER2 positive patients to ECX ± lapatanib will open in 2012. Trial sponsored and co-ordinated by the MRC Clinical Trials Unit and funded by Cancer Research UK (CRUK06/025, NCT00450203).
Combination of antiangiogenic therapy and cytotoxic chemotherapy for sarcomatoid renal cell carcinoma.
Authors: Michaelson M Dror , McDermott David F. , Atkins Michael B. , Cho Daniel C. , Olivier Kara M. , Schwarzberg Abraham B. , Choueiri Toni K.
Published: March 2020

4512

Background: Numerous treatment options exist for metastatic renal cell carcinoma (mRCC), but optimal treatment for patients (pts) with sarcomatoid features remains undefined. Sarcomatoid differentiation is a particularly unfavorable prognostic feature in mRCC. Cytotoxic chemotherapy has modest activity, with a response rate of 16% for doxorubicin plus gemcitabine (Gem). Retrospective data has suggested a response rate of 10% for antiangiogenic therapy. We prospectively studied the combination of antiangiogenic therapy, sunitinib (Su), with Gem chemotherapy in this mRCC subpopulation. Methods: Pts with mRCC and sarcomatoid differentiation were enrolled in a phase 2 clinical trial at 3 institutions. Treatment consisted of 21-day cycles of Su, 37.5 mg on a 2 weeks on/1 week off schedule, along with Gem 1000 mg/m2 on days 1 and 8. The primary endpoint was radiographic response rate (RR) by RECIST. Secondary endpoints included time to disease progression (TTP), safety, and overall survival (OS). Results: Among 35 pts treated in total, 7 were classified as MSKCC good risk, 26 as intermediate risk, and 2 as poor risk. There were 10 partial responses and 1 complete response, for a confirmed RR of 30%. An additional 10 pts exhibited stable disease (clinical benefit rate 60%). Among the 10 pts who had progressive disease as their best response, the majority had underlying non-clear cell histology. Median TTP was 3.5 months (range 0.5-12). Eight pts discontinued due to adverse events (AEs). The most common treatment-emergent grade 3 or higher AEs were neutropenia (8 pts), fatigue (5), anemia (2), and hypertension (2). No treatment-related deaths occurred. Median OS was 11 months (range 1-38+). Conclusions: To our knowledge, this is the largest prospective trial combining cytotoxic chemotherapy and antiangiogenic therapy in patients with RCC and sarcomatoid features. Our results suggest that combination therapy may be more efficacious than either treatment alone in this subtype of mRCC and supports an ongoing intergroup trial (NCT01164228). Further research is necessary to define prognostic factors, including histologic and molecular biomarkers, for distinct subpopulations within this heterogeneous disease. Clinical trial information: NCT00556049.
Multiplex testing of driver mutations in non-small cell lung cancer (NSCLCs) of African-American (AA) patients.
Authors: Gadgeel Shirish M. , Cote Michele L , Schwartz Ann G. , Bollig-Fischer Aliccia , Land Susan , Wenzlaff Angie , Chen Wei , Wozniak Antoinette J. , Sukari Ammar , Mantha Laura , Bepler Gerold
Published: March 2020

7561

Background: Recently driver genetic alterations have been identified in NSCLC that can be targeted for therapeutic interventions. Previous reports have suggested that rates of certain mutations may vary according to ethnic background. We conducted multiplex testing of NSCLCs of AA and white patients to assess variability in the mutation rates by race. Methods: We identified tumor tissues of 136 AA and 320 white NSCLC patients collected as part of three different institutional review board approved studies. Using the Sequenom MassArray system and a multiplexed panel, we analyzed tumor DNA for 214 oncogenic mutations in 26 genes previously identified in NSCLC. Estimated risk (Odds Ratios (OR)) of any mutation and specific gene mutations among AA patients compared to white patients were calculated after adjusting for age, sex, smoking status and histology (adenocarcinoma versus non-adenocarcinoma). Information on smoking status was unavailable on 46 patients and was not included in calculations of ORs for some genes (ORª). Results: The median age at diagnosis was 60 vs 66 years in AA vs white patients; 43% of AA patients and 66% of white patients were males; 69% of AA patients and 52% of white patients had adenocarcinoma; 66% of AA patients and 85% of white patients had stage I/II NSCLC and 10% of AA patients and 6% of white patients were never smokers. 43% of the AA patients and 47% of white patients had at least one mutation detected (OR = 0.78; 0.5-1.2). 19% of AA patients and 6% of white patients had more than 1 mutation detected (OR 2.3; 1.1-4.9). AA patients were more likely to harbor mutations in STK11 (LKB1) (OR=8.4; 3.2-21.8) and NOTCH1 (ORª=8.1; 2.2-30.8), and they were less likely to have MET mutations (ORª= 0.12; 0.02-0.9) then white patients. While not statistically significant, AA had lower prevalence of Kras mutations (OR=0.64, 0.3-1.4) and p53 mutations (OR= 0.82; 0.4-1.6). Conclusions: Our analysis of NSCLCs shows that AAs were more likely to have multiple genetic mutations than whites and the mutation profile differs by race.
Concomitant chemoradiotherapy of cervical carcinoma.
Authors: Naizabekova Svetlana Shamshykeevna
Published: March 2020

e16557

Background: In structure of cancer incidence among female population of Kyrgyzstan, cervical carcinoma takes the second place. incidence is 19.1 per 100 thousand of female population. growth of standardized cervical carcinoma index in Kyrgyzstan from 2002 to 2007 estimated as - 36.4% (from 14.0 to 19.1 per 100 thousand people). materials and methods. in the chemotherapy unit of the national center of oncology, ministry of health KR, from 2010 to 2012 were treated 51 patients with locally advanced cervical carcinoma IIb - stage IIIb with ftorafur as radiomodifier. all patients’ diagnosis were verified. histologically - squamous cell carcinoma. age of patients ranged from 29 to 74, median – 51 years. the main group consisted of patients with IIIb stage - 33 patients (64.7%), 18 patients with iib stage - 35.3%. all 51 patients with locally advanced cervical carcinoma received combined radiotherapy (external beam and intracavitary) on a radical program against ftorafur. ftorafur was taken orally dozed at 400 mg every 12 hours. absolute contraindications of use of ftorafur together with combined radiation therapy of patients with cervical carcinoma were not found. presence of severe comorbidity was one of the relative contraindication research results. evaluation of the effectiveness of the treatment was carried out according to WHO criteria, on the degree of regression of primary tumor. clinical results showed that complete regression occurred in 28 patients (54.9%), partial regression of the tumor in 16 patients (31.4%), stabilization of tumor in 7 (13.7%). objective response rates were 92.1%. side effects of the treatment were evaluated on a scale of toxicity (Common Toxicity Criteria NCIC). hematologic toxicity (anemia - 56.8%, leukopenia - 3,9%) I-II degree, gastrointestinal symptoms (nausea and vomiting - 3,9%) I-II toxicity. during the dynamical monitoring of patients, the III-IV toxicity stages were not found. conclusion. use of ftorafur as a radiomodifier together with concomitant radiation therapy on patients with locally advanced cervical carcinoma helped to accelerate the tumor regression. toxicity did not exceed I-II degrees. analysis of immediate results of treatment showed a high objective effect - 86.3% in the following category of patients.