Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors

Abstract

Background

Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT^® delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany.

Methods

Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan–Meier estimation.

Results

29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135 days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema.

Conclusion

Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS-PHP.

Electronic supplementary material

The online version of this article (doi:10.1007/s00432-017-2461-z) contains supplementary material, which is available to authorized users.

Introduction

Hepatocellular and cholangiocarcinoma (HCC/CCA) are primary liver tumors with dismal survival rates (Peixoto et al. 2015; Norstein and Silen 1997; de Ridder et al. 2016). Additionally, the liver is the dominant site of metastatic disease for a wide variety of tumor types including colorectal carcinoma (CRC) or adenocarcinoma of the pancreas (PCA) (Peixoto et al. 2015; Norstein and Silen 1997). Hepatic metastases also occur in a subgroup of patients with cutaneous or ocular melanoma (OM), breast and ovarian cancer among others (de Ridder et al. 2016; Egan et al. 1988; Ye et al. 2015; BacalbaSa et al. 2015) and can be life-limiting (Hughes et al. 2016).

Several types of treatment approaches are pursued in patients with primary or secondary liver tumors in order to control disease and to extend survival (Pearson et al. 1999; Braat et al. 2016; Habib et al. 2015). Among those, the Hepatic CHEMOSAT^® Delivery System (Delcath Systems Inc., New York, NY, USA) is an innovative medical device for the treatment of patients with unresectable primary or secondary liver tumors. This system is used to perform chemosaturation percutaneous hepatic perfusion (CS-PHP), in which a high dose of the chemotherapeutic agent melphalan is delivered directly to the liver while limiting systemic exposure.

The efficacy of CS-PHP has recently been demonstrated in a randomized phase 3 trial in patients with hepatic metastases of OM and cutaneous melanoma. CS-PHP significantly prolonged median overall and hepatic progression-free survival (PFS and hPFS) and hepatic objective response as compared to best alternative treatment (BAC) (Hughes et al. 2016). Within a phase 1 trial, six partial and two complete responses were observed in patients with solid tumors including hepatobiliary cancer after treatment with CS-PHP (Pingpank et al. 2005).

Since 2012, an improved second-generation filter is available with increased filtration efficacy. Results from prospective, randomized-controlled trials including the second-generation filter are pending, though.

In this study, we retrospectively analyzed the safety and efficacy of 54 CS-PHPs performed at Hannover Medical School, Germany, using the Generation 2 Hepatic CHEMOSAT^® Delivery System in patients with primary and secondary hepatic tumors as last-line treatment.

Patients and methods

Patient selection and data acquisition

In all patients, CS-PHP was regarded as the most appropriate therapy after discussion within a multidisciplinary local tumor board including the exclusion of standard treatment options including systemic and loco-regional treatments. Criteria for a CS-PHP were adequate hematologic, renal, and hepatic function [hemoglobin >8 g/dL; leukocyte count >2 thsd/μL; platelets >50 thsd/μL, serum creatinine >60 µmol/L, bilirubin ≤3× upper limit of normal (ULN), maximum Child-Pugh A]. Patients were not treated if they had a history of transient ischemic attacks, heart failure with a left ventricular ejection fraction <40% or significant chronic obstructive or restrictive pulmonary disorder.

Patient data were retrospectively evaluated for baseline characteristics and therapies using clinical, imaging, and laboratory reports. Toxicity was assessed according to the common terminology criteria for adverse events (CTCAEv4.03). Overall survival (OS) was analyzed from first diagnosis and first CS-PHP until last follow-up or death. PFS was analyzed from first CS-PHP until first radiological progression according to response evaluation criteria in solid tumors 1.1 (RECIST1.1), either hepatic and/or extra-hepatic, until last follow-up or death, whichever occurred first. Hepatic PFS (PFSh) was analyzed from first CS-PHP until first radiological hepatic progression, last follow-up or death, whichever occurred first. Information about deaths was obtained from registration offices. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the appropriate institutional review ethics committee from Hannover Medical School, Germany. Informed consent was not obtained due to the retrospective design of the study.

Procedures

Imaging—either computed tomography (CT) or magnetic resonance imaging (MRI) with slice thickness from 1 to 5 mm—was performed on an average of 8 weeks after CS-PHP. Contraindications for re-treatment were progressive disease (PD) as assessed by RECIST1.1 or intolerance to the procedure. The Hepatic CHEMOSAT^® Delivery System was used to conduct CS-PHP in general anesthesia in an interventional radiology suite. The procedure was performed according to the company’s recommendations (Brochure Chemosaturation, Delcath Systems Inc., New York, NY, USA).

