bluuebunny/crossref_metadata_2025 huggingface dataset:
Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview
Authors: Vanhoefer Udo , Harstrick Andreas , Achterrath Wolf , Cao Shousong , Seeber Siegfried , Rustum Youcef M.
Published: February 2017

PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I–interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer.

RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future.

CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.
Hematopoietic Stem-Cell Transplantation for Treatment-Related Leukemia or Myelodysplasia
Authors: Witherspoon Robert P. , Deeg H. Joachim , Storer Barry , Anasetti Claudio , Storb Rainer , Appelbaum Frederick R.
Published: February 2017

PURPOSE: This report describes results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998, and identifies patient and treatment characteristics associated with survival and relapse.

PATIENTS AND METHODS: At transplantation, 56 patients had treatment-related secondary acute myeloid leukemia (AML), 15 had refractory anemia with excess blasts in transition (RAEB-T), 23 had refractory anemia with excess blasts (RAEB), 15 had refractory anemia (RA), and two had refractory anemia with ringed sideroblasts (RARS). Conditioning regimens were total-body irradiation (TBI) and chemotherapy for 60 patients, busulfan (BU) 14 to 16 mg/kg and cyclophosphamide (CY) 120 mg/kg (BUCY) for 27 patients, BU targeted to 600 to 900 ng/mL plasma steady-state concentration with 120 mg/kg CY (BUCY-t) for 22 patients, and miscellaneous chemotherapy for two patients. The donors were HLA-identical or partially identical family members for 69 patients and unrelated donors for 42 patients.

RESULTS: The 5-year disease-free survival was 8% for TBI, 19% for BUCY, and 30% for BUCY-t (P = .006). The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for RAEB-T, 26% for RAEB, and 0% for RA or RARS (P = .0009). The 5-year cumulative incidence of nonrelapse mortality after TBI was 58%; after BUCY, 52%; and after BUCY-t, 42% (P = .02).

CONCLUSION: Patients at risk for treatment-related leukemia or myelodysplasia should be followed closely and be considered for stem-cell transplantation early in the course of myelodysplasia using conditioning regimens such as BUCY-t designed to reduce nonrelapse mortality.
Safety and Efficacy of Temozolomide in Patients With Recurrent Anaplastic Oligodendrogliomas After Standard Radiotherapy and Chemotherapy
Authors: Chinot Oliver-Louis , Honore Stephane , Dufour Henry , Barrie Maryline , Figarella-Branger Dominique , Muracciole Xavier , Braguer Diane , Martin Pierre-Marie , Grisoli François
Published: February 2017

PURPOSE: Most primary oligodendrogliomas and mixed gliomas (oligoastrocytoma) respond to treatment with procarbazine, lomustine, and vincristine (PCV), with response rates of approximately 80%. However, limited data on second-line treatments are available in patients with recurrent tumors. A novel second-generation alkylating agent, temozolomide, has recently demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme and anaplastic astrocytoma. This study describes the effects of temozolomide in patients with recurrent anaplastic oligodendroglioma (AO) and anaplastic mixed oligoastrocytoma (AOA).

PATIENTS AND METHODS: Forty-eight patients with histologically confirmed AO or AOA who had received previous PCV chemotherapy were treated with temozolomide (150 to 200 mg/m2/d for 5 days per 28-day cycle). The primary end point was objective response. Secondary end points included progression-free survival (PFS), time to progression, overall survival (OS), safety, and tolerability.

RESULTS: Eight patients (16.7%) experienced a complete response, 13 patients (27.1%) experienced a partial response (objective response rate, 43.8%), and 19 patients (39.6%) experienced stable disease. For the entire treatment group, median PFS was 6.7 months and median OS was 10 months. For objective responders, median PFS was 13.1 months and median OS was 16 months. For complete responders, PFS was more than 11. 8 months and OS was more than 26 months. Response correlated with improved survival. Temozolomide was safe and well tolerated. Twelve patients developed grade 1/2 thrombocytopenia and three patients developed grade 3/4 thrombocytopenia.

CONCLUSION: Temozolomide is safe and effective in the treatment of recurrent AO and AOA.
Strategies to Manage the Adverse Effects of Oral Morphine: An Evidence-Based Report
Authors: Cherny Nathan , Ripamonti Carla , Pereira Jose , Davis Carol , Fallon Marie , McQuay Henry , Mercadante Sebastiano , Pasternak Gavril , Ventafridda Vittorio ,   for the Expert Working Group of the European Association of Palliative Care Network
Published: February 2017

ABSTRACT: Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria, a substantial minority of patients treated with oral morphine (10% to 30%) do not have a successful outcome because of (1) excessive adverse effects, (2) inadequate analgesia, or (3) a combination of both excessive adverse effects along with inadequate analgesia. The management of excessive adverse effects remains a major clinical challenge. Multiple approaches have been described to address this problem. The clinical challenge of selecting the best option is enhanced by the lack of definitive, evidence-based comparative data. Indeed, this aspect of opioid therapeutics has become a focus of substantial controversy. This study presents evidence-based recommendations for clinical-practice formulated by an Expert Working Group of the European Association of Palliative Care (EAPC) Research Network. These recommendations highlight the need for careful evaluation to distinguish between morphine adverse effects from comorbidity, dehydration, or drug interactions, and initial consideration of dose reduction (possibly by the addition of a co analgesic). If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, opioid rotation, or switching route of systemic administration. The approaches are described and guidelines are provided to aid in selecting between therapeutic options.
Phase I Trial of Weekly Gemcitabine and Concurrent Radiotherapy in Patients With Inoperable Non–Small-Cell Lung Cancer
Authors: Trodella Lucio , Granone Pierluigi , Valente Salvatore , Turriziani Adriana , Macis Giuseppe , Corbo Giuseppe M. , Margaritora Stefano , Cesario Alfredo , D’Angelillo Rolando M. , Gualano Gina , Ramella Sara , Galetta Domenico , Cellini Numa
Published: February 2017

