Treatment of Advanced Disease (Stage IV)

Postgastrectomy Problems:

Postgastrectomy Problems

Dumping Syndrome:

Dumping Syndrome Dumping is a phenomenon caused by the destruction or bypass of the pyloric sphincter. Clinically significant dumping occurs in 5 to 10% of patients after pyloroplasty , pyloromyotomy , or distal gastrectomy , and consists of a constellation of postprandial symptoms

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early dumping occurs a bout 15 to 30 minutes after a meal, the patient becomes diaphoretic, weak, light-headed, and tachycardic . These symptoms may be ameliorated by recumbence or saline infusion. Crampy abdominal pain is not uncommon and diarrhea often follows. thought to be the result of the abrupt delivery of a hyperosmolar load into the small bowel.

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late dumping which usually occurs later (2 to 3 hours following a meal), and is relieved by the administration of sugar. A variety of hormonal aberrations have been observed in early dumping, including increased VIP, CCK, neurotensin , peripheral hormone peptide YY, renin-angiotensin-aldosterone , and decreased atrial natriuretic peptide. Late dumping is associated with hypoglycemia and hyperinsulinemia .

medical therapy:

medical therapy consists of dietary management and somatostatin analogue ( octreotide ). avoids liquids during meals. Avoid Hyperosmolar liquids (e.g., milk shakes) dietary fiber compounds at mealtime dietary manipulation fails, the patient is started on octreotide , 100 g subcutaneously twice daily. This can be increased up to 500 g twice daily if necessary. The - glucosidase inhibitor acarbose may be particularly helpful in ameliorating the symptoms of late dumping.

Surgical Mx:

Surgical Mx Most patients improve with time (months and even years), dietary management, and medication. takedown of gastrojejunostomy , interposition of a 10-cm reversed intestinal segment between the stomach and duodenum, conversion of Billroth II to Billroth I anastomosis , and conversion to Roux-en-Y anastomosis

Afferent loop syndrome:

Afferent loop syndrome

Diarrhea:

Diarrhea Possible mechanisms include intestinal dysmotility and accelerated transit, bile acid malabsorption , rapid gastric emptying, and bacterial overgrowth. The latter problem is facilitated by decreased gastric acid secretion and (even small) blind loops. Although bacterial overgrowth can be confirmed with the hydrogen breath test, a simpler test is an empirical trial of oral antibiotics. Some patients with diarrhea respond to cholestyramine , while in others codeine or loperamide may be useful.

Gastric stasis:

Gastric stasis Gastric stasis following surgery on the stomach may be due to a problem with gastric motor function or be caused by an obstruction. The gastric motility abnormality may have been pre-existing and unrecognized by the operating surgeon. Alternatively, it may be secondary to deliberate or unintentional vagotomy , or resection of the dominant gastric pacemaker. An obstruction may be mechanical (e.g., anastomotic stricture, efferent limb kink from adhesions or constricting mesocolon , or a proximal small-bowel obstruction) or functional (e.g., retrograde peristalsis in a Roux limb). Gastric stasis presents with vomiting (often of undigested food), bloating, epigastric pain, and weight loss.

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Once mechanical obstruction has been ruled out, medical treatment is successful in most cases of motor dysfunction following previous gastric surgery. This consists of dietary modification and promotility agents. Intermittent oral antibiotic therapy may be helpful in treating bacterial overgrowth, with its attendant symptoms of bloating, flatulence, and diarrhea .

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Billroth II anastomosis with Braun enteroenterostomy may be preferable to Roux-en-Y reconstruction. This latter option may be associated with persistent emptying problems that will subsequently require near-total or total gastrectomy , a nutritionally unattractive option. Gastroparesis following subtotal gastric resection is best treated with near-total (95%) or total gastric resection and Roux-en-Y reconstruction. If total gastrectomy is performed, a jejunal reservoir should be fashioned.

