Yttrium-90 Radioembolization of Nonconventional Liver Tumors

Abstract: Yttrium-90 selective internal radiation therapy (SIRT) is a treatment modality used for unresectable hepatic neoplasm, typically from primary hepatic malignancy such as hepatocellular carcinoma or colorectal and neuroendocrine metastases. Although extensive literature exists about SIRT for these indications, data are sparse for yttrium-90 therapy for nonconventional hepatic metastases, such as breast cancer, melanoma, pancreatic cancer, lung cancer, cholangiocarcinoma, and renal cell carcinoma. This article aims to systematically review and summarize the current literature to assess the effects of yttrium-90 radioembolization on nonconventional hepatic neoplasms. 

Key words: liver metastases, breast cancer, melanoma, cholangiocarcinoma, radioembolization, selective internal radiation therapy, SIRT, transarterial radioembolization, TARE, yttrium-90

___________________________________________________________________

Hepatic metastases are 40 times more common than primary hepatic neoplasm in the United States and Europe, with approximately half of extrahepatic primary cancers in the United States having hepatic metastasis.¹ Dual blood supply to the liver and easily penetrable and fenestrated endothelial lining of the hepatic sinusoids explain the high prevalence of metastatic liver disease.² Although first-line treatment for liver metastasis is surgical resection, over 75% of patients are precluded from surgery. As a result, chemotherapy and locoregional therapies are the next best options in these patients.³ Contraindications to surgical resection include extrahepatic disease, unfitness for surgery, and extensive hepatic disease burden, which may lead to poor postsurgical hepatic functional reserve.⁴

Isolated hepatic metastases amenable to local therapy are commonly associated with colorectal cancer.^5,6 Other neoplasms such as pancreatic cancer, breast cancer, lung cancer, neuroendocrine tumors, and melanoma often present with disseminated disease.⁴ Numerous studies on surgical resection of liver metastases with colorectal and neuroendocrine primaries have shown improved survival.^7-10 However, the utilization of locoregional therapy in nonconventional liver metastases remains less studied and more controversial.

Targeted catheter-based therapy, such as selective internal radiotherapy (SIRT) or transarterial radioembolization (TARE) using yttrium-90 (Y90) microspheres, is used to treat unresectable liver metastasis. Therapeutic efficacy relies on the fact that hepatic artery contributing blood supply to over 90% of tumor and that tumor neovascularity is greater than the adjacent parenchyma.¹¹ The procedure involves transarterial infusion of Y90 microspheres into the liver, and bead penetration and permanent implantation into the tumor vascular bed result in selective delivery of therapeutic radiation dose over time.

Y90 microspheres are produced commercially in glass (TheraSphere; BTG) or resin (SIR-Spheres; Sirtex) forms. In 1999 under a Humanitarian Device Exemption (HDE), the US Food and Drug Administration (FDA) approved Therasphere as radiation therapy or neoadjuvant to surgery for unresectable hepatoma. In 2002, the FDA approved SIR-Spheres for unresectable colorectal metastasis. Off-label use of Y90 radioembolization has been reported for treating liver metastases with other known primaries. Among the studies performed regarding Y90 for treatment of liver metastases, few include results from noncolorectal or nonneuroendocrine primaries.^6,11,12 This article aims to review the pre-existing literature to better assess the treatment response and survival outcomes of Y90 radioembolization in treating nonconventional liver tumors.

