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Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature

Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature review memo (2022) 15:26–28 https://doi.org/10.1007/s12254-021-00745-x Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature Konstantin Schlick Received: 16 June 2021 / Accepted: 4 August 2021 / Published online: 8 September 2021 © The Author(s) 2021 Summary Neoadjuvant therapy is well-accepted in Neoadjuvant therapy in the resectable disease set- the treatment of borderline resectable and locally ad- ting has known benefits. The prioritization of systemic vanced PC, the benefit of neoadjuvant chemotherapy therapy in patients who suffer from micrometastatic in patients with resectable disease, however, is cur- disease may have the potential to expand the popula- rently not so clear. Here we provide an up date on the tion of patients undergoing surgical resection to those literature. with favorable tumor biology. Patients may also derive benefit from a seemingly increased tolerability of mul- Keywords Pancreatic cancer · Surgery · Outcome · tidrug regimens like fluorouracil, leucovorin, irinote- Neo-adjuvant chemotheray can, and oxaliplatin (FOLFIRINOX) and gemcitabine with nab-paclitaxel administered in the neoadjuvant setting, compared to the adjuvant setting [7]. Finally, Pancreatic cancer (PC) is currently associated with sequencing chemotherapy before surgery delivers in- one of the lowest survival rates among malignancies valuable individualized prognostic information on with a 5-year overall mortality rate of 95% [1]. The the effectiveness of chemotherapy with key histologic incidence rate almost mirrors the mortality rate, since markers available from the surgical specimen includ- prognosisisdismal and has not changed over the last ing microscopic margin status, nodal metastases, and few decades although novel therapy strategies have tumor regression grade; however, prospective trials, been implemented in clinical routine [2]. The only institutional series, and large cancer registries con- potential chance for cure remains radical tumor resec- sistently report that up to 50% of patients are unable tion [3]. However, only 15–20% of all newly diagnosed to receive adjuvant therapy—generally due to early patients are potential candidates for surgical resec- cancer recurrence or poor performance status after tion, resulting in a median survival of up to 24 months surgery. A greater number of individuals are unable [4]. Inoperable, locally advanced and metastatic dis- to complete all intended cycles of adjuvant therapy ease are associated with significantly shorter survival [8]. For example, a recent study of Medicare patients [5]. The 5-year overall survival (OS) rate remains poor found that only 7% were able to receive all intended for nonsurgery candidates at 12% and 3% for locally adjuvant chemotherapy [9]. advanced and metastatic disease, respectively [6]. Furthermore, the delivery of neoadjuvant therapy While the use of neoadjuvant therapy is well- affords an important test of tumor biology to rule out accepted in the treatment of borderline resectable rapid disease progression, especially in light of an in- and locally advanced PC, the benefit of neoadjuvant determinate radiographic finding (e.g., liver or lung chemotherapy in patients with resectable disease has lesion) or elevated CA 19-9, which can potentially help been a topic of debate. avoid the morbidity of a nontherapeutic pancreatec- tomy. PD OA Dr.med.univ. K. Schlick () The randomized phase III PREOPANC-1 trial com- IIIrd Medical Department with Hematology & Medical pared preoperative chemoradiotherapy and upfront Oncology, Hemostaseology, Rheumatology & Infectious surgery for patients with borderline resectable and Diseases, Oncologic Center, Paracelsus Medical University resectable PC [10]. Notably, this was the first large- Salzburg, Müllner Hauptstrasse 48, 5020 Salzburg, Austria k.schlick@salk.at 26 Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature K review scale trial with accrual completion that reported re- perioperative mFOLFIRINOX or perioperative gem- sults evaluating patients with resectable PC. citabine/nab-paclitaxel with a planned 12 weeks of Patients enrolled in the study were randomized to neoadjuvant chemotherapy in each arm, followed by either preoperative gemcitabine-based chemoradio- surgical resection, and then by 12 weeks of adjuvant therapy followed by surgery and adjuvant gemcitabine chemotherapy of thesametype[12]. chemotherapy or upfront surgery followed by adju- Patients treated in the mFOLFIRINOX arm had vant gemcitabine chemotherapy. In total, 248 pa- a median OS of 22.4 months, while patients in the tients were randomized to treatment. After a median gemcitabine/nab-paclitaxel arm had a median OS of follow-up period of 27 months, there was no signifi- 23.6 months. The primary endpoint did not meet the cant difference in OS in patients who were random- prespecified statistical threshold in either arm of the ized to undergo preoperative therapy (16.0 months; trial. While preoperative therapy in this trial led to 95% confidence interval [CI] 13.0–20.9) compared to high rates of surgical resection, with margin-negative patients who were randomized to immediate surgery resection performed in 85% of patients in each arm, (14.3 months; 95% CI 12.7–17.9), which was the pri- the modest survival outcomes reported in this trial are mary endpoint for the study. However, there were likely contributed to the low percentage of patients clear benefits demonstrated in terms of OS, disease- completing the whole protocol-defined therapy. free survival (DFS), and rate of margin negative resec- The ALLIANCE A021806 trial seeks to definitively tion in the predefined analysis of patients with border- clarify the role of neoadjuvant chemotherapy in line resectable disease. These outcomes support the patients with resectable PC. This trial has recently premise that preoperative chemoradiation enhances opened for accrual in July of 2020 and aims to ran- locoregional disease control and is preferentially ad- domize patients