bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress biomarkers in advanced cancer patients experiencing the pain, fatigue, sleep disturbance symptom cluster.
Authors: Kwekkeboom Kristine L , Costanzo Erin S. , Campbell Toby Christopher
Published: February 2017

5

Background: Cancer symptom clusters such as co-occurring pain, fatigue, and sleep disturbance, are common and debilitating for patients with advanced disease. Stress-related neuorendocrine system alterations are thought to play a significant role in symptom co-occurrence. While studies have documented relationships between stress biomarkers and symptoms in persons with cancer, few have done so in the context of a specific symptom cluster or among persons receiving treatment for advanced disease. Objectives: This preliminary analysis describes biomarkers of neuroendocrine stress systems – salivary cortisol and salivary alpha amylase (sAA) – and their relationship with the pain, fatigue, sleep disturbance symptom cluster in cancer. Methods: We analyzed baseline data from 14 participants of a RCT of a cognitive-behavioral symptom cluster intervention. Participants were receiving chemotherapy for recurrent or metastatic cancer. The sample was largely female (93%), aged 50-74 years old (M=63.57), with lung (57%), breast (14%), GYN (22%) or prostate (7%) cancer. Participants reported symptom cluster severity and collected saliva over two days prior to a new chemotherapy cycle. Cortisol concentrations were determined by luminescence immunoassay and salivary alpha-amylase by enzyme kinetic reaction assay using standardized kits (Salimetrics, State College, PA). Results: Mean (SD) cortisol and sAA levels were within normal range and followed typical diurnal patterns (Table 1); although evening levels of cortisol appeared higher in this sample compared to those of healthy adults. Low to moderate observed correlations between symptom cluster severity and stress biomarkers (evening cortisol r = -.204; evening sAA r = .326) were not significant in this small sample. Conclusions: Elevated evening cortisol levels may suggest dysregulation of the stress response in this population. The ongoing study will further evaluate if alterations in neuroendocrine function contribute to the symptom cluster experience. Clinical trial information: NCT01954420. [Table: see text]
Feasibility of a pilot study of an intervention to Enhance Communication during Hospice care with Oncology (ECHO).
Authors: Bauman Jessica Ruth , Schleicher Stephen , Nipp Ryan David , El-Jawahri Areej , Pirl William F. , Greer Joseph A. , Temel Jennifer S.
Published: February 2017

51

Background: When patients with cancer transition to hospice, the role of oncology clinicians can be unclear. During this time, patients and families often feel abandoned by their oncology team. We assessed the feasibility of a novel intervention to enhance continuity of care between the oncology team and patients and their families after they enroll in hospice. Methods: Family caregivers (FCs) of patients with cancer (lung, head and neck, sarcoma, melanoma, and gynecological) who enrolled in home hospice from 3/2014-6/2015 were eligible to participate in the study. The ECHO intervention consisted of check-in phone calls from the oncology team to the FC (weekly x 4 weeks, biweekly x 4 weeks, then monthly), an optional in-person clinic visit, and a bereavement call. FC questionnaires assessing satisfaction, perceived stress, quality of EOL care, and regret were completed at enrollment, weeks 1 and 2, and then every 4 weeks, as well as at a phone interview post- death. The primary outcome was feasibility, which we defined as > 70% of the FCs receiving > 50% of the phone calls and > 70% of the FCs completing > 50% of the questionnaires. Results: Of 37 eligible FCs, 24 (80%) enrolled, 7 were not reached, and 6 declined. At the time of analysis, 19 were evaluable as 2 patients died before the intervention began, 1 FC withdrew, and 2 interventions were ongoing. Median time from hospice referral to study enrollment was 3 days (range 1-7) and from study enrollment to patient death was 34 days (range, 3-135). Clinicians completed 156 of the expected 172 calls (90.7%) to FCs. FCs completed 75 of the expected 91 (82.4%) questionnaires. 100% of the FCs received > 50% of scheduled phone calls and 79% of the FCs completed > 50% of the questionnaires. In qualitative interviews post-death, FCs indicated that the phone calls were appreciated and helpful. Conclusions: This intervention enhancing communication with the oncology team throughout hospice was well received by FCs. Additionally, the intervention proved feasible, as the majority of phone calls and questionnaires were completed. A randomized study is warranted of the impact of ECHO on the quality of EOL care and FC outcomes including satisfaction, bereavement adjustment, and mood. Clinical trial information: NCT02069769.
Actigraphy as an objective measure of performance status in patients with advanced cancer.
Authors: Pirl William F. , Fujisawa Daisuke , Stagl Jamie , Eusebio Justin , Traeger Lara , El-Jawahri Areej , Greer Joseph A. , Temel Jennifer S.
Published: February 2017

