Management of stomach cancer: Medical O ncology perspective

1. Management of stomach cancer: Medical Oncology perspective Presenter: Dr. MdShahriarKabir MD ( Thesis ) Medical Oncology NICRH

2. Stomach Cancer of USA in 2019 • About 27,510 new cases will be diagnosed in 2019 • 17,230 of them will be male and 10,280 are female. • 11,140 is estimated to die from stomach cancer in 2019. • Source: American cancer society

3. Incidence • Gastric cancer is the 4th most common cancer world wide and 2nd most common cause of cancer related death. • 70% of cases world wide in middle and eastern Asia, South America and Eastern Europe • It is likely that in 2020 Gastric cancer will Increase by 10% in developing countries. • More than 80% of patients with advanced cancer die of the disease or recurrence of the disease within 1 year after diagnosis. Source: 2010 American Cancer Society (ACS)

4. Epidemiology • Highest death rates are in Chile, Costa Rica, Japan, China and former soviet union. • Median age of diagnosis is 68 years old. • 6 out of every 10 people with age older than 65 are diagnosed with stomach cancer each year. • Ratio of Male : Female = 1.5 : 1

5. NICRH picture of Gastric cancer - 2018 • In 2018,Medical Oncology Department enrolled total 238 patient, male 153 and female patient was 75. Age range of patients are 23 to 85 yrs and mean age 52.78. • From Surgical Oncology audit 2018- total no of gastric cancer surgery 138. Stomach cancer 123, lower oesophageal cancer 15.

6. Tumor location • GE junction, Cardia and fundus : 35% • Diffused subtype • Incidence rising • Body : 25% • Antrum and distal stomach : 40% Intestinal subtype incidence falling

7. Intestinal Versus Diffuse Subtype • Intestinal Subtype • More commonly seen is patient > 40 years. • Less aggressive • Diffuse Subtype • Affects younger patients • More aggressive

8. Histology • Adenocarcinoma : 90% • Others : 10% • Sarcoma • GIST • Carcinoid • Small cell • Undifferentiated • MALT oma • leiomyosarcoma

9. Advanced genomic subtypes • Tumor containing EPV, amplification of JAK-2 and suppressor of PDl-1 & PDL-2 > about 10% • Tumor containing MSI/dMMR > about 20% • Chromosomally unstable > about 50% and commonly at GE junction • Genomically stable > about 20% with high metastatic potential

10. Acquired Risk factors: • Nutritional • High Salt Consumption • High nitrate consumption • Low dietary Vitamin A and C • Habitual • Poor food preparation (Smoked, Salt curved) • Lack of refrigeration • Poor drinking water (well water) • Smoking • Alcohol • Occupational : • Rubber worker • Coal worker

11. Infection : • H.pyloriinfection • Epstein – Barr virus • H/O • Radiation exposure • gastric surgery • Treated MALT lymphoma Acquired Risk factors:

12. Genetic Risk factors • Type A blood • Pernicious amaemia • Family history • Hereditary diffuse gastric cancer (CDH1 mutation) • Familial gastric cancer syndrome related to p53 mutation • Hereditary nonpolyposis colon cancer • Familial adenomenus polyposis • Li – Frauneni syndrome • BRCA 1 and BRCA 2

13. Genetic Risk factors • Precursor lesion : • Adenomatous gastric polyps • Chronic atrophic gastritis • Dysplasia • Intestinal metaphasia • Menetrier disease • Ethnicity • Obesity

14. Genetic counseling in Ca stomach • Gastric cancer before age 40 • Gastric cancer before age 50 or at any age with one or two first or second degree relative affected respectively • Gastric cancer and breast cancer before age 50 and or any age with family history of Breast cancer in first or second degree • An individual affected with gastric cancer at any age with family history of Juvenile polyposis or cancer associated with lynch syndrome

15. Workup • H&P • Upper GI endoscopy and biopsy • Chest/abdomen/pelvic CT with oral and IV contrast • PET/CT evaluation (skull base to mid-thigh) if no evidence of M1 disease and if clinically indicated • CBC and comprehensive profile • Endoscopic ultrasound (EUS) if early stage disease suspected or if early versus locally advanced disease needs to be determined (preferred) • Endoscopic resection (ER) is essential for the accurate staging of early-stage cancers (T1a or T1b)

