Gastric cancer is a global health problem. Although the incidence of this cancer is declining in many industrialized nations, gastric cancer remains the second most frequently diagnosed malignancy worldwide. It accounts for 9.9% of all new cancer diagnoses and is responsible for 12.1% of all cancer-related deaths. In the United States, it is estimated that 21,900 cases of gastric cancer will be diagnosed in 1999 and 13,500 persons will die of this disease.
Gastric cancer is often advanced and unresectable at diagnosis—a fact that contributes to its high morbidity and mortality. The stomach is a hollow organ, and the abdominal cavity is large and compliant to distention. Because of the large potential space, patients often develop symptoms only when the cancer is far advanced. Outside of Japan, an industrialized nation where gastric cancer is common, early detection of gastric cancer is not attempted.
Reports based on large German and Korean databases show that 57% to 63% of gastric cancer patients undergoing resection of the primary tumor have lymph node metastases.[3,4] In the United States, data suggest that 85% of patients enrolled in a recently completed adjuvant trial had lymph node metastases [personal communication, J. S. Macdonald, MD, November 1998].
Worldwide, large amounts of resources have been expended in the search for an effective adjuvant therapy to reduce the risk of postoperative relapse. Numerous phase III clinical trials have been published over the past few decades. The results of these trials, however, have often been disappointing or equivocal and are sometimes conflicting. Adjuvant therapy trials in western countries and Asia published between 1984 and 1997 were recently reviewed by Shimada and Ajani. In this article, we review various approaches to adjuvant therapy.
Selection of appropriate patients for adjuvant therapy is extremely important. In addition to TNM stage, recent advances in the field of molecular diagnostics will likely affect the selection of gastric cancer patients for such therapy, as well as identify new prognostic markers. Current studies correlating clinical outcomes with the status of genes, such as p53, thymidylate synthase, ERCC1, and many others, may help direct therapy for individual patients.
Based on TNM staging criteria, the depth of invasion (T), presence of lymph node metastases, and number of lymph nodes involved (N) predict the risk of relapse. This was confirmed in a large German multicenter trial published by Siewert et al in 1998. The study involved 1,654 patients undergoing surgical resection of gastric tumors.
A significant survival advantage was found for the 1,182 patients (71.5%) who underwent an R0 resection (ie, no residual disease and no cancer cells at the resection margins). In addition to the depth of invasion and nodal status, the ratio between involved and removed lymph nodes proved to be an important independent prognostic factor.
The prognostic importance of R0 resection, depth of invasion, nodal status, and the ratio between involved nodes and removed nodes was confirmed in a large Korean study involving 10,783 patients. In this study, an R0 resection was achieved in 4.8% of patients.
The American College of Surgeons also has published a large analysis of gastric cancer patients. This study was based on a tumor registry review of 25 consecutive patients from each participating institution seen in the years 1982 and 1987. Data on a total of 18,365 patients were analyzed.
Despite the large number of patients, however, the results of this analysis are not easy to interpret. This was a retrospective study that involved a large
number of heterogeneous institutions. Symptoms at presentation may have important prognostic value. Weight loss was the most common symptom, reported in 61.6% of patients. However, the presence or absence of weight loss was not correlated with clinical outcome, and the degree of weight loss was not specified. Similarly, 42% of patients who underwent surgical resection with clear margins received adjuvant chemotherapy or radiation therapy. However, patient characteristics and type of therapy given were not specified. The 5-year survival rates based on pathologic stage after resection were reported as 50%, 29%, 13%, 3% for stages I, II, III, and IV, respectively. These survival rates are significantly worse in every stage category than those reported in the German and Korean studies.
Histologic tumor type may influence patterns of failure. The liver is a frequent site of failure in intestinal-type tumors, whereas peritoneal carcinomatosis is more common with the diffuse type.[7-9] Diffuse histology is on the rise throughout the world.
Advances in molecular diagnostics have opened new avenues for predicting clinical outcome. One area of active research is the determination of p53 mutations. In early-stage, T1 tumors, p53 overexpression correlates with depth of invasion and lymph node involvement.
Another area of active research is the correlation of in vivo response to chemotherapy with genetic phenotype. Fluorouracil, which is the most commonly used agent for gastric cancer, targets the enzyme thymidylate synthase. Lenz et al found that low thymidylate synthase messenger RNA (mRNA) expression was predictive of response and survival in patients treated with fluorouracil and cisplatin (Platinol). More recently, however, Fata et al found high thymidylate synthase mRNA expression to be a predictor of favorable survival.