62

Background: Treatment decisions are often based on performance status (PS), a subjective rating of patient functioning derived from observation and patient-report. Devices that monitor physical activity, such as wrist actigraphs, can accurately measure the percent of time a person is immobile while awake (awake immobile). Thus, actigraphy may have potential to better estimate true PS. We compared actigraphy to both Eastern Cooperative Oncology Group PS (ECOG PS) and patient-reported physical activity as predictors of survival in patients with stage IV non-small cell lung cancer (NSCLC). Methods: Participants (n = 41) were ambulatory patients with stage IV NSCLC receiving care at MGH. Participants wore a watch-sized accelerometer device (ACTIWATCH 2) for three consecutive 24-hour periods (72 hours) and completed a self-report questionnaire about physical activity, scored as METS (metabolic equivalents) per week. Patients’ oncologists rated their ECOG PS (0-5) at the end of the 72-hour actigraphy period. Relationships among ECOG PS, awake immobile, and METs per week were tested with Pearson correlations. A ROC curve for 6-month survival was used to determine a meaningful cut-off for awake immobile. Unadjusted Cox regression models tested associations with survival from assessment times. Results: Participants’ ECOG PS ratings were: 0 (22%), 1 (63%), 2 (12%), and 3 (2%). ECOG PS and awake immobile were correlated (r = .42, p < .01). METS per week was correlated only with ECOG PS (r = -.35, p = .03). At time of analysis, 15 patients had died with a minimum follow up of 9 months. Among all patients, survival was predicted by ECOG PS, HR = 3.77 (95% CI 1.70-8.35), p < .01; awake immobile as both as a continuous (percentage points) and categorical ( > 23%) variable, HR = 1.04 (95% CI 1.00-1.09), p = .05 and HR = 4.12 (95% CI 1.37-12.39), p = .01, respectively; but not METS per week. Among patients with good EGOC PS (0-1), only awake immobile ( > 23%) predicted survival, HR = 5.80 (95% CI 1.39-24.12), p = .02. Moreover, within the largest ECOG group (PS1), awake immobile ( > 23%) still predicted survival, HR = 5.53 (95% CI 1.18-25.94), p = .03. Conclusions: Actigraphy, an objective measure of patient activity, may have utility in determining patient PS.
Effect of conversations about values and goals on anxiety in patients.
Authors: Paladino Joanna , Bernacki Rachelle , Hutchings Mathilde , Lipsitz Stuart R. , Neville Bridget A. , Gawande Atul , Block Susan
Published: February 2017

9

Background: Patients with serious illness routinely receive treatments that do not align with their goals. Earlier clinical conversations about patients’ values and priorities lead to more goal-concordant care and improved quality of life, but clinician concerns about harming patients and taking away hope are barriers to appropriately timed discussions. Methods: A cluster-randomized controlled trial with oncology patients at high risk of death, identified by the surprise question. The intervention included a structured, patient-centered discussion about values and priorities conducted by trained oncology clinicians using the Serious Illness Conversation Guide. Patient anxiety (GAD-7) was measured by survey at baseline and every 2 months; anxiety, patient acceptability, and patient-reported behavior change were measured by survey 1 week after the intervention and at a matching time point for controls. Results: 342 patients enrolled (median age 62y): 176 intervention; 166 control. 102 conversations were completed in the intervention group. The mean anxiety (GAD-7) score prior to the intervention in the intervention group was 3.75 and in the control group was 3.80 (p = 0.72). However, a week after the intervention conversation (on average, the conversation was 10.4 weeks from baseline, IQR 3-13 weeks), there were significant differences. At 11.4 weeks, the intervention anxiety mean was 2.87, and the control mean was 4.26 (p = 0.011). Reductions persisted for 2 months after the conversation. Among patients who had the serious illness conversation and completed the acceptability survey: 86% reported that the conversation was worthwhile; 66% reported positive behavior changes as a result of the discussion; more than 80% reported that their hopefulness, peacefulness, and sense of control over medical decisions increased or did not change. Conclusions: The Serious Illness conversation lowered patient anxiety; this reduction was sustained for at least 2 months after the conversation. Patients viewed the serious illness conversation as worthwhile and reported enacting concrete positive behavior changes as a result of the discussion. Clinical trial information: NCT01786811.
The prevalence of lymph node metastases in clinical T1N0 thoracic esophageal cancer from the results of JCOG0502.
Authors: Akutsu Yasunori , Kato Ken , Igaki Hiroyasu , Ito Yoshinori , Nozaki Isao , Daiko Hiroyuki , Yano Masahiko , Udagawa Harushi , Nakagawa Satoru , Takagi Masakazu , Okabe Hiroshi , Abe Tetsuya , Nakamura Tetsu , Hihara Jun , Toh Yasushi , Shibuya Yuichi , Mizusawa Junki , Katayama Hiroshi , Nakamura Kenichi , Kitagawa Yuko ,   Japan Esophageal Oncology Group of Japan Clinical Oncology Group (JCOG)
Published: February 2017

10

Background: Recently, a limited operation to avoid needless lymph node (LN) dissection in clinical T1bN0 esophageal cancer (EC) is considered. However, how LN dissection or radiation field should be decided for such cases has not yet been clarified. The information about prevalence of LN metastases (LNMs) would be valuable when the radiation field and extent of LN dissection are considered in the treatment of T1bN0 EC. Methods: JCOG0502 is a randomized controlled trial including a patient preference arm comparing surgery alone to definitive chemoradiotherapy in clinical T1bN0 EC. By using baseline clinical and pathological data of JCOG0502, diagnosis accuracy of LNM was evaluated by comparing clinical and pathologic findings. Then, the sites of pathologic LNMs were determined and the initial sites and the prevalence of LNM were estimated. Results: Between Dec 2006 and Feb 2013, 213 patients (pts) enrolled to the surgery arm in JCOG0502. Pts with multiple lesions or without esophagectomy were excluded and remaining 186 pts were analyzed. Of the 186 pts of clinical T1bN0, 137 pts were diagnosed as LNM negative (73.7%: accuracy of diagnosis), however, 49 pts (26.3%) had pathologic LNMs. Pathologic LNMs were seen at 106recR, 106recL (all in mediastinal region) in upper thoracic (Ut) EC, 101R, 101L, 104R, 104L (in the neck region), 106recR, 106recL, 106tbL, 105, 107, 108, 109L, 110 (in the mediastinal region), 1,2,3,7, 11 (in the abdominal region) in middle thoracic (Mt) EC, and 105, 106recL, 110 (in the mediastinal region), 1, 2, 3, 7 (in the abdominal region) in lower thoracic (Lt) EC, respectively. Of the 49 pts who had pathologic LNMs, 32 pts (65%) were of pathologically N2 or more. Furthermore, 18 pts (37%) had skip LNM (LNM of N2, N3 or N4 without N1). The solitary pathologic LNM was observed in 25 pts: N1 (106recR, 106recL) in Ut, N1 (106recR, 106recL, 108), N2 (101R, 105, 110, 1, 3, 7), in Mt, N1(110, 1), N2 (106recL, 3, 7) in Lt, respectively. Conclusions: In the current status of clinical diagnosis, limited LN dissection or limited field of radiation are not recommended. In surgery, D2 LN dissection is necessary and three-field LN dissection is recommended especially in middle thoracic EC even for clinical T1bN0. Clinical trial information: UMIN000000551.
Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma (JCOG0110): Final survival analysis.
Authors: Sano Takeshi , Sasako Mitsuru , Mizusawa Junki , Katayama Hiroshi , Katai Hitoshi , Yoshikawa Takaki , Yabusaki Hiroshi , Ito Seiji , Kaji Masahide , Imamura Hiroshi , Fukushima Norimasa , Fujitani Kazumasa , Iwasaki Yoshiaki , Kinoshita Taira
Published: February 2017

