Ann Surg Oncol DOI 10.1245/s10434-013-3421-8
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Early Recurrence After Liver Resection for Colorectal Metastases: Risk Factors, Prognosis, and Treatment. A LiverMetSurvey-Based Study of 6,025 Patients Luca Vigano`, MD1, Lorenzo Capussotti, MD1, Re´al Lapointe, MD, FCRSC2, Eduardo Barroso, MD3, Catherine Hubert, MD4, Felice Giuliante, MD5, Jan N. M. Ijzermans, MD, PhD6, Darius F. Mirza, MD, FRCS7, Dominique Elias, MD, PhD8, and Rene´ Adam, MD, PhD9 Department of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Turin, Italy; 2Department of Surgery, Hepatobiliary and Pancreatic Surgery Division, University of Montreal, Montreal, QC, Canada; 3Department of HPB Surgery and Transplantation, Curry Cabral Hospital, Lisbon, Portugal; 4Unit of HPB Surgery, Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium; 5Department of Surgery, Hepatobiliary Unit, Catholic University of the Sacred Heart School of Medicine, Rome, Italy; 6Department of Transplantation and Hepatobiliary Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands; 7Liver Unit, Queen Elizabeth Hospital, Birmingham, UK; 8Department of Surgery, Institute Gustave Roussy, Villejuif, France; 9Centre He´pato-Biliaire, AP-HP Hoˆpital Paul Brousse, Villejuif, France 1
ABSTRACT Purpose. The aims of this study were to assess the risk of early recurrence after liver resection for colorectal metastases (CRLM) and its prognostic value; identify early recurrence predictive factors; clarify the effect of perioperative chemotherapy on its occurrence; and elucidate the best early recurrence management. Methods. Patients of the LiverMetSurvey registry who underwent complete liver resection (R0/R1) between 1998 and 2009 were reviewed. Early recurrence was defined as any recurrence that occurred within 6 months after resection. Results. A total of 6,025 patients were included; 2,734 (45.4 %) had recurrence, including 639 (10.6 %) early recurrences. Early recurrence was mainly hepatic (59.5 vs. 54.4 % for late recurrences; p = 0.023). Independent risk factors of early recurrence were: T3–4 primary tumor (p = 0.0002); synchronous CRLM (p = 0.0001); [3 CRLM (p \ 0.0001); 0-mm margin liver resection (p = 0.003); and associated intraoperative radiofrequency ablation (p = 0.0005). Response to preoperative chemotherapy (complete/partial) and administration of adjuvant
Ó Society of Surgical Oncology 2013 First Received: 22 July 2013 L. Vigano`, MD e-mail: [email protected]
chemotherapy reduced early recurrence risk (p = 0.003 and p \ 0.0001, respectively). Intraoperative ultrasonography reduced hepatic early recurrence rate (p = 0.025). Early recurrence negatively affected prognosis: 5-year survival 26.9 versus 49.4 % for the late recurrence group (p \ 0.0001, median follow-up 34.4 months). Overall, 234 (36.6 %) patients with early recurrence underwent reresection. These patients had survival rates higher than non-re-resected patients (5-year survival 47.2 vs. 8.9 %; p \ 0.0001) and similar to re-resected patients for late recurrence (48.7 %). Chemotherapy before early recurrence resection improved later survival (5-year survival 61.5 vs. 43.7 %; p = 0.028). Conclusions. Early recurrence risk is enhanced for extensive disease after poor preoperative disease control and inadequate surgical treatment, but is reduced after adjuvant chemotherapy. Although early recurrence negatively affects prognosis, re-resection may restore better survival. Chemotherapy before early recurrence resection is advocated.
Liver resection is the gold-standard treatment for colorectal liver metastases (CRLM). Combined with chemotherapy, complete resection achieves 5-year survival rates of up to 60 %.1–5 Despite these excellent results, recurrence-free survival rates are lower and many surviving patients experience recurrence.6–9 Approximately 60 % of patients will develop recurrence during follow-up, the majority within the first
