bluuebunny/crossref_metadata_2025 huggingface dataset:
Embedding palliative care into bone marrow transplantation clinic.
Authors: Noreika Danielle M , Cassel Brian , Noland Felicia , Del Fabbro Egidio
Published: February 2017

157

Background: Stem cell/bone marrow transplantation (SC/BMT) is intensive therapy that creates the potential for a number of physical and emotional symptoms. Despite the symptom burden and support needs of these patients there are no publications describing palliative care involvement in the course of treatment. Methods: Retrospective chart review was performed on 37 patients followed over a 6-month period by a palliative care service embedded within the SC/BMT clinic. Results: 37 patients were referred by SC/BMT clinic physicians or nurses to a palliative care team embedded within the clinic (including a physician, physical therapist, and psychologist). Almost all patients were referred for symptom management rather than goals of care; only three (9%) died during the review period and for none of them was the reason for consultation goals of care/hospice referral. Patients were seen between once and eight times during the six month period by various members of the team. Most (77%) were allogenic transplant patients and most were seen within 6 months of their transplantation. The most common reasons for referral were fatigue (57%), anorexia (27%), pain (38%) and depression and/or anxiety (35%). At initial assessment the highest-rated symptoms were lack of appetite (mean 4.78, SD 3.08), fatigue (4.51 [2.59]), and diminished feeling of well-being (4.16, [2.51]). At initial assessment, 73% of patients had 3 or more different symptoms that they rated at 4+; this dropped to 39.1% at follow-up (n = 23). Of the 9 symptoms assessed at both initial and follow-up visits, 7 decreased significantly (all but fatigue and dyspnea) and none increased. For example appetite improved from 5.52 (2.98) to 3.13 (2.96); pain improved from 3.52 (2.92) to 1.78 (1.88) (n = 23, p < .01). SC/BMT providers requested an expansion of the service after three months of experience. Conclusions: Patients who have undergone SC/BMT experience many physical and emotional symptoms. Palliative care embedded within the bone marrow transplant clinic can provide benefit by lessening the symptomatic burden of patients.
Measuring the impact of integrating palliative care into a multidisciplinary brain and spine oncology clinic.
Authors: Manning Matthew , Larach Mary , Boyles Susan , Stern Abigail
Published: February 2017

163

Background: Recent literature indicates that palliative care (PC) improves the outcomes of patients with cancer. Integration of PC providers into cancer centers is increasingly recognized to enhance symptom management with a beneficial effect on patient survival. In order to predict the impact of widespread PC integration, we hypothesized that a small pilot program may provide evidence supporting broader implementation. The current study endeavors to measure the result of adding a dedicated PC provider to a multidisciplinary brain and spine oncology program. Methods: Over the six month study period, a PC nurse practitioner was integrated into an existing weekly multidisciplinary brain and spine oncology conference and clinic. The provider participated in the multidisciplinary conference reviewing recent MRIs and discussing current disease status and treatment options. Following conference, the PC provider would consult on up to four of the clinic patients. Data were recorded regarding patient characteristics, goals of care, and changes in therapy. Results: The PC provider participated in 14 multidisciplinary clinics with a total of 180 subjects. Of those, 24 subjects met with the PC provider in formal consultation. The most common diagnoses were 41.6% with metastatic lung cancer and 25% with glioblastoma. For goals of care, an Advanced Directive discussion was documented in 100%. Do Not Resuscitate (DNR) orders were activated in 37.5% and documented in 54%. Medical Orders for Scope of Treatment (MOST) forms were introduced in 87.5% and completed in 25%. For changes in therapy, enrollment in hospice occurred in 33.3%. Pain medication was changed in 33.3%. Other symptoms including fatigue, weakness, anorexia, constipation, anxiety, lymphedema, dysphagia, depression, insomnia, and alopecia were managed in 87.5%. Conclusions: This study suggests that the integration of a PC provider into an existing multidisciplinary cancer program can produce a high rate of establishing goals of care and result in changes in treatment in a significant number of cases. Further study on the impact of integrating PC in cancer centers seems to be warranted.
Would women with breast cancer prefer to receive an antidepressant for anxiety or depression from their oncologist?
Authors: McFarland Daniel Curtis , Shen Megan Johnson , Harris Kirk , Tiersten Amy , Mandeli John , Holland Jimmie
Published: February 2017

219

Background: Patient treatment preferences for the management of anxiety and depression influence adherence and treatment outcomes, yet breast cancer patient preferences for provider-specific pharmacologic management of anxiety and depression is unknown. This study examined breast cancer patients’ antidepressant prescriber preferences and their preferences for treatment by a mental health professional. Methods: Breast cancer patients (Stage 0-IV) were asked two questions: 1) “Would you be willing to have your oncologist treat your depression or anxiety with an antidepressant medication if you were to become depressed or anxious at any point during your treatment?”; and 2) “Would you prefer to be treated by a psychiatrist or mental health professional for problems with either anxiety or depression?” Additionally, the Distress Thermometer and Problem List, Hospital Anxiety and Depression Scale, Risky Families Questionnaire, and demographic information were assessed. Results: One hundred twenty-five participants completed the study. 60.4% were willing to accept an antidepressant from an oncologist and 26.3% preferred treatment by a mental health professional. 77.3% who were willing to receive an antidepressant from their oncologist reported either no preference or that treatment by a mental health professional didn’t matter (p = 0.01). Participants taking antidepressants (p = 0.02) or reporting high chronic stress (p = 0.03) preferred a mental health professional. Conclusions: The majority of patients accepted antidepressant prescribing by their oncologist; only a minority preferred treatment by a mental health professional. These findings suggest the benefit for promoting education of oncologists to assess psychological symptoms and manage anxiety and depression as a routine part of an outpatient visit.
Delivering more, earlier, and better goals-of-care conversations to seriously ill oncology patients.
Authors: Bernacki Rachelle , Paladino Joanna , Lamas Daniela , Hutchings Mathilde , Lakin Josh , Neville Bridget A. , Lipsitz Stuart R. , Gawande Atul , Block Susan
Published: February 2017