Statistical analysis

Statistical analyses were performed using SPSS 24.0 (SPSS Inc., Chicago, IL, USA). Continuous, related data of multiple (more than two) groups were tested for significant differences using the Friedman test. In case of significance, a pairwise testing was performed using the Wilcoxon signed-rank test. Correlation coefficients between two continuous variables were calculated using the two-sided Spearman`s test. Differences between categorical variables were calculated using Pearson’s Chi squared test. Survival was assessed using the Kaplan–Meier estimation. Change of survival rates in dependence of the tumor volume was calculated using cox regression’s survival function and regression coefficients. A probability (p) value less than 0.05 was considered significant.

Results

Patient characteristics

29 patients were treated with CS-PHP from October 2014 until June 2016 at Hannover Medical School. Five patients (17.2%) with CCA and five patients with HCC (17.2%) were included. Four of the patients had intrahepatic CCA and one patient had gallbladder carcinoma with hepatic metastases (all summarized as CCA). Patients with secondary liver tumors included patients with OM (n = 11; 37.9%), CRC (n = 2; 6.9%), PCA and periampular carcinoma (PAC; each n = 2; 6.9%) and breast and endometrial cancer (each n = 1; 3.4%). Three patients had extra-hepatic tumor manifestations (breast cancer and OM with bone metastases and one CCA with pulmonary metastases). The patient with OM had a metastasis in the femur, which had been irradiated before CS-PHP. In the two other patients, definite diagnosis of extra-hepatic manifestations was made not until the follow-up scans.

54 CS-PHPs were performed in total with a maximum of five procedures in one patient. Median time between first diagnosis and first CS-PHP was 27 (ICR 12.5–52) months indicating that CS-PHP was performed in a salvage setting following use of standard therapies (supplemental Table 1). Median time between first procedure and first imaging control was 56 (39–73.75) days and median time between first and second procedure was 70 (46–101.5) days.

Response assessment

26 patients were available for response assessment. One patient with OM died due to sepsis shortly after the first CS-PHP, another patient with OM died due to rapid tumor progression before imaging could be performed, and one patient with PCA was lost to follow-up after the first CS-PHP.

The overall response rate (ORR) was 19.2%. Three of the responders were patients with OM (33.3% of all patients with OM). One of these patients had a PR after the second CS-PHP following initial SD. One responder had hepatic metastases of CRC and one responder had hepatic metastases of PAC. There were no responders among patients with primary liver tumors. One patient with HCC, however, had a significant radiological hepatic (−36% of baseline target lesions) and a biochemical response [alpha-fetoprotein (AFP) decrease from 103293 to 5676 µg/L], but developed lung metastases at the same time.

16 patients had stable disease after first CS-PHP (55.2%). Two patients with CCA have an ongoing SD for 454 and 372 days, respectively. First response assessment after the initial procedure is represented in Fig. 1a. Percentual changes of target lesions and progression of non-target lesions are represented in Fig. 1b.

Fig. 1.

Response assessment. a Waterfall plot of baseline target lesions after first CS-PHP (maximum percentage change in baseline target lesions) with an overall response assessment including non-target lesions as indicated above the bars. Dashed lines are thresholds for progressive disease (PD) and partial response (PR). SD stable disease. b Spider plot showing changes from baseline target lesions. White circles indicate PD of non-target lesions

Survival

Median OS was 66 months from first diagnosis and 8 months (261 days) from first CS-PHP (n = 29). Median PFS was 117 days, whereas hPFS was 135 days (n = 29). Survival times from first CS-PHP until last follow-up or death including time to response, time to hepatic and extra-hepatic progression, and intervals between procedures are represented in Fig. 2a. Two patients with CCA and one patient with OM had the longest survival with 566, 465, and 477 days. CT follow-up of a patient with OM showing a PR is represented in Fig. 2b.

Fig. 2.

Survival and response assessment. a Survival times since first CS-PHP until last follow-up or death including time to response, to first hepatic and extra-hepatic progression and intervals between procedures subdivided by tumour entity. b 47-year-old female patient with hepatic metastasis of ocular melanoma. CT before CS-PHP showing intrahepatic metastasis of ocular melanoma and CT follow-up after 1st–4th treatment (from left to right) showing tumour shrinking

In total, ten patients are still on treatment and are being evaluated for further CS-PHS. Two patients with CCA, five patients with OM, two patients with HCC, and one patient with CRC are still on treatment. Among responders, one is still on treatment, another one has developed extra-hepatic PD and three of the five patients with a response have died. 6 out of 12 patients with a PD developed extra-hepatic PD (50%) with stable disease in the liver.

