bluuebunny/crossref_metadata_2025 huggingface dataset:
A curative intent trimodality approach for advanced isolated abdominal nodal metastasis in metastatic colorectal cancer: Update of a single-institutional experience.
Authors: Johnson Benny , Jin Zhaohui , Haddock Michael G. , Hallemeier Christopher Leigh , Martenson James A. , Smoot Rory L. , Larson David W. , Dozois Eric J. , Nagorney David M. , Grothey Axel
Published: September 2018

3556

Background: To define and update survival rates and relapse patterns in patients (pts) with isolated advanced abdominal nodal metastasis secondary to colorectal cancer (CRC), treated with curative intent using aggressive trimodality therapy. Methods: Fifty-seven pts with isolated advanced abdominal lymph node metastasis (retroperitoneal and mesenteric) secondary to colorectal cancer received trimodality therapy defined as chemotherapy delivered in conjunction with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-FU was the most common radiosensitizer used (66%, 38 pts). The median dose of EBRT was 50 Gy & the median dose of intraoperative radiotherapy was 12.5 Gy. End points included distant metastasis, toxicities, local failure within EBRT field, recurrence within the intraoperative radiotherapy field, and survival. Results: 49% of pts were male, median age 50.5 yrs. All patients had ECOG ≤ 1. 27 pts had primary right sided colon cancer, 16 left sided colon cancer and 14 rectal primaries. Median time from initial CRC diagnosis to development of abdominal lymph node metastatic disease was 24 months (95% CI, 23.5-45.1 months). 84% (48 pts) had paraaortic nodal metastases, 12% (7 pts) had mesenteric nodal metastases, and 3% (2 pts) had both. With a median follow up of 89.4 months, the median overall survival and 5-year estimated survival rate were 53.2 months (95% CI, 46.4-78.8 months) and 42%, respectively. Median progression free survival was 19.3 months (95% CI, 15.6-32.8 months). 21 (37%) pts never developed distant disease. Outcome was not affected by disease sidedness, rectal primary, or mutational profile. Treatment was well tolerated without any grade 3/4 toxicities. Conclusions: The use of trimodality therapy including EBRT with radiosensitizing chemotherapy, lymphadenectomy and IORT produces sustainable long-term survival in selected metastatic CRC pts presenting with isolated retroperitoneal/mesenteric nodal relapse.
The impact of cumulative toxicity on physical quality of life in patients with metastatic colorectal cancer receiving first line chemotherapy.
Authors: Schuurhuizen Claudia , Konings Inge , Braamse Annemarie , Buffart Laurien , Bloemendal Haiko , Dekker Joost , Verheul Henk M.W.
Published: September 2018

3564

Background: We have previously suggested that treatment related toxicity has impact on physical quality of life (QOL) scores, as opposed to global QOL. Moreover, the cumulative effect of experienced toxicities, including low-grades AEs, may be of more importance. The purpose of this observational cohort study was to evaluate the association between cumulative toxicity and physical and global QOL in patients with metastatic colorectal cancer (mCRC) receiving chemotherapy. Methods: 105 patients with mCRC starting first line chemotherapy were evaluated. All patients completed the EORTC-QLQ-C30 questionnaire at baseline and after 10 weeks. Toxicity, clinical outcomes and demographics were retrieved from patient records. For each patient, we calculated cumulative toxicity in three different ways: i) total number of adverse events (AEs) (all grades), ii) total number of grade 3-4 AEs, and iii) total number of AEs multiplied by their grade. The relation between each cumulative toxicity score and QOL assessed at 10 weeks, was studied. Results: The mean age of patients was 64.8 ± 9.7 years, 70.5% were male, and 83.8% received first line oxaliplatin based combination chemotherapy. AEs occurred in 98.1% of patients, grade 3-4 AEs in 37.1%, and grade 1-2 AEs in 61.0%. The mean number of experienced AEs (all grades) was 5.3 ± 2.7. The most common toxicities included diarrhea, neuropathy and fatigue. None of the toxicity scores was related to global QOL outcome. A higher total number of all grades AEs (β = - 2.2, 95%CI = -3.7; -6.6) and total number of AEs multiplied by grade (β = -1.3, 95%CI = -2.2; -3.5) were significantly associated with worse physical QOL. Conclusions: Cumulative toxicity, defined as the total of all grades AEs, significantly affects physical QOL in patients with mCRC receiving first line chemotherapy. Improvement of treatment related toxicity management by reducing the total number of AEs, may result in relevant improvements in patients’ QOL. Our results emphasize that future RCTs should present physical QOL outcomes instead of global QOL, as well as all grades and total number of toxicities for individual patients.
Impact of tumor location on outcomes in patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG): An interim analysis from the prospective, observational CORRELATE study.
Authors: Ducreux Michel , Öhler Leopold , Scheithauer Werner , Metges Jean-Philippe , Dourthe Louis-Marie , De Groot Jan Willem , Thaler Josef , Yeh Kun-Huei , Lin Jen-Kou , Falcone Alfredo , Punt Cornelis J. A. , Kalinovsky Jan , Fiala-Buskies Sabine , Cervantes Andres , O'Connor Juan Manuel ,   On Behalf of the CORRELATE Investigators
Published: September 2018

