Treatment of Gastric Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In the study by Cunningham et al. (July 6 issue),1 the effect of down-staging of tumor is unclear. At surgery, there were more patients with advanced disease according to tumor stage and nodal status in the surgery group than in the perioperative-chemotherapy group. Also, 31% of patients did not have tumor size documented before randomization. It would therefore be interesting to know the clinical tumor stage and nodal status of patients before randomization and at restaging before surgical resection. A discrepancy in which patients with smaller tumors were disproportionately being assigned to the perioperative-chemotherapy group could account for the apparent down-staging.
Jaswinder Singh, M.D.
Stephen K. Williamson, M.D.
Kansas University Medical Center
Kansas City, KS 66160
Ashok K. Malani, M.D.
Heartland Regional Medical Center
St. Joseph, MO 64507
drmalani@yahoo.com
References
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.
To the Editor: The findings of Cunningham and colleagues underscore the importance of preoperative endoscopic ultrasonography for accurate ascertainment of the tumor stage of gastric cancers. In this study, tumors were locally staged with the use of computed tomography (CT), which is inferior to endoscopic ultrasonography in determining the local tumor stage and nodal status of these cancers.1,2 Indeed, the addition of fine-needle aspiration has enhanced the ability of endoscopic ultrasonography to characterize perigastric lymph nodes.3 The fact that 37% of patients in the surgery group had tumor stage 1 or 2 disease and 30% had node-negative disease attests to the poor performance of CT in detecting locally invasive disease.
Gavin C. Harewood, M.D.
Beaumont Hospital
Dublin 9, Ireland
harewood.gavin@gmail.com
References
Ganpathi IS, So JB, Ho KY. Endoscopic ultrasonography for gastric cancer: does it influence treatment? Surg Endosc 2006;20:559-562.
Polkowski M, Palucki J, Wronska E, et al. Endosonography versus helical computed tomography for locoregional staging of gastric cancer. Endoscopy 2004;36:617-623.
Wiersema MJ, Vilmann P, Giovannini M, Chang KJ, Wiersema LM. Endosonography-guided fine-needle aspiration biopsy: diagnostic accuracy and complication assessment. Gastroenterology 1997;112:1087-1095.
To the Editor: Cunningham et al. report a survival benefit for perioperative chemotherapy among patients with gastric cancer, but approximately one fourth of the patients had esophageal or junctional tumors. The inclusion of this subgroup may have biased the results. In the case of gastric cancer alone, the 95% confidence interval for the hazard ratio for death crosses unity, as shown in Figure 2 in the article.
The authors suggest that chemotherapy resulted in down-staging of disease. This conclusion appears to be based on incomplete data. For only 65% of the perioperative-chemotherapy group and 72% of the surgery group was the tumor size recorded before treatment. In the perioperative-chemotherapy group, the tumor stage was recorded for only 75% of patients and nodal status for only 59%. The corresponding percentages in the surgery group were 79% and 64%. No explanation is offered. Although there is a difference in survival between the two groups, are the data sufficiently robust to conclude that perioperative chemotherapy should now be considered the standard of care for patients with gastric cancer?
John Fielding, M.D.
David Peake, M.B., Ch.B.
University Hospital Birmingham National Health Service Foundation Trust
Birmingham B15 2TH, United Kingdom
To the Editor: Cunningham et al. report that of the 250 patients who received only neoadjuvant chemotherapy, only 42% completed the prescribed protocol, whereas 34% underwent surgery after preoperative chemotherapy alone and did not complete postoperative chemotherapy. It would have been interesting to compare these two groups and to compare the group given preoperative chemotherapy alone with the surgery-alone group to determine whether preoperative chemotherapy and the subsequent tumor down-staging that it causes are responsible for the survival advantage in this group.
Kalpesh Jani, M.S.
Gem Hospital
Coimbatore 641045, India
kvjani@gmail.com
To the Editor: In the study by Cunningham et al., only 42% of the patients received all six cycles of perioperative chemotherapy, whereas in the study by Macdonald et al., 64% of the patients completed treatment as planned; moreover, the radiotherapy plan had to be adjusted for 35% of patients.1 Therefore, perioperative treatment of gastric cancer is harsh.
Data on patterns of treatment failure (distant vs. locoregional disease) are not provided by Cunningham et al. and may be related to the treatment actually administered. This information is of crucial importance for decisions about future treatment strategies. Is postoperative chemotherapy essential, and can it be optimized with the use of locoregional radiotherapy?
Henk Boot, M.D., Ph.D.
Edwin P.M. Jansen, M.D.
Annemiek Cats, M.D., Ph.D.
Netherlands Cancer Institute
1066 CX Amsterdam, the Netherlands
References
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;345:725-730.
To the Editor: The report by Cunningham et al. is encouraging, but given the high incidence of malnutrition among patients with gastrointestinal cancers, it is surprising that there is no record of the nutritional status of patients either at the time of diagnosis or at the time of surgery. Was there an attempt to correct nutritional deficiencies before surgery? The authors report that the median time from randomization to surgery was 14 days in the surgery group and 99 days in the perioperative-chemotherapy group. Could differences in nutritional interventions during these periods have affected overall survival?
