Adjuvant Chemotherapy after Successful Gastric Cancer Surgery: Yes, Maybe, or No
Adjuvant Chemotherapy after Successful Gastric Cancer Surgery: Yes, Maybe, or No
Abstract & Commentary
By William B. Ershler, MD, Editor
Synopsis: In a Phase III randomized trial of adjuvant chemotherapy using the platinum-based PELF (platinum, etoposide, leucovorin, and fluorouracil) regimen after potentially curative surgery for gastric cancer, no significant improvement in disease-free or overall survival was observed. The findings are discussed in the context of other trials and highlight the uncertainty surrounding the appropriate approach for the treatment of patients in this setting.
Source: Costanzo FD, et al. Adjuvant chemotherapy in completely resected gastric cancer: A randomized Phase III trial conducted by GOIRC. JNCI. 2008;100:388-398.
Even after complete surgical excision of gastric cancer, recurrence rates remain high and long-term survival rates are low. For those with Stage II or III disease, the 5-year survival rate is less than 20%.1 Thus, there has developed a strong interest in adjuvant chemotherapy and/or radiotherapy. Several clinical trials have been conducted, and the results, as summarized by meta-analyses2,3 suggest that postoperative chemotherapy improves, albeit slightly, overall survival. Di Costanzo and colleagues in the Italian Oncology Group for Cancer Research conducted a randomized controlled trial in which 258 patients were treated with surgery alone or surgery followed by chemotherapy. The chemotherapy selected was a combination of cisplatin, epirubicin, 5-fluorouracil and leucovorin (PELF), a regimen that has proven superior to others in the treatment of those with advanced gastric cancer with improved outcome in patients with metastatic gastric cancer.4
For the trial, 258 patients with histologically proven adenocarcinoma of the stomach of stages IB, II, IIIA and B, or IV(T4N2M0) and treated with potentially curative surgery were randomly assigned to follow-up alone (n = 128) or to intravenous treatment with four cycles (repeated every 21 days) of PELF (cisplatin [40 mg/m2 , on days 1 and 5], epirubicin [30 mg/m2 , days 1 and 5], L -leucovorin [100 mg/m2, days 1-4], and 5-fluorouracil [300 mg/m2, days 1-4] (n=130) in a hospital setting. Patient characteristics were well balanced between the two arms. Among those who received chemotherapy, grade 3 or 4 toxic effects including vomiting, mucositis, and diarrhea were experienced by 21.1%, 8.4%, and 11.8% of patients, respectively. Leucopenia, anemia, and thrombocytopenia of grade 3 or 4 were experienced by 20.3%, 3.3%, and 4.2% of patients, respectively. After a median follow-up of 72.8 months, 128 patients (49.6%) experienced recurrence and 139 (53.9%) deaths were observed, one toxicity-related. Relative to treatment with surgery alone, adjuvant chemotherapy did not increase disease-free survival (hazard ratio [HR] of recurrence = 0.92 ; 95% confidence interval [CI] = 0.66 to 1.27) or overall survival (HR of death = 0.90; 95% CI = 0.64 to 1.26).
Thus, in this trial there was no evidence that adjuvant chemotherapy with PELF significantly improved either overall survival or disease-free survival and the authors comment that the modest (and not statistically significant) reduction in the hazard of death or relapse was consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents.
Commentary
These results are disappointing, but must be examined in context. Based upon the impressive PELF experience in the setting of advanced disease, the study was powered to detect large differences, and it is likely that significant but modest improvement would have been observed had there been a larger number of randomized patients. The authors speculate that subgroups, for example those over the age of 60 years, or those who exhibit various biomarkers, such as P53, c-erbB2, MIB-1, TS, and Herg1 might identify patients most likely to benefit from therapy.
In an accompanying editorial,5 Drs. Aiwen Wu and Jiafu Ji of the Beijing Cancer Hospital and Institute discuss these results in the context of other recent studies that involved various chemotherapy or radiotherapy approaches. These included the intriguing findings published recently of S-1, an oral fluoropyrimidine, administered after curative resection in a randomized trial of 1059 patients in which the 3 year overall survival rate was 80.1% compared with 70.1% for those treated with surgery alone.6 It is too early to know whether that trial, conducted in Japan, will have the same level of efficacy against gastric carcinoma developing in western societies. Nonetheless, two additional trials, one in the United States7 and the other in the United Kingdom8 {Cunningham, 2006 #5566} demonstrated significant benefit of perioperative chemo-radiotherapy8 or chemotherapy {Cunningham, 2006 #5566} for selected gastric cancer patients when compared to surgery alone.
Thus, despite the overall negative tone of the current report, overall clinical trials have demonstrated benefit for adjuvant or neo-adjuvant treatment and this, in some form, has become the standard approach. Unresolved issues include the optimal selection of patients for more aggressive treatment (such as PELF), the development of more successful agents, and the timing of chemotherapy or radiation therapy.
References
1. Hundahl SA, Phillips, et al. The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis. Cancer. 2000;88(4):921-932.
2. Mari E, et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials. A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente). Ann Oncol. 2000;11(7):837-843.
3. Panzini I, et al. Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analyses. Tumori. 2002;88(1):21-27.
4. Cocconi G, et al. 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.
5. Wu A, Ji J. Adjuvant chemotherapy for gastric cancer or not: a dilemma? J Natl Cancer Inst. 2008;100(6):376-377.
6. Sakuramoto S, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810-1820.
7. Macdonald JS, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345(10):725-730.
8. Cunningham D, et al. N Engl J Med. 2006;355(1):11-20.
In a Phase III randomized trial of adjuvant chemotherapy using the platinum-based PELF (platinum, etoposide, leucovorin, and fluorouracil) regimen after potentially curative surgery for gastric cancer, no significant improvement in disease-free or overall survival was observed. The findings are discussed in the context of other trials and highlight the uncertainty surrounding the appropriate approach for the treatment of patients in this setting.Subscribe Now for Access
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