3567

Background: The anatomical location of the primary tumor has been associated with outcomes in mCRC, with left-sided (L) tumors having a better prognosis than right-sided (R) tumors and location predicting response to treatment. REG significantly improved overall survival (OS) vs placebo in patients with mCRC who progressed on available treatments in 2 randomized, phase 3 trials (CORRECT, CONCUR). This exploratory analysis evaluated outcomes by primary tumor location in patients with mCRC treated with REG in the CORRELATE study. Methods: CORRELATE is an observational study designed to characterize the safety and effectiveness of REG in unselected patients for whom the decision to treat with REG has been made by the treating physician according to the local health authority label. Primary L tumors were located in the rectum, splenic flexure, recto-sigmoid, descending, or sigmoid colon; R tumors were in the appendix, hepatic flexure, cecum, or ascending colon. OS was analyzed by the Kaplan–Meier method and comparisons were by a 2-sided log-rank test. Results: Primary tumor location was available for 474 patients (L, n = 375 [79%]; R, n = 99 [21%]). Median time from initial diagnosis and from diagnosis of metastatic disease to treatment was slightly longer in L vs R tumors (32 vs 28 months and 25 vs 22 months, respectively). A higher proportion of patients with L vs R tumors, respectively, had prior radiotherapy (34% vs 13%) and a lower proportion had a partial colectomy (40% vs 70%). Best response to prior systemic therapy (partial response + stable disease) was 72% for L tumors and 68% for R tumors with a median duration of treatment of 26 and 22 months, respectively. REG treatment duration was similar in the 2 groups. Median OS (95% CI) was 6.7 months (6.1, 7.7) for L tumors vs 6.3 months (4.9, 8.1) for R tumors (P = 0.3); median progression-free survival (95% CI) was 2.8 months (2.6, 3.0) vs 2.6 months (2.4, 3.0) (P = 0.5), respectively. Conclusions: Interim results from this observational study suggest that OS is similar in patients with R and L tumors treated with REG. Clinical trial information: NCT02042144.
Association between timing and duration of adjuvant chemotherapy and survival for colorectal cancer in korea, 2011-2014: A nationwide study based on the database of quality assessment and the health insurance.
Authors: Hwang In Gyu , Lee Ji Sung , Lee Sang-Cheol , Baek Sun Kyung , Kim Jong Gwang , Kim Tae Won
Published: September 2018

3605

Background: Few population-based analyses on treatment outcomes of colorectal cancer (CRC) have been conducted in Asian countries. We conducted a nationwide study to assess relationship between timing and duration of adjuvant chemotherapy (AC) and survival for patients with CRC in South Korea. Methods: Data from the Health Insurance Review and Assessment Service Database (HIRA) were analyzed for demographics, tumor characteristics, adjuvant chemotherapy, and survival of patients who underwent curative-intent surgical resection for CRC from 2011 to 2014. Results: From the HIRA data, a total of 61315 patients were identified: 15620 (25.5%) in stage I, 20525 (33.5%) in Stage II, and 25170 (41.0%) in stage III. Chemotherapy regimens were consisted: 11332 (18.5%) in 5-fluorouracil and leucovorin/capecitabine (FL/CAP), 13183 (21.5%) in FL/CAP plus oxaliplatin (FOLFOX/CAPOX), 357 (0.6%) in uracil and tegafur/doxifluridine (UFT/D) and 36443 (59.4%) in surgery alone. For patients with stage II and III CRC, the initiation of AC ≥ 8 weeks after surgery was associated with a significant decrease in overall survival (OS) (FL/CAP: HR, 1.82; 95% CI, 1.53 to 2.17, and FOLFOX/CAPOX: HR, 2.92; 2.47 to 3.45, respectively), however UFT/D regimens were not statistically significant. For patients with stage II and III colon cancer, receiving AC < 3 months had lower OS (FL/CAP: HR, 3.72; 95% CI, 2.80 to 4.94, FOLFOX/CAPOX: HR, 2.15; 1.87 to 2.47, and UFT/D: HR, 1.74; 0.56 to 5.41, respectively). For patients with stage II and III rectal cancer, receiving AC < 3 months regardless of chemotherapy regimens had a significant lower survival (FL/CAP: HR, 1.91; 1.66 to 2.20, FOLFOX/CAPOX: HR, 2.20; 1.75 to 2.77, and UFT/D: HR, 3.71; 1.45 to 9.44, respectively). Conclusions: Time to initiation and duration of AC after surgery were associated with survival. Based on our results, starting within 8 weeks and receiving more than 3 months of AC are needed to have an overall survival benefit.
Phase I study of trametinib with neoadjuvant chemoradiation (CRT) in patients with locally advanced rectal cancers (LARC).
Authors: Wu Christina Sing-Ying , Williams Terence Marques , Wei Lai , Umar Hamida , Mikhail Sameh , Ciombor Kristen Keon , Chan Emily , Noonan Anne M. , Roychowdhury Sameek , El-Dika Samer S , Krishna Somashekar , McCarthy Sean T , Arnold Mark , Harzman Alan , Abdel-Misih Sherif , Cirocco William , Traugott Amber , Bekaii-Saab Tanios S. , Wuthrick Evan John
Published: September 2018

