Short-term outcomes of preoperative chemotherapy with docetaxel, oxaliplatin, and S-1 for gastric cancer with extensive lymph node metastasis (JCOG1704).

BACKGROUND: The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial. METHODS: Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m2, day 1), oxaliplatin (100 mg/m2, day 1), and S-1 (80-120 mg/body, days 1-14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria. RESULTS: Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.

Early endpoints of a randomized phase II trial of preoperative chemotherapy with S-1/CDDP with or without trastuzumab followed by surgery for HER2-positive resectable gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger Study).

BACKGROUND: This randomized phase II study explored the superiority of trastuzumab plus S-1 plus cisplatin (SP) over SP alone as neoadjuvant chemotherapy (NAC) for HER2-positive resectable gastric cancer with extensive lymph node metastasis. METHODS: Eligible patients with HER2-positive gastric or esophagogastric junction cancer and extensive lymph node metastasis were randomized to receive three or four courses of preoperative chemotherapy with SP (arm A) or SP plus trastuzumab (arm B). Following gastrectomy, adjuvant chemotherapy with S-1 was administered for 1 year in both arms. The primary endpoint was overall survival, and the sample size was 130 patients in total. The trial is registered with the Japan Registry of Clinical Trials, jRCTs031180006. RESULTS: This report elucidates the early endpoints, including pathological findings and safety. The study was terminated early due to slow patient accruals. In total, 46 patients were allocated to arm A (n = 22) and arm B (n = 24). NAC was completed in 20 patients (91%) in arm A and 23 patients (96%) in arm B, with similar incidences of grade 3-4 hematological and non-hematological adverse events. Objective response rates were 50% in arm A and 84% in arm B (p = 0·065). %R0 resection rates were 91% and 92%, and pathological response rates (≥ grade 1b in Japanese classification) were 23% and 50% (p = 0·072) in resected patients, respectively. CONCLUSIONS: Trastuzumab can be safely added to platinum-containing doublet chemotherapy as NAC, and it has the potential to contribute to higher antitumor activity against locally advanced, HER2-positive gastric or esophagogastric junction cancer with extensive nodal metastasis.

5-year follow-up results of a JCOG1104 (OPAS-1) phase III non-inferiority trial to compare 4 courses and 8 courses of S-1 adjuvant chemotherapy for pathological stage II gastric cancer.

BACKGROUND: Postoperative adjuvant chemotherapy with S-1 for 1 year (corresponding to eight courses) is the standard treatment for pathological stage II gastric cancer. The phase III trial (JCOG1104) investigating the non-inferiority of four courses of S-1 to eight courses was terminated due to futility at the first interim analysis. To confirm the primary results, we reported the results after a 5-years follow-up in JCOG1104. METHODS: Patients histologically diagnosed with stage II gastric cancer after radical gastrectomy were randomly assigned to receive S-1 for eight or four courses. In detail, 80 mg/m2/day S-1 was administered for 4 weeks followed by a 2-week rest as a single course. RESULTS: Between February 16, 2012, and March 19, 2017, 590 patients were enrolled and randomly assigned to 8-course (295 patients) and 4-course (295 patients) regimens. After a 5-years follow-up, the relapse-free survival at 3 years was 92.2% for the 8-course arm and 90.1% for the 4-course arm, and that at 5 years was 87.7% for the 8-course arm and 85.6% for the 4-course arm (hazard ratio 1.265, 95% CI 0.846-1.892). The overall survival at 3 years was 94.9% for the 8-course arm, 93.2% for the 4-course arm, and that at 5 years was 89.7% for the 8-course arm, and 88.6% for the 4-course arm (HR 1.121, 95% CI 0.719-1.749). CONCLUSIONS: The survival of the four-course arm was slightly but consistently inferior to that of the eight-course arm. Eight-course S-1 should thus remain the standard adjuvant chemotherapy for pathological stage II gastric cancer.

Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial.

BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.

Protocol digest of a randomized controlled adaptive Phase II/III trial of neoadjuvant chemotherapy for Japanese patients with oesophagogastric junction adenocarcinoma: Japan Clinical Oncology Group Study JCOG2203 (NEO-JPEG).

