Prof. Constantinos T. Sofocleous
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The hepatic artery supplies nutrients for liver metastases, whereas the portal vein feeds most of the liver parenchyma. Thus, hepatic arterial directed therapies (infusion chemotherapy, chemoembolization, and radioembolization) are feasible, and target the liver metastases while sparing the normal liver. Chemotherapeutic agents of choice for intrarterial delivery have a high first-pass extraction such as Floxuridine (FUDR)[1]. FUDR is a pro-drug of fluorouracil (5-FU) with 99% extraction by the liver during first pass providing high drug concentration in the liver metastases and limited drug distribution to the liver parenchyma and minimal systemic exposure to the rest of the body [1].
Several studies demonstrated the superiority of HAI to systemic chemotherapy alone for colorectal cancer liver metastases (CLM) [2]. Subsequent trials from the US and Europe demonstrated higher response rates and prolonged survival in patients treated with HAI FUDR compared to those receiving oxaliplatin or irinotecan based chemotherapy regimens only [3-5]. Long-term toxicity from HAI includes biliary toxicity and gastric ulceration. Monitoring LFTs is critical. In the setting of hyperbilirubinemia, ruling out obstruction or surgical biliary stricture is necessary. Steroids and ursodiol can decrease or delay toxicity from HAI FUDR therapy. The resulting longer survival and longer exposure to HAI, however, will eventually lead to chemotherapy induced biliary sclerosis (CIBS) [11]. The complexity of hepatic pump placement, management of the HAI pump, and administration of HAI chemotherapy have limited the use of HAI to certain institutions with relevant multidisciplinary expertise. The NCCN guideline concludes that HAI infusion with or without systemic chemotherapy is an option as adjuvant or peri-operative therapy in the setting of CLM resection.
Unfortunately, liver recurrence rates of 60-70% and a modest disease free survival benefit with adjuvant 5-FU-based chemotherapy post CLM resection are documented [6]. Earlier studies confirmed the safety of HAI with FU or FUDR while decreasing the risk of cancer recurrence and prolonging disease free survival [3], whereas subsequent studies demonstrated patient survival benefit with the addition of HAI to systemic [7-8]. Adjuvant HAI with FUDR with systemic FU and resection was compared to resection alone and showed improved 4-year hepatic recurrence-free survival and overall recurrence-free survival. The longer median OS in the combined therapy arm (64 vs.49 mos) did not reach significance [9]. Other studies supported the combination of HAI with systemic post CLM resection with improved recurrence-free and patient survival with the use of a HAI pump [10]. The largest retrospective study on HAI therapy was published in 2017 in a cohort of 2,368 consecutive patients who underwent CLM resection at MSKCC. 785/2368 had HAI therapy and despite an initial increased disease burden they experienced a longer median overall survival (67 vs 44) compared to those treated without HAI (p < 0.01) [11].
Up to 38% of patients with initially unresectable liver metastases could be converted to resectable after therapy. HAI showed favorable conversion rates in several trials [12-13]. When combined with first line therapy, the conversion rate was as high as 53% [14]. A phase II trial evaluated the safety and efficacy of HAI plus systemic modern chemotherapy (FOLFOX, FOLFIRI with or without bevacizumab) as conversion therapy. ORR was 76% and 47% were downsized to complete resection. Resection was the only factor associated with prolonged survival with 3-year OS of 80% for resected vs. 26% for those that could not have CLM resection (p=0.005) [14]. This study was recently updated; successful conversion occurred in 52% of patients, 5-year OS reached 36%. Chemotherapy naïve patients had 5-year OS of 51% [15]. The addition of bevacizumab did not have an impact on the conversion rate or survival and increased biliary toxicity as seen in other trials [16,17]. This high toxicity maybe attributed to the anti-angiogenic effect of bevacuzimab that, in combination with chemotherapy induced biliary sclerosis by the HAI, increased or expedited the biliary artery ischemia and attenuated the biliary sclerosis. Thus, bevacizumab is not recommended in the setting of HAI therapy.
Another study assessed the role of the ECGR inhibitor cetuximab combined with HAI therapy for patients with wild-type Kras.
Almost 30% were downsized to complete liver metastasectomy. Similar to the first-line setting, HAI therapy in the second-line setting was associated with a higher conversion rate compared with the third-line or beyond (46.4% vs. 16.7%, p=0.014) [18]. A Randomized Phase II Trial of Adjuvant HAI and Systemic Therapy With or Without Panitumumab After Hepatic Resection of KRAS Wild-type Colorectal Cancer showed promising initial results with the addition of panitumumab [19].
In patients with CLM progressing on first or second-line systemic chemotherapy (oxaliplatin or irinotecan-based), combination therapies could consider third-line regimens if deemed appropriate. Available options include regorafenib (Stivarga) [20], trifluridine-tipiracil (TAS102 or lonsurf) [21], as well as HAI therapy [22]. In large randomized trials, Regorafenib and TAS102 demonstrated a very low RR of 1 and 1.6%, mOS of 6.4 and 7.1 months, respectively [21, 22]. Promising results with HAI therapy in 110 patients with refractory CLM showed a response rate of 33%, and a median overall survival of 20 months [22].
Progression upon HAI has been treated safely with Y90 Resin Microsphere in a phase I trial with oncologic outcomes and overall survival of 14.9 months in heavily pretreated patients [23]. Subsequent retrospective cohorts further indicated safety of radioemboilization in a larger number of patients treated for liver disease progression post-HAI [24-25]. A metabolic response was predictive of survival [24-27]. A predictive nomogram indicated a wide variability of survival in the salvage setting after radioembolization of CLM [25]. HAI was also administered after subsequent progression or in combination with radioembolization safely, provided that baseline bilirubin was under 1.5 (mg/dl) [23-25]. It would be useful to further explore strategies of combining these intrarterial therapies with modern systemic chemotherapy options in an effort to further improve oncologic outcomes in the setting of CLM progressing after first-line regiments.
Thermal ablation to treat small volume disease in patients previously treated with HAI or progressing while on HAI has been described [28]. A minimal ablation margin (MM) over 10 mm was associated with complete tumor eradication and no local tumor progression after thermal ablation (microwave /radiofrequency) in a large cohort [28]. In the HAI population, however, there was an increased incidence of biliary related complications (11% vs 0), likely the result of underlying chemotherapy induced biliary sclerosis (CIBS), especially if there was prior exposure to bevasuzimab and preexisting biliary dilatation [28]. In the HAI population, biliary complications of 21% vs 4% were noted for colorectal liver metastases (CLM) ablated with MM >10 vs 6-10 mm with corresponding LTP of 0 vs 27% respectively [28]. There is clearly a fine line between biliary complications and local tumor control in the HAI population. Strategies of biopsy proven complete tumor ablation with margins 6-10 mm confirmed by 3D software have been described for the safe and effective thermal ablation of CLM in patients with HAI [29-30].
Constantinos T. Sofocleous
Memorial Sloan Kettering Cancer Center, New York/NY/US