The excision repair cross-complementing gene (ERCC1) was studied in 33 patients treated with preoperative fluorouracil and cisplatin. In this study, ERCC1 expression correlated with response to therapy. Furthermore, when thymidylate synthase and ERCC1 expression were both low, 11 (85%) of 13 patients responded to therapy; in contrast, when both thymidylate synthase and ERCC1 expression were high, only 2 (20%) of 10 patients responded.
The current National Comprehensive Cancer Network (NCCN) practice guidelines for gastric cancer recommend the following tests and examinations as the minimum preoperative work-up: history, physical examination, complete blood counts (including platelets), SMA-12, computed tomography (CT) of the abdomen, chest roentgenogram, esophagogastroduodenoscopy, and, in female patients, CT or ultrasound of the pelvis.
Increasingly, laparoscopy also is being recommended prior to a major resection. The use of laparoscopy may be supported by the fact that an R0 resection cannot be performed in 30% to 40% of patients undergoing surgery. In the German study, 29.3% of the patients had M1 disease at laparotomy. In these patients, median survival was less than 12 months.
At the University of Texas M. D. Anderson Cancer Center, 83 patients were enrolled in preoperative chemotherapy trials, 73% of whom underwent a curative resection. In the group who could not receive a curative resection, 55% of patients avoided nontherapeutic laparotomy because of an extensive preoperative work-up.
A number of controversies exist in the surgical management of gastric cancer. The most important of these is the extent of lymphadenectomy.
A D1 resection entails a gastrectomy with the removal of all perigastric nodes and the removal of the greater and lesser omenta. In addition to these structures, for a D2 dissection the surgeon removes the omental bursa portion of the transverse mesocolon and the nodes along the left gastric, celiac , and splenic arteries. For a D3 dissection, in addition to the standard
D2 dissection, lymph nodes in the hepatoduodenal ligament, along the superior mesenteric vein, posterior to the common hepatic artery, and on the posterior surface of the pancreatic head are also removed. A D4 dissection involves the removal of lymph nodes around the abdominal aorta, in addition to all of the structures mentioned above.
In the East, extensive lymphadenectomy (D2 through D4) is commonly practiced without excessive complications. Recently, the Japan Clinical
Oncology Group conducted a randomized study of D2 dissection with or without para-aortic node dissection; these researchers reported no treatment-related deaths but a 6% rate of major complications. In the West, the extent of lymph node dissection is more controversial. Western surgeons usually do not perform D2 dissections due to the high rate of complications.
The Dutch Gastric Cancer Group randomized 711 patients with all stages of disease to either a D1 or D2 dissection. Patients who underwent a D2 resection had a higher rate of complications, more postoperative deaths, longer hospital stays, and no improvements in 5-year survival. However, assuming that the ratio of involved lymph nodes to resected nodes predicts outcome, removal of more negative nodes, which occurs during an extended node dissection, may improve long-term survival.
Subgroup analyses of the German and Korean databases show that D2 dissection benefited patients with stage II disease in both studies and benefited patients with stage IIIA disease in the Korean study. However, subgroup analyses are fraught with difficulties. The level of surgical expertise needed to perform an extended node dissection appears to have an impact on surgical morbidity and mortality.
An analysis by Estes et al shows that operative documentation needs improvement. These investigators reviewed operative reports from more than 300 surgeons given a checklist for documentation prior to participating in a national protocol. Inadequate documentation was common. The status of the primary tumor, lymph nodes, liver, peritoneum, and omentum was not stated in 6%, 10%, 17%, 28%, and 28% of operative reports, respectively. Also, the reports often lacked sufficient information about the extent of dissection.
At present, D1 dissection should be considered the minimum resection for patients with potentially curable gastric carcinoma. Estes et al found that 54.2% patients undergoing “curative” resection of gastric cancer had a D0 dissection. This indicates that adequate resection and staging are not being practiced. D2 resection, a proper oncologic surgical procedure, should be considered by experienced surgeons who frequently perform gastric cancer surgery.
1. Parkin D, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 49:33-64, 1999.
2. Landis S, Murray T, Bolden S, et al: Cancer statistics, 1999. CA Cancer J Clin 49:8-31, 1999.
3. Siewert JR, Bottcher K, Stein HJ, et al: Relevant prognostic factors in gastric cancer: Ten-year results of the German Gastric Cancer Study. Ann Surg 228:449-461, 1998.
4. Kim JP, Lee JH, Kim SJ, et al: Clinicopathologic characteristics and prognostic factors in 10783 patients with gastric cancer. Gastric Cancer 1:125-133, 1998.
5. Shimada K, Ajani JA: Adjuvant therapy for gastric carcinoma in the past 15 years: Review of western and oriental trials. Cancer, 1999 (in press).