with resectable PC to periopera- vantageous in patients with increasing vascular in- tive chemotherapy or up-front surgery and adjuvant volvement that pose a greater risk for margin-positive chemotherapy with mFOLFIRINOX. resection. However, the applicability of results high- lighting the use of single-agent gemcitabine adjuvant Conclusion therapy is limited in the current era. Currently neo-adjuvant chemotherapy in resectable In order to address the issues of novel chemother- pancreatic cancer is not endorsed in clinical guide- apeutic regiments in peri-operative setting in more lines, due to the lack of randomized phase III trials. detail, two trials are currently investigating FOLFOX/ Ongoing and future trials aim to further clarify FOLFIRINOX in the Panache Trial (upfront surgery the role of neoadjuvant treatment in patients who and adjuvant chemotherapy vs perioperative FOLFOX/ present with primary resectable disease. FOLFIRINOX) and neoadjuvant Folfirinox vs perioper- Future research is needed to establish predictive ative gemcitabine + RTX in resectable and borderline biomarkers, measures of therapeutic response, and resectable PDAC in the Preopanc-2 trial. multidisciplinary strategies to improve patient-cen- The Japanese randomized PREP-02/JSAP05 trial tered outcomes. compares neoadjuvant chemotherapy with gem- citabine and S-1, an oral 5-fluorouracil derivative Funding Open access funding provided by Paracelsus Medical with immediate surgery in patients with potentially University. resectable PC [11]. The median OS in neoadju- vant treated patients was 36.7 months, compared Conflict of interest K. Schlick declares that he has no com- peting interests. to 26.6 months in patients who underwent upfront surgery (p = 0.015; hazard ratio [HR] 0.72; 95% CI Open Access This article is licensed under a Creative Com- 0.55–0.94). However, there was a significant rate of mons Attribution 4.0 International License, which permits grade 3 and grade 4 adverse events (48.8 and 23.8%, use, sharing, adaptation, distribution and reproduction in respectively) in patients treated with neoadjuvant any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to therapy. Despite this, neoadjuvant chemotherapy led the Creative Commons licence, and indicate if changes were to a decreased rate of lymph node metastases com- made. The images or other third party material in this article pared to patients who underwent upfront surgery are included in the article’s Creative Commons licence, unless (59.6 vs. 81.5%; p<0.01) anddid not leadto worse indicated otherwise in a credit line to the material. If material postoperative outcome. Taken together, the JSAP-05 is not included in the article’s Creative Commons licence and trial is the first multi-institutional phase III trial that your intended use is not permitted by statutory regulation or demonstrates that the use of neoadjuvant chemother- exceeds the permitted use, you will need to obtain permis- sion directly from the copyright holder. To view a copy of this apy leads to an improvement in OS in patients with licence, visit http://creativecommons.org/licenses/by/4.0/. primary resectable PC. These results have a somewhat restricted applica- tion in Europe and North America, where the oral flu- oropyrimidine S-1 is not available. SWOG S1505, a randomized phase II trial, evalu- ates patients, with resectable PC, randomized to either K Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature 27 review for pancreatic cancer is uncommon yet associated with References improvedsurvival. Ann Surg Oncol. 2019;26:4108–16. 10. Versteijne E, Suker M, Groothuis K, et al. Preoper- 1. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treat- ative chemoradiotherapy versus immediate surgery for ment and survivorship statistics. CA Cancer J Clin. resectable and borderline resectable pancreatic cancer: re- 2019;69(2019):363–85. sults of the dutch randomized Phase III PREOPANC Trial. 2. Tesfaye AA, Kamgar M, Azmi A, et al. The evolution into per- J Clin Oncol. 2020;38:1763–73. sonalized therapies in pancreatic ductal adenocarcinoma: 11. MotoiF,Kosuge T,Ueno H,et al. Randomized phaseII/III challenges and opportunities. Expert Rev Anticancer Ther. trial of neoadjuvant chemotherapy with gemcitabine and 2018;18:131–48. S-1 versus upfront surgery for resectable pancreatic cancer 3. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49:190–4. Clin. 2019;69(2019):7–34. 12. Ahmad SA, Duong M, Sohal DPS, et al. Surgical Outcome 4. Bilimoria KY, Bentrem DJ, Ko CY, et al. National failure Results From SWOG S1505: A Randomized Clinical Trial to operate on early stage pancreatic cancer. Ann Surg. of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for 2007;246:173–80. Perioperative Treatment of Resectable Pancreatic Ductal 5. He J, Edil BH, Cameron JL, et al. Young patients undergoing Adenocarcinoma. Ann Surg. 2020;272:481–6. resection of pancreatic cancer fare better than their older counterparts. J GastrointestSurg. 2013;17:339–44. Publisher’s Note Springer Nature remains neutral with regard 6. Jin J, Teng C, Li T. Combination therapy versus gemcitabine to jurisdictional claims in published maps and institutional monotherapy in the treatment of elderly pancreatic cancer: affiliations. a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:475–80. 7. Neoptolemos JP, Palmer DH, Ghaneh P, etal. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine 7 For latest news from interna- monotherapy in patients with resected pancreatic cancer tional oncology congresses see: (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011–24. http://www.springermedizin.at/ 8. Valle JW, Palmer D, Jackson R, et al. Optimal duration and memo-inoncology timingofadjuvantchemotherapyafterdefinitivesurgeryfor ductal adenocarcinoma of the pancreas: ongoing lessons fromtheESPAC-3 study. J Clin Oncol. 2014;32:504–12. 9. Altman AM, Wirth K, Marmor S, et al. Completion of adjuvant chemotherapy after upfront surgical resection 28 Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature K http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png memo - Magazine of European Medical Oncology Springer Journals

Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature

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Springer Journals
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2021 The Author(s)
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1865-5041
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10.1007/s12254-021-00745-x
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Abstract

review memo (2022) 15:26–28 https://doi.org/10.1007/s12254-021-00745-x Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature Konstantin Schlick Received: 16 June 2021 / Accepted: 4 August 2021 / Published online: 8 September 2021 © The Author(s) 2021 Summary Neoadjuvant therapy is well-accepted in Neoadjuvant therapy in the resectable disease set- the treatment of borderline resectable and locally ad- ting has known benefits. The prioritization of systemic vanced PC, the benefit of neoadjuvant chemotherapy therapy in patients who suffer from micrometastatic in patients with resectable disease, however, is cur- disease may have the potential to expand the popula- rently not so clear. Here we provide an up date on the tion of patients undergoing surgical resection to those literature. with favorable tumor biology. Patients may also derive benefit from a seemingly increased tolerability of mul- Keywords Pancreatic cancer · Surgery · Outcome · tidrug regimens like fluorouracil, leucovorin, irinote- Neo-adjuvant chemotheray can, and oxaliplatin (FOLFIRINOX) and gemcitabine with nab-paclitaxel administered in the neoadjuvant setting, compared to the adjuvant setting [7]. Finally, Pancreatic cancer (PC) is currently associated with sequencing chemotherapy before surgery delivers in- one of the lowest survival rates among malignancies valuable individualized prognostic information on with a 5-year overall mortality rate of 95% [1]. The the effectiveness of chemotherapy with key histologic incidence rate almost mirrors the mortality rate, since markers available from the surgical specimen includ- prognosisisdismal and has not changed over the last ing microscopic margin status, nodal metastases, and few decades although novel therapy strategies have tumor regression grade; however, prospective trials, been implemented in clinical routine [2]. The only institutional series, and large cancer registries con- potential chance for cure remains radical tumor resec- sistently report that up to 50% of patients are unable tion [3]. However, only 15–20% of all newly diagnosed to receive adjuvant therapy—generally due to early patients are potential candidates for surgical resec- cancer recurrence or poor performance status after tion, resulting in a median survival of up to 24 months surgery. A greater number of individuals are unable [4]. Inoperable, locally advanced and metastatic dis- to complete all intended cycles of adjuvant therapy ease are associated with significantly shorter survival [8]. For example, a recent study of Medicare patients [5]. The 5-year overall survival (OS) rate remains poor found that only 7% were able to receive all intended for nonsurgery candidates at 12% and 3% for locally adjuvant chemotherapy [9]. advanced and metastatic disease, respectively [6]. Furthermore, the delivery of neoadjuvant therapy While the use of neoadjuvant therapy is well- affords an important test of tumor biology to rule out accepted in the treatment of borderline resectable rapid disease progression, especially in light of an in- and locally advanced PC, the benefit of neoadjuvant determinate radiographic finding (e.g., liver or lung chemotherapy in patients with resectable disease has lesion) or elevated CA 19-9, which can potentially help been a topic of debate. avoid the morbidity of a nontherapeutic pancreatec- tomy. PD OA Dr.med.univ. K. Schlick () The randomized phase III PREOPANC-1 trial com- IIIrd Medical Department with Hematology & Medical pared preoperative chemoradiotherapy and upfront Oncology, Hemostaseology, Rheumatology & Infectious surgery for patients with borderline resectable and Diseases, Oncologic Center, Paracelsus Medical University resectable PC [10]. Notably, this was the first large- Salzburg, Müllner Hauptstrasse 48, 5020 Salzburg, Austria