Methods

After a systematic literature search of PubMed, EMBASE, and Cochrane Library using terms “Yttrium-90,” “Y90,” “radioembolization,” and “liver metastasis,”28 studies containing nonconventional primaries with Y90 radioembolization were included for review. After excluding studies with only unified outcomes for multiple primary tumors, the literature categorized by primary tumor includes 10 studies with breast tumor, 6 with melanoma, 8 with cholangiocarcinoma, 3 with pancreatic origin, 2 with renal cell carcinoma, and 3 with thoracic primaries.^13-33 

Breast Cancer

The most common cancer in women is breast cancer, which accounts for approximately 29% of newly diagnosed cancers in women.³⁴ Approximately 20% to 30% of breast cancers metastasize distantly, with 5-year survival rates of 16% to 25%.^34,35 Estimated cumulative survival in metastatic breast cancer at time of diagnosis is 18.5 months, according to data collected by the National Cancer Institute between 1973 and 1995.³⁶ Median survival is 3 months to 10 months for patients with unresectable, chemoresistant breast cancer liver metastases (BRCLM).³⁷ 

Systemic chemotherapy is preferred to surgical resection as a treatment of BRCLM, in part because it is rare to have solitary liver metastases from breast cancer (<5%). Ultimately <20% of patients are eligible for surgery.^38-40 Therefore, it is crucial to research alternative treatments for unresectable, chemoresistant BRCLM. 

Breast cancer is the most studied among the literature on SIRT of nonconventional liver metastases; these studies are summarized in Table 1. Currently, 7 BRCLM SIRT studies are available^{14,16,18,22,30,31,33} along with 3 mixed primary studies that describe separate response data on the patient with breast primaries.^17,28,29

The earliest study assessing survival of BRCLM patients on SIRT was performed by Bangash et al in 2007 and involved 27 patients with progressive hepatic metastases on polychemotherapy. Complete or partial response by WHO criteria was seen in 39.1% of the 23 patients at 90-day follow-up CT. Positive tumor response was seen on PET in 63% of patients. Median survival for the 21 patients with tumor burden <25% was 9.4 months and that of 6 patients with tumor burden >25% was 2 months. While response to SIRT was encouraging, the effect on survival was unclear.¹⁴

The largest study of SIRT in 77 unresectable chemorefractory BRCLM patients in 2013 showed response rates consistent with previous studies with a partial response rate of 56% by RECIST criteria. Median survival of 11.5 months was seen. Patients with ECOG 0 with <25% tumor burden and no extrahepatic disease had median survival at 14.3 months.¹⁶

These studies all describe Y90 SIRT as an effective procedure for unresectable chemoresistant BRCLM. Analysis of existing literature showed response rates ranging from 18% to 61%, and median overall survival (OS) ranging from 6.6 months to 13.6 months. Although response rates and survival outcomes differ greatly based on selection criteria, overall they are improved over past controls. Prior studies with colorectal and neuroendocrine tumors have suggested that SIRT is useful for treatment of uniformly hypervascular and slow-growing tumors, which breast cancer metastases often are.^18,41,42 Typical presentation of BRCLM with widespread lesions at diagnosis limits the effects of other therapies, such as stereotactic radiotherapy or conventional chemoembolization. The role of SIRT is limited due to the tendency of BRCLM to present with extrahepatic involvement. Even though the effects of SIRT on breast cancer metastasis are being studied increasingly, only small, heterogeneous patient cohorts have been assessed to date. Therefore, larger multicenter control studies are of interest to establish SIRT as a potential first-line adjuvant to chemotherapy. 

Cholangiocarcinoma

As the second most common primary hepatic malignancy after hepatocellular carcinoma, incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing with median OS of patients currently at 22 months.⁴³ Median survival of untreated ICC is considerably lower at 3 months to 8 months.⁴⁴ Owing to advanced hepatic disease, few patients qualify for curative resection, the mainstay therapy for ICC. Advancements in nonoperative therapy have improved median survival in unresectable disease from 6 months before 2000 to 15 months more recently.⁴⁵ Liver-targeted procedures, such as transarterial infusion (TAI), TACE, and TARE, as well as application of newer palliative agents floxuridine and gemcitabine, have been practiced in the past decade.