3612

Background: The RAS/RAF/MEK signal transduction pathway is critical to the development of colorectal cancer, and tumors harboring KRAS, NRAS, and BRAF mutations were shown to be resistant to radiation. Thus, we conducted a phase I study of trametinib, a potent MEK1/2 inhibitor, in combination with CRT in patients with LARC. Methods: Phase I trial for patients with Stage II/III rectal cancers with a 3+3 design, and an expansion cohort of 12 patients at the maximum tolerated dose (MTD). Trametinib is given orally at 3 dose levels: 0.5mg, 1mg, and 2mg (Mon-Fri). CRT regimen is infusional 5-flourouracil (5FU) 225mg/m2/day (Mon-Fri) and daily fractions of 1.8 Gy (total 50.4Gy). There is a 5-day trametinib lead-in followed by trametinib and CRT. Six to 10 weeks after completion of CRT, patients then proceed to their surgery and adjuvant therapy. The primary endpoint is to identify the MTD and recommended phase 2 dose of trametinib with CRT. Immunohistochemistry staining for phosphorylated –ERK (pERK) and genomic profiling is performed on the tumor samples. Results: Enrollment is complete at all dose levels with18 patients, and 15 patients evaluable for toxicity and response as of Feb 6. One dose-limiting toxicity of diarrhea was observed at the 2mg dose. Grade 3 and most common toxicities are shown in Table 1. No grade 4/5 toxicities have been observed. At 2mg dose level, 3/9 (33%) patients had pathological complete response (pCR) and 2/9 (22%) had a near pCR. Correlative studies confirm decrease in pERK levels with increasing doses of trametinib. Correlation of genomic mutational status with toxicity, response, and outcomes is being analyzed. Conclusions: The combination of trametinib with 5FU CRT is tolerable with promising preliminary activity. Final results will be presented at the meeting. Toxicities. Clinical trial information: NCT01740648. [Table: see text]
Comparison of two different neoadjuvant chemoradiatiotherapy regimens for locally advanced rectal cancer: Results of a phase II, multicenter, randomized trial.
Authors: Zhu Ji , Guan Yun , Yan Senxiang , Xu Ye , Li Xinxiang , Cai Sanjun , Zhang Zhen
Published: September 2018

3614

Background: The aim of this study is to compare clinical outcomes between two groups of different chemoradiation Regimens. Methods: Eligible patients were randomly assigned to Patients received either IMRT to the pelvis of 50 Gy/25Fxs concurrent with oxaliplatin 50 mg/m2 weekly and capecitabine 625 mg/m2 bid d1–5 weekly (Arm A), or IMRT to the pelvis of 50 Gy/25Fxs and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, followed by a cycle of XELOX two weeks after the completion of chemoradiotherapy (Arm B). Surgery was scheduled eight weeks after the completion of CRT. All patients were recommended to receive adjuvant CT regardless of pathological stages. A total of six cycles of XELOX chemotherapy was recommended including neoadjuvant and adjuvant period. The primary end point was pCR. Results: From February 2010 to December 2011, a total of 120 patients were randomly assigned to Arm A (n = 60) or Arm B (n = 60). One hundred and ten patients (Arm A = 53, Arm B = 57) underwent surgery, the other 10 patients didn’t receive surgery because of unresectable disease. Eight and 14 cases were evaluated as pCR in two groups respectively ( p= .157). Tumor response was further classified into good response and poor response, the former was defined as ypT0N0, ypT1-2N0 and ypT0N1a. The rate of good responses were 30.0% and 55% ( p= .006). No significant differences were found in grade 3 or 4 acute adverse events during the treatment between the two groups. However, number of patients who had delayed incision healing was 13 and 3 patients ( p= .007). There were no statistical differences in OS ( p= .553), DFS ( p= .349) and local-regional control ( p= .856) between the two groups. In the univariate analysis, N stage, MRF involvement and tumor response had significant impacts on OS, DFS and LC. In the multivariate analysis, MRF involvement had significant impacts on OS ( p= .02), DFS ( p= .01) and LC ( p= .01). Conclusions: A dose-intensified radiotherapy in neoadjuvant chemoradiotherapy demonstrated contribution to tumor regression with acceptable toxicity, but led delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigation. Clinical trial information: NCT01064999.
Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.
Authors: Crocenzi Todd S. , El-Khoueiry Anthony B. , Yau Thomas Cheung , Melero Ignacio , Sangro Bruno , Kudo Masatoshi , Hsu Chiun , Trojan Jorg , Kim Tae-You , Choo Su-Pin , Meyer Tim , Kang Yoon-Koo , Yeo Winnie , Chopra Akhil , Baakili Adyb , Dela Cruz Christine Marie , Lang Lixin , Neely Jaclyn , Welling Theodore
Published: September 2018

4013

Background: Many pts with advanced HCC progress on SOC therapy. Nivo is a fully human anti–PD-1 IgG4 mAb that demonstrated durable responses (20% ORR with a median DOR of 9.9 mo; 9-mo OS rate was 74%) in pts with advanced HCC in the dose-expansion (EXP) phase of the CheckMate 040 study (NCT01658878; Melero et al. 2017). Here we present survival and durability of response data in both sor-naive and -experienced pts with advanced HCC in CheckMate 040. Methods: Pts naive to or previously treated with sor received nivo in phase 1/2 dose-escalation (ESC; 0.1–10 mg/kg) and -EXP (3 mg/kg) cohorts Q2W regardless of PD-L1 status. Primary endpoints were safety/tolerability (ESC) and ORR (EXP; ORR by investigator [INV] and blinded independent central review [BICR]) using RECIST v1.1. Secondary endpoints included DOR, DCR, and OS. Biomarkers were assessed using pre-treatment tumor samples. Results: Overall, pts (N=262) had a median follow-up of 12.9 mo, and 98% had Child-Pugh scores 5–6. In sor-naive pts (n=80), the ORR (INV) was 23%, with 44% of responses (8/18) ongoing (Table). The DCR was 63%; 40% of pts had stable disease ≥6 mo. In sor-experienced pts (n=182; 91% progressed on sor), the ORRs (INV) were 16%–19%. Overall, responses occurred regardless of etiology or tumor cell PD-L1 expression. Nivo had a manageable safety profile consistent with that reported in other tumor types. Updated data with additional 4 mo of follow-up will be presented. Conclusions: Nivo demonstrated durable responses with long-term survival and favorable safety in both sor-naive and -experienced pts with advanced HCC. Clinical trial information: NCT01658878. [Table: see text]
Results of interim analysis of the multicenter randomized phase III SENORITA trial of laparoscopic sentinel node oriented, stomach-preserving surgery versus laparoscopic standard gastrectomy with lymph node dissection in early gastric cancer.
Authors: Ryu Keun Won , Kim Young Woo , Min Jae Seok , Yoon Hong Man , An Ji Yeong , Eom Bang Wool , Hur Hoon , Lee Young-Joon , Cho Gyu Seok , Park Youngkyu , Jung Mi Ran , Park Ji-Ho , Hyung Woo Jin , Jeong Sang-Ho , Nam Byung-Ho
Published: September 2018

