Reply: What Is the Impact of Intraoperative Re-resection After a Positive Pancreatic Margin Frozen Section in the Era of Perioperative Therapies?

Reply: What Is the Impact of Intraoperative Re-resection After a Positive Pancreatic Margin... Letters to the Editor Annals of Surgery  Volume 267, Number 3, March 2018 8. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant log-rank test). Survival of patients in margin University Hospital Carl Gustav Carus chemotherapy with gemcitabine and long-term group III was lower than that of patients in TU Dresden, Germany. outcomes among patients with resected pancre- margin group I (13 months, P < 0.001; log- Nuh.Rahbari@uniklinikum-dresden.de atic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–1481. rank test) and margin group II (P ¼ 0.08; log- 9. O?Reilly EM, Perelshteyn A, Jarnagin WR, et al. rank test). Collectively, these data confirm the A single-arm, nonrandomized phase II trial of results of our initial report. neoadjuvant gemcitabine and oxaliplatin in REFERENCES The topic of margin clearance and out- patients with resectable pancreas adenocarci- come has been controversial owing to the lack 1. Nitschke P, Volk A, Welsch T, et al. Impact of noma. Ann Surg. 2014;260:142–148. intraoperative re-resection to achieve R0 status on of uniform guidelines for the processing of 10. Ferrone CR, Marchegiani G, Hong TS, et al. survival in patients with pancreatic cancer: a Radiological and surgical implications of neo- surgical specimens, reporting of pathological single-center experience with 483 patients. Ann adjuvant treatment with FOLFIRINOX for locally assessments and definition of margin positiv- Surg. 2016. Epub ahead of print. advanced and borderline resectable pancreatic 2 ity. It is correct that adjuvant chemotherapy 2. Esposito I, Kleeff J, Bergmann F, et al. Most cancer. Ann Surg. 2015;261:12–17. with either 5-FU/folinic acid or gemcitabine pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15:1651–1660. has been proven to prolong overall survival in 3,4 3. Neoptolemos JP, Stocken DD, Friess H, et al. A pancreatic cancer patients. While neither in randomized trial of chemoradiotherapy and che- the CONKO-001 trial nor in the ESPAC-1 trial motherapy after resection of pancreatic cancer. N resection margin status was associated with Engl J Med. 2004;350:1200–1210. Reply: What Is the Impact overall survival, one should note that only half 4. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant of the patients in these trials received adjuvant chemotherapy with gemcitabine and long-term of Intraoperative outcomes among patients with resected pancreatic chemotherapy. The results of the ESPAC-3 cancer: the CONKO-001 randomized trial. JAMA. trial, in which all patients received adjuvant Re-resection After a 2013;310:1473–1481. chemotherapy showed an adverse prognostic 5. Neoptolemos JP, Stocken DD, Bassi C, et al. Adju- Positive Pancreatic Margin impact of positive resection margin (though vant chemotherapy with fluorouracil plus folinic this association lost statistical significance acid vs gemcitabine following pancreatic cancer Frozen Section in the resection: a randomized controlled trial. JAMA. after adjustment for other clinicopathologic 5 2010;304:1073–1081. Era of Perioperative variables). 