CARCINOMA STOMACH- MANAGEMENT PRINCIPLES

CARCINOMA STOMACH- MANAGEMENT PRINCIPLES

1. CARCINOMA STOMACH - Management PROF MOHD MOJEEB AHSAN

2. SURGICAL THERAPY – the only potentially curative t/t Objective : Complete resection of gastric tumor with a wide margin (≥  5 cm). i.e., R0 resection  Adequate lymphadenectomy what is R status ? Describes tumor status after resection R0 –   microscopically margin-negative resection. R1 – macroscopic clearance   of tumor but microscopic margins are positive. R2 – gross residual disease.

3. Total gastrectomy should not be considered as a routine procedure for gastric cancer. Patients in whom R0 resection can be obtained, a more limited gastric resection (e.g., proximal esophago-gastrectomy or distal subtotal gastrectomy) provides the same survival result and less perioperative morbidity. Surgery Endoscopic sub-mucosal resection Hemi- gastrectomy Subtotal gastrectomy Total gastrectomy

4. Surgery Best chance for long-term survival - complete surgical eradication of a tumor with resection of adjacent nodes More than 15 resected lymph nodes are required for adequate staging. 6 factors determine the extent of gastric resection- Tumor stage Tumor histology or type Tumor location Nodal drainage Peri-operative morbidity Long-term gastro-intestinal function

5. Surgery Indications of unresectability Distant metastases Invasion of a major vascular structure such as the aorta Encasement or occlusion of the hepatic artery or celiac axis / proximal splenic artery Nodes behind or inferior to the pancreas, aorto- caval region, into the mediastinum, or in the porta hepatis  Distal splenic artery involvement is not an indicator of unresectability

6. EMR ( Endoscopic Mucosal resection) Injection of a substance under the targeted lesion to act as a cushion, lesion is then removed with a snare or suctioned into a cap and snared.

7. ESR (Endoscopic sub-mucosal resection)   Injection of a substance under the targeted lesion to act as a cushion, submucosa is instead dissected under the lesion with a specialized knife. This enables removal of larger and potentially deeper lesions  higher rates of R0 resections and a lower rate of local recurrence, but  technically demanding and has more adverse events .

8. ESR has three main advantages over surgery;  less invasive,  less expensive, and  better preserves physiological function.

9. Disadvantage Incomplete resection d/t  large tumor size or  unrecognised LN metastasis Guidelines for ESR  All intramucosal tumors (any size), without ulceration  Differentiated mucosal tumors of < 3cm, with/without ulceration  Limited submucosal invasion with size < 3 cm & without ulceration

10. Additional surgery after ESR Additional surgery with lymph node dissection is recommended when ER is histologically non-curative.  Non-curative ESR is defined as- the presence of cancer cells in the lateral or deep margins,  invasion to the deep layer,  the presence of lymphatic vessel invasion,  the presence of an undifferentiated cell type, a combination of above mentioned conditions.

11. Distal 1/3 rd tumor : Distal gastrectomy Hemigastrectomy Subtotal gastrectomy Middle 1/3 rd tumor : Subtotal gastrectomy Total gastrectomy

12. Proximal 1/3 rd tumor :  Proximal esophago-gastrectomy (if R0 resection possible)    - leads to symptomatic reflux  Total gastrectomy Gastric cancers within the proximal stomach  have worst prognosis 

13. Extent of lymph node dissection D1 Perigastric nodes (station 1-6 ) Conservative node dissection D2 D1 + left gastric, Common hepatic, celiac & splenic L.N . ( 7-11 ) Extended node dissection D3 D2 + Hepato-duodenal ligament, retropancreatic & mesenteric root ( 12-16 ) Super-extended lymphadenectomy D4 D3 + para-aortic and para colic LN dissection

14. Extended lymphadenectomy (D2 to D4) Performed by most of Japanese surgeons Removal of larger number of nodes Greater the probability of positive nodes More accurately stages disease extent Explain better survival results in Asian patients Bunt AM et al. J Clin Oncol 1995; 13:19.37 de Manzoni G et al. Br J Cancer 2002; 87:171

15. Two main arguments against the routine use of an extended lymphadenectomy Higher morbidity and mortality Lack of a survival benefit in most large randomized trials Medical Research Council (MRC) trial Prospective randomized trial 400 pts undergoing curative resection to D1 or D2 lymphadenectomy   Conclusion Postoperative morbidity was significantly greater in the D2 group - 46 vs 28%, operative mortality - 13 vs 6% Cuschieri A et al. Lancet 1996; 347:995

16. Extent of nodal dissection D1 v/s D2 most controversial area in gastric cancer management Non japanese literature D2 lymphadenectomy, when compared with a D1 dissection, has increased surgical morbidity, without a benefit in survival . Japanese literature Increased survival in patients undergoing a D2 dissection, with no increased or minimal increase in morbidity.

