bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical usefulness of postoperative serum carcinoembryonic antigen in colorectal cancer patients with liver metastases.
Authors: Yoshino Koichiro , Osumi Hiroki , Shinozaki Eiji , Ito Hiromichi , Kamiimabeppu Daisaku , Ooki Akira , Wakatsuki Takeru , Shimozaki Keitaro , Nakayama Izuma , Ogura Mariko , Takahari Daisuke , Chin Keisho , Oba Atsushi , Ono Yoshihiro , Sato Takafumi , Inoue Yosuke , Takahashi Yu , Yamaguchi Kensei
Published: January 2022

178

Background: Colorectal cancer with liver metastases (CLM) has high post operative recurrence rates, and optimizing the perioperative treatment is imperative. Post operative carcinoembryonic antigen (CEA) can help detecting minimal residual disease in colon cancer after curative resection. Methods: The aim of this study was to identify the potential role of serum CEA after liver resection in patients with CLM. This study was conducted at the Cancer Institute Hospital, Japanese Foundation for Cancer Research from 2004 to 2018. Patients with CLM who underwent complete resection of primary tumors and liver metastases were enrolled in this study. We studied the associations between the perioperative CEA levels and characteristics of recurrence. Results: Recurrence was detected during the median follow-up time of 50.9 months in 343 (54.1%) of the total 633 patients analyzed. Patients with postoperative CEA (>5) group had a significantly higher recurrence rate (75.7% vs 50.0%, p < 0.01), with a shorter time until recurrence (4.4 months vs 36.9 months, p < 0.01) than those with a postoperative CEA level (≤5) group. In multivariate analysis, a postoperative CEA level >5 ng/ ml was an independent predictor, with the highest hazard ratio for both recurrence free survival (RFS) and overall survival (OS) (RFS: 2.77, 95% confidence interval [CI] 2.14–3.60, p <0.01, OS: 3.18, 95% CI 2.41–4.19, p <0.01). In addition, there was a significantly shorter RFS in the postoperative CEA level (>5) group who did not have normalized CEA levels after adjuvant chemotherapy compared to normalized CEA group (3.3 months vs 18.5 months, p = 0.008). Conclusions: The postoperative CEA and postadjuvant chemotherapy CEA level in the CEA level (>5) group after surgery may be a predictor of RFS and OS.
Medullary carcinoma of the colon: A comprehensive analysis of a large cancer database.
Authors: Jabbal Iktej Singh , Nagarajan Arun , Rivera Carlos , Yaghi Marita , Liang Hong , Nahleh Zeina A. , Bejarano Pablo , Berho Mariana , Wexner Steven
Published: January 2022

180

Background: Medullary carcinoma (MC) of the colon was described first in 1999 and is characterized by undifferentiated sheets of epithelial cells in a solid growth pattern with pushing borders and prominent lymphoplasmacytic infiltrates. It frequently shows microsatellite instability (MSI). However, the clinicopathological and survival outcomes between MC and the more common adenocarcinoma of the colon (AC) are not well defined in a large database. Therefore, we used a large national registry to explore the association of survival characteristics with sociodemographic, geographic, and disease variables in this cohort of patients. Methods: We sampled the National Cancer Database (NCDB) for colon cancer patients diagnosed with MC from 2004-2018. Multivariate cox regression models were used to compare hazard ratios for demographic, geographic, and disease characteristics. In addition, Kaplan-Meier survival plots were utilized to assess survival rate differences between MC and AC tumors located in the ascending, transverse, or descending colon. A p-value<0.05 was considered statistically significant. Results: Only 2,709 (0.29%) of the 922,667 patients with AC had MC. MC was seen in older patients than AC (76 vs. 69 years). MC was also more common in females than AC (72.5 vs. 49%). The most striking finding in our analysis was the predominance of poorly differentiated (63%) and undifferentiated (21.7%) pathologies in MC. This was in sharp contrast to AC, where 15.8% of patients were poorly differentiated, and only 2% were undifferentiated. Furthermore, undifferentiated and poorly differentiated MC tumors had a poor prognosis (HR 1.45, 95% CI 1.26-1.68, p<0.001 and HR 1.44, 95% CI 1.29-1.62, p<0.001 respectively) as compared to the other histological grades. Another notable finding in our analysis was the high prevalence of MSI in MC vs. AC (82.4% vs. 25.9%). Cecal MC (HR 1) had the worst prognosis of any colonic site. Left-sided MC tumors also had an inferior prognosis compared to AC (63.21 vs. 87.72 months), although not statistically significant (p=0.217). Conclusions: Colon cancer presenting as undifferentiated or poorly differentiated with associated MSI should raise the possibility of a medullary carcinoma diagnosis. However, given the rarity and difficulty in its pathological delineation, MC may remain underdiagnosed. In the modern treatment era, with the approval of immunotherapy for metastatic MSI colon cancer patients, survival and outcomes for metastatic MC may be improved.
A single-center comparative surveillance strategies of ctDNA (Signatera), imaging, and CEA in the surveillance of resected colorectal cancer.
Authors: Sandhu Jaideep Singh , Wang Chongkai , Chen Yi-Jen , Chevalier Dawnyel , Walia Sabrina , Kim Jae Y. , Melstrom Kurt , Kaiser Andreas M , Fakih Marwan
Published: January 2022