103

Background: We conducted a RCT to compare splenectomy and spleen preservation in total gastrectomy and reported higher morbidity and larger blood loss in splenectomy at 2010 ASCO Annual Meeting. Survival analysis after 5-year follow-up is now complete. Methods: Proximal gastric adenocarcinoma of T2-4/N0-2/M0 not invading the greater curvature was eligible. During operation surgeons confirmed that R0 resection was possible with negative lavage cytology, and the patient was randomized into splenectomy or spleen-preserving arm. The primary endpoint was OS. The trial was designed to confirm non-inferiority of spleen preservation to splenectomy in OS with a non-inferiority margin of the hazard ratio (HR) as 1.21. The planned sample size was 500 pts with a power of 70% and a one-sided alpha of 5%. Results: Between June 2002 and March 2009, 505 patients (splenectomy 254, spleen-preservation 251) were enrolled from 36 institutions. The first 319 patients were treated without adjuvant therapy by protocol, but after the S-1 adjuvant effect was established in 2006, patients with pathological stage II and III tumors received adjuvant S-1 by amended protocol. The 5-year survivals were 75.1% and 76.4% in the splenectomy and spleen-preserving arms, respectively. The HR was 0.88 [90.7% CI 0.67-1.16] (<1.21); thus the non-inferiority of spleen preservation was confirmed (p=0.025). The 5-year RFS was 68.4% in splenectomy arm and 70.5% in spleen-preserving arm. The HR was 0.87 [95% CI 0.65-1.17]. Subset analyses showed slightly better survival of spleen preservation in patients having deeper tumors (T3/T4), lymph node metastases, tumors located mainly in the middle stomach, and in those enrolled in the first study period of no-adjuvant protocol. Conclusions: This is the largest RCT of splenectomy in gastric cancer, and demonstrated significant non-inferiority of spleen preservation for the first time. In total gastrectomy for proximal gastric cancer which does not invade the greater curvature, prophylactic splenectomy should be avoided not only for operative safety but also for survival benefit. Clinical trial information: NCT00112099.
A randomized phase II trial of capecitabine plus cisplatin (XP) versus S-1 plus cisplatin (SP) as a first-line treatment for advanced gastric cancer: XP ascertainment versus SP randomized PII trial (XParTS II).
Authors: Kobayashi Michiya , Tsuburaya Akira , Nishikawa Kazuhiro , Kawada Junji , Namikawa Tsutomu , Fukushima Ryoji , Kojima Hiroshi , Tanabe Kazuaki , Yamaguchi Kazuya , Yoshino Shigefumi , Takahashi Masazumi , Hirabayashi Naoki , Sato Seiji , Nemoto Hiroshi , Rino Yasushi , Yoshikawa Takaki , Nakajima Junta , Morita Satoshi , Sakamoto Junichi
Published: February 2017

105

Background: Capecitabine plus cisplatin (XP) is a standard global regimen for first-line treatment of advanced gastric cancer, however its efficacy compared to S-1 plus cisplatin (SP), a standard treatment in Japan has not been reported. To evaluate the efficacy of XP treatment, we conducted a multicenter randomized phase II trial comparing XP with SP for patients with advanced gastric cancer (ClinicalTrials.gov Identifier NCT0140624). Methods: Patients with unresectable metastatic or recurrent gastric cancer, 20–74 years of age and HER2-negative, were assigned to receive either S-1 40 mg/m2 bid for 21 days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), time to treatment failure, overall response rate (ORR) and safety. Planned sample size was 100 (50 in each arm) according to PFS at 24-weeks. Immunohistochemical evaluation of biomarkers was also implemented. Results: From November 2011 to June 2013, 116 patients were randomized: median age, 65 years; 79 (68%) male; 63 intestinal and 53 diffuse cancer subtypes. In 109 eligible patients, 24-week %PFS was higher in both groups than the protocol-specified threshold of 40%. Median PFS for SP vs. XP was 25 weeks vs. 23 weeks (HR, 0.76; 95%CI, 0.5-1.16; p=0.203); OS was 58 weeks vs. 56 weeks (HR, 0.90; 95%CI, 0.52-1.57; p=0.712); and ORR was 27.5% vs. 32.7% (p=0.562), respectively. Sub-group analysis by histological classification showed that SP gave better PFS than XP in the diffuse type (HR, 0.42; 95%CI, 0.20-0.86; p=0.015) with no other statistical difference. Most common grade ≥3 adverse events with SP and XP were anemia (16%/ 19%), neutropenia (9%/17%), anorexia (18%/13%), diarrhea (11%/0%), nausea or vomiting (11%/15%), fatigue (5%/6%) and hyponatremia (7%/13%), respectively. Conclusions: XP and SP are comparable and can be recommended as 1st line treatments for advanced gastric cancer. Further analysis for biomarkers related to histology is warranted. Clinical trial information: NCT0140624.
Lapatinib versus lapatinib plus capecitabine as second-line treatment in HER-2-overexpressing metastatic gastro-esophageal cancer (GC): A randomized phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: Lorenzen Sylvie , Riera-Knorrenschild Jorge , Haag Georg Martin , Pohl Michael , Thuss-Patience Peter C. , Bassermann Florian , Helbig Ulrike , Weissinger Florian , Schnoy Elisabeth , Becker Klaus , Stocker Gertraud , Ruschoff Josef , Eisenmenger Andreas , Karapanagiotou-Schenkel Irini , Lordick Florian
Published: February 2017