17. Resectable or not ? Involvement of other organ per se does not imply incurability, provided that it can be removed …. Bailey and love’s short practice of surgery 26 th ed. Therapeutic nihilism should be avoided &, in low risk patient, an aggressive attempt to resect all tumor should be made. The primary tumor may be resected en bloc with adjacent involved organs ( eg ., pancreas, transverse colon , or spleen ) …… Schwartz’ Princilpes of Surgery 10 th ed. A solitary metastatic nodule in liver is also no indication against curable resection. .. (CSDT) Current Diadnosis and Treatment, Surgery 14 th ed.

18. Steps in Total gastrectomy Long mid-line incision or bilateral subcostal incision (chevron) Detachment of greater omentum from colon anterior layer of mesocolon is dissected from mesocolonic vessels Dissect upto inferior border of pancreas and divide Rt GE vessels Dissect upto splenic hilum, ligate Lt. GE & short gastric dissect lesser omentum from the undersurface of the Liver extending back to the right crus and mobilizing the right aspect of G-E junction. Divide duodenum with GIA stapler

19. close the duodenal stump with interrupted horizontal 3-0 absorbable mattress sutures, essentially "dunking“ the duodenum. Dissection of porta , hepatic artery, & celiac axis is completed from above down Left gastric artery divided at its origin f/b clearance of right crus and celiac axis dissection of all the tissue from Lt. crus & paracardial LNs Mobilization of esophageal hiatus by detaching the peritoneal reflection from the diaphragm Divide esophogus sharply by knife or scissors

20. Steps in Subotal gastrectomy Mobilization of the greater curvature with omentectomy & division of left gastroepiploic vessels Infra-pyloric mobilization with ligation of the right gastroepiploic vessels Supra-pyloric mobilization with ligation of the right gastric vessels Duodenal transection D2 lymphadenectomy, with dissection of the porta hepatis, common hepatic artery, left gastric artery, celiac axis, & splenic artery, and ligation of left gastric vessels Gastric transection

21. Reconstruction after surgery After total gastrectomy  Roux-en-Y esophago-jejunostomy  Division of jejunum with GIA stapler end-to-side esopago -jejunostomy

22. full-thickness running suture Placement of the EEA stapler through the divided loop Completion of the stapled anastomosis and closure of the end of the loop with a stapler.

23. Completed Roux-en-Y reconstruction Post-op : Unless fever or ileus develops, the patient is allowed ice on the 1st day and can be given nutrient by the 5th day. Any concern clinically for anastomotic leak can be confirmed by a Gastrografin Swallow, which is not routine Jejunal loop should be at least 40 cm from the subsequent jejunojejunal anastomosis to minimize esophageal reflux. ​

24. After Subtotal gastrectomy   Loop gastro-jejunostomy ( Bilroth II)                   or Roux-en-Y gastrojejunostomy Stomach divided at greater curvature for 6-8 cm by knife (site of future anastamosis ) and then completely divided with GIA stapler Staple line inverted with suture Anticolic Bilroth II Retrocolic Bilroth II Bilroth II

25. After Subtotal gastrectomy  Roux-en-Y gastrojejunostomy jejunum is divided with GIA stapler approx. 20cm distal to the ligament of Treitz end-to-side Roux-en-Y gastrojejunostomy is created with a Roux limb at least 45cm in length to avoid reflux

26. Laparoscopic resection Meta-analysis of 5 randomized trials and 18 non –randomized comparisons of laparoscopic versus open gastrectomy came to following conclusions Mean number of lymph nodes retrieved by laparoscopic surgery was close to that retrieved by open procedure Less blood loss Lengthier operative times Conversion rate – 0 – 3% Significantly less postoperative morbidity after a laparoscopic procedure No difference in long term survival Revised Japanese Gastric Cancer Treatment Guidelines Laparoscopy-assisted gastrectomy eligible for - stage IA and IB (T1N1, T2N0) cancers.

27. Peri -operative Chemotherapy MAGIC trial Randomised controlled study of 503 pts. With stage II or higher gastric cancer that compared perioperative chemotherapy with surgery alone. CEF ( Cisplatin , Epirubicin , 5-FU) - 3 cycles as neo- adjuvent CT - 3 cycles as adjuvent CT 5-yr survival, rate of local recurrence & distant metastasis were improved in CT group UK National Cancer Institute trial OEX ( Oxaliplatin , Epirubicin , Capecitabine ) longer overall survival than with CEF and decreased incidence of thromboembolic phenomenon by substituting oxaliplatin for cisplatin

28. Intraperitoneal Chemotherapy (IPC) Recurrence following curative resection is likely due to peritoneal carcinomatosis. Systemic CT : blood-peritoneal barrier prevents the chemotherapeutic agents from achieving their cytotoxic effect. IPC : administering high doses of chemotherapy directly to the peritoneum whilst reducing the systemic effects.    increased risk of neutropaenia and intra-abdominal abscesses .