Treatment strategies for oesophagogastric junction adenocarcinoma have not been standardized despite its poor prognosis due to differences in the incidence rates between Western countries and Asia. This randomized Phase II/III trial was initiated in June 2023 to determine which neoadjuvant chemotherapy regimen, docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel, is a more promising treatment in Phase II and confirm the superiority of neoadjuvant chemotherapy with docetaxel, oxaliplatin and S-1 or fluorouracil, oxaliplatin and docetaxel followed by surgery and postoperative chemotherapy over upfront surgery and postoperative chemotherapy in terms of overall survival in patients with Clinical Stage III or IVA oesophagogastric junction adenocarcinoma in Phase III. A total of 460 patients, including 150 patients in Phase II and 310 patients in Phase III, are planned to be enrolled from 85 hospitals in Japan over 5 years. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031230182 (https://jrct.niph.go.jp/latest-detail/jRCTs031230182).

Clinical impact of skeletal muscle mass change during the neoadjuvant chemotherapy period in patients with gastric cancer: An ancillary study of JCOG1002.

BACKGROUND: Recent studies have revealed that sarcopenia is associated with postoperative complications and poor prognosis. Although neoadjuvant chemotherapy is a promising treatment for gastric cancer, its toxicity may lead to the loss of skeletal muscle mass. This study investigates the changes in skeletal muscle mass during neoadjuvant chemotherapy and its clinical impact on patients with locally advanced gastric cancer. METHODS: Fifty patients who completed two courses of neoadjuvant chemotherapy followed by surgery were included. Skeletal muscle mass was measured using computed tomography images before and after chemotherapy. The proportion of skeletal muscle mass change (%SMC) during neoadjuvant chemotherapy and its cutoff value was explored using the receiver operating characteristic for the overall survival of patients undergoing R0 resection. Risk factors of skeletal muscle mass loss were also evaluated. RESULTS: Overall, 64% of patients had skeletal muscle mass loss during neoadjuvant chemotherapy (median %SMC -3.4%; range: -18.9% to 10.3%). Multivariable analysis identified older age (≥70 years) as an independent predictor of skeletal muscle mass loss (mean [95% confidence interval]: -4.70% [-8.83 to -0.58], p = 0.026). Among 43 patients undergoing R0 resection, %SMC <-6.9% was an independent poor prognostic factor for overall survival (hazard ratio, 11.53; 95% confidence interval, 2.78-47.80) and relapse-free survival (hazard ratio 4.54, 95% confidence interval 1.50-13.81). CONCLUSIONS: Skeletal muscle mass loss occurs frequently during neoadjuvant chemotherapy for locally advanced gastric cancer and could adversely affect survival outcomes.

2023 Japan Society of clinical oncology clinical practice guidelines update for antiemesis.

BACKGROUND: The Japan Society of Clinical Oncology Clinical Practice Guidelines for Antiemesis 2023 was extensively revised to reflect the latest advances in antineoplastic agents, antiemetics, and antineoplastic regimens. This update provides new evidence on the efficacy of antiemetic regimens. METHODS: Guided by the Minds Clinical Practice Guideline Development Manual of 2017, a rigorous approach was used to update the guidelines; a thorough literature search was conducted from January 1, 1990, to December 31, 2020. RESULTS: Comprehensive process resulted in the creation of 13 background questions (BQs), 12 clinical questions (CQs), and three future research questions (FQs). Moreover, the emetic risk classification was also updated. CONCLUSIONS: The primary goal of the present guidelines is to provide comprehensive information and facilitate informed decision-making, regarding antiemetic therapy, for both patients and healthcare providers.

Non-pharmacological treatments for anticipatory nausea and vomiting during chemotherapy: a systematic review and meta-analysis of the Clinical Practice Guidelines for Antiemesis 2023.

BACKGROUND: Anticipatory chemotherapy-induced nausea and vomiting (CINV) is a conditioned response influenced by the severity and duration of previous emetic responses to chemotherapy. We aimed to evaluate the efficacy of non-pharmacologic interventions for anticipatory CINV among patients with cancer. METHODS: We conducted a systematic search in databases, including PubMed, the Cochrane Library, CINAHL, and Ichushi-Web, from January 1, 1990, to December 31, 2020. Randomized controlled trials, non-randomized designs, observational studies, or case-control studies that utilized non-pharmacological therapies were included. The primary outcomes were anticipatory CINV, with an additional investigation into adverse events and the costs of therapies. The risk-of-bias for each study was assessed using the Cochrane risk-of-bias tool, and meta-analysis was performed using Revman 5.4 software. RESULTS: Of the 107 studies identified, six met the inclusion criteria. Three types of non-pharmacological treatments were identified: systematic desensitization (n = 2), hypnotherapy (n = 2), and yoga therapy (n = 2). Among them, systematic desensitization significantly improved anticipatory CINV as compared to that in the control group (nausea: risk ratio [RR] = 0.60, 95% confidence interval [CI] = 0.49-0.72, p < 0.00001; vomiting: RR = 0.54, 95% CI = 0.32-0.91, p = 0.02). However, heterogeneity in outcome measures precluded meta-analysis for hypnotherapy and yoga. Additionally, most selected studies had a high or unclear risk of bias, and adverse events were not consistently reported. CONCLUSIONS: Our findings suggest that systematic desensitization may effectively reduce anticipatory CINV. However, further research is warranted before implementation in clinical settings.

