Research Invited Commentary
Locally Advanced Pancreatic Cancer
Invited Commentary
Prolonged Preoperative Chemotherapy for Locally Advanced Pancreatic Adenocarcinoma Curing Cancer or Simply Improving Patient Selection? L. Andrew DiFronzo, MD
Pancreas adenocarcinoma continues to be a challenge for both clinicians and patients, with relatively few patients being candidates for resection and overall 5-year survival after resection remaining at about 15% to 20%. Much of the recent focus in this field has centered on the use of neoadjuvant chemotherapy to improve patient outcomes. The study by Kadera et al1 suggests that prolonged administration of preoperative systemic chemotherapy results in better outcomes for locally advanced, unresectable pancreas adenocarcinoma. During a period of nearly 20 years, 49 patients with unresectable pancreas cancer were rendered resectRelated article page 145 able—mostly without vein resection—by using preoperative chemotherapy for a relatively prolonged period. The results of this study are impressive: three-fourths of patients had nodenegative tumors, 85% had negative surgical margins, and more than half had a complete or near-complete histopathologic response. The 5-year survival was almost astonishing: more than 40%. This compares very favorably with conventional modern approaches with adjuvant therapy using either postoperative chemoradiation or gemcitabine-based chemotherapy alone, with a 5-year survival rate of approximately 20%. This study’s excellent results are compelling because it is well known that adenocarcinoma of the pancreas is very much both a systemic and local disease, and it is clear that systemic therapy is critical for improving survival. However, the study has several issues that make the interpretation of the data challenging and raise additional questions. Notably, only about 2 to 3 patients per year were successfully treated with prolonged chemotherapy and rendered resectable in this high-volume center. The authors did not record how many patients were treated but did not demonstrate a response to chemotherapy and therefore could not be resected (although they estimate a successful downstage rate of 15%-25%). ARTICLE INFORMATION
REFERENCES
Author Affiliation: Department of Surgery, Kaiser Permanente, Los Angeles, California.
1. Kadera BE, Sunjaya DB, Isacoff WH, et al. Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival [published online December 4, 2013]. JAMA Surg. doi:10.1001 /jamasurg.2013.2690.
Corresponding Author: L. Andrew DiFronzo, MD, Department of Surgery, Kaiser Permanente, 3rd Flr, Los Angeles, CA 90027 ([email protected]). Published Online: December 4, 2013. doi:10.1001/jamasurg.2013.2719. Conflict of Interest Disclosures: None reported.
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More critically, compared with a standard course of preoperative chemotherapy, the specific question of whether prolongation of chemotherapy increased the percentage of patients who developed evidence of systemic disease prior to surgery—and therefore avoided a nontherapeutic operation— was not answered. Is prolonged chemotherapy in this setting really just a way to select the optimal patient for surgery? Another confounding factor is the different chemotherapy regimens used over the time frame of this nearly 20year study. It is uncertain how many patients in this study received a FOLFIRINOX (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) regimen, which has the best response rates to date for metastatic adenocarcinoma of the pancreas2 and has shown promise in a pilot study examining its use in unresectable pancreas cancer.3 Is it necessary to give prolonged chemotherapy in the emerging era of FOLFIRINOX? Additionally, it was noted that after treatment, 40% of patients still had evidence of vascular involvement based on computed tomography criteria, yet these patients were successfully resected. This raises the issue of the usefulness of computed tomography in detecting persistent vascular involvement and determining resectability after treatment. A recent study suggested that metabolic activity on positronemission tomography correlates well with histopathologic response after neoadjuvant chemotherapy for resectable pancreatic cancer.4 Perhaps positron-emission tomography should be incorporated in these patients when computed tomography still suggests vascular involvement. Although progress has been made in the treatment of pancreatic cancer, many questions remain. Future studies will need to address the issue of the optimal neoadjuvant chemotherapy regimen for pancreas cancer, in addition to the timing and duration of therapy. In addition, the best imaging study to determine posttreatment resectability will clearly need to be determined.
2. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
3. Hosein PJ, Macintyre J, Kawamura C, et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic carcinoma. BMC Cancer. 2012;12:199. 4. Heinrich S, Schäfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248(6):1014-1022.
JAMA Surgery February 2014 Volume 149, Number 2
Copyright 2014 American Medical Association. All rights reserved.