PURPOSE: To report the evidence of a phase I trial planned to determine the maximum-tolerated dose (MTD) and related toxicity of weekly gemcitabine (GEM) and concurrent radiotherapy in patients with non–small-cell lung cancer (NSCLC). In addition, the response to treatment was evaluated and reported.

PATIENTS AND METHODS: Thirty-six patients with histologically confirmed NSCLC deemed unresectable because of advanced stage were observed and treated according to a combined chemoradiation protocol with GEM as chemotherapeutic agent. GEM was given weekly for 5 consecutive weeks as a 30-minute intravenous infusion concurrent with radiotherapy (1.8 Gy/d; total dose, 50.4 Gy). The initial dose was 100 mg/m2. Pulmonary, esophageal, cardiac, hematologic, and skin toxicities were assessed. The dose of GEM was increased by 50 mg/m2 up to a dose of 250 mg/m2; an additional increase by 25 mg/m2 up to the MTD was planned and realized. Three patients were enrolled for each dose level.

RESULTS: Dose-limiting toxicity was identified for the 375-mg/m2 level with two episodes of grade 2 esophagitis and two of grade 3 pulmonary actinic interstitial disease. The weekly dose of GEM 350 mg/m2 was well tolerated.

CONCLUSION: A weekly GEM dose of 350 mg/m2 concurrent with radiotherapy was well tolerated. Promising results regarding response to treatment were observed and reported.
Clinical Factors Associated With Cancer-Related Fatigue in Patients Being Treated for Leukemia and Non-Hodgkin’s Lymphoma
Authors: Wang Xin Shelley , Giralt Sergio A. , Mendoza Tito R. , Engstrom Martha C. , Johnson Beth A. , Peterson Neomi , Broemeling Lyle D. , Cleeland Charles S.
Published: February 2017

PURPOSE: To describe fatigue severity, fatigue interference, and associated factors in hematologic malignancies.

PATIENTS AND METHODS: Patients being treated for leukemia and non-Hodgkin’s lymphoma (n = 228) completed the Brief Fatigue Inventory to rate fatigue severity and functional interference caused by fatigue. Data on patient demographics, Eastern Cooperative Oncology Group performance status, other physical symptoms, current treatments, and laboratory values were also collected. Descriptive statistics, bivariate correlation, and logistic regression were used for data analysis.

RESULTS: Fifty percent of the sample reported severe fatigue, which was defined as a “fatigue worst” rating of 7 or greater. More patients with acute leukemia (61%) reported severe fatigue compared with those with chronic leukemia (47%) and non-Hodgkin’s lymphoma (46%). Increased fatigue severity significantly compromised patients’ general activity, work, enjoyment of life, mood, walking, and relationships with others. Fatigue severity was strongly associated with performance status, use of opioids, blood transfusions, gastrointestinal symptoms, and sleep disturbance items, as well as with low serum hemoglobin and albumin levels. Regression analysis indicated that nausea was the significant clinical predictor of severe fatigue (odds ratio, 13), and low serum albumin was the significant laboratory value predictor (odds ratio, 3.8).

CONCLUSION: Disabling fatigue occurs with high frequency in hematologic malignancy, supporting a need to develop better methods of fatigue management. Better control of gastrointestinal and other symptoms may be of benefit. The mechanism and relationship between low albumin and severe fatigue needs to be investigated further, and longitudinal studies of the effects of treatment, host factors, and other symptoms are needed.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study.
Authors: Rummel Mathias J. , Niederle Norbert , Maschmeyer Georg , Banat Andre G. , von Gruenhagen Ulrich , Losem Christoph , Kofahl-Krause Dorothea , Heil Gerhard , Welslau Manfred , Balser Christina , Kaiser Ulrich , Weidmann Eckhart , Duerk Heinz A. , Ballo Harald , Stauch Martina , Barth Juergen , Hinke Axel , Brugger Wolfram ,   Study Group Indolent Lymphomas (StiL)
Published: February 2017