David A.J. Lloyd, M.R.C.P.
Simon M. Gabe, M.D., M.R.C.P.
St. Mark's Hospital
Harrow HA1 3UJ, United Kingdom
The authors reply: When the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial was recruiting patients, it was not possible to determine reliably the tumor and nodal stage before treatment. Baseline tumor measurement was limited to endoscopic measurement of the maximal tumor diameter. There was no difference in the available data on tumor diameter between the two study groups (median in each group, 5 cm). We would expect that among patients for whom data on tumor diameter were not available the tumor size would be distributed randomly and would not result in any imbalance between the groups. Endoscopic ultrasonography was not routinely performed, and CT could not provide accurate staging detail. CT was performed to identify patients who had locally advanced or distant disease that was clearly unsuitable for radical therapy and who were excluded from the trial. We accept that endoscopic ultrasonography has a role in the staging of disease in such patients and have incorporated it into the baseline assessments required for the follow-up study (United Kingdom National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group ST03 trial), in which patients with resectable gastric cancer will be randomly assigned to perioperative chemotherapy with epirubicin, cisplatin, and capecitabine with or without the antivascular endothelial growth factor antibody bevacizumab.
The survival outcomes of the study have been analyzed and reported on an intention-to-treat basis. The study was powered for overall treatment effect, and we would not expect to find significant results in any subgroup — for example, one defined according to tumor site. Nevertheless, we found no evidence of heterogeneity of treatment effect between the tumor sites (gastric vs. esophagogastric junctional vs. lower esophageal). Under these circumstances, it is generally accepted that the best estimate of treatment effect for an individual patient is the overall effect, rather than the subgroup estimate.1
We do not believe that subgroup analyses to evaluate separately the outcomes among patients who received preoperative chemotherapy only, as compared with either those who completed all six cycles or those assigned to surgery alone, would be helpful. The results would be difficult to interpret, because the patients in the perioperative-chemotherapy group who did not complete protocol treatment would not have done so because of early death or disease progression, which would significantly bias such an analysis.
David Cunningham, M.D.
Royal Marsden Hospital
Surrey SM2 5PT, United Kingdom
david.cunningham@rmh.nhs.uk
William H. Allum, M.D.
Royal Marsden Hospital
London SW3 6JJ, United Kingdom
Sally P. Stenning, M.Sc.
Medical Research Council Clinical Trials Unit, Cancer Group
London NW1 2DA, United Kingdom
Dr. Cunningham reports having received honoraria, consulting fees, and research funding from Roche.
References
Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98.
Jaswinder Singh, M.D.
Stephen K. Williamson, M.D.
Kansas University Medical Center
Kansas City, KS 66160
Ashok K. Malani, M.D.
Heartland Regional Medical Center
St. Joseph, MO 64507
drmalani@yahoo.com
References
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.
To the Editor: The findings of Cunningham and colleagues underscore the importance of preoperative endoscopic ultrasonography for accurate ascertainment of the tumor stage of gastric cancers. In this study, tumors were locally staged with the use of computed tomography (CT), which is inferior to endoscopic ultrasonography in determining the local tumor stage and nodal status of these cancers.1,2 Indeed, the addition of fine-needle aspiration has enhanced the ability of endoscopic ultrasonography to characterize perigastric lymph nodes.3 The fact that 37% of patients in the surgery group had tumor stage 1 or 2 disease and 30% had node-negative disease attests to the poor performance of CT in detecting locally invasive disease.
Gavin C. Harewood, M.D.
Beaumont Hospital
Dublin 9, Ireland
harewood.gavin@gmail.com
References
Ganpathi IS, So JB, Ho KY. Endoscopic ultrasonography for gastric cancer: does it influence treatment? Surg Endosc 2006;20:559-562.
Polkowski M, Palucki J, Wronska E, et al. Endosonography versus helical computed tomography for locoregional staging of gastric cancer. Endoscopy 2004;36:617-623.
Wiersema MJ, Vilmann P, Giovannini M, Chang KJ, Wiersema LM. Endosonography-guided fine-needle aspiration biopsy: diagnostic accuracy and complication assessment. Gastroenterology 1997;112:1087-1095.
To the Editor: Cunningham et al. report a survival benefit for perioperative chemotherapy among patients with gastric cancer, but approximately one fourth of the patients had esophageal or junctional tumors. The inclusion of this subgroup may have biased the results. In the case of gastric cancer alone, the 95% confidence interval for the hazard ratio for death crosses unity, as shown in Figure 2 in the article.
The authors suggest that chemotherapy resulted in down-staging of disease. This conclusion appears to be based on incomplete data. For only 65% of the perioperative-chemotherapy group and 72% of the surgery group was the tumor size recorded before treatment. In the perioperative-chemotherapy group, the tumor stage was recorded for only 75% of patients and nodal status for only 59%. The corresponding percentages in the surgery group were 79% and 64%. No explanation is offered. Although there is a difference in survival between the two groups, are the data sufficiently robust to conclude that perioperative chemotherapy should now be considered the standard of care for patients with gastric cancer?