6. Wanebo HJ, Kennedy BJ, Chmiel J, et al: Cancer of the stomach: A patient care study by the American College of Surgeons. Ann Surg 218:583-592, 1993.
7. Esaki Y, Hirayama R, Hirokawa K: A comparison of patterns of metastasis in gastric cancer by histologic type and age. Cancer 65:2086-2090, 1990.
8. Maehara Y, Moriguchi S, Kakeji Y, et al: Pertinent risk factors and gastric carcinoma with synchronous peritoneal dissemination or liver metastasis. Surgery 110:820-823, 1991.
9. Jakesz R, Dittrich C, Funovics J, et al: The effect of adjuvant chemotherapy in gastric carcinoma is dependent on tumor histology: 5-Year results of a prospective randomized trial. Recent Results Cancer Res 110:44-51, 1988.
10. Aranda M, Naquira N, Karque R, et al: Mutations of the p53 suppressor gene in gastric adenocarcinoma. Rev Med Chil 126:525-532, 1998.
11. Brito MJ, Williams GT, Thompson H, et al: Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa. Gut 35:1697-1700, 1994.
12. Lenz HJ, Leichman CG, Danenberg KD, et al: Thymidylate synthase mRNA level in adenocarcinoma of the stomach: A predictor for primary tumor response and overall survival. J Clin Oncol 14:176-182, 1996.
13. Fata F, Baylor R, Lipton R, et al: Low thymidylate synthase (TS) is not an independent predictor of outcome in patients with operable gastric cancer (abstract). Proc Am Soc Clin Oncol 18:A241, 1999.
14. Metzger R, Leichman CG, Danenberg KD, et al: ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol 16:309-316, 1998.
15. NCCN practice guidelines for upper gastrointestinal carcinomas. Oncology 12(11A):179-223, 1998.
16. Lowy AM, Mansfield PF, Leach SD, et al: Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Ann Surg 229:303-308, 1999.
17. Sano T, Sasako M: Low operative morbidity and mortality in extended lymphadenectomy for gastric cancer in Japan: JCOG study 9501 (abstract). Proc Am Soc Clin Oncol, 18:A273, 1999.
18. Bonenkamp JJ, Hermans J, Sasako M, et al: Extended lymph-node dissection for gastric cancer: Dutch Gastric Cancer Group. N Engl J Med 340:908-914, 1999.
19. Estes NC, MacDonald JS, Touijer K, et al: Inadequate documentation and resection for gastric cancer in the United States: A preliminary report. Am Surg 64:680-685, 1998.
20. Longmire WP, Kuzma JW, Dixon WJ: The use of triethylenethiophosphoramide as an adjuvant to the surgical treatment of gastric carcinoma. Ann Surg 167:293-312, 1968.
21. Veterans Administration Surgical Oncology Study Group: Use of thio-TEPA as an adjuvant to the surgical management of carcinoma of the stomach. Cancer 18:291-297, 1965.
22. Imanaga H, Nakazato H: Results of surgery for gastric cancer and effect of adjuvant mitomycin C on cancer recurrence. World J Surg 2:213-221, 1977.
23. Alcobendas F, Milla A, Estape J, et al: Mitomycin C as an adjuvant in resected gastric cancer. Ann Surg 198:13-17, 1983.
24. Grau JJ, Estape J, Alcobendas F, et al: Positive results of adjuvant mitomycin-C in resected gastric cancer: A randomised trial on 134 patients. Eur J Cancer 29A:340-342, 1993.
25. Gastrointestinal Tumor Study Group: Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer. Cancer 49:1116-1122, 1982.
26. Higgins GA, Amadeo JH, Smith DE, et al: Efficacy of prolonged intermittent therapy with combined 5-FU and methyl-CCNU following resection for gastric carcinoma.: A Veterans Administration Surgical Oncology Group report. Cancer 52:1105-1112, 1983.
27. Engstrom PF, Lavin PT, Douglass HO Jr et al: Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer patients: Eastern Cooperative Oncology Group Study (Est 3275). Cancer 55:1868-1873, 1985.
28. Macdonald JS, Fleming TR, Peterson RF, et al: Adjuvant chemotherapy with 5-FU, Adriamycin, and mitomycin-C (FAM) vs surgery alone for patients with locally advanced gastric adenocarcinoma: A Southwest Oncology Group study. Ann Surg Oncol 2:488-494, 1995.
29. Lise M, Nitti D, Marchet A, et al: Prognostic factors in resectable gastric cancer: Results of EORTC study no. 40813 on FAM adjuvant chemotherapy. Ann Surg Oncol 2:495-501, 1995.
30. Coombes RC, Schein PS, Chilvers CE, et al: A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer: International Collaborative Cancer Group. J Clin Oncol 8:1362-1369, 1990.