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jamasurgery.com
Locally Advanced Pancreatic Cancer
Invited Commentary
Prolonged Preoperative Chemotherapy for Locally Advanced Pancreatic Adenocarcinoma Curing Cancer or Simply Improving Patient Selection? L. Andrew DiFronzo, MD
Pancreas adenocarcinoma continues to be a challenge for both clinicians and patients, with relatively few patients being candidates for resection and overall 5-year survival after resection remaining at about 15% to 20%. Much of the recent focus in this field has centered on the use of neoadjuvant chemotherapy to improve patient outcomes. The study by Kadera et al1 suggests that prolonged administration of preoperative systemic chemotherapy results in better outcomes for locally advanced, unresectable pancreas adenocarcinoma. During a period of nearly 20 years, 49 patients with unresectable pancreas cancer were rendered resectRelated article page 145 able—mostly without vein resection—by using preoperative chemotherapy for a relatively prolonged period. The results of this study are impressive: three-fourths of patients had nodenegative tumors, 85% had negative surgical margins, and more than half had a complete or near-complete histopathologic response. The 5-year survival was almost astonishing: more than 40%. This compares very favorably with conventional modern approaches with adjuvant therapy using either postoperative chemoradiation or gemcitabine-based chemotherapy alone, with a 5-year survival rate of approximately 20%. This study’s excellent results are compelling because it is well known that adenocarcinoma of the pancreas is very much both a systemic and local disease, and it is clear that systemic therapy is critical for improving survival. However, the study has several issues that make the interpretation of the data challenging and raise additional questions. Notably, only about 2 to 3 patients per year were successfully treated with prolonged chemotherapy and rendered resectable in this high-volume center. The authors did not record how many patients were treated but did not demonstrate a response to chemotherapy and therefore could not be resected (although they estimate a successful downstage rate of 15%-25%). ARTICLE INFORMATION
REFERENCES
Author Affiliation: Department of Surgery, Kaiser Permanente, Los Angeles, California.
1. Kadera BE, Sunjaya DB, Isacoff WH, et al. Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival [published online December 4, 2013]. JAMA Surg. doi:10.1001 /jamasurg.2013.2690.
Corresponding Author: L. Andrew DiFronzo, MD, Department of Surgery, Kaiser Permanente, 3rd Flr, Los Angeles, CA 90027 ([email protected]). Published Online: December 4, 2013. doi:10.1001/jamasurg.2013.2719. Conflict of Interest Disclosures: None reported.
154
More critically, compared with a standard course of preoperative chemotherapy, the specific question of whether prolongation of chemotherapy increased the percentage of patients who developed evidence of systemic disease prior to surgery—and therefore avoided a nontherapeutic operation— was not answered. Is prolonged chemotherapy in this setting really just a way to select the optimal patient for surgery? Another confounding factor is the different chemotherapy regimens used over the time frame of this nearly 20year study. It is uncertain how many patients in this study received a FOLFIRINOX (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) regimen, which has the best response rates to date for metastatic adenocarcinoma of the pancreas2 and has shown promise in a pilot study examining its use in unresectable pancreas cancer.3 Is it necessary to give prolonged chemotherapy in the emerging era of FOLFIRINOX? Additionally, it was noted that after treatment, 40% of patients still had evidence of vascular involvement based on computed tomography criteria, yet these patients were successfully resected. This raises the issue of the usefulness of computed tomography in detecting persistent vascular involvement and determining resectability after treatment. A recent study suggested that metabolic activity on positronemission tomography correlates well with histopathologic response after neoadjuvant chemotherapy for resectable pancreatic cancer.4 Perhaps positron-emission tomography should be incorporated in these patients when computed tomography still suggests vascular involvement. Although progress has been made in the treatment of pancreatic cancer, many questions remain. Future studies will need to address the issue of the optimal neoadjuvant chemotherapy regimen for pancreas cancer, in addition to the timing and duration of therapy. In addition, the best imaging study to determine posttreatment resectability will clearly need to be determined.
2. Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
3. Hosein PJ, Macintyre J, Kawamura C, et al. A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic carcinoma. BMC Cancer. 2012;12:199. 4. Heinrich S, Schäfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg. 2008;248(6):1014-1022.
JAMA Surgery February 2014 Volume 149, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archsurg.jamanetwork.com/ by a Nanyang Technological University User on 05/20/2015
jamasurgery.com