L. Vigano` et al.
2 years.6 Aggressive treatment of recurrence, including chemotherapy and re-resection when feasible, has been adopted worldwide for both hepatic and extrahepatic disease in selected patients.10–12 Survival results after recurrence resection are similar to those after the first hepatectomy provided that complete resection is performed.10–12 The benefit of surgery may be questioned in patients with early recurrence after liver resection. To date, management of early recurrences is not well-defined, and questions of whether re-resection should be performed and whether preoperative chemotherapy should be added are open for discussion.13,14 The aims of the present study were to depict the incidence of early recurrence and analyze the outcome of patients with early recurrence in a large, multicentric setting; to identify predictive factors of early recurrence; and to evaluate the outcome of re-resection of early recurrence, either with or without preoperative chemotherapy. METHODS Data Collection LiverMetSurvey (LMS; www.livermetsurvey.org) is a prospective international registry of patients undergoing surgery for CRLM. The registry characteristics have been reported previously.15 In brief, data concerning the characteristics of the primary tumor and metastases, liver resection, perioperative treatments, recurrence, and survival are entered into the registry, using a standardized questionnaire completed online. Data about recurrence include its site, date of appearance, and treatment. Data quality control is assessed by online queries and offline requests. Follow-up data are updated online by each center, with a global review by the data manager every 6 months. Study Design Patients undergoing liver resection between January 1998 and June 2009 were included. A minimum follow-up of 6 months was mandatory for all patients. Patients with a follow-up \6 months, or with an incomplete resection (R2 resection) or a two-stage hepatectomy were excluded from the present analysis. Patients with operative mortality (noncancer-related 90-day mortality) were also excluded. Follow-up was updated to 31 December 2011.
within 6 months after liver resection have the poorest outcome. According to these data, early recurrence was defined as any recurrence occurring within 6 months after liver resection. The same time interval was adopted by Malik et al.13 in their study about early recurrences after liver resection for CRLM. Patient characteristics and details of surgical treatment and perioperative chemotherapy were analyzed to identify predictive factors of early recurrence. Primary tumor was staged according to the 6th edition of the TNM staging system for colorectal cancer17. The carcinoembryonic antigen (CEA) value and the characteristics of metastases, including number and diameter, were registered at the time of diagnosis. Synchronous metastases were defined as liver metastases diagnosed before colorectal resection or at the time of surgery. Response to chemotherapy was classified according to WHO criteria,18 which present an absolute agreement with RECIST criteria.19 In case of multiple chemotherapy lines, the response to the last regimen was considered. Overall survival (OS) for early and late recurrence groups were computed and compared. The OS after early recurrence resection was analyzed and compared with the OS of untreated early recurrences and the OS after resection of late recurrences. The analyses of OS after recurrence only included patients with at least a 6-month follow-up after recurrence. Statistical Analysis Categorical variables were compared using the v2 test. A multivariate analysis was performed using a logistic regression model to identify independent factors associated with early recurrence. The Kaplan–Meier method was used to estimate survival probabilities, which were compared using the Log-rank test. A multivariate analysis was performed using a Cox proportional hazard model to identify independent prognostic factors of OS after early recurrence resection. A p value B 0.05 was considered statistically significant. Multivariate analysis was completed for factors with a p value B 0.10 upon univariate analysis. RESULTS As of December 2011, 16,779 patients have been registered in the LMS database by 235 centers in 63 countries. The present study included 6,025 patients who had onestage liver resection between January 1998 and June 2009, complete surgery, and no 90-day mortality.
Parameters Studied Patient Characteristics and Chemotherapy Details In 2006, Takahashi et al.16 showed that time to recurrence after liver resection for CRLM correlates with prognosis and that patients with disease recurrence
Among the 6,025 patients, CRLM were synchronous to the primary tumor in 3,015 (50.0 %) patients; [3 metastases
Recurrence After Colorectal Metastases Resection
(synchronous or metachronous) were noted in 1,046 (17.4 %) patients, and metastases [50 mm were observed in 1,103 (18.3 %) patients. Associated extrahepatic disease was present in 417 (6.9 %) patients, and was pulmonary in one-third of patients (n = 139). Preoperative staging included hepatic magnetic resonance imaging (MRI) in 37.8 % of patients, and positron emission tomography/computed tomography (PET– CT) in 35.2 % of patients. A total of 4,682 patients (77.7 %) had intraoperative hepatic ultrasonography (IOUS). In total, 2,249 (37.3 %) patients had chemotherapy before liver resection. Of these, chemotherapy was ‘conversion’ type in 587 initially unresectable patients. The last chemotherapy regimen included oxaliplatin in 1,086 (48.3 %) patients, irinotecan in 546 (24.3 %) patients, and both agents in 134 (6.0 %) patients. Bevacizumab was administered in 382 (17.0 %) patients and cetuximab was administered in 127 (5.6 %) patients. Preoperative chemotherapy included [6 cycles in 829 (36.9 %) patients, and at least two lines in 331 (14.7 %) patients. The tumor response to the last chemotherapy line before surgery was complete response (CR) in 75 (3.8 %) patients, partial response (PR) in 1,318 (66.9 %) patients, stable disease (SD) in 435 (22.1 %) patients, and disease progression (PD) in 143 (7.2 %) patients. In all, 2,820 (46.8 %) patients received adjuvant chemotherapy (median 6 cycles).