200

Background: Signatera (S) assay is a CLIA certified minimal residual disease ctDNA assay that has become widely used for monitoring of disease relapse in patients (pts) with resected colorectal cancer. In a longitudinal study, S+ recurrence (SR) occurred at median > 10 months (mo) prior to radiographic disease recurrence (RDR) in a prospective clinical trial. However, the radiographic surveillance frequency in that study was inadequate by US standard practices. Methods: We retrospectively evaluated, in a single center, the sensitivity (ss), specificity (sp), positive predictive value (ppv) and negative predictive value (npv) of S, CT/MRI imaging (Im), and CEA in curatively resected stage II, III, IV pts against True Disease Recurrence (TDR). We considered TDR as any SR, RDR confirmed by pathology, RDR associated with CEA elevation, or RDR with sequential growth on imaging or regression with chemo. S and CEA were performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs. Im was performed Q3 mo x 2 yrs and then Q6 mo x 3 yrs in resected stage IV, Q6 mo x 2 yrs and then Q yr x 3 in stage III/high-risk stage II, and Q yr x 5 yrs in low-risk stage II. Results: 48 pts underwent curative resection (31 stage II-III, 17 stage IV). 15 patients recurred during surveillance (6 stage II-III, 9 stage IV). The ss, sp, ppv, and npv of S, Im, CEA, and (Im and/or CEA) are tabulated below. S, Im, CEA, and Im or CEA were positive for recurrence at the diagnosis of TDR in 8, 9, 4, and 12, respectively. S sensitivity was poor for lung recurrence with 5/6 pts with lung-only mets (3 confirmed by path) being negative by S at the time of Im relapse. S was negative at the time of CNS recurrence and liver recurrence in 2 pts. 2 Pts with negative imaging at SR developed subsequent liver metastases. 2 Pts, counted as TDR, were SR and remain NED without any therapy, by CEA and Im > 1.5 years from S positivity. Conclusions: S does not appear to provide definitive advantages as a surveillance strategy over standard Im frequency- when performed as per NCCN guidelines. Sensitivity of S is particularly poor for low volume lung-only disease recurrence.[Table: see text]
A randomized controlled phase III trial comparing two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant treatment for locally advanced esophageal cancer, JCOG1109 NExT study.
Authors: Kato Ken , Ito Yoshinori , Daiko Hiroyuki , Ozawa Soji , Ogata Takashi , Hara Hiroki , Kojima Takashi , Abe Tetsuya , Bamba Takeo , Watanabe Masaya , Kawakubo Hirofumi , Shibuya Yuichi , Tsubosa Yasuhiro , Takegawa Naoki , Kajiwara Takeshi , Baba Hideo , Ueno Masaki , Machida Ryunosuke , Nakamura Kenichi , Kitagawa Yuko
Published: January 2022

238

Background: Neoadjuvant treatment is the standard care for locally advanced esophageal squamous cell cancer (ESCC). JCOG1109 (UMIN000009482) compared the doublet and triplet of chemotherapy and chemoradiotherapy as neoadjuvant treatment. Methods: Eligible patients (pts) with ESCC of clinical stage IB, II, III (excluding T4) (UICC 7th) from 44 institutions were randomized 1:1:1 to neoadjuvant CF (cisplatin 80 mg/m2 on day1 plus 5-FU 800 mg/m2 on days 1-5 Q3W/2course), DCF (docetaxel 70 mg/m2 on day 1, cisplatin 70 mg/m2 on day1, plus 5-FU 750 mg/m2 on days 1-5 Q3W/3 course), or CF-RT (cisplatin 75 mg/m2 on day 1 plus 5-FU 1000 mg/m2 on days 1-4 Q4W/2course, radiation 41.4 Gy/23 fr). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), %R0 resection, %objective response by neoadjuvant therapy, %pathological complete response (pCR) and safety. Differences in OS was assessed in the ITT using the stratified log-rank test. The data cutoff date for the analysis was July 20, 2021. Results: Of 601 pts 199 CF, 202 DCF, and 200 CF-RT were enrolled from December 5, 2012 to July 20, 2018, respectively. Among 601 pts, 88.2% were male, median (range) age was 65 (30-75), clinical stage III (nonT4) pts were 62.6%. Median follow-up time (range) was 4.2 years (y) (0-8.5). Median OS in CF, DCF, and CF-RT arm were 4.6 y, not reached (NR), and 6.0y, and 3-year OS was 62.6%, 72.1%, and 68.3%, respectively (stratified log-rank test: p = 0.006 for CF vs. DCF and p = 0.12 for CF vs. CF-RT). By stratified Cox regression analysis for OS, hazard ratios (HR) [95% CI] was 0.68 [0.50–0.92] for CF vs. DCF and 0.84 [0.63–1.12] for CF vs. CF-RT. Median PFS in CF, DCF, and CF-RT arm were 2.7 y, NR, and 5.3 y, and 3-year PFS was 47.7%, 61.8%, and 58.5%, respectively. R0 resection was achieved in 168 (84.4%), 173 (85.6%), and 175 (87.5%), and pCR was 4 (2.1%), 40 (19.8%), and 77 (38.5%), respectively. During neoadjuvant therapy, febrile neutropenia in CF, DCF, and CF-RT arm were 1.0%, 16.3% and 4.7%, and esophagitis (grade>3) were 1.0%, 1.0% and 8.9%, respectively. The treatment-related death was seen in 3 (1.5%), 4 (2.0%), and 2 (1.0%), in CF, DCF, and CF-RT arm, respectively. Conclusions: DCF significantly improved OS over CF as neoadjuvant therapy for locally advanced ESCC, with a manageable toxicity profile. DCF represents a new standard neoadjuvant treatment for ESCC. Clinical trial information: UMIN000009482.
Survival expressed in best-case, typical and worst-case scenarios for patients with nonmetastatic esophagogastric cancer: A population-based study.
Authors: Kuijper Steven , Pape Marieke , Vissers Pauline A.J. , Jeene Paul M. , Kouwenhoven Ewout , Haj Mohammad Nadia , Sosef Meindert , Verhoeven Rob , Van Laarhoven Hanneke W.M.
Published: January 2022

