Chemotherapy for Pancreatic Cancer
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《新英格兰医药杂志》
To the Editor: Neoptolemos et al. (March 18 issue)1 report the results of a trial conducted by the European Study Group for Pancreatic Cancer (ESPAC-1), which showed a survival advantage for adjuvant chemotherapy, but a deleterious effect of chemoradiotherapy. We would like to emphasize the suboptimal nature of the radiotherapy delivered in this trial. The regimen of chemoradiotherapy used was taken from the Gastrointestinal Tumor Study Group (GITSG) trial,2 which was reported in 1985 but conceived in the early 1970s. The use of a split-course technique prolongs the overall treatment time and is known to reduce the rate of local control.3 It is now well established that fluorouracil can be safely delivered with radiotherapy in doses of 45 to 54 Gy, given in fractions of 1.8 Gy daily.4 The routine availability of computed tomography for planning and delivery of conformal treatment permits precise targeting and minimizes the risk to normal organs. Improvements in quality assurance and technique have established the benefit of chemoradiotherapy after surgery for stomach cancer, whereas previously it was thought that there was none.5,6 We believe that the role of optimal chemoradiotherapy after resection of pancreatic cancer remains unclear and that it is worthy of consideration in future trials.
Stephen L. Morris, M.R.C.P., F.R.C.R.
Matthew Beasley, M.R.C.P.
Martin Leslie, M.D., F.R.C.R., F.R.C.P.
Guy's and St. Thomas' Cancer Center
London SE1 7EH, United Kingdom
References
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-1210.
Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.
Board of the Faculty of Clinical Oncology. Guidelines for the management of the unscheduled interruption or prolongation of a radical course of radiotherapy. 2nd ed. London: The Royal College of Radiologists, 2002.
Abrams RA. Adjuvant therapy for pancreatic adenocarcinoma: what have we learned since 1985? Int J Radiat Oncol Biol Phys 2003;56:Suppl 4:3-9.
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.
Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 1994;343:1309-1312.
To the Editor: The survival of the patients who received chemoradiotherapy in the ESPAC-1 study was worse than that in other, similar studies.1,2,3 Local recurrence was common, constituting 62 percent of all recurrences. Considering the usually dominant, competing risk of distant recurrence in pancreatic cancer, this finding represents an unsatisfying result of local treatment (surgery and chemoradiotherapy). It is universally accepted that interrupting radiotherapy, as in this trial, leads to worse outcomes. In comparison, there was a 6 percent rate of local tumor recurrence in another study.1
There was no central review of radiotherapy fields, and protocol compliance was poor. Radiotherapy quality assurance was critical in the landmark trial of postoperative chemoradiotherapy for gastric cancer by Macdonald et al., in which approximately 35 percent of treatment plans were corrected before radiotherapy.4 An analysis of modern doses, schedules, equipment, and techniques with quality assurance is currently under way. Comparison of rates of local control between the studies will be very instructive.
Because of the shortcomings of the ESPAC-1 study, the authors' general conclusion that chemoradiotherapy is not effective in patients with resected pancreatic cancer is not supported by the data, and this trial should not change the standard of care.
Christopher H. Crane, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
ccrane@mdanderson.org
Edgar Ben-Josef, M.D.
University of Michigan
Ann Arbor, MI 48109
William Small, Jr., M.D.
Northwestern University
Chicago, IL 60611
References
Breslin TM, Hess KA, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123-132.
Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas -- 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567-579.
Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74-85.
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: Neoptolemos et al. examined adjuvant techniques for macroscopically resected pancreatic cancer and convincingly demonstrated that their chemoradiotherapy technique was inferior to fluorouracil chemotherapy alone. They attributed survival differences to a delay in the initiation of full-dose chemotherapy.
However, survival in the chemoradiotherapy group was worse than that in the group of patients assigned only to observation. The excess mortality appeared in the second year, suggesting that it may have been the result of late toxic effects of radiation — in particular, kidney damage.1 Unfortunately, the radiation techniques are not fully described. They appear to be the same radiation techniques as those used in the original GITSG trial.2 Such outdated methods limit the tolerable dose to ineffective levels but at the same time can result in the delivery of excessive doses to normal tissues. Furthermore, no systematic quality assurance of radiotherapy was undertaken during the trial.
We agree with the authors that this radiotherapy technique should be abandoned. However, we advise caution in their conviction that well-done modern radiotherapy would also be harmful.
Sean Bydder, M.B., Ch.B.
William Buckland Radiotherapy Centre
Melbourne, VIC 3181, Australia
s_bydder@hotmail.com
Nigel Spry, M.B., B.S.
Sir Charles Gairdner Hospital
Perth, WA 6009, Australia
References
Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 1995;31:1249-1256.
Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.
