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A challenge to the therapeutic nihilism of ESPAC-1
Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 4, pp. 965–966, 2005 Copyright © 2005 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/05/$–see front matter
doi:10.1016/j.ijrobp.2004.11.018
EDITORIAL
A CHALLENGE TO THE THERAPEUTIC NIHILISM OF ESPAC-1 MARY C. KOSHY, M.D.,* JEROME C. LANDRY, M.D.,* SEAN X. CAVANAUGH, M.D., PH.D.-C,† CLIFTON D. FULLER, B.S.,† CHRISTOPHER G. WILLETT, M.D.,‡ ROSS A. ABRAMS, M.D.,§ JOHN P. HOFFMAN, M.D.,储 AND CHARLES R. THOMAS, JR., M.D.† *Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Center, Atlanta, GA; †Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX; ‡Department of Radiation Oncology, Duke University Medical Center, Durham, NC; §Department of Radiation Oncology, Rush University Medical Center, Chicago, IL; 储Division of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA
A recent publication in the New England Journal of Medicine by Neoptolemos et al. (1), along with the accompanying editorial, describe the mature results of the ESPAC-1 trial of adjuvant therapy for resected pancreatic adenocarcinoma (2). The authors must be commended for completing and reporting on one of the largest randomized trials of adjuvant therapy for pancreatic cancer, involving 289 patients from 11 European countries and 61 treatment centers (1). In the United States, the results of the Gastrointestinal Study Group randomized trials of patients with pancreatic cancer concluded that in unresectable patients, 5-fluorouracil (5-FU)– based chemoradiation followed by chemotherapy was superior to chemotherapy alone, and for resectable (margin-negative) patients, that 5-FU– based chemoradiotherapy followed by chemotherapy was more effective than no adjuvant therapy (3– 6). Other single-institution trials, as well as the randomized underpowered European Organization for Research and Treatment of Cancer trial, have suggested a benefit to adjuvant chemoradiotherapy (7, 8). Preliminary results from RTOG 97– 04 will be reported within the next 18 months. However, we are concerned about the results and corresponding methodology of this study design, which led the authors to nihilistically conclude that chemoradiotherapy has no role in the adjuvant therapy of resected pancreatic cancer. Several aspects of the radiotherapy techniques used in this trial are archaic and need to be addressed. The recommended 40 Gy was given “split course,” which is no longer done because of the prolonged treatment time and subsequent inferior radiobiologic efficiency as a result of the accelerated repopulation of tumor clonogens with this technique. Although the recommended dose was 40 Gy, radiation oncologists had the choice of giving up to 60 Gy, and 30% of patients received either a nonuniform dose of radiation or no radiation at all. Critical details regarding the
radiation fields used, machine and dosimetry specifications, and overall radiotherapy quality assurance are not described. To decrease the volume of normal tissue irradiated, patients are no longer treated in an AP-PA fashion, as they likely were in this study. Inappropriate radiation technique could certainly contribute to treatment-related toxicity, which may have been the cause of decreased survival in those patients receiving chemoradiation compared with those receiving no adjuvant therapy. As a result of the authors’ (mis)use of an area under the curve (AUC) method to compare toxicities, reported toxicity may be questioned. On page 1202, the statement that “clinicians were asked to record the most severe episode” can be open to interpretation. We believe that the AUC approach is useful to summarize a rather crude product of time and severity. In the AUC article (9) that was referenced by Neoptolemos et al. (1), the toxicity was graded from 0 to 3 (ordinal scale) at regular times and included variation in the time interval and some missing data (hence the word “messy” in the title of the reference). However, the ESPAC-1 design did not provide a subjective filter, such as asking the physicians to record the “most severe episode.” Hence, we question the validity of using a time summary method that is designed to add up all of the small and large events, if all of the small events are essentially eliminated from the model, because the present study asks physicians to record only the most severe episode (1). Moreover, even if the authors had used the AUC approach as intended, concerns remain, because the AUC approach treats ordinal data as if it were interval data, such that a Grade 2 toxicity is considered exactly twice as bad as a Grade 1 toxicity in the model. For example, a patient with Grade 1 toxicity for 6 weeks and a patient with Grade 3 toxicity for 2 weeks would have the same AUC. Toxicity scales do not have the property of consistent intervals;
Reprint requests to: Charles R. Thomas, Jr., M.D., Radiation Oncology, University of Texas Science Center at San Antonio, 7979 Wurzbach Rd., San Antonio, TX 78229. Tel: (210) 616-
5684; Fax: (210) 949-5085; E-mail: [email protected] Received Oct 29, 2004. Accepted for publication Nov 1, 2004. 965
966
I. J. Radiation Oncology
● Biology ● Physics
therefore, integrated areas where the y axis is toxicity are suspect, in our opinion, although they are common. In fact, Neoptolemos et al. partially acknowledge this shortcoming in the “Discussion,” with the statement that AUC analysis “may be influenced by the defined numerical value for each category of a symptom” (1). The reported toxicity may erroneously influence laypersons and community oncologists who are unprepared to appreciate the challenges inherent with the use of AUC toxicity (9, 10). There exists also a bias in favor of chemotherapy alone during the time from surgery to the initiation of treatment. The mean time after surgery to start chemotherapy was 48 days compared with 61 days for chemoradiation. Did the chemoradiation patients have a worse performance status? The time to initiation of therapy was not analyzed. The fact that over one-third of the patients failed to complete their chemotherapy regimen and 17% did not receive any chemotherapy at all is of
Volume 61, Number 4, 2005
concern, as is the lack of an explanation for this nonadherence to the protocol. The stated 4-month inferior time to recurrence for those receiving chemoradiation actually implies that chemoradiation somehow accelerates the biology of disease recurrence and represents one of the inherent weaknesses of the 2 ⫻ 2 factorial design. It would be helpful if the data on recurrence (local vs. distant), broken down by treatment modality, could be retrieved to determine whether the chemoradiation arm reduced local recurrence. Finally, the inclusion of patients with positive margins, as well as the failure to analyze the role of chemoradiotherapy in subsequent chemotherapy adherence, causes us to question the validity of these results and the stated conclusion that there is no role for chemoradiation in resected pancreatic cancer. Consequently, we believe that it is premature to alter the current recommendations for adjuvant therapy in completely resected pancreatic adenocarcinoma.
