Trends in the Care of Locally Advanced Pancreatic Cancer in the Modern Era of Chemotherapy.
access to care
guideline recommended treatment
healthcare utilization
pancreatic cancer
pancreatic neoplasms
socioeconomic disparities in health
Journal
Journal of surgical oncology
ISSN: 1096-9098
Titre abrégé: J Surg Oncol
Pays: United States
ID NLM: 0222643
Informations de publication
Date de publication:
30 Sep 2024
30 Sep 2024
Historique:
revised:
04
08
2024
received:
02
04
2024
accepted:
18
08
2024
medline:
30
9
2024
pubmed:
30
9
2024
entrez:
30
9
2024
Statut:
aheadofprint
Résumé
Current guidelines for treatment for locally advanced pancreatic cancer recommend chemotherapy ± radiation, or radiation alone when multimodal therapy is contraindicated. In a subset of patients, guideline-recommended treatment (GRT) achieves sufficient response to qualify for potentially curative resection. This study evaluated trends in treatment utilization and aimed to identify barriers to GRT. Patients with clinical T4M0 disease in the National Cancer Database from 2010 to 2017 were included. Potential predictors were assessed by relative risk regression with Poisson distribution and compared by log-link function. In total, 28 056 patients met the criteria. Among 17 059 (67.67%) patients treated primarily with chemotherapy, 41.19% also had radiation and 8.89% went onto resection. Many received no cancer-directed treatment or failed to receive GRT. Another 710 patients had radiation (±surgery) without chemotherapy despite few contraindications to chemotherapy. Over time, patients were more likely to undergo resection after chemotherapy (aRR = 1.58; p < 0.0001) and less likely to have chemoradiation (aRR = 0.78; p < 0.0001) or go untreated (aRR = 0.90; p < 0.0001). Socioeconomic factors (race, education, income, and insurance status) affected the likelihood of receiving chemotherapy and surgery. Median overall survival (OS) was significantly improved for patients treated with chemotherapy and particularly in those patients who went on to receive RT or undergo surgical resection. OS was also longer for patients treated at high-volume academic centers. Patients insured by Medicaid, Medicare, or those without insurance had worse OS. Despite improvement over time, many patients go untreated. Clinical factors were influential, but the impact of vulnerable social standing suggests persistent inequity in access to care.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The authors received no specific funding for this work
Informations de copyright
© 2024 Wiley Periodicals LLC.
Références
“Cancer Facts & Figures 2022,” American Cancer Society, accessed March 15, 2022, https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html.
W. Kwon, A. Thomas, and M. D. Kluger, “Irreversible Electroporation of Locally Advanced Pancreatic Cancer,” Seminars in Oncology 48, no. 1 (2021): 84–94, https://doi.org/10.1053/j.seminoncol.2021.02.004.
E. Poplin, Y. Feng, J. Berlin, et al., “Phase III, Randomized Study of Gemcitabine and Oxaliplatin Versus Gemcitabine (Fixed‐Dose Rate Infusion) Compared With Gemcitabine (30‐Minute Infusion) in Patients With Pancreatic Carcinoma E6201: A Trial of the Eastern Cooperative Oncology Group,” Journal of Clinical Oncology 27, no. 23 (2009): 3778–3785, https://doi.org/10.1200/JCO.2008.20.9007.
P. J. Loehrer, Y. Feng, H. Cardenes, et al., “Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial,” Journal of Clinical Oncology 29, no. 31 (2011): 4105–4112, https://doi.org/10.1200/JCO.2011.34.8904.
P. Hammel, F. Huguet, J. L. van Laethem, et al., “Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial,” JAMA 315, no. 17 (2016): 1844–1853, https://doi.org/10.1001/jama.2016.4324.
B. Chauffert, F. Mornex, F. Bonnetain, et al., “Phase III Trial Comparing Intensive Induction Chemoradiotherapy (60 Gy, Infusional 5‐FU and Intermittent Cisplatin) Followed by Maintenance Gemcitabine With Gemcitabine Alone for Locally Advanced Unresectable Pancreatic Cancer. Definitive Results of the 2000‐01 FFCD/SFRO Study,” Annals of Oncology: Official Journal of the European Society for Medical Oncology 19, no. 9 (2008): 1592–1599, https://doi.org/10.1093/annonc/mdn281.