112

Background: HER2 amplification is present in a subgroup of gastroesophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-EGFR and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. Methods: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250 mg per day 1-21 plus capecitabine (CAP) 2000mg/m² on days 1-14 of a 21-day cycle or LAP 1500 mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary endpoint was the objective response rate (ORR) as assessed by the investigator using RECIST 1.1 criteria. We aimed to include 38 pts per arm to show a response rate of >20% in either of the two arms. Results: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines, however, the treatment was intended to be tested as a second-line treatment. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% CI: 1.37 – 34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38 to 61) days in the LAP group and 83 (95% CI: 42 to 86) days in the LAP+CAP group. Other secondary efficacy endpoints (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhea were higher with LAP+CAP (61%; 95% CI: 35 to 83) compared to 26% (95%CI 9 to 51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] vs. 17 [90%]). Conclusions: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. Clinical trial information: NCT01145404.
Laparoscopic D2 subtotal gastrectomy versus conventional open surgery for advanced gastric cancer: The safety analysis from a multicenter prospective randomized controlled trial in China (CLASS-01 trial).
Authors: Hu Yanfeng , Huang Changming , Sun Yihong , Su Xiangqian , Li Ziyu , Xue Yingwei , Hu Jiankun , He Xianli , Tao Kaixiong , Zhao Gang , Suo Jian , Wei Hong-Bo , Hu Weiguo , Ying Mingang , Du Xiaohui , Li Guoxin ,   The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group
Published: February 2017

122

Background: The efficacy of laparoscopic D2 gastrectomy for the treatment of advanced gastric cancer (AGC) with curative intent is still controversial. Thus, the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) group conducted a multicenter prospective randomized controlled trial, aiming to evaluate the surgical safety and long-term outcomes of laparoscopic D2 gastrectomy compared with conventional open surgery for AGC. (NCT01609309) Methods: The patients with tumor located at distal stomach at clinical T2-4a, N0-3, M0 stage were eligible for enrollment, treated by either laparoscopic D2 distal subtotal gastrectomy (LG) or open D2 gastrectomy (OG) after randomization. Seventeen institutions currently participated in the study. The morbidity and mortality within postoperative 30 days were compared between the two groups. Results: A total of 607 consecutive eligible patients were randomly assigned to either LG group (n=308) or OG group (n=299) between September 2012 and January 2014. The compliance rates of D2 lymphadenectomy in the LG group and OG group were similar (97.4% vs. 98.3%; P=0.591). Open conversion rate was 4.5%. There was no significant differences between the LG group and OG group in the incidence of intraoperative complication (5.8% vs. 4.3%; P=0.402), postoperative morbidity (18.8% vs. 14.7%; P=0.175), and mortality (0.6% vs. 0; P=0.499). The severity grade pattern was also similar according to the Clavien-Dindo classification (P=0.372). Conclusions: Laparoscopic D2 distal subtotal gastrectomy for AGC could be safely performed by experienced surgeons. Thus, our multicenter prospective study on long-term outcomes can be ongoing. Clinical trial information: NCT01609309.
Novel chemotherapy combinations for metastatic gastric adenocarcinoma (mAGC): An updated meta-analysis.
Authors: Wagner Anna Dorothea , Moehler Markus , Grothe Wilfried , Haerting Johannes , Unverzagt Susanne
Published: February 2017