Currently, a few studies focusing on liver-directed Y90 SIRT on ICC have been reported and are summarized in Table 2. In our literature search, most of the 8 ICC-only SIRT studies were published in 2013-2014, and 5 of these studies were included in a systematic review and meta-analysis by Boehm et al.^3,46-49 The meta-analysis revealed the highest median OS with TAI (22.8 months) compared to TARE (13.9 months), conventional TACE (12.4 months), and drug-eluting TACE (12.3 months). However, the authors suggest caution over potential selection bias when interpreting the results.⁴³

Boehm et al excluded 3 more recent studies in the analysis.^50-52 In the first study, Mouli et al added 22 patients to the previous cohort to broaden the pilot study done by Ibrahim et al. The study showed 25% of patients with partial response by WHO criteria. Solitary and multifocal lesions demonstrated significant variation in OS, 14.6 months vs 5.7 months, respectively.⁵² The second study, performed by Camacho et al with 21 chemorefractory ICC patients, noted 16.3 months median survival. The third study, by Filippi et al, assessed 18 ICC patients and described 82.5% response rate by PET scan and a median OS of 14.8 months.⁵¹ Therefore, 13.9 months OS from meta-analysis by Boehm et al is consistent with survivability data of these 3 recent reports.⁴³

For low-tumor burden ICC, Y90 SIRT is recognized as preferred first-line therapy at some centers since previously unresectable ICC can be downstaged for curative resection.⁵² Despite median OS data being less than that of TAI, Y90 therapy holds fewer risks such as not having to implant chemoinfusion port.

Ocular and Cutaneous Melanoma

Melanoma is responsible for 75% of deaths among skin cancers. Metastases of ocular (uveal) melanoma tend to involve the liver (95% of metastatic disease) compared to 15% to 20% liver metastasis of cutaneous melanomas. Hepatic spread in either type indicates a grave prognosis and is frequently the cause of death.⁵³ Median OS is documented at 2.4 months with liver metastases.⁵⁴ To reduce tumor burden and improve OS in patients with chemorefractory liver metastases, liver-directed therapy may be preferable, but the majority (91%) of patients are not eligible for surgical resection owing to extensive hepatic or extrahepatic involvement.²⁰ In unresectable liver metastases, transcatheter therapy via TAI chemotherapy and TACE have shown favorable response rates and improved clinical outcomes.³² Six studies including results on Y90 SIRT of melanoma liver metastases are summarized in Table 3.^{20,23-25,29,32} 

The hypervascular and aggressive nature of melanoma liver metastases suggests locoregional treatment with SIRT as a reasonable approach to potentially decreasing disease progression. Median OS of less than 3 months from previous decades has drastically improved, ranging from 7.6 months to 10.1 months with SIRT.⁵⁴ Like many other tumor types, survival rates are better with SIRT in patients with less hepatic involvement and the absence of extrahepatic disease. Although these few small cohort studies revealed SIRT as a safe and effective therapy in prolonging survival, additional comparative studies are required for the ideal selection criteria and benefit over other regional therapies.

Pancreatic Cancer

Metastatic pancreatic adenocarcinoma bears a bleak prognosis with median OS of approximately 5 months to 7 months.^55-57 Surgical resection of liver metastases at the time of pancreatic resection is reported to carry high complication rates and poor long-term outcomes.^58,59 Locoregional treatment with Y90 SIRT has been researched as an adjunct to hinder disease progression.

Very limited clinical data exist on Y90 SIRT treatment for liver metastasis from pancreatic adenocarcinoma, summarized in Table 4. Out of two small single-center studies published so far, the first by Cao et al in 2010 evaluated 7 pancreatic adenocarcinoma patients with liver metastases. Two patient fatalities occurred prior to initial follow-up; 2/5 remaining patients had partial response by RECIST criteria. Average median survival time was not described, but one patient survived approximately 15 months after SIRT therapy.¹⁵ In 2014, Michl et al performed a slightly larger study on 19 chemorefractory pancreatic patients with hepatic metastases, revealing median OS at 9 months. This study had 5 patient deaths and 1 patient omission due to disease progression prior to initial follow-up. At initial follow-up, a partial response by RECIST criteria was seen in 64.3% of patients. Adjuvant chemotherapy following surgery was given to 9 patients. A correlation between CA 19-9, CRP, and shorter OS was also established.²⁶

While the limitation of available data creates unclear survivability benefits, salvage treatment seems encouraging in initial studies. Designing proper patient selection criteria for optimal patient outcome necessitates additional studies.