Bile Reflux Gastritis:

Bile Reflux Gastritis Most patients who have undergone ablation or resection of the pylorus have bile in the stomach on endoscopic examination, along with some degree of gross or microscopic gastric inflammation. it is generally accepted that a small subset of patients have bile reflux gastritis, and present with nausea, bilious vomiting, and epigastric pain, and quantitative evidence of excess enterogastric reflux. Curiously, symptoms often develop months or years after the index operation.

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differential diagnosis includes afferent or efferent loop obstruction, gastric stasis, and small-bowel obstruction. Plain abdominal x-rays, upper endoscopy, upper GI series, abdominal CT scan, and gastric emptying scans are helpful in evaluating these possibilities. Typically, enterogastric reflux is greatest after Billroth II gastrectomy or gastrojejunostomy , and least after vagotomy and pyloroplasty , with Billroth I gastrectomy giving intermediate values.

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Bile reflux gastritis after distal gastric resection may be treated by one of the following options: Roux-en-Y gastrojejunostomy ; interposition of a 40-cm isoperistaltic jejunal loop between the gastric remnant and the duodenum (Henley loop); or Billroth II gastrojejunostomy with Braun enteroenterostomy .

Roux Syndrome:

Roux Syndrome A subset of patients who have had distal gastrectomy and Roux-en-Y gastrojejunostomy will have great difficulty with gastric emptying in the absence of mechanical obstruction. These patients present with vomiting, epigastric pain, and weight loss. This clinical scenario has been labeled the Roux syndrome . Endoscopy may show bezoar formation, dilation of the gastric remnant, and/or dilation of the Roux limb. An upper GI series confirms these findings and may show delayed gastric emptying. This is better quantified by a gastric emptying scan , which always shows delayed solid emptying, and may show delayed liquid emptying as well.

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Medical treatment consists of promotility agents. Surgical treatment consists of paring down the gastric remnant. If gastric motility is severely disordered, 95% gastrectomy should be done. The Roux limb should be resected if it is dilated and flaccid, unless doing so puts the patient at risk for short bowel problems. GI continuity may be re-established with another Roux, a Billroth II with Braun enteroenterostomy , or an isoperistaltic jejunal interposition between the stomach and the duodenum (Henley loop).

Gallstones:

Gallstones is thought to be secondary to vagal denervation of the gallbladder with attendant gallbladder dysmotility . Although prophylactic cholecystectomy is not justified with most gastric surgery, it should be considered if the gallbladder appears abnormal, especially if subsequent cholecystectomy is likely to be difficult. If preoperative evaluation reveals sludge or gallstones, or if intraoperative evaluation reveals stones, cholecystectomy should be done if it appears straightforward and the gastric operation has gone well.

Weight Loss:

Weight Loss The causes of weight loss after gastric surgery generally fall into one of two categories: altered dietary intake or malabsorption . If a stool stain for fecal fat is negative, it is likely that decreased caloric intake is the cause. small stomach syndrome, postoperative gastroparesis , or self-imposed dietary modification because of dumping and/or diarrhea . bacterial overgrowth and malabsorption , or an unrecognized preoperative problem (commonly a motor disorder).

Anemia:

Anemia Iron absorption takes place primarily in the proximal GI tract, and is facilitated by an acidic environment. Intrinsic factor, essential for the enteric absorption of vitamin B12, is made by the parietal cells of the stomach. Vitamin B 12 bioavailability also is facilitated by an acidic environment. Pt should be monitored with periodic determination of hematocrit , red blood cell indices, iron and transferrin levels, B 12 , and folate levels. Marginal nutrient status should be corrected with oral and/or parenteral supplementation.

Bone Disease:

Bone Disease Calcium absorption occurs primarily in the duodenum, which is bypassed with gastrojejunostomy . Fat malabsorption may occur because of blind loop syndrome and bacterial overgrowth, or because of inefficient mixing of food and digestive enzymes. This can significantly affect the absorption of vitamin D, a fat-soluble vitamin. The problems usually manifest as pain and/or fractures years after the index operation. Musculoskeletal symptoms should prompt a study of bone density. Dietary supplementation of calcium and vitamin D may be useful in preventing these complications.

