Phase I/II study of a combination of capecitabine, cisplatin, and intraperitoneal docetaxel (XP ID) in advanced gastric cancer patients with peritoneal metastasis

Cho, Hyungwoo; Ryu, Min‐Hee; Kim, Kyu-Pyo; Ryoo, Baek‐Yeol; Park, Sook Ryun; Kim, Bum Soo; Kim, Beom Su; Kim, Hee‐Sung; Yoo, Moon‐Won; Yook, Jeong Hwan; Oh, Seung Won; Kim, Byung Sik; Kang, Yoon‐Koo

doi:10.1007/s10120-017-0710-0

Cited by 18 publications

(28 citation statements)

References 23 publications

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“…Peritoneal metastasis (PM) is the most common mode of metastasis in gastric cancer and a critical indicator of poor prognosis [ 2 – 4 ]. Although various approaches to the treatment of PM have been assessed, including systemic and/or intraperitoneal chemotherapy [ 5 – 8 ], hyperthermic intraperitoneal chemotherapy (HIPEC) [ 9 , 10 ], and aggressive surgery (peritonectomy) [ 11 , 12 ], satisfactory outcomes have not been achieved. PM is characterized by rapid infiltration and proliferation of cancer cells accompanied by extensive stromal fibrosis, causing potentially fatal disorders such as bowel obstruction, hydronephrosis, and jaundice [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

et al. 2020

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Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. Methods Immuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry. Results The number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P < 0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P < 0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P < 0.05, P < 0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression. Conclusions This model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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Section: Introductionmentioning

confidence: 99%

Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

et al. 2020

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“…assessed, including systemic and/or intraperitoneal chemotherapy [5][6][7][8], hyperthermic intraperitoneal chemotherapy (HIPEC) [9, 10], and aggressive surgery (peritonectomy) [11,12], satisfactory outcomes have not been achieved. PM is characterized by rapid in ltration and proliferation of cancer cells accompanied by extensive stromal brosis, causing potentially fatal disorders such as bowel obstruction, hydronephrosis, and jaundice [13].…”

Section: Discussionmentioning

confidence: 99%

Established fibrous peritoneal metastasis in an immunocompetent mouse model accurately reflects the real clinical immune microenvironment of gastric cancer

Fujimori

Koyama

Yamaguchi

et al. 2020

Preprint

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Background Peritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients. MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with a-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P<0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P=0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P<0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P=0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P<0.05, P<0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.ConclusionsThis model is the first immunocompetent mouse model to accurately reflect the TME of human clinical PM. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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“…Therefore, the optimal dose should be tested for agents used in IP chemotherapy. In determining the recommended dose (RD) of IP docetaxel, Cho et al [59] tried IP docetaxel at 3 different dose levels (100, 80, or 60 mg/m 2 ). As a result, they found that the RD of intraperitoneal docetaxel (100 mg/m 2 ) was effective with manageable toxicities in the treatment of GC patients with PM.…”

Section: Conversion Therapy Of Gastric Cancer Patients With Peritoneamentioning

confidence: 99%

“…And researchers considered that the frequent grade 3/4 abdominal pain was due to bowel irritation caused by IP chemotherapy [60]. However, it was treatable by dose reduction and the therapy of analgesics in majority of the patients, and none of them discontinued treatment due to bellyache [59].…”

Section: Conversion Therapy Of Gastric Cancer Patients With Peritoneamentioning

confidence: 99%

Issues on peritoneal metastasis of gastric cancer: an update

et al. 2019

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BackgroundPeritoneal metastasis (PM) is one of the most common forms of metastasis with a very poor prognosis in patients with gastric cancer (GC). The mechanisms, diagnosis, and management of PM remain controversial.Main bodyStephen Paget’s “seed-and-soil” hypothesis gives us an illustration of the mechanisms of PM. Recently, hematogenous metastasis and exosomes from GC are identified as novel mechanisms for PM. Diagnostic accuracy of conventional imaging modalities for PM is not satisfactory, but texture analysis may be a useful adjunct for the prediction of PM. Biological markers in peritoneal washings are helpful in identifying patients at high risk of PM, but many limitations remain to be overcome. Response of PM from systemic chemotherapy alone is very limited. However, conversion therapy is confirmed to be safe and able to prolong the survival of GC patients with PM. As an important part of conversion therapy, intraperitoneal chemotherapy with taxanes has become an ideal approach with several advantages. Additionally, gastrectomy should be considered in patients who would tolerate surgery if a remarkable response to chemotherapy was observed.ConclusionTexture analysis is a reliable adjunct for the prediction of PM, and conversion therapy provides a new choice for GC patients with PM. The underlying mechanisms and new biological markers for GC patients with PM should be the direction of future studies. Furthermore, significant aspects of conversion therapy, such as timing and method of the operation, and the indications remain to be clarified.

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Phase I/II study of a combination of capecitabine, cisplatin, and intraperitoneal docetaxel (XP ID) in advanced gastric cancer patients with peritoneal metastasis

Abstract: Our study indicated that XP ID was effective, with manageable toxicities, in AGC patients with peritoneal metastasis. As the cumulative incidence of abdominal pain was probably related to bowel irritation by ID, it might be necessary to modify the dose.

Cited by 18 publications

References 23 publications

Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

Established fibrous peritoneal metastasis in an immunocompetent mouse model accurately reflects the real clinical immune microenvironment of gastric cancer

Issues on peritoneal metastasis of gastric cancer: an update

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