Liver-Directed Therapy and Systemic Chemotherapy for Pancreatic Adenocarcinoma with Liver Metastases: Experience of 12-years

Muhammad W. Saif, MD

Professor, Department of Internal Medicine, UCF School of Medicine, Orlando, FL 32827, USA; Deputy Director, Orlando Health Cancer Institute, Orlando, FL, USA; E-mail: Wsaif@outlook.Com

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death in the United States.¹ In 2023, there are expected to be 64,050 new cases and 50,550 deaths from PDAC.² The only potentially curative treatment option for PDAC is surgical resection. Unfortunately, only 10-20% of patients are eligible for resection at the time of diagnosis presentation, and the majority of them eventually relapse following surgery.^3,4 More than 50% of all PDAC patients have metastases at the time of diagnosis. Newer chemotherapy regimens such as FOLFIRINOX, or the combination of gemcitabine with nab-paclitaxel have improved outcomes for patients with metastatic PDAC with a median overall survival time of 8.5-11 months.^5,6 The liver is the most common site of metastasis in patients with PDAC both following resection of primary PDAC or at the time of initial diagnosis. Pancreatic adenocarcinoma with liver metastases (PCLM) has a poor prognosis with a median survival of ≤6-months.^7,8

Improvement in surgical technology has led to effective treatment for selected patients with hepatic metastases in solid tumors, but this remains to be a rare situation in patients with PDAC.^6,7,8,9 The role of locoregional therapies such as liver-directed therapy (LDT) is less defined at present, albeit combining LDT as an adjunct to systemic therapies makes sense, a strategy proven to be beneficial with the use of radiotherapy with chemotherapy.¹⁰ LDT is of different types such as trans-arterial radioembolization (TARE), trans-arterial chemoembolization (TACE), and radiofrequency ablation (RFA). TARE is a form of liver-directed brachytherapy that allows intra-arterial delivery of Yttrium-90 (Y90) radioactive particles into tumor tissue and has been shown to shrink tumors and enhance survival in other gastrointestinal tumors, such as hepatocellular carcinoma,^11,12 metastatic colorectal cancer,^13,14 and neuroendocrine cancer.^15,16 TACE either using conventional chemotherapeutic agents such as mitomycin C, cisplatin, and gemcitabine or administration of lipiodol has been shown to control the growth of liver metastases, especially in metastatic colorectal cancer.^17,18 RFA by inducing thermal injury to the tissue through electromagnetic energy deposition has been employed in select patients with liver metastases from many different primaries including pancreatic cancer.^19,20,21 However, the grave prognosis of PCLM may restrict the value of these modalities.

The purpose of this retrospective study was to evaluate the efficacy of incorporating LDT (TARE with Y90, TACE, and RFA) with systemic chemotherapy in the treatment of PCLM.

PATIENTS AND METHODS

The retrospective study reported in this paper was approved by the local institutional review board. We retrospectively evaluated 42 patients between February 2007 and March 2019, with data available on 39 patients with PCLM who underwent LDT including TARE with Y90 (SIR-Spheres, Sirtex Medical), TACE, and RFA. The majority of these patients underwent concurrent systemic chemotherapy for the treatment of PCLM.

Eligible patients had predominant hepatic disease with unresectable liver metastasis/metastases from pancreatic adenocarcinoma, e.g., the M1 no-surgery control group included patients who did not undergo surgical resection, but completed palliative chemotherapy instead. All patients were presented at a multidisciplinary pancreas board meeting where management decisions were discussed. Eligibility included limited extra-hepatic metastasis defined as <6 nodules with no nodule greater than 1.5 cm in lungs and stable for at least >4-months,  abdominal lymph nodes, stable pancreatic primary which is <4 cm in size, absolute neutrophil count >1,500 /mL, hemoglobin >9 g/dL, platelets >100,000 /mL, bilirubin <2.0 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio of <5 times higher than normal limit, creatinine level of <2.0 mg/dL, absence of hepatic cirrhosis (except for RFA), Eastern Cooperative Oncology Group (ECOG) performance score 0-1, and <20% lung shunting fraction (LSF).

Patients were excluded if the above criteria were not met, or those with a contraindication to angiography, extensive tumor replacement in the liver defined as >50% of liver involved with tumor, clinical evidence of peritoneal metastasis or ascites, or any serious ongoing infection.

Institutional guidelines were followed for any LDT procedures and at the discretion of the operating interventional radiologist. The treatment dose of resin Y90 was calculated according to the patient’s body surface area for TARE. Precautions were adopted to minimize potential gastrointestinal ulceration using standard procedures. Dose reduction was performed for high lung shunts as per manufacturer recommendations. Patient demographics including history, physical laboratory, chemotherapy regimen, radiological imaging, and outcomes were collected.