16. Workup • Assess Siewert category • Nutritional assessment and counseling • Smoking cessation advice, counseling, and pharmacotherapy as indicated • Screen for family history • Biopsy of metastatic disease as clinically indicated

17. Advanced Workup • Overexpression and amplification of HER2> Metastatic Adenocaricnoma > Targeted therapy • MSI>if metastatic > High > Immunotherapy • dMMR> if metastatic> defficient> Immunotherapy • PD-L1 testingHER2> Metastatic Adenocaricnoma > over expression > Immune check point inhibitors

18. Management of Ca stomach depends on the staging • Early stage disease • Loco regional disease • Metastatic disease

19. Management of Early stage Stomach Cancer Non-Surgical candidates Endoscopic Survellence ER cTis / cT1a ER/Surgery Medically fit

20. Management of Loco-regional Disease cT1b Surgery Medically Fit, potentially resect able Surgery or Perioperative Chemotherapy or Preoperative Chemoradiation cT2 or Higher, Any N Locoregional Disease(cM0) Surgically unresectable Chemoradiation or Systemic therapy or Palliative Management Non-Surgical Candidates Chemoradiation(Definitive) or Palliative Management

21. Management of Metastatic Disease Metastatic Disease(cM1) Palliative Management

22. Adjuvant management(patient who don't receive pre-operative therapy) pTis/pT1N0 Surveillance Surveillance or Fluoropyrimidine Then Fluoropyrimidine based chemoradiation then Fluoropyrimidine for selected patient pT2N0 R0 resection pT3,pT4,Any N/Any pT,N+ Surveillance or Fluoropyrimidine Then Fluoropyrimidine based chemoradiation then Fluoropyrimidine if less than D2 dissection Or Chemotherapy for patients who have undergone D2 dissection

23. Continue…….. R1 resection Fluoropyrimidine based Chemoradiation Fluoropyrimidine based chemoradiation Or Palliative Management as clinically indicated R2 resection Palliative Management pM1

24. Continue…….. Observation until progression(if received preoperative chemo radiotherapy) Or Chemotherapy if received preoperatively Node negative (yp Any T,N0) R0 resection Node positive (yp Any T,N+) Chemoradiation(if not received preoperatively) Or Chemotherapy(if received pre-operatively) Or Consider Re-resection R1 resection

25. Continue…….. Chemoradiation(if not received preoperatively) Or Palliative Management as clinically indicated R2 resection ypM1 Palliative Management

26. Post Treatment Assessment Resectable Surgery • Restaging • Chest/abdomen/pelvic CT With oral and IV contrast • CBC and comprehensive chemistry profile • PET/CT scan as clinically indicated Unresectable disease or non-surgical candidates following primary treatment • Unresectable • Inoperable • Metastatic disease Palliative management

27. Principles of Systemic Therapy • In Advanced esophageal and EGJ adenocarcinoma, squamous cell carcinoma of the esophagus and gastric carcinoma regimens may be used interchangeably (except as indicated) • Regimens should be chosen in context of PS, Medical comorbidities and toxicity profile. • Two drugs regimens should be preferred over three drugs regimen in advanced case • Modification of category 1 regimen or use of Category 2A or 2B may be preferred without compromising efficacy within safety toxicity profile

28. Continue…. • Perioperative or postoperative plus chemo- radiation is the preferred option for localized Gastric cancer. • Postoperative CT is recommended following primary D2 lymph node dissection. • Trastuzumab should be added to CT in HER2 overexpressed metastatic adenocarcinoma. • Patient should be monitored for long time therapy related complications. Source: NCCN guide line 2.2018

29. More advanced treatment is clinical trial

30. Major Phase-3 Trials in Pre-operative settings Cunningham et al (MAGIC) ECF->Surgery->ECF vs Surgery alone HR for OS 0.75(.009) CF->Surgery->CF vs Surgery alone HR for OS 0.69(.02) Ychou et al (FNLCC/FFCP) HR for OS 0.16 CFL->Surgery vs Surgery Schumscher et al (EORTC 40954)

