Up-front Surgery, Biologics Do Not Improve Survival in Resectable CRC With Liver Metastases

Chemotherapy has demonstrated mixed findings in patients with resectable colorectal hepatic metastases, and long-term data suggest incorporating it into treatment algorithms have little impact on overall survival (OS), medical oncologist Patrick M. Boland, MD, said during a presentation at the 39th Annual CFS^®, a program hosted by the Physicians’ Education Resource^® (PER^®), LLC. He was on hand to discuss optimal treatments for patients with liver-only metastatic colorectal cancer (CRC), while debating the evidence with up-front surgery and biologic therapies.¹

“When we’re talking to a patient at the clinic, we can confidently tell…resectable patients that we do cure patients by giving them FOLFOX [leucovorin/5-fluorouracil (5-FU)/oxaliplatin], we just don't have conclusive proof that it changes long-term survival,” said Boland, a member of the Gastrointestinal Oncology team at RWJ Barnabas Health and an assistant professor of medicine at Rutgers Cancer Institute of New Jersey.

Treatment is “dealer’s choice” in resectable patients, he added. Physicians should consider the tumor and patient characteristics, then work with the patient and the surgeon to determine whether the patient is best served with up-front surgery or with neoadjuvant chemotherapy.

For patients whose tumors are not initially resectable, Boland recommended giving the treatment with the best chance of response. “My own approach, if [the patient is] a candidate for FOLFOX, is I still tend to steer towards FOLFOX.”

He added that he will include bevacizumab (Avastin), because data from previous studies have shown that adding the biologic agent improves long-term outcomes. He will also consider leucovorin/5-FU/irinotecan (FOLFIRI) or leucovorin/5-FU/oxaliplatin/irinotecan (FOLFOXIRI) with or without a biologic for some patients.

“That is really my preference for many more fit, young patients,” he said. “In patients who are unresectable, this represents a very good option.”

In his CFS^® presentation, Boland focused on resectable disease. He noted that even when surgery is an option, physicians often prefer to limit exposure to chemotherapy as much as possible and to conduct frequent imaging, sometimes as often as every 6 or 8 weeks.

The choice to have surgery or chemotherapy first is often driven by institutional and provider preference rather than clear evidence, he said. He cited data from 2 studies suggesting there is little if any value to chemotherapy before surgery.

In the randomized, controlled, parallel-group, phase 3 EORTC Intergroup trial 40983 (EPOC; NCT00006479), investigators in Europe, Australia, and China recruited adults with histologically proven CRC and up to 4 liver metastases. Patients were randomly assigned to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles before and after surgery. A total of 152 patients in each group underwent resection.

At a median follow-up of 8.5 years (range, 7.6-9.5), the median OS was 61.3 months (95% CI, 51.0-83.4) in the perioperative chemotherapy group vs 54.3 months (95% CI, 41.9-79.4) in the surgery alone group (HR, 0.88; 95% CI, 0.68-1.14; P = .34).² The 5-year OS rate was 51.2% (95% CI 43.6-58.3) vs 47.8% (40.3-55.0), respectively, a difference of just 3.8%.

“When we look at just the population that underwent resection, we actually did see a significant difference of 9% improvement with use of perioperative chemotherapy,” Boland said. “However, it did not translate to a survival benefit.”

In recently published findings from the phase 2/3 JCOG0603 trial (UMIN000000653), investigators recruited patients aged 20 to 75 years with confirmed CRC and an unlimited number of liver metastatic lesions from March 2007 to January 2019. Patients were then randomly assigned to hepatectomy alone (n = 149) or 12 courses of adjuvant mFOLFOX6 after hepatectomy (n = 151). The primary end point of the phase 3 portion was disease-free survival (DFS) in the intention-to-treat analysis.

Investigators terminated the trial at the third interim analysis with a median follow-up of 53.6 months because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy.³ At a median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4%-46.8%) for hepatectomy alone compared with 49.8% (95% CI, 41.0%-58.0%) for chemotherapy (HR, 0.67; 95% CI, 0.50-0.92; one-sided P = .006). However, the updated 5-year OS rate was 83.1% (95% CI, 74.9%-88.9%) with hepatectomy alone compared with 71.2% (95% CI, 61.7%-78.8%) with hepatectomy followed by chemotherapy.

“This study conclusively demonstrated a DFS benefit that was significant at 3 years, significant at 5 years,” Boland said. “However, just like the prior study, when we look at OS, there’s really no difference. The Kaplan-Meier curves here are driven by a relatively small number of events.

“I don’t think I would say that chemotherapy is worse than surgery alone. But I think we do overestimate what we’re doing in terms of changing survival.”

No Clear Survival Advantage With the Addition of Biologics

Boland noted that the addition of biologic agents improves response and survival in unresectable patients. However, as noted, it does not appear that those agents improve survival in the resectable population.

In the multicenter, open-label, randomized, controlled phase 3 New EPOC trial (ISRCTN; 22944367), adults with KRAS wild-type resectable or suboptimally resectable CRC with liver metastases and a World Health Organization performance status of 0 to 2 were randomly assigned to perioperative FOLFOX with (n = 129) or without (n = 128) cetuximab (Erbitux) before and after liver resection.

In the updated analysis taken at a median follow-up of 66.7 months, the median PFS was 22.2 months (95% CI, 18.3-26.8) in the chemotherapy-alone group and 15.5 months (95% CI, 13.8-19.0) in the chemotherapy-plus-cetuximab arm (HR, 1.17; 95% CI, 0.87-1.56; P = 0.304).⁴

“What’s distressing here is patients who got to cetuximab, despite having higher response rates, had worse PFS,” Boland said. “When you sort of look through the data try to figure out why, it's honestly not clear that there are obvious surgical differences that explain it. But it certainly gives [one] pause about adding some of these biologics, at least in the up-front resectable setting. I would really say we should not [give biologics in this setting] based on those data.”

References

1. Boland PM. Treatment options for patients with liver-only metastatic colorectal cancer based on the data: what works best? Presented at: 39th Annual CFS®; November 3-5, 2021; New York, NY.
2. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208-1215. doi: 10.1016/S1470-2045(13)70447-9
3. Kanemitsu Y, Shimizu Y, Mizusawa J, et al. Hepatectomy followed by mFOLFOX6 versus hepatectomy alone for liver-only metastatic colorectal cancer (JCOG0603): a phase II or III randomized controlled trial. J Clin Oncol. Published online September 14, 2021. doi:10.1200/JCO.21.01032
4. Bridgewater JA, Pugh SA, Maishman T, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(3):398-411. doi:10.1016/S1470-2045(19)30798-3