4028

Background: The benefits and hazards of laparoscopic sentinel node oriented stomach-preserving surgery, compared to those of laparoscopic standard gastrectomy with lymph node dissection in early gastric cancer (EGC), are unknown. The SENORITA trial investigated the clinical impact of laparoscopic sentinel node oriented stomach-preserving surgery in EGC. Methods: Other than those with absolute indication for endoscopic resection, eligible patients had EGC confined to the mucosa and submucosa, with diameter ≤ 3cm, regardless of histology on preoperative evaluation. Patients were randomized for laparoscopic standard gastrectomy or laparoscopic stomach-preserving surgery. Patients were stratified based on depth (mucosa vs. submucosa) and size (≤ 2cm vs. 2 < ≤ 3cm) of the EGC and by participating institution. The primary endpoint was 3-year disease-free survival (3yDFS). The expected 3yDFS was 97% and non-inferior margin was 5%. 580 patients and 24 events were needed to show non-inferiority with 80% power. One interim analysis was planned after 12 events (50%) occurred. Using the O’Brien-Fleming error spending function, the two-sided nominal significance level for the interim analysis would be 0.0054. Results: From March 2013 to May 2016 462 patients were randomized; analysis was performed in 421 after a dropout of 41 patients. Laparoscopic stomach-preserving surgery was possible in 75.6% by study protocol. Interim analysis was conducted based on 12 events (median follow-up: 15.89 months). The 3yDFS in the laparoscopic standard gastrectomy arm was 96%; the 3yDFS in the laparoscopic stomach-preserving surgery arm was 93%, (99.46% CI: -3.18%, 9.18%). The postoperative complication rates were 15.0% and 12.9%, respectively (p = 0.542). Conclusions: In this interim analysis, laparoscopic sentinel node oriented stomach-preserving surgery did not show non-inferiority for 3yDFS. The follow-up time was not mature enough to evaluate non-inferiority. Further follow-up will elucidate the role of laparoscopic sentinel node oriented stomach-preserving surgery. Clinical trial information: NCT01804998.
Exclusive chemoradiotherapy with or without dose escalation in locally advanced esophageal carcinoma: The CONCORDE study (PRODIGE 26).
Authors: Crehange Gilles , Bertaut Aurelie , Peiffert Didier , Le Prise Elisabeth , Etienne Pierre-Luc , Rio Emmanuel , Pereira Renata , Noel Georges , Benezery Karen , Bonnetain Franck , Seitz Jean Francois
Published: September 2018

4037

Background: In esophageal cancer (EC), 20 to 45% of patients suffer from local failure after 50Gy concomitant chemoradiation (cCRT). Improvements in staging together with target definitions led us to test dose escalation in the modern era of new technologies. Methods: Patients were randomly assigned cCRT to 40Gy elective nodal irradiation with either a 10Gy boost (Arm A) or 26Gy boost (Arm B) combined with FOLFOX-4. The primary endpoint of this phase II was acute toxicity according to the NCIC-CTCAE (version 4.0). Quality of life according to the EORTC QLQ-C30 and OG25 was a secondary endpoint. All analyses were performed in intent-to-treat. Results: 160 patients were randomized between Jun 2011 and Feb 2016: 81 patients in arm A and 79 patients in arm B. The mean age at diagnosis was 61.9 (7.9) years and 62.1 (7.8) years, respectively. Seventy patients in each arm had squamous cell carcinoma (86.4% in arm A and 88.6% in arm B) and 59 patients (72.8%) and 58 patients (73.4%) had stage III disease in arms A and B, respectively. IMRT was performed in 57 (70.4%) and 55 (69.6%) patients in arms A and B. The rates of grade ≥3 (G3+) non-hematological toxicity were not significantly different between arms A and B (76.5% vs 86.0%, p = 0.12). The rates of G3+ hematological toxicity were not significantly different between arms A and B (82.7% vs 88.6%, p = 0.29). The rates of G3+ non-hematological toxicity were not significantly different between patients treated with 3DRT (83.3%) and IMRT (81.3%) (p = 0.77). The mean global health scores at baseline and 3 months were 63.9 (sd = 21.4) vs 69.6 (sd = 23.1) in arm A (p = 0.10) and 65.27 (sd = 19.54) vs 58.8 (sd = 19.9) in arm B (p = 0.16). The presence of dysphagia was neither significantly different between arm A (89.23%) and arm B (86.21%) (p = 0.61) at baseline nor at 3 months (77.78% vs 86.84%, p = 0.29). Odynophagia was present at baseline in 78.46% in arm A and 75.86% in arm B (p = 0.73) while the rates observed at 3 months were 68.18% and 73.68%, respectively (p = 0.59). Conclusions: Dose escalated cCRT in patients with EC is feasible with no increased acute toxicity and no deterioration of QOL. A phase III trial is on-going to conclusively address the issue of local control with cCRT. Clinical trial information: NCT01348217.
The Nationwide Cancer Genome Screening Project in Japan SCRUM-Japan, GI-screen: Efficient identification of cancer genome alterations in advanced gastric cancer.
Authors: Kadowaki Shigenori , Shitara Kohei , Yuki Satoshi , Hironaka Shuichi , Kato Takeshi , Hara Hiroki , Kajiwara Takeshi , Izawa Naoki , Iwasa Satoru , Moriwaki Toshikazu , Naruge Daisuke , Esaki Taito , Saeki Hiroshi , Kudo Toshihiro , Cho Haruhiko , Tamura Takao , Ebi Hiromichi , Nomura Shogo , Ohtsu Atsushi , Yoshino Takayuki
Published: September 2018