39

Background: Patients with serious illness routinely receive treatments that are not aligned with their goals. Earlier clinical conversations about patients’ values and priorities lead to more goal-concordant care and improved quality of life, but these conversations often happen too late or not at all. The Serious Illness Care Program has designed a systematic approach to train and support clinicians in conducting more, earlier, and better conversations about goals of care with their patients. Objectives: Evaluate clinician adoption and acceptability of the training program and the Serious Illness Conversation Guide; determine the frequency, timing, and quality of goals of care documentation before death. Methods: Cluster-randomized trial including oncology clinicians and their patients. Intervention: clinician identification of high risk patients; 2½ hour clinician training on the Serious Illness Conversation Guide; email trigger/reminder; EMR documentation. Preliminary chart review to extract goals-of-care conversations for deceased patients in intervention and control. Results: 90 oncology clinicians: 47 intervention; 43 control. Of 47 intervention clinicians, 46 are trained and rate the training as effective (4.3/5). 97% of trained clinicians who have been triggered have adopted the Conversation Guide and find it acceptable (4.2/5). 342 patients enrolled: 176 intervention; 166 control; 38% have died (n = 131). A preliminary chart review revealed more goals-of-care conversations occurred before death in intervention compared to control (92% versus 70%, p = 0.0037); intervention conversations took place four months earlier than control (median 143 days versus 63 days, p = 0.0008). In addition, conversations were more patient centered (95% versus 45%, p < 0.001) and more readily retrievable in the EMR (68% versus 28%, p < 0.001). Conclusions: Preliminary data about the Serious Illness Care systematic approach demonstrate strong clinician adoption and acceptability. The intervention results in more, earlier, and better conversations about patient values and priorities, in addition to more patient-centered and retrievable documentation of goals of care in the medical record. Clinical trial information: NCT01786811.
Goals of care discussions and subsequent health care utilization among adults hospitalized for advanced incurable malignancy.
Authors: Buchanan Laurie , Tooze Janet , Klepin Heidi , Streer Nathan Paul
Published: February 2017

46

Background: Patients with advanced cancer are at risk for repeated hospitalizations and aggressive therapy near the end of life. For these patients, an unscheduled hospitalization predicts survival of < 6 months and represents an opportunity to discuss goals of care which may decrease subsequent health care utilization. Our objective was to describe healthcare utilization for inpatients with advanced malignancies and investigate the association between goals-of-care discussion and subsequent healthcare utilization. Methods: We conducted a chart review of 100 patients with end-stage malignancies consecutively admitted to an academic medical center’s Oncology services beginning January 2013. Eligible patients had advanced incurable malignancy and an unscheduled admission. Exclusion criteria included hematologic malignancies, and hormone therapy responsive breast and prostate cancer. Descriptive statistics were used to characterize the population; variables were compared by code status using chi-square for categorical variables and t-tests for continuous variables. Results: Among 100 patients, the mean age was 62 (range 19-86), and 61% were male. Common cancer types were GI (32%) and lung (31%). Average # of lines of prior chemotherapy was 1.3 (SD 1.5), and 48% had received chemotherapy within 4 weeks of admission. Common reasons for admission were infection (25%), neurologic (13%), and pulmonary complaints (10%). During the hospitalization, 21% required an ICU setting; in-hospital mortality was 1%. Following discharge, 54% were readmitted to the hospital, and, of those patients, 56% spent time in an ICU. On the index admission, only 51% of patients had resuscitation preference documented which increased to 65% by discharge. The patients who had a discussion of code status while inpatient were more likely to be enrolled in hospice at discharge (40% vs. 0%, p < 0.0001) and had fewer readmissions following discharge (1.1 vs. 2.0 readmissions, p = 0.05). Conclusions: Patients with end-stage malignancies have high rates of healthcare utilization. Enhancing goals of care discussions during hospitalization may have a positive impact on readmissions and hospice enrollment.
A comparison of monthly symptom reports for older (≥ 70 years) versus younger (< 70 years) women with recurrent ovarian cancer over 1 year.
Authors: Thaker Premal H. , Sereika Susan M. , Arida Janet , Edwards Robert P. , Donovan Heidi
Published: February 2017

85

Background: Approximately 30% of ovarian cancer patients are 70 or older at diagnosis. Evidence to guide treatment in this age group is limited in the recurrent setting due to clinician concerns about toxicities and quality of life. Evidence based on patient-reported outcomes is scarce. The objective of this exploratory analysis is to compare patient-reported symptoms for women with recurrent ovarian cancer > age 70 vs. < age 70. Methods: Ancillary analysis of data from a 3-arm web-based symptom management RCT (NR010735; GOG-259). Eligibility criteria included recurrent or persistent ovarian, fallopian, or primary peritoneal cancer; experiencing 3 or more cancer or treatment-related symptoms. 497 women were accrued; of those, 60 (12%) were > age 70. Monthly severity data for 11 cancer- and treatment-symptoms rated “at their worst in the past week” on a 0 to 10 Likert-type scale are included in this analysis. Time (linear, quadratic, and cubic), age (young vs. old), and time by age group interactions were evaluated using random coefficient modeling for each of the symptoms over 12 months. Results: In general, the severity of these selected symptoms declined significantly (p < .05) either linearly (memory problems and anxiety) or nonlinearly (fatigue, pain, constipation, peripheral neuropathy, nausea, lack of appetite, depression, and sleep disturbances) over time, except for vomiting which did not demonstrate a significant change over time. Age effects or age by time interactions (significant, p < .05, or a trend, .05 < = p < .10) were found for pain, constipation, peripheral neuropathy, vomiting, and sleep disturbances, with generally higher initial values for younger ( < = 70 years) women for pain and sleep disturbances and higher overall means for younger women for vomiting. For constipation and peripheral neuropathy, the nonlinear change over time varied significantly by age group, with the decline over time being more precipitous for older women. Conclusions: A better understanding of the different propensity for symptoms based on age can help clinicians not only address them but also choose chemotherapies to minimize them.
Using individual quality-of-life information as a clinical tool in patients with advanced cancer.
Authors: McInerney Veronica B , Waldron Dympna , Mannion Eileen
Published: February 2017

