Advantages and advances in neoadjuvant therapy of pancreatic cancer

doi:10.16139/j.1007-9610.2024.01.12

Abstract

Abstract:

Due to the characteristics of the insidious onset, difficult early diagnosis and high malignancy of pancrea-tic cancer, only a minority of patients still have the chance of surgical resection at the time of diagnosis. In recent years, chemotherapy-based preoperative neoadjuvant therapy has been increasingly applied to pancreatic cancer without distant metastases to help achieve tumor downstaging, increase R0 resection rate and improve patient survival. A large number of clinical trials have proven the advantages of neoadjuvant therapy for pancreatic cancer, but there are still many issues to be gradually addressed by further research to reach a consensus.

Key words: Pancreatic Cancer, Neoadjuvant chemotherapy, Neoadjuvant radiochemotherapy

CLC Number:

R735.9

HU Binwei, SHEN Baiyong. Advantages and advances in neoadjuvant therapy of pancreatic cancer[J]. Journal of Surgery Concepts & Practice, 2024, 29(01): 74-80.

Figures/Tables 2

References 62

[1]	SIEGEL R L, MILLER K D, WAGLE N S, et al. Cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(1):17-48.
[2]	ZHAO C, GAO F, LI Q, et al. The distributional characteristic and growing trend of pancreatic cancer in China[J]. Pancreas, 2019, 48(3):309-314.
[3]	OETTLE H, NEUHAUS P, HOCHHAUS A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial[J]. JAMA, 2013, 310(14):1473-1481. doi: 10.1001/jama.2013.279201 pmid: 24104372
[4]	VAN DAM J L, JANSSEN Q P, BESSELINK M G, et al. Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: a meta-analysis of randomised controlled trials[J]. Eur J Cancer, 2022,160:140-149.
[5]	TEMPERO M A, MALAFA M P, AL-HAWARY M, et al. Pancreatic adenocarcinoma, version 2.2021, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2021, 19(4):439-457.
[6]	中国抗癌协会胰腺癌专业委员会. 中国胰腺癌综合诊治指南(2020版)[J]. 中华外科杂志, 2021, 59(2):E001.
	Pancreatic Cancer Professional Committee of China Anti-cancera Assosiation. Comprehensive guidelines for the diagnosis and treatment of pancreatic cancer (2020 version)[J]. Chin J Surg, 2021, 59(2):E001.
[7]	KATZ M H, PISTERS P W, EVANS D B, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease[J]. J Am Coll Surg, 2008, 206(5):833-848.
[8]	ISAJI S, MIZUNO S, WINDSOR J A, et al. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017[J]. Pancreatology, 2018, 18(1):2-11. doi: S1424-3903(17)30886-4 pmid: 29191513
[9]	HEINRICH S, LANG H. Neoadjuvant therapy of pancreatic cancer: definitions and benefits[J]. Int J Mol Sci, 2017, 18(8):1622.
[10]	LIU J, MROCZEK M, MACH A, et al. Genetics, geno-mics and emerging molecular therapies of pancreatic cancer[J]. Cancers (Basel), 2023, 15(3):779.
[11]	Johns Hopkins Medicine. Pancreatic Cancer Types[EB/OL]. https://www.hopkinsmedicine.org/health/conditions-and-diseases/pancreatic-cancer/pancreatic-cancer-types. [2022-06-29].
[12]	POUW RE, BARRET M, BIERMANN K, et al. Endoscopic tissue sampling - Part 1: upper gastrointestinal and hepatopancreatobiliary tracts. European society of gastrointestinal endoscopy (ESGE) Guideline[J]. Endoscopy, 2021, 53(11):1174-1188. doi: 10.1055/a-1611-5091 pmid: 34535035
[13]	HASEGAWA S, KUBOTA K, YAGI S, et al. Covered metallic stent placement for biliary drainage could be pro-mising in the coming era of neoadjuvant chemo-radiation therapy for all pancreatic cancer[J]. J Hepatobiliary Pancreat Sci, 2021, 28(7):617-624.
[14]	YAO W, CHEN X, FAN B, et al. Multidisciplinary team diagnosis and treatment of pancreatic cancer: current landscape and future prospects[J]. Front Oncol, 2023,13:1077605.
[15]	KIRKEGÅRD J, AAHLIN E K, AL-SAIDDI M, et al. Multicentre study of multidisciplinary team assessment of pancreatic cancer resectability and treatment allocation[J]. Br J Surg, 2019, 106(6):756-764. doi: 10.1002/bjs.11093 pmid: 30830974
