This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roukos, D. H. Search for Related Content PubMed PubMed Citation Articles by Roukos, D. H.

Adjuvant Chemoradiotherapy in Gastric Cancer: Wave Goodbye to Extensive Surgery?

From the Department of Surgery, University of Ioannina Medical School, Ioannina, Greece.

Correspondence: Address correspondence to: Dimitrios H. Roukos, MD, P.O. Box 105 Neochoropoulo, Ioannina 455 00, Greece; Fax: +30-6510-70800; E-mail: droukos{at}cc.uoi.gr

Worldwide, gastric cancer remains one of the most common malignancies and a leading cause of cancer death, despite declining incidence. Although in the United States only 22,600 new cases are expected in 2002, real case-mortality remains high, indicating little progress in the treatment of diagnosed gastric cancer. However, hopes for an improved patient outcome provides a most recent report from the United States.¹ Because up until now there was no credible evidence for the effectiveness of adjuvant treatment after gastric resection for cancer,^2–4 this randomized trial is clinically important but simultaneously raises several important questions.

In this large, carefully monitored, multi-institutional trial, 556 patients after resection for adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of fluorouracil plus leucovorin followed by 4500 cGy of radiation. Chemoradiotherapy improved significantly the median overall survival by 9 months. The hazard ratio for death was 1.35 (95% confidence interval, 1.09 to 1.66; P = .005). Three patients (1%) died from toxic effects of the chemoradiotherapy; grade 3 and grade 4 toxic effects occurred in 41% and 32% of the patients in the chemoradiotherapy group, respectively. Macdonald et al.¹ concluded that postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.

Given that most patients (90%) studied had undergone limited (D0 or D1) lymph node dissection and only 10% had undergone extended (D2) lymph node dissection, two key questions emerge: (1) should all patients, including those who have undergone D2 dissection, receive adjuvant chemoradiotherapy? (2) Is a multidisciplinary approach consisting of limited (D0 or D1) lymph node dissection plus this adjuvant treatment more safe and effective than D2 resection alone?

A working hypothesis seems useful to approach these questions. According to an our own recently described concept,⁵ limited node dissection, as compared with extended dissection, is associated with substantially increased risk of residual positive nodes. This risk can be calculated accurately by studying established histopathological data among patients who have undergone a curative D2 dissection. Analysis of these data from Japan^6,7 and the Western world⁴ consistently indicates that among patients who underwent curative D2 dissection, approximately 30%⁸ had cancer disease in the extraperigastric level II nodes, i.e., around the celiac axis and in hepatoduodenal ligament, representing N2 disease according to the Japanese classification. These extraperigastric nodes are left behind after D1 dissection. Consequently, because 90% of the patients in the study by Macdonald et al.¹ had a D0 or D1 node dissection, at least one third of the patients had residual disease after surgery. If we look at the treatment plan of the study, we assess that radiation was delivered to the tumor bed and to these regional nodes, which were left behind by limited surgery in the study. Therefore, it is likely that these certain patients with N2 disease are those who benefited from adjuvant treatment. Thus it is reasonable to question whether control of the disease in the regional lymph nodes can be better achieved by chemoradiotherapy or by surgical resection.

Comparison of treatment-related morbidity and mortality between D2 dissection alone and combined treatment consisting of limited surgery plus adjuvant chemoradiotherapy is useful in making treatment decisions. Evidence for the safety of D2 dissection is provided in a preliminary report of a recent well-designed and well-conducted Japanese multi-institutional randomized trial.⁹ The study demonstrates a low risk of mortality (1%) and morbidity (approximately 20%) associated with extended (D2 or D4) lymph node dissection. These data are consistent with those of many nonrandomized studies from specialized institutions^5–7,10 and confirm the safety of D2 dissection when it is performed with a systematic and standardized pancreas-preserving technique by experienced surgeon.¹¹ This lack of experience with the D2 dissection technique of the surgeons who participated in the two European randomized trials is the main reason¹¹ for the high mortality rate (>10%) of D2 dissection that occurred in these trials.^12,13 These data indicate that D2 dissection–related complication rates are much lower than the incidence of major toxic effects, which occurred very frequently (54% hematologic, 33% gastrointestinal) in the chemoradiotherapy group, particularly if we add the limited-surgery related complications, which are not reported.¹

Although comparison of safety between these two treatments is feasible and valid, there are substantial limitations for long-term survival comparison. The 3-year survival rate of 50% in the chemoradiotherapy group is clearly worse or similar to the 5-year survival rates recently reported after D2 dissection from Japan (>60%),⁶ from Western specialized institutions (approximately 50%),^5,10 and the Dutch randomized trial (47%).¹² However, it is hard to draw conclusions from such a long-term survival comparison between limited surgery plus chemoradiotherapy and D2 dissection alone, particularly because of differences in the distribution of early and advanced stages. Indeed, in the chemoradiotherapy study, the proportion of patients with more advanced stages was higher than that reported in studies with D2 dissection from specialized institutions. This decreases the overall survival rate and makes an appropriate comparison difficult.