3

Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in indolent lymphoma and MCL and was presented at ASH 2009 including a comprehensive safety analysis. Here we present an updated analysis with a cut-off date for 31 Oct 2011. Methods: 549 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a max of 6 cycles. The primary endpoint was PFS. Results: 514 pts randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. At a median follow-up of 45 months, PFS was significantly prolonged with B-R compared with CHOP-R (HR 0.58, 95% CI 0.44–0.74; P<0.001). Median PFS was 69.5 versus 31.2 months, respectively. The PFS benefit with B-R was maintained in all histological subtypes except marginal zone lymphoma. The PFS benefit with B-R was independent of age; HR 0.52 (P=0.002) in pts ≤60 years (n=199), and HR 0.62 (P=0.002) in pts >60 years (n=315). In pts with normal LDH (62%), PFS was significantly prolonged with B-R compared with CHOP-R (P<0.001), while in the elevated LDH group (38%) PFS was numerically, but not significantly increased with B-R compared with CHOP-R (P=0.118). In patients with follicular lymphoma, FLIPI subgroups defined by 0–2 factors (favorable) and 3–5 factors (unfavorable) had a longer PFS with B-R than with CHOP-R (P=0.043 and P=0.068 for the favorable and unfavorable FLIPI subgroups, respectively). Seventy four salvage treatments had been initiated in the B-R group; compared with 116 in the CHOP-R group, of those in the CHOP-R group 52 pts received B-R as salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the B-R and CHOP-R arms, respectively. Twenty secondary malignancies were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R). Conclusions: In patients with previously untreated indolent lymphoma, and elderly patients with MCL, B-R demonstrates a PFS benefit and improved tolerability compared with CHOP-R.
Prognostic impact of the 21-gene recurrence score (RS) on disease-free and overall survival of node-positive, ER-positive breast cancer patients (pts) treated with adjuvant chemotherapy: Results from NSABP B-28.
Authors: Mamounas Eleftherios P. , Tang Gong , Paik Soonmyung , Baehner Frederick L. , Liu Qing , Jeong Jong-Hyeon , Kim Seong-Rim , Butler Steven M , Jamshidian Farid , Cherbavaz Diana B. , Shak Steven , Julian Thomas B. , Lembersky Barry C. , Wickerham D. Lawrence , Costantino Joseph P. , Wolmark Norman
Published: February 2017

1

Background: RS predicts outcome in node- and node+, ER+ pts treated with adjuvant endocrine therapy as well as benefit from adjuvant chemotherapy, with high RS receiving most of the benefit. We studied the prognostic impact of RS in node+, ER+ pts treated with adjuvant chemotherapy plus endocrine therapy as part of the NSABP B-28 trial. Methods: B-28 compared doxorubicin/cyclophosphamide (ACX4) with ACX4 followed by paclitaxel X4. Pts >50 yrs and those<50 yrs with ER+ and/or PR+ tumors also received 5 yrs of tamoxifen concurrently with chemotherapy. Between 8/95 and 5/98 3060 pts were accrued. The present study includes 1,065 pts ER+ by central tissue microarray IHC assay, tamoxifen treated, assessed by RS. Median follow-up time was 11.2 yrs. Results: Of the 1,065 pts, 386 (36%) had low RS<18; 364 (34%) intermediate RS,18-30; and 315 (30%) high RS≥31. In univariate analyses RS was a significant predictor of DFS, distant recurrence-free interval (DRFI) and OS (Table). In multivariate analyses, RS provided independent prognostic information for all three endpoints beyond clinical and pathologic factors, e.g., treatment, age, tumor size, tumor grade, number of + nodes and type of surgery (p<0.001). Conclusions: The 21-gene RS maintains significant prognostic impact in ER+, node+ pts who have received anthracycline- or anthracycline/taxane-based adjuvant chemotherapy. These findings emphasize the need to target pts with high residual risk for recurrence with additional therapies to overcome unfavorable biology, potential endocrine and/or chemotherapy resistance. Supported by: NCI, HHS, PHS, grants U10-CA-12027, -69651, -37377, -69974, and U24-CA-114732, and grants from Susan G. Komen for the Cure and Bristol-Myers Squibb Pharmaceutical Research Institute. [Table: see text]
Final overall survival (OS) and safety analyses of RIBBON-2, a randomized phase III trial of bevacizumab (BEV) versus placebo (PL) combined with second-line chemotherapy (CT) for HER2-negative BEV-naive metastatic breast cancer (MBC).
Authors: Brufsky Adam M. , Hurvitz Sara A. , Perez Edith A. , Yamamoto Hideharu , Valero Vicente , O'Neill Vincent , Rugo Hope S.
Published: February 2017

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Background: Combining BEV with CT significantly improved progression-free survival (primary endpoint) in the E2100, AVADO, and RIBBON-1 trials in the 1st-line setting and the RIBBON-2 trial in the 2nd-line setting. Primary efficacy and safety results from RIBBON-2 have been published; here we present final OS results. Methods: Eligible patients (pts) had MBC that had progressed on 1st-line CT without BEV. 2nd-line CT (taxane, gemcitabine, capecitabine, or vinorelbine) was chosen before 2:1 randomization to CT with either BEV (10 mg/kg q2w or 15 mg/kg q3w) or PL continued until progression. Stratification factors were 2nd-line CT, hormone receptor status, and time from MBC diagnosis to 1st progression. All pts could receive BEV at progression. The primary endpoint was PFS. Final analysis of OS, a secondary endpoint, in the intent-to-treat population was planned after 557 events and provided 80% power to detect a hazard ratio (HR) of 0.77 (median OS increased from 14.0 to 18.2 months) at α=0.04. Results: At the time of data cutoff (Oct. 31, 2011), 184 (82%) of 225 pts in the CT/PL arm and 376 (82%) of 459 pts in the CT/BEV arm had died. BEV was administered in subsequent treatment lines in 12% vs 6% of pts, respectively. There was no difference in OS between treatment arms: HR 1.013 (95% CI 0.845–1.215), log-rank p=0.8843. Median OS was 17.8 months with CT/PL vs 18.6 months with CT/BEV. The 1-year OS rates were 69% vs 71%, respectively. Subgroup analyses by CT cohort showed HRs ranging from 0.86 (95% CI 0.58–1.29) in the capecitabine cohort (n=144) to 1.44 (95% CI 0.82–2.53) in the vinorelbine cohort (n=76). HRs were close to 1 for the two largest CT cohorts (taxane and gemcitabine). Exploratory analysis in the subgroup of patients with triple-negative MBC showed a HR of 0.85 (95% CI 0.58–1.26). Updated safety results were similar to those previously reported from the primary analysis. There were fewer fatal adverse events in the CT/BEV arm (1.5%) than in the CT/PL arm (3.2%). Conclusions: Final OS results from RIBBON-2 reveal no difference between treatment arms. No new safety signals were observed.
Safety of everolimus in estrogen receptor–positive advanced breast cancer.
Authors: Perez Alejandra T.
Published: February 2017