91

Background: Use of quality of life information as a tool to aide decision making in routine clinical practice is uncommon. The Schedule of Evaluation for Individual Quality of Life Direct Weighting (SEIQoL DW) is a measurement tool that captures the multidimensionality and uniqueness of the individual allowing him/her to define areas of importance to their quality of life and to demonstrate its measure of importance. It was hypothesised that routine quality of life measurement of patients followed by graphical presentation of this information to the clinician, may bridge views of clinicians and patients to improve quality of life outcome. Methods: A randomised controlled trial of 65 patients receiving chemotherapy for advanced cancer was conducted to measure differences in perception of quality of life over 4 time-points of patients in the intervention group whose quality of life was reported to the clinical team compared to patients in the control group whose quality of life information was not reported to the clinical team .The primary objective was to compare quality of life outcome and examine differences between groups. Results: Findings demonstrated improvement in quality of life of all patients from baseline to time point 4. (P = > 0.05). The top four cues nominated by patients as important to their quality of life were health (92%), social activity (64%), keeping active (58%) and family support (43%).Closer analysis of these individual cues showed interesting differences between the intervention and control group. Participants in the intervention group demonstrated a 51% improvement in perception of health functioning compared to 19% improvement in perception of health functioning in the control group (p = 0.014).Paradoxically there was a decline in patient perception of functioning in other cues (social activity, keeping active and family support) with no significant difference between groups. Conclusions: Review of Individual QoL assessments by the clinican had a clinically significant impact on the patients reported measurement of ‘health’ thus suggesting that utilisation of QoL measurements by the clinician positively impacts the patient.
NEOHX study: Perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER-2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—18 m DFS analysis.
Authors: Rivera Fernando , Jiménez-Fonseca Paula , Garcia Alfonso Pilar , Gallego Javier , Limon M. Luisa , Alsina Maria , Lopez-Gomez Luis , Galan MaCarmen , Falco Esther , Manzano Jose Luis , González Encarnación , Aranda Enrique , Fernandez Eva , Jorge Monica
Published: February 2017

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Background: Perioperative chemotherapy has demonstrated better OS and DFS than surgery alone in resectable stomach or EGJ adenocarcinoma. Trastuzumab has improved OS when added to chemotherapy in pts with HER-2 + metastatic gastric cancer and is interesting to explore its role in the perioperative setting. Methods: A Spanish, multicenter, open-label phase II study evaluated the efficacy and toxicity profile of perioperative XELOX-T (Capecitabine 1000 mg/m2/12h po days 1-14, oxaliplatin 130 mg/m2 day 1, trastuzumab 8 mg/kgà6 mg/kg day 1, q3w ; 3 preoperative cycles and 3 postsurgery cycles followed by 12 cycles of trastuzumab monotherapy) in patients with T1-2N+M0 or T3-4NxM0 resectable stomach or EGJ adenocarcinoma, HER-2+ ( IHQ3+ or IHQ2+/FISH+). The primary endpoint was 18 months DFS, secondary endpoint included pCR, R0 resection rate, ORR, toxicity of preoperative treatment (NCI CTC v3.0 criteria) and biomarker analysis. Results: From June 2010 to March 2012, 36 pts were included: median age 65 (39-85); ECOG 0/1/2: 16/19/1 pts; localization: stomach 21 pts, EGJ 15 pts; histologic type: intestinal: 23 pts, diffuse: 4 pts, mixed: 1pt, not specified 8 pts; TNM: T 4: 7 pts; N+: 31 pts. Preoperative XELOX-T: Response: PR: 14 pts (39%), SD: 18 pts, PD: 0 pts, NE: 4 pts. Surgery was performed in 31 pts: R0: 28 pts (78%, 95% CI: 61-90%), R1: 1 pt, R2: 2 pts (1 had peritoneal carcinomatosis); pCR was observed in 3 pts (8.3 %; 95% CI: 2-22%). Two pts died due to surgical complications. After R0/R1 resection, postoperative XELOX-T was administered to 24 patients, 22 of whom underwent T monotherapy. G3-4 toxicity (>5% of pts): diarrhea 33%, nauseas and vomiting 8% and pneumonia, anemia, neutropenia, anorexia, asthenia and pleural effusion with pneumothorax: 5.5%. With a median follow up of 24.1 months, 18m DFS is 71% (95% CI: 53-83%), 24 m DFS is 60% and median DFS and OS has not been reached. Conclusions: These data suggest that perioperative XELOX+T in HER-2 positive resectable stomach or esophagogastric junction adenocarcinoma is feasible and has promising activity. Clinical trial information: NCT01130337.
A randomized phase II factorial design trial of CPT-11 versus PTX versus each combination with S-1 in patients with advanced gastric cancer refractory to S-1: Final results of OGSG0701.
Authors: Nishikawa Kazuhiro , Imamura Hiroshi , Kawase Tomono , Gotoh Masahiro , Kimura Yutaka , Ueda Shugo , Matsuyama Jin , Kawada Junji , Sugimoto Naotoshi , Fujita Junya , Tamura Takao , Fukushima Norimasa , Sakai Daisuke , Shimokawa Toshio , Kurokawa Yukinori , Satoh Taroh , Tsujinaka Toshimasa , Furukawa Hiroshi
Published: February 2017