Treatment of Advanced Disease (Stage IV):

Treatment of Advanced Disease (Stage IV)

Palliative Systemic Chemotherapy:

Palliative Systemic Chemotherapy

Chemotherapy versus Best Supportive Care:

Chemotherapy versus Best Supportive Care Regimen No. of Patients Median Survival (mo) BSC 10 3 FEMTX 17 12 BSC 19 3 ETOPLF 10 10

Single Agent Chemotherapy:

Single Agent Chemotherapy FLUORINATED PYRIMIDINES 5-fluorouracil 21 UFT 28 S1 49 JCOG 9912 Capecitabine 26 Korean trial HEAVY METALS Cisplatin 19 TAXANES Paclitaxel 17 Docetaxel 19 CAMPTOTHECANS Irinotecan hydrochloride 23

COMBINATION CHEMOTHERAPY :

COMBINATION CHEMOTHERAPY A meta-analysis that included trials performed in patients with advanced gastric cancer (predominantly using older combination regimens) concluded that first-line combination therapy was associated with a modest but statistically significant survival benefit when compared to single agent therapy. The hazard ratio for death was 0.83 in favor of combination chemotherapy, but this translated into only a one-month survival advantage .

Older cisplatin-based regimens :

Older cisplatin -based regimens Study Drug Dose ( mg/ mL Schedule (days) No. of Patients RR (%) Median TTP/PFS (mo) Med Survival (mo) 2 Y Survival (%) EORTC (201) C F 100 1,000 1 1-5 127 20 4.1 7.2 ~10 JCOG (199) C F 20 800 1-5 1-5 105 36 7.3 3.9 7 Dank et al. (202) C F 100 1,000 1 1-5 163 26 4.2 8.7 ~10 TAX325 (200) C F 100 1,000 1 1-5 224 25 3.7 8.6 9 REAL-2 (212) E C F 50 60 200 1 1 Daily 289 41 6.2 9.9 ~15

SPIRITS trial:

SPIRITS trial significant benefit for combined S1 plus cisplatin over S1 alone in terms of both response rate (54 versus 31 percent) and median survival (13 versus 11 months, p = 0.04) in an Asian population. Rates of grade 3 or 4 neutropenia (40 versus 11 percent), anemia (26 versus 4 percent), nausea (11 versus 1 percent), and anorexia (30 versus 6 percent) were also significantly higher.

FLAGS trial:

FLAGS trial which randomly assigned 1053 patients to cisplatin plus either 5-FU or S-1. Median overall survival (the primary endpoint) was not significantly inferior with cisplatin /S-1 as compared to cisplatin /5-FU (8.6 versus 7.9 months) . Furthermore, cisplatin /S1 had a more favorable side effect profile than cisplatin /5-FU (grade 3 or 4 neutropenia in 32 versus 64 percent, stomatitis in 1 versus 14 percent, and hypokalemia in 4 versus 11 percent), and fewer treatment-related deaths (2.5 versus 4.9 percent).

ECF and the REAL trial :

ECF and the REAL trial The REAL trial was a landmark large randomized trial reported in 2008 that compared four different chemotherapy regimens in 1002 patients with advanced gastric cancer.

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ECF Epirubicin 50 mg/m 2 IV 1 Every 3 weeks Cisplatin 60 mg/m 2 IV 1 PVI 5-FU 200 mg/m 2 /D b 1 EOF Epirubicin 50 mg/m 2 IV 1 Every 3 weeks Oxaliplatin 130 mg/m 2 IV 1 PVI 5-FU 200 mg/m 2 /D b 1 ECX Epirubicin 50 mg/m 2 IV 1 Every 3 weeks Cisplatin 60 mg/m 2 IV 1 Capecitabine 625 mg/m 2 /BD 1 EOX Epirubicin 50 mg/m 2 IV 1 Every 3 weeks Oxaliplatin 130 mg/m 2 IV 1 Capecitabine 625 mg/m 2 BD 1

Results:

Results the trial showed that outcomes were comparable when capecitabine was substituted for infusional 5-FU in the ECF regimen. They also showed that outcomes were comparable when oxaliplatin was substituted for cisplatin in the ECF regimen. However, when the four groups were considered separately, median survival in patients treated with EOX was modestly longer when compared to ECF (median 11.2 versus 9.9 months, hazard ratio 0.80, 95% CI 0.66 to 0.97). These data have led some to conclude that EOX is preferred over ECF for first-line therapy.