Long-term outcomes after non-curative endoscopic resection for esophageal squamous cell carcinoma followed by additional chemoradiotherapy.

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is evaluated pathologically, and additional treatment is recommended for cases resulting in non-curative resection, defined as pMM with lymphovascular invasion (LVI), pSM, or positive vertical margin. This study aimed to assess long-term outcomes and risk factors for recurrence in patients with ESCC treated with non-curative ER followed by additional chemoradiotherapy (CRT). We retrospectively reviewed the clinical courses of patients who underwent non-curative ER followed by additional CRT for ESCCs between August 2007 and December 2017. Recurrence rates and risk factors for recurrence were analyzed. Among 97 patients with non-curative ER, 73 underwent additional CRT. With a median follow-up period of 71 months, recurrences were observed in 10 (14%) of 73 patients, with a median interval of 24.5 (1-59 months). The 3- and 5-year recurrence-free survival were 89 and 85%, respectively, and the 3- and 5-year overall survival rates were 96 and 91%, respectively. Multivariate analysis showed that lymphatic invasion was an independent risk factor for recurrence in patients with non-curative ESCC receiving additional CRT. Among the 10 patients with recurrence, 4, 3, 2, and 1 underwent surgery, chemotherapy, supportive care, and CRT, respectively. Notably, all four patients who underwent surgery survived, regardless of regional and/or distant lymph node metastasis. Lymphatic invasion is an independent risk factor for the recurrence of non-curative ESCCs. Careful follow-up is required for at least 5 years after ER with additional CRT.

Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. METHODS: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. DISCUSSION: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. TRIAL REGISTRATION: jRCTs041220120.

Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.

BACKGROUND: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking. METHODS: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer. DISCUSSION: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer. TRIAL REGISTRATION: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.

Prognostic Factors of Bone Metastases From Colorectal Cancer in the Era of Targeted Therapy.