125

Background: Despite the successful integration of targeted therapies, chemotherapy remains the mainstay of treatment for mAGC. Uncertainty remains regarding the choice of the regimen. Methods: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE until February 2014; proceedings from ECCO, ESMO, ASCO until June 2014 with Selection criteria: Randomised controlled trials on chemotherapy in mAGC. Objectives: To assess and compare the effects on overall survival of regimens containing: 1) irinotecan (I) vs non-I, 2) docetaxel (D) vs non-D, 3) capecitabine (C) vs 5-FU, 4) S-1 vs 5-FU, 5) oxaliplatin (O) vs the same regimen containing cisplatin. For 1) and 2), substitutive (other chemotherapy substituted by I or D) and additive comparisons (I or D added) were analyzed separately. Results: The meta-analyses of overall survival included: Comparison 1) a. Substitutive: 5 trials, 724 patients (pts), with a HR of 0.85 (95% CI 0.73-0.99), b. Additive: 3 trials, 500 pts, with a HR of 0.88 (95% CI 0.76-1.03), both in favor of the I-containing regimens. Comparison 2) In total, 6 trials, 1702 pts, with a HR of 0.89 (95% CI 0.80-0.99) in favor of patients treated with D. a. Substitutive: 3 trials, 479 pts, with a HR of 1.05 (95% CI 0.87-1.27) in favor of patients treated without D. b. Additive: 3 trials, 1223 pts, with a HR of 0.82 (95% CI 0.87-0.93), in favor of D-containing regimens. If only studies (2 trials, 588 pts) are considered, in which D is added to a platinum/5-FU doublet, the HR is 0.79 (95% CI 0.64-0.98) in favor of the D-containing regimen. Comparison 3) 2 trials, 401 pts, with a HR of 0.85 (95% CI 0.68-1.06) in favor of the C-containing-regimen. Comparison 4) 2 trials, 1497 pts, with a HR of 0.89 (95% CI 0.80-1.0) in favor of the S-1-containing regimen. Comparison 5) 1 trial, 220 pts, with a HR of 0.82 (0.47-1.45) in favor of the O-containing regimen. Conclusions: All different chemotherapy combinations including I, D, O or oral 5-FU prodrugs are valid treatment options for mAGC. Among the comparisons analyzed above, only D-containing combinations, in which D was added to a single-agent or two-drug (platinum/5-FU) combination show a significant advantage in overall survival as compared to regimens without D.
Association of extensive delayed overmethylation influenced by advanced atrophy with risk for gastric cancer.
Authors: Oh Jung Hwan , Jung Sung Hoon , Cheung DaeYoung , Rhyu Mun Gan , Hong Seung Jin
Published: February 2017

13

Background: Helicobacter pylori (HP) infection facilitates overmethylation of CpG-island genes, which can be delayed by advanced mucosal atrophy. Delayed overmethylation results in unstable cell phenotypes responsible for gastric cancer. To delineate cancer risk period, the overmethylation period from HP infection to severe atrophy was traced in the gastric cancer and dysplasia. Methods: A pair of normal-appearing mucosal specimens was obtained from the antrum and body of 110 HP-positive and 95 HP-negative controls, 99 cancer patients, and 118 dysplasia patients. Gastric mucosal atrophy was assessed using the endoscopic atrophic border score. Eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, TRAPPC2L) and LTR retroelements (MMP2, CDKN2A, RUNX2, RUNX3) and the TFF3 gene lacking CpG island were chosen. The methylation-variable sites in gene-control regions were analyzed using radioisotope-labeling methylation-specific PCR. Results: The antrum-specific TFF3 gene on the antrum tended to be overmethylated earlier than Alu-type CpG-island genes on the body in the HP-positive controls with mild mucosal atrophy (mean age; 50 years vs. 52 years). In moderate atrophic cases, the antrum-site TFF3 overmethylation was delayed four years compared with the whole cases (58 years vs. 54 years) and the Alu-type overmethylation on the body was early detected (49 years). Gastric cancer patients with moderate atrophy induced a late overmethylation on both the antrum and body site (56 and 58 years) and increased LTR-type slow overmethylation (OD, 5.3; 95% CI, 2.0-14.1). Dysplasia patients (65 years) older than gastric cancer sustained an early Alu-type overmethylation on the body site. Conclusions: Moderate atrophy of the gastric mucosa can delay overmethylation of CpG-island genes, which leads to unstable cancer period and subsequent stable dysplasia period.
A phase I, dose-finding study of orally administered S-1 in combination with epirubicin and oxaliplatin (EOS) in patients (pts) with advanced or metastatic gastrointestinal cancer (AGIC) and chemonaïve advanced esophagogastric cancer (AEGC).
Authors: Moehler Markus Hermann , Heinemann Volker , Obermannova Radka , Kubala Eugen , Melichar Bohuslav , Mahlberg Rolf , Weinmann Arndt , Scigalla Paul , Tesarova Marietta , Janda Petr , Biville-Hedouin Fabienne , Mansoor Wasat
Published: February 2017

140

Background: S-1 (Teysuno), an oral fluoropyrimidine registered in Europe since 2011, provides a good efficacy and safety profile for the treatment (trt) of AEGC in combination with cisplatin. (FLAGS Study; J.A. Ajani. EJC2013). Because triplets with platinum compounds and anthracyclines are commonly used in AEGC, a phase I evaluating S-1 with fixed doses of oxaliplatin (130 mg/m² D1) and epirubicin (50 mg/m² D1) q3w in AGIC pts [cohorts 1 (C1) and 2 (C2)] and in chemonaïve AEGC pts [cohort 3 (C3)] was performed. Methods: Pts >18 years, ECOG/PS 0/1 were enrolled. Standard dose-limiting toxicity (DLT) evaluation was used. The maximum tolerate dose (MTD) was defined as the highest dose level at which less than <2/6 of pts experienced a DLT during Cycle 1. Once MTD was established, the cohort was expanded up to 12 pts. C1 and C2: S-1 dose was defined in cohort of pts (3+3 design): C1 20mg/m² BID (40 mg/m²/day); C2 25 mg/m² BID (50 mg/m²/d). Escalation to dose level (DL) 2 occurred only after DL1 (20mg/m²/BID) was safe according to DLT criteria. In C3 pts received S-1 25mg/m² BID. Results: 23 pts were evaluated. C1 and C2 included AGIC pts at all lines of trt. As in C1: 3 pts had no DLT, dose was increased and 3 pts were included in C2: after 1 DLT (≥Gr3 non-hematological toxicity), 2 more pts were included in C2 with a second DLT (febrile neutropenia). These 2 DLTs occurred in heavily pre-treated pts (3rd line) and led to closing of C2 and 3 additional pts were enrolled in expanded C1. MTD of S-1 was established 20 mg/m² BID. No DLT reported for chemo-naïve pts treated. Since EOS is used to treat AEGC in first line, a new C3 cohort with chemo-naïve pts was opened to again determine MTD of S-1: 6 pts in C3 were included. Here no DLT occurred and additional 6 pts confirmed dose of 25 mg/m² as the MTD. Conclusions: Based on these results, the recommended doses of S-1 in EOS regimen are 20 mg/m²/BID in heavily pre-treated AGIC pts and 25 mg/m²/BID in chemo-naïve AEGC pts. The triplets EOS could represent a well-tolerated alternative first line trt for AEGC pts. Clinical trial information: 2011-003471-11.
Distribution of FDG-avid nodes in esophageal cancer: Implications for radiotherapy target delineation.
Authors: Garcia Brandon , Goodman Karyn A. , Cambridge Lajhem , Dunphy Mark , Wu Abraham Jing-Ching
Published: February 2017