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Background: S1 + platinum (SP) is recognized as standard first-line chemotherapy for advanced gastric cancer(AGC), and S1 monotherapy is suggested for frail AGC patients or adjuvant setting in Japan. However, taxane or CPT-11 were often employed as second-line treatment for the patients who were resistant to S1-containing regimen. A retrospective analysis has reported that S1 combination chemotherapy extended overall survival as second-line treatment for AGC. Methods: Patients with AGC who confirmed disease progression by imaging after the first-line therapy with S1 or SP were randomized in four groups; CPT-11 150 mg/m2, day1, q2w (Group A), PTX 80 mg/m2, day1, 8,15, q4w (Group B), CPT-11 80 mg/m2, day1, 15, S-1 80 mg/m2, day1-21, q5w (Group C1), PTX 50 mg/m2,day1, 8, S1 80 mg/m2, day1-14, q3w (Group C2). Primary endpoint was overall survival (OS), and secondary endpoints were progression free survival (PFS), overall response rate (ORR) and safety. Sample size was set at 100 to 120 to achieve 2 months improvement of OS by using CPT-11 or by adding S1 with approximately 80% probability of the correct selection. Results: From July 2008 to March 2012, 127 patients were enrolled. The OS was 11.3/11.3/14.6/10.5 months(M) (Group A/B/C1/C2), 11.8M in Group A+C1 and 11.1M in Group B+C2 (p=0.922, HR: 0.981 [0.679-1.419]), 11.3M in Group A+B and 11.1M in Group C1+C2 (p=0.808, HR: 0.952 [0.643-1.412]), respectively. The PFS was 3.0/4.4/3.8/3.5M (Group A/B/C1/C2), 3.6M in Group A+C1 and 4.1M in Group B+C2 (p=0.035, HR:0.674 [0.468-0.972]) 3.7M in Group A+B and 3.7M in Group C1+C2 (p=0.931, HR: 1.017 [0.643-1.412]). The ORR was 7.1/16.3/4.5/5.0% (Group A/B/C1/C2), 4.7%[1.7-15.2] in Group A+C1 and 12.7%[5.6-23.5] in Group B+C2 (p=0.241), 11.8%[5.8-20.6] in Group A+B and 4.6%[0.6-16.2] in Group C1+C2 (p=0.572).Major Grade 3/4 toxicity (Group A/B/C1/C2, %), was leukopenia (12/7/5/0), neutropenia (29/16/24/24), nausea (7/2/10/5), diarrhea (5/0/10/0), and fatigue (5/2/10/5). Conclusions: From our results, we do not recommend consecutive use of S1 but CPT-11 or PTX monotherapy as second-line treatment in AGC refractory to S1 or SP. Clinical trial information: 000000677.
Exposure-response (E-R) relationship of ramucirumab (RAM) from two global, randomized, double-blind, phase 3 studies of patients (Pts) with advanced second-line gastric cancer.
Authors: Tabernero Josep , Ohtsu Atsushi , Muro Kei , Van Cutsem Eric , Oh Sang Cheul , Bodoky Gyorgy , Shimada Yasuhiro , Hironaka Shuichi , Ajani Jaffer A. , Tomasek Jiri , Safran Howard , Chandrawansa Kumari , Hsu Yanzhi , Heathman Michael , Khan Azhar Z , Ni Lan , Melemed Allen S. , Gao Ling , Ferry David , Fuchs Charles S.
Published: February 2017

121

Background: We evaluated the E-R relationship of RAM in pts with advanced gastric cancer from the REGARD and RAINBOW trials. Methods: Pts received RAM (8 mg/kg) or placebo (PL) q2w in REGARD; or RAM (8 mg/kg) or PL q2w + paclitaxel (PAC) 80 mg/m2 on days 1, 8, and 15 (28-day cycle) in RAINBOW. Sparse pharmacokinetic (PK) samples were collected; a population PK analysis was conducted. A model-predicted minimum concentration after first RAM dose (Cmin,1) was used for correlation with efficacy and safety variables. Kaplan-Meier, Cox regression, and logistic regression analyses evaluated E-R relationships. Results: Analyses included 72 RAM and 35 PL pts from REGARD and 321 RAM+PAC and 335 PL+PAC pts from RAINBOW. Conclusions: Ram was safe and effective at 8 mg/kg q2w. Population PK suggests higher RAM exposures were associated with longer PFS and OS, better hazard ratios, and increased toxicity. Further studies to validate the PK model and evaluate RAM dosing are warranted. [Table: see text]
A phase II trial of 5-weekly S-1 plus cisplatin (CDDP) combination with trastuzumab (Tmab) for HER2-positive advanced gastric or esophagogastric junction (EGJ) cancer: WJOG7212G (T-SPACE) study.
Authors: Miura Yuji , Takano Toshimi , Sukawa Yasutaka , Nosho Katsuhiko , Hironaka Shuichi , Mori Misuzu , Nishikawa Kazuhiro , Tokunaga Shinya , Okuda Hiroyuki , Tsuda Masahiro , Taku Keisei , Nishikawa Kazuo , Moriwaki Toshikazu , Yoshimura Kenichi , Boku Narikazu , Hyodo Ichinosuke
Published: February 2017