Considering technical data, early recurrence risk was decreased among patients undergoing anatomic resections (9.6 vs. 12.0 %; p \ 0.0001) and increased among patients who had intraoperative radiofrequency ablation associated with resection (18.3 vs. 9.9 %; p \ 0.0001), patients with a 0-mm liver resection margin (17.4 vs. 10.5 %; p \ 0.0001), and patients requiring perioperative blood transfusions (12.8 vs. 10.3 %; p = 0.026). The results of univariate analysis are summarized in Table 1. Chemotherapy and Early Recurrence Risk The early recurrence rate was not reduced by preoperative chemotherapy overall; however, it was associated with the tumor response to treatment. Early recurrence rate was 5.3 % in patients with CR, 14.2 % in patients with PR, 19.3 % in patients with SD, and 23.1 % in patients with PD (p \ 0.0001). The risk of early recurrence was increased among patients with [6 cycles of chemotherapy (20.7 vs. 11.9 %; p \ 0.0001) and among those receiving at least two chemotherapy lines (21.5 vs. 14.0 %; p \ 0.0001). Chemotherapy regimen and targeted therapies did not affect early recurrence risk. Early recurrence was reduced among patients who received adjuvant chemotherapy (9.4 vs. 14.5 %; p \ 0.0001).
Recurrences Recurrences were noted in 2,734 (45.4 %) patients, including 639 (10.6 %; 23.4 % of recurrences) early recurrences (B6 months after liver resection). Hepatic recurrences were more common in the early recurrence group than in the late recurrence group (59.5 vs. 54.4 %; p = 0.023), while extrahepatic recurrences were more common in the late recurrence group (33.6 vs. 27.4 %; p = 0.003). Hepatic?extrahepatic recurrences were similar in the two groups. Patient Characteristics and Early Recurrence Risk The risk of early recurrence was increased among patients with advanced T stage (T3–4, 11.5 % vs. T0–2, 6.9 %; p = 0.0002), node-positive primary tumor (11.8 vs. 8.9 %; p = 0.001), synchronous metastases (13.4 vs. 7.8 %; p \ 0.001), [3 liver deposits (17.1 vs. 9.1 %; p \ 0.0001), bilobar lesions (15.0 vs. 8.9 %; p \ 0.0001), and CEA value [ 200 ng/dL (16.2 vs. 10.6 %; p = 0.006). Patients resectable at diagnosis had early recurrence in 9.8 % of cases versus 17.4 % of initially unresectable cases (p \ 0.0001). Preoperative hepatic MRI and PET-CT did not reduce early recurrence risk (10.7 % if MRI vs. 10.7 % if not; p = not significant; 11.8 % if PET-CT vs. 11.3 % if not; p = not significant). In patients without extrahepatic disease, IOUS lowered the risk of early hepatic recurrence (5.2 vs. 7.2 %; p = 0.025).
Multivariate Analysis of Factors Associated with Early Recurrence At multivariate analysis (Table 1), the response to preoperative chemotherapy (CR/PR vs. SD/PD) and the administration of adjuvant chemotherapy were independent protective factors against early recurrence [p = 0.003, odds ratio (OR) 0.588; and p \ 0.0001, OR 0.430, respectively]. Five independent risk factors of early recurrence were identified: T3–4 stage of the primary tumor (p = 0.0002, OR 2.017); synchronous CRLM (p = 0.0001, OR 1.579); [3 liver metastases (p \ 0.0001, OR 1.835); 0-mm margin of liver resection (p = 0.003, OR 1.564); and intraoperative radiofrequency ablation associated with liver resection (p = 0.0005, OR 1.768). A separate multivariate analysis was performed focusing on patients with hepatic early recurrence (patients with extrahepatic recurrence were excluded). The same independent risk factors were identified. Patient Outcome After a median follow-up of 34.4 months, 3-, 5- and 10-year OS rates were 69.8, 52.3, and 34.8 %, respectively (median survival 65.4 months). Survival was decreased in patients with early recurrence: 5-year OS was 26.9 vs. 49.4 % in the late recurrence group (p \ 0.0001; Fig. 1).
