Journal of the National Cancer Institute Advance Access originally published online on March 11, 2008
JNCI Journal of the National Cancer Institute 2008 100(6):376-377; doi:10.1093/jnci/djn055
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© The Author 2008. Published by Oxford University Press.
EDITORIALS |
Adjuvant Chemotherapy for Gastric Cancer or Not: A Dilemma?
Affiliation of authors: Department of Gastrointestinal Surgery, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China
Correspondence to: Aiwen Wu, MD, Department of Gastrointestinal Surgery, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China 100036 (e-mail: wuaw{at}sina.com).
In this issue of the Journal, Di Costanzo et al. (1) report the result of a randomized phase III trial of the Italian Oncology Group for Cancer Research. They conclude that despite very promising previous results in the setting of advanced gastric cancer (2), there are no positive effects of cisplatin, epirubicin, leucovorin, and 5-fluorouracil (PELF) as adjuvant chemotherapy on overall and disease-free survival of gastric cancer patients who have undergone complete surgical resection. In the trial, 258 patients were randomly assigned to chemotherapy or surgery alone over a 5-year period. Fifty-five percent of the patients underwent D2 or more extended nodal dissection, and the median number of lymph nodes harvested per patient was greater than 15. The study not only demonstrates that PELF as an adjuvant regimen cannot improve patient survival but also suggests that data obtained in the setting of advanced gastric cancer may not be applicable to the adjuvant setting.
Here we do not think it meaningful to criticize the shortcomings of this study (including, as always, the low rate of D2 nodal dissection that is common to Western studies), but it would be helpful to rethink the strategies on which this and similar studies are based. The usefulness of adjuvant chemotherapy for gastric cancer has been debated for a long time. Randomized controlled clinical trials that investigated the efficacy and toxicity of different adjuvant regimens among different gastric cancer patient groups have yielded inconsistent results (3–7), and meta-analyses of data regarding the benefit of adjuvant chemotherapy for patients with gastric cancer have found hazards reduction of death to be 0.12–0.20 (8–11). We are still not able to draw a definite conclusion as to whether adjuvant chemotherapy confers advantages to gastric cancer patients who have undergone curative resection.
It is appropriate to ask how these negative results can help patients (12) and how we as professionals in the field of gastric cancer management can resolve the dilemma as to whether adjuvant chemotherapy should be used in gastric cancer patients after curative surgical resection. More and more studies on adjuvant chemotherapy of gastric cancer are forthcoming, and the dilemma persists.
The negative overall result may reflect a positive effect in one subgroup and a negative effect in another. Therefore, one strategy is to identify the subgroup(s) that actually benefit from adjuvant chemotherapy. Di Costanzo et al. (1) analyzed the interaction between covariates and adjuvant treatment and showed that the benefit of treatment, if any, was confined to older patients over 60 years old. In this article, the authors also reported some suggestive results from a parallel study that sought to determine the prognostic value of additional biomolecular factors (P53, c-erbB2, MIB-1, TS, and Herg1), and the strategy of using biologic markers to identify subgroups of patients that would benefit from therapy has been pursued in other kinds of human cancers. The National Surgical Adjuvant Breast and Bowel Project investigated the value of high-degree microsatellite instability (MSI-H) as a marker to predict benefit from adjuvant chemotherapy in colon cancer and found that there was a strong inverse relationship between MSI-H and mutant p53 status (P < .001), although the data did not support the use of MSI-H as a predictive marker of chemotherapy benefit. Hazard ratios (HRs) for relapse-free survival for MSI-H vs microsatellite-stable and low-degree MSI patients were 0.77 (95% confidence interval [CI] = 0.40 to 1.48) in the untreated patient group and 0.60 (95% CI = 0.30 to 1.19) in the treated group (13). With molecular classification, gastric cancer patients with a high risk of recurrence may eventually be identified, just as breast cancer patients with a high risk of recurrence are now identified based on HER-2/neu overexpression as candidates for specific adjuvant therapy regimens, as recommended by the National Comprehensive Cancer Network.
It has been hypothesized that some cytoxic regimens or therapeutic models are not effective in the adjuvant setting. However, recently, Sakuramoto et al. (7) reported the very promising result of S-1, an oral fluoropyrimidine, as adjuvant chemotherapy for stage II and III gastric cancer patients who underwent curative gastrectomy and extended (D2) lymph node dissection. A total of 1059 patients were randomly assigned to treatment with S-1 or surgery alone. The 3-year overall survival rate was 80.1% in the S-1 group and 70.1% among those treated with surgery alone. The hazard ratio for death in the S-1 group compared with the surgery-only group was 0.68 (95% CI = 0.52 to 0.87, P = .003). Adverse events of grade 3 or 4 were not common (7). However, before we translate this promising result into clinical practice in Western countries, further clinical trials will be needed to confirm its efficacy in this new setting. Furthermore, subdivision of stage II and III gastric cancer patients to identify those most likely to benefit from S-1 adjuvant chemotherapy is also needed, as suggested above.
A US intergroup study has provided evidence as to the potential value of postoperative adjuvant chemoradiation in that treatment consisting of 5-fluorouracil plus leucovorin combined with radiotherapy led to an improvement in overall survival relative to surgery alone (14). The median overall survival in the surgery-only group was 27 months, compared with 36 months in the chemoradiotherapy group, and the hazard ratios for death and relapse were 1.35 (95% CI = 1.09 to 1.66, P = .005) and 1.52 (95% CI = 1.23 to 1.86, P < .001), respectively. More than 40% of patients in the chemoradiotherapy group had grade 3 or 4 toxic effects (14). The high rate of morbidity and low rate of D2 nodal dissection underscored the value of this treatment, although the benefits seen with chemotherapy may be due in part to the inadequacy of surgical resection. The value of this approach in patients whose gastric cancer has been treated by complete surgical resection is unknown.
Another landmark trial in the treatment of gastric cancer is the United Kingdom' s Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, which investigated the role of perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil in patients with potentially operable gastroesophageal cancer (15). After a median follow-up of 4 years, 149 patients in the perioperative chemotherapy group and 170 in the surgery group had died. The perioperative chemotherapy group had a higher likelihood of overall survival (HR for death = 0.75, 95% CI = 0.60 to 0.93, P = .009), 5-year survival (36% vs 23%), and progression-free survival (HR for progression = 0.66, 95% CI = 0.53 to 0.81, P < .001). The MAGIC study offers the first convincing evidence of the long-term effect of perioperative chemotherapy on gastric cancer patient survival.
To date, the existing evidence seems to support the use of adjuvant chemotherapy and/or radiotherapy, either postoperatively or perioperatively, especially when the diseases are in their advanced stage, as is commonly the case in Europe, North America, and some parts of Asia. Surgery alone is no longer the standard treatment for patients with resectable gastric cancer, independent of the patient population or the practice location. Randomized controlled trials and meta-analyses should be dedicated to exploring the indications, regimen, and timing of adjuvant treatment for gastric cancer.
Funding
National Key Technology R&D Program (2006BAI02A06); Beijing Municipal Science & Technology Commission NOVA program (2007B-057).
NOTES
No potential conflict of interest relevant to this article was reported.
REFERENCES
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2. Cocconi G, Carlini P, Gamboni A, et al. Italian Oncology Group for Clinical Research. Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Ann Oncol (2003) 14(8):1258–1263.
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Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 388-398.
J Natl Cancer Inst 2008 100: 375.
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