126

Background: Five-weekly schedule of S-1 plus CDDP (5-weekly SP) is the standard first-line chemotherapy for the patients (pts) with advanced gastric cancer (AGC) in Japan. Tmab with fluoropyrimidine plus CDDP chemotherapy has shown a survival benefit for pts with HER2-positive AGC and EGJ cancer. However, little information on the efficacy and safety of 5-weekly SP combined with Tmab is available. Methods: We conducted a prospective, single arm, multicenter, phase II trial of 5-weekly SP (S-1 40-60 mg bid for 21 days plus CDDP 60 mg/m2on day 8, every 5 weeks) combined with Tmab (8 mg/kg as a loading dose then 6 mg/kg, every 3 weeks) for pts with HER2-positive (IHC 3+ or IHC 2+ and FISH positive) AGC or EGJ cancer. Primary endpoint was response rate (RR) evaluated by independent review committee, using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. With power of 80% and one-sided alpha of 10%, thirty-five pts were required to reject 40% of RR under expected 60% RR. During the study, protocol was amended based on the favorable accrual rate. Pts were enrolled over 35 to improve precision, until pts enrollment up to 55 (power 85% and alpha 5%) or the end of predetermined accrual period, whichever came first. Results: Between August 2012 to January 2014, 44 pts were enrolled. Pts’ characteristics were: males 34 (77%), median age 62.6 years, PS 0-1 42 (95%), primary tumor site of stomach 37 (84%), histology of diffuse type 18 (41%). IHC 3+ was recorded in 32 (73%) pts. The RR was 64% (95% CI 48-78, one-sided p<0.001). The median PFS was 6.0 months (95% CI 5.1-10.9). The median OS was not reached. The toxicities in the first four courses were assessed. The most common grade 3 to 4 adverse events were anorexia (23%), diarrhea (11%), neutropenia (23%), anemia (16%), and thrombocytopenia (11%). One (2%) treatment-related death was reported. Conclusions: 5-weekly SP combined with Tmab showed a good efficacy with acceptable toxicities for pts with advanced AGC or EGJ cancer. Clinical trial information: UMIN000008389.
The prognostic value of signet ring cell histology in resected gastric cancer.
Authors: Postlewait Lauren McLendon , Squires Malcolm Hart , Kooby David A. , Poultsides George A. , Weber Sharon M. , Bloomston Mark , Fields Ryan C. , Pawlik Timothy M. , Votanopoulos Konstantinos Ioannis , Schmidt Carl Richard , Ejaz Aslam , Acher Alexandra W. , Worhunsky David J. , Saunders Neil , Swords Doug S. , Jin Linda X. , Cho Clifford Suhyun , Cardona Kenneth , Staley Charles A. , Maithel Shishir Kumar
Published: February 2017

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Background: Conflicting data exist on the prognostic implication of signet ring cell (SRC) histology in gastric adenocarcinoma (GAC). Our aim was to assess the association of SRC with recurrence and survival in patients undergoing resection of GAC. Methods: All pts who underwent curative intent resection for GAC from 2000 to 2012 at 7 academic institutions comprising the US Gastric Cancer Collaborative were included. 30-day mortalities were excluded. Survival analyses included Kaplan Meier log rank and multivariate Cox regression. Primary endpoints were recurrence-free survival (RFS) and overall survival (OS). Stage-specific analysis was performed. Results: Of 965 pts, 768 met inclusion criteria. SRC was present in 39.5% and was associated with female gender (52.9% vs 38.6%; p<0.001), younger age (61 vs 67 yrs; p<0.001), poor differentiation (94.8% vs 50.3%; p<0.001), perineural invasion (PNI: 41.4% vs 23%; p<0.001), distal location (82.2% vs 70.1%; p<0.001), receipt of adjuvant therapy (63% vs 51.2%; p=0.002), and more advanced stage (Stage 3: 55.2% vs 36.5%; p<0.001). SRC was associated with earlier recurrence (56.7mo vs median not reached (MNR); p=0.009) and decreased OS (33.7mo vs 46.6mo; p=0.011). When accounting for other adverse pathologic features, PNI (HR 1.57; p=0.016) and higher TNM stage (HR 2.63; p<0.001) were associated with decreased RFS, but SRC was not. PNI (HR 1.53; p=0.006), higher TNM Stage (HR 2.10; p<0.001), greater size (HR 1.05; p=0.014), and adjuvant therapy (HR 0.50; p<0.001) were associated with OS. SRC was not an independent predictor of OS. Stage-specific analysis showed no association between SRC and RFS or OS in Stage 1 or 3. In Stage 2, SRC was associated with earlier recurrence (38.1mo vs MNR; p=0.005) but not OS. The negative association of SRC with decreased RFS persisted in multivariate analysis (HR 3.11; p=0.015). Conclusions: Signet ring histology is associated with other adverse pathologic features including higher grade and higher TNM stage but is not independently associated with reduced RFS or OS. Identification of signet ring histology during preoperative evaluation should not, in isolation, dictate treatment strategy.
Doubling of 30-day mortality by 90 days after esophagectomy: A measure of outcomes for quality improvement.
Authors: In Haejin , Palis Bryan E. , Posner Mitchell , Ferguson Mark K. , Winchester David P , Pezzi Christopher M
Published: February 2017