There is no doubt that the goal in gastric cancer management is the complete removal of the primary tumor and of the affected regional lymph nodes (curative resection). If the disease is localized but has spread to the extraperigastric lymph nodes, this goal seems to be attainable only by extended lymph node dissection. This goal cannot be achieved by limited D0 or D1 node dissection, and in these cases, postoperative chemoradiotherapy may be effective. However, the data of the United States trial are unable to suggest either a survival benefit for adjuvant chemoradiotherapy after D2 dissection or replacement of D2 dissection by this combined treatment. These questions can be addressed by future randomized trials, but at the present time, D2 dissection is the treatment of choice when it can adequately be performed.

Received for publication January 22, 2002. Accepted for publication February 1, 2002.

REFERENCES

1. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–30.[Abstract/Free Full Text]
2. Hermans J, Bonenkamp JJ, Boon MC, et al. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomised trials. J Clin Oncol 1993; 11: 1441–7.[Abstract/Free Full Text]
3. 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 1994; 343: 1309–12.[CrossRef][Medline]
4. Roukos DH. Current status and future perspectives in gastric cancer management. Cancer Treat Rev 2000; 26: 243–55.[CrossRef][Medline]
5. Roukos DH, Lorenz M, Encke A. Evidence of survival benefit of extended (D2) lymphadenectomy in western patients with gastric cancer based on a new concept: a prospective long-term follow-up study. Surgery 1998; 123: 573–8.[CrossRef][Medline]
6. Marujama K, Okabayashi K, Kinoshita T. Progress in gastric cancer surgery in Japan and its limits of radicality. World J Surg 1987; 11: 418–25.[CrossRef][Medline]
7. Fujii M, Sasaki J, Nakajima T. State of the art in the treatment of gastric cancer: from the 71st Japanese gastric cancer congress. Gastric Cancer 1999; 2: 151–7.[CrossRef][Medline]
8. Roukos DH. Extended (D2) lymph node dissection for gastric cancer: do patients benefit?(editorial) Ann Surg Oncol 2000; 7: 253–5.[CrossRef][Medline]
9. Sano T, Sasako M. Randomized controlled trial to evaluate para-aortic lymphadenectomy for gastric cancer (JCOG 9501): An update [Abstract]. 4th International Gastric Cancer, New York, NY, 2001. S45, p. 663.
10. Siewert JR, Boettcher K, Stein HJ, et al. Relevant prognostic factors in gastric cancer. Ten-year results of the German Gastric Cancer Study. Ann Surg 1998; 228: 449–461.[CrossRef][Medline]
11. Brennan MF. Lymph-node dissection for gastric cancer (editorial). N Engl J Med 1999; 340: 956–8.[Free Full Text]
12. Bonnenkamp JJ, Hermans J, Sasako M, van de Velde CJH, et al. Extended lymph-node dissection for gastric cancer. N Engl J Med 1999; 340: 908–14.[Abstract/Free Full Text]
13. Cuschieri A, Weeden S, Fielding J, et al. Patient survival after D1 and D2 resection for gastric cancer: long-term results of the MRC randomised surgical trial. Surgical co-operation group. Br J Cancer 1999; 79: 1522–30.[CrossRef][Medline]

This article has been cited by other articles:

				T. Liakakos and E. Fatourou Stage-Specific Guided Adjuvant Treatment for Gastric Cancer Ann. Surg. Oncol., September 1, 2008; 15(9): 2622 - 2623. [Full Text] [PDF]

				D. Ziogas and T. Liakakos Lessons from Laparoscopic Gastrectomy: Preventing Surgical Complications Ann. Surg. Oncol., September 1, 2008; 15(9): 2624 - 2625. [Full Text] [PDF]

				D. Ziogas, P. Tsekeris, and E. Fatourou Benefits, Limitations, and Harm of Local Excision for Rectal Cancer Ann. Surg. Oncol., September 1, 2008; 15(9): 2628 - 2629. [Full Text] [PDF]

				D. Ziogas, E. Ignatiadou, and M. Fatouros Lumpectomy and Partial Breast Irradiation - Risks and Benefits for Early Breast Cancer Ann. Surg. Oncol., August 1, 2008; 15(8): 2352 - 2353. [Full Text] [PDF]

				E. Briasoulis, D. Ziogas, and M. Fatouros Prophylactic Surgery in the Complex Decision-Making Management of BRCA Mutation Carriers Ann. Surg. Oncol., June 1, 2008; 15(6): 1788 - 1790. [Full Text] [PDF]

