Liver-directed therapies for hepatic dominant stage IV colorectal cancer remain an attractive oncological concept
Robert P Jones MBChB PhD
School of Cancer Studies, Institute of Translational Medicine, University of Liverpool, UK
Stefan Stättner MD FRCS
HPB Service, Paracelsus Medizinische Privatuniversität Universitätsklinik für Chirurgie, Salzburg, Austria
Stephen W Fenwick MD FRCS
Graeme J Poston MS FRCS
Hassan Z Malik MD FRCS
Liverpool Hepatobiliary Unit, Aintree University Hospital, Liverpool, UK
Over half of patients with colorectal cancer will develop metastatic disease, with one quarter having metastatic spread at the time of presentation. Surgical resection is the only potentially curative option, with reported five-year survival approaching 40%.(1) For patients with unresectable liver limited disease, the primary aim of first line systemic chemotherapy is to bring patients to potentially curative resection. Secondary resection rate clearly correlates with tumour response,(2) and these patients are now treated with the aim of maximising tumour response and therefore chance of conversion to curative resection.
Liver-directed therapies to maximise tumour response
The unique blood supply of the liver, with portal flow supplying healthy hepatic parenchyma and arterial flow supplying metastatic disease, has led to the concept of delivering liver-only chemotherapy in an effort to increase tumour response whilst reducing systemic dose and off-target side-effects. Hepatic arterial infusion (HAI) was initially trialled as a replacement for systemic adjuvant chemotherapy.
A catheter is inserted at laparotomy into the umbilical vein remnant, through which a portable pump delivers an infusion of chemotherapeutic agent. A meta-analysis by Mocellin et al(3) found no benefit for HAI compared to systemic chemotherapy in the treatment of irresectable colorectal metastases and so interest focused on the use of HAI as an adjunct to first line systemic therapy.
A phase III randomised trial considering FUDR HAI as adjuvant treatment alongside systemic 5-FU after resection of CRLM showed a two-year recurrence free survival of 90%, compared with 60% for those receiving systemic chemotherapy alone.(4) These impressive results stimulated interest in whether the high response rates to HAI could be harnessed to bring more patients to resection, with a systematic review of neoadjuvant hepatic arterial infusion alongside systemic chemotherapy in irresectable CRLM reporting secondary resection rates between 6% and 47% in unselected series.(5) Although these results are promising, technical and toxic complications remain a concern with 16% of HAI pumps failing within two years of insertion.(6)
Drug-eluting beads with irinotecan (DEBIRI-TACE)
Attempts to minimise the technical complications associated with HAI have led to the development of novel drug delivery methods. Conventional TACE (cTACE) involves the injection of chemotherapeutic agent into blood vessels supplying tumour, followed by embolic material in an effort to occlude the feeding blood vessels. This approach offers several theoretical advantages. The ischaemic effect of embolisation will lead to tumour infarct resulting in cell death as well as increasing vascular permeability, encouraging diffusion of chemotherapeutic agents into tumour.(7) Reduced perfusion after embolisation also reduces chemotherapeutic washout, increasing local concentrations of the drug and increasing total tumour exposure.
Drug eluting beads (DEBIRI, marketed as DC Bead in Europe) are compressible beads that can be loaded with irinotecan, and offer a theoretical advantage over hepatic arterial infusion and conventional TACE because of simplified delivery (embolisation and chemotherapy are combined, with no need for a pump) and offers the potential to add locoregional irinotecan to systemic FOLFOX with the aim of achieving comparable response rates to that seen after FOLFOXIRI while minimising morbidity. DC Bead loaded with irinotecan is CE Marked in Europe for the treatment of metastatic colorectal cancer.
LC Bead does not yet have market approval in the US to be used in combination with irinotecan but is used in Food and Drug Administration approved investigational clinical trials, and has previously shown impressive results in both chemo-naïve and heavily pre-treated irresectable patients.(8,9)
DC beads are 100–300µm embolic microspheres produced from polyvinyl alcohol (PVA) hydrogel. The beads contain multiple negatively charged sulfonate groups which form ionic bonds with positively charged drugs, allowing for rapid loading.
Liquid chromatographic analysis has shown that beads are stable for up to seven days after loading, with analysis confirming all of the drug can be recovered from the bead, that is, no irreversible chemical reaction occurs between the drug and the bead.(10) Loading beads with drug has no effect on handling or compressibility, making them appropriate for selective embolisation using narrow gauge radiological catheters.(11)
A pilot study assessed the safety and feasibility of DEBIRI-TACE in patients with heavily pretreated unresectable CRLM.(12) Eleven patients received up to four cycles of DEBIRI-TACE at three-weekly intervals (median total dose 293mg). Only minor adverse events were noted, with 63% of patients developing abdominal pain, nausea and vomiting. No irinotecan-related toxicities were observed. Administration of DEBIRI-TACE was technically feasible in all cases, with a 64% disease response rate after nine weeks. Median time to progression was 154 days from first treatment.