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Background: Delivery of high-quality cancer care critically relies on the ability to measure and compare quality for continuous improvement. For esophageal cancer, operative mortality has traditionally been assessed at 30 days. Ninety-day mortality has been suggested as a more appropriate indicator of quality particularly after complex cancer surgery. Our objectives were to: 1) compare 30- and 90-day mortality rates after esophagectomy; 2) compare drivers of 30- and 90-day mortality; and 3) examine whether 90-day mortality affects hospital rankings. Methods: Esophagectomies for non-metastatic esophageal cancer patients diagnosed between 2007 and 2011 were identified in the National Cancer Data Base (NCDB). Mortality rates were examined by patient demographics, tumor characteristics and hospital procedural volume. Risk-adjusted hierarchical logistic regression models examined hospital performance for mortality. Results: 15,805 esophagectomy patients at 977 hospitals were available for analysis. Ninety-day overall mortality was more than double the 30-day mortality (8.9% vs 4.2%, p<0.0001). In multivariate analysis, while both 30- and 90-day mortality were associated with patient factors such as age, comorbidity and hospital volume, only 90-day mortality was influenced by tumor and management related variables such as stage, tumor location and receipt of neoadjuvant therapy. Hospital performance was examined as top 10%, middle 10-90% and lowest 10% as ranked using risk-adjusted odds of mortality. There was moderate correlation between ranking based on 30- and 90-day mortality [weighted kappa = 0.45 (95% CI 0.39 - 0.52)]. Compared to 30-day mortality rankings, nearly 20% of hospitals changed their ranking category when 90-day mortality rankings were used. Conclusions: Ninety-day mortality provides additional information for surgical risk assessment and has the potential to greatly enhance data for quality improvement efforts. Data provided for hospital quality improvement should include 90-day mortality, along with 30-day mortality and annual volume.
Comparison of efficacy and tolerance of first-line palliative chemotherapy EOX and mDCF regimens in patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors.
Authors: Ochenduszko Sebastian , Konopka Kamil , Puskulluoglu Miroslawa , Urbanczyk Katarzyna , Budzynski Andrzej , Matlok Maciej , Lazar Agata , Sinczak-Kuta Anna , Krzemieniecki Krzysztof
Published: February 2017

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Background: The aim of the study was to compare efficacy and tolerance of first-line palliative chemotherapy EOX (epirubicin/oxaliplatin/capecitabine) and mDCF (docetaxel/cisplatin/5FU/leucovorin) regimens in patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors. Methods: Each chemotherapy regimen was assigned with 21 patients. Planned treatment consisted of 12 every-two-weeks mDCF cycles (docetaxel 40 mg/m2 day 1, leucovorin 400 mg/m2 day 1, 5FU 400 mg/m2 bolus day 1, 5FU 1000 mg/m2/d days 1 and 2, cisplatin 40 mg/m2 day 3) or 8 every-three-weeks EOX cycles (epirubicin 50mg/m2 day 1, oxaliplatin 130mg/m2 day 1, capecitabine 1250mg/m2/d days 1 to 21). The primary endpoint was overall survival in all patients who commenced at least one chemotherapy cycle. Results: Median progression-free survival was 5.8 months in EOX group and 7.5 months in mDCF group (p=0.11), and median overall survival was 8.5 months and 12.0 months respectively (p=0.219). Due to toxicity, patients in the EOX arm had more frequent reductions of cytostatics doses (42.9% vs 5.0%; p=0.009) as well as delays in the administration of subsequent chemotherapy cycles (81.0% vs 65.0%; p=0.424). Rates of all grade 3 or 4 adverse events were comparable between both arms (76.19% in the EOX vs 70.0% in the mDCF; p=1.000). Toxicities that occurred more frequently in the EOX group compared to mDCF group were: nausea (28.6% vs 5.0%; p=0.093), thromboembolic events (19.0% vs 10%; p=0.663) and grade 3 or 4 neutropenia (71.4% vs 55.0%; p=0.443). Conclusions: In this patients population with locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma without overexpression of HER2 receptors treatment with mDCF regimen was associated with a statistically non-significant 3.5 month longer median overall survival without increase in toxicity. Updated data will be presented.
ACEIs/ARBs to improve survival in advanced gastric cancer patients receiving S-1 plus cisplatin.
Authors: Kumekawa Yosuke , Wakatsuki Takeru , Osumi Hiroki , MATSUSHIMA TOMOHIRO , Nakayama Izuma , Ogura Mariko , Ichimura Takashi , Takahari Daisuke , Ozaka Masato , Suenaga Mitsukuni , Shinozaki Eiji , Chin Keisho , Mizunuma Nobuyuki
Published: February 2017

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Background: Gastric cancer is heterogeneous disease and male predominant incidence is recognized across the world. Interactions between tumor cells and microenvironments, such as cancer-associated fibroblasts (CAFs) and M2 macrophage, play an important role in cancer progression and CAFs and M2 macrophage predict worse outcomes in several types of cancer. Angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) are widely used in cardiovascular disease because these drugs reduced cardiovascular events via inhibiting fibroblasts and inflammation. Moreover these drugs improved survival in advanced pancreatic cancer gemcitabine (Br J Cancer, Nakai, 2010). Given that CAFs and M2 macrophage are associated worse outcomes and ACEIs/ARBs may inhibit these factors, we hypothesized that these drugs may improve survival in advanced gastric cancer. Methods: Two-hundred and twenty advanced gastric cancer patients were enrolled between Jan. 2007 and Dec. 2011. These patients were received S-1 plus cisplatin (SP) as the first-line therapy in our institute. We retrospectively analyzed whether ACEIs/ARBs could predict better survival. Primary endpoint was overall survival (OS) and endpoint was estimated using by Kaplan-Meier methods and compared by the log-rank test. Results: Median age was 61 years old and 68.1% of the patients were male. Eighteen of 220 patients took ACEIs and/or ARBs. No significant difference was shown in patient characteristics between two groups. Median survival time (MST) of all patients was 416 days. There was marginal differences between two groups; MST in ACEI/ARB group was 763 days and 412 days in non-ACEI/ARB group, respectively (HR, 0.59 ; 95% CI 0.34-1.05 ; P=0.071). After analyzing according to gender, MST in male was 997 days in ACEI/ARB group vs. 412 days in non-ACEI/ARB group (HR, 0.42 ; 95% CI 0.18-0.97 ; P=0.037); however, no significant difference was found in female (HR, 0.84 ; 95% CI 0.38-1.86 ; P=0.67). Conclusions: ACEIs/ARBs may have a favorable effect in gastric cancer; however, gender difference may be involved in their efficacy. Further clinical validations and molecular correlation analyses are warranted.
Randomized phase II study of FOLFOX +/- MET inhibitor, onartuzumab (O), in advanced gastroesophageal adenocarcinoma (GEC).
Authors: Shah Manish A. , Cho Jae Yong , Huat Iain Tan Bee , Tebbutt Niall C. , Yen Chia-Jui , Kang Alice , Shames David S. , Bu Lilian , Kang Yoon-Koo
Published: February 2017