151

Background: Clinical target volumes (CTV) for radiation therapy (RT) in esophageal cancer (EC) are based on standard expansions of the primary tumor volume. Data is needed to better define the regions at highest risk for occult disease, based on histology and location of the primary tumor. We therefore reviewed PET scans in EC patients to characterize the frequency and location of FDG-avid lymph node metastases (LNM). Methods: We identified 474 EC patients with reviewable pre-treatment PET-CT scans who received RT. Tumors were classified by histology and location: upper esophageal (above carina, 15%), or lower/GE junction (85%). Locations of suspicious LNM were classified using standard radiographic nodal atlases, and distances from primary tumor to paraesophageal LNM were also measured. Results: FDG-avid LNM were identified and characterized in 204 patients. The most common LNM in upper EC were supraclavicular (1), retrotracheal (3P) and paratracheal (4). The most common LNM in lower EC were paraesophageal (8), and those in the gastrohepatic space (abdominal stations 1, 3 and 7). Overall, 55% of paraesophageal LNM were adjacent to the primary tumor. Of upper esophageal tumors with paraesophageal LNM, 87% were adjacent to the tumor and none were >6cm from tumor. However, 57% of lower esophageal tumors with paraesophageal LNM had non-adjacent paraesophageal nodes, half of which were >5cm from the tumor. Conclusions: A more data-driven and individualized approach to CTV delineation could improve the therapeutic ratio of RT in esophageal cancer. These results can guide CTV delineation by indicating the potential distribution of nodal involvement in esophageal cancer according to tumor location and histology. Because most paraesophageal LNM are adjacent to primary tumor, the necessity for uniformly large, longitudinal CTV expansions along the esophagus is unclear. [Table: see text]
Efficacy and safety of perioperative chemotherapy with 5FU-cisplatine-cetuximab in gastric and gastroesophageal junction adenocarcinomas (GGOJA): A single-arm multicenter phase II trial (FFCD 0901).
Authors: Mariette Christophe , Piessen Guillaume , Monterymard Carole , Pezet Denis , Ferru Aurelie , Baconnier Mathieu , Adhoute Xavier , Tavan David , Bouche Olivier
Published: February 2017

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Background: Whilst perioperative chemotherapy (CT) combined with radical surgery offers a survival benefit over surgery alone in GGOJA, 3-year survival still needs to be improved. The purpose of this phase II study was to evaluate the efficacy and safety of the perioperative use of cetuximab combined with 5-fluorouracil and cisplatin in operable GGOJA. Methods: Untreated operable patients with a WHO Performance Status (PS) ≤ 2 and age ≤ 75 years, with localised GGOJA received 6 cycles of intravenous Cetuximab (500mg/m²), Cisplatine (50mg/m²) and LV5FU2s (folinic acid 400mg/m², 5FU bolus 400mg/m², and continuous infusion of 5FU 2400mg/m²) every 2 weeks. Surgery was planned 3-4 weeks after the end of neaodjuvant CT and postoperative CT planned for 6-8 weeks after surgery. The primary objective was a combined evaluation of tumoral response, assessed by centrally reviewed computed tomography, and major toxicities leading to neoadjuvant CT being discontinued. Sample size (63 patients) was calculated using Bryant and Day design (α=5%, Power=80%), expecting a rate of objective response of 45% and a percentage of patients without major toxicities of 90%. Results: 65 patients were enrolled from 2011 to 2013 with a median age of 60.5 years. 83.1% were men, 98.5% had a WHO PS<2, 30.8% had a gastric and 69.2% a junctional tumour, 28.5% had a stage II and 71.4% of patients a stage III tumour. With regard to the primary endpoint, 64 patients were evaluated, 29.7% (n=19) had an objective morphological tumour response and 95.3% (n=61) did not stop treatment prematurely due to major toxicity. 58 patients (89.2%) completed neoadjuvant CT as planned. The median duration of CT was 2.3 months and grade 3-4-5 toxicities were observed in 61.5% of patients. 60 patients (92.3%) underwent surgical resection with 24 significant complications (41.7%) and 2 postoperative deaths (3.4%). On histological analysis, 40 patients (71.4%) were non responders. Conclusions: Adding cetuximab to the neoadjuvant chemotherapy regimen in operable GGOJA is safe but does not show enough efficacy in the present study to meet the primary endpoint. Clinical trial information: NCT01360086.
Surgical treatment in extremely aged patients with gastric cancer.
Authors: Sudo Masanori , Nashimoto Atsushi , Matsuki Atsushi , Yabusaki Hiroshi , Aizawa Masaki
Published: February 2017

