Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival

Abstract

Objective: To evaluate the long-term survival of patients resected for primarily unresectable colorectal liver metastases (CRLM) downstaged by systemic chemotherapy and to use prognostic factors of outcome for a model predictive of survival on a preoperative setting.

Summary background data: Surgery of primarily unresectable CRLM after downstaging chemotherapy is still questioned, and prognostic factors of outcome are lacking.

Methods: From a consecutive series of 1439 patients with CRLM managed in a single institution during an 11-year period (1988-1999), 1104 (77%) initially unresectable (NR) patients were treated by chemotherapy and 335 (23%) resectable were treated by primary liver resection. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined to oxaliplatin (70%), irinotecan (7%), or both (4%) given as chronomodulated infusion (87%). NR patients were routinely reassessed every 4 courses. Surgery was reconsidered every time a documented response to chemotherapy was observed. Among 1104 NR patients, 138 "good responders" (12.5%) underwent secondary hepatic resection after an average of 10 courses of chemotherapy. At time of diagnosis, mean number of metastases was 4.4 (1-14) and mean maximum size was 5.2 cm (1-25). Extrahepatic tumor was present in 52 patients (38%). Multinodularity or extrahepatic tumor was the main cause of initial unresectability. All factors likely to be predictive of survival after liver resection were evaluated by uni- and multivariate analysis. Estimation of survival was adjusted on risk factors available preoperatively.

Results: Seventy-five percent of procedures were major hepatectomies (> or =3 segments) and 93% were potentially curative. Liver surgery was combined to portal embolization, to ablative treatment, or to a second-stage hepatectomy in 42 patients (30%) and to resection of extrahepatic tumor in 41 patients (30%). Operative mortality within 2 months was 0.7%, and postoperative morbidity was 28%. After a mean follow-up of 48.7 months, 111 of the 138 patients (80%) developed tumor recurrence, 40 of which were hepatic (29%), 12 extrahepatic (9%), and 59 both hepatic and extrahepatic (43%). Recurrence was treated in 52 patients by repeat hepatectomy (71 procedures) and in 42 patients by extrahepatic resection (77 procedures). Survival was 33% and 23% at 5 and 10 years with a disease-free survival of 22% and 17%, respectively. It was decreased as compared with that of patients primarily resected within the same period (48% and 30% respectively, P = 0.01). At the last follow-up, 99 patients had died (72%) and 39 (28%) were alive; 25 were disease free (18%) and 14 had recurrence (10%). At multivariate analysis, 4 preoperative factors were independently associated to decreased survival: rectal primary, > or =3 metastases, maximum tumor size >10 cm, and CA 19-9 >100 UI/L. Mean adjusted 5-year survival according to the presence of 0, 1, 2, 3, or 4 factors was 59%, 30%, 7%, 0%, and 0%.

Conclusions: Modern chemotherapy allows 12.5% of patients with unresectable CRLM to be rescued by liver surgery. Despite a high rate of recurrence, 5-year survival is 33% overall, with a wide use of repeat hepatectomies and extrahepatic resections. Four preoperative risk factors could select the patients most likely to benefit from this strategy.

FIGURE 1. Paul Brousse Experience (1988–1999) in the management of colorectal liver metastases.

FIGURE 2. a, A 40-year-old man presenting huge liver metastases not amenable to primary resection because of too large liver involvement and close contact with portal bifurcation, hepatic veins, and vena cava. (b) Tumor downstaging by chemotherapy allowed secondary liver resection by right hepatectomy. The patient is currently alive without recurrence at 5.5 years.

FIGURE 3. A 50-year-old patient with 7 liver metastases requiring both resection of the right liver (segments: 5, 6, 7, 8) (a), and of the left lobe (Segment 2 and 3) (b) impossible to perform in a single procedure. After tumor downstaging by chemotherapy, performance of bisegmentectomy 2, 3 with concomitant right portal branch embolization. Further hypertrophy of segment 4 and segment 1 with right liver atrophy permitted a second-stage right hepatectomy (c). Remnant liver consisted of only segment 4 and segment 1 (d). The patient was alive without recurrence 4.5 years after resection.

FIGURE 4. a, A 56-year-old patient with a 16-cm central synchronous metastasis progressing despite 3 lines of chemotherapy and considered as unresectable. (b) Reduction in size (16 to 6 cm) after chronomodulated chemotherapy with 5-fluorouracil, folinic acid, and oxaliplatin allowed potentially curative left hepatectomy (segments 2, 3, 4) extended to segment 1. No hepatic recurrence but pelvic recurrence of the rectal primary was responsible for the patient's death at 3.2 years after liver resection.

FIGURE 5. Overall and disease-free survival of 138 patients resected for initially unresectable colorectal liver metastases, turned resectable by systemic chemotherapy.

FIGURE 6. Compared survival of liver resection for primarily resectable (n = 335 patients) versus primarily unresectable metastases downstaged by chemotherapy (n = 138 patients).

FIGURE 7. Survival after liver resection in relation to preoperative risk factors: a, rectal primary versus colon primary; b, number of metastases ≥3; c, CA 19–9 >100 UI/L; and d, maximum tumor size >10 cm.

FIGURE 7. Continued.