Median tumor volume was 10.9% (3.2–32.5%) prior first CS-PHP. Tumor volume was negatively correlated with OS [correlation index (CI) = −0.44; p < 0.05], PFS (CI = −3.33; p = 0.081) (Fig. 3a, b) and hPFS (CI = −3.34; p = 0.073). The 100-days OS and PFS rates significantly decreased with increase of tumor volume (Fig. 3c, d). Using binary logistic regression, baseline tumor volume (>10.9%) was no predictor of achieving a response [odds ratio (OR) 1.2; p = ns) (Fig. 3a, b). One patient with a high tumor volume (72.9%) died 3 days after CH-PHP. Liver enzymes (>20xULN), LDH (>20xULN) were massively elevated, indicative of a combination of liver failure due to tumor progression und tumor lysis syndrome.

Fig. 3.

Correlation of tumour volume with survival times. Correlation of overall (a) and progression-free survival times (b) from 1st CS-PHP and responses (marked as black diamonds). Change of overall (c) and progression-free survival (d) rates at day 100 in dependence of tumor volume. CI correlation index

Toxicity

Median time of hospitalization after the first CS-PHP was 8 (6.5–14) days. There was a significant deterioration of hematologic function as assessed by platelet, leukocyte count and hemoglobin, but myelosuppression was transient and recovered within 21 days after the procedure (p < 0.001; Fig. 4a, b; suppl. Figure 1a). The overall rate of grade 3/4 thrombocytopenia, anemia and leukopenia was 89.7, 41.3, and 34.5%, respectively (Table 1).

Fig. 4.

Laboratory values from day 0 of CS-PHO until day 21. Assessment of hematologic function by platelet and leukocyte count (a, b), hepatic function by bilirubin and albumin (c, d) and liver injury by AST and ALT (e, f). Pairwise analyses were performed using the Wilcoxon signed-rank test. ***p<0.001; **p < 0.01; *p < 0.05

Table 1.

Adverse events as assessed by CTCAE v4.03 after first and after overall CS-PHS

	After 1st CS-PHP		Overall
	n	%	n	%
Total	29	100	29	100
Fever (>38.5 °C)	3	10.3	6	20.7
Antibiotics	16	55.2	18	62.1
G-CSF	10	34.5	11	37.9
Platelet concentrate	10	34.5	11	37.9
Erythrocyte concentrate	9	31	12	41.4
Grade 3 thrombopenia	9	31.0	16	55.2
Grade 4 thrombopenia	5	17.2	10	34.5
Grade 3 anemia	7	24.1	11	37.9
Grade 4 anemia	0	0	1	3.4
Grade 3 leukopenia	3	10.3	4	13.8
Grade 4 leukopenia	4	13.8	6	20.7
Grade 3 AST increase	6	20.7	8	27.6
Grade 4 AST increase	4	13.8	4	13.8
Grade 3 ALT increase	3	10.3	3	10.3
Grade 4 ALT increase	1	3.4	2	6.9
Grade 3 hyperbilirubinemia	3	10.3	5	17.2
Grade 4 hyperbilirubinemia	0	0	0	0

There was a significant, but transient, increase of c-reactive protein (CRP) as marker of inflammation (p < 0.001, suppl. figure  1b). In respect to liver toxicity, there was a significant increase of aminotransferases as markers of hepatic injury [p < 0.001 for aspartate transaminase (AST); p < 0.05 for alanine transaminase (ALT); Fig. 4e, f]. 41.4, 17.2, and 17.2% of patients developed grade 3/4 AST and ALT elevation and hyperbilirubinemia, respectively (Table 1).

Intra- and postinterventional complications

There was one case of dissection of the common hepatic artery caused by the guide wire, which was treated by prolonged angioplasty. One patient developed a pseudoaneurysm at the puncture site (left common femoral artery) after removal of the sheath following the procedure and had to be treated by open surgery. This patient received three more CS-PHPs with arterial access through the contralateral common femoral artery.

Cardiac complications included ST-segment elevation in electrocardiogram (ECG) in one patient with coronary heart disease during the filtration phase under high doses of catecholamines, which was completely normalized after the procedure. Another patient developed a total atrioventricular block, which was successfully cardioverted by a precordial thump.

Ulcerous bleedings occurred in two patients following PHP (Forrest III). In one of them, the ulcer was refractory to endoscopic and medical treatments with chronic bleeding and was finally treated with surgery. Generalized edema, ascites, and/or pleural effusion due to overhydration and/or hypoalbuminemia occurred in four patients and were treated with diuretics and paracentesis.