BACKGROUND: Various prognostic factors have been reported for bone metastases from different primary tumor sites. However, bone metastases from colorectal cancer are very rare, and the prognostic factors have not been investigated in detail. OBJECTIVE: This study aimed to identify prognostic factors of bone metastases from colorectal cancer. DESIGN: This is a retrospective cohort study using data from a prospectively collected database. SETTINGS: This study was conducted at a single tertiary care cancer center in Japan. PATIENTS: Patients who developed bone metastases from colorectal cancer during the study period among all patients who received initial treatment for colorectal cancer at our hospital between 2005 and 2016 (n = 4538) were included. MAIN OUTCOME MEASURES: Overall survival after diagnosis of bone metastases from colorectal cancer was the main outcome measure. RESULTS: Ninety-four patients developed bone metastases during the study period. The 5-year overall survival rate was 11.0%. Multivariable analysis identified the following independent risk factors associated with poor prognosis: ≥70 years of age at diagnosis of bone metastases (HR, 2.48; 95% CI, 1.24-4.95; p < 0.01), curative surgery not performed as initial treatment (HR, 2.54; 95% CI, 1.24-5.19; p = 0.01), multiple bone metastases (HR, 2.44; 95% CI, 1.30-4.57; p < 0.01), albumin level <3.7 g/dL (HR, 3.80; 95% CI, 1.95-7.39; p < 0.01), CEA ≥30 ng/mL (HR, 1.94; 95% CI, 1.09-3.46; p = 0.02), and less than 3 chemotherapy options remaining at diagnosis of bone metastases (HR, 2.83; 95% CI, 1.51-5.30; p < 0.01). The median survival times for patients with 0-2, 3, and 4-6 risk factors were 25.0, 8.8, and 4.3 months, respectively. LIMITATIONS: The main limitation is the single-center, retrospective design of this study. CONCLUSIONS: Our results may facilitate multidisciplinary decision-making in patients with bone metastases from colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B930 . FACTORES PRONSTICOS DE LAS METSTASIS SEAS DEL CNCER COLORRECTAL EN LA ERA DE LA TERAPIA DIRIGIDA: ANTECEDENTES:Se han reportado varios factores pronósticos para las metástasis óseas de diferentes sitios de tumores primarios. Sin embargo, las metástasis óseas del cáncer colorrectal son muy raras y los factores pronósticos no se han investigado en detalle.OBJETIVO:Identificar los factores pronósticos de las metástasis óseas del cáncer colorrectal.DISEÑO:Estudio de cohorte retrospectivo utilizando datos de una base de datos recolectada prospectivamente.ENTORNO CLINICO:Un solo centro oncológico de atención terciaria en Japón.PACIENTES:Se seleccionaron pacientes que desarrollaron metástasis óseas de cáncer colorrectal durante el período de estudio entre todos los pacientes que recibieron tratamiento inicial para el cáncer colorrectal en nuestro hospital entre 2005 y 2016 (n = 4538).MEDIDA DE RESULTADO PRINCIPAL:Supervivencia general después del diagnóstico de metástasis óseas por cáncer colorrectal.RESULTADOS:Noventa y cuatro pacientes desarrollaron metástasis óseas, lo que representa el 2,0% de todos los pacientes con cáncer colorrectal que comenzaron el tratamiento durante el período de estudio. La tasa de supervivencia global a 5 años fue del 11,0 %. El análisis multivariable identificó los siguientes factores de riesgo independientes asociados con mal pronóstico: edad ≥70 años al momento del diagnóstico de metástasis óseas (hazard ratio 2,48, CI del 95 % 1,24-4,95, p < 0,01), cirugía curativa no realizada como tratamiento inicial (hazard ratio 2,54, CI 95 % 1,24-5,19, p = 0,01), metástasis óseas múltiples (hazard ratio 2,44, CI del 95 % 1,30-4,57, p < 0,01), nivel de albúmina <3,7 g/dL (hazard ratio 3,80, CI del 95 % 1,95 -7,39, p < 0,01), antígeno carcinoembrionario ≥30 ng/mL (hazard ratio 1,94, CI del 95 % 1,09-3,46, p = 0,02) y menos de 3 opciones de quimioterapia restantes al momento del diagnóstico de metástasis óseas (hazard ratio 2,83, 95 % CI 1,51-5,30, p < 0,01). La mediana de los tiempos de supervivencia para los pacientes con 0-2, 3 y 4-6 factores de riesgo fue de 25,0, 8,8 y 4,3 meses, respectivamente.LIMITACIONES:Diseño retrospectivo de un solo centro.CONCLUSIÓN:Nuestros resultados pueden facilitar la toma de decisiones multidisciplinares en pacientes con metástasis óseas de cáncer colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B930 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Evaluation of clinical effects of a multidisciplinary-collaborated cancer support team for gastrointestinal cancer chemotherapy: prospective observational study protocol of M-CAST study.

BACKGROUND: Although the multidisciplinary-collaborated team approach in cancer treatment has recently become popular, prospectively evaluated evidence is limited. We started a multidisciplinary-collaborated cancer support team (MCST) to facilitate cooperation across multidisciplinary medical staff in our hospital and established clinical evidence of supportive care. This study aimed to prospectively evaluate the clinical activity and effect of MCST in patients with gastrointestinal cancer receiving chemotherapy. METHODS: This is a single-center, single-arm, observational study. Patients with gastrointestinal cancer scheduled to receive chemotherapy are enrolled and supported by the MCST. The primary endpoints are the number of interventions by medical staff and the number of patients who showed improvement in side effects. The secondary endpoints are the severity of side effects, medical expenses, number of consultations, the acceptance rate of prescription recommendations, adjuvant chemotherapy completion rates, dose intensity, and time required for co-medical intervention. In addition, medical staff and attending physicians evaluate all adverse events. DISCUSSION: This study is expected to contribute to establishing new cancer-supportive care teams for patients with gastrointestinal cancer receiving chemotherapy and those with cancer receiving chemotherapy. TRIAL REGISTRATION: This trial was registered in the Japan Registry of Clinical Trials (jRCT) as jRCT1030220495. The date of first registration, 29/11/2022, https://jrct.niph.go.jp/search.