259

Background: In recent years new treatment options and the centralization of surgery have improved survival for patients with non-metastatic esophageal and gastric cancer. However, it is currently unknown which patients have mostly benefitted from these treatment advances. The aim of this study was to use population-based data to identify best-case, typical and worst-case scenarios in terms of survival time, and to assess if the survival of these scenarios have changed over time. Methods: Patients diagnosed between 2006-2019 with non-metastatic esophageal (including gastro-esophageal junction tumors) or gastric cancer were selected from the Netherlands Cancer Registry. Best-case, typical, and worst-case scenarios were calculated from the 20th (best-case scenario), 40th (upper-typical), 50th (median), 60th (lower-typical) and 80th (worst-case scenario) percentiles of the survival curves. Linear trend analysis was used to investigate the change in survival time for each scenario across diagnosis years. Results: We identified 23350 patients with non-metastatic esophageal cancer and 10150 patients with non-metastatic gastric cancer. Linear trend analyses across diagnosis years showed that for esophageal cancer patients, survival of all scenarios significantly increased over time: the best-case scenario increased from 55 to 112 months (p =.003); the upper typical increased from 18 to 33 months (p <.001); the median increased from 13 to 23 months (p <.001); the lower typical increased from 8 to 15 months (p <.001) and the worst-case scenario increased from 4 to 7 months (p <.001). For patients with gastric cancer, all scenarios also improved significantly: the best-case scenario increased from 73 to 99 months (p =.045); the upper-typical increased from 22 to 33 months (p <.001); the median increased from 14 to 18 months (p <.001); the lower-typical increased from 14 to 18 months (p <.001) and the worst-case scenario increased slightly from 2.9 months to 3.0 (p =.017). Conclusions: All patients with non-metastatic esophageal and gastric cancer have improved their survival over time.The largest survival advantage was among the best-case and upper-typical scenarios. Therefore, treatment advances over the last years have improved survival for all patients with non-metastatic esophagogastric cancer.
Update analysis: Clinical outcomes following regionalization of gastric cancer care in a U.S. integrated health care system.
Authors: Teh Swee H. , Li Robert , Lin Teresa , Shiraga Sharon , Li Yan , Gong I-Yeh , Sundaresan Tilak Kumar , Herrinton Lisa J.
Published: January 2022

265

Background: The role of laparoscopic gastrectomy and D2 lymphadenectomy is not yet fully defined in patients treated with modern perioperative chemotherapy. In 2016, Kaiser Permanente Northern California regionalized gastric cancer care, introducing a regional comprehensive multidisciplinary care team, standardizing staging and chemotherapy, and implementing laparoscopic gastrectomy and D2 lymphadenectomy for eligible patients with curative-intent surgery. We previously reported a retrospective cohort study comparing treatments and outcomes before and after regionalization, including 2-year overall survival. Here we present updated 3-year overall survival. Methods: As we described previously ( https://ascopubs.org/doi/full/10.1200/JCO.21.00480 ), the study included all 1429 patients with gastric cancer diagnosed during January 2010 to May 2018, of whom 942 were pre-regionalization, and 487 were post. Of the 1429, 650 had Stage I-III disease, and 394 patients underwent curative intent gastrectomy. 34.9% received neoadjuvant chemotherapy, and 18.4 % of patients received laparoscopic gastrectomy in the pre-regionalization period. In contrast, 66.2% received neoadjuvant chemotherapy, and 91.8% received laparoscopic gastrectomy with D 2 lymphadenectomy in the post regionalization period (p < 0.0001). Lymph node metastasis was noted in 50.7% and 45.1% pre- and post-regionalization periods, respectively (p = 0.29). Survival was analyzed using Kaplan-Meier analysis with entry on the diagnosis date, the outcome on the death date, and censoring on disenrollment or the end of the study. In this updated analysis, the end of the study was increased by one year to December 31, 2019. Results: The statistical analysis showed no difference in patients’ selection for surgery between the pre-and post-regionalization period and no change in the rate of surgical complications. At three years, overall survival among Stage I-III patients who received surgery was 66.0% in the pre-regionalization cohort and 83.0% in the post-regionalization cohort (p < 0.002), a more significant difference than was observed at two years. Conclusions: The utilization of laparoscopic surgery and radical D2 lymphadenectomy in the era of perioperative chemotherapy continues to demonstrate improved postoperative overall disease survival.[Table: see text]
First-line treatment with immune checkpoint inhibitors (ICI) for metastatic gastric and esophagogastric junction (EGJ) adenocarcinoma in Latin America: Sociedad Latinoamericana de Gastroenterología Oncológica (SLAGO) evidence-based recommendations.
Authors: Diaz Maria Celeste , Della Valle Adriana , Diaz Consuelo , Mendez Guillermo , O'Connor Juan Manuel , Garrido Marcelo , Montenegro Paola Catherine , Peixoto Renata D'Alpino , Gallardo Jorge
Published: January 2022

269

Background: Gastric and EGJ cancer in Latin America are associated with a high burden of disease and mortality. Treatment with combination chemotherapy (CT) is the current standard of care for metastatic disease, but with poor benefit. ICI appears as a new option in this setting improving survival and no local guidelines have been found addressing this issue. Methods: We carried out a comprehensive systematic review up to August 2021 and meta-analysis according to PRISMA guidelines and used the GRADE approach to summarize each question in evidence tables. Judgments regarding risk of bias, precision, consistency, directness, and likelihood of publication bias were made and categorized into 4 levels of evidence’s certainty ranging from very low to high. SLAGO formed a guideline panel composed of medical professionals from 6 countries in Latin America and prioritized 2 relevant questions. We provided de novo recommendations for the local setting using the Evidence-to-Decision (EtD) frameworks provided by GRADE to discuss benefits and harms, values and preferences, use of resources, feasibility, acceptability, and equity. Results: The panel agreed on 3 recommendations. For question 1, regarding the use of CT+ICI vs CT, the global certainty of evidence was rated as high. For question 2 (CT vs ICI), the global certainty of evidence was rated as low due to imprecision. The recommendation for question 1 was conditional for the use of CT+ICI among the population with CPS > 1 and strong among those with CPS > 5. For question 2, the recommendation was conditional against the treatment with ICI, regardless of CPS score. Concerns about the lack of economic evidence addressing the treatment's cost-effectiveness were identified. The panel highlighted the complexity of the Latin America health systems for the implementation of CT+ICI and its equity impact. Finally, some research priorities were highlighted (effectiveness in HER2+, CPS 1-4, or MSI-H tumours). Conclusions: The panel agreed on the net clinical benefit of CT+ICI for selected patients (CPS > 5). Nonetheless, cost-effectiveness data are still lacking, especially in Latin America.
Multicenter, randomized double-blind placebo-controlled trial of definitive concurrent chemoradiotherapy plus megestrol acetate/placebo in local-advanced esophageal cancer.
Authors: Jia Ruinuo , Li Wanying , Li Mian , Li Ruonan , Kong Dejiu , Li Shuoguo , Shan Tanyou , Gao Shegan
Published: January 2022