An Italian group published preliminary results from a small phase II safety and efficacy study on ten patients with irresectable CRLM treated with irinotecan loaded beads(13) with a demonstrable radiological response in 70% of treated lesions. The same group progressed to a larger single arm phase II study assessing tumour response and survival in heavily pre-treated patients with CRLM.(14) Eighty-two patients who had failed first line systemic therapy were treated with DEBIRI-TACE (median 2.2 per patient) at three-weekly intervals. There was a 78% three-month mRECIST response rate, with a median duration of response of six (range three to ten) months. Median survival was 25 (range 6–34) months with progression free survival of eight (range 4–16) months, comparable with first-line systemic therapies.
These impressive results led the same group to develop a phase III randomized control study comparing DEBIRI-TACE versus systemic FOLFIRI as first-line treatment for liver limited metastatic colorectal cancer.(15) However, patients were eligible for inclusion if they had received systemic therapy more than three months prior to enrollment in the study and in fact many of these patients had been heavily pretreated.
Patients were randomised to FOLFIRI or DEBIRI stratified by percentage liver involvement, lines of previous therapy, weight loss, KRAS status and p53 expression. The systemic therapy arm received FOLFIRI for four months while the DEBIRI arm received drug-eluting beads loaded with irinotecan twice a month for the same time period. Overall mRECIST response rate after DEBIRI-TACE was 69%, compared to 20% after FOLFIRI with two-year survival of 56% for the DEBIRI-TACE group, compared to 32% for the FOLFIRI group (p=0.03). Subgroup analysis by KRAS status found that wild-type patients had a median survival of 26 months after DEBIRI-TACE, compared to 19 months for KRAS mutants. Comparison of toxicity between the two arms demonstrated grade 3 neutropenia in 4% and 44% (p<0.0001), diarrhoea in 6% and 18% (p=0.07) and mucositis in 1% and 20% (p=0.00002) of the DEBIRI and FOLFIRI groups respectively. This trial suggested that DEBIRI-TACE offers improved response rate, overall survival and reduced toxicity when compared with systemic FOLFIRI.
A multi-institute registry of patients with irresectable CRLM treated with irinotecan DEBIRI-TACE considered 55 patients who underwent 99 embolisations for irresectable colorectal liver metastases.(8) The treatment approach in this registry involved whole lobe embolisation, rather than selective embolisation adopted in the previous studies. A lobar approach aims to destroy previously unidentified occult disease, as well as targeted lesions.
All patients had received a minimum of FOLFOX/FOLFIRI as first line treatment, with the majority having failed all second line treatments felt appropriate by a medical oncologist (including biologic agents). A median of two embolisations (range 1–5) were performed for each patient with a median dosage of 100 mg per embolisation (range 50–200mg) and a median total hepatic exposure of 185mg (range 150–650mg). Adverse event rate after embolisation was 28%, with the majority of events consisting of grade 2 nausea, vomiting and transient liver dysfunction.
Three-month mRECIST response rate was 65% (12% complete response, 53% partial response), which reduced to 50% at six months and 40% at 12 months suggesting durable disease response. Median overall survival from time of first treatment was 19 months, with an overall progression free survival of 11 months and a hepatic progression free survival of 15 months. These impressive results contrast favourably with the median survival time for patients who have failed systemic chemotherapy. Eleven patients (20%) had their disease sufficiently downstaged to allow further treatment,(16) with four undergoing resection and two undergoing radiofrequency ablation.
A US-led prospective phase I study by the same group is currently recruiting chemo-naïve patients with liver dominant irresectable metastatic colorectal cancer. Patients are treated with FOLFOX6 +/- DEBIRI-TACE in the off-week of FOLFOX therapy. At a median of 12 cycles of FOLFOX/2 cycles DEBIRI, four of ten patients recruited so far (40%) had been converted to resectability with no evidence of drug induced liver injury in background parenchyma.(9)
There is limited evidence surrounding the use of DEBIRI in the true neoadjuvant setting. In the single-arm, prospective phase II safety and efficacy PARAGON study, easily resectable colorectal liver metastases were embolised using a nominal dose of 200mg DEBIRI four weeks prior to surgery. Treatment was well tolerated and safe.17 Post-resection analysis showed impressive rates of tumour destruction with no residual disease in 17% of lesions, <50% residual disease in 59% and >50% residual disease in 22%.
However, neither RECIST nor mRECIST accurately predicted pathological tumour destruction.18 These findings have clear clinical implications for the design of any future trials involving DEBIRI where early assessment of tumour response is used to guide management. The future role of DEBIRI is likely to be alongside systemic therapy for liver-dominant disease, and it is therefore important that any trial design involves early administration of DEBIRI followed by multiple cycles of systemic therapy to allow adequate time for tissue inflammation to settle and to allow a more accurate assessment of tumour response. Such accurate assessment of response is essential for disease where the primary aim of treatment is salvage surgery.
Conclusions
Liver-directed therapies for hepatic dominant stage IV colorectal cancer remain an attractive oncological concept. DEBIRI offers a safe and effective approach, with promising response rates. Evidence supports the use of DEBIRI as salvage therapy, as well as alongside existing systemic therapies for patients with liver-dominant disease. Resection after neoadjuvant DEBIRI is feasible and safe, with tumour pathologic response similar to that seen after protracted systemic chemotherapy. DEBIRI may therefore have a role in first-line conversion therapy for irresectable disease as well as the palliative setting, with future trials helping to guide the optimal use of this exciting technology in the management of these complex patients.
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