4041

Background: We have conducted the Nationwide Cancer Genome Screening Project in Japan since April 2015 using Next Generation Sequencing in advanced non-colorectal gastrointestinal (GI) cancer (aNon-CRC), called as the SCRUM-Japan GI-SCREEN. Methods: This study is ongoing with 20 major cancer centers. Patients with aNon-CRC, who plan to or receive chemotherapy were eligible. DNA and RNA were extracted from FFPE tumor samples and were analyzed by the Oncomine Cancer Research Panel (OCP) which allows to detect gene mutation, copy number variant (CNV) and fusions across 143 genes in a CLIA certified CAP accredited laboratory. The detected genomic variant data were classified according to whether genetic drivers of cancer including gain- and loss-of-function or single nucleotide variant based on the Oncomine Knowledgebase. In this presentation, we show the results of advanced gastric cancer (aGC) cohort. Results: As of October 31st in 2016, a total of 565 aGC samples were analyzed. The sequence with the OCP was successfully performed in 425 (75.2%). Out of 475 patients except for the 90 patients in which precise data is not collected, the proportion of histology type is followed; intestinal type 44.6%, diffuse type 54.5%, other 0.6%, unknown 0.2%. Out of 406 samples of which results were available, the frequently detected mutations were TP53 (47.8%), PIK3CA (8.6%), KRAS (5.4%), SMAD4 (4.9%), TET2 (4.4%), APC (3.9%), ERBB2 (3.7%) and CNVs were ERBB2 (10.8%), CCNE1 (9.4%), KRAS (3.7%), ZNF217 (3.2%), FGFR2 (2.7%), and MET (2.5%). FGFR3-TACC3 fusion, WIPF2- ERBB2 fusion and EGFR vIII were detected in 2, 1, and 2 cases, respectively. Conclusions: This nationwide screening system is efficient to detect rare gene alterations in aGC. This novel knowledge provides an intriguing background to investigate new target approaches and represents a progress toward more precision medicine. Clinical trial information: UMIN000016344.
Is surgical resection beneficial in recurrent or metastatic gastric cancer?
Authors: Choi Yong Won , Ann Mi Sun , Lee Hyun Woo , Kang Seok Yun , Choi Jin-Hyuk
Published: September 2018

4043

Background: Although chemotherapy is currently established as a standard treatment in recurrent or metastatic gastric cancer, the role of palliative surgical resection is still controversial. We investigated the survival benefit of surgical resection in patients (pts) with recurrent or metastatic gastric cancer who received systemic chemotherapy. Methods: A retrospective review was conducted on 698 pts who received palliative chemotherapy for recurrent (n = 307) or primary metastatic (n = 391) gastric cancer. Overall survival (OS) of pts who underwent surgical resection followed by chemotherapy was compared to that of pts who received chemotherapy alone. Results: Among 140 pts (primary metastatic: 97, recurrent: 43) with surgical resection, gastrectomy, metastasectomy, and gastrectomy with metastasectomy were performed in 83 (primary metastatic: 81), 44, and 13 pts, respectively. Higher surgical resection rate was observed in pts with young age ( < 70) (p = 0.010), ECOG PS 0 or 1 (p = 0.010), primary metastatic (p < 0.0001), absence of liver metastasis (p = 0.002), and signet ring cell histology (p = 0.002). The median OS of pts who underwent surgical resection before chemotherapy was significantly longer than that of pts who received chemotherapy alone (19 vs. 9 months, p <0.0001). The OS benefit of surgical resection was consistent across subgroups in terms of baseline characteristics including age, ECOG PS, disease status (primary metastatic vs. recurrent), peritoneal metastasis, and first-line chemotherapy regimen (single vs. combination). In multivariate analysis, surgical resection was independently associated with favorable OS (hazard ratio = 0.41, p < 0.0001) along with ≥second-line chemotherapy (p < 0.0001), whereas ECOG PS 2 or 3 (p = 0.013), signet ring cell histology (p < 0.0001), and peritoneal metastasis (p = 0.046) were independent prognostic factors of poor OS. Conclusions: The present study suggests that judicious use of surgical resection before chemotherapy in recurrent or metastatic gastric cancer pts may result in favorable outcome, although large scale phase III trials are essential to establish this treatment approach as a standard practice.
Nomogram for lymph node metastasis prediction with early gastric cancer patients: To decide additional gastrectomy after endoscopic dissection.
Authors: Kim Su Mi , Min Byung-Hoon , An Ji Yeong , Choi Min-Gew , Ryu Keun Won , Kim Young Woo , Jung Sin-Ho , Sohn Tae Sung , Bae Jae-Moon , Kim Sung , Kim Jae J. , Lee Jun Ho
Published: September 2018