275

Background: To determine Quality-of-Life (QoL) improvement by Megestrol Acetate (MA) in local advanced esophageal squamous cell carcinoma (ESCC) with definitive concurrent chemoradiotherapy (DCRT). Secondary aims were to examine the safety and the impact of MA on the efficacy of DCRT. Methods: Patients (with previously untreated T1bN+M0 or T2-4aN0-2M0 ESCC) were randomly assigned at a one-to-one ratio to receive MA or placebo (blind). All received 5-FU based chemotherapy with concurrent radiotherapy (50Gy/25F). QoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaires at pretreatment and 3, 6, 16 weeks of DCRT. The good status (GS) rate of appetite loss (AL), nausea and vomiting (NV), weight (WT) and performance status (PS) were chosen as predefined primary end points. GS defined as the score were ≤ 0 for AL or NV and ≥ 0 for WE or PS when the designed time points compared with last one. Secondary end points were the comprehensive QoL (remaining items of QLQ-C30 changes analysis at 16th week), myelosuppression (MS), and deep vein thrombosis (DVT). The exploratory end points were the objective response rate (ORR), 1-year overall survival (OS) and progression-free survival (PFS). Results: 84 completed the follow-up and were analyzed from which 120 patients randomly assigned. The GS rates of AL (3th week: P = 0.011; 6th week: P < 0.001; 16th week: P = 0.001), NV (6th week: P = 0.001) and PS (6th week: P = 0.01) were higher in MA than Placebo. There were no statistical differences between MA and Placebo on WT. At 16th week, the change degree analysis shown the fatigue was worse in MA than Placebo ( p = 0.031). There were no differences on MS, DVT, ORR, OS and PFS between two arms. Nevertheless the rate of DVT was slightly higher in MA than Placebo (12.5% vs. 2.8%, P = 0.113). Conclusions: MA is helpful for ESCC patients receiving DCRT as well as the risk of DVT needed be careful.
Effectiveness of third- or later-line therapy in patients with HER2-positive advanced gastric cancer: Results from an observational retrospective study in Japan.
Authors: Omori Takeshi , Sakai Daisuke , Fumita Soichi , Fujita Junya , Kawabata Ryohei , Matsuyama Jin , Yasui Hisateru , Hirao Motohiro , Kawase Tomono , Kishi Kentaro , Taniguchi Hirokazu , Miyazaki Yasuhiro , Miura Tomoko , Miyake Akimitsu , Kurokawa Yukinori , Yamasaki Makoto , Yamada Tomomi , Satoh Taroh , Eguchi Hidetoshi , Doki Yuichiro
Published: January 2022

277

Background: The real-world effectiveness of third- or later-line (3L+) therapies in patients (pts) with HER2-positive gastric cancer remains unknown. We report a multicenter, retrospective, observational study at 20 centers in Japan to investigate the outcomes of 3L+ therapy in pts with HER2-positive advanced gastric/gastroesophageal junction (G/GEJ) cancer previously receiving trastuzumab (UMIN000040853). Methods: Pts aged ≥20 years with HER2-positive advanced G/GEJ cancer who were previously treated with trastuzumab and newly initiated on nivolumab, irinotecan, or trifluridine/tipiracil monotherapy as 3L+ therapy (Sep 2017 to Mar 2020) were evaluated for overall survival (OS), progression-free survival (PFS), duration of response (DOR), time to treatment failure (TTF), objective response rate (ORR), and disease control rate (DCR). An exploratory analysis for factors affecting OS was conducted using a multivariate Cox regression model, with HER2 status as a covariate. Results: The overall analysis population was 117 pts (median: age, 71 years; number of prior treatment lines, 2; days since the initiation of first-line treatment, 431 days). Median (95% confidence interval) OS, PFS, and TTF were 6.2 months (4.5–8.0), 1.9 months (1.5–2.3), and 1.8 months (1.5–2.2), respectively, at a median follow-up of 150 days. Outcomes by treatment groups are shown in the Table. ORR and DCR in 100 pts with evaluable target lesions were 9.0% and 32.0%, respectively, and median DOR was 8.4 months. A higher neutrophil-lymphocyte ratio (≥2.540), Glasgow prognostic score (≥1), ECOG PS (≥2), and hepatic metastasis significantly impacted OS. Conclusions: The real-world effectiveness of 3L+ therapies was limited in this study. New HER2 treatment agent is expected to improve outcomes in pts with HER2-positive G/GEJ cancer.[Table: see text]
Randomized, phase 3 study of second-line tislelizumab versus chemotherapy in advanced or metastatic esophageal squamous cell carcinoma, RATIONALE 302: Asia subgroup.
Authors: Zhao Kuaile , Kim Sung-Bae , Kato Ken , Hsu Chih-Hung , Hu Sheng , Wang Feng , Kojima Takashi , Kim Young Saing , Van Cutsem Eric , Ajani Jaffer A. , Li Liyun , Ding Ningning , Tao Aiyang , Shen Lin
Published: January 2022