Taxane based regimen:

Taxane based regimen DCF Van Cutsem, E; 2006 Docetaxel 75 mg/ m2 day 1 21 days Cisplatin: 75 mg/m2 day 1 5-FU: 750mg/m2/day continuous infusion, days 1 through 5 Modified DCF Kelsen, D; 2009 Docetaxel: 40 mg/m2 day 1 14 days LV: 400 mg/m2 day 1 5-FU: 400 mg/m2 IV bolus then 1000 mg/m2 per day, days 1 and 2 by IV continuous infusion Cisplatin : 40 mg/m2 day 3

TAX-325 trial:

TAX-325 trial Compared DCF (75/75/750) v/s CF(100/1000) The group receiving docetaxel did significantly better in terms of response rates (37 versus 25 percent), time to tumor progression (TTP, 5.6 versus 3.7 months) and two-year survival (18 versus 9 percent). Although the incidence of grade 3 or 4 diarrhea (20 versus 8 percent) and neutropenia (30 versus 14 percent) was higher with triple therapy, rates of any grade 3 or 4 toxicity during therapy were high in both groups (81 and 75 percent, respectively ).

Oxaliplatin combinations:

Oxaliplatin combinations A variety of different regimens have been studied in phase II trials (FOLFOX, EOF, XELOX [CAPOX]), all of which are associated with response rates in the range of 40 to 67 percent, with median survival durations between 8 and 15 months

FLO v/s FLP:

FLO v/s FLP a phase III trial comparing the FLO regimen ( infusional 5-FU 2600 mg/m2 over 24 hours, leucovorin 200 mg/m2, and oxaliplatin 85 mg/m2, all drugs cycled every 14 days) versus FLP (5-FU 2000 mg/m2 over 24 hours plus leucovorin 200 mg/m2 weekly and cisplatin 50 mg/m2 every 14 days) in 220 patients with metastatic gastroesophageal adenocarcinoma . There were no statistically significant differences between the two arms in terms of median PFS (the primary endpoint, 5.7 versus 3.9 months), response rate (35 versus 25 percent), or median survival (10.7 versus 8.8 months). FLO was associated with significantly less nausea and vomiting, fatigue, renal toxicity and alopecia, but more grade 3 or 4 sensory neuropathy (14 versus 2 percent, respectively).

Biologic Agents:

Biologic Agents

Trastuzumab:

Trastuzumab Approx. 25% of the gastric cancer overexpress Her2-type 2 EGFR. Her2 positivity more common in intestinal type than diffuse type,(32 v/s 6%).

ToGA trial:

ToGA trial which compared standard chemotherapy (six courses of infusional 5-FU or capecitabine plus cisplatin ) with and without trastuzumab (8 mg/kg loading dose, then 6 mg/kg every three weeks until disease progression) . The objective response rate was significantly higher with trastuzumab (47 versus 35 percent). At a median follow-up of 17.1 to 18.6 months, median overall survival (the primary endpoint) was significantly better with trastuzumab (13.8 versus 11.1 months). The toxicities in the two arms were comparable, except that a higher number of trastuzumab -treated patients had grade 3 or 4 diarrhea (9 versus 4 percent) and an asymptomatic decrease in left ventricular ejection fraction (LVEF, 5 versus 1 percent). Only one patient developed grade 3 to 4 cardiac failure (versus two in the control group ).