4045

Background: Accurate prediction of metastatic lymph node is critical to avoid unnecessary gastrectomy and improve quality of life for patients with early gastric cancer. The aim of this study was to develop and validate a nomogram for prediction of lymph node metastasis in early gastric cancer patients. Methods: We reviewed the clinicopathological data of 10595 patients who underwent curative resection for early gastric cancer from 2001 to 2015 at Samsung Medical Center. This model was externally validated by 2100 patients who underwent curative resection for gastric cancer in National Cancer Center. Multivariate analysis using the Cox proportional hazard regression model was performed to develop the nomogram, and discrimination and calibration were evaluated by external validation. Overall survival, disease free survival, and recurrence free survival were compared between gastrectomy groups of 6641 patients and endoscopic dissection group of 999 patients who was performed the treatment in Samsung Medical Center for early gastric cancer by risk on nomogram to demonstrate the efficacy of nomogram. Results: Multivariate analyses revealed that age, tumor size, lymphatic invasion, depth of invasion, and histologic differentiation were significant prognostic factors for lymph node metastasis. The nomogram had good discrimination with a concordance index of 0.845 [95% confidence interval 0.832-0.858], supported by an external validation point of 0.813[95% confidence interval 0.786-0.84]. In low risk on nomogram, endoscopic dissection group had similar overall survival (P = 0.319), disease free survival (P = 0.469) and recurrence free survival (P = 0.091) compared to gastrectomy group. Conclusions: We developed and validated a nomogram predicting lymph node metastasis for early gastric cancer based on a large database. This personalized nomogram is useful to avoid unnecessary gastrectomy after endoscopic dissection resulting in improved quality of life for early gastric cancer patients.
A phase II study (KSCC/HGCSG/CCOG/PerSeUS1501B) of trastuzumab plus S-1 and oxaliplatin for HER2-positive advanced gastric cancer.
Authors: Shinozaki Katsunori , Yuki Satoshi , Kashiwada Tomomi , Kusumoto Tetsuya , Iwatsuki Masaaki , Satake Hironaga , Kobayashi Kazuma , Esaki Taito , Nakashima Yuichiro , Kubo Nobuhide , Tokunaga Shoji , Shimose Takayuki , Makiyama Akitaka , Saeki Hiroshi , Oki Eiji , Baba Hideo , Maehara Yoshihiko
Published: September 2018

4059

Background: A combination of S-1 and cisplatin (SP) has been the standard regimen for advanced gastric cancer (AGC) in East Asia. The combination of S-1 and oxaliplatin (SOX100) was demonstrated to be non-inferior to SP in the randomized phase III study. The ToGA study demonstrated that trastuzumab (T-mab) combination therapies with cisplatin and fluoropyrimidines improved the overall survival of patients with HER2-positive AGC. This multicenter study is the first phase II trial to assess the efficacy and safety of T-mab in combination with S-1 and oxaliplatin (HER-SOX130) in HER2-positive AGC. Methods: Patients with HER2-positive AGC or recurrent gastric cancer defined to be IHC 3+ or IHC 2+/FISH positive received 80 mg/m2 S-1 per day orally on days 1–14, 130 mg/m2 oxaliplatin intravenously on day 1, and T-mab (8-mg/kg loading dose and 6 mg/kg thereafter) intravenously on day 1 of a 21-day cycle until one of the criteria for withdrawal of the study treatment occurred. The primary end-point was the response rate (RR). Adverse events were recorded based on the NCI-CTCAE Vers.4.0. The threshold response rate was defined as 50%, and the expected rate was set at 70%, with an 80% power and a 1-sided alpha value of 0.05. The calculated sample size was 37 patients. Results: For this study, 42 patients (median age, 66 years) were enrolled from June 2015 to May 2016. Three patients were excluded owing to ineligibility. Efficacy and safety analyses were conducted in the full analysis set of 39 patients. The proportion of patients with IHC 3+ was 87%. The confirmed RR assessed by the independent review committee was 82.1(32/39) % (95% confidence interval [CI]: 67.3–91.0), and the disease control rate was 87.2(34/39) % (95% CI: 73.3–94.4). The incidence rates of grade 3 or 4 adverse events were as follows: neutropenia, 12.8%; thrombocytopenia, 17.9%; anemia, 10.3%; sensory neuropathy, 5.1%; anorexia, 17.9%; diarrhea, 7.7%; and teary eyes, 2.6%. Conclusions: HER-SOX130 demonstrated encouraging efficacy with a favorable safety profile. The survival benefit of this regimen needs to be validated by conducting further follow-up of patients. Clinical trial information: 000017552.
Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).
Authors: Soria Jean-Charles , Strickler John H. , Govindan Ramaswamy , Chai Seungjean , Chan Nancy , Quiroga-Garcia Vanesa , Bahleda Rastislav , Hierro Cinta , Zhong Bob , Gonzalez Martha , Santiago-Walker Ademi E. , Parekh Trilok V. , Luo Feng Roger , Sullivan-Chang Loretta , Xie Hong , Tabernero Josep
Published: September 2018

4074

Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.
Pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-120 in patients with IDH1-mutant cholangiocarcinoma from a phase 1 study of advanced solid tumors.
Authors: Fan Bin , Goyal Lipika , Lowery Maeve Aine , Pandya Shuchi Sumant , Manyak Erika , Le Kha , Jiang Liewen , Auer Julia , Dai David
Published: September 2018

