Hepatectomy Plus Adjuvant mFOLFOX6 Improves DFS in Liver-Only Metastatic CRC

Yukihide Kanemitsu, MD

Adjuvant chemotherapy with modified fluoropyrimidine, leucovorin, and oxaliplatin (mFOLFOX6) improved disease-free survival (DFS) among patients with liver-only metastases from colorectal cancer (CRC) who were treated with hepatectomy, according to updated results from a phase 2/3 trial (JCOG0603) published in the Journal of Clinical Oncology.¹ However, it remains unclear whether chemotherapy improves overall survival (OS).

At a median follow-up of 59.2 months (range, 26.5-95.3), the updated 5-year DFS rate was 49.8% (95% CI, 41.0%-58.0%) with mFOLFOX6 vs 38.7% (95% CI, 30.4%-46.8%) with hepatectomy alone (HR, 0.67; 95% CI, 0.50-0.92; P = .006). However, adjuvant mFOLFOX6 resulted in an updated 5-year OS rate of 71.2% (95% CI, 61.7% to 78.8%) vs 83.1% (95% CI, 74.9% to 88.9%) with hepatectomy alone.

“Adjuvant chemotherapy with mFOLFOX6 improves DFS compared with hepatectomy alone but causes severe adverse effects [AEs] in approximately half of the patients,” lead study author Yukihide Kanemitsu, MD, of the National Cancer Center, and colleagues, wrote. “Further follow-up and study are needed to determine whether improved DFS translates into improved OS. At this point, routine use of adjuvant FOLFOX is not universally recommended after hepatectomy for liver-only metastatic CRC.”

Hepatectomy is currently considered to be the most effective therapeutic approach for patients with liver-only metastatic CRC, as long-term survival is often unachievable with other treatment modalities. However, hepatectomy alone does not always result in complete cure. Moreover, relapse occurs in 70% to 80% of patients at 5 years—even after curative resection.²

In prior studies, post-hepatectomy adjuvant chemotherapy was found to improve DFS, but determining the OS benefit derived from this approach continues to be controversial. The current recommendations for adjuvant regimens of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were extrapolated from the EORTC Intergroup trial 40983 (NCT00006479), which demonstrated that perioperative FOLFOX resulted in a progression-free survival benefit, but not an OS benefit.^3,4

In this trial, investigators sought to examine the safety and efficacy of post-hepatectomy, adjuvant FOLFOX compared with hepatectomy alone for patients with liver-only metastatic CRC.

The trial enrolled patients between the ages of 20 and 75 years who had histologically confirmed, liver-only metastatic CRC. To be eligible for participation, patients had to have an R0 resection for both the primary tumor and liver metastasis, an ECOG performance status of 0 or 1, and sufficient organ function.

Patients could not have extrahepatic metastasis or recurrence, nor could they have received prior chemotherapy with oxaliplatin or other chemotherapy or radiotherapy within 3 months of enrollment. Prior adjuvant therapy without oxaliplatin following primary resection was permitted if more than 3 months had passed since the last administration.

A total of 300 participants were randomly assigned in a 1:1 fashion to receive adjuvant chemotherapy (n = 151; eligible, n = 146) or hepatectomy alone (n = 149; eligible, n = 137) via a minimization method with a random component to balance the arms on the basis of liver metastatic status (synchronous vs metachronous), number of liver metastases (≤ 3 or ≥ 4), maximum liver metastatic lesion size (< 5 cm vs ≥ 5 cm), number of metastatic lymph nodes from the primary lesion (≤ 3 vs ≥ 4), and institution.

In the adjuvant chemotherapy arm, mFOLFOX6 was initiated 56 to 84 days following hepatectomy; this course was repeated every 2 weeks for 12 courses until progressive disease or intolerable toxicity.

Treatment was discontinued if recurrence was diagnosed clinically or based on imaging findings. Discontinuation was also elected if a serious AE occurred, if the treatment course was delayed for more than 28 days because of an AE, if a third dose reduction because of AEs was required, if the patient declined treatment, or if judged necessary by the attending physician for other reasons.

The primary end point of the trial was DFS, and the key secondary end points included OS, incidence of AEs, and patterns of recurrence.

Patient characteristics were well balanced between the treatment arms. The median age of the hepatectomy-alone group was 65 years (range, 58-69) compared with 63 years (range, 56-69) in the mFOLFOX6 group. In the investigative and control arms, 83% and 81% of patients, respectively, had 0 to 3 metastatic lymph nodes from the primary tumor and 17% and 19% of patients, respectively, had 4 or more nodes.

Regarding the number of liver metastases, 91% of patients in the hepatectomy-alone arm had 1 to 3, as did 90% of those in the chemotherapy arm; 9% and 10% of patients, respectively, had 4 or more. Moreover, in the control and investigative arms, 55% and 56% of patients, respectively, had synchronous liver metastasis, and 45% and 44% of patients, respectively, had metachronous liver metastasis. The maximum liver metastatic lesion size was less than 5 cm in 87% and 85% of patients, respectively; it was 5 cm or larger in 13% and 15% of patients, respectively.

In the chemotherapy arm, 85 patients (56%) completed the 9 courses of mFOLFOX6, and 67 (44%) completed the planned 12 courses. Additionally, 10 patients (7%) did not start treatment and were excluded from the safety analysis.

Additional data showed that the 3-year DFS rates with chemotherapy and hepatectomy-alone were 52.7% (95% CI, 44.0%-60.7%) and 42.6% (95% CI, 34.3%-50.6%), respectively. The 3-year OS rates in the investigative and control arms were 87.2% (95% CI, 80.2%-91.9%) and 91.8% (95% CI, 85.7%-95.4%), respectively.

DFS subgroup analyses revealed an advantage with chemotherapy over hepatectomy alone except primary site and prior treatment received. In contrast, OS subgroup analyses indicated that no subsets derived benefit from chemotherapy. Another observation was that those who received adjuvant chemotherapy without oxaliplatin following primary resection experienced poorer prognosis than those who did not have prior treatment.

“There was a tendency for an interaction between primary site and treatment for DFS and between prior treatment and treatment for OS,” the study authors noted.

Additionally, more patients who received hepatectomy alone experienced disease recurrence vs those who received chemotherapy, at 56% and 45%, respectively. Recurrence in the remnant liver proved to be more prevalent in the control arm vs the investigative arm, at 51% and 37%, respectively. However, recurrence in the lungs and other distant metastasis proved to be more prevalent in the investigative arm vs the control arm, at 63% and 48%, respectively.

In terms of safety, the most common grade 3 or higher severe AEs in the chemotherapy arm (n = 141) were neutropenia (50%), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after receiving 3 courses of mFOLFOX6.

“A future prospective randomized study is needed to investigate the role of biomarkers in determining subgroups that might benefit from chemotherapy after hepatectomy for liver-only metastatic CRC,” the study authors concluded.

References

1. 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. 2021;39(34):3789-3799. doi:10.1200/JCO.21.01032
2. Kemeny N. The management of resectable and unresectable liver metastases from colorectal cancer. Curr Opin Oncol. 2010;22(4):364-73. doi:10.1097/CCO.0b013e32833a6c8a
3. 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
4. Nordlinger B, Sorbye H, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007-1016. doi:10.1016/S0140-6736(08)60455-9