Local and overall disease response was evaluated using response evaluation criteria in solid tumors (RECIST), Version 1.1 including disease response, median overall survival (mOS) from the time of diagnosis of metastatic disease, and mOS following receipt of LDT.²² Follow-up imaging assessment was carried out usually two to three months after the final LDT session. Treatment-related adverse events were assessed using common terminology criteria for adverse events (CTACE), Version 5.0.²³

Descriptive statistics were used to summarize patients’ demographic features as well as treatment parameters. Statistical analysis software (SAS) software version 9.3 (SAS Inc., NC, USA) was utilized in the data analysis.

RESULTS

Of 39 patients, 56% underwent TARE, 36% RFA, and 7.8% TACE. The selection of modality was based on institutional standards and at the discretion of the referring physician. A summary of baseline patient characteristics is outlined in Table 1.

All patients had received at least one line of prior concurrent chemotherapy (range: 1-3) at the time of LDT. Thirty-six (36) patients (92%) underwent systemic chemotherapy concurrently during LDT sessions/sessions. Eighteen patients were receiving a 5-fluorouracil (5-FU)-based regimen, most commonly FOLFIRINOX or liposome irinotecan with 5-FU and leucovorin; nine patients were receiving concurrent gemcitabine-based therapy, including gemcitabine with nab-paclitaxel, gemcitabine-oxaliplatin, and gemcitabine-capecitabine and the rest with single agents, such as capecitabine, sutent, etc. Systemic therapy was stopped on average 12-days (range 11 to 22-days) before LDT and was resumed on average 21-days (range 14-28 days) after LDT. Table 2 summarizes the treatment parameters. All patients received a single course of TARE for each diseased liver lobe. In 20% of patients who had bilobar liver disease, the combination treatments for both diseased lobes were defined in a single course. The mean Y90 radiation dose delivered to the right lobe was 1.00 GBq and to the left lobe was 0.64 GBq. There was an average interval of 28-days (range: 21 to 36-days) in between treatments for the patients receiving bilobar treatments.

Eleven of the 39 patients were alive at the time of this retrospective analysis. The mPFS was 5-months (range 4 to 5.5-months) from the application of LDT and the one-year mOS was 7.8-months (6.5 to 9.5-months) (Table 3).

Overall liver-specific disease response included complete response in 2.5%, partial response in 59%, stable disease in 21%, and progression of disease in 18% of patients. Overall disease control (PR+SD) was 62% while one patient was not evaluable and median duration of response was 2.5-months (range: 2-6). Responses according to type of LDT were: RFA: (10/11)=90%, TACE: (1/3) 33% and, TARE: partial response (PR): (5/16) 31%. Majority of the patients (>50%) developed extra-hepatic metastases (lymph node (n=14), lung (n=5), peritoneal (n=4) and other (n=2) while or new liver metastases were noticed in 20% of the patients.

Grade 3 toxicities included abdominal pain in 13%, hyperbilirubinemia in 7.7%, fever in 7.7%, abscess in 2.6%, and thrombocytopenia in 5.1% of patients. No treatment-related grade 4 or 5 toxicities were seen.

DISCUSSION

Our retrospective study provides further evidence that incorporating multi-modality LDT with systemic chemotherapy, including newer cytotoxic agents in the treatment of liver-dominant Pancreatic adenocarcinoma with liver (PCL) can improve efficacy in this deadly disease with acceptable toxicity. With this heterogeneous disease and heterogeneous utilization of different modalities of LDT can be challenging to analyze. All methods of transvascular or thermal ablation techniques are limited by the size of the ablation zones developing following the procedure as well as by the number of lesions. A safety margin of at least 1 cm around the tumor is necessary for achieving complete ablation. Therefore, the maximum size of a lesion that can be successfully ablated is approximately 4-5 cm in diameter. For metastases too large for ablative therapy alone, downsizing can be achieved via TACE. Like ours, many institutions that offer expertise care in the field offer LDT with a qualitatively perceived benefit in patients who would otherwise have limited options for PCL. In the present study, all patients received systemic chemotherapy in conjunction with LDT. The commonly used regimens in the decreasing order were FOLFIRINOX, gemcitabine with nab-paclitaxel, gemcitabine-oxaliplatin, gemcitabine-capecitabine, liposome irinotecan with 5-FU and leucovorin, and capecitabine. One patient was on sutent as a maintenance therapy. Due to the small size, different chemotherapy regimens used, and retrospective nature of the study, we did not perform a comparison to the chemotherapy-only population or historical control. Previous reports have also suggested that LDT had a complementary effect when combined with systemic chemotherapy in PCL with manageable toxicities.^{24,25,26,27,28,29}