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Background: Average life expectancy is increased to 82.6-year-old nowadays in Japan, and there is the increase of the number of elderly patients diagnosed with gastric cancer. Methods: From 1991 to 2011, 5330 operations have been performed for patients diagnosed with gastric cancer in our hospital, and 78 patients (1.5%) were over 85-year-old (elder group). To analyze the problems of surgical treatment for the extremely aged patients, the clinic-pathological findings were investigated retrospectively and compared with those in 4494 patients under 75 years old (control group). Results: Median age of elderly group was 86 (85-95) and control group was 63 (19-75). Preoperative morbidity was higher in the elderly group than in control group (73.1% vs 23.2%,p<0.001). The operative prosedures such as local/proximal/distal/total were 9/0/49/20 in elderly group and 216/172/2983/1123 in control group. The ratio of D2/D3 nodal dissection was lower in elderly group than in control group (30.8/0% vs 48.1/5.4%). Operation-time/blood-loss was less invasive in elderly group (135min/70ml vs 165min/100ml,p<0.001), but the postoperative morbidity rate was higher in elderly group (24.4% vs 15.3%,p=0.029). Although the frequency of postoperative complications was similar in surgical field, (14.1% vs 13.1%), other morbidity such as pneumonia, cerebral infarction and renal impairment were more common in elderly group. There was no difference in postoperative hospital stay in two groups (15 days). The ratio of postoperative adjuvant chemotherapy was lower in elderly group (Stage II/III; 10.0/13.3% vs 54.2/67.9%). The best supportive care is highly selected in elderly group in case of recurrence (66.7% vs 11.9%). The overall 5-year survival rate of Stage I/II/III/IV was 70.6/70.0/30.3/0% in elderly group and 92.0/80.0/60.5/13.3% in control group. The ratio of non-cancer death was higher in elderly group (41% vs 14%,p<0.001). Conclusions: The postoperative morbidity and non-cancer death is higher in elderly group. With the restriction for treatment failure, appropriate surgical procedures such as minimally invasive surgery and attentive care for the morbidity would need for the extremely aged patients for their better quality of life.
Actionable locoregional failures (LRFs) after therapy of localized esophageal carcinoma (LEC): Surveillance strategies and their benefits.
Authors: Elimova Elena , Wang Xuemei , Qiao Wei , Sudo Kazuki , Wadhwa Roopma , Shiozaki Hironori , Planjery Venkatram , Charalampakis Nikolaos , Skinner Heath Devin , Lee Jeffrey H. , Weston Brian , Bhutani Manoop S. , Komaki Ritsuko , Rice David C. , Swisher Stephen , Blum Mariela A. , Maru Dipen M. , Hofstetter Wayne Lewis , Ajani Jaffer A.
Published: February 2017

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Background: The goal of surveillance after local therapy (trimodality or bimodality) is to salvage patients with actionable LRF, however, the benefits of current surveillance strategies are not well documented. We report on a large cohort of LEC patients with actionable LRF. Methods: Between 2000 and 2013, 127 patients with actionable LRF were assessed. Histologic/cytologic confirmation of LRF was the gold standard. All surveillance tools (imaging and endoscopy) were assessed. Results: The majority of the patients were men (89%), had adenocarcinoma (79%), had their LRF identified through surveillance (85%) and most had no new symptoms (72%). For the 41 LRFs after trimodality, the sensitivity of PET/CT alone was 93% but the specificity was 67%. In trimodality patients with a positive PET/CT for LRF, only 44% had LRF confirmed by endoscopy and 56% LRFs confirm by additional testing (e.g., FNA, etc). Alternatively, in bimodality patients, endoscopy confirmed LRF in 81% (n=85; 1 patient not evaluable). Trimodality patients were at higher risk of subsequent (e.g., distant) relapse after LRF was documented than were bimodality patients (p=0.03); 78% of the relapses were distant. In bimodality patients, 99% of relapses (LRF and/or distant) occurred within 36 months of therapy while in trimodality patients, 90% of relapses occurred within 36 months of surgery. Conclusions: Our data suggest that PET/CT is more likely to detect LRFs than endoscopy in trimodality patients. However, in bimodality patients, endoscopy is more valuable than PET/CT for documenting LRFs. At least 3 years of surveillance are needed for all LEC patients. However, even after the salvage, distant relapses are common. From U. T. M. D. Anderson Cancer Center (UTMDACC), Houston, Texas, USA. (Supported in part by UTMDACC, and CA 138671 and CA172741 from the NCI).
Multimodality therapy for locally advanced esophageal cancer.
Authors: Paryani Nitesh N. , Ko Stephen , Hobbs Corey James , Kowalchik Kristin , Johnson Elizabeth , Kim Siyong , Vallow Laura , Peterson Jennifer Layton , Tzou Katherine S. , Buskirk Steven J.
Published: February 2017