279

Background: In the global Phase 3 study RATIONALE 302 (NCT03430843), tislelizumab (TIS) demonstrated statistically and clinically significant improvement in overall survival (OS) vs chemotherapy (chemo) (median OS 8.6 vs 6.3 months; HR 0.70, 95% CI 0.57–0.85; p=0.0001) in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Here, we report data from the Asia subgroup. Methods: Eligible patients who had disease progression after first-line systemic therapy were randomized 1:1 to receive TIS 200 mg intravenously once every three weeks or chemo (paclitaxel, docetaxel, or irinotecan) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS in all randomized patients (Intent-to-treat population). The key secondary endpoint was OS in patients with PD-L1 Tumor Area Positivity Score* ≥ 10%; other secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), health-related quality of life, and safety. Results: Of the 512 randomized patients, 404 (79%) were enrolled from China, Taiwan, Japan, and Korea and constituted the Asia subgroup (n=201 TIS, n=203 chemo). At data cut-off (December 1, 2020), median follow-up was 6.9 months in the Asia subgroup. Median OS was 8.5 months with TIS vs 6.3 months with chemo (HR 0.73; 95% CI 0.59, 0.90). Median PFS was 1.5 months with TIS vs 1.7 months with chemo (HR 0.81; 95% CI 0.64, 1.02). TIS resulted in a higher ORR (20.4% [95% CI 15.1, 26.6] vs 9.4% [95% CI 5.7, 14.2]) and longer median DoR (7.4 vs 4.0 months; HR 0.42, 95% CI 0.21, 0.84) vs chemo. In the safety analysis set (n=201 TIS, n=191 chemo), patients treated with TIS had fewer treatment-related adverse events (TRAEs) (74.1% vs 95.3%), fewer ≥ Grade 3 TRAEs (19.4% vs 57.1%), fewer serious TRAEs (15.4% vs 20.9%), and a similar incidence of TRAEs leading to death (2.5% vs 2.6%) vs chemo. Conclusions: In the Asia subgroup, TIS improved OS and tumor response vs chemo as second-line treatment in patients with advanced or metastatic ESCC and showed a well-tolerated safety profile. These findings were consistent with published results in the overall population. *The TAP score methodology has been previously referred to as visually-estimated combined positive score (vCPS) and was previously presented at the American Society of Clinical Oncology 2021, June 4–8, 2021, ESMO World Gastrointestinal Congress 2021, June 30–July 3, 2021, and The Chinese Society of Clinical Oncology 2021, September 25–29, 2021. Clinical trial information: NCT03430843.
A randomized phase II trial of preoperative chemotherapy of S-1/CDDP with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).
Authors: Tokunaga Masanori , Machida Nozomu , Mizusawa Junki , Yabusaki Hiroshi , Yasui Hirofumi , Hirao Motohiro , Watanabe Masaya , Yasuda Takushi , Kinoshita Takahiro , Imamura Hiroshi , Hihara Jun , Boku Narikazu , Kataoka Tomoko , Yoshikawa Takaki , Sano Takeshi , Sasako Mitsuru , Terashima Masanori
Published: January 2022

285

Background: The efficacy of trastuzumab has been established for HER2-positive advanced gastric cancer patients with metastatic disease. However, it remains unclear if the addition of trastuzumab to preoperative chemotherapy is effective for treatment of HER2-positive locally advanced gastric cancer. Methods: Eligible patients with HER2-positive gastric cancer with extensive lymph node metastasis were randomized to preoperative S-1/cisplatin (SP) (group A) or SP plus trastuzumab (group B). In both groups, patients received S-1, 80–120 mg/body, on days 1–14 and cisplatin, 60 mg/m2, on day 1, q21, 3-4 courses. Additionally, in group B, patients received infusions of trastuzumab (first course 8 mg/kg followed by 6 mg/kg, day 1). After gastrectomy, adjuvant chemotherapy with S-1 was performed for 1 year in both groups. The primary endpoint was overall survival, and the sample size was planned to be 130 patients in total, expecting a 10% increase in the 3-year overall survival (70% vs 80%) with a 1-sided alpha of 0.2, a power of 0.75. Results: The study was terminated in March 2021 due to slow patient accrual. In total, 46 patients were randomized to either group A (22 patients) or group B (24 patients). Patient characteristics were well balanced between the groups. Planned preoperative chemotherapy was completed in 20 patients (90.9%) in group A and in 23 patients (95.8%) in group B, and R0 resection was achieved in 20 patients (90.9%) in group A and 22 patients (91.7%) in group B. The incidences of grade 3 or 4 hematological/non-hematological adverse events during preoperative chemotherapy were 27.3/18.2% in group A and 4.2/8.3% in group B. Objective response rate (CR/PR) tended to be higher in group B (66.7% [16/24]) than in group A (36.4% [8/22], p = 0.08). Pathological response rate (> grade 1b in Japanese classification, 22.7% [5/22] vs. 50.0% [12/24], p = 0.07) and the proportion of patients achieving downstage to ypStage 0/I/II (22.7% [5/22] vs. 50.0% [12/24], p = 0.07) were also higher in group B than in group A. Conclusions: Preoperative chemotherapy with SP plus trastuzumab was feasible, and tended to show better radiological and pathological response rates. Better survival outcomes are expected by adding trastuzumab to preoperative chemotherapy with SP for locally advanced gastric cancer with extensive nodal metastasis. Clinical trial information: UMIN000016920.
FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E)—Short-term results for cohorts C and D.
Authors: Matsuda Satoru , Yamamoto Shun , Kato Ken , Daiko Hiroyuki , Kojima Takashi , Hara Hiroki , Abe Tetsuya , Tsubosa Yasuhiro , Kawakubo Hirofumi , Nagashima Kengo , Aoki Kazunori , Yachida Shinichi , Kitagawa Yuko
Published: January 2022