The authors reply: In the ESPAC-1 trial, the median survival among patients assigned to combination chemoradiotherapy plus chemotherapy was 19.9 months. Of the five studies1,2,3,4,5 cited by the correspondents, only three specifically dealt with pancreatic ductal adenocarcinoma,1,3,5 with median survival times of 15.9, 19, and 20 months, respectively. In the trial of neoadjuvant therapy,2 which excluded a large proportion of patients who had progression during treatment — such patients were included in the ESPAC-1 trial — the median survival was 21 months. In the small population study, based on multiple cross-referencing of selected Surveillance, Epidemiology, and End Results and Medicare registration data (which are prone to considerable errors), the median survival was 25.1 months.4 Four of the studies1,2,3,4 were retrospective; hence, there was little scope for quality control of either the treatment delivered or the data captured. All four groups of investigators1,2,3,4 reported survival data only for the patients who actually received treatment, whereas the ESPAC-1 trial investigators reported intention-to-treat survival data, which should have resulted in lower survival estimates; this was not the case. Whereas the GITSG trial5 excluded patients with positive resection margins, the ESPAC-1 trial did not. Despite the biases that should have depressed the apparent survival rate, the actual results of chemoradiotherapy followed by chemotherapy in ESPAC-1 were comparable to those in these other studies.1,2,3,4,5
Discussion about local recurrence has scientific validity only if undertaken within the complete context. In the study of neoadjuvant therapy, the rate of local recurrence alone was 27 percent2 (after the exclusion of patients who had progression before surgery), as compared with 35 percent in the whole ESPAC-1 trial, but with many fewer actual recurrences among those who received chemotherapy. Moreover, a relationship between local control by chemoradiotherapy and survival has never been established for pancreatic cancer, simply because it is a systemic disease from the moment of diagnosis.
The evidence base in favor of chemoradiation and chemotherapy resides in a randomized trial involving only 43 patients.5 This seems untenable in the present day. The aim of the ESPAC-1 trial was to determine whether this survival benefit5 was due to chemoradiotherapy, chemotherapy, or their combination. The ESPAC-1 trial unequivocally showed that chemotherapy was beneficial (five-year survival rate of 29 percent) but chemoradiotherapy overall was not, almost certainly because there was a delay in the initiation of systemic chemotherapy. Although the role of chemoradiotherapy (with use of the newer radiotherapy techniques) in subgroups of patients such as those with positive resection margins still needs to be addressed, we believe that the new standard of care is resection followed by adjuvant chemotherapy.
John P. Neoptolemos, M.D.
Royal Liverpool University Hospital
Liverpool L69 3GA, United Kingdom
j.p.neoptolemos@liv.ac.uk
Deborah Stocken, M.Sc.
University of Birmingham
Birmingham B15 2TT, United Kingdom
Markus Büchler, M.D.
University of Heidelberg
D-69120 Heidelberg, Germany
References
Abrams RA, Grochow LB, Chakravarthy A, et al. Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose, and CA19-9 levels. Int J Radiat Oncol Biol Phys 1999;44:1039-1046.
Breslin TM, Hess KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123-132.
Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas -- 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567-579.
Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74-85.
Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.
Stephen L. Morris, M.R.C.P., F.R.C.R.
Matthew Beasley, M.R.C.P.
Martin Leslie, M.D., F.R.C.R., F.R.C.P.
Guy's and St. Thomas' Cancer Center
London SE1 7EH, United Kingdom
References
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-1210.
Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.
Board of the Faculty of Clinical Oncology. Guidelines for the management of the unscheduled interruption or prolongation of a radical course of radiotherapy. 2nd ed. London: The Royal College of Radiologists, 2002.
Abrams RA. Adjuvant therapy for pancreatic adenocarcinoma: what have we learned since 1985? Int J Radiat Oncol Biol Phys 2003;56:Suppl 4:3-9.
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.
Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up. Lancet 1994;343:1309-1312.
To the Editor: The survival of the patients who received chemoradiotherapy in the ESPAC-1 study was worse than that in other, similar studies.1,2,3 Local recurrence was common, constituting 62 percent of all recurrences. Considering the usually dominant, competing risk of distant recurrence in pancreatic cancer, this finding represents an unsatisfying result of local treatment (surgery and chemoradiotherapy). It is universally accepted that interrupting radiotherapy, as in this trial, leads to worse outcomes. In comparison, there was a 6 percent rate of local tumor recurrence in another study.1
There was no central review of radiotherapy fields, and protocol compliance was poor. Radiotherapy quality assurance was critical in the landmark trial of postoperative chemoradiotherapy for gastric cancer by Macdonald et al., in which approximately 35 percent of treatment plans were corrected before radiotherapy.4 An analysis of modern doses, schedules, equipment, and techniques with quality assurance is currently under way. Comparison of rates of local control between the studies will be very instructive.
Because of the shortcomings of the ESPAC-1 study, the authors' general conclusion that chemoradiotherapy is not effective in patients with resected pancreatic cancer is not supported by the data, and this trial should not change the standard of care.