[16]	CONROY T, DESSEIGNE F, YCHOU M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer[J]. N Engl J Med, 2011, 364(19):1817-1825.
[17]	SADOT E, DOUSSOT A, O'REILLY E M, et al. FOLFIRINOX induction therapy for stage 3 pancreatic adenocarcinoma[J]. Ann Surg Oncol, 2015, 22(11):3512-3521. doi: 10.1245/s10434-015-4647-4 pmid: 26065868
[18]	JANSSEN Q P, BUETTNER S, SUKER M, et al. Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis[J]. J Natl Cancer Inst, 2019, 111(8):782-794. doi: 10.1093/jnci/djz073 pmid: 31086963
[19]	VON HOFF D D, ERVIN T, ARENA F P, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine[J]. N Engl J Med, 2013, 369(18):1691-1703.
[20]	PHILIP P A, LACY J, PORTALES F, et al. Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study[J]. Lancet Gastroenterol Hepatol, 2020, 5(3):285-294.
[21]	INOUE Y, SAIURA A, OBA A, et al. Neoadjuvant gemcitabine and nab-paclitaxel for borderline resectable pancreatic cancers: intention-to-treat analysis compared with upfront surgery[J]. J Hepatobiliary Pancreat Sci, 2021, 28(2):143-155. doi: 10.1002/jhbp.844 pmid: 33058515
[22]	DAMM M, EFREMOV L, BIRNBACH B, et al. Efficacy and safety of neoadjuvant gemcitabine plus nab-paclitaxel in borderline resectable and locally advanced pancreatic cancer-a systematic review and meta-analysis[J]. Cancers (Basel), 2021, 13(17):4326.
[23]	CUI H, GUAN J, DENG G, et al. A Chinese retrospective multicenter study of first-line chemotherapy for advanced pancreatic cancer[J]. Med Sci Monit, 2020,26:e927654.
[24]	CHIOREAN E G, CHEUNG W Y, GIORDANO G, et al. Real-world comparative effectiveness of nab-paclitaxel plus gemcitabine versus FOLFIRINOX in advanced pancreatic cancer: a systematic review[J]. Ther Adv Med Oncol, 2019,11:1758835919850367.
[25]	YAMAGUCHI J, YOKOYAMA Y, FUJII T, et al. Results of a phase Ⅱ study on the use of neoadjuvant chemotherapy (FOLFIRINOX or gemcitabine with nab-paclitaxel) for borderline-resectable pancreatic cancer (NUPAT-01)[J]. Ann Surg, 2022, 275(6):1043-1049.
[26]	BURRIS H A 3rd, MOORE M J, ANDERSEN J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial[J]. J Clin Oncol, 1997, 15(6):2403-2413. doi: 10.1200/JCO.1997.15.6.2403 pmid: 9196156
[27]	KUNZMANN V, SIVEKE J T, ALGÜL H, et al. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial[J]. Lancet Gastroenterol Hepatol, 2021, 6(2):128-138.
[28]	MURPHY J E, WO J Y, RYAN D P, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial[J]. JAMA Oncol, 2019, 5(7):1020-1027. doi: 10.1001/jamaoncol.2019.0892 pmid: 31145418
[29]	VERSTEIJNE E, SUKER M, GROOTHUIS K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase Ⅲ PREOPANC trial[J]. J Clin Oncol, 2020, 38(16):1763-1773.
[30]	VERSTEIJNE E, VAN DAM J L, SUKER M, et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the dutch randomized PREOPANC trial[J]. J Clin Oncol, 2022, 40(11):1220-1230.
[31]	CLOYD J M, CRANE C H, KOAY E J, et al. Impact of hypofractionated and standard fractionated chemoradiation before pancreatoduodenectomy for pancreatic ductal adenocarcinoma[J]. Cancer, 2016, 122(17):2671-2679. doi: 10.1002/cncr.30117 pmid: 27243381
[32]	PERRI G, PRAKASH L, MALLEO G, et al. The sequential radiographic effects of preoperative chemotherapy and (chemo) radiation on tumor anatomy in patients with localized pancreatic cancer[J]. Ann Surg Oncol, 2020, 27(10):3939-3947.
[33]	KATZ M H, FLEMING J B, BHOSALE P, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators[J]. Cancer, 2012, 118(23):5749-5756. doi: 10.1002/cncr.27636 pmid: 22605518
[34]	DUDEJA V, GREENO E W, WALKER S P, et al. Neoadjuvant chemoradiotherapy for locally advanced pancreas cancer rarely leads to radiological evidence of tumour regression[J]. HPB (Oxford), 2013, 15(9):661-667.
[35]	FERRONE C R, MARCHEGIANI G, HONG T S, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer[J]. Ann Surg, 2015, 261(1):12-17. doi: 10.1097/SLA.0000000000000867 pmid: 25599322
