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[Ç׾Ͽä¹ýÀ» ÇÏÁö ¾Ê´Â Àǻ縦 À§ÇÑ À§¾ÏÇ×¾ÏÄ¡·á. Chemotherapy for gastric cancer] - ðû

2024-9-27 KINGCA. ¶ó¼±¿µ ±³¼ö´Ô °­ÀÇ Áß¿¡¼­

0. Introduction

1. Neoadjuvant chemotherapy

2. Adjuvant chemotherapy º¸Á¶ Ç׾Ͽä¹ý

3. Palliative systemic therapy °í½ÄÀû Ç׾Ͽä¹ý

4. HER2-positive gastric cancer

5. Immunotherapy ¸é¿ªÄ¡·á

6. Ramucirumab (VEGFR2 inhibitor)

7. Claudin 18.2

8. IP chemotherapy

9. Conversion surgery Àüȯ ¼ö¼ú

10. Symposiums

11. FAQs

12. References

2022 KGCA guideline Ç×¾ÏÄ¡·á statements


0. Introduction

À§¾Ï Ç×¾ÏÄ¡·á´Â flow »ó 5´Ü°è·Î »ý°¢ÇÏ°í ÀÖ½À´Ï´Ù.

Steps of systemic therapy
  • Neoadjuvant chemotherapy   
  • Adjuvant chemotherapy
  • First-line palliative
  • Second-line palliative
  • Third-line palliative


1. Neoadjuvant chemotherapy (NACT)

Rationale for neoadjuvant chemotherapy
Biologic rationaleMonitoring
Downstage and downsize
More R0 resection
Advantage of treating an untouched neoplasia with intact vessels and without fibrotic remodeling of the tumor bed following surgery
Targets micrometastases
Adjuvant treatment has no chance to demonstrate its efficacy on an individual basis (no indicating lesions)
The efficacy of NACT can be assed during its administration
NACT can be adjusted according to patient response

¼­¾ç¿¡¼­´Â ´ëºÎºÐÀÇ À§¾Ï ȯÀÚ°¡ ¼ö¼ú Àü Ç×¾ÏÄ¡·á(neoadjuvant chemotherapy)¸¦ ¹Þ°í ÀÖ½À´Ï´Ù. ±×·¯³ª µ¿¾ç¿¡¼­´Â ¼ö¼ú Àü Ç×¾ÏÄ¡·á¸¦ ¹Þ´Â À§¾Ï ȯÀÚ´Â °ÅÀÇ Ã£¾Æº¸±â ¾î·Æ½À´Ï´Ù. ÀϺ»ÀÇ JCOG0501 trial¿¡¼­ negative result°¡ ³ª¿Â °ÍÀÌ ¿µÇâÀ» ¹ÌÄ£ °ÍÀ¸·Î »ý°¢µË´Ï´Ù.

ÃÖ±Ù ¿ì¸®³ª¶óÀÇ PRODIGY ¿¬±¸(JCO 2021, û³âÀÇ»ç 2023)¿Í Áß±¹ÀÇ RESOLVE ¿¬±¸(Lancet Oncol 2021)°¡ ¹ßÇ¥µÇ¾î 2022 KGCA °¡À̵å¶óÀο¡ ¾ð±ÞµÇ¾úÁö¸¸ ¾ÆÁ÷ ÀÓ»ó¿¡ ³Î¸® µµÀÔµÇÁö ¸øÇß½À´Ï´Ù. ±×·¯³ª ÀÌ¹Ì 2022 KGCA °¡À̵å¶óÀο¡ ¾ð±ÞµÇ¾ú°í º¸Çèµµ µË´Ï´Ù. ÀÓ»óÀÇ»çÀÇ ÆÇ´Ü¿¡ µû¶ó ¿ì¸®³ª¶ó¿¡¼­µµ NACT¸¦ »ç¿ëÇÒ ¼ö Àִ ȯ°æÀº ¸¶·ÃµÇ¾ú½À´Ï´Ù.

PRODIGY. JCO 2021 3³â progression free survivalÀÌ 66% ´ë 60%·Î ÀǹÌÀÖ´Â Â÷À̸¦ º¸¿´½À´Ï´Ù. 71.4%°¡ Á¤ÇØÁø Ç×¾ÏÄ¡·á¸¦ ¸¶Ä¥ ¼ö À־ tolerable ÇÑ ÆíÀ̾úÁö¸¸, 2¸íÀÌ neoadjuvant chemotherapy °ü·Ã »ç¸ÁÀ» º¸¿´½À´Ï´Ù. ºñ·Ï »ç¸ÁÀÚ´Â ¸Å¿ì Àû¾úÁö¸¸ potentially curable disease¿¡ ´ëÇÑ Ä¡·á¿¡¼­ ¼ö¼ú Àü »ç¸ÁÀÚ°¡ ÀÖ´Ù´Â °ÍÀº ´Ã °ÆÁ¤ÀÔ´Ï´Ù. Stage 1 ȯÀÚ°¡ Æ÷ÇԵǸé NACT°¡ overtreatmentÀÎ ¼ÀÀÌ°í, NACT ÈÄ ¼ö¼ú ½Ã peritoneal seedingÀÎ °ÍÀ¸·Î ³ª¿À¸é °ï¶õÇÑ Á¡ÀÌ ÀÖÀ¸¹Ç·Î stagingÀÌ ¸Å¿ì Áß¿äÇÕ´Ï´Ù. PRODIGY ¿¬±¸ÀÇ Àå±â ÃßÀû°üÂû ½Ã 5³âºÎÅÍ 10³â »çÀÌ survival benefitÀ» º¸¿´´Ù°í ÇÕ´Ï´Ù.