103

Background: Despite advances in treatment of estrogen receptor–positive (ER+) breast cancer (BC), resistance to endocrine therapy remains a frequent cause of disease recurrence. The mTOR pathway has been identified as a point of deregulation in patients resistant to standard therapy. Everolimus (EVE), an oral mTOR inhibitor, was evaluated as a potential antitumor therapy. Treatment-emergent adverse events (AEs) and their management are presented. Methods: BOLERO-2 (NCT00863655), a phase III trial, evaluated EVE in postmenopausal women with ER+ advanced BC refractory to letrozole or anastrozole. Patients with documented recurrence or progression were randomized 2:1 to receive daily oral EVE (10 mg) or matching placebo, in addition to exemestane (EXE; 25 mg/d), stratified by sensitivity to prior hormonal therapy and the presence of visceral metastasis. Results: At 12.5 months’ follow-up, PFS was 7.4 months in the EVE + EXE arm (n = 485) vs 3.2 months in the EXE-only arm (n = 239) (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.36-0.53; p < 1 × 10-l6). Notable AEs (all grades) in the EVE + EXE vs EXE-only treated patients included stomatitis (59% vs 11%), rash (39% vs 6%), pneumonitis (15% vs 0), and hyperglycemia (14% vs 2%). Grade 3-4 AEs of interest in the EVE + EXE vs EXE-only treated patients were stomatitis (8% vs <1%), anemia (7% vs <1%), hyperglycemia (5% vs <1%), pneumonitis (3% vs 0), and rash (1% vs 0). EVE doses could be reduced or interrupted for the management of AEs. Exploratory analyses of antitumor effects of EVE in patients who received time-averaged EVE doses <7.5 mg/d compared with ≥7.5 mg/d were consistent (HR, 0.4 [95% CI, 0.31-0.52] vs HR, 0.45 [95% CI, 0.37-0.56], respectively). Stomatitis was managed with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics. Noninfectious pneumonitis was managed by a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment. Conclusions: Addition of EVE to EXE significantly prolonged PFS and was generally well tolerated. AEs were manageable with appropriate care. Knowledge of AE management strategies is essential to optimize EVE tolerability and patient outcomes.
Safety of everolimus for women over age 65 with advanced breast cancer (BC): 12.5-month follow-up of BOLERO-2.
Authors: Rugo Hope S. , Burris Howard A. , Gnant Michael , Baselga José , Piccart-Gebhart Martine J. , Noguchi Shinzaburo , Dakhil Shaker R. , Srimuninnimit Vichien , Puttawibul Puttisak , Csoszi Tibor , Heng Daniel Yick Chin , Bourgeois Hugues , Gonzalez-Martin Antonio , Osborne Karen , Mukhopadhyay Pabak , Taran Tanya , Campone Mario , Hortobagyi Gabriel N. , Sahmoud Tarek , Pritchard Kathleen I.
Published: February 2017

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Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE), but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily), in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 months’ median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients <65 (HR, 0.37; p < .05) or ≥65 years of age (HR, 0.56; p < .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infection (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3-4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3-4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.
Patient-reported outcomes (PRO) in patients with metastatic breast cancer (MBC) from the VIRGO observational cohort study (OCS).
Authors: Kaufman Peter Andrew , Mayer Musa , Dreyer Nancy A. , Yim Yeun Mi , Yu Elaine , Su Zhaohui , Mun Yong , Sloan Jeff A. , Cleeland Charles S.
Published: February 2017

