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[8]
Pharmacokinetic analysis revealed that there was no to the phase I trial reported by Pingpank et al. The tumor
degradation of melphalan during the 30 min infusion and rapid response included 1 CR seen in the cholangiocarcinoma
intrahepatic clearance occurred within 10 min of completing patient, and 6 PRs (ocular melanoma: n = 3, cutaneous
the infusion. No renal, cardiac, or pulmonary complications melanoma: n = 3). Stable disease was observed in
were observed in patients after treatment with melphalan 5 patients (ocular melanoma: n = 3, breast cancer
in PHP. The treatment course for this study was planned and gastric cancer). Toxicity was similar to that
approximately every 4 to 6 weeks for a total of 4 treatments, seen in previous series including melphalan-related
and patients were required to recover from the previous thrombocytopenia, anemia and pancytopenia. In this
treatment toxicity to grade II or less prior to embarking on the series, second generation filters were used in a select
next perfusion. The investigators evaluated responses in the number of patients. These filters are reported to have
27 evaluable patients using standard RECIST criteria. Reported increased melphalan extraction efficiency. In the
[15]
antitumor activity included minor responses (n = 10), partial portion of patients treated with the second generation
responses (PR) (n = 6) and complete responses (CR) (n = 2). filters, the toxicity was found to be milder and patients
At the time of the trial’s publication the duration of responses experienced a faster recovery. Similar to other groups
[14]
included 2 PRs ongoing for 9 and 11 months and 2 CRs at 10 with experience in PHP, Vogl et al. concluded that PHP
[14]
and 12 months. The overall radiographic objective response for non-resectable liver metastasis is a feasible treatment.
rate was found to be 30%, and impressively in a subgroup of
patients with ocular melanoma the overall objective response Phase III multicenter trial
rate was found to be 50%. The authors concluded that PHP, These single-center phase I and II studies established the
as a regional treatment of hepatic metastasis, can be safely framework for a multicenter phase III trial with melphalan
[16]
performed with predictable and manageable toxicity. in 2005. Hughes et al. published results of the phase III,
multicenter randomized trial comparing PHP with melphalan
Moffitt cancer center experience (PHP-Mel) to best alternative care (BAC) for patients with
Another trial described by Forster et al. retrospectively cutaneous or ocular melanoma metastatic to the liver. The
[13]
reviewed patients treated with PHP at their single institution trial accrued 93 patients between February 2006 and July
over a 7 years period. The patients included those with 2009. Those enrolled were randomized to PHP-Mel (n = 44)
unresectable melanoma or sarcoma hepatic metastases. or BAC (n = 49). Primary BAC treatment included systemic
Between 2008 and 2013, 10 patients were treated - a total chemotherapy, chemoembolization, radioembolization,
of 27 PHP treatments were administered with the median immunoembolization and supportive care. The trial design
number of treatments reported at 3 per patient. Nine of 10 allowed for crossover to PHP-Mel for patients who experienced
(90%) patients treated had stable disease (SD) or a PR, with a hepatic progression in the BAC arm, provided they still met
median partial response of a 33% decrease in tumor burden enrollment criteria. The percutaneous procedure involved
from baseline. The median follow up for the evaluation was delivery of high dose melphalan directly to the liver via the
[13]
11.5 months in which the hepatic progression free survival hepatic artery over 30 min. The initial dose of melphalan
(hPFS) was 240 days. At last 60% of the patients treated at administered was 3.0 mg/kg based on ideal body weight.
the institution died from their disease. The median overall If a dose-limiting toxicity was encountered, the melphalan
survival from time of diagnosis of hepatic metastases was dose was decreased to 2.5 mg/kg in subsequent PHPs. Those
12.6 months and from time of first PHP was 8.7 months. randomized to PHP-Mel received treatment every 4-8 weeks
They also reported a median postoperative hospital stay when hematologic toxicity resolved to a grade 2 or less.
of 3 days following PHP. The most common adverse event Patients were eligible to receive up to 6 PHP procedures in
was myelosuppression which was treated on an outpatient the absence of progressive disease. [9]
basis. Seven of the patients in the cohort experienced a
[16]
mild elevation in their serum troponin levels with the 1 The primary endpoint reported by Hughes et al. includes
patient having a value greater than 1.0 ng/mL. There was hPFS, with secondary endpoints including xPFS (date of
no electrocardiography or echocardiographic evidence of randomization to the first observation of extrahepatic
myocardial ischemia, dyskinesia or dysfunction. The authors disease progression or death due to any cause), hepatic
concluded from these results that for select patients with objective response (hOR), objective response rate (ORR),
unresectable melanoma or sarcoma hepatic metastases, PHP overall progression-free survival (oPFS), overall survival (OS),
is a safe and promising management option. [13] and safety. The results of the trial include a median hPFS in
PHP-Mel of 7 months compared to 1.6 months in BAC. The
European experience median oPFS was 5.4 months and 1.6 months in PHP-Mel
Vogl et al. reported a European experience of patients and BAC, respectively. The hOR for PHP-Mel was noted to be
[14]
with hepatic metastases treated with PHP using 36.4% with a SD rate of 52.3%; hepatic disease control was
melphalan. Fourteen patients were treated between observed in 75% of patients. The authors report a significant
January 2012 and February 2013 at 2 centers with the improvement in response favoring PHP-Mel patients including
following histologies: ocular or cutaneous melanoma, an ORR of 27.3% (median duration 6.3 months) in the PHP-Mel
breast cancer, gastric cancer, and cholangiocarcinoma. group compared to 4.1% (median duration 3.7 months) in
These patients received 3.0 mg/kg of melphalan similar those who received BAC. There was no significant difference
Hepatoma Research | Volume 2 | July 13, 2016 201