PRODIGY ¿¬±¸ PI ¾Æ»êº´¿ø Á¾¾ç³»°ú ±èÇüµ· ±³¼ö´Ô °­ÀÇ. 2022-8-26. AMC symposium

2022³â KGCA °¡À̵å¶óÀο¡ ÀϺΠȯÀÚ¿¡¼­ NACT¸¦ »ç¿ëÇÒ ¼ö ÀÖ´Â °ÍÀ¸·Î ÃßõµÇ¾ú½À´Ï´Ù. Statement 28: Neoadjuvant chemotherapy as part of perioperative chemotherapy can be considered for patients with resectable locally advanced gastric cancer. ¾ÆÁ÷Àº ºñ±Þ¿©ÀÔ´Ï´Ù. NACT ÈÄ ¼ö¼ú¿¡¼­ stage°¡ 1À¸·Î ³ª¿À¸é Ç×¾ÏÄ¡·á°¡ º¸Çè ±Þ¿©°¡ µÇ´ÂÁö ºÒ¸íÈ®ÇÏÁö¸¸ ¼ö¼ú Àü stage¸¦ Á¸ÁßÇÏ¿© adjuvant chemotherapy°¡ °¡´ÉÇÒ °Í °°½À´Ï´Ù.

2022 KGCA guideline

Neoadjuvant themotherapy + alpha: 2022³â Áß±¹¿¡¼­ FLOT¿¡ durvalumabÀ» ´õÇÑ regimenÀ» »ç¿ëÇÑ Matterhorn ¿¬±¸¸¦ ¹ßÇ¥ÇÏ¿´½À´Ï´Ù (Matterhorn ¿¬±¸). HER2, claudin18.2, FGFR2 µî¿¡ ´ëÇÑ ¾àÁ¦´Â ¾ÆÁ÷ °í·Á ÁßÀÎ °Í °°½À´Ï´Ù.

* Lecture ´Ù½Ã º¸±â: Past, present, and future of neoadjuvant chemotherapy in Korea ·ù¹ÎÈñ. 2024 KGCA symposium - memo 1, 2. ÇöÀçÀÇ unanswered questionÀº (1) patient selection (cStage T4?), (2) adjuvant chemotherapy (stage°¡ ³ôÀ¸¸é S1º¸´Ù XELOX), (3) chemo+alpha¶ó°í ¿ä¾àÇϼ̽À´Ï´Ù.


[Radiologic evaluation before and after Neoadjuvant chemotherapy (NACT)] 2024-3-23 KGCA ½ÉÆ÷Áö¾ö. ±¹¸³¾Ï¼¾ÅÍ ±è¼öÁø ±³¼ö´Ô. ´Ù½Ã º¸±â

Exclusion of peritoneal seeding: Ascites, irregular peritoneal thickening, soft tissue stranding in intra-abdominal fat, Soft tissue nodule/plaque: most reliable, , omental cake

Unexpedted, intraoperative proven peritoneal seeding: >cT3, T4, Borrmann type 3 or 4, >5.2-8cm, GC/AW, LNE, Praque, ascites

RECIST v 1.1Àº irregular shaped GI tract tumor¿¡¼­´Â Àû´çÇÏÁö ¾Ê½À´Ï´Ù. ycTNM restagingÀº Ç×¾ÏÄ¡·á Àü staging¿¡ ºñÇÏ¿© Àü¹ÝÀûÀ¸·Î ¼ºÀûÀÌ ³·½À´Ï´Ù. CT or MR volumetry°¡ ´õ À¯¿ëÇÕ´Ï´Ù. À̸¦ À§ÇÏ¿© protocolÀÌ ÅëÀϵǾî ÀÖ¾î¾ß ÇÕ´Ï´Ù.


[Biomarkers for NACT in gastric cancer] 2024-3-23 KGCA ½ÉÆ÷Áö¾ö. °¡Å縯ÀÇ´ë À̼ºÇÐ ±³¼ö´Ô. ´Ù½Ã º¸±â

TRG (tumor regression grade): tumor bed¿¡¼­ ³²¾ÆÀÖ´Â residual tumorÀÇ ºñÀ²À» ÃøÁ¤ÇÏ´Â ¹æ¹ý°ú residual tumor¿Í fibrosis¸¦ °í·ÁÇÑ ¹æ¹ýÀÌ ÀÖ½À´Ï´Ù.

Çѱ¹ º´¸®ÇÐȸ¿¡¼­ Á¦½ÃÇÑ ¹æ¹ýÀÌ ÀÖ½À´Ï´Ù. (JTPM 2023) It is a descriptive fourtier system that evaluates residual cancer rather than fibrosis as none, single cells or rare small groups, more than single cells but evident tumor response, and extensive residual cancer cells.

¿©·¯ TRG¸¦ ºñ±³ÇÏ¸é ¾Æ·¡ Ç¥¿Í °°½À´Ï´Ù. ¹«Ã´ Çò°¥¸³´Ï´Ù.


[Surgical approach after NACT] 2024-3-23 KGCA ½ÉÆ÷Áö¾ö. ¿¬¼¼´ëÇб³ ±èÇüÀÏ ±³¼ö´Ô. ´Ù½Ã º¸±â

NACT ÈÄ ¼ö¼ú¿¡¼­ ÇÕº´ÁõÀÌ Áõ°¡ÇÏÁö ¾Ê´Â´Ù´Â °ÍÀ» º¸¿©ÁØ ±èÇüÀÏ ±³¼ö´ÔÀÇ ÀλóÀûÀÎ ½½¶óÀ̵å. µü 3°³ ³í¹® »©°í ³ª¸ÓÁö´Â ¸ðµÎ Â÷ÀÌ°¡ ¾ø¾ú´Ù°í ÇÕ´Ï´Ù.


2. Adjuvant chemotherapy. º¸Á¶Ç׾Ͽä¹ý

Indication: stage 2 or more (stage 1Àº ÇØ´çÇÏÁö ¾ÊÀ½)

ÀϹÝÀûÀΠǥÁØ Ä¡·á: XELOX - Oral pyrimidine-based doublet regimens can be a more favorable treatment option than S-1 alone for pathological stage II with positive LN or stage III gastric cancer.

À§¾Ï ¼ö¼ú ÈÄ º¸Á¶Ç׾Ͽä¹ý. È«Á¤¿ë ±³¼ö´Ô.