Renal Cell Carcinoma

Accounting for 2% to 3% of malignancies in the United States, renal cell carcinoma (RCC) has been increasing in incidence with over 63,000 new cases and over 13,000 deaths in 2014.³⁴ Liver metastases are seen in 20% to 40% of RCC. Median OS at 7.4 months was documented for patients with hepatic involvement.⁶⁰ Utilization of locoregional SIRT to treat RCC liver metastases is very limited (Table 5).  

In 2012, Abdelmaksoud et al completed a pilot study of Y90 SIRT for chemorefractory RCC liver metastases. The study reported median OS at 12 months for 6 patients. By RECIST criteria, complete response was documented in 3 of 5 patients at initial follow-up and partial response in 1 patient. There were 2 deaths within 2 months of therapy from unrelated extrahepatic causes.¹³ In 2013, Hamoui et al published a case report on a 76-year-old woman with metastatic sarcomatoid RCC undergoing palliative SIRT on both a left renal tumor and the right hepatic lobe. Both tumors’ spread remained stable on CT scan at 8 weeks and 3 months. Metastasis of the RCC progressed after 9 months and the patient died 23 months after TARE.²¹

Treatment of liver metastasis from RCC with SIRT looks promising due to its hypervascular nature, much like neuroendocrine tumors. Furthermore, TAI treatment may better benefit patients with many metastatic foci that are difficult to treat with ablation and stereotactic techniques. However, SIRT use is limited by the rarity of liver-dominant metastases from RCC and the known resistance to radiation.¹³ Nonetheless, SIRT seems promising as a palliative rather than curative treatment for metastases from RCC based on initial reports on a few patients.

Lung Cancer

As the leading cause of cancer-related death, lung cancer contributed to over 159,000 deaths in 2014. A 4% chance of 5-year survival is observed in both stage IV non-small-cell lung cancer and small-cell lung cancer.³⁴ Palliative chemotherapy is used to treat stage IV lung cancer. 

Yttrium-90 SIRT for lung cancer has been rarely studied, therefore only limited data are available (Table 6). A retrospective study by Murthy et al in 2008 followed 6 patients with various lung cancer types. Two patients were reported to have partial response, 1 patient had stable disease, and 3 patients developed progressive disease. Median OS was noted to be 2.7 months from TARE to death.²⁷ A case report published by Gaba et al in 2012 showed complete response of liver metastases to SIRT in 2 chemorefractory squamous-cell lung cancer patients. Both patients were alive at the time of the study at 11 months and 2 months after SIRT therapy respectively.¹⁹

To date, only a few cases of Y90 SIRT in lung cancer liver metastases have been assessed, but these cases reveal its potential as an effective salvage treatment. Additional studies are required to better assess and define the criteria in which SIRT are considered a worthwhile treatment in metastatic lung cancer. 

Conclusion

Despite less well-defined indications for Y90 SIRT in nonconventional hepatic metastasis, a few small studies have produced favorable initial results. The study limitations are heterogeneity of patient cohort, lack of standardized treatment response criteria, and difference in treatment dosage. Many factors may contribute to discrepancy in median OS among tumor types. Examples include small patient cohort size and variable tumor burden, difference in disease progressiveness, time to first follow-up, and presence and severity of extrahepatic disease. According to the studies, a justifiable benefit (or lack thereof) from Y90 SIRT on any given patient depends largely upon both tumor type and patient status. In order to improve patient outcomes, larger, multicenter studies and established clinical guidelines are necessary.

Editor’s note: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no financial relationships or conflicts of interest regarding the content herein.

Manuscript received May 3, 2016; manuscript accepted May 31, 2016.