Bevacizumab:

Bevacizumab I n the global phase III AVAGAST trial , in which 774 patients with previously untreated locally advanced unresectable or metastatic (98 percent) gastric or GEJ cancer were randomly assigned to capecitabine (1000 mg/m2 twice daily for 14 of every 21 days) plus cisplatin (80 mg/m2 on day 1) with either bevacizumab (7.5 mg/kg day 1) or placebo . Cycles were repeated every three weeks for a maximum of six cycles of cisplatin ; thereafter, capecitabine plus either bevacizumab or placebo was continued until disease progression.

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In a preliminary report presented at the 2010 ASCO meeting, there was no significant benefit from bevacizumab in median overall survival (the primary endpoint, 12.1 versus 10.1 months, HR 0.87, 95% CI 0.73 to 1.03). However, the use of bevacizumab significantly improved both objective response rate (46 versus 37 percent) and median progression-free survival (6.7 versus 5.3 months, HR 0.80, 95% CI 0.68 to 0.93]). The incidence of venous and arterial thrombosis did not differ between the two groups and although rates of hypertension and bleeding were slightly higher, most of the bleeding was grade 1 nasal bleeding.

Other Agents:

Other Agents Cetuximab Gefitinib Erlotinib Sunitinib and sorafenib

SUMMARY AND RECOMMENDATIONS:

SUMMARY AND RECOMMENDATIONS First-line chemotherapy Despite a large number of randomized trials, there is no consensus as to the best agent or regimen. In general, combination chemotherapy regimens provide higher response rates than do single agents, but this translates into only modestly longer durations of disease control and survival that are measured in weeks to a few months. In randomized trials, the ECF or DCF combinations have emerged as standard regimens for first-line treatment. A major problem with these regimens is the need for central venous access and an ambulatory infusion pump.

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the addition of trastuzumab to chemotherapy in patients with HER2-positive tumors (as defined by 3+ immunohistochemical staining or FISH positivity), as long as they do not have a contraindication to trastuzumab ( Grade 2B ). For elderly patients or those with a poor performance status, we suggest leucovorin -modulated 5-FU alone or single agent capecitabine ( Grade 2B ). Other reasonable alternatives include single agent irinotecan , or low-dose weekly taxanes .

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Response is assessed using a combination of interval radiographic evaluation (typically every two to three cycles), serum tumor markers such as carcinoembryonic antigen (CEA) (if elevated at baseline), and clinical status of the patient. Radiographic tumor response is usually quantified using RECIST (Response Evaluation Criteria In Solid Tumors ). While persistently rising levels of a serum tumor marker suggests disease progression, this should be confirmed by radiologic studies prior to a change in therapeutic strategy

Second line chemotherapy:

Second line chemotherapy In general, clinical trials assessing the efficacy of a variety of second-line chemotherapy regimens after failure of the first-line regimen have shown that response rates are lower than they are in previously untreated patients, and toxicity rates tend to be higher. The criteria to select patients for second-line chemotherapy have not been established. In one study, five factors were identified that were independently associated with poor survival: performance status 2, hemoglobin ≤11.5 g/ dL , serum carcinoembryonic antigen (CEA) level >50 ng / mL , three or more metastatic sites, and time to progression ≤6 months after the first-line regimen . A prognostic index was developed which divided patients into low- (no risk factors), intermediate- (one or two risk factors) or high-risk (three or more risk factors) groups with different median survival durations (12.7, 7.1, and 3.3 months, respectively).

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Data from the REAL-2 trial suggest that outcomes are comparable if capecitabine is substituted for infusional 5-FU, and when oxaliplatin is substituted for cisplatin in the ECF regimen. When both oxaliplatin and capecitabine are substituted in the ECF regimen, outcomes may be better than with ECF. While the use of capecitabine allows patients to avoid infusion pumps and a central venous catheter, the costs of capecitabine and oxaliplatin are significantly higher than with 5-FU and cisplatin , and toxicity is not necessarily less. FOLFOX is another reasonable option.