111

Background: Limited data exist on patient (pt) experience and work productivity (WP) in MBC. VIRGO is a prospective OCS following >1,200 pts with locally advanced or MBC receiving 1st-line hormonal therapy (HT) or chemotherapy (CT) in a real-world setting. We report baseline characteristics of 277 pts from the VIRGO PRO substudy and correlations between health-related quality of life (HRQoL), symptoms, activities of daily living, and WP. Methods: Symptom severity and interference (M.D. Anderson Symptom Inventory [MDASI]), functional status (Activity Level Scale [ALS] from the Rotterdam Symptom Checklist) and WP (Work Productivity and Activity Impairment Questionnaire) were assessed. Pts rated their HRQoL during the past week on a scale of 0–10. Results: See table. The five most severe symptoms at baseline were fatigue, decreased sexual interest, disturbed sleep, drowsiness, and emotional distress; these were reported with less severity in the HT cohort (24%-37% vs 42%-59%). Overall MDASI severity and interference correlated with WP measures in the CT (R=0.46 to 0.78) and HT cohorts (0.36 to 0.94). Mean of the 5 most severe symptoms also significantly correlated with WP indices (R=0.47 to 0.66). HRQoL correlated (p<0.05) with all WP measures (R=-0.46 to -0.56) in the CT cohort and with % impairment while working (R=-0.65) and % overall work impairment (R=-0.71) in the HT cohort. In univariate regression analysis, MDASI symptom interference score was the best predictor of reduced WP (R2=0.52 while working; R2=0.48 for non-work activities). Conclusions: MBC pts receiving CT and HT report significant work impairment. Results indicate moderate correlations between WP indices, HRQoL and symptom burden. [Table: see text]
Response of angiogenic factors to the treatment with melatonin in breast cancer cell lines.
Authors: Jardim Bruna Victorasso , Moschetta Marina Gobbe , Borin Thaiz Ferraz , Gelaleti Gabriela Bottaro , Leonel Camila , Ferreira Livia Carvalho , Lopes Juliana Ramos , Maschio Larissa Bazela , Goncalves Naiane do Nascimento , Zuccari Debora Aparecida Pires de Campos
Published: February 2017

120

Background: Tumor growth and metastasis are the leading cause of death in breast cancer patients. The tumor growth requires neoangiogenesis, stimulated by vascular endothelial growth factor (VEGF) expressed under control of hypoxia-inducible factor-1α (HIF-1α). Melatonin, a natural hormone has been suggested as a new therapeutic agent to inhibit angiogenesis factors in several types of cancers. We evaluated the HIF-1α and VEGF expression in breast cancer cell line after hypoxia and treatment with melatonin. Methods: Breast cancer cell lines ER-positive (MCF-7) and ER-negative (MDA-MB-231) were cultured in DMEM at 37°C in 5% CO2. The cells were treated with CoCl2 to mimic hypoxia, and then treated with melatonin. Cell viability was measured by MTT assay with five melatonin concentrations (0.5mM, 1mM, 2mM, 5mM, 10mM). For the pharmacological concentration of melatonin (1mM) the protein and gene expression of HIF-1α and VEGF were detected by immunocytochemistry and real time PCR, respectively. Results: There was a significantly decrease in MCF-7 cells viability after treatment with all concentrations of melatonin and in MDA-MB-231 cells just with 1mM (p<0.05). The melatonin treatment did not alter the protein and gene expression of HIF-1α in MCF-7 cells (p>0.05), however, it significantly decreased the VEGF protein expression (p<0.05). In MDA-MB-231 cells there was significant decreased in the HIF-1α protein expression (p<0.05). Conclusions: Our results showed that 1mM of melatonin decreased the cell viability and HIF-1α protein expression in ER-negative cells, and VEGF protein expression in ER-positive cells. This study is the first that evaluated the expression of these angiogenic factors in breast cancer cells after treatment with melatonin that can be a potential therapeutic agent. Thus, we are performing in vivo study to confirm the potential effectiveness of melatonin in the control of angiogenesis in breast cancer.
BOLERO-2: Health-related quality-of-life (HRQoL) in metastatic breast cancer patients treated with everolimus and exemestane versus exemestane.
Authors: Rugo Hope S. , Beck J. Thaddeus , Baselga José , Noguchi Shinzaburo , Gnant Michael , Lebrun Fabienne , Neven Patrick , Nunzi Martina , Komorowski Anna , Chouinard Edmond , Young Robyn R. , Anderson Ian , Bennett Lee , Ricci Jean-Francois , Hortobagyi Gabriel N. , Sahmoud Tarek , Burris Howard A.
Published: February 2017

125

Background: BOLERO-2, a phase III study, randomized 724 patients with hormone-receptor–positive metastatic breast cancer, who had recurrence or progression on/after prior nonsteroidal aromatase inhibitor therapy, to everolimus (EVE) + exemestane (EXE) or EXE + placebo. A preplanned 12-mo median time interim analysis demonstrated that EVE + EXE significantly improved progression-free survival (PFS) vs EXE + placebo, but EVE + EXE resulted in a higher rate of grade 3-4 toxicity. Per-protocol patients reported HRQoL data are limited; here we report on additional post hoc analyses of these outcomes. Methods: Using the EORTC QLQ-C30 questionnaire, HRQoL was assessed at baseline and every 6 weeks thereafter until progression. QLQ-C30 consists of 30 items combined into 15 subscales, including a Global Health Status (GHS), where higher scores (range, 0-100) indicate better HRQoL. Analysis included a protocol-specified time to definitive deterioration (TTD) analysis at a 5% decrease in QoL relative to baseline, with no subsequent increase above this threshold. We report additional sensitivity analyses using 10-point minimally important difference (MID) decreases in QLQ-C30 score relative to baseline. Treatment arms were compared using a stratified log-rank test and a Cox proportional hazards model adjusted for trial stratum (visceral metastases and previous hormone sensitivity), age, sex, race, baseline score, ECOG performance status, prognostic risk factors, and treatment history. Results: Baseline QLQ-C30 GHS scores were not statistically significantly different across treatment groups (64.7 vs 65.3; difference –0.7 [95% CI, –4.3-3.0]). Median TTD in HRQoL was 7.0 mo (95% CI, 5.6-8.3) for EVE + EXE vs 5.6 (95% CI, 4.2-7.0) for EXE (p = .0792). Adjusted HR (0.80) approached significance (95% CI, 0.63-1.02). At the 10-point MID, median TTD for EVE + EXE was 9.7 mo (95% CI, 8.3-11.2) vs 8.4 mo (95% CI, 6.3-12.5) for EXE. Adjusted HR was 0.90 (95% CI, 0.69-1.18). Conclusions: These additional analyses from the BOLERO-2 study demonstrate that in addition to significantly improving PFS, EVE + EXE does not compromise HRQoL.
Maximizing metastatic breast cancer therapy selection: Physician practice patterns and competence assessment.
Authors: Stacy Tina Boyd , Haas Maureen E. , Heintz Alison A.
Published: February 2017