ACTS-GC (Sakuramuto NEJM 2007)¿Í CLASSIC (XELOX regimen: capecitabine + oxaliplatin) (Bang Lancet 2012)ÀÇ ºñ±³ - KBDCA À̱ٿí/¾È»óÈÆ webinar

CLASSIC ¿¬±¸ 5³â °á°ú(Noh Lancet Oncol 2014)¿¡¼­ AJCC 6ÆÇ º´±âº° º¸Á¶Ç×¾ÏÄ¡·áÀÇ È¿°ú - KBDCA À̱ٿí/¾È»óÈÆ webinar

2022 KGCA guideline Statement 23

2022 KGCA guideline Statement 23 Forest flot

AJCC stagingÀÌ ¹Ù²î¸é¼­ º´±â°¡ ´Þ¶óÁø ÀϺΠȯÀÚ¿¡¼­ º¸Á¶Ç׾Ͽä¹ýÀÇ ±Ù°Å°¡ ¸íÈ®ÇÏÁö ¾ÊÀº ȯÀÚ±ºÀÌ »ý°å½À´Ï´Ù. º´±â º¯È­¿¡ µû¶ó °ú°Å ¿¬±¸¿¡¼­µµ ºüÁö°í »õ ¿¬±¸¿¡¼­µµ ºüÁö°í... It should be noted that there is currently no evidence to support the use of adjuvant chemotherapy for patients who fall into the category of stage IB by the AJCC 6th edition but stage IIA by the AJCC 7th and 8th editions (pT1N2M0 and pT3N0M0). (2022 KGCA guideline p52)

KBDCA À̱ٿí/¾È»óÈÆ webinar

2024³â ÇöÀç ¿ì¸®³ª¶ó¿¡¼­ adjuvant Ä¡·á´Â doublet chemotherapy°¡ Ç¥ÁØÀÔ´Ï´Ù (¿¹. XELOX). Palliative first-line Ä¡·á¿¡¼­ nivolumabÀÇ È¿°ú°¡ ÀÔÁõµÇ¸é¼­ adjuvant chemotherapy¿¡ nivolumabÀ» ´õÇÏ´Â °ÍÀÌ È¿°ú°¡ ÀÖ´ÂÁö ´Ù±¹°¡ ÀüÇâÀû ¿¬±¸°¡ ÁøÇàµÇ¾ú½À´Ï´Ù. ¾Æ½±°Ôµµ °á°ú´Â negative¿´½À´Ï´Ù (ATTRACTION-5 ¿¬±¸. °­À±±¸ Lancet Gastroenterol Hepatol 2024). °á·ÐÀ» ¿Å±é´Ï´Ù. "The results of this trial do not support the addition of nivolumab to postoperative adjuvant therapy for patients with untreated, locally advanced, resectable gastric or GEJ cancer."

* Âü°í: 5-fluorouracil (5-FU) °æ±¸Á¦Á¦


3. Palliative systemic therapy. °í½ÄÀû Ç׾Ͽä¹ý

2017³â Cochrane Review¿¡ ÀÇÇϸé best supportive care¿¡ ºñÇÑ Ç×¾ÏÄ¡·áÀÇ survival benefit´Â 6.7°³¿ùÀ̾ú½À´Ï´Ù (Cochrane Database Syst Rev 2017).

¼º±Õ°ü´ëÇб³ »ï¼ºÃ¢¿øº´¿ø¿¡¼­ de novo stage IV À§¾Ï°ú recurrent stage IV À§¾ÏÀÇ survivalÀ» ºñ±³ÇÏ¿© ¹ßÇ¥ÇÏ¿´½À´Ï´Ù. 2012³âºÎÅÍ 2022³â¿¡ enrollµÈ ȯÀÚµéÀε¥ ¸é¿ªÇ×¾ÏÁ¦°¡ µµÀԵDZâ ÀÌÀü ¿ì¸®³ª¶óÀÇ Æò±ÕÀûÀÎ 4±â À§¾Ï Ä¡·á ¼ºÀûÀ» º¸¿©ÁÖ°í ÀÖ´Ù°í »ý°¢µÇ¾î ¼Ò°³ÇÕ´Ï´Ù. ¸é¿ªÇ×¾ÏÁ¦°¡ µµÀÔµÈ ÀÌÈÄ¿¡´Â ¼ºÀûÀÌ ¸¹ÀÌ ÁÁ¾ÆÁ³½À´Ï´Ù.

PFM 2023

À§¾Ïµµ molecular phenotypeÀ» ³ª´©°í biomarker¿¡ µû¶ó Ä¡·áÇÏ´Â ½Ã´ë°¡ ¿À°í ÀÖ½À´Ï´Ù.

Nakamura. Nat Rev Clin Oncol 2021

Nakamura. Nat Rev Clin Oncol 2021

Nakamura. Nat Rev Clin Oncol 2021

À§¾Ï ȯÀÚÀÇ Ã¹ ³»½Ã°æ Á¶Á÷°Ë»ç¸¦ ó¹æÇÒ ¶§ À§¾ÏÀÇ subtype ºÐ·ù¿Í Ãß°¡ Ä¡·á¸¦ À§ÇÏ¿© ¸î °¡Áö marker °Ë»ç¸¦ ÇÏ°í ÀÖ½À´Ï´Ù. 2023³â 9¿ù 1ÀϺÎÅÍ palliative settingÀÇ À§¾Ï 1Â÷ Ç×¾ÏÄ¡·á¿¡¼­ ¸é¿ªÄ¡·áÁ¦ÀÎ OPDIVO (nivolumab)¸¦ º¸ÇèÀ¸·Î »ç¿ëÇÒ ¼ö ÀÖ°Ô µÇ¾ú½À´Ï´Ù. AGC¿¡¼­´Â PD-L1 28-8 °Ë»ç¸¦ ÇÏ°í ÀÖ½À´Ï´Ù. 2024³â 6¿ù ½ÃÁ¡¿¡¼­ °¡Àå minimalÇÑ °Ë»ç´Â ¾Æ·¡¿Í °°½À´Ï´Ù. Á¶±âÀ§¾ÏÀ¸·Î ÆǴܵǴ °æ¿ì´Â 2 °¡Áö, ÁøÇ༺ À§¾ÏÀ¸·Î ÆǴܵǴ °æ¿ì´Â 3°¡Áö °Ë»çÀÔ´Ï´Ù. ±×·¯³ª Á¡Â÷ È®´ëµÇ°í ÀÖ½À´Ï´Ù. 2025³âºÎÅÍ´Â claudin¿¡ ´ëÇÑ °Ë»ç¿Í Åõ¾àÀÌ °¡´ÉÇÕ´Ï´Ù. ³»½Ã°æ½Ç¿¡¼­´Â ÀÏ¹Ý Á¶Á÷°Ë»ç(H&E ¿°»ö)±îÁö¸¸ ó¹æÇÏ°í ¸é¿ª¿°»öÀº º´¸®°ú¿¡¼­ ÇÊ¿äÇÑ °ÍµéÀ» Ãß°¡ ÀÔ·ÂÇÏ°í ÀÖ½À´Ï´Ù (2024³â 9¿ù º¯°æµÈ Á¤Ã¥ÀÔ´Ï´Ù).

