Radiation Oncology/Stomach/Randomized

Level I Evidence for Gastric Cancer

In the process of being cross-linked ...

Extent of gastrectomy

 * Prince of Wales Hospital (Hong Kong)(1987-1991) -- subtotal vs. total gastrectomy
 * Randomized. 55 patients with adeno CA of the antrum. Arm 1) R1 subtotal gastrectomy (6 cm proximal resection margin, greater/lesser omentectomy, no further LN dissection) vs. Arm 2) R3 total gastrectomy (omentectomy, splenectomy, distal pancreatectomy, celiac axis LN clearance, skeletonization of porta hepatis vessels)
 * 1994 PMID 8053740 -- "A prospective randomized trial comparing R1 subtotal gastrectomy with R3 total gastrectomy for antral cancer." (Robertson CS, Ann Surg. 1994 Aug;220(2):176-82.)
 * Outcome: median OS R1 4.2 years vs. R3 2.5 years (SS)
 * Conclusion: R3 total gastrectomy should not be routinely used for antral cancer


 * Italy (1982-1993) -- subtotal vs. total gastrectomy
 * Randomized. 622 patients, distal half of the stomach. At surgery, had to have proximal edge of tumor >=6 cm from cardia, no hepatic/intraperitoneal spread, no level 3 LN+. Arm 1) subtotal gastrectomy vs. Arm 2) total gastrectomy. D2 gastrectomy recommended
 * 1999 PMID 10450730 -- "Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group." (Bozzetti F, Ann Surg. 1999 Aug;230(2):170-8.) Median F/U 6 years
 * Outcome: 5-year OS subtotal 65% vs. total 62% (NS)
 * Conclusion: Both procedures similar survival; SG should be procedure of choice, provided proximal margin can be obtained

Surgery for Cancer arising in Proximal Stomach

 * Ivor-Lewis Procedure"
 * Total Gastrectomy versus Proximal Gastrectomy"
 * Transhiatal Approach versus Left Thoraco-abdominal Approach for "Total Gastrectomy"
 * NG drainage vs No gastric drainage after "Total Gastrectomy""

Extent of lymph node dissection
D1 versus D2 dissection
 * Dutch Gastric Cancer Group (1989-1993) -- D1 vs D2 resection
 * Randomized. 711/996 patients (285 found to have incurable disease), adenoCA of stomach. Arm 1) D1 gastrectomy vs. Arm 2) D2 gastrectomy
 * 5-years; 1999 PMID 10089184 -- "Extended lymph-node dissection for gastric cancer." (Bonenkamp JJ, N Engl J Med. 1999 Mar 25;340(12):908-14.)
 * Outcome: 5-year OS D1 45% vs. D2 47% (NS). Similar recurrence patterns, 5-year RFS 63% vs. 62% (NS)
 * Toxicity: surgical complications D1 25% vs. D2 43% (SS), post-op deaths 4% vs. 10% (SS).
 * Conclusion: Results do not support routine use of D2 lymph node dissection

D2 versus D3 dissection
 * MRC ST01 (1986-1993) -- D1 vs. D2 resection
 * Randomized. 400 patients, staging laparotomy, Stage I-III. Arm 1) D1 resection (removal of LN within 3.0 cm of tumor en bloc with greater omentum and stomach) vs. Arm 2) D2 resection (additional removal of omental bursa, and en bloc distal hemipancreatico-splenectomy for middle/upper lesions, or hepatoduodenal and retroduodenal LN for antral lesions to include Level 1-2 regional LNs)
 * 5-years; 1999 PMID 10188901 -- "Patient survival after D1 and D2 resections for gastric cancer: long-term results of the MRC randomized surgical trial. Surgical Co-operative Group." (Cuschieri A, Br J Cancer. 1999 Mar;79(9-10):1522-30.) Median F/U 6.5 years
 * Outcome: 5-year OS D1 35% vs. D2 33% (NS); death from gastric cancer NS
 * Conclusion: Classic Japanese D2 resection offers no survival benefit over D1
 * Japan COG (1995-2001) -- D2 resection vs. D2 + para-aortic LND
 * 5-years; 2008 PMID 18669424 -- "D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer." (Sasako M, N Engl J Med. 2008 Jul 31;359(5):453-62.)
 * Randomized. 523 patients, curable T2b-T4. Arm 1) D2 lymphadenectomy vs. Arm 2) D2 lymphadenectomy + para-aortic LND. No adjuvant therapy
 * Outcome: PA LN+ in 8%. 5-year OS D2 69% vs. D2+PALND 70% (NS)
 * Toxicity: surgery complications D2 21% vs D2+PALND 28% (p=0.07); death rate 0.8% in both groups
 * Conclusion: Para-aortic LND doesn't improve survival in patients undergoing D2 dissection
 * Meta-analysis; 2010 PMID: 20123339 Meta-analysis of 3 trials: "Meta-analysis of effectiveness and safety of D2 plus para-aortic lymphadenectomy for resectable gastric cancer"(Chen XZ. et al. J Am Coll Surg. 2010;210(1):100)
 * Outcome: The authors concluded that there was no definite indication that D2 plus para-aortic lymphadenectomy should be used to treat resectable gastric cancer.