4082

Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) produce the oncometabolite D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class selective inhibitor of mutant IDH1 (mIDH1) under evaluation in an ongoing phase 1 study in patients with mIDH1 advanced solid tumors, including cholangiocarcinoma (CC) (NCT02073994). Objectives for this abstract were to 1) characterize the PK profile of AG-120 and the relationship between AG-120 exposure and 2-HG suppression, and 2) evaluate the influence of intrinsic patient factors on AG-120 clearance, in patients with mIDH1 CC. Methods: AG-120 was administered orally once daily (QD) or twice daily (BID) in continuous 28-day cycles. As of Dec 5, 2016, 60 of 73 patients enrolled with mIDH1 CC had PK/PD samples available for analysis at 100 mg BID, 300 mg QD, 400 mg QD, 500 mg QD, 800 mg QD, and 1200 mg QD in dose escalation (n = 24) and 500 mg QD (n = 36) in dose expansion. Blood (n = 60) and fresh tumor biopsy samples (n = 14) were collected to assess AG-120 and 2-HG using qualified liquid chromatography-tandem mass spectrometry methods. Results: Following both single and multiple doses, AG-120 plasma exposure increased less than dose proportionally from 100 to 1200 mg. Mean terminal half-life was 38.4–85.8 h, supporting a QD dosing regimen. Following multiple doses, steady state was reached within 15 days, with approximately 2-fold accumulation in plasma AG-120 exposure. No patient-specific factors were identified as clinically significant covariates affecting AG-120 plasma clearance. After multiple doses, plasma 2-HG levels were reduced (up to 98.4% inhibition, achieving levels similar to those in healthy volunteers) and tumor biopsy 2-HG levels were also substantially reduced (by up to 99.9%) at all dose levels tested. The 500 mg QD dose resulted in the largest magnitude of 2-HG inhibition vs. other dose levels. Conclusions: AG-120 demonstrated a long half-life in patients with mIDH1 CC and robustly inhibited 2-HG in plasma and tumor samples. These PK/PD data, along with emerging safety and clinical activity data, support the selection of 500 mg QD for future clinical investigation. Clinical trial information: NCT02073994.
Predictors of outcome in patients treated with peptide radio-labelled receptor target therapy (PRRT).
Authors: Mandair Dalvinder , Demetriou George , Diamantopoulos Leonidas-Nikolaos , Devakumar Haran , Popat Rickin , Laskaratos Faidon , Caplin Martyn E. , Toumpanakis Christos
Published: September 2018

4090

Background: The efficacy of peptide-radiolabelled receptor targeted therapy (PRRT) in patients with well differentiated neuroendocrine tumours has been demonstrated in Phase II and Phase III studies. The recently completed phase IV NETTER-01 demonstrated disease stabilisation or partial response in approximately 80% of patients. However, more studies are needed to identify predictors of PRRT response. We sought to investigate the clinic-pathological characteristics in patients that had radiological progression or death within 12 months of completion of treatment with PRRT. Methods: We performed a retrospective analysis of all patients who had PRRT from 2011-2016. Patient with at least one year of follow-up data from the last treatment dose were included. Patients with evidence of radiological progression within one year of finishing treatment (Group 1) were compared to a similar group with disease stabilisation/response (Group 2)that were matched for age, grade, primary and distribution of metastases. The indication for PRRT was defined as either small volume progression ( < 20%) or progression by RECIST. Results: 307 patients underwent PRRT with Lu-177 or Y-90 DOTATATE during this period. 66 patients in Group 1 were compared to 64 patients in Group 2. There was a significant difference in median overall survival, Group 1 = 21 months compared to Group 2 = 35 months, (p < 0.002). A significantly higher proportion of patients in group 1 had more than 50% liver volume (p < 0.0001). Mean CgA was significantly higher in Group 1, 1250 pg/ml vs 608 pg/ml in Group 2 ( p < 0.03). 18 patients in Group 2 had small volume progression prior to treatment commencement compared to 6 in Group 1 (p < 0.003). Conclusions: Radiological progression within 12 months of completion of PRRT is associated with a worse outcome in terms of OS. Patients with greater liver involvement and highest CgA levels are more likely to progress within 12 months of treatment completion. Earlier treatment with PRRT in patients with radiological progression not meeting RECIST criteria may need to be conisdered. There may be a greater survival benefit if PRRT is given prior to the development of large volume disease.
Comprehensive molecular characterization and analysis of muscle-invasive urothelial carcinomas.
Authors: Lerner Seth P. , Robertson Gordon , Kim Jaegil , Cherniack Andrew , Guo Guangwu , Akbani Rehan , Kanchi Rupa S , Hoadley Katherine A. , Hinoue Toshinori , Laird Peter W. , Al-Ahmadie Hikmat , Bellmunt Joaquim , Castro Mauro , Gordenin Dmitry , Mills Gordon B. , Sanchez-Vega Francisco , Shukla Sachet A , Gibb Ewan A , Weinstein John N. , Kwiatkowski David J. ,   TCGA Network
Published: September 2018