Address for correspondence: Edward Lee, MD, PhD, UCLA Medical Center, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095, United States. Email: ewlmdphd@gmail.com

Suggested citation: Park JK, Phyu W, Zaw T, Walsworth M, Lee HY, Lee EW. Yttrium-90 radioembolization of nonconventional liver tumors. Intervent Oncol 360. 2016;4(7):E115-E129.

References

1. World Health Organization International Agency for Research on Cancer. Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press/Oxford University Press (distributor); 2000.
2. Ananthakrishnan A, Gogineni V, Saeian K. Epidemiology of primary and secondary liver cancers. Semin Intervent Radiol. 2006;23(1):47-63.
3. Hoffmann RT, Paprottka PM, Schön A, et al. Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival. Cardiovasc Intervent Radiol. 2012;35(1):105-116.
4. Niederhuber JE. Abeloff’s Clinical Oncology. Philadelphia: Elsevier; 2014.
5. Khatri VP, Petrelli NJ, Belghiti J. Extending the frontiers of surgical therapy for hepatic colorectal metastases: is there a limit? J Clin Oncol. 2005;23(33):8490-8499.
6. Mayo SC, Pawlik TM. Current management of colorectal hepatic metastasis. Expert Rev Gastroenterol Hepatol. 2009;3(2):131-144.
7. Benevento A, Boni L, Frediani L, Ferrari A, Dionigi R. Result of liver resection as treatment for metastases from noncolorectal cancer. J Surg Oncol. 2000;74(1):24-29.
8. Berney T, Mentha G, Roth AD, Morel P. Results of surgical resection of liver metastases from non-colorectal primaries. Br J Surg. 1998;85(10):1423-1427.
9. Chen H, Hardacre JM, Uzar A, Cameron JL, Choti MA. Isolated liver metastases from neuroendocrine tumors: does resection prolong survival? J Am Coll Surg. 1998;187(1):88-92; discussion 92-93.
10. van Ruth S, Mutsaerts E, Zoetmulder FA, van Coevorden F. Metastasectomy for liver metastases of non-colorectal primaries. Eur J Surg Oncol. 2001;27(7):662-667.
11. Lewandowski RJ, Salem R. Yttrium-90 radioembolization of hepatocellular carcinoma and metastatic disease to the liver. Semin Intervent Radiol. 2006;23(1):64-72.
12. Vente MA, Wondergem M, van der Tweel I, et al. Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis. Eur Radiol. 2009;19(4):951-959.
13. Abdelmaksoud MH, Louie JD, Hwang GL, Kothary N, Minor DR, Sze DY. Yttrium-90 radioembolization of renal cell carcinoma metastatic to the liver. J Vasc Interv Radiol. 2012;23(3):323-330.e321.
14. Bangash AK, Atassi B, Kaklamani V, et al. 90Y radioembolization of metastatic breast cancer to the liver: toxicity, imaging response, survival. J Vasc Interv Radiol. 2007;18(5):621-628.
15. 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(6):955-958.
16. Cianni R, Pelle G, Notarianni E, et al. Radioembolisation with (90)Y-labelled resin microspheres in the treatment of liver metastasis from breast cancer. Eur Radiol. 2013;23(1):182-189.
17. 17. Cianni R, Urigo C, Notarianni E, et al. Radioembolisation using yttrium 90 (Y-90) in patients affected by unresectable hepatic metastases. Radiol Med. 2010;115(4):619-633.
18. Coldwell DM, Kennedy AS, Nutting CW. Use of yttrium-90 microspheres in the treatment of unresectable hepatic metastases from breast cancer. Int J Radiat Oncol Biol Phys. 2007;69(3):800-804.
19. Gaba RC, Lakhoo J. Yttrium-90 microsphere radioembolization for treatment of lung cancer hepatic metastases. Case Rep Oncol. 2012;5(2):479-486.
20. Gonsalves CF, Eschelman DJ, Sullivan KL, et al. Radioembolization as salvage therapy for hepatic metastasis of uveal melanoma: a single-institution experience. AJR Am J Roentgenol. 2011;196(2):468-473.