Neoadjuvant chemotherapy

 * MRC MAGIC Trial (1994-2002) -- surgery alone vs peri-operative ECF
 * Randomized. 503 patients. Resectable Stage II+ adenocarcinoma of stomach or lower esophagus and GE junction. Enrolled at time of diagnosis (vs. after resection in INT0116). Arm 1) Perioperative chemo given as preop ECF (epirubicin, cisplatin, 5-FU) x3 cycles -> surgery -> postop ECF x3 cycles vs. Arm 2) surgery alone. Surgeon decided extent of LND. 42% completed entire chemo course
 * 2006 PMID 16822992 -- "Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer." (Cunningham D, NEJM 2006 July 6;355(1):11-20.) Median F/U 4 years
 * Outcome: 5-year OS chemo 36% vs surgery 23% (SS); PFS also better. Chemotherapy decreased tumor size and stage. Curative resection chemo 69% vs surgery 66%.
 * Conclusion: Survival benefit for chemotherapy in the neoadjuvant/adjuvant setting


 * Dutch FAMTX -- surgery alone vs perioperative FAMTX
 * Randomized. Closed early due to poor outcome in FAMTX arm. 59 patients with adenocarcinoma of the stomach. Arm 1) pre-operative FAMTX (5-FU, doxorubicin, MTX) vs. Arm 2) surgery alone
 * 2004 PMID 15256239 -- Neo-adjuvant chemotherapy for operable gastric cancer: long term results of the Dutch randomised FAMTX trial. (Hartgrink HH, Eur J Surg Oncol. 2004 Aug;30(6):643-9)
 * Outcome: Same resectability rate. Progressive disease in 44%. Median OS FAMTX 1.5 years vs. surgery alone 2.5 years (NS)
 * Conclusion: Early closure due to inadequate rates of curative resection in CT group. No benefit.
 * Comment (in PMID 16822992): Result may reflect inferiority of FAMTX to ECF seen in advanced disease

Neoadjuvant Chemo versus neoadjuvant Chemo-RT

 * German Oesophageal Cancer Study Group (2000-2005) -- Neoadjuvant Chemo vs. neoadjuvant Chemo-RT
 * Randomized. Trial terminated early due to poor accrual. 119 of expected 354 patients with locally advanced T3-4 adenocarcinoma of the lower oesophagus and gastric cardia. Arm 1) 2.5 courses PLF (cisplatin, fluorouracil, leucovorin) vs. Arm 2) 2.0 courses PLF followed by Chemo-RT (30/2) and 1 course of EP (etoposid, cisplatin). Surgery 3-4 weeks after completion of neoadjuvant treatment.
 * 2009 PMID 19139439 -- "Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction." (Stahl M, J Clin Oncol. 2009 Feb 20;27(6):851-6) Median F/U 3.8 years
 * Outcome: 3-y OS: 47% vs. 28% (p=0.07). Higher rates of pCR and ypN0 with RCT than with CT
 * Toxicity: Postoperative mortality 10% vs. 4% (NS).
 * Conclusion: Although study underpowered (due to early closure) to demonstrate a survival benefit through RCT, strong trend towards OS-benefit through RCT.