6. Butturini G, Stocken DD, Wente MN, et al. Influ- However, to dissect out the efficacy of ence of resection margins and treatment on survival Therapies? adjuvant therapy for patients with different in patients with pancreatic cancer: meta-analysis of resection margin status the subgroup analyses randomized controlled trials. Arch Surg. 2008; 143:75–83. provided for both trials are of critical Reply: importance. Remarkably, for both trials these e would like to thank the authors for analyses failed to demonstrate a survival W their interest in our recent study on advantage of adjuvant chemotherapy in the 3,4 frozen section analysis and impact of intra- subset of patients with R1 resections. These operative margin clearance on survival of data are confirmed by a meta-analysis of 4 1 30-day Readmission After patients with pancreatic cancer. Given the randomized controlled trials that demon- survival benefit of adjuvant chemotherapy in strated a 35% risk reduction for adjuvant Operative Management of patients with pancreatic ductal adenocarci- chemotherapy in the R0 group [hazard ratio Adhesive Small Bowel noma (PDAC) in the CONKO-001 trial, the (HR): 0.65; 95% confidence interval (CI): question of adjuvant chemotherapy and its 0.53–0.80], whereas adjuvant chemotherapy Obstruction prognostic value in our study cohort was failed to improve survival in patients with R1 raised. The authors pointed out that adjuvant resections (HR: 1.04; 95% CI: 0.78–1.40). chemotherapy but not resection margin status These data together with the prognos- was associated with survival in the CONKO- tic value of resection margin status in the To the Editor: 001 trial, which may justify questioning ESPAC-3 trial may challenge the notion e read with interest the article by the prognostic value of resection margin that the prognostic value of resection W Aquina et al, which provides a con- status in the setting of effective perioperative margin status is diminished by current adju- vincing answer to an important research therapies. vant chemotherapy regimens. If resection question. We would like to comment on In our study cohort, adjuvant chemo- margin status looses prognostic value with one of the study’s conclusions relating to therapy was not associated with a survival the increasingly used, more intensive chemo- 30-day readmission. The authors conclude benefit (P ¼ 0.351; log-rank test), which therapy protocols such as FOLFIRINOX that in cases of operative management, may be explained by more frequent presence remains to be determined in future studies. use of a primary medical service increased of high-risk pathological features such as poor These studies should apply standardized 30-day readmission (17.9% vs 14.0%). This differentiation, large tumor size and presence guidelines for the processing of pancreatic appears to be based on results from crude of perineural invasion in patients who received specimens and reporting of pathology results. bivariate analysis included in Table 2 in the adjuvant chemotherapy. Among the 3 margin article. However, as results from the multi- groups described in our study the proportion of Disclosure: The authors declare no variable regression in Table 4 control for patients who received adjuvant chemotherapy conflicts of interest. patient, physician, and hospital level factors was 58.8% for margin group I, 86.4% for (whereas the bivariate analysis does not), margin group II and 79.0% for margin group Philipp Nitschke, MD perhaps we should conclude that there is not III (P ¼ 0.001). Survival analyses restricted to Ju¨rgen Weitz, MD, MSc sufficient evidence to reject the null hypoth- patients who received adjuvant chemotherapy Nuh N. Rahbari, MD esis (H0: primary medical and primary showed similar survival for patients in margin Department of Visceral surgical management effects on 30-day groups I and II (24 vs 26 months, P ¼ 0.880; Thoracic, and Vascular Surgery readmissions are equal.) Indeed, Table 4 e56 | www.annalsofsurgery.com  2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Surgery Wolters Kluwer Health