L. Vigano` et al. TABLE 1 Univariate and multivariate analysis of factors associated with occurrence of early recurrence after resection of colorectal liver metastases Parameter (n)
Early recurrence [n (%)]
Univariate analysis
Multivariate analysis— whole series (n = 6,025)
Multivariate analysis— patients with preop CTx (n = 2,249)
p value
p value
p value
NS
–
–
0.014
NS
NS
T3-4 vs. T0-2 0.005
0.0002
0.001
NS
NS
NS
–
–
\0.0001
0.0001
\0.0001
NS
\0.0001
\0.0001
NS
–
–
NS
–
–
0.006
NS
NS
253 (15.0) 383 (8.9)
\0.0001
NS
NS
Yes (4,794)
470 (9.8)
\0.0001
NS
NS
No (707)
123 (17.4)
OR (95 % CI)
OR (95 % CI)
Patient characteristics Sex Male (3,689)
372 (10.1)
Female (2,336)
267 (11.4)
Age, years [70 (1,530)
137 (9.0)
B70 (4,480)
502 (11.2)
Primary tumor characteristics T stage 0 (19) 1 (90)
2 (10.5) 4 (4.4)
2 (617)
44 (7.1)
3 (3,465)
395 (11.4)
4 (847)
101 (11.9)
2.017 (1.388–2.930)
0.002
2.614 (1.427–4.787)
N status Negative (1,918)
170 (8.9)
Positive (3,139)
374 (11.8)
Rectal tumor Yes (1,998)
225 (11.3)
No (3,791)
407 (10.7)
Liver metastases characteristics Synchronous metastases Yes (3,015)
405 (13.4)
No (2,982)
234 (7.8)
Single metastasis Yes (2,880) No (2,937)
231 (8.0)
1.579 (1.251–1.991)
NS
NS
384 (13.1)
[3 metastases Yes (1,046)
179 (17.1)
No (4,771)
436 (9.1)
1.835 (1.415–2.380)
0.0001
Metastases diameter [ 50 mm Yes (1,103)
125 (11.3)
No (4,142)
431 (10.4)
Metastases diameter [ 100 mm Yes (197)
20 (10.2)
No (5,048)
536 (10.6)
CEA [ 200 ng/dL Yes (253)
41 (16.2)
No (3,404)
361 (10.6)
Bilobar metastases Yes (1,686) No (4,310) Resectability at diagnosis
1.953 (1.388–2.748)
Recurrence After Colorectal Metastases Resection TABLE 1 continued Parameter (n)
Early Univariate recurrence analysis [n (%)]
Multivariate analysis— whole series (n = 6,025)
Multivariate analysis— patients with preop CTx (n = 2,249)
p value
p value
p value
NS
–
–
NS
NS
OR (95 % CI)
OR (95 % CI)
Extrahepatic disease Yes (417)
52 (12.5)
No (5,608)
587 (10.5)
Surgical procedures and operative outcome Type of hepatectomy AR (2,837)
271 (9.6) \0.0001
NAR (1,636)
197 (12.0)
AR ? NAR (1,298)
161 (12.4)
Associated intraoperative radiofrequency ablation 85 (18.3) \0.0001 547 (9.9)
0.0005
Yes (112)
10 (8.9)
–
No (5,508)
580 (10.5)
Yes (464) No (5,498)
1.768 (1.282–2.439) 0.030
1.610 (1.046–2.478)
Laparoscopic resection NS
–
Surgical margin 0 mm (602)
105 (17.4) \0.0001
[0 mm (4,079)
430 (10.5)
0.003
1.564 (1.163–2.104) 0.047
Blood transfusion Yes (946)
121 (12.8) 0.026
No (3,644)
374 (10.3)
NS
NS
–
–
Chemotherapy After colorectal surgery (synchronous metastases excluded) Yes (1,614)
137 (8.5)
No (1,064)
82 (7.7)
NS
Before liver resection Yes (2,249)
339 (15.1) \0.0001
No (3,345)
286 (8.6)
NS
Last chemotherapy regimen Oxaliplatin (1,086)
159 (14.6) NS
Irinotecan (546)
89 (16.3)
Oxaliplatin?irinotecan (134)
29 (21.6)
Other (297)
52 (17.5)
–
Associated bevacizumab Yes (382)
62 (16.2)
No (1,682)
264 (15.7)
NS
–
26 (20.5) NS 301 (15.5)
–
Yes (331)
71 (21.5) \0.0001
NS
No (1,918)
268 (14.0)
Associated cetuximab Yes (127) No (1,937) [1 line
[6 cycles Yes (829)
172 (20.7) \0.0001
No (1,036)
123 (11.9)
NS
1.477 (1.005–2.171)
L. Vigano` et al. TABLE 1 continued Parameter (n)
Early Univariate recurrence analysis [n (%)] p value
Multivariate analysis— whole series (n = 6,025)
Multivariate analysis— patients with preop CTx (n = 2,249)
p value
p value
OR (95 % CI)
OR (95 % CI)
[6 cycles at the last line Yes (655)
130 (19.8) \0.0001
No (1,202)