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Perioperative TAS-118 plus oxaliplatin in patients with locally advanced gastric cancer: APOLLO-11 study.

BACKGROUND: We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. METHODS: Patients with clinical T3-4N1-3M0 gastric cancer received four courses of TAS-118 (40-60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). RESULTS: Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0-95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7-99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6-99.5) for Step 1 and 80.0% (95% CI 59.9-92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9-78.4) and 84.4% (95% CI 70.1-92.3), respectively. CONCLUSIONS: Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.

Evaluating the efficacy of post-operative chemotherapy after curative resection of stage IV gastric cancer with synchronous oligo metastasis: a multicenter retrospective study.

BACKGROUND: Surgical resection of oligo-metastasis in gastric cancer (GC) is weakly recommended for patients without other incurable factors in the Japanese GC Treatment Guidelines. While post-operative chemotherapy is the standard treatment in patients with stage II or III GC, its efficacy for resected stage IV GC is unclear. This study aimed to evaluate the efficacy of post-operative chemotherapy after curative resection of GC with oligo-metastasis. METHODS: We retrospectively reviewed the medical records of patients with GC who were diagnosed with synchronous oligo-metastasis at 20 institutions in Japan between 2007 and 2012. The selection criteria were: adenocarcinoma, stage IV with oligo-metastasis at liver or lymph node without other distant metastasis, curative resection including synchronous oligo-metastasis, and no prior treatment of GC before surgery. RESULTS: A total of 110 patients were collected. Of the 94 eligible patients, 84 underwent gastrectomy with surgical resection of oligo-metastasis (39 [41%] liver metastasis and 55, [59%] distant lymph node metastasis), followed by post-operative chemotherapy with S-1 (S1: n = 55), S1 plus cisplatin (CS: n = 22), or Others (n = 7). Moreover, 10 patients did not receive post-operative chemotherapy (Non-Cx). The median overall survival (OS) was 35.2 and 11.1 months in the post-operative chemotherapy and Non-Cx groups (hazard ratio, 3.56; 95% confidence interval, 1.74-7.30; p < 0.001), respectively. In multivariable analysis, Non-Cx and age over 70 years were identified as poor prognostic factors for OS (p < 0.05). CONCLUSIONS: Curative resection followed by post-operative chemotherapy in patients with GC with synchronous oligo-metastasis showed favorable survival.

Randomized phase II study comparing neoadjuvant 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for patients with type 4 or large type 3 gastric cancer.

Macroscopic type 4 and large type 3 gastric cancer, mostly overlapping with scirrhous or linitis plastica type, exhibit a highly invasive nature and show unfavorable prognosis after curative surgery, even with adjuvant chemotherapy. A randomized phase III trial (JCOG0501) failed to demonstrate a survival advantage of neoadjuvant chemotherapy with S-1 plus cisplatin for this population. The current authors initiated a randomized phase II study comparing neoadjuvant chemotherapy with 5-fluorouracil/oxaliplatin/docetaxel versus docetaxel/oxaliplatin/S-1 for type 4 and large type 3 gastric cancer. 76 patients are planned to be enrolled over two years. The primary end point is the proportion of patients with a pathological response (grade 1b or higher) and secondary end points include overall survival and adverse events. Clinical Trial Registration: jRCTs031230231 (rctportal.niph.go.jp).

Late complication after gastrectomy for clinical stage I cancer: supplementary analysis of JCOG0912.

BACKGROUND: Late complications following gastric cancer surgery, including postgastrectomy syndromes, are complex problems requiring a solution. Reported risk factors for developing late complications include surgery-related factors, such as the surgical approach and the extent of resection and reconstruction. However, this has not been assessed in a prospective study with a large sample size. Therefore, this study aimed to evaluate associations between surgery-related factors and the development of late complications. Data from the JCOG0912 trial were used. It compared laparoscopy-assisted distal gastrectomy (LADG) to open distal gastrectomy (ODG) in clinical stage I gastric cancer patients. METHODS: This study included 881/921 patients enrolled in the JCOG0912 trial. The incidence of late complications was compared between the ODG and the LADG arms. In addition, associations between surgery-related factors and the development of late complications were assessed by multivariable analyses using the proportional odds model to identify relevant risk factors. RESULTS: There was no difference in the type or number of patients with late complications between the LADG and the ODG arms. The multivariable analysis for each late complication revealed that the Billroth-I reconstruction (vs. R-en-Y or Billroth-II) had a lower risk of cholecystitis [odds ratio (OR) 0.187, 95% confidence interval (CI) 0.039-0.905, P = 0.037] or ileus (OR 0.116, 95%CI 0.033-0.406, P < 0.001), and pylorus-preserving gastrectomy (vs. R-en-Y or Billroth-II) had a higher risk of reflux esophagitis (OR 3.348, 95% CI 1.371-8.176, P = 0.008). The surgical approach was not a risk factor for any late complications. CONCLUSION: Differences in surgical approaches did not constitute a risk for developing late complications after gastrectomy. Billroth-I reconstruction reduced the risk of ileus and cholecystitis, but pylorus-preserving gastrectomy carried a risk for reflux esophagitis.