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Background: Due to the volume and pace of scientific advances within oncology, peer discussion and professional reflection regarding appropriate therapeutic decision making is necessary to provide the highest quality patient care. Increasing awareness in the breast cancer community of similarities and differences amongst practice management strategies helps to identify and benchmark individual practice patterns against one’s professional peers, ultimately leading to increased competence in therapy selection. Methods: During 2011 and 2012, educational outcomes assessments were gathered during 85 independent continuing medical education (CME) activities held within community practices and institutions across the USA. Participants were asked a series of case-based questions via an audience response system to assess baseline knowledge, competence, and identify practice patterns. Assessments were repeated post a 1-hour CME certified activity, with an additional 6-week electronic follow-up. Results: To date, over 330 physicians have participated in the program. Number of years in practice ranged from < 10 to > 30. The number of breast cancer patients seen per month ranged from ≤ 10 to > 40. Provider competency and preferences in applying guideline based therapy was assessed. Results of participant preferences including single-agent, combination, first-line, and second-line therapy preferences as well as toxicity management for select patient case scenarios in advanced breast cancer will be presented. Self-rated competence for the physician audience improved by approximately 50% as a result of participation. Conclusions: The results highlight the diversity of clinical opinion in selecting therapy for advanced breast cancer and need for continued dialogue and scientific advancement. Education and peer discussion of how to optimize translation of new scientific information into patient care contributes to maximizing physician competence in therapy selection for metastatic breast cancer.
A review of clinical endpoints and use of quality-of-life outcomes in phase III metastatic breast cancer clinical trials.
Authors: Tatla Raman , Landaverde Denis , Victor Charles , Miles David , Verma Sunil
Published: February 2017

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Background: The management of metastatic breast cancer (MBC) is often considered to be palliative, with most interventions intended to relieve disease symptoms, minimize treatment effects and prolong patient survival. The impact of disease and treatment on a patient's funcitonal abilities has led to an emphasis of incorporating quality of life (QoL) measures into clinical trials. The main objective of this study is to evaluate phase III clinical trials in MBC, and assess the inclusion of QOL as an endpoint, in addition to conventional efficacy endpoints. Methods: A structured PubMed search was conducted to identify phase III clinical trials published between Jan. 1990 and Aug. 2011, evaluating systemic treatment in MBC patients. Data pertaining to treatment regimens, study endpoints and clinical findings were collected, with a particular focus on progression-based (PB), overall survival (OS), and QoL endpoints. Results: Of 520 publications identified, 122 phase III MBC clinical trials met the inclusion criteria. Of these studies, 98.4% and 95.9% included PB and OS respectively, as clinical endpoints, while QoL was assessed in only 46 (37.7%) studies. While the inclusion of QoL was not associated with the significance of PB results, there was an association between the inclusion of QoL and OS results, with 59% of significant OS studies and 32% of non-significant OS studies including QoL as a clinical endpoint (p=0.016). When stratified by treatment arm, it was found that studies favouring standard therapy were more likely to include QoL (75%, p=0.045), compared to those favouring the intervention (56%), and those without significant differences (32%). Conclusions: Although the importance of QoL is often emphasized in MBC management and treatment decisions, only one-third of identified phase III clinical trials included an assessment of QoL. About half of these trials showed no statistically significant differences in the QoL endpoint; of not, instruments of varying validity were utilized. There needs to be a greater emphasis on the evaluation of QoL, with the use of standard and validated QoL tools in MBC clinical trials, especially as we increasingly focus on progression-based endpoints.
Long-term survivor (LTS) characteristics in HER2+ metastatic breast cancer (MBC).
Authors: Yardley Denise Aysel , Tripathy Debu , Brufsky Adam M. , Rugo Hope S. , Kaufman Peter Andrew , Mayer Musa , Feng Shibao , Abidoye Oyewale O. , Ulcickas Yood Marianne
Published: February 2017