k.schlick@salk.at 26 Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature K review scale trial with accrual completion that reported re- perioperative mFOLFIRINOX or perioperative gem- sults evaluating patients with resectable PC. citabine/nab-paclitaxel with a planned 12 weeks of Patients enrolled in the study were randomized to neoadjuvant chemotherapy in each arm, followed by either preoperative gemcitabine-based chemoradio- surgical resection, and then by 12 weeks of adjuvant therapy followed by surgery and adjuvant gemcitabine chemotherapy of thesametype[12]. chemotherapy or upfront surgery followed by adju- Patients treated in the mFOLFIRINOX arm had vant gemcitabine chemotherapy. In total, 248 pa- a median OS of 22.4 months, while patients in the tients were randomized to treatment. After a median gemcitabine/nab-paclitaxel arm had a median OS of follow-up period of 27 months, there was no signifi- 23.6 months. The primary endpoint did not meet the cant difference in OS in patients who were random- prespecified statistical threshold in either arm of the ized to undergo preoperative therapy (16.0 months; trial. While preoperative therapy in this trial led to 95% confidence interval [CI] 13.0–20.9) compared to high rates of surgical resection, with margin-negative patients who were randomized to immediate surgery resection performed in 85% of patients in each arm, (14.3 months; 95% CI 12.7–17.9), which was the pri- the modest survival outcomes reported in this trial are mary endpoint for the study. However, there were likely contributed to the low percentage of patients clear benefits demonstrated in terms of OS, disease- completing the whole protocol-defined therapy. free survival (DFS), and rate of margin negative resec- The ALLIANCE A021806 trial seeks to definitively tion in the predefined analysis of patients with border- clarify the role of neoadjuvant chemotherapy in line resectable disease. These outcomes support the patients with resectable PC. This trial has recently premise that preoperative chemoradiation enhances opened for accrual in July of 2020 and aims to ran- locoregional disease control and is preferentially ad- domize patients with resectable PC to periopera- vantageous in patients with increasing vascular in- tive chemotherapy or up-front surgery and adjuvant volvement that pose a greater risk for margin-positive chemotherapy with mFOLFIRINOX. resection. However, the applicability of results high- lighting the use of single-agent gemcitabine adjuvant Conclusion therapy is limited in the current era. Currently neo-adjuvant chemotherapy in resectable In order to address the issues of novel chemother- pancreatic cancer is not endorsed in clinical guide- apeutic regiments in peri-operative setting in more lines, due to the lack of randomized phase III trials. detail, two trials are currently investigating FOLFOX/ Ongoing and future trials aim to further clarify FOLFIRINOX in the Panache Trial (upfront surgery the role of neoadjuvant treatment in patients who and adjuvant chemotherapy vs perioperative FOLFOX/ present with primary resectable disease. FOLFIRINOX) and neoadjuvant Folfirinox vs perioper- Future research is needed to establish predictive ative gemcitabine + RTX in resectable and borderline biomarkers, measures of therapeutic response, and resectable PDAC in the Preopanc-2 trial. multidisciplinary strategies to improve patient-cen- The Japanese randomized PREP-02/JSAP05 trial tered outcomes. compares neoadjuvant chemotherapy with gem- citabine and S-1, an oral 5-fluorouracil derivative Funding Open access funding provided by Paracelsus Medical with immediate surgery in patients with potentially University. resectable PC [11]. The median OS in neoadju- vant treated patients was 36.7 months, compared Conflict of interest K. Schlick declares that he has no com- peting interests. to 26.6 months in patients who underwent upfront surgery (p = 0.015; hazard ratio [HR] 0.72; 95% CI Open Access This article is licensed under a Creative Com- 0.55–0.94). However, there was a significant rate of mons Attribution 4.0 International License, which permits grade 3 and grade 4 adverse events (48.8 and 23.8%, use, sharing, adaptation, distribution