The liver is the most common site for metastases in PDAC and is associated with a worse prognosis. Surgical resection of liver metastases is generally not performed in such patients and the use of systemic chemotherapy is preferred. Newer chemotherapy regimens including FOLFIRINOX and gemcitabine with nab-paclitaxel as first-line chemotherapies do offer an improvement in survival compared to gemcitabine monotherapy, a standard approved in 1996.^5,6,30 Only a few targeted agents have been approved for use in these patients, notably BReast CAncer gene 1 and BReast CAncer gene 2 (BRCA1/2), microsatellite instability (MSI)-high, and neurotrophic receptor tyrosine kinase (NTRK).^31,32,33 Immunotherapy has yet to show a breakthrough in the outcome of pancreatic cancer.³⁴ This all underlines the fact that treatment options remain limited for patients with PCLM. Therefore, it is logical to consider minimally invasive LDT as an alternative modality to treat these patients. It is of comfort and benefit that physicians have ample experience in treating other gastrointestinal tumors with these modalities, especially hepatocellular carcinoma (HCC).^10,11,12

Medical literature shows recent reports of improved outcomes in PCLM patients who had metachronous or synchronous liver oligometastases of pancreatic cancer after radical surgery, in which patients exhibit long-term survival without recurrence after hepatectomy, are reported from major cancer centers.^35,36,37,38 Hepatectomy may result in a longer survival in a few patients, however, factors such as to number of metastases, extra-hepatic disease and time to post-operative recurrence are considered important criteria.³⁹ Although liver resection was a common type of LDT, there were few candidates for PCLM, and the surgical indications are debatable. Therefore, patients who received aggressive surgery were excluded from this study. This also requires a multidisciplinary and multi-modality approach with experts in the field and at high-volume cancer centers.

LDT can be repeated in some patients if clinically indicated and may provide survival benefits. In a study performed by Ouyang et al⁴⁰ the median overall survival (OS) improved several times TACE was performed at 14.1-months, 8.1-months, and 7.5-months in patients who underwent the procedure thrice, twice, and once respectively. Similar reports were published by Azizi et al.⁴¹

Though our study in addition to previous studies by other investigators showed that LDT can provide effective and safe treatment options for patients with PCLM, modalities of LDT are heterogeneous. As with any radical treatment options, the results of this study should be evaluated with regard both to acute and long-term toxicities of the combination therapy. Our patients had grade 3 toxicities consisting of abdominal pain in 13%, hyperbilirubinemia in 7.7%, fever in 7.7%, abscess in 2.6%, and thrombocytopenia in 5.1% of patients. These results of toxicities are those of previous studies.^{24,25,26,27,28,39,40}

We acknowledge the limitations that accompany our study. This was carried out in a retrospective nature which included inherent biases such as the possibility of selection bias and lack of a control group for comparison. A relatively small sample size is also a limitation as this was conducted solely at our institutions as a retrospective analysis. However, keeping these points in mind, we believe our patients represented a reasonably similar profile to the general population in this patient population with PCLM. All patients were treated at the discretion of the treating physician. Patients were monitored as they would be in any clinical setting. However, we still believe that our cohort adds significance to adding LDT safely to systemic therapy in these patients resulting in a survival benefit for liver dominate PCLM.

Offers a better outcome Pancreatic ductal adenocarcinoma continues to be one of the leading causes of cancer-related mortality in the United States and surgery is the only potentially curative treatment option for these patients. Multidisciplinary coordination is of paramount significance in these circumstances.

CONCLUSION

LDT can be safely combined with systemic chemotherapy for the treatment of PCLM. Patient outcomes following this treatment strategy are promising but prospective evaluations are needed to validate these preliminary findings. Liver-directed therapies represent a target for future study.

Funding

The research reported in this publication in part (patients were managed) was supported by the award numbers UL1 TR001064 and 2UG1CA189850 under the following institutions: Tufts Medical Center and NorthwellHealth Cancer Institute.

INSTITUTIONAL REVIEW BOARD PERMISSION

Yes.

PATIENT’S CONSENT

Not required.

CONFLICT OF INTEREST

The authors declare that they have no conflicts of interest.

1. Ma J, Siegel R, Jemal A. Pancreatic cancer death rates by race among US men and women, 1970–2009. J Natl Cancer Inst. 2013; 105: 1694-1700. doi: 10.1093/jnci/djt292

2. American Cancer Society^®. Cancer Facts and Figures 2023. 2023. Website. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.html. Accessed June 8, 2023.