REFERENCES 1. 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. 2. Choti MA. Adjuvant therapy for pancreatic cancer—the debate continues. N Engl J Med 2004;350:1249 –1251. 3. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads ⫹ 5-fluorouracil), and high dose radiation ⫹ 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 1981;48:1705–1710. 4. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 1988;80:751–755. 5. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899 –903. 6. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy fol-
7.
8.
9. 19.
lowing curative resection of pancreatic cancer. Cancer 1987;59:2006 –2010. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, singleinstitution experience. Ann Surg 1997;225:621– 633. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: Phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999;230:776 –782. Qian W, Parmar MKB, Sambrook RJ, Fayers PM, Girling DJ, Stephens RJ. Analysis of messy longitudinal data from a randomized clinical trial. Stat Med 2000;19:2657–2674. Werner-Wasik M, Pequignot E, Leeper D, Hauck W, Curran W. Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with nonoperative therapy. Int J Radiat Oncol Biol Phys 2000;48: 689 – 696.
doi:10.1016/j.ijrobp.2004.11.018
EDITORIAL
A CHALLENGE TO THE THERAPEUTIC NIHILISM OF ESPAC-1 MARY C. KOSHY, M.D.,* JEROME C. LANDRY, M.D.,* SEAN X. CAVANAUGH, M.D., PH.D.-C,† CLIFTON D. FULLER, B.S.,† CHRISTOPHER G. WILLETT, M.D.,‡ ROSS A. ABRAMS, M.D.,§ JOHN P. HOFFMAN, M.D.,储 AND CHARLES R. THOMAS, JR., M.D.† *Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Center, Atlanta, GA; †Department of Radiation Oncology, University of Texas Health Science Center at San Antonio, San Antonio, TX; ‡Department of Radiation Oncology, Duke University Medical Center, Durham, NC; §Department of Radiation Oncology, Rush University Medical Center, Chicago, IL; 储Division of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA
A recent publication in the New England Journal of Medicine by Neoptolemos et al. (1), along with the accompanying editorial, describe the mature results of the ESPAC-1 trial of adjuvant therapy for resected pancreatic adenocarcinoma (2). The authors must be commended for completing and reporting on one of the largest randomized trials of adjuvant therapy for pancreatic cancer, involving 289 patients from 11 European countries and 61 treatment centers (1). In the United States, the results of the Gastrointestinal Study Group randomized trials of patients with pancreatic cancer concluded that in unresectable patients, 5-fluorouracil (5-FU)– based chemoradiation followed by chemotherapy was superior to chemotherapy alone, and for resectable (margin-negative) patients, that 5-FU– based chemoradiotherapy followed by chemotherapy was more effective than no adjuvant therapy (3– 6). Other single-institution trials, as well as the randomized underpowered European Organization for Research and Treatment of Cancer trial, have suggested a benefit to adjuvant chemoradiotherapy (7, 8). Preliminary results from RTOG 97– 04 will be reported within the next 18 months. However, we are concerned about the results and corresponding methodology of this study design, which led the authors to nihilistically conclude that chemoradiotherapy has no role in the adjuvant therapy of resected pancreatic cancer. Several aspects of the radiotherapy techniques used in this trial are archaic and need to be addressed. The recommended 40 Gy was given “split course,” which is no longer done because of the prolonged treatment time and subsequent inferior radiobiologic efficiency as a result of the accelerated repopulation of tumor clonogens with this technique. Although the recommended dose was 40 Gy, radiation oncologists had the choice of giving up to 60 Gy, and 30% of patients received either a nonuniform dose of radiation or no radiation at all. Critical details regarding the
radiation fields used, machine and dosimetry specifications, and overall radiotherapy quality assurance are not described. To decrease the volume of normal tissue irradiated, patients are no longer treated in an AP-PA fashion, as they likely were in this study. Inappropriate radiation technique could certainly contribute to treatment-related toxicity, which may have been the cause of decreased survival in those patients receiving chemoradiation compared with those receiving no adjuvant therapy. As a result of the authors’ (mis)use of an area under the curve (AUC) method to compare toxicities, reported toxicity may be questioned. On page 1202, the statement that “clinicians were asked to record the most severe episode” can be open to interpretation. We believe that the AUC approach is useful to summarize a rather crude product of time and severity. In the AUC article (9) that was referenced by Neoptolemos et al. (1), the toxicity was graded