286

Background: The standard neoadjuvant chemotherapy (NAC) in Japan for locally advanced esophageal squamous cell carcinoma (ESCC) consists of CDDP + 5-FU (CF). Recently, neoadjuvant DTX plus CF (DCF) therapy has shown promising efficacy for locally advanced ESCC. In addition, immune checkpoint inhibitors (ICIs) have demonstrated a survival benefit in ESCC and potential as an NAC in several cancers, including lung, breast, skin, and bladder. We previously reported that neoadjuvant CF plus nivolumab (Nivo) therapy was tolerable and showed promising efficacy for ESCC; however, the efficacy of ICI with DCF as an NAC and the safety of subsequent surgery for ESCC patients remain unclear. Methods: FRONTiER is a multi-cohort phase I study designed to evaluate the safety and efficacy of ICI combined with NAC in ESCC. The eligibility criteria were histologically proven ESCC with cT1N1-3M0 or cT2-3N0-3M0 (8th-UICC TNM classification), patient age of 20-75 years, PS ≤1, and no prior cancer therapies. The primary endpoint was the incidence of dose-limiting toxicities (DLT) from the initial dose to the 30th postoperative day. This study contained 5 experimental cohorts: cohort C received 3 courses of DTX (70 mg/m2), CDDP (70 mg/m2), and Nivo (360 mg/body) on day 1 and 5-FU (750 mg/m2) on days 1–5 every three weeks. Cohort D received one administration of Nivo (240 mg/body) 2 weeks before chemotherapy followed by the same regimen as cohort C. Results: Twelve patients were enrolled in cohort C (n = 6) and D (n = 6) (median age [range]: 60 [31-74] years, PS 0/1: 11/1, clinical stage I/II/III/IVA: 2/2/7/1). Only one patient in cohort D developed DLT (grade 3 dyspnea and rash); no other DLT were seen. Grade ≥3 adverse events were neutropenia (n = 1), leukopenia (n = 7), anorexia (n = 3), hyponatremia (n = 2), febrile neutropenia (n = 1), nausea (n = 1), and lymphopenia (n = 1) during NAC, and lung infection (n = 2), peritoneal infection (n = 1), anemia (n = 1), lymph leakage (n = 1), vagal reflex (n = 1), dyspnea (n = 1), rash (n = 1), septic shock (n = 1), pleural effusion (n = 1), and pneumatosis intestinalis (n = 1) during the postoperative period. No treatment-related deaths were observed. All patients received 3 courses of NAC, and 11 patients (91.7%) achieved an R0 resection without treatment interruption. One patient (16.7%) in cohort C and 3 patients (50.0%) in cohort D achieved pathological complete responses. Conclusions: Neoadjuvant DCF + Nivo with/without prior Nivo administration followed by surgery for locally advanced ESCC was well tolerated and showed an extremely promising efficacy. Clinical trial information: NCT03914443.
A multicenter, open-label phase II trial of second-line apatinib plus irinotecan in patients with advanced gastric cancer.
Authors: Peng Jianjun , Li Yong , Xiao Jianjun , Liu Huaqiang
Published: January 2022

287

Background: The best choice of second-line chemotherapy regimen for patients with advanced gastric cancer is still debated. Anti-VEGF target therapy is proven to be effective both in second and third line settings. Apatinib, a highly selective VEGFR2 inhibitor, has been demonstrated to be efficacious and well-tolerated for third line of treatment in gastric cancer. The aim of this study is to evaluate the safety and efficacy of apatinib in combination with irinotecan in the second line treatment of advanced gastric cancer. Methods: With the expectation of improving PFS to 4.4m, this investigator-initiated, single arm, multi-center, registered phase II prospective study was designed to enroll 62 eligible patients diagnosed with advanced gastric cancer. Each participant was expected to receive chemotherapy plus apatinib (irinotecan 1800mg/m2, d1, Q2W; apatinib 500mg po qd). The severity of side effects was established according to Common Terminology Criteria for Adverse Events (CTCAE),Version 4.0. Efficacy assessed every three cycles (6 weeks) during the study. The primary endpoint was PFS. The secondary endpoint was OS, ORR, and DCR. The tumor response was determined according to RECIST 1.1 criteria. Results: Baseline characteristics (FAS population): From March 2019 to April 2021, 31 patients from 4 centers in Guangdong province were enrolled. Among them, 28 are eligible for analysis. There are 16 females and 15 males, median age 55 years old. Safety: 82.4% patients reported adverse events (AEs). The incidence of grade 3-4 AEs was 52.9%. Main 3-4 AEs were neutropenia (32.4%), leucopenia (17.6%), anorexia (8.8%), hypoalbuminaemia (8.8%), thrombocytopenia (5.9%), nausea (5.9%). Efficacy: By Aug 31th, 2021, 28 patients were evaluable for response and survival, 1 of them achieved complete response (CR), 10 of them achieved partial response (PR), 8 achieved stable disease (SD), and 9 experienced progression disease (PD). The ORR is 35.48%, the DCR is 61.29%. Median PFS is 4.40m, median OS is 6.64m. Conclusions: Adding apatinib to irinotecan chemotherapy as the second line treatment would be well tolerant in patients with advanced gastric cancer. This indicated the combination could be a potential treatment option for patients with advanced gastric cancer. Clinical trial information: ChiCTR1900021377.
Efficacy and toxicity of neoadjuvant immune checkpoint inhibitors in resectable gastric cancer: A meta-analysis and systematic review.
Authors: Li Song , Xu Qian , Dai Xin , Zhang Xue , Huang Miao , Huang Kai , Wang Jian , Chu Jiahui , Liu Lian
Published: January 2022

291

Background: Immune checkpoint inhibitors (ICI) have made significant breakthroughs in late-stage gastric cancer. It is an attractive issue whether ICIs also function in the neoadjuvant setting. Methods: A systematic review was performed using combined terms related to “stomach cancer”, “gastric cancer”, “gastroesophageal cancer”, “immune checkpoint inhibitor”, “PD-1”, “PD-L1” and “neoadjuvant” in PubMed and annual meeting of ASCO, ASCO GI, ESMO, and ESMO GI from 2019 to 2021. Complete pathological response (CPR) rates, major pathological response (MPR) rates, R0 resection rates, and side effects were pooled and analyzed. MPR was defined as ≤10% viable tumor cells and included CPR. Study outcomes were pooled using the function METAPHOR in the META package in R.3.6.1. The I2 and P statistics were used to evaluate heterogeneity among studies. Funnel plots were used for publication bias assessment. Results: A total of 13 phase I/II clinical trials, including 332 resectable gastric cancer (T2-4 or N+) patients with neoadjuvant ICI-containing treatments, were collected. The pooled rates of CPR, MPR, and R0 resection were 0.16 (95% credible intervals (CI), 0.12-0.22), 0.36 (95% CI, 0.24-0.51), and 0.97 (95% CI, 0.94-0.99), respectively. As a comparison, outcomes from 25 studies on neoadjuvant chemotherapy were also pooled, with rates of CPR 0.08 (95% CI, 0.06-0.11), MPR 0.22 (95% CI, 0.19-0.26), and R0 resection 0.84 (95% CI, 0.80-0.87). Besides, the overall grade 3 or higher toxicity rates were 0.24 (95% CI 0.03-0.54) vs. 0.28 (95% CI 0.13-0.47) in ICI-based treatment and chemotherapy groups. Stratified by treatment strategies, ICI alone showed the lowest efficacy (CPR 0.07, 95% CI 0.02-0.19 and MPR 0.16, 95% CI 0.03-0.29). Addition of chemotherapy to ICI promoted the CPR (0.15, 95% CI 0.10-0.22) and MPR (0.36, 95% CI 0.22-0.50). Further addition of radiotherapy displayed the highest CPR (0.35, 95% CI 0.21-0.52) and MPR (0.74, 95% CI 0.54-0.93). Only four trials reported the outcomes of dMMR/MSI-H patients, with superior CPR (0.39, 95% CI 0.20-0.62) and MPR (0.82, 95% CI 0.82-1.00), while those of pMMR/MSS patients were 0.05 (95% CI 0.00-0.13) and 0.20 (95% CI 0.20-0.31) respectively, among which 2 trials used ICI only. Conclusions: Neoadjuvant ICI plus chemotherapy/radiotherapy, instead of ICI alone, has better pathological responses and R0 resection rates than chemotherapy. dMMR/MSI-H is a superior biomarker for neoadjuvant ICI therapy for resectable gastric cancer. The value or biomarker of immunotherapy in pMMR/MSS patients remains exploring.[Table: see text]
Trastuzumab combined with irinotecan in patients with HER2-positive metastatic colorectal cancer: A phase II multicenter single-arm study and exploratory biomarker analysis.
Authors: Xu Ting , Wang Xicheng , Xin Ying , Wang Zhenghang , Wang Yakun , Qi Changsong , Liu Dan , Li Yanyan , Gong Jifang , Li Jian , Huang Depei , Shen Lin
Published: January 2022