29. Adjuvent Radiotherapy Improvement in DFS and OS with post-operative chemoradiation than with surgery alone. Radiotherapy is limited, due to its position near vital organs like kidney spinal cord, pancreas, liver & bowel. Stomach itself is highly sensitive, tends to bleed and ulcerate with EBRT. Intraoperative radiotherapy (IORT) Still it needs to define the role of IORT in gastric carcinoma.

30. Treatment of Advanced Disease (Stage IV) Palliative Systemic Chemotherapy versus Best Supportive Care Problems with Systemic Chemotherapy-  the modest activity and  substantial toxicity  advantage  of early initiation of systemic therapy versus best supportive care -  CONTROVERSIAL

31. The average quality-adjusted survival for chemotherapy patients was superior to best supportive care patients (6 months vs. 12 months). Single-Agent Chemotherapy Fluorouracil - parent fluorinated pyrimidine. One method involved the use of rapid intravenous injections on a weekly basis or daily for 5 consecutive days. the major toxicities reported are mucositis, diarrhea, or mild myelosuppression.

32. Platinum compounds - cisplatin Response rate of approximately 15% was reported. Taxanes - paclitaxel and docetaxel The overall response rate was 19.1%

33. Irinotecan- Both as a single agent and in combination.  When used alone, response rates of 15% to 25% have been reported in both previously treated and untreated patients. Anthracyclines   response rate for doxorubicin of 17%, and for epirubicin of 19%.

34. Single-Agent versus Combination Chemotherapy In the recent Cochrane review - The difference in average survival, however, was quite modest, 7 months for combination chemotherapy versus slightly less than 6 months for single agents.

35. Combination Chemotherapy Cisplatin-Fluorouracil One of the most widely used.  Cycles were given on an every 28-day basis.   Tumour regression was reported in 20% to 30% of patients.

36. Docetaxel, Cisplatin, and Fluorouracil The median time to progression was 3.7 months for patients receiving cisplatin-fluorouracil, and 5.6 months for those receiving DCF.

37. Epirubicin, Cisplatin, and Fluorouracil ECF was more effective  both in terms of response rate and for median survival 8.7 months. Cisplatin Plus Irinotecan Response rates were encouraging, and toxicity was tolerable. Fluorouracil-Leucovorin-Oxaliplatin Median overall survival of 10 to 12 months.

38. Targeted Therapy Bevacizumab     A humanized monoclonal antibody that binds the vascular endothelial growth factor ligand.   Bevacizumab was given at 15 mg/kg on a once every 3-week basis. Bevacizumab could safely be given with cytotoxic chemotherapy, including in patients in whom the primary tumor was still in place.

39. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Erlotinib and Gefitinib Cetuximab

40. Surgery for Palliation Because the survival for patients with advanced gastric cancer is so poor, any proposed operation should have a good chance of providing sustained symptomatic relief while minimizing the attendant morbidity and need for prolonged hospitalization. Resection may provide palliation of symptoms ; however, survival after total gastrectomy is exceedingly poor, ranging from 3 months to 1yr.

41. Distal obstructions may now be alleviated by the endoscopic placement of self-expanding endoluminal stents .  Such stents are effective in up to 85% of patients, with an uninterrupted duration of function of 5-6 months. Thus, whenever possible, patients who have M1 disease should be approached by nonoperative means .

42. Radiation for Palliation To date, no studies have evaluated the use of radiation therapy in patients with locally recurrent or metastatic carcinoma. Its use is limited to palliation of symptoms such as bleeding controlling pain secondary to local tumor.

43. Summary >= 5 cm margin clearance of tumor is recommended. Lymphadenectomy is essential. Resection of greater & lesser omentum is necessary. For proximal lesions varying length of esophagus should be excised. Judicious decision should be taken for total, proximal & distal gastrectomy. All patient should receive chemoradiation .

44. Summary EUS and CT are primary staging modalities PET useful in staging, recurrence detection and measuring response to therapy Laparoscopy useful in loco-regional gastric cancer (M0) to guide further management Japanese classification focuses on anatomic location of the nodes (designated by stations) In AJCC classification nodal stage is based on number of involved nodes Proximal gastric cancers – TG preferred because of less incidence of complication

45. Summary Distal gastric tumors – SG preferred Assessment of adjacent organ invasion by preoperative CT or intra-operative assessment is unreliable Extended lymphadenectomy (D2 to D4) More accurately stages disease extent Explain better survival results in Asian patients Higher morbidity and mortality Lack of a survival benefit in most large randomized trials

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