F. Huguet, T. André, P. Hammel, et al., “Impact of Chemoradiotherapy After Disease Control With Chemotherapy in Locally Advanced Pancreatic Adenocarcinoma in GERCOR Phase II and III Studies,” Journal of Clinical Oncology 25, no. 3 (2007): 326–331, https://doi.org/10.1200/JCO.2006.07.5663.
J. E. Faris, L. S. Blaszkowsky, S. McDermott, et al., “FOLFIRINOX in Locally Advanced Pancreatic Cancer: The Massachusetts General Hospital Cancer Center Experience,” Oncologist 18, no. 5 (2013): 543–548, https://doi.org/10.1634/theoncologist.2012-0435.
I. Matsumoto, K. Kamei, K. Omae, et al., “FOLFIRINOX for Locally Advanced Pancreatic Cancer: Results and Prognostic Factors of Subset Analysis From a Nation‐Wide Multicenter Observational Study in Japan,” Pancreatology 19, no. 2 (2019): 296–301, https://doi.org/10.1016/j.pan.2019.01.001.
L. Marthey, A. Sa‐Cunha, J. F. Blanc, et al., “FOLFIRINOX for Locally Advanced Pancreatic Adenocarcinoma: Results of an AGEO Multicenter Prospective Observational Cohort,” Annals of Surgical Oncology 22, no. 1 (2015): 295–301, https://doi.org/10.1245/s10434-014-3898-9.
P. A. Philip, J. Lacy, F. Portales, et al., “Nab‐Paclitaxel Plus Gemcitabine in Patients With Locally Advanced Pancreatic Cancer (LAPACT): A Multicentre, Open‐Label Phase 2 Study,” Lancet Gastroenterology & Hepatology 5, no. 3 (2020): 285–294, https://doi.org/10.1016/S2468-1253(19)30327-9.
H. Shinchi, S. Takao, H. Noma, et al., “Length and Quality of Survival After External‐Beam Radiotherapy With Concurrent Continuous 5‐Fluorouracil Infusion for Locally Unresectable Pancreatic Cancer,” International Journal of Radiation Oncology, Biology, Physics 53, no. 1 (2002): 146–150, https://doi.org/10.1016/S0360-3016(01)02806-1.
E. P. Balaban, P. B. Mangu, A. A. Khorana, et al., “Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline,” Journal of Clinical Oncology 34, no. 22 (2016): 2654–2668, https://doi.org/10.1200/JCO.2016.67.5561.
M. Ducreux, A. S. Cuhna, C. Caramella, et al., “Cancer of the Pancreas: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow‐Up,” supplement, Annals of Oncology 26, no. S5 (2015): v56–v68, https://doi.org/10.1093/annonc/mdv295.
M. A. Tempero, M. P. Malafa, M. Al‐Hawary, et al., “Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology,” Journal of the National Comprehensive Cancer Network 19, no. 4 (2021): 439–457, https://doi.org/10.6004/jnccn.2021.0017.
M. A. Tempero, M. P. Malafa, M. Al‐Hawary, et al., “Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology,” Journal of the National Comprehensive Cancer Network 15, no. 8 (2017): 1028–1061, https://doi.org/10.6004/jnccn.2017.0131.
M. D. Kluger, I. Epelboym, B. A. Schrope, et al., “Single‐Institution Experience With Irreversible Electroporation for T4 Pancreatic Cancer: First 50 Patients,” Annals of Surgical Oncology 23, no. 5 (2016): 1736–1743, https://doi.org/10.1245/s10434-015-5034-x.
M. D. Kluger, M. F. Rashid, V. L. Rosario, et al., “Resection of Locally Advanced Pancreatic Cancer Without Regression of Arterial Encasement After Modern‐Era Neoadjuvant Therapy,” Journal of Gastrointestinal Surgery 22, no. 2 (2018): 235–241, https://doi.org/10.1007/s11605-017-3556-1.