Adjuvant Chemo-RT

 * Intergroup INT-0116 (1991-1998) -- Observation vs. Concurrent Chemo-RT + Adjuvant Chemo
 * Randomized. 556 patients. Completely resected (R0) adenocarcinoma of the stomach or GE junction. Stage IB to IV(M0) [1988 staging; IB=T1N1 or T2N0]. Arm 1) Observation vs. Arm 2) Bolus 5-FU (425 mg/m2/d) + LV (20 mg/m2/d) x 1 cycle, followed by concurent chemo-RT one month later. Chemotherapy given on first 4 and last 3 days of RT (5-FU 400 mg/m2 + LV 20 mg/m2). Adjuvant chemo one month following RT with two 5-day cycles of 5-FU/LV given one month apart. A D2 lymph node dissection was recommended, but most (54%) had a less than D1 dissection or had a D1 dissection (31%). 64% completed protocol
 * RT technique: 45 Gy to tumor bed, regional nodes, 2 cm beyond proximal and distal margins of resection. Defined tumor bed by pre-op CT. Lymph nodes included were: perigastric, celiac, local para-aortic, splenic, hepatoduodenal or hepatic-portal, and pancreaticoduodenal. Exclusion of the splenic nodes was allowed in patients with antral lesions if it was necessary to spare the left kidney. For tumors of GE junction, included paracardial and paraesophageal lymph nodes.
 * 2001 PMID 11547741 &mdash; "Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction." (MacDonald JS, N Engl J Med. 2001 Sep 6;345(10):725-30.) Median F/U 5 years
 * Outcome: Median survival observation 2.2 years vs chemo-RT 3.0 year (SS, HR for death 1.35). 3-year OS 41% vs 50%. 3-year RFS 31% vs 48%, median 19 months vs 30 months (SS, HR for relapse 1.52). LR 29% vs 19%, regional relapse 72% vs 65% (largely abdominal carcinomatosis), DM higher 18% vs 33%. Regional failure included peritoneal spread or liver mets.
 * Toxicity: Grade 3+ hematologic 54%, GI 33%. 17% stopped treatment due to toxic effects. 32% of pts in chemo/RT group experienced grade 4 toxic effects; 1% had treatment-related deaths.
 * Conclusion: Postop chemo-RT should be considered for patients at high risk for recurrence after curative resection

Adjuvant Chemotherapy

 * ACTS-GC, Japan (2001-2005) -- S1 chemo vs observation
 * Randomized. Trial stopped prematurely after significant survival benefit for adjuvant chemo group. 1034 patients, surgery with D2 LND, SM-, Stage II-IIIB. Arm 1) chemo S1 (tegafur + gimeracil + oteracil) x1 years vs Arm 2) surgery only. Primary endpoint OS
 * 2007 PMID 17978289 -- "Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine." (Sakuramoto S, N Engl J Med. 2007 Nov 1;357(18):1810-20.)
 * Outcome: 3-year OS S1 80% vs surgery 70% (HR 0.68, SS); 3-year DFS 72% vs 60%. Local relapse 1% vs 3%, LN relapse 5% vs 9%, peritoneal relapse 11% vs 16%
 * Toxicity: Grade 3-4 anorexia 6%, nausea 4%, diarrhea 3%
 * Conclusion: S1 is effective adjuvant treatment for patients undergoing D2 dissection


 * GOIM 9602 (Italy)(1996-2001) -- observation vs. ELFE (epirubicin/leucovorin/5-FU/etoposide)
 * Randomized. 228 patients, radically resected with total/subtotal gastrectomy and D1 LND, Stage IB-IIIB. Arm 1) observation vs. Arm 2) adjuvant ELFE x6 cycles
 * 2007 PMID 17525087 -- "Adjuvant chemotherapy with epirubicin, leucovorin, 5-fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study)." (De Vita F, Ann Oncol. 2007 Aug;18(8):1354-8. Epub 2007 May 24.) Median F/U 5 years
 * Outcome: 5-year OS control 43% vs. chemo 48% (NS); DFS 39% vs. 44% (NS)
 * Conclusion: No survival benefit for adjuvant chemo


 * GOIRC (Italy)(1995-2000) -- observation vs. PELF (cisplatin/epirubicin/Leucovorin/5-FU)
 * Randomized. 258 patients, stage IB-IV (T4N2) treated with potentially curative surgery. Arm 1) observation vs. Arm 2) PELF x4 cycles. Median time-to-chemo 46 days, 10% never started therapy
 * 2008 PMID 18334706 -- "Adjuvant Chemotherapy in Completely Resected Gastric Cancer: A Randomized Phase III Trial Conducted by GOIRC." (Di Costanzo F, J Natl Cancer Inst. 2008 Mar 11 [Epub ahead of print]) Median F/U 6.1 years
 * Outcome: 5-year OS observation 49% vs. chemo 48% (NS); DFS 42% vs. 42% (NS)
 * Recurrence: no difference between arms; liver 28%, peritoneum 27%, LN 16%
 * Toxicity: Grade 3-4 vomiting 21%, leucopenia 20%; one toxicity-related death
 * Conclusion: No benefit for adjuvant PELF


 * ITMO (Italy)(1992-1997) -- observation vs. EAP (etoposide/adriamycin/cisplatin)
 * Randomized. 274 patients, poor prognisis gastric cancer, s/p subtotal or total gastrectomy with D2 dissection, Stage T3-4 or N+ (90%). Arm 1) observation vs. Arm 2) adjuvant EAP + 5-FU/Leucovorin
 * 2002 PMID 11886009 -- "Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group." (Bajetta E, Ann Oncol. 2002 Feb;13(2):299-307.) Median F/U 5.5 years
 * Outcome: 5-year OS control 48% vs. chemo 52% (NS); DFS 44% vs. 49% (NS)
 * Toxicity: Grade 3-4 leukopenia 21%, N/V 14%; 2 deaths due to sepsis
 * Conclusion: No benefit for adjuvant EAP