ÇÊ¿äÇÑ °æ¿ì EBV, claudin18.2 µîÀÇ °Ë»ç¸¦ Ãß°¡ÇÏ¿© ¾à¹°¼±ÅÃÀÇ °¡À̵å·Î »ï°í ÀÖÀ¸¸ç, °¡´ÉÇϸé NGS (next generation sequencing) °Ë»ç¸¦ ÅëÇÏ¿© º¸´Ù ¸¹Àº Á¤º¸¸¦ ȹµæÇÏ¿© ´Ù¾çÇÑ °¡´É¼ºÀ» Ž»öÇÏ°í ÀÖ½À´Ï´Ù. ÀϹÝÀûÀ¸·Î HER2 ¾ç¼ºÀÌ 15%, Claudin 18.2 ¾ç¼ºÀÌ 30%, PD-L1 CPS >= 5°¡ 35% Á¤µµÀÎ °ÍÀ¸·Î »ý°¢µË´Ï´Ù.

2022³â ´ëÇÑÀ§¾ÏÇÐȸ °¡À̵å¶óÀÎÀÇ flow chartÀÔ´Ï´Ù. First-line chemotherapy´Â HER2¿Í PD-L1¿¡ µû¶ó ¼±ÅÃÇÏ°í second-lineºÎÅÍ´Â ´Ù¾çÇÑ ¼±ÅÃÀÌ °¡´ÉÇÑ °ÍÀ¸·Î ±â¼úµÇ¾î ÀÖ½À´Ï´Ù.

2022 KGCA guideline Statement 24-26 Flow chart

Palliative chemotherapyÀÇ ¾àÁ¦ ¼±ÅÃÀÌ °è¼Ó ´Þ¶óÁý´Ï´Ù. 2024³â 9¿ù ÇöÀç´Â ¾Æ·¡¿Í °°½À´Ï´Ù.

2024-9-27 KINGCA. ¶ó¼±¿µ ±³¼ö´Ô °­ÀÇ Áß¿¡¼­

Palliative 1st-line chemotherapy ºÎºÐÀº ¿ö³« º¯È­°¡ ¸¹¾Æ¼­ µû¶ó°¡±â ¾î·Æ½À´Ï´Ù. À§¾ÏÇÐȸ¿¡¼­ 2024³â ¸» °ËÅäÇÑ ÀÇ°ßÀº ¾Æ·¡¿Í °°½À´Ï´Ù.


4. HER2 positive gastric cancer

HER2´Â 4±â À§¾ÏÀÇ 15%¿¡¼­ ¾ç¼ºÀ̸ç EGJ cancer¿¡¼­ Á¶±Ý ´õ ÈçÇÕ´Ï´Ù.

c-erB-2 positive (+)

¹æ¿µÁÖ ±³¼ö´ÔÀÇ ToGA trial (Bang. Lancet 2010) ÀÌÈÄ HER2 ¾ç¼º À§¾ÏÀÇ palliative chemotherapy´Â trastuzumab ±â¹ÝÀ¸·Î ÁøÇàµÇ°í ÀÖ½À´Ï´Ù.

ÇöÀç »ç¿ëÇÏ°í ÀÖ´Â IHC ±âÁØÀ» Àû¿ëÇÑ ºÐ¼®

2022³â ´ëÇÑÀ§¾ÏÇÐȸ °¡À̵å¶óÀÎ Statement 24-2´Â ¾Æ·¡¿Í °°½À´Ï´Ù.

Statement 24-2: Palliative first-line trastuzumab combined with capecitabine or FU plus cisplatin is recommended in patients with HER2 IHC 3+ or IHC 2+ and ISH-positive advanced gastric cancer (evidence: high, recommendation: strong for). [Âü°í] 3+¸é ¹Ù·Î »ç¿ëÇÏ°í 2+¸é Ãß°¡ °Ë»ç¸¦ ÇÑ ÈÄ »ç¿ëÇÑ´Ù´Â ÀǹÌÀÔ´Ï´Ù.

Topoisomeraze 1 inhibitor¸¦ ºÙÀÎ antibody-drug congugate (ADC) trastuzumab deruxtecan (T-Dxd, ENHERTU, ¿£ÇãÅõ)ÀÌ HER2 ¾ç¼º À§¾Ï¿¡¼­ »ç¿ëµÉ ¼ö ÀÖ½À´Ï´Ù (Kotani and Shitara. Ther Adv Med Oncol 2021). 2024³â 4¿ùºÎÅÍ HER2 ¾ç¼º ÁøÇ༺/ÀüÀ̼º À§¾Ï 3Â÷ ÀÌ»ó Ä¡·á¿¡ °Ç°­º¸Çè ±Þ¿©Àû¿ëÀÌ °¡´ÉÇØÁ³½À´Ï´Ù (°ü·Ã´º½º). 1Â÷ ¶Ç´Â 2Â÷ Ä¡·á¿¡ ´ëÇÑ È¿°úµµ ±â´ëµÇ¾î ÀÓ»ó ¿¬±¸°¡ ÁøÇàµÇ°í ÀÖ½À´Ï´Ù.