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Background: Data characterizing LTS with HER2+ MBC are limited. The objective of this analysis is to describe LTS in terms of demographics, disease characteristics, and treatment history. Methods: registHER is an observational cohort of patients (pts) (N=1,001) with HER2+ MBC diagnosed w/in 6 mos of enrollment and followed until death, disenrollment, or 6/09 (median follow-up 27 mos). LTS were defined as pts who survived ≥36 mos from metastatic diagnosis (dx) (n=404). Baseline characteristics were examined. Multivariate analyses assessed factors associated with overall survival (OS) in all registHER pts. Results: Median progression-free survival in LTS was 17.9 mos (95% confidence interval (CI) 15.5-20.2). Similar to all registHER pts, median age at enrollment for LTS was 52 y (range 22,82), the majority were white (85.4%), and initial dx in over half of pts was stage I-III, MBC >12 mos (57.4%). LTS, however, were more likely to have estrogen receptor (ER)+ or progesterone receptor (PR)+ disease (61.6% and 52.9%, respectively) and a lower rate of underlying cardiovascular disease (CVD) (12.4% and 17.2%, respectively). First-line taxane and first-line trastuzumab use was higher in LTS pts. Physician-assessed first-line complete response was 40% in LTS and 22.8% in all registHER pts. Factors associated with OS in all registHER pts are shown in the table. Conclusions: This descriptive study examines factors commonly associated with long-term survival in pts with HER2+ MBC. LTS were primarily white, with ER+ or PR+ disease, and low rates of underlying CVD. Further study is needed to quantify the contribution of these factors to prolonging survival. [Table: see text]
Multiplex layered immunohistochemistry to predict response of HER2-positive breast cancer patients to trastuzumab therapy.
Authors: Park Soon Sik , Gillespie John Williams , James Bill , Lebowitz Michael
Published: February 2017

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Background: Since only 40% of HER2-positive breast cancer patients respond to trastuzumab therapy, there is a great clinical need for a test that will better predict which patients would be responders to trastuzumab therapy. Since no single biomarker will likely improve identification of responders, this study will determine the efficacy of multiple biomarkers to predict response of patients to trastuzumab therapy. Our company has developed a protein analysis platform, layered immunohistochemistry (L-IHC), for the analysis of multiple protein biomarkers from a single FFPE tissue section while retaining the histologic orientation. L-IHC is being used to develop a companion diagnostic test in which multiple protein biomarkers are analyzed in HER2-positive breast cancer specimens to predict which patients will respond to trastuzumab therapy. Methods: In this ongoing clinical exploratory study, analysis of pretreatment archival HER2-positive FFPE breast cancer tissue sections from patients whose subsequent therapy included trastuzumab and whose response to therapy (responders and non-responders) is known was performed using L-IHC. Tissue sections were probed using a panel of 14 biomarkers along the HER2 and mTOR pathways were analyzed. In a blinded fashion to the response data, the intensity of specific biomarker signals corresponding to cancer regions on an H&E was visually scored (0,1,2,3, & 4+). The pattern of biomarker expression was correlated with the responder status of the patient. Results: A total of 24 responders and 9 non-responders were analyzed. The sum of four of the 14 biomarkers including p-mTOR, p-4EBP1, pERK, and HIF1-alpha discriminated the responders and non-responders. Using 7 as a cutoff, this test correctly identified 21/24 responders and 7/9 non-responders for a sensitivity of 87%, specificity of 78%, and an accuracy of 82%. Conclusions: Results of this study strongly suggests that analysis of p-mTOR, p-4EBP1, pERK, and HIF1-alpha using L-IHC improves twofold the prediction of patient response to trastuzumab compared to Her2 alone.
Correlation of quantitative p95HER2, HER2, and HER3 protein expression with pathologic complete response (pCR) in HER2-positive breast cancer patients (pts) treated with neoadjuvant chemotherapy and trastuzumab.
Authors: Villasboas Jose Caetano , Hurley Judith , Weidler Jodi Marie , Paquet Agnes , Fernandez Carmen Gomez , Cioffi Lavina Maureen , Sperinde Jeff , Chenna Ahmed , Haddad Mojgan , Lie Yolanda , Winslow John William , Huang Weidong , Petropoulos Christos J. , Pegram Mark D.
Published: February 2017

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Background: Elevated p95HER2 [HER2-M611-CTF (carboxy-terminal-fragment) also known as p95] expression has been correlated with poor outcomes in HER2+ pts with metastatic breast cancer treated with trastuzumab (T); however, limited data is available on the correlation between p95 and pCR to T in the neoadjuvant (NEO) setting, where p95 was measured by immunohistochemistry. The current study aims to determine whether quantitative p95, HER3 and HER2 expression correlated with pCR in pts treated with T + chemotherapy in the NEO setting. Methods: pCR data and quantitative HER2 (H2T), p95, and HER3 (H3T) results by HERmark/VeraTag assays were available in 45 patient cases with pre-therapy, formalin-fixed, paraffin-embedded breast tumors. pCR was defined as the absence of invasive disease in the breast. Quantitative biomarker data were correlated with pCR according to previously published or presented biomarker cutoffs. Results: The overall pCR rate was 46.7% (ER+: 14.3% vs. ER-: 75%; p<0.0001) and was significantly associated with higher H2T levels (p=0.02) and lower H3T levels (p=0.04). In ER- subjects (N=24), no difference in H2T levels was observed between pCR vs non-pCR groups (median H2T=111.5 vs 150.5, respectively; p=0.721). However, within the ER+ group (N=21), H2T levels were significantly higher in the pCR group vs non-pCR group (median H2T=254 vs 37.3; p=0.024). Using multivariate logistic regression, increasing log(H2T) (p = 0.012), ER-negativity (p = 0.027) and low p95 (p = 0.074) were found to correlate or trend with pCR. Conclusions: pCR was significantly associated with high H2T, particularly in ER+ HER2+ breast cancer pts who received NEO therapy with T + chemotherapy. Lower H3T was also associated with pCR. A trend towards pCR was seen in tumors with low p95. These data suggest that quantitative H2T, H3T and p95 may provide additional information on response to T-based regimens in breast cancer stratified by ER status. Additional investigation into the relationship between quantitative H2T, p95 and H3T expression and T response in the NEO setting in larger cohorts is warranted.
Reduced re-excisions while conserving tissue volume resected in DCIS patients.
Authors: Freedman Beth Cutler , Boolbol Susan K. , Cocilovo Costanza , Tafra Lorraine
Published: February 2017