2

Background: Aberrant up-regulation of the MET/HGF pathway is associated with poor prognosis in multiple malignancies, including GEC. Onartuzumab (O) is a fully humanized, monovalent anti-MET antibody that inhibits HGF binding and receptor activation. We examined the efficacy and safety of mFOLFOX6 and O in the first-line setting for metastatic, HER2-negative GEC. Methods: This was a double-blind, placebo controlled phase II study in which patients were randomized 1:1 to mFOLFOX6 + O 10 mg/kg. Eligibility included no prior treatment for metastatic disease, age >18, ECOG 0-1, retained organ function, HER2-negative, and evaluable disease. The primary objectives were to detect a meaningful improvement in progression free survival (PFS) in the ITT population or the MET-positive (≥ 50% of tumor with moderate-strong intensity staining by IHC based on central review) subgroup. With 120 patients enrolled and 84 PFS events observed, the target HR was 0.7 in the ITT population, and 0.6 in the MET-positive subgroup (estimated 50% of total). Results: 123 patients (83 Asia/Pacific, 40 US) from 25 sites were from 7/2012-5/2013. The treatment arms were well balanced: median age (57 placebo (P), 58.5 O), male (n=36 (59%) P, n=40 (65%) O), and MET-positive (n=19 (33%) P, n=16 (28%) O). Serious adverse events were more frequent with O (55%) vs placebo (40%). Selected grade 3-5 adverse events observed at least 5% more commonly with O included neutropenia (58% vs 45%), thrombocytopenia (10% vs 3%), peripheral edema (10% vs 0), and pulmonary embolism (7% vs 2%). At data cutoff (29 Jan 2014), 96 patients had PFS events (n=46 (74%) O, n=50 (82%) P), with median PFS of 6.77 and 6.97 months, respectively (HR 1.08, 95% CI 0.71-1.63). In the MET-positive subgroup, median PFS was 5.95 months for O and 6.8 months for placebo (HR 1.38 [0.60-3.20]). No difference in efficacy was noted with alternate MET-positive definitions (50% vs 90% MET staining, and 1, 2, or 3+ intensity). Conclusions: The addition of O to mFOLFOX6 in metastatic GEC did not improve PFS in either an unselected population or in MET-positive patients as defined by IHC. Additional biomarker analyses are ongoing to identify patients that may benefit from MET inhibition. Clinical trial information: NCT01662869.
Urinary metabolomics of gastric cancer.
Authors: Chan Angela W , Mercier Pascal , Schiller Dan E. , Eurich Dean , Broadhurst David , Sawyer Michael B.
Published: February 2017

22

Background: Gastric cancer (GC) has 70-75% mortality, attributable to delayed diagnosis. There is no standard screening in North America. Metabolomics is a systems biology approach to measure low molecular weight chemicals (metabolites) in body fluids or tissues to provide a phenotypic “fingerprint” of disease etiology. In this preliminary study it was hypothesized that metabolic profiling of urine samples using 1H-NMR spectroscopy could discriminate between resectable gastric adenocarcinoma (GC), benign gastric disease (BN), and healthy (HE) patients (pts). Methods: Midstream urine samples were collected, processed, and biobanked at -80°C, from 30 BN, 30 HE and 16 of 29 GC pts visiting three Edmonton clinics from August 2013 – January 2014. Thirteen of 29 samples were retrieved from a 2009-13 GC biobank. Samples were matched on age, gender and BMI. Using a validated standard operating procedure each sample was analyzed using high resolution 1H-NMR spectroscopy. Resulting spectral traces were converted into annotated and quantified metabolite profiles of 58 metabolites. Univariate and multivariate statistical analysis uncovered a disease specific biomarker profile. Partial Least Squares Discriminant Analysis (PLS-DA) developed a GC vs. HE discriminative model. A Receiver Operator Characteristic (ROC) curve was constructed. Results: There was no significant difference in metabolite profiles between GC and BN pts. However, univariate analysis revealed 13 metabolites that differed significantly between GC and HE (p<0.05). Correlation analysis, followed by PLS-DA produced a discriminative model with an area under ROC curve of 0.996, such that for a specificity of 100% the corresponding sensitivity was 93%. Conclusions: GC pts have a distinct urinary metabolite profile compared to HE controls; however in this study metabolic profiling was unable to discriminate GC from BN pts. This was probably due to sample size and phenotypic heterogeneity of BN patients. This preliminary study shows clinical potential for metabolic profiling for early GC detection.
Phase II study of front-line dovitinib (TKI258) versus sorafenib in patients (Pts) with advanced hepatocellular carcinoma (HCC).
Authors: Cheng Ann-Lii , Thongprasert Sumitra , Lim Ho Yeong , Sukeepaisarnjaroen Wattana , Yang Tsai-Sheng , Wu Cheng-Chung , Chao Yee , Chan Stephen Lam , Kudo Masatoshi , Ikeda Masafumi , Kang Yoon-Koo , Pan Hongming , Numata Kazushi , Han Guohong , Balsara Binaifer , Zhang Yong , Rodriguez Ana-Maria , Zhang Yi , Wang Yongyu , Poon Ronnie Tung-Ping
Published: February 2017

