Based on our experience, the survival time of patients with liver metastasis has increased with the changing times, and the approval of the new drugs after 2005 appears to have influenced this trend. We evaluated the impact on the survival of repeat hepatectomy in the age of advanced systemic chemotherapy. Does systemic chemotherapy alone, repeat hepatectomy, or a multidisciplinary approach improve the prognosis of liver metastases? There are many factors relevant to long-term survival of recurrent liver metastases, improvement of diagnostic imaging like multislice CT, PET, enhanced MRI; surgical instruments; surgeons’ learning curve; perioperative management; anesthesia; and supportive care. Although only a randomized controlled study can answer that question, such a study is prohibitive due to cost, time, and ethical concerns. Especially indication of surgical procedure is important, our principle indication does not change during all the period studied. We investigated the significance of repeat hepatectomy with systemic chemotherapy on outcomes of patients who have undergone standard treatment since 2005.
After the development of FOLFOX and FOLFIRI (5-FU + CPT-11 + leucovorin), the basic current standard treatment regimens since 2005, remnant liver recurrence occurred in 118 (50%) of 236 patients following the initial hepatectomy. Although this result was not noticeably different from that of the previous period, 59 (50%) of the 118 patients underwent repeat hepatectomy. OS time after the last hepatectomy decreased as the number of hepatectomies increased. However, patients who underwent repeat hepatectomy experienced survival time after the initial hepatectomy comparable to that in patients who underwent single hepatectomy. However, in a group of patients who were treated before the new drugs were approved, the survival time increased as the number of hepatectomies increased. Moreover, conversion cases (i.e., cases in which surgical resection was possible after chemotherapy) might have been included in this study. Preoperative chemotherapy was administered to 23 (96%) of the 24 patients with factor H3. Overall, 12 (50%) of the 24 patients were retrospectively regarded as conversion cases and were previously considered not favorable for surgery. Thus, the survival-prolonging effect of surgery alone appears to have diminished accordingly. Conversely, patients with remnant liver recurrence who underwent systemic chemotherapy alone had poor outcomes, with a survival time of 28.7 months. This group of patients could not receive operation for various reasons, e.g., too advanced and poor general condition. Otherwise, randomized study is the only method to clarify which is better for remnant liver metastases, chemotherapy, operation, or combination chemotherapy with repeated operation. But such a study is also prohibitive due to ethical concerns. The 5-year survival rate in multi hepatectomy cases and in chemotherapy cases are 40~50% and 24.2%, respectively. This rate shows operation with systemic chemotherapy achieves cure as well as single hepatectomy cases for the cases with poor prognostic factors of repeat metastases. Thus, combining repeat hepatectomy with systemic chemotherapy is considered beneficial. In previous reports, Jones et al. [
3] stated that repeat hepatectomy was not sufficient for prolonging survival time, whereas Battula et al., Freire, and Andreou et al. reported the effectiveness of aggressive repeat hepatectomy for prolonging survival time [
6‐
9]. Recent reports have documented the survival-prolonging effects of repeat hepatectomy; thus, it is speculated that perioperative and backup drugs have a survival-prolonging effect. On the other hand, Lee et al. reported that repeat hepatectomy for multiple recurrent foci does not contribute to prognosis. Therefore, indications for repeat hepatectomy warrant further discussion [
10]. There was one (1.7%) death due to complications in a patient who underwent two hepatectomies. Although this finding was consistent with previous reports by various investigators [
11], death occurred in two (15.3%) patients who underwent ≥ 3 hepatectomies, which signifies a rather high percentage, and it is possible that surgical stress was too high or underlying liver status was poor in these two patients. Therefore, when performing a second or subsequent hepatectomy, it is critical to carefully assess the functional reserve of the remnant liver. Other complications included infection, bile leak, embolism, and pleural effusion/ascites; however, hospital stay was not increased, indicating that the surgery was safe and feasible. Advances in systemic chemotherapy prolonged survival ≥ 30 months in patients with unresectable advanced/recurrent CRC. In addition, some studies have reported conversion of unresectable metastasis cases to resectable status due to the advent of molecular-targeted drugs with a survival-prolonging effect, and such conversion cases have prolonged survival [
12‐
15]. However, these reports provided only limited data on repeat resection following remnant liver recurrence. In the present study, we administered 2–5 systemic chemotherapy regimens to 55 patients, and 93% of patients undergoing repeat hepatectomy underwent multiple chemotherapy regimens. We believe in aggressively planning repeat hepatectomy when systemic chemotherapy has caused conversion to resectable status. Though the significance of preoperative chemotherapy in patients with resectable foci at the time of recurrence remains unclear [
16‐
18], hepatectomy should be performed whenever possible, and multimodality treatment, including chemotherapy, should be performed in such patients.