1. Kathryn Chapman University Hospital Southampton NHS Foundation Trust
PERCUTANIOUS HEPATIC PERFUSION: A REVIEW OF THE CHEMOSAT® DELIVERY SYSTEM
Kathryn Chapman
University Hospital Southampton NHS Foundation Trust
13/11/2018
Kathryn Chapman

2. BACKGROUND
Patients diagnosed with Ocular Melanoma have a 95% chance of the cancer metastasising to the Liver.
Metastasis will occur within 2-10 years of primary diagnosis.
Initial treatment for Ocular Melanoma is well established and will control the primary tumour, controlling liver metastasis can be daunting.
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Kathryn Chapman

3. METASTASES
Once hepatic metastases develops, the disease typically behaves in a very aggressive fashion
Conventional methods to treat hepatic metastases include surgery and ablation.
Without further intervention, death will result within 2-7 months.
UHS is tertiary referral centres where high risk UM patients are referred to after primary tumour resection
In the absence of effective methods of local disease control – such as surgery, ablation or Melphalan-Percutaneous Hepatic Perfusion (M-PHP) -results in death in almost all cases ( Margo, 2004) with median overall survival (OS) duration of 2-7 months and only 10-15% of patients will survive the year (Sileno, et al., 2017; Kath, et al., 1993; Rajpal, et al., 1983). Therefore it is essential to control hepatic metastases to extend patient survival.
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Kathryn Chapman

4. CHEMOSAT® DELIVERY SYSTEM
In the absence of established treatments known to significantly improve outcomes for patients with unresectable metastatic UM, the focus has shifted into utilising liver directed therapies.
The Hepatic CHEMOSAT® Delivery System is a medical device designed to administer high dose Melphalan Hydrochloride to the liver percutaneously.
Filters-talk about filters
The diagram shows the complete set up of the CHEMOSAT® Delivery System at UHS. The figure shows the double balloon catheter where the retrohepatic IVC becomes isolated allowing the return of the Melphalan infused blood to the circuit via the fenestrated catheter. The circuit then shows the double catheter line into the circuit where the centrifugal head and the priming lines meet. The flow probe leads up to a junction where blood can either flow through the bypass line or into the chemofiltration cartridges. After this point, the return line to the patient including an arterial line filter to return the filtered blood during M-PHP back through the venous return sheath into the IJV. The introducer sheath shows the infusion catheter which is connected up to the drug delivery system
13/11/2018
Kathryn Chapman

5. AUDIT AT UNIVERSITY HOSPITAL SOUTHAMPTON
The audit focuses on 25 patients receiving treatment between August 2012 and June 2016.
43 treatment cycles were performed in total; the range for individual patients was 1 to 4 with the median being 2.
Since mid-2016, M-PHP is only available within the NHS as part of the Phase III randomised controlled FOCUS trial.
If randomised to M-PHP, procedures are scheduled to take place every 6-8 weeks with the aim of delivering 6 treatments.
Between the focus study at UHS and private patients reciecing treatments at Spire, Southampton have administered 118 treatments in total.
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Kathryn Chapman

6. TREATMENT RELATED INCIDENTS
No treatment related fatalities.
Immediate toxicities: 1 case of pulmonary oedema, 1 case of ventricular arrhythmia and 1 case of SVT.
There were 2 cases of vascular access complications: 1 case of intraabdominal haemorrhage and 1 case of IVC thrombus with subsequent pulmonary embolism.
Late toxicities occurred in 7 cases: (4/25) thromboembolic, 3 cases of PE and 1 Deep vein thrombosis diagnosed within 3 months of procedure.
Filter clotting
13/11/2018
Kathryn Chapman