One patient with CCA developed a hemiparesis one day after the fifth procedure. Cerebral MRI revealed a vascular, ischemic insult within the left sided precentral cortex most likely due to a thromboembolic event. Intracranial vessels were not occluded, but microangiopathic alterations were found periventricular and subcortical. Doppler ultrasound revealed normal cervical vessels. A persistent foramen ovale was excluded with transthoracic echocardiography, which revealed a slightly impaired left ventricular function with an ejection fraction of 53%. 24-h ECG showed consistent sinus rhythm. Lysis was not performed in view of the mild symptoms, which improved spontaneously within hours. Subsequently, the patient received physiotherapy and logopedics and all symptoms have completely resolved.

Discussion

CS-PHP is a novel technique, which delivers high doses of chemotherapy directly to liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. In this study, we retrospectively analyzed the safety and efficacy of 54 treatments with CS-PHP performed at Hannover Medical School using the novel, second-generation filter of the CHEMOSAT^® Delivery System. Our data provide evidence that second-generation CS-PHP has manageable toxicity and is effective treatment option for selected patients with primary and secondary liver tumors in the salvage setting.

CS-PHP has previously been studied in various cancer types and is currently most widely used in patients with OM (Hughes et al. 2016; Pingpank et al. 2005). The second-generation hemofiltration system was introduced in the EU and was CE Marked in 2012. So far, no results from prospective trials using the second-generation hemofiltration system have been reported. Prospective, randomized controlled trials for patients with OM (ClinicalTrials.gov Identifier: NCT0268572) and hepatobiliary cancer [ClinicalTrials.gov Identifier: NCT02406508 (US)/ClinicalTrials.gov Identifier: NCT02415036 (EU)] are currently recruiting patients.

The majority of our patients were patients with OM (37.9%). Patients with OM represent particularly eligible candidates for CS-PHP as several patients with OM exclusively develop hepatic metastases, which are highly sensitive to melphalan (Feldman et al. 2004; Jovanovic et al. 2013). Patients with hepatobiliary cancers represented the second largest subgroup in our cohort (34.5%). There is currently little evidence whether CS-PHP could be used in patients with liver metastases from other solid malignancies than OM (Alexander et al. 2005; van Iersel et al. 2008; Alexander et al. 2009; Feldman et al. 2004; Grover et al. 2004).

Patients with hepatobiliary tumors are frequently diagnosed at locally advanced stages, but are often no candidates for curative treatments such as surgery due to tumor burden and/or impaired liver function (Kirstein et al. 2017a; Blechacz and Gores 2008). In the palliative setting, the intent of therapy is to extend life, and to maintain and improve quality of life. Systemic treatment options for patients with hepatobiliary cancers are very limited emphasizing the high medical need to develop novel innovative therapies for these patients (Llovet et al. 2008; Valle et al. 2014; Lamarca et al. 2014). Currently, several local therapies such as radiofrequency ablation, high-dose-rate brachytherapy, as well as transarterial approaches such as hepatic arterial infusion chemotherapy, transarterial chemoembolization and ⁹⁰Yttrium radioembolization are increasingly used. Most of them have been shown to be well tolerated and may contribute to tumor control in the context of a comprehensive oncologic treatment strategy (Kirstein et al. 2017b). However, only few prospective trials have elucidated the precise value of these local treatments alone or in combination with systemic chemotherapy.

In our cohort, ORR was 19.2%. Most of the responders were patients with OM (ORR for OM 33.3%) and disease control was achieved in 77.8% of the patients with OM after the first CS-PHP. Median hPFS and PFS were 135 and 117 days (3.9 months), respectively. In agreement with our data, a recent phase 3 study has shown improved control of liver disease in patients with melanoma treated with CS-PHP compared with BAC (Hughes et al. 2016). Importantly, this benefit extended to overall PFS, although the treatment was limited to the liver. The high crossover of BAC patients to CS-PHP confounded the ability to analyze any survival advantage in this trial.

There is so far only very limited experience with CS-PHP in patients with hepatobiliary tumors. Patients with hepatobiliary cancers have been included in the phase 1 trial of CS-PHP and in a retrospective multi-center study (Pingpank et al. 2005; Vogl et al. 2014). In our study, patients with hepatobiliary tumors were characterized by a long-lasting tumor stabilization. The overall SD rate was 40% and all patients with SD are still on treatment. In addition, no patient with CCA and only two patients with HCC developed hepatic PD. There were no radiological responders, but one patient with HCC had a hepatic and biochemical response.