Prognostic factors associated with the transition in treatment methods for brain metastases from colorectal cancer.

BACKGROUND: Treatment of brain metastases (BMs) from colorectal cancer (CRC) has transitioned with the expansion of indications for stereotactic radiotherapy. Our study aimed to assess changes in prognosis and prognostic factors associated with changes in treatment for BMs from CRC. METHODS: We retrospectively surveyed treatments for and outcomes of BMs from CRC in 208 patients treated during 1997-2018. Patients were divided into two groups according to time of BM diagnosis, i.e., 1997-2013 ("first period") and 2014-2018 ("second period"). We compared overall survival between the periods and assessed how the transition impacted prognostic factors affecting overall survival, including the following prognostic factors such as Karnofsky performance status (KPS), volume-related factors (BM number and diameter), and BM treatment modalities as covariates. RESULTS: Of the 208 patients, 147 were treated in the first period and 61 in the second period. Whole-brain radiotherapy use decreased from 67 to 39% in the second period, and stereotactic radiotherapy use increased from 30 to 62%. Median survival after BM diagnosis improved from 6.1 to 8.5 months (p = 0.0272). Multivariate analysis revealed KPS, control of primary tumor, stereotactic radiotherapy use, and chemotherapy history as independent prognostic factors during the entire observation period. Hazard ratios of KPS, primary tumor control, and stereotactic radiotherapy were higher in the second period, whereas prognostic impact of chemotherapy history before BM diagnosis was similar in both periods. CONCLUSION: Overall survival of patients with BMs from CRC improved since 2014, which can be attributed to advances in chemotherapy and the more widespread use of stereotactic radiotherapy.

Clinical factors associated with noncurative endoscopic submucosal dissection for the expanded indication of intestinal-type early gastric cancer: Post hoc analysis of a multi-institutional, single-arm, confirmatory trial (JCOG0607).

OBJECTIVES: The multi-institutional, single-arm, confirmatory trial JCOG0607 showed excellent efficacy of endoscopic submucosal dissection (ESD) for the expanded indication of intramucosal intestinal-type early gastric cancer (EGC), which consists of two groups: lesions >2 cm if clinical finding of ulcer (cUL)-negative, or those ≤3 cm if cUL-positive because of the expected low risk of lymph node metastasis. However, the proportion of noncurative resections (NCR) requiring additional surgery was high (32.4%). This post hoc analysis aimed to explore the clinical factors associated with NCR. METHODS: As the expanded indication includes two different groups, we explored the clinical factors associated with NCR separately in cUL-negative (>2 cm) and cUL-positive (≤3 cm) groups using the log-linear model. RESULTS: Two hundred and sixty cUL-negative and 206 cUL-positive EGCs were analyzed. The proportions of NCR were 33.8% in the cUL-negative group and 29.6% in the cUL-positive group. A multivariable analysis demonstrated that moderately differentiated predominant histology diagnosed in pretreatment biopsy (risk ratio [RR] 1.93, 95% confidence interval [CI] 1.34-2.77, P < 0.001) and lesion in the upper stomach (RR 1.75, 95% CI 1.03-2.96, P = 0.038) in the cUL-negative EGCs, and tumor size >2 cm (RR 1.78, 95% CI 1.22-2.58, P = 0.003) and female sex (RR 1.62, 95% CI 1.07-2.44, P = 0.021) in the cUL-positive EGCs were independent factors associated with NCR. CONCLUSIONS: Clinical risk factors associated with NCR were different between cUL-negative and cUL-positive EGCs. To avoid NCR, we need to take these factors into account when deciding expanded indications for ESD.