301

Background: HER2 overexpression has proven to be an effective treatment target in several malignancies. Trastuzumab plus chemotherapy showed favorable clinical efficacy and safety in HER2-positive gastric cancer and breast cancers. In this study, we aimed to evaluate the antitumor activity of trastuzumab plus irinotecan in pretreated patients with HER2-postive unresectable metastatic CRC and explore biomarkers for response and resistance to this treatment. Methods: mCRC patients with confirmed HER2 positivity (defined as IHC3+ or IHC2+/FISH+ on archival tissue) and wild-type RAS gene that progressed after ≥ 1 prior systemic treatment were enrolled in this phase II clinical trial. Patients received trastuzumab (6mg/kg q3w) plus irinotecan (120mg/m2, d1,8 q3w) for the first six cycles and trastuzumab (6mg/kg q3w) as maintenance treatment sequentially. Primary end point is objective response rate (ORR) and secondary endpoints are progression-free survival (PFS) and safety. Pretreatment tumor tissue, plasma at baseline and after disease progression were collected and analysed using a customized NGS panel covering 733 cancer-related genes in a CAP/CLIA-approved laboratory (3DMed). Results: Between June 2019 and December 2020, 21 HER2 positive patients were enrolled, with median age 55(30-67). At data cutoff (August 1, 2021), six (28.6%) of 21 patients achieved a partial response, and 12 (57.1%) patients had stable disease. The median progression-free survival was 4.3 months (95% CI, 2.65 to 5.95 months). Treatment-related adverse events of grade 3 or 4 occurred in 9.5% of patients, with the most common being neutropenia. No treatment-related death was reported. HER2 3+ expression and higher tumor tissue HER2 copy number were associated with durable response (p for PFS = 0.09 and 0.019, respectively). Two patients with KRAS amplification and one patient with BRAF amplification and fusion mutation at baseline all experienced primary resistance. In the after-progression plasma samples, heterogeneous and complicated genomic alterations potentially contribute to the acquired resistance were observed, with RAS/MAPK pathway (n = 4), cyclin/CDK-RB-E2F pathway (n = 4), PI3K/AKT/mTOR pathway (n = 3), and HER2 gene (n = 1) involved. Intriguingly, except for the SNV, copy number variation and gene fusion may represent an important resistance mechanism of HER2 targeted therapy. Conclusions: Trastuzumab plus irinotecan showed promising efficacy and well tolerated safety profile in HER2-positive mCRC. This combination therapy might present a feasible option for patients with HER2-positive unresectable metastatic colorectal adenocarcinoma. ctDNA sequencing provides novel insights into genomic alteration underlying HER2 targeted therapy in HER2-positive mCRC. Clinical trial information: NCT03185988.
Efficacy of prophylactic pegfilgrastim on day three of preoperative DCF chemotherapy in elderly patients with resectable esophageal cancer.
Authors: Ikeda Go , Ohara Akihiro , Itoyama Mai , Azuma Ikuko , Yamamoto Shun , Honma Yoshitaka , Oguma Junya , Ishiyama Koshiro , Daiko Hiroyuki , Kato Ken
Published: January 2022