7. TREATMENT RELATED EVENTS
Grade 1 2 3 4
Anaemia
4 (16%)
10 (40%)
Thrombocytopenia
5 (20%)
11 (44%)
3 (12%)
Neutropenia
1 (4%)
2 (4%)
Showing adverse toxic events according to Common Terminology Criteria for Adverse Events.
Each of the symptoms are graded from 1 to 5; 1 being mild and 5 being death related to adverse event. The table shows nearly the majority of patients experiencing anaemia, thrombocytopenia and 8 patients had severe grades of neutropenia. Grade 2-4 neutropenia was seen in 8/25 (32%) patients in the month following M-PHP; 2 episodes of neutropenic sepsis were documented.
If at any point during M-PHP due to the balloons not being occlusive, or the CHEMOSAT® delivery filters not performing optimally patients are at risk of highly myelotoxic Melphalan exposure.
To counteract the effects of Melphalan on the bone marrow, patients are clinically managed with a prophylactic administration of granulocyte colony stimulating factor (GCSF) (Vogel, et al., 2016; Forster, et al., 2014; Yamamoto & Zager, 2014; Hickson, et al., 2015); in addition blood products are used as necessary to maintain red blood cell and platelet numbers within clinically safe limits.
However, other studies (Pingpank, et al., 2005) that have looked into systemic toxicity and responses have found that although their study doesn’t have any statistically significant data, they speculate that cumulative toxicity occurs after multiple treatments. They also suggest that the more treatments patients have successively, the longer the recovery for systemic toxicity can be between treatments.
Before M-PHP provides a baseline measure of cumulative bone-marrow toxicity from all previous treatments, therefore when observing the patients platelet count before M-PHP one must be aware of previous treatments that may affect the platelet count as repeat treatments cause sustained cumulative toxicity (Pingpank, et al., 2005). Two days post M-PHP will be a true representative of the patients own platelet count post M-PHP.
13/11/2018
Kathryn Chapman

8. FILTER CLOTTING
Very rare occurring in 4.2% of total treatments performed
No link between these 5 adverse events
Practices remain safe and effective
Out of 118 patients treated between Southampton Hospital and Spire Southampton, there have been 5 events of filter clotting reported.
Filter clotting during Melphalan treatment means the patient could be exposed to highly myelotoxic Melplalah before the drug can be fully re absorbed into the chemofilteers.
Two weeks post treatment would show the full affect of the circuit clotting where severe neutopenia and thrombocytopenia will be observed due to bone marrow supression as a result of Melphalan exposure.
Research carried out at UHS tried to find a link between these events observing flow, pressure, RPM and bypass time. Unfortunately, no link could be ascertained from the small data set. However it is reassuring that at 4.2%, these adverse events seem rare
Due to the relative rarity of these events, where only 5 significant coagulopathic complications arose, it will be difficult to draw any strong conclusions from such a small sample of data. However, it remains reassuring that with such a small amount of adverse clinical events seen at UHS, practices remain safe and effective.
13/11/2018
Kathryn Chapman

9. PATIENT OUTCOMES
A recent audit from (Karydis, 2016) at UHS analysed the clinical effectiveness of the CHEMOSAT® delivery system.
25 UM patients received treatment between August 2012 and June 2016 with 30 cycles administered since Not total number of patients seen at UHS and Spire
Median Overall Survival of 511 days
12/25 patients were still alive after a median of 315 days
Progression free survival (PFS) showed that 3/25 patients have ongoing disease response
Median overall PFS was ~182 days and
Median liver PFS was ~242 days.
Results are better as we’ve got one patient that’s survived 5 years!
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Kathryn Chapman

10. CONCLUSION CHEMOSAT® Delivery System is safe and effective treatment.
Without systemic treatments, patients have very low chance of survival.
Southampton’s results might be more promising than indicated.
The current 1 year survival rate was approximately 65% shown when the audit was terminated in The current audit at UHS will show a higher median OS as the audit was terminated when there were patients were still alive. The comparative studies median OS and PFS were accurate as reports were conducted after clinical trials therefore the data from UHS might be more promising than indicated in the audit.
13/11/2018
Kathryn Chapman