31. Major Phase-3 Trials in Post-operative Chemoradiotherapy Macdonald et al (INT-0116) Surgery->FL/CTRT(45gy+FL)/FL vs Surgery alone HR for OS 1.32(.004) Surgery->ECF/CTRT+FL/ECF vs Surgery->FL/CTRT+FL/FL HR for OS 1.03(.80) Fuchs et al (CALGB 80101) Surgery->XP/XRT/XP vs Surgery->XP HR for OS 1.13(.52) Park et al (ARTIST)

32. Major Phase-3 Trials in Post-operative Chemotherapy Sakuramoto et al (ACTS-GC) Surgery->S-1 vs Surgery alone HR for OS 0.68(.003) Surgery->CapOxvs Surgery HR for OS 0.56(<.0001) Bang et al (CLASSIC) HR for DFS 0.81(.0043) for monotherapy (0.151) for non-inferiority of UFT Surgery->UFT vs S urgery->paclitaxel+UFTvs Surgery->paclitaxel+S-1 Tsuburaya et al (SAMIT)

34. Newer Phase-3 trials S-1 adjuvant CT at 1 year showed remarkable survival results for type 4 or type 3 gastric cancer and NACT is not recommended Neo adjuvant chemotherapy (CPL+S-1)->surgery->Adjavant Chemotherapy(S-1) vs Surgery->Adjuvant Chemotherapy (S-1) JCOG 0501

36. Newer Phase-3 trials Pre operative chemotherapy (ECF)->CTRT->surgery->Adjuvant Chemotherapy(ECF) vs Neo-Adjuvant CT(ECF)->Surgery->Adjuvant Chemotherapy (ECF) Part 1 study is completed and Part 2 study is ongoing & results not published Leong et al (TOPGEAR)

38. Newer Phase-3 trials Post operative chemo radiotherapy did not improve OS compared with post operative chemotherapy in patient with resectable gastric cancer after adequate preoperative chemotherapy and surgery Pre operative chemotherapy (ECF)->surgery->CTRT + Adjuvant Chemotherapy(CX) vs Neo-Adjuvant CT(ECx)->Surgery->Adjuvant Chemotherapy (ECx) Dikken et al (CRITICS)

39. Targeted therapy in gastric cancer • Transtuzumab was first drug established as standard treatment of un resectable HER-2+ve Stomach cancer • Many other Targets are recognized as new therapeutic targets • Agents targeting epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR), MET, or the mammalian target of rapamycin (mTOR) have been investigated

40. Follow up/Surveillance • H&P every 3-6 mo for 1-2 y, every 6-12 mo for 3-5 y, and annually thereafter • CBC & chemistry profile as clinically indicated • Upper GI endoscopy 6 mo for 1 y then annually for 3 year • Routine imaging(CT chest/abdomen/pelvis with contrast) as clinically indicated based on symptoms and concern for recurrence Tis successfully treated by ER

41. Follow up/Surveillance • H&P every 3-6 mo for 1-2 y, every 6-12 mo for 3-5 y, and annually thereafter • CBC & chemistry profile as clinically indicated • For ER patients Upper GI endoscopy 6 mo for 1 y then annually for 3 year • For surgically resected patients Upper GI endoscopy as clinically indicated • Routine imaging(CT chest/abdomen/pelvis with contrast) as clinically indicated • Monitor for nutritional deficiency(B12& iron) in surgically treated patient and treat as indicated P stage 1(T1a,T1b,N0-1 treated by surgical resection or T1a treated by ER

42. Follow up/Surveillance • H&P every 3-6 mo for 1-2 y, every 6-12 mo for 3-5 y, and annually thereafter • CBC & chemistry profile as clinically indicated • For surgically resected patients Upper GI endoscopy as clinically indicated • Routine imaging(CT chest/abdomen/pelvis with contrast) every 6-12 mo for first 2 y,then annually upto 5 years ± PET/CT as clinically indicated • Monitor for nutritional deficiency(B12& iron) in surgically treated patient and treat as indicated P stage 2/3 or yp stage 1-3 (treated with neoadjuvant± adjuvant therapy)

43. THANK YOU

44. Definition of Primary Tumor Staging of Stomach Cancer

45. Definition of Primary Tumor Staging of Stomach Cancer

46. Newer Trials of Targeted therapy

47. Staging of Stomach Cancer

48. Pathological TNM Staging of Stomach Cancer

49. Pathological TNM Staging of Stomach Cancer

50. Staging of Stomach Cancer