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Adjuvant therapy in gastric cancer: updating

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

March 2002.     Review Article.   

To the first article about adjuvant therapy in GC
To the second updating

A phase II study of sequential high-dose methotrexate and fluorouracil, combined with doxorubicin, as neoadjuvant chemotherapy was conducted by Takahashi et al, in an attempt to evaluate the efficacy of this regimen in improving the survival of patients with scirrhous gastric cancer. It did not improve the survival rate in spite of improving the curative resection rate ( 1 ).

A Gochi et al.underline that although there has been remarkable development of gastroscopy for the early detection of gastric cancer as well as improvement of surgical techniques during the last 3 decades, the 5 year survival rate of advanced gastric cancer patients undergoing curative resection has remained at 20 to 49% for stage III and 5 to 15% for stage IV.
Nevertheless, the majority of such patients die of a recurrence based on microscopic residual tumours.
In order to eradicate those microscopical residual disease postoperative adjuvant chemotherapy with intravenous mitomycin C ( MMC ) and oral 5-FU or 5 FU derivates like tegafur has been routinely performed for advanced gastric cancer patients in Japan for the last 20 years ( Inokuchi et al, 1984; Maehara et al, 1991; Nakazato, 1994).
Subsequently, systemic nonspecific immunotherapy with OK-432 has been widely combined with adjuvant chemotherapy, because immunotherapy is generally more effective when the residual tumour mass is quite small ( Arinaga et al, 1992 ).
On the basis of such adjuvant chemoimmunotherapy for gastric cancer patients, the authors conducted a multi-institutional randomized control trial of adjuvant chemoimmunotherapy consisting of MMC, tegafur, intradermal injection of OK-432 with or without preoperative OK-432 it in gastric cancer patients between June 1985 and December 1986.
According to the UICC: TNM classification of gastric cancers ( 4th edition ), they found that OK-432 it significantly improved the 10-year survival of gastric cancer patients with stage IIIA+IIIB, positive TILs ( tumour-infiltrating lymphocytes ), pN2 lymph node metastases. In particular, OK 432 it was useful for patients with positive TILs and pN+ when used in combination with adjuvant chemoimmunotherapy ( 2 ).

Intergroup 0116 (Southwest Oncology Group 9008), a national, multicenter, two-armed, prospective, randomized trial of adjuvant postoperative chemoradiotherapy, has demonstrated significant benefit.
But Scott et al note that MI (the Maruyama Index of Unresected Disease ) a measure of unresected regional nodal disease in gastric cancer, proved an independent predictor of survival. Surgical undertreatment, as observed in this trial, clearly undermined survival ( 3 ).
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? Roukos riaffirms that 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 and the Western world consistently indicates that among patients who underwent curative D2 dissection, approximately 30% 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. 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. 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 and confirm the safety of D2 dissection when it is performed with a systematic and standardized pancreas-preserving technique by experienced surgeon. 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.

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 ( 4, 5, 6, 7, 8, 9, 10, 11 ).

Yoshida et al. in a retrospective study recapitulated the results of the previous phase II study of a combination of CPT-11 and CDDP, with respect to efficacy and feasibility.
The previous phase II study showed that a combination of irinotecan ( CPT-11 ) with cisplatin (CDDP ) was effective for advanced gastric cancers, but was associated with substantial neutropenia and diarrhea. These side effects are especially critical for patients with bowel obstruction, because SN-38, an active metabolite of CPT-11 is excreted to the duodenum via the bile duct and accumulates beyond the tolerable limit in such patients with bowel obstruction. Clinically, about half of the patients with gastric cancer have peritoneal dissemination. Moreover, antitumor effects may be assessed only in the primary tumor in most of them.
In conclusion this regimen is a feasible treatment option for patients with peritoneal dissemination, provided they can have sufficient oral intake ( 12 ).

In gastric cancer several studies have shown that TS expression has an inverse relationship with response to chemotherapy and survival in patients with locally advanced or metastatic disease receiving sytemic chemotherapy with 5-FU-containing regimens. Moreover TS expression also predicted poor disease-free and overall survival in a few reports that investigated gastric cancer patients treated with 5 FU- based adjuvant chemotherapy after surgical resection.
J-H Choi et al evaluated the expression of TS using immunohistochemistry in primary tumours of locally advanced gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between TS expression and various clinicopathologics characteristic including prognosis of the patients.
There were no statistically significant differences in 4-year disease free survival and overall survival between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection ( 13 ).

In conclusion the role of adjuvant chemotherapy in gastric cancer has been studied extensively over the past three decades in an attempt to further improve the prognosis of patients with gastric cancer who have undergone curative surgery. To date, no definitive conclusions have been drawn from randomized clinical trials of adjuvant chemotherapy for gastric cancer, because few studies have shown a significant positive impact on survival as compared with surgery alone. The negative results of most previous clinical studies do not necessarily mean that the adjuvant chemotherapy approach to treatment of gastric cancer does not work. Recent published reports of meta-analyses concerning adjuvant chemotherapy of gastric cancer revealed small but clear survival advantages for adjuvant therapy over surgery alone. The positive data from meta-analyses suggests that there are potential survival advantages of adjuvant chemotherapy, but this must be proven in the future by well-designed clinical trials that compare adjuvant chemotherapy with surgery alone, in which sufficient numbers of patients are enrolled and effective chemotherapeutic regimens with appropriate dose intensity are employed. Newly developed anticancer agents and/or newer therapeutic combinations or strategies ( neoadjuvant chemotherapy, chemoradiotherapy, intraperitoneal chemotherapy ) have the potential to benefit high-risk patients ( 14 ).


1) Shinichiro Takahashi et al. Phase II study of sequential high-dose methotrexate and fluorouracil combined with doxorubicin as a neoadjuvant chemotherapy for scirrhous gastric cancer. Gastric Cancer, volume 4, issue 4 ( 2001 ), 192-197.

2) A Gochi et al. The prognostic advantage of preoperative intratumoral injection of OK-432 for gastric cancer patients. British Journal Cancer, ( 2001 ), 84 ( 4 ), 443-451.

3) Scott A. Hundahl, MD, John S. Macdonald, MD, Jacqueline Benedetti, PhD and Thomas Fitzsimmons, MD for the Southwest Oncology Group and the Gastric Intergroup. Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: the effect of undertreatment. Annals of Surgical Oncology 9:278-286 (2002)

4) Dimitrios H. Roukos, MD. Adjuvant chemoradiotherapy in gastric cancer: wave goodbye to extensive surgery? Annals of Surgical Oncology 9:220-221 (2002)

5) 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.

6) Roukos DH. Extended (D2) lymph node dissection for gastric cancer: do patients benefit?(editorial) Ann Surg Oncol 2000; 7: 253-5.

7) Roukos DH. Current status and future perspectives in gastric cancer management. Cancer Treat Rev 2000; 26: 243-55.

8) 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.

9) Brennan MF. Lymph-node dissection for gastric cancer (editorial). N Engl J Med 1999; 340: 956-8.

10) 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.

11) 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.

12) Motoki Yoshida et al. Combination chemotherapy of irinotecan plus cisplatin for advanced gastric cancer: efficacy and feasibility in clinical practice. Gastric Cancer, (2001) 4: 144-149.

13) J-H Choi et al.Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. British Journal Cancer ( 2001 ), 84 ( 2 ), 186-192.

14) Yoshihiko Maehara et al. Review article: adjuvant chemotherapy for gastric cancer: a comprehensive review. Gastric Cancer, Volume 4, issue 4, ( 2001 ) pp 175-184.

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