Liver-Directed Therapies Crucial in Metastatic Colorectal Cancer

“All patients with metastatic disease to [the] liver have options available; basically, what we’re doing with liver-directed therapies is trying to turn back the clock on the progression, which is the primary, most aggressive part of the disease that ultimately leads to the patient progressing and unfortunately dying,” said David M. Liu, MD, interventional radiologist, associate clinical professor, University of British Columbia, Canada, in an interview withTargeted Oncology.

CONVERSION TOWARD RESECTION

In a multidisciplinary presentation during the 2016 ASCO Annual Meeting, Liu and colleagues examined methods for converting patients to resection if they are not initially able to undergo resection. Liu noted that the study focused on ways to ‘reset the clock’ on the liver to allow for greater survival in patients with mCRC who have liver metastases.

For those unable to undergo immediate resection, computed tomography (CT) scans show that resectability is increased following chemotherapy ‘conversion’ regimens.¹

In the CELIM study, patients with nonresectable liver metastases or with at least 5 metastases were selected to receive cetuximab with either FOLFOX-6 (oxaliplatin, fluorouracil, and folinic acid) or FOLFIRI (irinotecan, fluorouracil, and folinic acid). Patients were assessed by CT scan every 2 months to check if the metastases had become surgically resectable.

At baseline, 32% were eligible for resection. Follow-up showed that 60% of patients were able to undergo resection after chemotherapy treatment (P <.01). Most patients who responded were able to receive surgical intervention between the 4-month and 6-month CT scan periods. However, after 8 months it was unlikely that surgical intervention would become possible.

The FOLFOX-6 arm was favored with a 68% (36 of 53 patients) objective response rate (ORR) versus 57% (30 of 53 patients) ORR in the FOLFIRI group. Resection with negative margins (R0), was possible in 20 patients (38%) in the FOLFOX-6 group and in 16 patients (30%) in the FOLFIRI group.

PORTAL VEIN EMBOLIZATION AND RADIOFREQUENCY ABLATION

&ldquo;One of the things that we can do in interventional radiology is perform certain types of adjunctive procedures to help facilitate the regeneration of remnant livers to minimize the chance of liver failure as a result of surgery,&rdquo; Liu said in the presentation.

Portal vein embolization (PVE) is one of the most common adjunct liver-directed procedures, and it can also be used as an alternative to surgical resection. The procedure redirects portal blood flow to liver remnants, thereby increasing the potential for the patient to be a surgical candidate. PVE has achieved similar survival rates to surgical patients who do not require PVE.²

Radiofrequency ablation similarly shows the same clinical outcomes as surgical resection in liver metastases. &ldquo;For solitary lesions we can alter and eliminate the lesion and alter the biology with radiofrequency ablation, in recurrent disease; in a similar fashion it can be thought of as potentially an equivalent or alternative to surgical resection,&rdquo; Liu explained.

The EORTC CLOCC trial considered the use of radiofrequency ablation in a first-line setting by examining radiofrequency ablation with systemic therapy against standard therapy alone in patients with metastases in the liver.³

The radiofrequency ablation arm showed a median progression-free survival (PFS) benefit of 16.82 months (range, 11.01-21.88 months) over a median PFS of 9.92 months for the control group (range, 9.07-12.85 months). Follow-up revealed an 8-year PFS of 22.3% for the radiofrequency group and 2.0% for the control (HR, 0.57; 95% CI, 0.38- 0.85;P= .005).

SELECTIVE INTERNAL RADIATION THERAPY

When the metastases are surgically unresectable, liver-directed therapies are still beneficial. Selective internal radiation therapy (SIRT) is a viable cytoreductive method for these types of patients.

SIRT, in combination with chemotherapy, was considered as a first-line therapy in the SIRFLOX phase III trial. The study randomized patients with liver-dominant disease to either modified FOLFOX- 6 with or without bevacizumab, or to modified FOLFOX-6 plus SIRT using yttrium-90 (Y-90) resin microspheres, also plus or minus bevacizumab.⁴

The PFS rate for any site showed no measurable difference or statistical significance (P = .43) in favor of the SIRT arm. However, looking at rates in the liver revealed a 7.9-month improvement in the median PFS with the addition of SIRT.

FOLFOX plus bevacizumab had a median PFS of 12.6 months in the liver and the investigational SIRT group had a median PFS of 20.5 months (HR, 0.69; 95% CI, 0.55-0.9;P= .002). There was also a 31% reduction in the risk of disease progression within the liver with added SIRT.

Volker Heinemann, MD, professor of Medical Oncology, University of Munich, Germany, presented updated findings from the SIRFLOX study during a poster presentation at ASCO. Updated data showed that there was a 4% greater decrease in the median liver tumor volume in the SIRT group (-91%) over the control arm (-87%;P= .036). A greater depth of response, higher PFS rate, and longer time to nadir were all observed in patients with >12% hepatic tumor burden in the SIRT group versus the control.⁵

&ldquo;Professor Heinemann&rsquo;s poster drives the point home that SIRT therapy creates a deeper response and therefore alters the biology of the disease within the liver, which ultimately should translate into survival,&rdquo; Liu said in the interview.

Further investigation of the benefits of SIRT is being studied, including in the FOXFIRE trial exploring interventional SIRT in the first-line setting, which is expected to release findings in 2017. &ldquo;I&rsquo;m very much looking forward to the survival data of the SIRFLOX trial that&rsquo;s going to be reported with the FOXFIRE trial in 2017. That&rsquo;s really going to be the finish line, so to speak. But all indications of the published data so far [are] that we&rsquo;re kind of heading along that course towards a revolutionary therapy within liver-directed therapies,&rdquo; said Liu.

References:

1. Folprecht G, Gruenberger T, Bechstein WO, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial.Lancet Oncol.2010;11(1):38-47.
2. Madoff DC, Adballa EK, Vauthey JN. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care.J Vasc Interv Radiol.2005;16(6):779-790.
3. Ruers T, Punt CJA, van Coevorden F, et al. Radiofrequency ablation (RFA) combined with chemotherapy for unresectable colorectal liver metastases (CRC LM): Long-term survival results of a randomized phase II study of the EORTC-NCRI CCSG-ALM Intergroup 40004 (CLOCC).J Clin Oncol.2015;33(suppl; abstr 3501).
4. van Hazel GA, Heinemann V, Sharma NK, et al. SIRFLOX: randomized phase III trial comparing first-line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer.J Clin Oncol.2016;34(15):1723-1731.
5. Heinemann V, Van Hazel GA, Sharma VK, et al. SIRFLOX study: Novel approach to define depth of response (DpR) within a volumetric model in patients with metastatic colorectal cancer (mCRC).J Clin Oncol.2016;34(suppl; abstr 3542).