trastuzumab deruxtecanÀÇ ±¸Á¶ (www.biochempeg.com)

trastuzumab deruxtecanÀÇ ±¸Á¶ (www.adcreview.com)

DESTINY-Gastric01 ¿¬±¸

HER2 ¾ç¼º À§¾ÏÀº trastuzumab ±â¹ÝÀÇ Ç×¾ÏÄ¡·á°¡ ±âº»ÀÌÁö¸¸ pembronizumabÀ» ´õÇÏ¿© µµ¿òÀÌ µÈ´Ù´Â °á°ú°¡ ÀÖ½À´Ï´Ù (Lancet 2023). ¾ÆÁ÷ interim analysis ¼öÁØÀÌÁö¸¸ °ð ÃÖÁ¾ °á°ú°¡ ³ª¿Ã °Í °°½À´Ï´Ù.


5. ¸é¿ªÄ¡·á. Immunotherapy. Immune checkpoint inhibitor

Immune checkpoint inhibitors (ICI)´Â ¾Æ·¡ ±×¸²¿¡¼­ º¸ÀÌ´Â ¹Ù¿Í °°ÀÌ Å©°Ô ¼¼°³ÀÇ target moleculeÀÌ ÀÖ½À´Ï´Ù.

source: The Pharmaceutical Journal 2018
The T-cell receptor binds to an antigen found on the major histocompatibility complex on the surface of the cancer cell.
1) This is a stimulatory response and activates T cells to remove pathogens or cancer cells (shown as the positive circles). A co-stimulatory receptor also exists (CD28), which binds to a ligand (CD80). This results in an increased immune response toward the cancer cell
2) CTLA-4 has a stronger affinity to CD80 and so competes with the co-stimulatory pathway to inhibit the response and ¡®switch it off¡¯
3) When a strong TCR stimulus exists, the inhibitor molecule CTLA-4 is upregulated and transported to the surface of the cell; a similar process occurs with PD-1
4) The checkpoint inhibitors act by blocking the inhibitory response by targeting CTLA-4, PD-1 or the ligand PD-L1.


[ÁÖ¿ä ¿¬±¸]

Trial È«¼öÀÔ´Ï´Ù. (2023³â)

5 major landmark trials in gastric cancer
StudySettingPrimary endpointCondition
Attraction-2 (Lancet 2017)3L - Nivo > PlaceboOS 5.3 mo vs. 4.1 moAny patients
Keynote-061 (Lancet 2018)2L - Pem = PTXOS 9.1 mo vs. 8.3 moPD-L1 CPS >1
Checkmate-649 (Lancet 2021)1L - Nivo-Chemo > ChemoOS 14.4 mo vs. 11.1 moPD-L1 CPS >5
Keynote-859 (Lancet Oncol 2023)1L - Pembro-Chemo > ChemoOS 13.0 mo vs. 11.4 moPD-L1 CPS >1
Keynote-811 (Lancet 2023)1L - Pem-Tmab-Chemo > Tmab-ChemoOS 20.0 mo vs. 16.9 moHER2 (+)

1) Attraction 2 (Lancet 2017) 3rd-lineÀ¸·Î heavily pretreated ¾Æ½Ã¾Æ HER2 À½¼º À§¾Ï¿¡¼­ nivolumabÀÇ È¿°ú¸¦ óÀ½À¸·Î ÀÔÁõ. Median overall survival was 5¡¤26 months (95% CI 4¡¤60-6¡¤37) in the nivolumab group and 4¡¤14 months (3¡¤42-4¡¤86) in the placebo group (hazard ratio 0¡¤63, 95% CI 0¡¤51-0¡¤78; p<0¡¤0001).

2) Keynote-061 (Lancet 2018) 2nd-lineÀ¸·Î previously heavily treated ȯÀÚ¿¡¼­ pembronizumab°ú paclitaxelÀ» ºñ±³ÇÏ¿© ºñ½ÁÇÏ¿´´Ù´Â °á·Ð.

3) Keynote-062 (JAMA Oncol 2020) Pembronizumab¿¡ ´ëÇÑ negative study. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested.

4) Attraction 4 (Lancet Oncol 2022) ¾Æ½Ã¾ÆÀÎ ´ë»ó (ÀϺ», Çѱ¹, ´ë¸¸). First-line palliative setting HER2 À½¼º À§¾Ï¿¡¼­ nivolumabÀÌ overall survivalÀº ¿¬Àå½ÃÅ°Áö ¸øÇßÁö¸¸ progression free survivalÀº À¯ÀÇÇÏ°Ô Áõ°¡½ÃÅ´.

5) CheckMate-649 (Lancet 2021) ¼­¾çÀÎ ´ë»ó. First-line palliative setting HER2 À½¼º À§¾Ï¿¡¼­¿¡¼­ nivolumabÀÌ progression free survival°ú overall survivalÀ» ¸ðµÎ À¯ÀÇÇÏ°Ô Áõ°¡½ÃÅ´. The median follow-up for OS was 13¡¤1 months (IQR 6¡¤7-19¡¤1) for nivolumab plus chemotherapy and 11¡¤1 months (5¡¤8-16¡¤1) for chemotherapy alone. PD-L1 IHC 28-8 (DAKO)¸¦ »ç¿ëÇÏ¿© CPS¸¦ °è»ê

CPS¿¡ µû¸¥ Â÷ÀÌ

Overall

6) Keynote-859 (Lancet Oncol 2023) ¿¬¼¼´ë ¶ó¼±¿µ ¼±»ý´ÔÀÌ first authorÀÎ ³í¹®. First-line palliative setting HER2 À½¼º À§¾Ï¿¡¼­ pembronizumabÀÌ overall survivalÀ» À¯ÀÇÇÏ°Ô Áõ°¡½ÃÅ´. Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12¡¤9 months [95% CI 11¡¤9-14¡¤0] vs 11¡¤5 months [10¡¤6-12¡¤1]; hazard ratio [HR] 0¡¤78 [95% CI 0¡¤70-0¡¤87]; p<0¡¤0001), in participants with a PD-L1 CPS of 1 or higher (13¡¤0 months [11¡¤6-14¡¤2] vs 11¡¤4 months [10¡¤5-12¡¤0]; 0¡¤74 [0¡¤65-0¡¤84]; p<0¡¤0001), and in participants with a PD-L1 CPS of 10 or higher (15¡¤7 months [13¡¤8-19¡¤3] vs 11¡¤8 months [10¡¤3-12¡¤7]; 0¡¤65 [0¡¤53-0¡¤79]; p<0¡¤0001). PD-L1 IHC 22C3 (Agilent)¸¦ »ç¿ëÇÏ¿© CPS¸¦ °è»ê.