4500

Background: We reported the integrated molecular analysis of 131 tumors in 2014 (Nature 507:315, 2014) and now report on the entire cohort of 412 tumors from the TCGA project in chemotherapy-naïve, muscle-invasive urothelial bladder cancer. Methods: Following strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations (WES), DNA methylation, mRNA, non-coding RNA (lncRNA and miRNA) and (phospho-) protein expression, gene fusions, viral integration, pathway perturbation, clinical correlates, outcomes, and histopathology. Results: There was a high overall somatic mutation rate (8.2/Mb), as previously reported. There were 58 significantly mutated genes (SMGs) (MutSig_2CV), increased from 32 in the original report. We identified 5 mutation signatures including APOBEC-a and b, ERCC2, C > T_CpG, and a single ultra-mutated sample with a functional POLE mutation. APOBEC mutagenesis explained 70% of the mutation burden and was associated with survival (p = 0.0013). High mutation burden and neoantigen load were also associated with improved outcome (p = 0.00014 and 0.00078). The previously identified four mRNA subtypes were predicted on the larger set and also identified a novel poor-survival ‘neuronal’ subtype that nevertheless lacked small cell or neuroendocrine histology. Clustering converged for mRNA, lncRNA and miRNA expression, and for inferred activity of gene sets associated with regulator expression. We identified subsets with differential epithelial-mesenchymal transition scores, carcinoma-in-situ scores, and survival, with implications for distinct therapeutic potential. Conclusions: This integrated analysis of 412 TCGA patient samples validates and extends observations from the first 131 patients and significantly increases our power to detect additional low-frequency aberrations. The results provide unique insights into mechanisms of bladder cancer development, and identify novel subsets of MIBC that may benefit from differential treatment approaches.
Subclonal mutational heterogeneity and survival in cisplatin-resistant muscle-invasive bladder cancer.
Authors: Liu David , Abbosh Philip , Keliher Daniel , Reardon Brendan , Mouw Kent William , Taylor-Weiner Amaro , Mullane Stephanie Anne , Han Garam , Teo MinYuen , Kim Jaegil , Al-Ahmadie Hikmat , Iyer Gopa , Dulaimi Essel , Chen David , Hoffman-Censits Jean H. , Carter Scott L. , Bellmunt Joaquim , Plimack Elizabeth R. , Rosenberg Jonathan E. , Van Allen Eliezer Mendel
Published: September 2018

4512

Background: Biomarkers of survival and resistance in chemotherapy-resistant muscle-invasive bladder cancer (MIBC) are not well-characterized, but may inform management in this setting. Methods: Matched pre- and post-neoadjuvant cisplatin-based chemotherapy (NAC) tumor samples were obtained from 30 MIBC patients with gross residual disease (≥ pT2) at cystectomy, followed by whole exome sequencing of these “trios” (pre- and post-NAC tumor with matched germline samples). Phylogenetic analysis of matched tumor samples was performed to identify subclones, their associated mutations, and the corresponding enrichment in post-treatment tumors. Intratumoral heterogeneity was assessed by the proportion of mutations that were subclonal; the number of inferred subclones; and associated with overall survival using a Cox Proportional Hazards model. Results: Increased proportion of subclonal mutations in post-treatment tumors was associated with worse overall survival (HRR 1.86 [95% CI 1.12-3.06], p = 0.02), whereas pre-treatment proportion of subclonal mutations was only borderline statistically significant (HRR 1.48 [95% CI 0.99-2.20], p = 0.052). The total number of inferred tumor subclones in pre- or post-treatment tumor (or both) was associated with overall survival (HRR 1.60 [95% CI 1.05-2.43], p = 0.03), interpreted as a 60% increase in death rate per additional inferred subclone. While no single gene was statistically significantly enriched for new alterations in the post-chemotherapy resistant samples, we observed new post-treatment amplifications in cell-cycle genes ( E2F3, c-JUN), biallelic events in cell-cycle regulators ( FBXW7), and amplification of immune checkpoint genes ( PDL1/2). Conclusions: These results suggest that intratumoral heterogeneity (particularly post-therapy) predicts survival in a chemotherapy-resistant cohort. Further, alterations in cell cycle regulation may contribute to the mechanism of chemotherapy resistance. Finally, we observe evidence of immune checkpoint gene amplification post-treatment, suggesting that testing immune checkpoint blockade during NAC or, in high risk patients, following NAC may be warranted.
Phase II study of pazopanib in patients with von Hippel-Lindau disease.
Authors: Jonasch Eric , Gombos Dan S. , Waguespack Steven G. , Marcott Valerie , Liu Diane D , Weldon Justin Alexander , Bird Shelly , Robichaux Christine , Tannir Nizar M. , Woodson Ashley Henriksen , Fuller Greg , McCutcheon Ian E. , Matin Surena F.
Published: September 2018

4516

Background: Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited disorder. Affected individuals develop vascular neoplastic lesions in multiple sites including eye, brain, pancreas, adrenal and kidney. Standards of care include surveillance imaging and surgical intervention. We hypothesized that treatment of VHL related lesions with an antiangiogenic agent would result in shrinkage of all lesion types. We chose the multikinase inhibitor pazopanib to test this hypothesis. Methods: After obtaining IRB approval, patients with clinical features or genetic confirmation of VHL disease and with measurable lesions were treated with pazopanib 800mg PO daily for two 12-week cycles. Efficacy was determined by RECIST after two cycles. Patients had the option to continue therapy if considered in patient’s best interest. Continuous monitoring for any lesion progression and drug discontinuation due to toxicity during the whole period of the treatment was planned. Results: Patients were enrolled (N=32) and treated (N=31) between 1/2012 and 6/2016. Median age was 37 (range 19-67). 23 patients had genomically confirmed VHL disease; four had family and personal history but had not undergone genetic testing, and five patients had clinical features of VHL disease and negative genetic testing. A median of two cycles (range 1-12) of therapy was administered. Of 31 evaluable patients, 13 (42%) showed a response, 18 patients had stable disease and no patients had PD as best response. Responses were seen in renal (2 CR and 29 PR/59 total), pancreatic (9 PR/17 total) and CNS 2 PR/49 total) target lesions. The most common side effect was diarrhea (grades 1 and 2) experienced in 14 patients. Twelve patients dose reduced to 600 mg and 6 to 400 mg pazopanib PO daily. Eight patients discontinued therapy due to adverse events of whom 4 experienced transaminitis. One patient experienced a grade V CNS hemorrhage. Conclusions: This is the largest prospective VHL disease specific therapeutic study performed to date. Pazopanib resulted in significant and sustained disease control for the majority of VHL patients enrolled on the study, with an acceptable safety profile. This agent may be considered as an alternative to surgical intervention in patients with VHL disease. Clinical trial information: NCT01436227.