[36]	KATZ M H, SHI Q, AHMAD S A, et al. Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancrea-tic cancer: alliance for clinical trials in oncology trial A021101[J]. JAMA Surg, 2016, 151(8):e161137.
[37]	HABIB J R, KINNY-KÖSTER B, VAN OOSTEN F, et al. Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: surgical planning with the "halo sign" and "string sign"[J]. Surg, 2021, 169(5):1026-1031.
[38]	CHIOREAN E G, VON HOFF D D, RENI M, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase Ⅲ trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer[J]. Ann Oncol, 2016, 27(4):654-660.
[39]	LUO G, JIN K, DENG S, et al. Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter[J]. Biochim Biophys Acta Rev Cancer, 2021, 1875(2):188409.
[40]	MELLON E A, JIN W H, FRAKES J M, et al. Predictors and survival for pathologic tumor response grade in borderline resectable and locally advanced pancreatic cancer treated with induction chemotherapy and neoadjuvant stereotactic body radiotherapy[J]. Acta Oncol, 2017, 56(3):391-397. doi: 10.1080/0284186X.2016.1256497 pmid: 27885876
[41]	COPPOLA A, LA VACCARA V, FIORE M, et al. CA19-9 serum level predicts lymph-nodes status in resectable pancreatic ductal adenocarcinoma: a retrospective single-center analysis[J]. Front Oncol, 2021,11:690580.
[42]	AOKI S, MOTOI F, MURAKAMI Y, et al. Decreased serum carbohydrate antigen 19-9 levels after neoadjuvant therapy predict a better prognosis for patients with pancreatic adenocarcinoma: a multicenter case-control study of 240 patients[J]. BMC Cancer, 2019, 19(1):252. doi: 10.1186/s12885-019-5460-4 pmid: 30898101
[43]	BOONE B A, STEVE J, ZENATI M S, et al. Serum CA 19-9 response to neoadjuvant therapy is associated with outcome in pancreatic adenocarcinoma[J]. Ann Surg Oncol, 2014, 21(13):4351-4358. doi: 10.1245/s10434-014-3842-z pmid: 25092157
[44]	AL ABBAS A I, ZENATI M, REISER C J, et al. Serum CA19-9 response to neoadjuvant therapy predicts tumor size reduction and survival in pancreatic adenocarcinoma[J]. Ann Surg Oncol, 2020, 27(6):2007-2014. doi: 10.1245/s10434-019-08156-3 pmid: 31898105
[45]	TSAI S, GEORGE B, WITTMANN D, et al. Importance of normalization of CA19-9 levels following neoadjuvant therapy in patients with localized pancreatic cancer[J]. Ann Surg, 2020, 271(4):740-747. doi: 10.1097/SLA.0000000000003049 pmid: 30312198
[46]	LIU H, ZENATI M S, RIESER C J, et al. CA19-9 change during neoadjuvant therapy may guide the need for additional adjuvant therapy following resected pancreatic cancer[J]. Ann Surg Oncol, 2020, 27(10):3950-3960. doi: 10.1245/s10434-020-08468-9 pmid: 32318949
[47]	LORDICK F, OTT K, KRAUSE BJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase Ⅱ trial[J]. Lancet Oncol, 2007, 8(9):797-805.
[48]	GOODMAN K A, OU F S, HALL N C, et al. Randomized phase Ⅱ study of PET response-adapted combined modality therapy for esophageal cancer: mature results of the CALGB 80803 (alliance) trial[J]. J Clin Oncol, 2021, 39(25):2803-2815.
[49]	GIANNINI V, MAZZETTI S, BERTOTTO I, et al. Predicting locally advanced rectal cancer response to neoadjuvant therapy with 18F-FDG PET and MRI radiomics features[J]. Eur J Nucl Med Mol Imaging, 2019, 46(4):878-888.
[50]	EVANGELISTA L, ZUCCHETTA P, MOLETTA L, et al. The role of FDG PET/CT or PET/MRI in assessing response to neoadjuvant therapy for patients with borderline or resectable pancreatic cancer: a systematic literature review[J]. Ann Nucl Med, 2021, 35(7):767-776. doi: 10.1007/s12149-021-01629-0 pmid: 34047926
[51]	LEE W, OH M, KIM J S, et al. Metabolic activity by FDG-PET/CT after neoadjuvant chemotherapy in borderline resectable and locally advanced pancreatic cancer and association with survival[J]. Br J Surg, 2021, 109(1):61-70. doi: 10.1093/bjs/znab229 pmid: 34378010