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Background: The current standard of care for locally advanced esophageal cancer includes chemoradiotherapy with or without surgery. Radiation is usually delivered via a 3D technique. IMRT has been utilized in the treatment of multiple tumors and demonstrated similar efficacy while offering the possibility of decreased toxicity. Methods: Thirty-six patients were treated with IMRT and chemotherapy. Twenty-one patients underwent surgical resection. Eleven underwent open surgery and the remainder underwent minimally invasive surgery. Chemotherapy consisted primarily of 5-FU with oxaliplatin or cisplatin. All but two patients received 50.4 Gy; one patient received 41.4 Gy without surgery and one patient discontinued treatment after 25.2 Gy. Eleven patients required a treatment break during radiotherapy. The median age was 69 (range 46-87). Approximately two-thirds of tumors were adenocarcinomas located in the lower thorax. Two thirds of patients were staged as T3 and had positive lymph nodes. The median tumor size was 5 cm (range 2-13). Results: With a median follow-up of 21.3 months (range 2.4-44.8) and 33.9 months for survivors (range 3.7-44.8), overall survival at 24 months was 55%. The 24 month overall survival was 75% vs 24% for surgical and non-surgical patients, respectively. Seven patients had a complete pathologic response. Twenty-four patients experienced grade 3 or higher acute toxicity and there was one grade 5 toxicity. Acute toxicity was similar between surgery and non-surgery patients. Fourteen patients experienced grade 3 or higher late toxicity; 9 surgery and 5 non-surgery patients. The most frequent late toxicity was grade 3 stricture (21%). On multivariate analysis, advanced age (RR [10 year increase] 2.01, p=0.032) and heart maximum dose >55 Gy (RR 3.73, p=0.011) were associated with decreased survival. Conclusions: Patients who undergo surgery after chemoradiotherapy demonstrate improved survival; however, this may be related to underlying comorbidities that preclude surgery. IMRT appears to be a reasonable treatment option that may reduce complications from radiotherapy. Careful attention should be given to heart dose during treatment planning.
Effects of lanreotide autogel/depot (LAN) in pancreatic neuroendocrine tumors (pNETs): A subgroup analysis from the CLARINET study.
Authors: Phan Alexandria T. , Caplin Martyn E. , Pavel Marianne E. , Cwikla Jaroslaw B , Raderer Markus , Sedláčková Eva , Cadiot Guillaume , Wolin Edward M. , Capdevila Jaume , Wall Lucy , Rindi Guido , Langley Alison , Gomez-Panzani Edda , Ruszniewski Philippe B. ,   on behalf of the CLARINET Study Group
Published: February 2017

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Background: The prognosis for patients with metastatic pNETs is generally poor and current treatment options can be complicated by safety considerations. In CLARINET, progression-free survival (PFS) was significantly prolonged with the somatostatin analog LAN 120 mg vs. placebo (PBO) in patients with metastatic grade 1 or 2 (Ki-67 <10%) non-functioning enteropancreatic NETs (hazard ratio [HR] for progressive disease [PD]/death: 0.47 [95% CI: 0.30, 0.73]. Here, we more fully characterize treatment effects in the pNET subgroup. Methods: CLARINET was a 96-week randomized double-blind trial. Patients received LAN 120 mg or PBO every 4 weeks, administered by deep s.c. injection (NCT00353496). Subgroup analyses were undertaken to investigate only the consistency of treatment effects as the study was not otherwise designed or powered for such analyses. Results: 91 patients with pNETs received LAN (n=42) or PBO (n=49). At baseline, mean age was 64 years in both groups; overall, 37% had hepatic tumor loads >25%, 95% had stable disease, 77% had received no previous treatment, and 38% had had previous surgery on the tumor. Median PFS in the pNET subgroup was not reached at study end with LAN vs. 12.1 months [95% CI: 9.4, 18.3] with PBO (HR for PD/death: 0.58 [0.32, 1.04]). (Median PFS for LAN at first planned analysis in the open-label extension study was 29.7 months [12.0, 32.4].) The incidence of adverse events (AEs) in the core study was 88% with both LAN and PBO, and the most common AE was diarrhea (LAN, 43%; PBO, 37%). Treatment-related AEs occurred in 55% of the LAN group and 24% of the PBO group. Serious AEs (SAEs) occurred in 29% vs. 43%, respectively; only three of these patients had treatment-related SAEs (two with LAN, one with PBO). Two patients in each group had AEs leading to withdrawal. Conclusions: The evidence in the pNET subgroup suggesting antitumor effects with LAN together with the favorable long-term safety profile support a positive benefit:risk profile for LAN as a first-line treatment for pNETs. Clinical trial information: NCT00353496.
Racial/ethnic disparities in liver cancer-attributable hepatitis infections in the U.S. population.
Authors: Moore Kevin J. , Dunn Erin , Tannenbaum Stacey L. , Koru-Sengul Tulay
Published: February 2017

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Background: According to the American Cancer Association, hepatitisB and Cinfections may raise liver cancer risk. We identify population-specific cancer-attributable hepatitis prevalence to discern disparities across race/ethnicity for liver cancer risk. Methods: Data from 1999-2012 National Health and Nutrition Examination Survey (NHANES) were used to determine prevalence, unadjusted odds ratios (OR) with 95% confidence intervals (95%CI) for non-Hispanic-Whites (NHW), non-Hispanic-Blacks (NHB), Mexican-Americans, other Hispanics, and other race of hepatitis, taking complex sampling design into account. Results: Among those sampled, the overall highest prevalence of hepatitis infection was 66.4% in NHW for hepatitis-C and the lowest prevalence was 1.4% in Mexican-Americans for hepatitis-B surface-antigen. NHB were more likely than NHW to have hepatitis-B infections of surface-antibody (OR=1.9; 95%CI=1.8-2.0), core-antibody (3.3; 3.1-3.6), surface-antigen (5.3; 3.6-7.7), and hepatitis-C infections (1.7; 1.5-2.0). Compared to NHW, other Hispanics had a higher burden of hepatitis-B infection of surface-antibody (1.5; 1.4-1.7) and core-antibody (2.5; 2.1-2.8); other race had the same higher infection pattern as other Hispanics in surface-antibody (2.4; 2.2-2.6) and core-antibody (6.7; 6.0-7.5). Surface-antibody was more prevalent (1.5; 1.4-1.6) while core-antibody was less prevalent (0.9; 0.8-0.9) among Mexican-Americans compared with NHW. Conclusions: The prevalence of hepatitis B and C infections varies across different race/ethnicities with NHB having the greatest burden compared with NHW. Population-based databases should collect more information regarding infection burden in at-risk groups in order to understand more about these disparities. Appreciating such gaps across demographics could assist in future efforts to decrease the burden of hepatitis and to provide a base for targeted liver cancer prevention programs via screening, vaccination, health promotion, and literacy.