John Fielding, M.D.
David Peake, M.B., Ch.B.
University Hospital Birmingham National Health Service Foundation Trust
Birmingham B15 2TH, United Kingdom
To the Editor: Cunningham et al. report that of the 250 patients who received only neoadjuvant chemotherapy, only 42% completed the prescribed protocol, whereas 34% underwent surgery after preoperative chemotherapy alone and did not complete postoperative chemotherapy. It would have been interesting to compare these two groups and to compare the group given preoperative chemotherapy alone with the surgery-alone group to determine whether preoperative chemotherapy and the subsequent tumor down-staging that it causes are responsible for the survival advantage in this group.
Kalpesh Jani, M.S.
Gem Hospital
Coimbatore 641045, India
kvjani@gmail.com
To the Editor: In the study by Cunningham et al., only 42% of the patients received all six cycles of perioperative chemotherapy, whereas in the study by Macdonald et al., 64% of the patients completed treatment as planned; moreover, the radiotherapy plan had to be adjusted for 35% of patients.1 Therefore, perioperative treatment of gastric cancer is harsh.
Data on patterns of treatment failure (distant vs. locoregional disease) are not provided by Cunningham et al. and may be related to the treatment actually administered. This information is of crucial importance for decisions about future treatment strategies. Is postoperative chemotherapy essential, and can it be optimized with the use of locoregional radiotherapy?
Henk Boot, M.D., Ph.D.
Edwin P.M. Jansen, M.D.
Annemiek Cats, M.D., Ph.D.
Netherlands Cancer Institute
1066 CX Amsterdam, the Netherlands
References
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;345:725-730.
To the Editor: The report by Cunningham et al. is encouraging, but given the high incidence of malnutrition among patients with gastrointestinal cancers, it is surprising that there is no record of the nutritional status of patients either at the time of diagnosis or at the time of surgery. Was there an attempt to correct nutritional deficiencies before surgery? The authors report that the median time from randomization to surgery was 14 days in the surgery group and 99 days in the perioperative-chemotherapy group. Could differences in nutritional interventions during these periods have affected overall survival?
David A.J. Lloyd, M.R.C.P.
Simon M. Gabe, M.D., M.R.C.P.
St. Mark's Hospital
Harrow HA1 3UJ, United Kingdom
The authors reply: When the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial was recruiting patients, it was not possible to determine reliably the tumor and nodal stage before treatment. Baseline tumor measurement was limited to endoscopic measurement of the maximal tumor diameter. There was no difference in the available data on tumor diameter between the two study groups (median in each group, 5 cm). We would expect that among patients for whom data on tumor diameter were not available the tumor size would be distributed randomly and would not result in any imbalance between the groups. Endoscopic ultrasonography was not routinely performed, and CT could not provide accurate staging detail. CT was performed to identify patients who had locally advanced or distant disease that was clearly unsuitable for radical therapy and who were excluded from the trial. We accept that endoscopic ultrasonography has a role in the staging of disease in such patients and have incorporated it into the baseline assessments required for the follow-up study (United Kingdom National Cancer Research Institute Upper Gastrointestinal Clinical Studies Group ST03 trial), in which patients with resectable gastric cancer will be randomly assigned to perioperative chemotherapy with epirubicin, cisplatin, and capecitabine with or without the antivascular endothelial growth factor antibody bevacizumab.
The survival outcomes of the study have been analyzed and reported on an intention-to-treat basis. The study was powered for overall treatment effect, and we would not expect to find significant results in any subgroup — for example, one defined according to tumor site. Nevertheless, we found no evidence of heterogeneity of treatment effect between the tumor sites (gastric vs. esophagogastric junctional vs. lower esophageal). Under these circumstances, it is generally accepted that the best estimate of treatment effect for an individual patient is the overall effect, rather than the subgroup estimate.1
We do not believe that subgroup analyses to evaluate separately the outcomes among patients who received preoperative chemotherapy only, as compared with either those who completed all six cycles or those assigned to surgery alone, would be helpful. The results would be difficult to interpret, because the patients in the perioperative-chemotherapy group who did not complete protocol treatment would not have done so because of early death or disease progression, which would significantly bias such an analysis.
David Cunningham, M.D.
Royal Marsden Hospital
Surrey SM2 5PT, United Kingdom
david.cunningham@rmh.nhs.uk
William H. Allum, M.D.
Royal Marsden Hospital
London SW3 6JJ, United Kingdom
Sally P. Stenning, M.Sc.
Medical Research Council Clinical Trials Unit, Cancer Group
London NW1 2DA, United Kingdom
Dr. Cunningham reports having received honoraria, consulting fees, and research funding from Roche.
References
Yusuf S, Wittes J, Probstfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98.