Featured Article: Phase II Trial of Hepatic Artery Infusional and Systemic Chemotherapy for Patients With Unresectable Hepatic Metastases From Colorectal Cancer: Conversion to Resection and Long-term Outcomes. D’angelica MI, Correa-Gallego C, Paty PB, et al. Ann Surg. 2014 Mar 21. [Epub ahead of print]
The rate of conversion of unresectable colorectal liver metastases (CRLM) to resectable CRLM has improved with modern systemic chemotherapy and biologic therapy. Results of recent studies, including randomized trials, report conversion rates of 20-38%. The combination of hepatic artery infusional (HAI) chemotherapy with systemic chemotherapy has become an attractive option for the treatment of unresectable CRLM owing to the high response rates observed in previous published studies.
This prospective phase II trial aimed to evaluate, as a primary endpoint, the conversion rate to complete resection (resectability rate) in patients with unresectable CRLM treated with HAI fluorodeoxyuridine (FUDR) in combination with systemic chemotherapy including bevacizumab.
Technical and biological criteria were used to define unresectability. Technically unresectable CRLM were those that required resection of 3 hepatic veins, both portal veins, or the retrohepatic vena cava to achieve a negative margin, or those requiring a resection that would leave fewer than 2 adequately perfused and drained segments. Biologically unresectable CRLM were those that included >6 metastases in one lobe, including 1 metastasis ≥5 cm, or those with ≥6 bilobar metastases.
Forty-nine patients with liver-only disease were treated with HAI FUDR in combination with irinotecan and fluorouracil or irinotecan and oxaliplatin with bevacizumab. Sixty-five percent had previously received systemic therapy. The rate of overall grade 3 or 4 toxicity was 41%. After the first 24 patients were enrolled, bevacizumab was removed from the treatment owing to high biliary toxicity (13%; 3 patients required biliary stent placement), and the authors do not recommend the use of the combination of HAI FUDR and bevacizumab. The overall response rate, according to World Health Organization criteria, was 76%; the response rate was 82% in chemotherapy-naïve patients and 72% in previously treated patients. Such response rates led to a resectability rate of 47% (23 patients) at a median period of 6 months from treatment initiation. Resections included a combination of anatomic (17 patients) and non-anatomic multiple resections (6 patients). Radiofrequency ablation was used in 16 patients, and 5 of the 23 patients (22%) had positive margins. Fifteen of the 23 specimens showed a significant pathologic response to chemotherapy (more than 75%), including 3 complete pathologic responses. The median overall survival duration for all patients was 38 months and the median progression-free survival duration was 13 months. As expected, resectability rate was the only factor associated with prolonged overall survival in a multivariate analysis. The 3-year overall survival rate in patients undergoing resection was 80% (compared with 26% in patients who did not undergo resection). After a median follow-up period of 38 months, 20% of patients were disease-free.
The authors conclude that HAI chemotherapy has a potential role in the treatment of unresectable CRLM. How this approach compares with aggressive combination chemotherapy and biologic therapy remains to be studied.
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1) Usually the future liver remnant is the main factor considered in the definition of unresectability, but in this study, the authors define unresectability as involvement of all 3 hepatic veins or the inferior vena cava. This definition is different from the definition of unresectability used by the Americas Hepato-Pancreato-Biliary Association. That definition specifies complete R0 resection of intrahepatic and extrahepatic disease with preservation of at least 2 adjacent liver segments with adequate vascular inflow and outflow, as well as biliary drainage and an adequate volume of liver (i.e., the future liver remnant) after resection (which usually means at least 20% of the total estimated volume of the liver for normal parenchyma, or 30-60% if the liver is injured by chemotherapy, steatosis, or hepatitis). Should the definition of resectability be limited to anatomical considerations such as those including vascular involvement, as reported by the authors, or should it include functional considerations?
2) The inferior vena cava is rarely invaded in colorectal liver metastases and usually is not a site of local recurrence. Moreover, definite vascular involvement or attachment of the hepatic veins is rarely reversed by conversion therapy. What is your opinion about alternative technical approaches for unresectable disease (e.g., 2-stage resection with portal vein embolization, vascular reconstruction of the inferior vena cava or hepatic veins, radiofrequency ablation)? The authors also define biological unresectability as >6 metastases in a single lobe with 1 metastasis ≥5 cm or ≥6 bilobar metastases. Do you use number, size, or bilobar versus unilobar as appropriate criteria to define biological unresectability? Should response to therapy be used as a biological criterion for resectability? Should mutational status of the tumor (RAS) be considered?
3) Sixty-five percent of patients received the treatment as second-line therapy after first-line therapy failed. Recent studies indicate adequate safety ratings and a resectability rate of up to 67% with aggressive combined systemic chemotherapy (METHEP trial) in well-defined unresectable CRLM. With the data from recent trials, would you consider more aggressive systemic chemotherapy with the combination of oxaliplatin and irinotecan with or without biologic therapy as an initial approach for all patient s rather than the implantation of a pump?
4) HAI chemotherapy with a pump requires a surgical procedure associated with technical complications (a 14% complication rate was reported in the current study), FUDR is not widely available as a pharmacologic agent, and refill and maintenance of the pump requires special expertise. Other centers have reported success with arterial infusion therapy with oxaliplatin, including high resectability rates. Should arterial infusion therapy with oxaliplatin be preferred to HAI FUDR with a pump?
Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers. This article can be accessed for free.