G. Gemenetzis, V. P. Groot, A. B. Blair, et al., “Survival in Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy and Surgical Resection,” Annals of Surgery 270, no. 2 (2019): 340–347, https://doi.org/10.1097/SLA.0000000000002753.
D. Kwon, K. McFarland, V. Velanovich, and R. C. G. Martin, “Borderline and Locally Advanced Pancreatic Adenocarcinoma Margin Accentuation With Intraoperative Irreversible Electroporation,” Surgery 156, no. 4 (2014): 910–922, https://doi.org/10.1016/j.surg.2014.06.058.
R. C. G. Martin, D. Kwon, S. Chalikonda, et al., “Treatment of 200 Locally Advanced (Stage III) Pancreatic Adenocarcinoma Patients With Irreversible Electroporation: Safety and Efficacy,” Annals of Surgery 262, no. 3 (2015): 486–494, https://doi.org/10.1097/SLA.0000000000001441.
R. C. G. Martin, K. McFarland, S. Ellis, and V. Velanovich, “Irreversible Electroporation Therapy in the Management of Locally Advanced Pancreatic Adenocarcinoma,” Journal of the American College of Surgeons 215, no. 3 (2012): 361–369, https://doi.org/10.1016/j.jamcollsurg.2012.05.021.
Y. Zhou, S. Liao, J. You, and H. Wu, “Conversion Surgery for Initially Unresectable Pancreatic Ductal Adenocarcinoma Following Induction Therapy: A Systematic Review of the Published Literature,” Updates in Surgery 74, no. 1 (May 2022): 43–53, https://doi.org/10.1007/s13304-021-01089-1.
A. Hamad, M. DePuccio, B. N. Reames, et al., “Disparities in Stage‐Specific Guideline‐Concordant Cancer‐Directed Treatment for Patients With Pancreatic Adenocarcinoma,” Journal of Gastrointestinal Surgery 25, no. 11 (2021): 2889–2901, https://doi.org/10.1007/s11605-021-04984-5.
M. Noel and K. Fiscella, “Disparities in Pancreatic Cancer Treatment and Outcomes,” Health Equity 3, no. 1 (2019): 532–540, https://doi.org/10.1089/heq.2019.0057.
R. A. Azap, A. Diaz, J. M. Hyer, et al., “Impact of Race/Ethnicity and County‐Level Vulnerability on Receipt of Surgery Among Older Medicare Beneficiaries With the Diagnosis of Early Pancreatic Cancer,” Annals of Surgical Oncology 28, no. 11 (April 2021): 6309–6316, https://doi.org/10.1245/s10434-021-09911-1.
M. M. Murphy, J. P. Simons, J. S. Hill, et al., “Pancreatic Resection: A Key Component to Reducing Racial Disparities in Pancreatic Adenocarcinoma,” Cancer 115, no. 17 (2009): 3979–3990, https://doi.org/10.1002/cncr.24433.
A. Abraham, W. B. Al‐Refaie, H. M. Parsons, V. Dudeja, S. M. Vickers, and E. B. Habermann, “Disparities in Pancreas Cancer Care,” Annals of Surgical Oncology 20, no. 6 (2013): 2078–2087, https://doi.org/10.1245/s10434-012-2843-z.
J. I. Chang, B. Z. Huang, and B. U. Wu, “Impact of Integrated Health Care Delivery on Racial and Ethnic Disparities in Pancreatic Cancer,” Pancreas 47, no. 2 (2018): 221–226, https://doi.org/10.1097/MPA.0000000000000981.
J. P. Neoptolemos, D. D. Stocken, H. Friess, et al., “A Randomized Trial of Chemoradiotherapy and Chemotherapy After Resection of Pancreatic Cancer,” New England Journal of Medicine 350, no. 12 (2004): 1200–1210, https://doi.org/10.1056/NEJMoa032295.
V. L. Shavers, L. C. Harlan, M. Jackson, and J. Robinson, “Racial/Ethnic Patterns of Care for Pancreatic Cancer,” Journal of Palliative Medicine 12, no. 7 (2009): 623–630, https://doi.org/10.1089/jpm.2009.0036.