21. Hamoui N, Gates VL, Gonzalez J, Lewandowski RJ, Salem R. Radioembolization of renal cell carcinoma using yttrium-90 microspheres. J Vasc Interv Radiol. 2013;24(2):298-300.
22. Jakobs TF, Hoffmann R-T, Fischer T, et al. Radioembolization in patients with hepatic metastases from breast cancer. J Vasc Interv Radiol. 2008;19(5):683-690.
23. Kennedy AS, Nutting C, Jakobs T, et al. A first report of radioembolization for hepatic metastases from ocular melanoma. Cancer Invest. 2009;27(6):682-690.
24. Lim L, Gibbs P, Yip D, et al. Prospective study of treatment with selective internal radiation therapy spheres in patients with unresectable primary or secondary hepatic malignancies. Intern Med J. 2005;35(4):222-227.
25. Memon K, Kuzel TM, Vouche M, et al. Hepatic yttrium-90 radioembolization for metastatic melanoma: a single-center experience. Melanoma Res. 2014;24(3):244-251.
26. 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(1):24-32.
27. Murthy R, Mutha P, Lee JH, Oh Y. Yttrium-90-labeled microsphere radioembolotherapy of liver-dominant metastases from thoracic malignancies. J Vasc Interv Radiol. 2008;19(2):299-300.
28. Pöpperl G, Helmberger T, Münzing W, Schmid R, Jacobs TF, Tatsch K. Selective internal radiation therapy with SIR-Spheres in patients with nonresectable liver tumors. Cancer Biother Radiopharm. 2005;20(2):200-208.
29. Reiner CS, Morsbach F, Sah B-R, et al. Early treatment response evaluation after yttrium-90 radioembolization of liver malignancy with CT perfusion. J Vasc Interv Radiol. 2014;25(5):747-759.
30. Saxena A, Kapoor J, Meteling B, Morris DL, Bester L. Yttrium-90 radioembolization for unresectable, chemoresistant breast cancer liver metastases: a large single-center experience of 40 patients. Ann Surg Oncol. 2014;21(4):1296-1303.
31. Seyal AR, Parekh K, Velichko YS, Salem R, Yaghmai V. Tumor growth kinetics versus RECIST to assess response to locoregional therapy in breast cancer liver metastases. Acad Radiol. 2014;21(8):950-957.
32. Xing M, Prajapati HJ, Dhanasekaran R, et al. Selective internal yttrium-90 radioembolization therapy (90Y-SIRT) versus best supportive care in patients with unresectable metastatic melanoma to the liver refractory to systemic therapy: safety and efficacy cohort study. Am J Clin Oncol. 2014.
33. Gordon AC, Gradishar WJ, Kaklamani VG, et al. Yttrium-90 radioembolization stops progression of targeted breast cancer liver metastases after failed chemotherapy. J Vasc Interv Radiol. 2014;25(10):1523-1532 e1522.
34. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
35. Purushotham A, Shamil E, Cariati M, et al. Age at diagnosis and distant metastasis in breast cancer--a surprising inverse relationship. Eur J Cancer. 2014;50(10):1697-1705.
36. Kato I, Severson RK, Schwartz AG. Conditional median survival of patients with advanced carcinoma: surveillance, epidemiology, and end results data. Cancer. 2001;92(8):2211-2219.
37. Porkka K, Blomqvist C, Rissanen P, Elomaa I, Pyrhönen S. Salvage therapies in women who fail to respond to first-line treatment with fluorouracil, epirubicin, and cyclophosphamide for advanced breast cancer. J Clin Oncol. 1994;12(8):1639-1647.
38. Adam R. Chemotherapy and surgery: new perspectives on the treatment of unresectable liver metastases. Ann Oncol. 2003;14:ii13-ii16.
39. Mariani P, Servois V, De Rycke Y, et al. Liver metastases from breast cancer: Surgical resection or not? A case-matched control study in highly selected patients. Eur J Surg Oncol. 2013;39(12):1377-1383.