				T. Liakakos Minimal Residual Disease in Breast Cancer: Can It Be Used as a Prognostic Marker? Ann. Surg. Oncol., June 1, 2008; 15(6): 1793 - 1794. [Full Text] [PDF]

				M. Fatouros and D. Ziogas Controversy in the Treatment of Gastric Cancer Ann. Surg. Oncol., June 1, 2008; 15(6): 1795 - 1797. [Full Text] [PDF]

				T. Liakakos and E. G. Lykoudis Local Control, Aggressive Surgery, and Overall Survival for Breast Cancer Ann. Surg. Oncol., May 1, 2008; 15(5): 1544 - 1546. [Full Text] [PDF]

				T. Liakakos and D. H. Roukos More Controversy than Ever - Challenges and Promises Towards Personalized Treatment of Gastric Cancer Ann. Surg. Oncol., April 1, 2008; 15(4): 956 - 960. [Full Text] [PDF]

				T. Liakakos Laparoscopic Gastrectomy: Feasibility, Safety and Efficacy Ann. Surg. Oncol., April 1, 2008; 15(4): 1249 - 1250. [Full Text] [PDF]

				E. Hanisch, D. Ziogas, D. Roukos, and C. Hottenrott Advances in Laparoscopic Gastrectomy Expand Clinical Use Ann. Surg. Oncol., April 1, 2008; 15(4): 1251 - 1252. [Full Text] [PDF]

				H. Harissis and M. Fatouros Nodal Micrometastases Status--Will It Influence Decisions on Surgical and Adjuvant Treatment for Breast Cancer? Ann. Surg. Oncol., April 1, 2008; 15(4): 1256 - 1257. [Full Text] [PDF]

				E. Lykoudis, N. Xeropotamos, D. Ziogas, and M. Fatouros Breast Conservation Therapy: Multiple Reexcisions or Subcutaneous and Nipple-Sparing Mastectomy? Ann. Surg. Oncol., March 1, 2008; 15(3): 943 - 944. [Full Text] [PDF]

				L. Theodore Reexcisions in Breast-Conserving Surgery for Breast Cancer: Can They Be Avoided? Ann. Surg. Oncol., March 1, 2008; 15(3): 945 - 946. [Full Text] [PDF]

				T. Liakakos and G. Baltogiannis Reducing Local Recurrence after Breast-Conserving Surgery for Breast Cancer Ann. Surg. Oncol., March 1, 2008; 15(3): 949 - 950. [Full Text] [PDF]

				T. Liakakos Peritoneal Recurrence for Gastric Cancer: Can It Be Prevented? Ann. Surg. Oncol., January 1, 2008; 15(1): 382 - 382. [Full Text] [PDF]

				T. Liakakos and D. H. Roukos Does Lymphadenectomy Improve Survival of Patients with Solid Tumors? Ann. Surg. Oncol., January 1, 2008; 15(1): 385 - 385. [Full Text] [PDF]

				D. Ziogas, G. Baltogiannis, and M. Fatouros Lymphadenectomy in Surgical Oncology Ann. Surg. Oncol., January 1, 2008; 15(1): 386 - 387. [Full Text] [PDF]

				E. Briasoulis, M. Fatouros, and D. H. Roukos Level I Evidence in Support of Perioperative Chemotherapy for Operable Gastric Cancer: Sufficient for Wide Clinical Use? Ann. Surg. Oncol., October 1, 2007; 14(10): 2691 - 2695. [Full Text] [PDF]

				A. M. Kappas, M. Fatouros, and D. H. Roukos Editorial: Is it Time to Change Surgical Strategy for Gastric Cancer in the United States? Ann. Surg. Oncol., August 1, 2004; 11(8): 727 - 730. [Full Text] [PDF]

				H.H. Hartgrink, C.J.H. van de Velde, H. Putter, J.J. Bonenkamp, E. Klein Kranenbarg, I. Songun, K. Welvaart, J.H.J.M. van Krieken, S. Meijer, J.T.M. Plukker, et al. Extended Lymph Node Dissection for Gastric Cancer: Who May Benefit? Final Results of the Randomized Dutch Gastric Cancer Group Trial J. Clin. Oncol., June 1, 2004; 22(11): 2069 - 2077. [Abstract] [Full Text] [PDF]

				D. H. Roukos, E. Briasoulis, K. M. Michos, M. Elisaf, N. J. Agnantis, and A. M. Kappas Breast and Gastric Cancer: Comparing What We Learn Ann. Surg. Oncol., January 1, 2003; 10(1): 92 - 94. [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roukos, D. H. Search for Related Content PubMed PubMed Citation Articles by Roukos, D. H.