7) Keynote-811 (Lancet 2023) First-line palliative setting HER2 ¾ç¼º À§¾ÏÀº trastuzumab ±â¹Ý Ç×¾ÏÄ¡·á°¡ Ç¥ÁØÀÌÁö¸¸ pembronizumabÀ» ´õÇÏ¸é µµ¿òÀÌ µÈ´Ù´Â ¿¬±¸ÀÇ interim analysisÀÔ´Ï´Ù. Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastro-oesophageal cancer, specifically in patients with tumours with a PD-L1 combined positive score of 1 or more. Overall survival follow-up is ongoing and will be reported at the final analysis.


[Good response factors]

(1) PD-L1: 2022 KGCA guideline¿¡´Â palliative first-line setting¿¡¼­ immunue checkpoint inhibitor¿¡ ´ëÇÑ statement¿Í Forest plotÀÌ Á¦½ÃµÇ¾ú½À´Ï´Ù. 2023³â 9¿ù 1ÀϺÎÅÍ CheckMate-649 (Lancet 2021) ¿¬±¸¿¡ ÀÇ°Å PD-L1 (28-8) CPS 5 ÀÌ»ó(»ï¼º¼­¿ïº´¿øÀÇ ÈÄÇâÀû ºÐ¼®¿¡ ÀÇÇϸé Àüü ȯÀÚÀÇ 45%·Î ÃßÁ¤µÊ)ÀΠȯÀÚ¿¡¼­ nivolumabÀÌ ±Þ¿©·Î ÀÎÁ¤µÇ¾ú½À´Ï´Ù. CPS°¡ 5º¸´Ù ³·Àº ȯÀÚ¿¡¼­ nivolumabÀÇ È¿°ú°¡ ¾ø´Â °ÍÀÌ ¾Æ´Ï¾î¼­ ÀÎÁ¤ºñ±Þ¿©·Î »ç¿ëÇÒ ¼ö ÀÖ½À´Ï´Ù. ±×·±µ¥ PD-L1 22C3À» »ç¿ëÇÑ ¿¬±¸¿¡¼­ pembronizumabÀÌ È¿°úÀûÀ̶ó´Â Keynote-859 (Lancet Oncol 2023) ¿¬±¸°¡ ¹ßÇ¥µÇ¸é¼­ È¥¶õÀÌ ¿¹»óµË´Ï´Ù. Nivolumab ¿¬±¸¿Í pembronizumab ¿¬±¸ÀÇ PD-L1 °Ë»ç ¹æ¹ýÀÌ ´Þ¶ú±â ¶§¹®ÀÔ´Ï´Ù. ¾ÕÀ¸·Î µÎ ¾àÀ» ¸ðµÎ »ç¿ëÇÏ°Ô µÇ¸é PD-L1À» µÎ °¡Áö ¹æ¹ýÀ¸·Î ÃøÁ¤ÇÏ¿© ¼öÄ¡°¡ ³ôÀº ¾àÁ¦¸¦ ¼±ÅÃÇØ¾ß ÇÒ Áöµµ ¸ð¸£°Ú½À´Ï´Ù. (28-8 ¹æ¹ýÀÇ CPS°¡ ³ôÀ¸¸é nivolumabÀ» »ç¿ëÇÏ°í 22C3 ¹æ¹ýÀÇ CPS°¡ ³ôÀ¸¸é pembronizumabÀ» »ç¿ëÇÑ´Ù?) ±×·¯³ª ÇÑ Ç׸ñ¿¡ ´ëÇÏ¿© ¼­·Î ´Ù¸¥ µÎ °Ë»ç°¡ ÀÎÁ¤µÉÁö °ÆÁ¤ÀÔ´Ï´Ù. ´ÙÇེ·´°Ô µÎ °Ë»ç¹ýÀÌ comparable ÇÏ´Ù´Â ¿¬±¸°¡ ÀÖ½À´Ï´Ù (J Gastrointest Oncol 2021).

Statement 24-3: Palliative first-line nivolumab (¿ÉƼº¸) combined with capecitabine or FU plus oxaliplatin (XELOX or FOLFOX) is recommended in patients with PD-L1 CPS ¡Ã5 and HER2-negative advanced gastric cancer (evidence: high, recommendation: strong for).

Comments on immune checkpoint inhibitors in 2022 KGCA guideline

Forest plot for palliative first-line immune checkpoint inhibitor in 2022 KGCA guideline

(2) MSI high: MSI highÀΠȯÀÚ¿¡¼­ ICIÀÇ È¿°ú°¡ ÁÁ½À´Ï´Ù. 4±â À§¾Ï ȯÀÚÀÇ 10-15%°¡ MSI-HÀÔ´Ï´Ù. Á¶°ÇÀÌ º¹ÀâÇÕ´Ï´Ù¸¸ pembrolizumabµµ »ç¿ëÇÒ ¼ö´Â ÀÖ½À´Ï´Ù. 2022 KGCA guideline¿¡´Â ´ÙÀ½°ú °°ÀÌ ¾ð±ÞµÇ¾î ÀÖ½À´Ï´Ù. "In Korea, pembrolizumab was approved in patients with several inoperable or metastatic solid tumors, including gastric cancer with MSI-H or dMMR, who have progressed following prior treatment and who have no satisfactory alternative treatment options."