 * EORTC/ICCG (1990-1998) -- 2 trials: observation vs. FAMTX or FEMTX
 * Randomized. 2 trials reported together. Both closed prematurely due to poor accrual. 397 patients, Adeno CA of stomach or GE junction, curative resection (R0-R1), D2 LND, Stage IB-IVM0.
 * EORTC (n=206): observation vs. FAMTX
 * ICCG (n=191): observation vs. FEMTX
 * 2006 PMID 16293676 -- "Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG." (Nitti D, Ann Oncol. 2006 Feb;17(2):262-9. Epub 2005 Nov 17.)
 * Outcome: Combined analysis 5-year OS control 44% vs. chemo 43% (NS); DFS 42% vs. 41% (NS)
 * Conclusion: Neither FAMTX nor FEMTX should be used as adjuvant treatment


 * FFCD 8801 (France)(1989-1997) -- observation vs. 5-FU/cisplatin
 * Randomized. Closed early due to poor accrual. 260 patients, curative resection, Stage II-IVM0 (N+ 80%). Arm 1) observation vs. Arm 2) adjuvant 5-FU/cisplatin x4 cycles
 * 2005 PMID 15939717 -- "Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801)." (Bouche O, Ann Oncol. 2005 Sep;16(9):1488-97. Epub 2005 Jun 6.) Median F/U 8.1 years
 * Outcome: 5-year OS control 42% vs. chemo 47% (NS)
 * Toxicity: Only 49% received >80% of planned chemo dose
 * Conclusion: No benefit for adjuvant 5-FU/cisplatin

Adjuvant chemo vs Adjuvant chemo-RT

 * HeCOG, Greece (2002-2005) -- Taxol/Carbo +/- RT
 * Randomized. Trial stopped early due to slow accrual. 147 out of 200 patients. Gastric CA, stage T3-T4 or N+. Surgery, SM-. LND D0 54%, median LN examined 14. Arm 1) Docetaxel 75 mg + cisplatin 75 mg (replaced with carboplatin AUC 5 due to excessive vomiting) Q3W x 6 cycles vs Arm 2) same chemo + RT 45/25. RT given after 3rd cycle of chemo (delivered in 85%). Immunohistochemistry done on 67 patients
 * 2010 PMID 20130877 -- "A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer." (Bamias A, Cancer Chemother Pharmacol. 2010 Feb 4. [Epub ahead of print]) Median F/U 4.5 years
 * Outcome: Local recurrence chemo 10% vs. chemo-RT 5% (NS). 3-year OS 61% vs 57% (NS); 3-years DFS 51% vs. 48% (NS). Patients with ERCC1+ significantly better OS (median 5.2 years vs 1.6), no difference for Her2 and AMP-Tau
 * Toxicity: Neutropenia 20% vs 24%; diarrhea 7% vs 4%
 * Conclusion: Addition of RT to chemo did not improve outcomes

Advanced

 * Multinational V325 (1999-2003) -- DCF vs. CF
 * Randomized, multinational. 445 patients with advanced gastric or GE junction CA treated with docetaxel 75 mg/m2, cisplatin 75 mg/m2, fluorouracil 750mg/m2 C.I. (DCF) vs. cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 (CF)
 * 2-years, 2006 PMID 17075117 -- "Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group." (Van Cutsem E, J Clin Oncol. 2006 Nov 1;24(31):4991-7.)
 * 2-year outcome: OS: DCF 18% vs. CF 9% (SS)
 * Toxicity: Grade 3-4 events (neutropenia, stomatitis, diarrhea, lethargy) DCF 69% vs. CF 59%
 * Conclusion: Adding docetaxel to CF significantly improved TTP and OS


 * EORTC GI 213 (1992-1995) -- ECF vs. FAMTX
 * 1997 PMID 8996151 -- "Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer." (Webb A, J Clin Oncol. 1997 Jan;15(1):261-7.)
 * Randomized. 274 patients, inoperable carcinoma of esophagus, GE junction, or stomach. Arm 1) ECF x8 cycles vs. Arm 2) FAMTX x8 cycles
 * Outcome: median OS ECF 9 months vs. FAMTX 6 months (SS); 1-year OS 36% vs. 21% (SS)
 * Toxicity: tolerable, 3 toxic deaths
 * Conclusion: ECF results in survival advantage and tolerable toxicity