European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm
Chemotherapy infusions directly to organs
Professor James Pingpank – University of Pittsburgh School of Medicine, USA
Thank you very much. This represents the compilation of a multi-centre trial looking at this phase III drug delivery devised for the treatment of patients with metastatic melanoma to the liver. Just as a background, the incidence of ocular melanoma in the United States is approximately 3,500 – 4,000 cases per year with the majority of patients, 50-60% of them, experiencing recurrent disease during their lifetime. The median survival for those patients who recur is between 2 and 7 months and approximately 10% of patients will be alive at one year. The natural history of this is that the vast majority of these patients, the recurrence will be in the liver, either as a sole site of disease or the life limiting site of disease and therefore it has been an interest of ours and other centres to look at liver directed therapies in order to attack this disease.
Because it’s a relatively rare disease, systemic chemotherapy and immunotherapy have really not shown any meaningful impact. We reported the initial results of this study at ASCO in 2010 and this is a follow-up to that. So, very briefly, this is a device-drug combination which is marketed, I should say, in the EU purely as a device. Melphalan, the chemotherapeutic agent, is infused into the hepatic artery and allowed to infuse throughout the entirety of the liver. You can see here a double balloon catheter behind the liver which allows collection of all blood leaving the liver which has the high doses of chemotherapy. That blood is then brought out of the body through a catheter based system, brought through two in-line filters, the chemotherapy is filtered out and then returned to the patient. The drug is administered over thirty minutes and there is a thirty minute period of wash-out to make sure there is no delayed release of drug.
This trial was accrued, it initially started at the NCI in Bethesda, Maryland, and then rolled out to nine other centres. So for ten centres, 46 patients per arm was the goal, one extra patient was accrued. It was a randomisation between the experimental trial and best alternative care which was available to the patients. The Melphalan dose was 30mg/kg over thirty minutes which actually represents nearly a bone marrow ablative dose of drug and disease was stratified versus cutaneous melanoma.
The results of this trial showed that the majority of the toxicities that were seen were based upon systemic delivery of drug, the filters were quite efficient and quite reproducible. However, only about 77% of the drug was filtered on a routine basis so we did see the drug get into the systemic circulation with the majority of the patients having treatable neutropenia or thrombocytopenia, so decreased white blood cell count, decreased platelet counts and they were treated every 4-6 weeks after their counts had recovered. Even with extensive heavily pre-treated livers involved with tumours, we saw that there was minimal liver directed toxicity. So the mortality rate in 116 procedures done was 3 out of 116 procedures or 2.6%, which is relatively similar to invasive procedures. The mortality was associated with bone marrow suppression in two patients who had neutropenia or overwhelming infection due to low blood counts, and then one patient who had massive hepatic replacement was the first and only patient we’ve seen in this programme who died of hepatic failure. This was thirty days after his treatment.
When we look at the primary endpoint of the trial, and the trial is designed as a crossover trial, meaning that patients were randomised to the standard of care arm of the trial, when they progress in their liver, if they progress in their liver, they are then offered the experimental trial. All analyses are based upon how they are primarily assigned at the time of their randomisation and what we see is an 8 versus 1.6 month difference in hepatic progression free survival, which has a p-value of less than 0.0001 with a hazard ratio of 0.35, indicating a highly significant result with the experimental arm being in red and the grey arm being the standard of care arm.
Since we are only treating the disease in the liver and certainly disease in the rest of the body is able to take the patient’s life, what we also looked at, it doesn’t make sense just to target the liver, so what happened to the overall progression free survival in the patient, including disease outside of the liver. And even when we do that we see a p-value of less than 0.001 with a 6.1 versus 1.6 month median overall progression free survival with a very significant hazard ratio again.
Because of the crossover and 58% of all patients who were assigned to the primary, to the best alternative care arm, subsequently crossed over and received experimental treatment, we did not see any difference in overall survival within this trial.
So, in conclusion, increased drug delivery achieved through this novel regional approach may increase the given efficacy of a drug such as melphalan which has really limited use with systemic administration for these types of malignancies. Melphalan delivered via this system significantly prolonged hepatic progression free survival versus standard regimens available to patients with liver dominant metastatic melanoma, thereby meeting the primary endpoint of the study. Expansion to multiple clinical centres, all the patients treated outside of the NCI in Bethesda, Maryland, were the first patients treated with this device in those centres and so the expansion proved itself to be quite safe and effective.
Thank you very much.