305

Background: Preoperative neoadjuvant chemotherapy with cisplatin plus 5-FU (CF) is the standard treatment for resectable esophageal cancer (EC). Docetaxel plus CF (DCF) is also a promising preoperative treatment; however, a high frequency (5%-30%) of febrile neutropenia (FN) has been reported in patients (pts) receiving DCF, and elderly pts reportedly have a high risk of FN. The use of primary prophylactic pegfilgrastim (PG) on day 3 of DCF in resectable EC pts might prevent FN. We conducted a retrospective review to assess the efficacy of primary prophylactic PG administration on day 3 of preoperative DCF in elderly pts with resectable EC. Methods: EC pts who had received preoperative DCF between 2009 and 2021, were ≥70 years old, and had adequate organ functions and an adequate PS were eligible for this retrospective study. Pts were assigned to receive either PG-containing DCF (day3 prophylactic PG: D3PG) or standard DCF (non-prophylactic PG: NPG). Three courses of DCF (DTX [day 1]: 70 mg/m2, CDDP [day 1]: 70 mg/m2, 5-FU [continuous infusion on days 1-5]: 750 mg/m2, every 3 weeks) were planned, and antibiotic prophylaxis was mandatory on days 5-15 in each group. In the D3PG group, PG was administered subcutaneously on day 3. We retrospectively evaluated the relative dose intensity (RDI), histopathological efficacy, and adverse events (CTCAE ver5.0). Results: A total of 52 pts (D3PG, 17; NPG, 35) with a median age of 72 years were identified. The PS (0/1/2) and clinical stage (I/II/III/IVB [only supraclavicular lymph node]) were 10 (58.8%)/5 (29.1%)/2 (11.8%) and 0/1 (5.9%)/10 (58.8%)/6 (35.4%) in the D3PG group and 20 (57.1%)/15 (42.9%)/0 and 2 (5.7%)/5 (14.3%)/24 (68.6%)/4 (11.4%) in the NPG group, respectively. Three pts discontinued treatment because of toxicity (FN and nausea in D3PG and FN and diarrhea in NPG) and progression in each group, and all the pts underwent surgery. The RDIs (DTX/CDDP/5-FU) were 0.870/0.862/0.871 in the D3PG group and 0.833/0.829/0.830 in the NPG group. Five (29.4%) pts in the D3PG group and 10 (28.6%) in the NPG achieved a pCR. The common grade ≥3 adverse events (D3PG/NPG) were leukopenia (17.6%/51.4%), neutropenia (11.8%/71.4%) and FN (5.9%/20.0%). Conclusions: The use of primary prophylactic PG on day 3 of preoperative DCF improved the treatment safety treatment in elderly pts with resectable EC. No significant differences in treatment efficacy were seen between the D3PG and NPG groups despite the higher number of pts with a worse general condition or more advanced disease in the D3PG group than in the NPG group.
Safety and efficacy of intraperitoneal paclitaxel plus systemic FOLFOX for gastric cancer with peritoneal metastasis: Phase I results.
Authors: Kang So Hyun , Min Sa-Hong , Kim Jin Won , Lee Eunju , Lee Sangjun , Oh Hyeon Jeong , Park Young Suk , Lee Yoon Jin , Kim Ji-Won , Ahn Sang-Hoon , Suh Yun-Suhk , Lee Keun-Wook , Lee Hye Seung , Kim Hyung-Ho
Published: January 2022

309

Background: Peritoneal metastasis (PM) still remains a major obstacle in the treatment of stage IV gastric cancer. This study was designed as a dose-escalation study of intraperitoneal (IP) paclitaxel combined with intravenous (IV) fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to determine the recommended phase II dose in gastric cancer patients. Methods: Patients with gastric adenocarcinoma with PM were enrolled. Peritoneal cancer index (PCI) score was evaluated, and IP + IV chemoport insertion was done. The initial dose of IP paclitaxel was 40mg/m2, then stepped up to 60 then 80mg/m2. Target dose was 100mg/m2. IV FOLFOX was administered on the same day (oxaliplatin 100mg/m2, leucovorin 100mg/m2, fluorouracil 2400mg/m2). Dose limiting toxicity (DLT) was defined as leukopenia ≥ grade 4, thrombocytopenia ≥ grade 3, febrile neutropenia ≥ grade 3, and other nonhematologic toxicity ≥ grade 3. Results: Fifteen patients were enrolled, and two patients were dropped due to patient consent withdrawal. There was no DLT at 40 and 60mg/m2 doses. Two patients had grade 3 febrile neutropenia at dose 80mg/m2, and thus the final recommended phase II dose was 60mg/m2. Other patients underwent IP paclitaxel and FOLFOX without serious adverse events. Seven patients underwent second-look diagnostic laparoscopy, and the average change in PCI score was -5.6 ± 9.3. Four patients received gastrectomy, and the ascites conversion rate was 4/5 (80%). Median survival time was 16.6 months (95% CI, 7.2 – N/A). Conclusions: The biweekly regimen of IP paclitaxel and FOLFOX is safe and the recommended dose for a phase II trial is 60mg/m2. Clinical trial information: NCT03618758.
A prospective clinical trial of camrelizumab in combination with chemoradiotherapy in patients with metastatic esophageal squamous cell carcinoma.
Authors: Chen Yongshun , Zhao Wensi , Zuo Zhigang , Ke Shaobo , Shi Wei , Li Bin , Qiu Hu , Wang Jing , Gong Yi , CAI Xiaojun
Published: January 2022

326

Background: Patients with metastatic esophageal squamous cell carcinoma (mESCC) have dismal prognosis, immune checkpoint inhibitors (ICIs) have been reported to offer objective response rate (ORR) of approximately 30% with a median progression-free survival (PFS) of 3.6 months for mESCC. Emerging evidence suggests that radiation might be a potent immunomodulator in multiple malignancies. In this trial, we aimed to assess the efficacy and safety of the combination of camrelizumab with radiotherapy and chemotherapy in mESCC. Methods: Patients with ECOG performance status of 0-1 and normal renal, liver and bone marrow function who initially diagnosed with mESCC or progressed after prior systemic treatments were received camrelizumab 200 mg of 21-day cycles plus radiotherapy (30-50Gy/10-25f) and platinum-based combination chemotherapy. The primary endpoint was disease control rate (DCR); secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) and safety. Chinese Clinical Trial Registry identifier: ChiCTR2000040533. Results: From September 2018 to March 2021, 34 patients (85.3% men; median age, 60 years; 85.3% ECOG PS=1; 61.8% ≥2 organ metastases) were recruited. At a median follow-up of 14.3 months, the DCR was 70.6% (24 of 34; 95%CI, 52.3 to 84.3); ORR was 38.2% (13 of 34; 95%CI, 22.7 to 56.4); 44.1% had decrease in measurable disease; ≥6 months clinical benefit rate (CBR) was 41.2% (14 of 34; 95%CI, 25.1 to 59.2). Median PFS and OS of 9.5 months (95% CI, 7.1 to NR) and 19.5 months (95% CI, 13.9 to NR), respectively. Of the 34 patients, 32 (94.1%) had treatment-related adverse events (TRAEs) of any grade and 13 (38.3%) had grade 3-4 TRAEs that including reactive cutaneous capillary endothelial proliferation (17.6%), myelotoxicity (23.5%) and interstitial pneumonia (2.9%). No treatment-related death occurred. To the cut-off date of observation, 15 (44.1%) patients died and 12 (35.3%) are still receiving the treatment without events. Conclusions: The combination of camrelizumab with radiotherapy and chemotherapy has notable efficacy compared with historical controls in mESCC with manageable safety. This combination therapy strategy should be validated in a larger trial in the future. Variable N=34 Clinical trial information: ChiCTR2000040533. [Table: see text]