and reproduction in respectively) in patients treated with neoadjuvant any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to therapy. Despite this, neoadjuvant chemotherapy led the Creative Commons licence, and indicate if changes were to a decreased rate of lymph node metastases com- made. The images or other third party material in this article pared to patients who underwent upfront surgery are included in the article’s Creative Commons licence, unless (59.6 vs. 81.5%; p<0.01) anddid not leadto worse indicated otherwise in a credit line to the material. If material postoperative outcome. Taken together, the JSAP-05 is not included in the article’s Creative Commons licence and trial is the first multi-institutional phase III trial that your intended use is not permitted by statutory regulation or demonstrates that the use of neoadjuvant chemother- exceeds the permitted use, you will need to obtain permis- sion directly from the copyright holder. To view a copy of this apy leads to an improvement in OS in patients with licence, visit http://creativecommons.org/licenses/by/4.0/. primary resectable PC. These results have a somewhat restricted applica- tion in Europe and North America, where the oral flu- oropyrimidine S-1 is not available. SWOG S1505, a randomized phase II trial, evalu- ates patients, with resectable PC, randomized to either K Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature 27 review for pancreatic cancer is uncommon yet associated with References improvedsurvival. Ann Surg Oncol. 2019;26:4108–16. 10. Versteijne E, Suker M, Groothuis K, et al. Preoper- 1. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treat- ative chemoradiotherapy versus immediate surgery for ment and survivorship statistics. CA Cancer J Clin. resectable and borderline resectable pancreatic cancer: re- 2019;69(2019):363–85. sults of the dutch randomized Phase III PREOPANC Trial. 2. Tesfaye AA, Kamgar M, Azmi A, et al. The evolution into per- J Clin Oncol. 2020;38:1763–73. sonalized therapies in pancreatic ductal adenocarcinoma: 11. MotoiF,Kosuge T,Ueno H,et al. Randomized phaseII/III challenges and opportunities. Expert Rev Anticancer Ther. trial of neoadjuvant chemotherapy with gemcitabine and 2018;18:131–48. S-1 versus upfront surgery for resectable pancreatic cancer 3. Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49:190–4. Clin. 2019;69(2019):7–34. 12. Ahmad SA, Duong M, Sohal DPS, et al. Surgical Outcome 4. Bilimoria KY, Bentrem DJ, Ko CY, et al. National failure Results From SWOG S1505: A Randomized Clinical Trial to operate on early stage pancreatic cancer. Ann Surg. of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for 2007;246:173–80. Perioperative Treatment of Resectable Pancreatic Ductal 5. He J, Edil BH, Cameron JL, et al. Young patients undergoing Adenocarcinoma. Ann Surg. 2020;272:481–6. resection of pancreatic cancer fare better than their older counterparts. J GastrointestSurg. 2013;17:339–44. Publisher’s Note Springer Nature remains neutral with regard 6. Jin J, Teng C, Li T. Combination therapy versus gemcitabine to jurisdictional claims in published maps and institutional monotherapy in the treatment of elderly pancreatic cancer: affiliations. a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:475–80. 7. Neoptolemos JP, Palmer DH, Ghaneh P, etal. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine 7 For latest news from interna- monotherapy in patients with resected pancreatic cancer tional oncology congresses see: (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011–24. http://www.springermedizin.at/ 8. Valle JW, Palmer D, Jackson R, et al. Optimal duration and memo-inoncology timingofadjuvantchemotherapyafterdefinitivesurgeryfor ductal adenocarcinoma of the pancreas: ongoing lessons fromtheESPAC-3 study. J Clin Oncol. 2014;32:504–12. 9. Altman AM, Wirth K, Marmor S, et al. Completion of adjuvant chemotherapy after upfront surgical resection 28 Neoadjuvant versus adjuvant management of resectable pancreas cancer: A review of the literature K

Journal

memo - Magazine of European Medical OncologySpringer Journals

Published: Feb 1, 2022

Keywords: oncology; medicine/public health, general

References