Reply: What Is the Impact of Intraoperative Re-resection After a Positive Pancreatic Margin Frozen Section in the Era of Perioperative Therapies?

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Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Abstract

Letters to the Editor Annals of Surgery  Volume 267, Number 3, March 2018 8. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant log-rank test). Survival of patients in margin University Hospital Carl Gustav Carus chemotherapy with gemcitabine and long-term group III was lower than that of patients in TU Dresden, Germany. outcomes among patients with resected pancre- margin group I (13 months, P < 0.001; log- Nuh.Rahbari@uniklinikum-dresden.de atic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–1481. rank test) and margin group II (P ¼ 0.08; log- 9. O?Reilly EM, Perelshteyn A, Jarnagin WR, et al. rank test). Collectively, these data confirm the A single-arm, nonrandomized phase II trial of results of our initial report. neoadjuvant gemcitabine and oxaliplatin in REFERENCES The topic of margin clearance and out- patients with resectable pancreas adenocarci- come has been controversial owing to the lack 1. Nitschke P, Volk A, Welsch T, et al. Impact of noma. Ann Surg. 2014;260:142–148. intraoperative re-resection to achieve R0 status on of uniform guidelines for the processing of 10. Ferrone CR, Marchegiani G, Hong TS, et al. survival in patients with pancreatic cancer: a Radiological and surgical implications of neo- surgical specimens, reporting of pathological single-center experience with 483 patients. Ann adjuvant treatment with FOLFIRINOX for locally assessments and definition of margin positiv- Surg. 2016. Epub ahead of print. advanced and borderline resectable pancreatic 2 ity. It is correct that adjuvant chemotherapy 2. Esposito I, Kleeff J, Bergmann F, et al. Most cancer. Ann Surg. 2015;261:12–17. with either 5-FU/folinic acid or gemcitabine pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15:1651–1660. has been proven to prolong overall survival in 3,4 3. Neoptolemos JP, Stocken DD, Friess H, et al. A pancreatic cancer patients. While neither in randomized trial of chemoradiotherapy and che- the CONKO-001 trial nor in the ESPAC-1 trial motherapy after resection of pancreatic cancer. N resection margin status was associated with Engl J Med. 2004;350:1200–1210. Reply: What Is the Impact overall survival, one should note that only half 4. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant of the patients in these trials received adjuvant chemotherapy with gemcitabine and long-term of Intraoperative outcomes among patients with resected pancreatic chemotherapy. The results of the ESPAC-3 cancer: the CONKO-001 randomized trial. JAMA. trial, in which all patients received adjuvant Re-resection After a 2013;310:1473–1481. chemotherapy showed an adverse prognostic 5. Neoptolemos JP, Stocken DD, Bassi C, et al. Adju- Positive Pancreatic Margin impact of positive resection margin (though vant chemotherapy with fluorouracil plus folinic this association lost statistical significance acid vs gemcitabine following pancreatic cancer Frozen Section in the resection: a randomized controlled trial. JAMA. after adjustment for other clinicopathologic 5 2010;304:1073–1081. Era of Perioperative variables). 6. Butturini G, Stocken DD, Wente MN, et al. Influ- However, to dissect out the efficacy of ence of resection margins and treatment on survival Therapies? adjuvant therapy for patients with different in patients with pancreatic cancer: meta-analysis of resection margin status the subgroup analyses randomized controlled trials. Arch Surg. 2008; 143:75–83. provided for both trials are of critical Reply: importance. Remarkably, for both trials these e would like to thank the authors for analyses failed to demonstrate a survival W their interest in our recent study on advantage of adjuvant chemotherapy in the 3,4 frozen section analysis and impact of intra- subset of patients with R1 resections. These operative margin clearance on survival of data are confirmed by a meta-analysis of 4 1 30-day Readmission After patients with pancreatic cancer. Given the randomized controlled trials that demon- survival benefit of adjuvant chemotherapy in strated a 35% risk reduction for adjuvant Operative Management of patients with pancreatic ductal adenocarci- chemotherapy in the R0 group [hazard ratio Adhesive Small Bowel noma (PDAC) in the CONKO-001 trial, the (HR): 0.65; 95% confidence interval (CI): question of adjuvant chemotherapy and its 0.53–0.80], whereas adjuvant chemotherapy Obstruction prognostic value in our study cohort was failed to improve survival in patients with R1 raised. The authors pointed out that adjuvant resections (HR: 1.04; 95% CI: 0.78–1.40). chemotherapy but not resection margin status These data together with the prognos- was associated with survival in the CONKO- tic value of resection margin status in the To the Editor: 001 trial, which may justify questioning ESPAC-3 trial may challenge the notion e read with interest the article by the prognostic value of resection margin that the prognostic value of resection W Aquina et al, which provides a con- status in the setting of effective perioperative margin status is diminished by current adju- vincing answer to an important research therapies. vant chemotherapy regimens. If resection question. We would like to comment on In our study cohort, adjuvant chemo- margin status looses prognostic value with one of the study’s conclusions relating to therapy was not associated with a survival the increasingly used, more intensive chemo- 30-day readmission. The authors conclude benefit (P ¼ 0.351; log-rank test), which therapy protocols such as FOLFIRINOX that in cases of operative management, may be explained by more frequent presence remains to be determined in future studies. use of a primary medical service increased of high-risk pathological features such as poor These studies should apply standardized 30-day readmission (17.9% vs 14.0%). This differentiation, large tumor size and presence guidelines for the processing of pancreatic appears to be based on results from crude of perineural invasion in patients who received specimens and reporting of pathology results. bivariate analysis included in Table 2 in the adjuvant chemotherapy. Among the 3 margin article. However, as results from the multi- groups described in our study the proportion of Disclosure: The authors declare no variable regression in Table 4 control for patients who received adjuvant chemotherapy conflicts of interest. patient, physician, and hospital level factors was 58.8% for margin group I, 86.4% for (whereas the bivariate analysis does not), margin group II and 79.0% for margin group Philipp Nitschke, MD perhaps we should conclude that there is not III (P ¼ 0.001). Survival analyses restricted to Ju¨rgen Weitz, MD, MSc sufficient evidence to reject the null hypoth- patients who received adjuvant chemotherapy Nuh N. Rahbari, MD esis (H0: primary medical and primary showed similar survival for patients in margin Department of Visceral surgical management effects on 30-day groups I and II (24 vs 26 months, P ¼ 0.880; Thoracic, and Vascular Surgery readmissions are equal.) Indeed, Table 4 e56 | www.annalsofsurgery.com  2017 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Journal

Annals of SurgeryWolters Kluwer Health

Published: Mar 1, 2018

References

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