from 0 to 3 (ordinal scale) at regular times and included variation in the time interval and some missing data (hence the word “messy” in the title of the reference). However, the ESPAC-1 design did not provide a subjective filter, such as asking the physicians to record the “most severe episode.” Hence, we question the validity of using a time summary method that is designed to add up all of the small and large events, if all of the small events are essentially eliminated from the model, because the present study asks physicians to record only the most severe episode (1). Moreover, even if the authors had used the AUC approach as intended, concerns remain, because the AUC approach treats ordinal data as if it were interval data, such that a Grade 2 toxicity is considered exactly twice as bad as a Grade 1 toxicity in the model. For example, a patient with Grade 1 toxicity for 6 weeks and a patient with Grade 3 toxicity for 2 weeks would have the same AUC. Toxicity scales do not have the property of consistent intervals;
Reprint requests to: Charles R. Thomas, Jr., M.D., Radiation Oncology, University of Texas Science Center at San Antonio, 7979 Wurzbach Rd., San Antonio, TX 78229. Tel: (210) 616-
5684; Fax: (210) 949-5085; E-mail: [email protected] Received Oct 29, 2004. Accepted for publication Nov 1, 2004. 965
966
I. J. Radiation Oncology
● Biology ● Physics
therefore, integrated areas where the y axis is toxicity are suspect, in our opinion, although they are common. In fact, Neoptolemos et al. partially acknowledge this shortcoming in the “Discussion,” with the statement that AUC analysis “may be influenced by the defined numerical value for each category of a symptom” (1). The reported toxicity may erroneously influence laypersons and community oncologists who are unprepared to appreciate the challenges inherent with the use of AUC toxicity (9, 10). There exists also a bias in favor of chemotherapy alone during the time from surgery to the initiation of treatment. The mean time after surgery to start chemotherapy was 48 days compared with 61 days for chemoradiation. Did the chemoradiation patients have a worse performance status? The time to initiation of therapy was not analyzed. The fact that over one-third of the patients failed to complete their chemotherapy regimen and 17% did not receive any chemotherapy at all is of
Volume 61, Number 4, 2005
concern, as is the lack of an explanation for this nonadherence to the protocol. The stated 4-month inferior time to recurrence for those receiving chemoradiation actually implies that chemoradiation somehow accelerates the biology of disease recurrence and represents one of the inherent weaknesses of the 2 ⫻ 2 factorial design. It would be helpful if the data on recurrence (local vs. distant), broken down by treatment modality, could be retrieved to determine whether the chemoradiation arm reduced local recurrence. Finally, the inclusion of patients with positive margins, as well as the failure to analyze the role of chemoradiotherapy in subsequent chemotherapy adherence, causes us to question the validity of these results and the stated conclusion that there is no role for chemoradiation in resected pancreatic cancer. Consequently, we believe that it is premature to alter the current recommendations for adjuvant therapy in completely resected pancreatic adenocarcinoma.
REFERENCES 1. 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. 2. Choti MA. Adjuvant therapy for pancreatic cancer—the debate continues. N Engl J Med 2004;350:1249 –1251. 3. Moertel CG, Frytak S, Hahn RG, et al. Therapy of locally unresectable pancreatic carcinoma: A randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads ⫹ 5-fluorouracil), and high dose radiation ⫹ 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 1981;48:1705–1710. 4. Gastrointestinal Tumor Study Group. Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. J Natl Cancer Inst 1988;80:751–755. 5. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899 –903. 6. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy fol-
7.
8.
9. 19.
lowing curative resection of pancreatic cancer. Cancer 1987;59:2006 –2010. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, singleinstitution experience. Ann Surg 1997;225:621– 633. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: Phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999;230:776 –782. Qian W, Parmar MKB, Sambrook RJ, Fayers PM, Girling DJ, Stephens RJ. Analysis of messy longitudinal data from a randomized clinical trial. Stat Med 2000;19:2657–2674. Werner-Wasik M, Pequignot E, Leeper D, Hauck W, Curran W. Predictors of severe esophagitis include use of concurrent chemotherapy, but not the length of irradiated esophagus: A multivariate analysis of patients with lung cancer treated with nonoperative therapy. Int J Radiat Oncol Biol Phys 2000;48: 689 – 696.