Christopher H. Crane, M.D.
University of Texas M.D. Anderson Cancer Center
Houston, TX 77030
ccrane@mdanderson.org
Edgar Ben-Josef, M.D.
University of Michigan
Ann Arbor, MI 48109
William Small, Jr., M.D.
Northwestern University
Chicago, IL 60611
References
Breslin TM, Hess KA, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123-132.
Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas -- 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567-579.
Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74-85.
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: Neoptolemos et al. examined adjuvant techniques for macroscopically resected pancreatic cancer and convincingly demonstrated that their chemoradiotherapy technique was inferior to fluorouracil chemotherapy alone. They attributed survival differences to a delay in the initiation of full-dose chemotherapy.
However, survival in the chemoradiotherapy group was worse than that in the group of patients assigned only to observation. The excess mortality appeared in the second year, suggesting that it may have been the result of late toxic effects of radiation — in particular, kidney damage.1 Unfortunately, the radiation techniques are not fully described. They appear to be the same radiation techniques as those used in the original GITSG trial.2 Such outdated methods limit the tolerable dose to ineffective levels but at the same time can result in the delivery of excessive doses to normal tissues. Furthermore, no systematic quality assurance of radiotherapy was undertaken during the trial.
We agree with the authors that this radiotherapy technique should be abandoned. However, we advise caution in their conviction that well-done modern radiotherapy would also be harmful.
Sean Bydder, M.B., Ch.B.
William Buckland Radiotherapy Centre
Melbourne, VIC 3181, Australia
s_bydder@hotmail.com
Nigel Spry, M.B., B.S.
Sir Charles Gairdner Hospital
Perth, WA 6009, Australia
References
Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 1995;31:1249-1256.
Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.
The authors reply: In the ESPAC-1 trial, the median survival among patients assigned to combination chemoradiotherapy plus chemotherapy was 19.9 months. Of the five studies1,2,3,4,5 cited by the correspondents, only three specifically dealt with pancreatic ductal adenocarcinoma,1,3,5 with median survival times of 15.9, 19, and 20 months, respectively. In the trial of neoadjuvant therapy,2 which excluded a large proportion of patients who had progression during treatment — such patients were included in the ESPAC-1 trial — the median survival was 21 months. In the small population study, based on multiple cross-referencing of selected Surveillance, Epidemiology, and End Results and Medicare registration data (which are prone to considerable errors), the median survival was 25.1 months.4 Four of the studies1,2,3,4 were retrospective; hence, there was little scope for quality control of either the treatment delivered or the data captured. All four groups of investigators1,2,3,4 reported survival data only for the patients who actually received treatment, whereas the ESPAC-1 trial investigators reported intention-to-treat survival data, which should have resulted in lower survival estimates; this was not the case. Whereas the GITSG trial5 excluded patients with positive resection margins, the ESPAC-1 trial did not. Despite the biases that should have depressed the apparent survival rate, the actual results of chemoradiotherapy followed by chemotherapy in ESPAC-1 were comparable to those in these other studies.1,2,3,4,5
Discussion about local recurrence has scientific validity only if undertaken within the complete context. In the study of neoadjuvant therapy, the rate of local recurrence alone was 27 percent2 (after the exclusion of patients who had progression before surgery), as compared with 35 percent in the whole ESPAC-1 trial, but with many fewer actual recurrences among those who received chemotherapy. Moreover, a relationship between local control by chemoradiotherapy and survival has never been established for pancreatic cancer, simply because it is a systemic disease from the moment of diagnosis.
The evidence base in favor of chemoradiation and chemotherapy resides in a randomized trial involving only 43 patients.5 This seems untenable in the present day. The aim of the ESPAC-1 trial was to determine whether this survival benefit5 was due to chemoradiotherapy, chemotherapy, or their combination. The ESPAC-1 trial unequivocally showed that chemotherapy was beneficial (five-year survival rate of 29 percent) but chemoradiotherapy overall was not, almost certainly because there was a delay in the initiation of systemic chemotherapy. Although the role of chemoradiotherapy (with use of the newer radiotherapy techniques) in subgroups of patients such as those with positive resection margins still needs to be addressed, we believe that the new standard of care is resection followed by adjuvant chemotherapy.
John P. Neoptolemos, M.D.
Royal Liverpool University Hospital
Liverpool L69 3GA, United Kingdom
j.p.neoptolemos@liv.ac.uk
Deborah Stocken, M.Sc.
University of Birmingham
Birmingham B15 2TT, United Kingdom
Markus Büchler, M.D.
University of Heidelberg
D-69120 Heidelberg, Germany
References
Abrams RA, Grochow LB, Chakravarthy A, et al. Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose, and CA19-9 levels. Int J Radiat Oncol Biol Phys 1999;44:1039-1046.
Breslin TM, Hess KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123-132.
Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas -- 616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567-579.
Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74-85.
Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.