3. Gleisner AL, Assumpcao L, Cameron JL, et al. Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer. 2007; 110: 2484-2492. doi: 10.1002/cncr.23074

4. Saif MW. Is liver resection in metastases of exocrine pancreatic carcinoma justified? JOP. 2011; 12(1): 68-69. doi: 10.6092/1590-8577/3390

5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364: 1817-1825. doi: 10.1056/NEJMoa1011923

6. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013; 369: 1691-1703. doi: 10.1056/NEJMoa1304369

7. Crippa S, Cirocchi R, Weiss MJ, et al. A systematic review of surgical resection of liver-only synchronous metastases from pancreatic cancer in the era of multiagent chemotherapy. Updates Surg. 2020; 72(1): 39-45. doi: 10.1007/s13304-020-00710-z

8. Klein F, Puhl G, Guckelberger O, et al. The impact of simultaneous liver resection for occult liver metastases of pancreatic adenocarcinoma. Gastroenterol Res Pract. 2012; 2012: 939350. doi: 10.1155/2012/939350

9. Takada T, Yasuda H, Amano H, Yoshida M, Uchida T. Simultaneous hepatic resection with pancreato-duodenectomy for metastatic pancreatic head carcinoma: Does it improve survival? Hepatogastroenterology. 1997; 44(14): 567-573.

10. Vogl TJ, Mohamed SA, Albrecht MH, et al. Transarterial chemoembolization in pancreatic adenocarcinoma with liver metastases: MR-based tumor response evaluation, apparent diffusion coefficient (ADC) patterns, and survival rates. Pancreatology. 2018; 18(1): 94-99. doi: 10.1016/j.pan.2017.11.014

11. Mazzaferro V, Sposito C, Bhoori S, et al. Yttrium-90 radioembolization for intermediate-advanced hepatocellular carcinoma: A phase 2 study. Hepatology. 2013; 57: 1826-1837. doi: 10.1002/hep.26014

12. Kokabi N, Camacho JC, Xing M, et al. Open-label prospective study of the safety and efficacy of glass-based yttrium 90 radioembolization for infiltrative hepatocellular carcinoma with portal vein thrombosis. Cancer. 2015; 121: 2164-1274. doi: 10.1002/cncr.29275

13. Cosimelli M, Golfieri R, Cagol PP, et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. Br J Cancer. 2010; 103: 324-331. doi: 10.1038/sj.bjc.6605770

14. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy. J Clin Oncol. 2010; 28: 3687-3694. doi: 10.1200/JCO.2010.28.5643

15. John PK, Saif MW. Radioembolization in the treatment of neuroendocrine tumors of the pancreas. JOP. 2014; 15(4): 332-334. doi: 10.6092/1590-8577/2688

16. Tsang ES, Loree JM, Davies JM, et al. Efficacy and prognostic factors for Y-90 radioembolization (Y-90) in metastatic neuroendocrine tumors with liver metastases. Can J Gastroenterol Hepatol. 2020; 2020: 5104082. doi: 10.1155/2020/5104082

17. Malagari K, Kiakidis T, Moschouris H, et al. Prospective series of transarterial chemoembolization of metastatic colorectal cancer to the liver with 30-60 μm microspheres loaded with irinotecan. Cardiovasc Intervent Radiol. 2023; 46(7): 880-890. doi: 10.1007/s00270-023-03446-6

18. Carconi C, Cerreti M, Roberto M, et al. The management of oligometastatic disease in colorectal cancer: Present strategies and future perspectives. Crit Rev Oncol Hematol. 2023; 186: 103990. doi: 10.1016/j.critrevonc.2023.103990

19. Yang G, Wang G, Sun J, et al. The prognosis of radiofrequency ablation versus hepatic resection for patients with colorectal liver metastases: A systematic review and meta-analysis based on 22 studies. [Int J Surg. 2021; 87: 105896]. Int J Surg. 2021; 89: 105954. doi: 10.1016/j.ijsu.2021.105896

20. Oh SJ. Long-Term survival of two patients with liver metastases from advanced gastric cancer treated with radiofrequency ablation and chemotherapy. Case Rep Oncol. 2021; 14(1): 67-72. doi: 10.1159/000507849

21. Al-Jumah R, Urits I, Viswanath O, Kaye AD, Hasoon J. Radiofrequency ablation and alcohol neurolysis of the splanchnic nerves for a patient with abdominal pain from pancreatic cancer. Cureus. 2020; 12(10): e10758. doi: 10.7759/cureus.10758

22. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228-247. doi: 10.1016/j.ejca.2008.10.026

23. Common Terminology Criteria for Adverse Events (CTCAE). 2017. Website. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5×11.pdf. Accessed June 8, 2023.