40. Schneebaum S, Walker MJ, Young D, Farrar WB, Minton JP. The regional treatment of liver metastases from breast cancer. J Surg Oncol. 1994;55(1):26-31; discussion 32.
41. Kennedy AS, Coldwell D, Nutting C, et al. Resin 90Y-microsphere brachytherapy for unresectable colorectal liver metastases: modern USA experience. Int J Radiat Oncol Biol Phys. 2006;65(2):412-425.
42. Memon K, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for neuroendocrine liver metastases: safety, imaging, and long-term outcomes. Int J Radiat Oncol Biol Phys. 2012;83(3):887-894.
43. Boehm LM, Jayakrishnan TT, Miura JT, et al. Comparative effectiveness of hepatic artery based therapies for unresectable intrahepatic cholangiocarcinoma. J Surg Oncol. 2015;111(2):213-220.
44. Park J, Kim M-H, Kim KP, et al. Natural history and prognostic factors of advanced cholangiocarcinoma without surgery, chemotherapy, or radiotherapy: a large-scale observational study. Gut Liver. 2009;3(4):298-305.
45. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248(1):84-96.
46. Haug AR, Heinemann V, Bruns CJ, et al. 18F-FDG PET independently predicts survival in patients with cholangiocellular carcinoma treated with 90Y microspheres. Eur J Nucl Med Mol Imaging. 2011;38(6):1037-1045.
47. Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer. 2008;113(8):2119-2128.
48. Rafi S, Piduru SM, El-Rayes B, et al. Yttrium-90 radioembolization for unresectable standard-chemorefractory intrahepatic cholangiocarcinoma: survival, efficacy, and safety study. Cardiovasc Intervent Radiol. 2013;36(2):440-448.
49. Saxena A, Bester L, Chua TC, Chu FC, Morris DL. Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol. 2010;17(2):484-491.
50. Camacho JC, Kokabi N, Xing M, Prajapati HJ, El-Rayes B, Kim HS. Modified response evaluation criteria in solid tumors and European Association for The Study of the Liver criteria using delayed-phase imaging at an early time point predict survival in patients with unresectable intrahepatic cholangiocarcinoma following yttrium-90 radioembolization. J Vasc Interv Radiol. 2014;25(2):256-265.
51. Filippi L, Pelle G, Cianni R, Scopinaro F, Bagni O. Change in total lesion glycolysis and clinical outcome after (90)Y radioembolization in intrahepatic cholangiocarcinoma. Nucl Med Biol. 2015;42(1):59-64.
52. Mouli S, Memon K, Baker T, et al. Yttrium-90 radioembolization for intrahepatic cholangiocarcinoma: safety, response, and survival analysis. J Vasc Interv Radiol. 2013;24(8):1227-1234.
53. Bakalian S, Marshall J-C, Logan P, et al. Molecular pathways mediating liver metastasis in patients with uveal melanoma. Clin Cancer Res. 2008;14(4):951-956.
54. Balch CM, Soong SJ, Murad TM, Smith JW, Maddox WA, Durant JR. A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III). J Clin Oncol. 1983;1(2):126-134.
55. Burris HA 3rd, 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.
56. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27(33):5513-5518.
57. Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25(15):1960-1966.
58. Kitami CE, Kurosaki I, Koyama Y, Makino H, Hatakeyama K. Long-term survival after hepatectomy for hepatic recurrence of carcinoma of the papilla of Vater. J Hepatobiliary Pancreat Surg. 2005;12(4):321-323.
59. Ko K, Fujioka S, Kato K, et al. Resection of liver metastasis after a pancreatoduodenectomy for pancreatic cancer: a case report. Hepatogastroenterology. 2001;48(38):375-377.
60. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol. 1999;17(8):2530-2540.