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Background: HCC is a highly vascularized tumor, and inhibition of angiogenesis by sorafenib (Sor)—a VEGFR and PDGFR inhibitor—delays tumor progression. However, angiogenic escape from Sor may result from activation of the FGFR pathway, which also plays an important role in angiogenesis. Dovitinib (Dov) inhibits FGFR as well as VEGFR and PDGFR. Here, we study frontline Dov vs Sor in pts with advanced HCC. Methods: Eligible pts in this open-label study had ≥ 1 measurable lesion at baseline. All pts were ineligible for or had disease progression after surgical and/or locoregional therapies. Prior systemic HCC therapy was not allowed. Pts were randomized to receive Dov (500 mg/day, 5 days on/2 days off) or Sor (400 mg twice daily) until disease progression, unacceptable toxicity, or death. No treatment crossover was allowed. The primary endpoint was overall survival (OS). The key secondary endpoint was time to tumor progression (TTP) by local investigator’s assessment (per RECIST v1.1). Results: Pts received Dov (n = 82) or Sor (n = 83). Most pts—43 (52.4%) in the Dov arm and 60 (72.3%) in the Sor arm—discontinued treatment due to progressive disease. Median OS (95% CI) was 34.6 wk (28.6-39.4 wk) for Dov and 36.7 wk (23.3-49.3 wk) for Sor; Kaplan-Meier HR, 1.27; 95% CI, 0.89-1.80. Median TTP (95% CI) was 17.6 wk (12.3-18.4 wk) and 17.9 wk (12.3-18.9 wk), respectively. In pts who received ≥ 1 dose of study drug, median duration of exposure was 2.5 mo for Dov (n = 79) and 3.2 mo for Sor (n = 83). The most common adverse events, regardless of cause, were diarrhea (62.0%), decreased appetite (43.0%), nausea and vomiting (40.5% each), fatigue (35.4%), rash (34.2%), and pyrexia (30.4%) in the Dov arm and palmar-plantar erythrodysesthesia syndrome (66.3%), diarrhea (42.2%), and decreased appetite (31.3%) in the Sor arm. VEGFR1 and HGF baseline plasma levels appear to be associated with OS only in the Dov arm. Median OS in the lower biomarker group for both VEGFR1 and HGF was 11 mo while it was 5.6 and 5.9 mo for VEGFR1 and HGF, respectively, in the higher biomarker group. Conclusions: Activity of Dov was not greater than that of Sor in frontline HCC. The safety profile was similar to that observed in other single-agent Dov trials. Clinical trial information: NCT01232296.
Randomized phase II trial comparing the efficacy and safety of nintedanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Palmer Daniel H. , Ma Yuk Ting , Peck-Radosavljevic Markus , Ross Paul J. , Graham Janet Shirley , Fartoux Laetitia , Deptala Andrzej , Wenz Arne , Hocke Julia , Loembe Arsene-Bienvenu , Meyer Tim
Published: February 2017

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Background: Nintedanib (N) is an oral, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptors. This randomized, multicenter, open-label, phase II study (NCT01004003; 1199.37) evaluated the efficacy and safety of N versus sorafenib (S) in patients with advanced HCC. Methods: Enrolled patients had unresectable advanced HCC, ECOG-PS ≤2, Child–Pugh score 5–6, alanine/aspartate aminotransferase (ALT/AST) ≤2× upper limit of normal, and ≥1 untreated measurable lesion or a previously treated lesion with progression (by RECIST 1.0). Patients were randomized 2:1 to N 200 mg bid or S 400 mg bid continuously in 28-day cycles, until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. Primary endpoint was time to progression (TTP) by independent central review (ICR; RECIST 1.0), and secondary endpoints were overall survival (OS) and investigator-assessed (IA) TTP. Results: Ninety-three patients were randomized to receive N (n=62) or S (n=31). At the cutoff date (15 July 2014), 77% of patients had a TTP event, and 70% had an OS event; 3 patients remained on treatment with 1 patient beyond PD. IA TTP was comparable between N and S (median 5.5 vs 3.8 months; HR 1.05 [95% CI: 0.63–1.76]), as was OS (median 11.9 vs 11.4 months; HR 0.88 [95% CI: 0.52–1.47]). ICR TTP data are pending. All patients reported an AE (CTCAE 3.0); more patients treated with S had Grade ≥3 AEs (68% vs 90%). AEs leading to dose reduction were higher with S (19% vs 42%), whereas AEs leading to drug discontinuation were higher with N (45% vs 23%). The only tyrosine kinase inhibitor class-specific AE reported in >15% of patients was hand-foot skin reaction in the S arm. AEs previously observed with N and higher in this arm were diarrhea, vomiting, nausea, and AST increase, while blood bilirubin increase was higher with S. Rash was reported in >15% of patients only in the S arm. Conclusions: N shows similar efficacy to S with respect to TTP and OS, with a manageable safety profile. Further studies of N in patients with advanced HCC are warranted. Clinical trial information: NCT01004003.