24. Cao C, Yan TD, Morris DL, Bester L. Radioembolization with yttrium-90 microspheres for pancreatic cancer liver metastases: Results from a pilot study. Tumori. 2010; 96: 955-958. doi: 10.1700/548.6515

25. Michl M, Haug AR, Jakobs TF, et al. Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: Efficacy, safety and prognostic factors. Oncology. 2014; 86: 24-32. doi: 10.1159/000355821

26. Kennedy A, Nag S, Salem R, et al. Recommendations for radioembolization of hepatic malignancies using yttrium-90 microsphere brachytherapy: A consensus panel report from the radioembolization brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys. 2007; 68: 13-23. doi: 10.1016/j.ijrobp.2006.11.060

27. Du YQ, Bai XM, Yang W, et al. Percutaneous ultrasound-guided radiofrequency ablation for patients with liver metastasis from pancreatic adenocarcinoma. Int J Hyperthermia. 2022; 39(1): 517-524. doi: 10.1080/02656736.2022.2048907

28. Hua Y-Q, Wang P, Zhu X-Y, et al. Radiofrequency ablation for hepatic oligometastatic pancreatic cancer: An analysis of safety and efficacy. Pancreatology. 2017; 17(6): 967-973. doi: 10.1016/j.pan.2017.08.072

29. Obed A, Siyam M, Jarrad AA, et al. Unexpected long-term survival of Stage IV pancreatic cancer patient with synchronic liver metastases after multimodal therapy including upfront surgery. J Surg Case Rep. 2023; 2023(1): rjac638. doi: 10.1093/jscr/rjac638

30. Burris HA, Moore MJ, 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 Clin Oncol. 1997; 15(6): 2403-2413. doi: 10.1200/JCO.1997.15.6.2403

31. Chi J, Chung SY, Parakrama R, Fayyaz F, Jose J, Saif MW. The role of PARP inhibitors in BRCA mutated pancreatic cancer. Therap Adv Gastroenterol. 2021; 14: 17562848211014818. doi: 10.1177/17562848211014818

32. Newman J, Seetharamu N, Saif MW. Burden of proof: Evaluating the efficacy of tumor mutational burden (TMB) in predicting response to immune checkpoint inhibitors. Cancer Med J. 2020; 3(Suppl 2): 17-21.

33. Lange AM, Lo HW. Inhibiting TRK proteins in clinical cancer therapy. Cancers (Basel). 2018; 10(4): 105. doi: 10.3390/cancers10040105

34. Liu F, Saif MW. T cell optimization for the treatment of pancreatic cancer. Expert Opin Biol Ther. 2017; 17(12): 1493-1501. doi: 10.1080/14712598.2017.1369948

35. Kolbeinsson H, Hoppe A, Bayat A, et al. Recurrence patterns and postrecurrence survival after curative intent resection for pancreatic ductal adenocarcinoma. Surgery. 2021; 169(3): 649-654. doi: 10.1016/j.surg.2020.06.042

36. Tachezy M, Gebauer F, Janot M, et al. Synchronous resections of hepatic oligometastatic pancreatic cancer: Disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis. Surgery. 2016; 160(1): 136-144. doi: 10.1016/j.surg.2016.02.019

37. Zanini N, Lombardi R, Masetti M, Giordano M, Landolfo G, Jovine E. Surgery for isolated liver metastases from pancreatic cancer. Updates Surg. 2015; 67(1): 19-25. doi: 10.1007/s13304-015-0283-6

38. Klempnauer J, Ridder GJ, Piso P, Pichlmayr R. Is liver resection in metastases of exocrine pancreatic carcinoma justified? Chirurg. 1996; 67: 366-370.

39. Ouyang H, Ma W, Liu F, et al. Factors influencing survival of patients with pancreatic adenocarcinoma and synchronous liver metastases receiving palliative care. Pancreatology. 2017; 17(5): 773-781. doi: 10.1016/j.pan.2017.07.002

40. Ouyang H, Ma W, Zhang T, et al. Systemic chemotherapy in combination with liver-directed therapy improves survival in patients with pancreatic adenocarcinoma and synchronous liver metastases. Pancreatology. 2018; 18(8): 983-989. doi: 10.1016/j.pan.2018.09.015

41. Azizi A, Naguib NNN, Mbalisike E, Farshid P, Emami AH, Vogl TJ. Liver metastases of pancreatic cancer: Role of repetitive transarterial chemembolization (TACE) on tumor response and survival. Pancreas. 2011; 40: 1271-1275. doi: 10.1097/MPA.0b013e318220e5b9