(3) Host related factor¸¦ ICIÀÇ ¹ÝÀÀÀ» ¿¹ÃøÇÏ´Â ÁöÇ¥·Î »ç¿ëÇÏ´Â ¿¬±¸µéÀÌ ÀÖ½À´Ï´Ù. MicrobiomeÀ̳ª metabolomics µî

2023³â 9¿ùºÎÅÍ PDS 5 ÀÌ»óÀÎ °æ¿ì nivolumab (¿ÉƼº¸)°¡ º¸Çè ±Þ¿©°¡ ½ÃÀ۵Ǿú½À´Ï´Ù. ±×·±µ¥ PDS°¡ ³·´õ¶óµµ È¿°ú°¡ ¾ø´Â °ÍÀÌ ¾Æ´Õ´Ï´Ù. PDS 4ÀÌÇÏ¿¡¼­´Â ºñ±Þ¿©·Î »ç¿ëÇÒ ¼ö ÀÖ½À´Ï´Ù. PDS 5 ÀÌ»óÀÎ °æ¿ì°¡ 45%À̹ǷΠ55%ÀÇ È¯ÀÚ´Â ±Þ¿© ÇýÅÃÀ» º¼ ¼ö ¾ø´Â ¹®Á¦°¡ ÀÖ½À´Ï´Ù.

CheckMate-649 (Lancet 2021) Nivolumab (¿ÉƼº¸)ÀÇ È¿°ú. CPS 5ÀÌ»óÀΠȯÀÚ¿¡¼­ »ýÁ¸±â°£À» 3°³¿ù ¿¬Àå. KBDCA À̱ٿí/¾È»óÈÆ webinar


[Áú¹®]


6. Ramucirumab (VEGFR2 inhibitor)

Rainbow ¿¬±¸ (Lancet Oncol 2014)


7. Claudin 18.2

Claudin 18.2 (CLDN18.2) is an important component of tight junction proteins that regulates tissue permeability, paracellular transport, and signal transduction.

75%¶ó´Â cutoff°¡ ³Ê¹« strictÇÏ¿© ÇâÈÄ ÀûÀÀÁõ È®´ë¿¡ ´ëÇÏ¿© ¿ì·Á°¡ ÀÖ¾î »ó¼¼ÇÑ report¸¦ ¿ä±¸ÇÏ´Â ¸ñ¼Ò¸®°¡ ÀÖ½À´Ï´Ù.

4±â À§¾Ï¿¡¼­ CLDN 18.2´Â 30-40%¿¡¼­ ¾ç¼ºÀ» º¸ÀÔ´Ï´Ù. ¾ÕÀ¸·ÎÀÇ Áß¿äÇÑ Ä¡·á targetÀÔ´Ï´Ù.

Claudin 18.2 ¾ç¼º À§¾Ï¿¡¼­ claudin 18.2¿¡ ´ëÇÑ ´ÜÀÏŬ·ÐÇ×üÀÎ zolbetuximabÀ» Ãß°¡ÇÑ °æ¿ì ÀüÀ̼º À§¾Ï ȯÀÚÀÇ »ýÁ¸±â°£ÀÌ ¿¬ÀåµÇ¾ú½À´Ï´Ù.

2024-9-26 KINGCA. CPS¿Í ClaudinÀÌ ¸ðµÎ ¾ç¼ºÀÏ ¶§ ¾î¶² ¾àÁ¦¸¦ ¼±ÅÃÇØ¾ß ÇÏ´ÂÁö hot discussionÀÌ ÀÖ¾ú½À´Ï´Ù. 2024 KGCA guideline¿¡¼­´Â ¿¬±¸ °á°ú°¡ ºÎÁ·ÇϹǷΠ°á·ÐÀ» Á¦½ÃÇÏÁö ¾ÊÀ» °Í °°½À´Ï´Ù.

ZolbetuximabÀÌ 2024³â 10¿ù approval µÇ¾ú°í 2025³âºÎÅÍ Ã³¹æµÉ ¼ö ÀÖÀ» °ÍÀ¸·Î »ý°¢µË´Ï´Ù.


8. IP chemotherapy

Ishigami Hironori µîÀÇ Phoenix-GC study (JCO 2018)¿¡¼­ IP chemotherapy¿¡ ´ëÇÑ ÁÁÀº °á°ú¸¦ º¸¿©ÁÖ¾ú½À´Ï´Ù. ±×·¯³ª 2023³â ÇöÀç ¿ì¸®³ª¶ó¿¡¼­ IP chemotherapy´Â º¸Çè Àû¿ëÀ» ¹ÞÁö ¸øÇÏ´Â ÀûÀÀÁõ¿Ü Ä¡·áÀÔ´Ï´Ù. ¾ÈŸ±õ½À´Ï´Ù. Àӻ󿬱¸·Î enroll ÇÒ ¼ö ¹Û¿¡ ¾ø´Â »óȲÀÔ´Ï´Ù.

ºÐ´ç¼­¿ï´ëº´¿ø °­¼ÒÇö, ±èÇüÈ£ ±³¼ö´ÔÀÇ ÃÖ±Ù ¸®ºä¸¦ ¼Ò°³ÇÕ´Ï´Ù. Intraperitoneal chemotherapy for gastric cancer: A contemporary perspective (Chin J Cancer Res 2023)

2023³â 12¿ù 9ÀÏ À§¾Ïº¹¸·ÀüÀÌ¿¬±¸È¸ ½ÉÆ÷Áö¾öÀÇ ÃÊû°­»ç·Î ¿À½Å Ishigami Hironori ¼±»ý´Ô²²¼­ ¼¼ °¡Áö ¹æ¹ýÀ» ¾Æ·¡¿Í °°ÀÌ ºñ±³Çϼ̽À´Ï´Ù.