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Background: The ability to obtain negative margins with a single surgical procedure remains a challenge, particularly in patients with ductal carcinoma in situ (DCIS). Many techniques have been reported to lower the positive margin rate, at a cost of additional tissue resected. A novel device (MarginProbe, Dune Medical Devices, Inc.) is intended to provide surgeons with real time, intraoperative detection of cancerous tissues at the margins of excised specimens. An analysis was performed to determine the impact on tissue volume of the previously reported improvement in candidates for re-excision associated with device use for patients with a DCIS component. Methods: 596 patients undergoing breast conservation using wire localization were randomized in a prospective, international, multicenter (n=21) study. Randomization occurred in the operating room, following standard of care lumpectomy, including palpation and any indicated additional resections. Positive readings required additional resections of the cavity; device was used on main lumpectomy specimen only. Pathologists were blinded to study arm. Tissue volume of all specimens and resections was recorded. Since reducing candidates for re-excision requires removing additional tissue associated with cancer, we looked at total tissue volume removed across all surgeries, to assess the final impact to the patient. Results: Total tissue volumes removed during all surgeries (lumpectomy and re-excisions) for patients with DCIS alone was similar between the study group and control group, while the decrease in candidates for re-excision was significant (13% vs. 37%, p=0.004). For patients with DCIS and invasive carcinoma, the total volume excised was also similar, and the decrease in re-excision candidates was significant (13% vs. 33%, p<0.001). Conclusions: Unlike other techniques for reducing re-excisions, device use does not require an increase in tissue volume to achieve a significant reduction in the number of candidates for re-excision. [Table: see text]
Clinical efficacy of 2-day versus 5-day accelerated partial breast irradiation delivered via balloon-based brachytherapy: Results of a matched pair analysis.
Authors: Chen Peter Y. , Shah Chirag , Wilkinson John Ben , Wallace Michelle , Ye Hong , Fowler Ashley , Dekhne Nayana , Benitez Pamela , Martinez Alvaro A. , Vicini Frank
Published: February 2017

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Background: This analysis compares the efficacy of a 2-day vs. 5-day accelerated partial breast irradiation (APBI) schedule in treatment of early-stage breast cancer. Methods: Patients were treated between 6/2000 and 1/2011 with balloon-based brachytherapy using a 2-day (700 cGy x 4 BID) or a 5-day (340 cGy x 10 BID) fractionation. The CTV was a 1cm expansion from the balloon surface with a single-lumen device used in all cases. To compare efficacy between the two treatment groups, a matched-pair analysis was performed using a 1:2 ratio which paired 38 two-day with 76 five-day patients. Match criteria included minimal follow-up (FU) > 1.0 yr, clinical stage, age (+/- 3 yrs), and ER status. Clinical outcomes analyzed include local-regional recurrence [LR, RR] distant metastases (DM), disease-free, cause-specific and overall survival [DFS, CSS, and OS]. Results: No significant differences were noted for age (p=0.838), clinical stage (p=1.000), ER (p=1.000), tumor size (p=0.236), margin status (p=0.556), nodal stage (p=0.381), PR (p=0.749), use of chemotherapy (p=0.927) or endocrine therapy (p=0.129). Per the ASTRO Consensus Guidelines, no differences were noted in the clinical groups between the 2-and 5-day treatments with the majority categorized as suitable or cautionary (2-day: 92% vs. 5-day: 87% p=0.436). With a mean FU of 4.7 yrs (4.9 yrs for 2-day vs. 4.5 yrs for 5-day, p=0.279), no differences were seen in the 5-year actuarial rates of LR (0.0% vs. 2.6%, p=0.359), DFS (94.4% vs. 96.1%, p=0.618), CSS (100% vs. 94.9 %, p=0.207), or OS (97.3% vs. 92.5%, p=0.811) between the 2-and 5-day groups, respectively. There was no RR in either group. DM rates were similar for both (5.6% vs. 1.3 %, p=0.456). Conclusions: With near 5-year FU for the 2-day schedule, APBI with the 2-day regimen yielded outcomes equivalent to the 5-day schema. Reduced on-treatment days by such hypofractionation offers flexibility in clinical and patient scheduling. Further FU and more patients will be needed to substantiate equivalence of hypofractionated APBI. An HIC-approved protocol randomizing patients between the 2 vs. 5-day treatments is currently open for accrual at our institution.