W. B. Al‐Refaie, B. Muluneh, W. Zhong, et al., “Who Receives Their Complex Cancer Surgery at Low‐Volume Hospitals?,” Journal of the American College of Surgeons 214, no. 1 (2012): 81–87, https://doi.org/10.1016/j.jamcollsurg.2011.10.003.
A. J. Epstein, “Racial and Ethnic Differences in the Use of High‐Volume Hospitals and Surgeons,” Archives of Surgery 145, no. 2 (2010): 179–186, https://doi.org/10.1001/archsurg.2009.268.
R. W. Eppsteiner, N. G. Csikesz, J. T. McPhee, J. F. Tseng, and S. A. Shah, “Surgeon Volume Impacts Hospital Mortality for Pancreatic Resection,” Annals of Surgery 249, no. 4 (2009): 635–640, https://doi.org/10.1097/SLA.0b013e31819ed958.
M. C. Cheung, R. Yang, M. M. Byrne, C. C. Solorzano, A. Nakeeb, and L. G. Koniaris, “Are Patients of Low Socioeconomic Status Receiving Suboptimal Management for Pancreatic Adenocarcinoma?,” Cancer 116, no. 3 (2010): 723–733, https://doi.org/10.1002/cncr.24758.
N. Khanal, S. Upadhyay, S. Dahal, V. R. Bhatt, and P. T. Silberstein, “Systemic Therapy in Stage IV Pancreatic Cancer: A Population‐Based Analysis Using the National Cancer Data Base,” Therapeutic Advances in Medical Oncology 7, no. 4 (2015): 198–205, https://doi.org/10.1177/1758834015579313.
K. A. Mirkin, C. S. Hollenbeak, N. J. Gusani, and J. Wong, “Trends in Utilization of Neoadjuvant Therapy and Short‐Term Outcomes in Resected Pancreatic Cancer,” American Journal of Surgery 214, no. 1 (2017): 80–88, https://doi.org/10.1016/j.amjsurg.2016.08.015.
C. R. Shubert, J. R. Bergquist, R. T. Groeschl, et al., “Overall Survival Is Increased Among Stage III Pancreatic Adenocarcinoma Patients Receiving Neoadjuvant Chemotherapy Compared to Surgery First and Adjuvant Chemotherapy: An Intention to Treat Analysis of the National Cancer Database,” Surgery 160, no. 4 (2016): 1080–1096, https://doi.org/10.1016/j.surg.2016.06.010.
A. A. Mokdad, R. M. Minter, H. Zhu, et al., “Neoadjuvant Therapy Followed by Resection Versus Upfront Resection for Resectable Pancreatic Cancer: A Propensity Score Matched Analysis,” Journal of Clinical Oncology 35, no. 5 (2017): 515–522, https://doi.org/10.1200/JCO.2016.68.5081.
I. Nassour, M. A. Adam, S. Kowalsky, et al., “Neoadjuvant Therapy Versus Upfront Surgery for Early‐Stage Left‐Sided Pancreatic Adenocarcinoma: A Propensity‐Matched Analysis From a National Cohort of Distal Pancreatectomies,” Journal of Surgical Oncology 123, no. 1 (2021): 245–251, https://doi.org/10.1002/jso.26267.
J. Zhong, J. Switchenko, M. Behera, et al., “Chemotherapy With or Without Definitive Radiation Therapy in Inoperable Pancreatic Cancer,” Annals of Surgical Oncology 25, no. 4 (2018): 1026–1033, https://doi.org/10.1245/s10434-017-6322-4.
A. Torgeson, S. Lloyd, D. Boothe, et al., “Multiagent Induction Chemotherapy Followed by Chemoradiation Is Associated With Improved Survival in Locally Advanced Pancreatic Cancer,” Cancer 123, no. 19 (2017): 3816–3824, https://doi.org/10.1002/cncr.30780.
D. W. Nelson, S. C. Chang, G. Grunkemeier, et al., “Resectable Distal Pancreas Cancer: Time to Reconsider the Role of Upfront Surgery,” Annals of Surgical Oncology 25, no. 13 (2018): 4012–4019, https://doi.org/10.1245/s10434-018-6765-2.