Key factorsHIPECPIPACLong-term IP
Potency of the drug******
Intraperitoneal concentration******
Duration of tumor exposure******
Depth of drug infiltration********
Frequency and duration of treatment******


9. Conversion surgery. Àüȯ ¼ö¼ú

Conversion surgeryÀÇ conversionÀº ¹«½¼ ¶æÀϱî¿ä? Palliative intentÀÇ Ä¡·á¿¡¼­ curative intentÀÇ Ä¡·á·Î ÀüȯÇÑ´Ù´Â ÀǹÌÀÔ´Ï´Ù.

Palliative chemotherapy°¡ ¹ßÀüÇϸ鼭 conversion surgery¿¡ ´ëÇÑ °ü½ÉÀÌ ³ô¾ÆÁö°í ÀÖ½À´Ï´Ù. ÃÖ±Ù ±¹Á¦ ´Ù±â°ü ÈÄÇâÀû ¿¬±¸°¡ ¹ßÇ¥µÇ¾ú½À´Ï´Ù (Yoshida. Ann Gastroenterol Surg 2021). ´Ù¾çÇÑ È¯ÀÚ°¡ ¼¯ÀÎ ¸Å¿ì º¹ÀâÇÑ °á°úÀÔ´Ï´Ù.

Yoshida. Ann Gastroenterol Surg 2021

ÀÌ Áß¿¡¼­ R0 resectionÀÌ µÇ¾ú´ø ȯÀÚÀÇ survival graph¸¦ º¸¸é ³î¶ø½À´Ï´Ù. R0 resectionÀÌ µÈ ȯÀÚÀÇ 5³â »ýÁ¸À²ÀÌ 50%¿¡ °¡±õ±â ¶§¹®ÀÔ´Ï´Ù. ¸ðµç 4±â À§¾Ï ȯÀÚ¿¡¼­ ÀÌ·± °á°ú°¡ ³ª¿Â °ÍÀÌ ¾Æ´Ï¶ó´Â Á¡¿¡¼­ ÁÖÀÇÇØ¾ß ÇÏ°Ú½À´Ï´Ù. Ç×¾ÏÄ¡·á¸¦ ÇÏ¿© ¹ÝÀÀÀÌ ¾ÆÁÖ ÁÁ¾Æ¼­ ¼ö¼ú±îÁö ÇÏ°Ô µÇ¾ú´ø ȯÀÚ Áß R0 resectionÀÎ °æ¿ìÀ̹ǷΠ¾ÆÁÖ ¼Ò¼öÀÇ È¯ÀÚ¿¡ ÇØ´çÇÑ´Ù°í ÇÒ ¼ö ÀÖ½À´Ï´Ù.

Yoshida. Ann Gastroenterol Surg 2021 - KBDCA À̱ٿí/¾È»óÈÆ webinar

ÀϺ»¿¡¼­ÀÇ ¶Ç ´Ù¸¥ ¿¬±¸ÀÔ´Ï´Ù (BMC Surgery 2022)

Kaplan-Meier survival curves for patients stratified by the initial status of stage IV disease (a) and the residual tumor status (b). IR=initially resectable disease, including patients with category 1 stage IV gastric cancer; UR=unresectable disease, including patients with category 2-4 stage IV gastric cancer.

´ÙÀ½Àº »ï¼º¼­¿ïº´¿øÀÇ conversion surgery °á°úÀÔ´Ï´Ù (Biomedicines 2023).

Palliative chemotherapy ȯÀÚÀÇ 3.9%¿¡¼­ conversion surgery°¡ ½ÃµµµÇ¾ú½À´Ï´Ù.

R0 resectionÀÌ °¡´ÉÇÏ¿´´ø ȯÀÚÀÇ 5 YSR°¡ Àý¹ÝÀ̶ó´Â ´Ù±â°ü ¿¬±¸(Ann Gastroenterol Surg 2021)¿Í ÀÏÄ¡ÇÏ´Â ´ÜÀϱâ°üÀÇ ¿¬±¸°á°úÀÔ´Ï´Ù. ƯÈ÷ 17.7% (21/118)´Â º´¸®ÇÐÀû CRÀ̾ú°í À̵éÀº ¿¹ÈÄ°¡ ¾ÆÁÖ ÁÁ¾Ò½À´Ï´Ù.

¸Å¿ì happyÇÑ Áõ·ÊÀÔ´Ï´Ù.


[Symposiums]

[2023-6-13] IGCC 2013

[2023-12-9] À§¾Ïº¹¸·ÀüÀÌ¿¬±¸È¸ (°í·Á´ëÇб³ ±¸·Îº´¿ø »õ·Ò±³À°°ü 1F ´ë°­´ç)

[2024-11-15] KDDW

2024-11-15. KDDW


[FAQ]

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TS-1ÀÇ À̸§¿¡ ¹«½¼ ¶æÀÌ ¼û°ÜÁ® ÀÖ³ª Àá½Ã ÀÎÅÍ³Ý °Ë»öÀ» Çغôµ¥, À¯·´¿¡¼­ Teysuno¶ó´Â »óÇ°¸íÀ¸·Î Æȸ®¸ç, TS-1°ú ¹ßÀ½ÀÌ À¯»çÇÑ ¿Ü¿£ ¾î¶² Àǹ̵µ ¸øã¾Ò½À´Ï´Ù. ´Ù¸¸ pubmed¿¡¼­ °Ë»ö ½Ã, ¾Æ·¡ ±×¸² ÆÄÀÏó·³ 2011³âµµ¿¡ ½Ç¸° ³í¹®ÀÌ ÀÖ´øµ¥, ¾Æ¹«¸® »ý°¢ÇغÁµµ TS-1ÀÌ titanium silicate´Â ¾Æ´Ñ °Í °°¾Æ¼­¿ä?

[2015-2-5. ÀÌÁØÇà ´äº¯]

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[References]

1) À§¾ÏÇ×¾ÏÄ¡·á 2023-9-21. ÀÓ¼ºÈñ ±³¼ö´Ô (ºñ°ø°³)

© ÀÏ¿ø³»½Ã°æ±³½Ç ¹Ù¸¥³»½Ã°æ¿¬±¸¼Ò ÀÌÁØÇà. EndoTODAY Endoscopy Learning Center. Lee Jun Haeng.