In our study, tumor volume negatively correlated with survival suggesting that specifically patients with low tumor volume should be considered for CS-PHP. One OM patient with a high tumor volume of more than 70% died only 3 days after CS-PHP due to a combination of liver failure and tumor lysis syndrome. Accordingly, inclusion criteria of the phase 3 melanoma trial were amended to include only patients with a hepatic tumor volume of less than 50% after one patient with high tumor volume had died following the procedure. A maximum tumor volume of 50% is used as a cut-off value for inclusion in the currently recruiting trials [ClinicalTrials.gov Identifier: NCT02406508 (US); ClinicalTrials.gov Identifier: NCT02415036 (EU); ClinicalTrials.gov Identifier: NCT02678572].

Toxicity associated with therapy was significant but manageable and transient in our study. Hematotoxicity and in particular thrombocytopenia was most prevalent. In agreement with our findings, manageable grade 3 and 4 neutropenia and thrombocytopenia were also observed in the majority of patients in phase 3 melanoma trial. Due to the expected bone marrow-related toxicities, the use of prophylactic bone marrow growth factors and close monitoring of laboratory values have been recommended after treatment. Moreover, dose reduction of melphalan can be used to prevent the melphalan-induced bone marrow suppression, which becomes typically clinical evident between day 7 and 14. The initial and immediate decrease of platelets and proteins such as albumin is most likely a side effect of the filtration system and is not related to the chemotherapy (Moeslein et al. 2014).

Hepatic injury and dysfunction, which manifested as transient increase of transaminases and bilirubin, was frequently seen following CS-PHP. This may be of relevance in patients with hepatobiliary tumors due to their underlying chronic liver disease. In our study, only patients with well-controlled Child-Pugh A liver cirrhosis were included. Despite the transient increase of liver enzymes, we did not observe a long-term deterioration of liver function in patients with chronic liver diseases after CS-PHP.

Some clinically relevant peri- and post-interventional complications occurred including cardiovascular events with cerebral ischemia in one case and gastroduodenal ulcer in two patients (one refractory to conventional therapy). Similar to our observations, few cases with gastroduodenal ulcer, cerebral ischemia and cardiac toxicity including myocardial infarction and arrhythmias have been reported in the phase 3 melanoma trial.

One patient died following CS-PHP due to hepatic failure in combination with tumor lysis syndrome. Within the phase 3 melanoma trial, four deaths were attributed to PHP—one death occurred due to hepatic failure, two deaths due to complications of myelosuppression (sepsis and neutropenia), and one patient died from gastric perforation—indicating that careful patient selection and close follow-up monitoring needs to be applied.

It is important to note that toxicities and complications may be underestimated due to the retrospective nature of this study. Our results stress the complexity of the procedures, which should be performed with utmost caution by interventional radiologists and anesthesiologists with great expertise. The limitations of our study are its retrospective nature with a lack of a control group, low number of patients, and small subgroups. Nevertheless, our data on safety and efficacy of CS-PHP in patients with liver dominant tumors support the rationale to pursue prospective clinical trials specifically in patients with OM and hepatobiliary cancers.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Abbreviations

AFP

Alpha-fetoprotein

ALT

Alanine transaminase

AST

Aspartate transaminase

BAC

Best alternative treatment

CCA

CHOLANGIOCARCINOMA

CI

Correlation index

CRC

Colorectal carcinoma

CRP

c-Reactive protein

CTCAE

Common Terminology Criteria for adverse Events

CS-PHP

Chemosaturation percutaneous hepatic perfusion

CT

Computed tomography

ECG

Electrocardiogram

ECOG

Eastern Cooperative Oncology Group

HCC

Hepatocellular carcinom

OM

Occular melanoma

ORR

Overall response rate

PR

Partial response

PD

Progressive disease

PS

Performance status

RECIST

Response Evaluation Criteria In Solid Tumours

SD

Stable disease

ULN

Upper limit of normal

Compliance with ethical standards

Financial support

Martha M. Kirstein was supported by the Ellen Schmidt program from Hannover Medical School.

Conflict of interest

Arndt Vogel and Steffen Marquardt have received honoraria from Delcath Systems Inc for AdVisiory Boards and speakers activities. Frank Wacker reports grants and personal fees from Delcath Systems, Inc. during the conduct of the study; grants from Siemens Healthineers, Promedicus Ltd., personal fees from Novartis Pharma GmbH, outside the submitted work.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was not obtained from all patients included in the study due to the retrospective nature of this study in accordance with the institutional research committee.