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in OS observed between the 2 groups - the median OS of 10.6 possibilities and results. Eur J Cancer 2002;38:1023-33.
months observed in PHP-Mel vs. 10.0 months in BAC was due 2. Reddy SK, Kesmodel SB, Alexander HR Jr. Isolated hepatic perfusion
to the built in crossover design. for patients with liver metastases. Ther Adv Med Oncol 2014;6:180-94.
[16]
3. Alexander HR Jr, Butler CC. Development of isolated hepatic perfusion
via the operative and percutaneous techniques for patients with isolated
Hughes et al. described immediate peri-procedural events and unresectable liver metastases. Cancer J 2010;16:132-41.
[16]
(within 72 h) observed in 90% of PHP-Mel treated patients to 4. Magge D, Choudry HA, Zeh HJ 3rd, Cunningham DE, Steel J, Holtzman
include mostly self-limited thrombocytopenia and anemia. MP, Jones HL, Pingpank JF, Bartlett DL, Zureikat AH. Outcome analysis
These events were attributed to platelet sequestration in of a decade-long experience of isolated hepatic perfusion for unresectable
the filters and/or hemodilution. The delayed post-procedural liver metastases at a single institution. Ann Surg 2014;259:953-9.
events, defined as occurring between 3 to 20 days after 5. Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ. High-dose
the melphalan exposure or until the next treatment cycle, recombinant tumor necrosis factor alpha in combination with interferon
were thought to be hematologic due to imperfect filtration. gamma and melphalan in isolation perfusion of the limbs for melanoma
Neutropenia, thrombocytopenia and anemia were observed 6. and sarcoma. J Clin Oncol 1992;10:52-60.
Ravikumar TS, Pizzorno G, Bodden W, Marsh J, Strair R, Pollack J,
in most PHP-Mel patients and thought to be related to the Hendler R, Hanna J, D’Andrea E. Percutaneous hepatic vein isolation
effects of bone marrow suppression. Hyperbilirubinemia was and high-dose hepatic arterial infusion chemotherapy for unresectable
observed in 10 patients. Some fatalities were observed on liver tumors. J Clin Oncol 1994;12:2723-36.
this trial and each death lead to further safety maneuvers in 7. Curley SA, Newman RA, Dougherty TB, Fuhrman GM, Stone DL,
the development of improved filters. [15,16] Mikolajek JA, Guercio S, Guercio A, Carrasco CH, Kuo MT, Hohn DC.
Complete hepatic venous isolation and extracorporeal chemofiltration as
The authors concluded that the results of their phase III treatment for human hepatocellular carcinoma: a phase I study. Ann Surg
study demonstrate the efficacy of PHP-Mel. They report 8. Oncol 1994;1:389-99.
Pingpank JF, Libutti SK, Chang R, Wood BJ, Neeman Z, Kam AW, Figg
that the toxicity is significant but manageable in order to WD, Zhai S, Beresneva T, Seidel GD, Alexander HR. Phase I study of
provide effective therapy for this select cohort of patients. hepatic arterial melphalan infusion and hepatic venous hemofiltration
Overall, given the improved hepatic PFS, oPFS, and using percutaneously placed catheters in patients with unresectable
hOR, Hughes et al. conclude that PHP with melphalan hepatic malignancies. J Clin Oncol 2005;23:3465-74.
[16]
should provide a new treatment strategy for patients with 9. Pingpank JF, Hughes MS, Alexander HR, Faries MB, Zager JS, Royal
unresectable metastatic melanoma to the liver. R, Whitman ED, Nutting CW, Siskin GP, Agarwala SS. A phase III
random assignment trial comparing percutaneous hepatic perfusion
CONCLUSION with melphalan (PHP-mel) to standard of care for patients with hepatic
metastases from metastatic ocular or cutaneous melanoma. J Clin Oncol
2010;28 suppl:LBA8512.
PHP has been shown to be an innovative and promising 10. Minor DR, Allen RE, Alberts D, Peng YM, Tardelli G, Hutchinson J. A
technique for delivering regional chemotherapy to the liver. clinical and pharmacokinetic study of isolated limb perfusion with heat
The evaluation of its use for different tumor histologies, has and melphalan for melanoma. Cancer 1985;55:2638-44.
been, and continues to be studied in numerous trials. PHP 11. Parsons PG, Carter FB, Morrison L, Regius Mary Sister. Mechanism
has significant potential for the control of tumor burden in of melphalan resistance developed in vitro in human melanoma cells.
metastatic melanoma, particularly for ocular melanoma, Cancer Res 1981;41:1525-34.
which seems to be less responsive to checkpoint inhibition 12. Miao N, Pingpank JF, Alexander HR, Steinberg SM, Beresneva T,
Quezado ZM. Percutaneous hepatic perfusion in patients with metastatic
and other immunotherapies in comparison to cutaneous liver cancer: anesthetic, hemodynamic, and metabolic considerations.
melanoma. The advantage of PHP lies in the ability to Ann Surg Oncol 2008;15:815-23.
[17]
administer multiple therapies using a less invasive approach, 13. Forster MR, Rashid OM, Perez MC, Choi J, Chaudhry T, Zager JS.
in contrast to the laparotomy required for a single therapy Chemosaturation with percutaneous hepatic perfusion for unresectable
with IHP. Currently, PHP in the United States is only available metastatic melanoma or sarcoma to the liver: a single institution
on study or compassionate use, however it does have the experience. J Surg Oncol 2014;109:434-9.
European mark and is being aggressively evaluated in seven 14. Vogl TJ, Zangos S, Scholtz JE, Schmitt F, Paetzold S, Trojan J, Orsi
F, Lotz G, Ferrucci P. Chemosaturation with percutaneous hepatic
different European countries. In the current landscape of perfusions of melphalan for hepatic metastases: experience from two
[14]
liver directed therapy, PHP is a viable option for those with European centers. Rofo 2014;186:937-44.
unresectable metastatic disease to the liver. 15. Moeslein FM, McAndrew EG, Appling WM, Hryniewich NE, Jarvis
KD, Markos SM, Sheets TP, Uzgare RP, Johnston DS. Evaluation of
Financial support and sponsorship Delcath Systems’ Generation 2 (GEN 2) melphalan hemofiltration
This research was supported by the NIH grant: NCI 04-C-0273 system in a porcine model of percutaneous hepatic perfusion. Cardiovasc
(http://grantome.com/grant/NIH/ZIA-BC011012-06). Intervent Radiol 2014;37:763-9.
16. Hughes MS, Zager J, Faries M, Alexander HR, Royal RE, Wood B, Choi
Conflicts of interest J, McCluskey K, Whitman E, Agarwala S, Siskin G, Nutting C, Toomey
MA, Webb C, Beresnev T, Pingpank JF. Results of a randomized
There are no conflicts of interest. controlled multicenter phase III trial of percutaneous hepatic perfusion
compared with best available care for patients with melanoma liver
REFERENCES metastases. Ann Surg Oncol 2016;23:1309-19.
17. Niederkorn JY. Immune escape mechanisms of intraocular tumors. Prog
1. Ruers T, Bleichrodt RP. Treatment of liver metastases, an update on the Retin Eye Res 2009;28:329-47.

202 Hepatoma Research | Volume 2 | July 13, 2016