[52]	ZIMMERMANN C, DISTLER M, JENTSCH C, et al. Evaluation of response using FDG-PET/CT and diffusion weighted MRI after radiochemotherapy of pancreatic cancer: a non-randomized, monocentric phase Ⅱ clinical trial-PaCa-DD-041 (Eudra-CT 2009-011968-11)[J]. Strahlenther Onkol, 2021, 197(1):19-26.
[53]	WANG Z J, BEHR S, CONSUNJI M V, et al. Early response assessment in pancreatic ductal adenocarcinoma through integrated PET/MRI[J]. Am J Roentgenol, 2018, 211(5):1010-1019. doi: 10.2214/AJR.18.19602 pmid: 30063366
[54]	PANDA A, GARG I, TRUTY M J, et al. Borderline resectable and locally advanced pancreatic cancer: FDG PET/MRI and CT tumor metrics for assessment of pathologic response to neoadjuvant therapy and prediction of survival[J]. Am J Roentgenol, 2021, 217(3):730-740.
[55]	SCHORN S, DEMIR I E, REYES C M, et al. The impact of neoadjuvant therapy on the histopathological features of pancreatic ductal adenocarcinoma — a systematic review and meta-analysis[J]. Cancer Treat Rev, 2017,55:96-106.
[56]	KUBO H, OHGI K, SUGIURA T, et al. The association between neoadjuvant therapy and pathological outcomes in pancreatic cancer patients after resection: prognostic significance of microscopic venous invasion[J]. Ann Surg Oncol, 2022, 29(8):4992-5002. doi: 10.1245/s10434-022-11628-8 pmid: 35368218
[57]	BIRRER D L, GOLCHER H, CASADEI R, et al. Neoadjuvant therapy for resectable pancreatic cancer: a new standard of care. Pooled data from 3 randomized controlled trials[J]. Ann Surg, 2021, 274(5):713-720.
[58]	CZOSNYKA N M, BORGERT A J, SMITH T J. Pancrea-tic adenocarcinoma: effects of neoadjuvant therapy on post-pancreatectomy outcomes - an American College of Surgeons National Surgical Quality Improvement Program targeted variable review[J]. HPB (Oxford), 2017, 19(10):927-932.
[59]	HANK T, SANDINI M, FERRONE C R, et al. Association between pancreatic fistula and long-term survival in the era of neoadjuvant chemotherapy[J]. JAMA Surg, 2019, 154(10):943-951. doi: 10.1001/jamasurg.2019.2272 pmid: 31411659
[60]	DAHDALEH F S, NAFFOUJE S A, HANNA M H, et al. Impact of neoadjuvant systemic therapy on pancreatic fistula rates following pancreatectomy: a population-based propensity-matched analysis[J]. J Gastrointest Surg, 2021, 25(3):747-756.
[61]	KAMARAJAH S K, NAFFOUJE S A, SALTI G I, et al. Neoadjuvant chemotherapy for pancreatic ductal adenocarcinoma is associated with lower post-pancreatectomy readmission rates: a population-based cohort study[J]. Ann Surg Oncol, 2021, 28(4):1896-1905. doi: 10.1245/s10434-020-09470-x pmid: 33398644
[62]	DEIG C R, SUTTON T L, BENEVILLE B, et al. Neoadjuvant therapy is associated with improved chemotherapy delivery and overall survival compared to upfront resection in pancreatic cancer without increasing perioperative complications[J]. Cancers (Basel), 2022, 14(3):609.

Stage	Involved vessels	NCCN 2021^[5]
Borderline resectable	CA	Head/uncinate process: tumor contacted <180° Body/tail: tumor contacted ≥180° without involvement of the aorta and with uninvolved GDA
	CHA	Tumor contacted without extension to CA or hepatic artery bifurcation allowing for safe resection and reconstruction
	SMA	Tumor contacted ≤180°
	PV/SMV	Tumor contacted >180°, contact of ≤180° with contour irregularity of the vein or thrombosis of the vein, allowing for safe and complete resection and vein reconstruction
Locally advanced	CA	Head/uncinate process: tumor contacted >180° Body/tail process: tumor contacted and aortic involvement
	SMA	Tumor contacted >180°, or 1st jejunal brunch of SMA involved
	PV/SMV	Unresconstructible because of tumor involvement or occlusion

Regimen	Treatment	Recommended group^[5]
FOLFIRINOX	Oxaliplatin + irinotecan + leucovorin + 5-fluorouracil	Good physical condition, PS 0-1
AG	Gemcitabine + nab-paclitaxel	Good physical condition, PS 0-2
GEM	Gemcitabine	Poor physical condition