31. Hallissey MT, Dunn JA, Ward LC, et al: The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: Five-year follow-up. Lancet 343:1309-1312, 1994.
32. Krook JE, O’Connell MJ, Wieand HS, et al: A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer. Cancer 67:2454-2458, 1991.
33. Neri B, de Leonardis V, Romano S, et al: Adjuvant chemotherapy after gastric resection in node-positive cancer patients: A multicentre randomised study. Br J Cancer 73:549-552, 1996.
34. Allum WH, Hallissey MT, Kelly KA: Adjuvant chemotherapy in operable gastric cancer: 5 Year follow-up of First British Stomach Cancer Group trial. Lancet 1:571-574, 1989.
35. Grau JJ, Estape J, Fuster J, et al: Randomized trial of adjuvant chemotherapy with mitomycin plus ftorafur vs mitomycin alone in resected locally advanced gastric cancer. J Clin Oncol 16:1036-1039, 1998.
36. Bleiberg H, Sahmoud T, Di Leo A, et al: Adequate number of patients are needed to evaluate adjuvant treatment in gastric cancer (letter). J Clin Oncol 16:3714, 1998.
37. Carrato A, Diaz-Rubio E, Medrano J, et al: Phase III trial of surgery vs adjuvant chemotherapy with mitomycin C (MMC) and tegafur plus uracil (UFT), starting within the first week after surgery, for gastric adenocarcinoma (abstract). Proc Am Soc Clin Oncol 14:A468, 1995.
38. Italian Gastrointestinal Tumor Study Group: Adjuvant treatments following curative resection for gastric cancer. Br J Surg 75:1100-1104, 1988.
39. Gastrointestinal Tumor Study Group: The concept of locally advanced gastric cancer. Effect of treatment on outcome. Cancer 66:2324-2330, 1990.
40. Schiessel R, Funovics J, Schick B, et al: Adjuvant intraperitoneal cisplatin therapy in patients with operated gastric carcinoma: Results of a randomized trial. Acta Med Austriaca 16:68-69, 1989.
41. Sautner T, Hofbauer F, Depisch D, et al: Adjuvant intraperitoneal cisplatin chemotherapy does not improve long-term survival after surgery for advanced gastric cancer. J Clin Oncol 12:970-974, 1994.
42. Hagiwara A, Takahashi T, Kojima O, et al: Prophylaxis with carbon-adsorbed mitomycin against peritoneal recurrence of gastric cancer. Lancet 339:629-631, 1992.
43. Rosen HR, Jatzko G, Repse S, et al: Adjuvant intraperitoneal chemotherapy with carbon-adsorbed mitomycin in patients with gastric cancer: Results of a randomized multicenter trial of the Austrian Working Group for Surgical Oncology. J Clin Oncol 16:2733-2738, 1998.
44. Yu W, Whang I, Suh I, et al: Prospective randomized trial of early postoperative intraperitoneal chemotherapy as an adjuvant to resectable gastric cancer. Ann Surg 228:347-354, 1998.
45. Yonemura Y, Fujimura T, Fushida S, et al: Hyperthermo-chemotherapy combined with cytoreductive surgery for the treatment of gastric cancer with peritoneal dissemination. World J Surg 15:530-535, 1991.
46. Hamazoe R, Maeta M, Kaibara N: Intra-peritoneal thermochemotherapy for prevention of peritoneal recurrence of gastric cancer: Final results of a randomized controlled study. Cancer 73:2048-2052, 1994.
47. Ikeguchi M, Kondou A, Oka A, et al: Effects of continuous hyperthermic peritoneal perfusion on prognosis of gastric cancer with serosal invasion. Eur J Surg 161:581-586, 1995.
48. Fujimura T, Yonemura Y, Muraoka K, et al: Continuous hyperthermic peritoneal perfusion for the prevention of peritoneal recurrence of gastric cancer: Randomized controlled study. World J Surg 18:150-155, 1994.
49. Ajani JA, Mayer RJ, Ota DM, et al: Preoperative and postoperative combination chemotherapy for potentially resectable gastric carcinoma. J Natl Cancer Inst 85:1839-1844, 1993.
50. Ajani JA, Ota DM, Jessup JM, et al: Resectable gastric carcinoma. An evaluation of preoperative and postoperative chemotherapy. Cancer 68:1501-1506, 1991.
51. Leichman L, Silberman H, Leichman CG, et al: Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: A University of Southern California pilot program. J Clin Oncol 10:1933-1942, 1992.
52. Kelsen DP: Adjuvant and neoadjuvant therapy for gastric cancer. Semin Oncol 23:379-389, 1996.