A. Gaffney and D. McCormick, “The Affordable Care Act: Implications for Health‐Care Equity,” Lancet 389, no. 10077 (2017): 1442–1452, https://doi.org/10.1016/S0140-6736(17)30786-9.
G. F. Kominski, N. J. Nonzee, and A. Sorensen, “The Affordable Care Act's Impacts on Access to Insurance and Health Care for Low‐Income Populations,” Annual Review of Public Health 38 (2017): 489–505, https://doi.org/10.1146/annurev-publhealth-031816-044555.
R. J. Vidri, A. O. Vogt, D. C. Macgillivray, I. J. Bristol, and T. L. Fitzgerald, “Better Defining the Role of Total Neoadjuvant Radiation: Changing Paradigms in Locally Advanced Pancreatic Cancer,” Annals of Surgical Oncology 26, no. 11 (2019): 3701–3708, https://doi.org/10.1245/s10434-019-07584-5.
“About the National Cancer Database,” ACS, accessed May 25, 2022, https://www.facs.org/quality-programs/cancer-programs/national-cancer-database/about/.
S. S. Joshi, E. R. Handorf, M. C. Smaldone, and D. M. Geynisman, “What Can the National Cancer Database Tell Us About Disparities in Advanced Bladder Cancer Outcomes?,” Translational Andrology and Urology 7, no. 4 (2018): 732–735, https://doi.org/10.21037/tau.2018.06.16.
“puf_data_dictionary_2017.pdf,” accessed April 19, 2022, https://www.facs.org/-/media/files/quality-programs/cancer/ncdb/puf_data_dictionary_2017.ashx.
W. Park, A. Chawla, and E. M. O'Reilly, “Pancreatic Cancer: A Review,” JAMA 326, no. 9 (2021): 851–862, https://doi.org/10.1001/jama.2021.13027.
M. M. Murphy, J. P. Simons, S. C. Ng, et al., “Racial Differences in Cancer Specialist Consultation, Treatment, and Outcomes for Locoregional Pancreatic Adenocarcinoma,” Annals of Surgical Oncology 16, no. 11 (2009): 2968–2977, https://doi.org/10.1245/s10434-009-0656-5.
J. A. Zell, J. M. Rhee, A. Ziogas, S. M. Lipkin, and H. Anton‐Culver, “Race, Socioeconomic Status, Treatment, and Survival Time Among Pancreatic Cancer Cases in California,” Cancer Epidemiology, Biomarkers & Prevention 16, no. 3 (2007): 546–552, https://doi.org/10.1158/1055-9965.EPI-06-0893.
C. J. Wray, E. Castro‐Echeverry, E. J. Silberfein, T. C. Ko, and L. S. Kao, “A Multi‐Institutional Study of Pancreatic Cancer in Harris County, Texas: Race Predicts Treatment and Survival,” Annals of Surgical Oncology 19, no. 9 (2012): 2776–2781, https://doi.org/10.1245/s10434-012-2361-z.
R. Nipp, A. C. Tramontano, C. Y. Kong, et al., “Disparities in Cancer Outcomes Across Age, Sex, and Race/Ethnicity Among Patients With Pancreatic Cancer,” Cancer Medicine 7, no. 2 (2018): 525–535, https://doi.org/10.1002/cam4.1277.
O. Moaven, J. S. Richman, S. Reddy, T. Wang, M. J. Heslin, and C. M. Contreras, “Healthcare Disparities in Outcomes of Patients With Resectable Pancreatic Cancer,” American Journal of Surgery 217, no. 4 (2019): 725–731, https://doi.org/10.1016/j.amjsurg.2018.12.007.
R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer Statistics, 2015,” CA: A Cancer Journal for Clinicians 65, no. 1 (2015): 5–29, https://doi.org/10.3322/caac.21254.
S. B. Bateni, A. A. Gingrich, J. S. Hoch, R. J. Canter, and R. J. Bold, “Defining Value for Pancreatic Surgery in Early‐Stage Pancreatic Cancer,” JAMA Surgery 154, no. 10 (2019): e193019, https://doi.org/10.1001/jamasurg.2019.3019.
M. A. Alvarez, K. Anderson, J. L. Deneve, et al., “Traveling for Pancreatic Cancer Care Is Worth the Trip,” American Surgeon 87, no. 4 (2021): 549–556, https://doi.org/10.1177/0003134820951484.
M. Derogar, J. Blomberg, and O. Sadr‐Azodi, “Hospital Teaching Status and Volume Related to Mortality After Pancreatic Cancer Surgery in a National Cohort,” British Journal of Surgery 102, no. 5 (2015): 548–557, https://doi.org/10.1002/bjs.9754.
J. Young, A. Thompson, I. Tait, L. Waugh, and G. McPhillips, “Centralization of Services and Reduction of Adverse Events in Pancreatic Cancer Surgery,” World Journal of Surgery 37, no. 9 (2013): 2229–2233, https://doi.org/10.1007/s00268-013-2108-4.
U. Güller, R. Warschkow, C. J. Ackermann, B. Schmied, T. Cerny, and S. Ess, “Lower Hospital Volume Is Associated With Higher Mortality After Oesophageal, Gastric, Pancreatic and Rectal Cancer Resection,” Swiss Medical Weekly 147 (2017): 14473, https://doi.org/10.4414/smw.2017.14473.
A. D. Parmar, G. M. Vargas, N. P. Tamirisa, K. M. Sheffield, and T. S. Riall, “Trajectory of Care and Use of Multimodality Therapy in Older Patients With Pancreatic Adenocarcinoma,” Surgery 156, no. 2 (2014): 280–289, https://doi.org/10.1016/j.surg.2014.03.001.
K. J. Chang, G. Parasher, C. Christie, J. Largent, and H. Anton‐Culver, “Risk of Pancreatic Adenocarcinoma: Disparity Between African Americans and Other Race/Ethnic Groups,” Cancer 103, no. 2 (2005): 349–357, https://doi.org/10.1002/cncr.20771.
D. R. Heller, N. G. Nicolson, N. Ahuja, S. Khan, and J. W. Kunstman, “Association of Treatment Inequity and Ancestry With Pancreatic Ductal Adenocarcinoma Survival,” JAMA Surgery 155, no. 2 (2020): e195047, https://doi.org/10.1001/jamasurg.2019.5047.
A. M. Fagenson, S. M. Grossi, K. Musgrove, et al., “Ethnic and Racial Disparities of Pancreatic Adenocarcinoma in Florida,” HPB 22, no. 5 (2020): 735–743, https://doi.org/10.1016/j.hpb.2019.09.013.
T. S. Riall, C. M. Townsend, Y. F. Kuo, J. L. Freeman, and J. S. Goodwin, “Dissecting Racial Disparities in the Treatment of Patients With Locoregional Pancreatic Cancer: A 2‐Step Process,” Cancer 116, no. 4 (2010): 930–939, https://doi.org/10.1002/cncr.24836.
A. Shah, K. S. C. Chao, T. Østbye, et al., “Trends in Racial Disparities in Pancreatic Cancer Surgery,” Journal of Gastrointestinal Surgery 17, no. 11 (2013): 1897–1906, https://doi.org/10.1007/s11605-013-2304-4.
N. Wasif, D. Etzioni, E. B. Habermann, et al., “Racial and Socioeconomic Differences in the Use of High‐Volume Commission on Cancer‐Accredited Hospitals for Cancer Surgery in the United States,” Annals of Surgical Oncology 25, no. 5 (2018): 1116–1125, https://doi.org/10.1245/s10434-018-6374-0.
S. N. Khawja, S. Mohammed, E. J. Silberfein, B. L. Musher, W. E. Fisher, and G. Van Buren, “Pancreatic Cancer Disparities in African Americans,” Pancreas 44, no. 4 (2015): 522–527, https://doi.org/10.1097/MPA.0000000000000323.
A. D. Vick, D. N. Hery, S. F. Markowiak, and F. C. Brunicardi, “Closing the Disparity in Pancreatic Cancer Outcomes: A Closer Look at Nonmodifiable Factors and Their Potential Use in Treatment,” Pancreas 48, no. 2 (2019): 242–249, https://doi.org/10.1097/MPA.0000000000001238.