161 (13.4)
NS
Response CR (75)
4 (5.3)
PR (1,318)
187 (14.2)
SD (435)
84 (19.3)
PD (143)
33 (23.1)
CR/PR vs. SD/PD \ 0.0001
0.003
0.588 (0.412–0.835)
After liver resection Yes (2,820)
264 (9.4) \0.0001
No (1,982)
287 (14.5)
\0.0001 0.451 (0.360–0.563) \0.0001 0.430 (0.312–0.592)
Preop preoperative, CTx chemotherapy, OR odds ratio, NS not significant, CEA carcinoembryonic antigen, AR anatomic resection, NAR nonanatomic resection, CR complete response, PR partial response, SD stable disease, PD disease progression
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence
639
478
262
130
73
42
Late recurrence
2095
2006
1595
1054
638
366
FIG. 1 Overall survival of patients with early recurrence versus those with late recurrence (p \ 0.0001)
Early Recurrence Treatment A total of 234 (36.6 %) patients with early recurrence underwent re-resection; this re-resection rate was lower than in
patients with late recurrence (47.2 %; p \ 0.0001). This difference was observed for all recurrence sites (hepatic: 46.6 vs. 60.1 %, p \ 0.0001; extrahepatic: 29.8 vs. 37.2 %, p = 0.042; hepatic?extrahepatic: 7.1 vs. 19.5 %, p = 0.004).
Recurrence After Colorectal Metastases Resection
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence resection
223
184
137
77
52
28
No early recurrence resection
354
204
81
23
14
6
FIG. 2 Overall survival of patients with resected early recurrence versus those with unresected early recurrence (p \ 0.0001)
In the early recurrence group, re-resected patients had higher OS than non-re-resected patients (Fig. 2). After a median follow-up after recurrence of 24.3 months, 5-year OS was 47.2 % in re-resected patients versus 8.9 % in unresected patients (p \ 0.0001). The same results were observed regarding both hepatic recurrences (5-year OS 51.3 vs. 8.3 %; p \ 0.0001) and extrahepatic/hepatic? extrahepatic recurrences (35.7 vs. 10.4 %; p \ 0.0001). Early recurrence resection achieved OS results similar to those achieved after late recurrence resection, both considering hepatic recurrences (5-year OS 51.3 vs. 48.7 %; p = not significant; Fig. 3a) and extrahepatic/hepatic?extrahepatic recurrences (5-year OS 35.7 vs. 45.0 %; p = not significant; Fig. 3b). Prognostic Factors After Early Recurrence Resection The administration of chemotherapy before early recurrence resection improved survival (5-year OS 61.5 vs. 43.7 %; p = 0.021), as did the response to preoperative chemotherapy (5-year OS CR/PR 63.0 vs. SD/PD 46.5 %; p = 0.014). Multivariate analysis confirmed the positive prognostic role of chemotherapy administration before recurrence resection [p = 0.028, hazard ratio (HR) 0.529], but did not confirm the prognostic role of response to chemotherapy. Two additional negative prognostic factors were identified at multivariate analysis: [3 liver
metastases at first liver resection (5-year OS 3.7 vs. 32.5 %; p = 0.003; HR 2.387) and recurrence diameter [ 50 mm (5-year OS 0 vs. 20 %; p = 0.0003; HR 4.748). The results of uni- and multivariate analysis are summarized in Table 2. DISCUSSION Liver resection in association with perioperative chemotherapy increases the survival of patients with CRLM.1–3 Despite the reported excellent outcomes,1–5 recurrence after resection is common and may occur in up to 60 % of patients.6 Re-resection is indicated whenever feasible because it achieves results similar to the first liver resection.10–12 However, these recommendations do not consider the timing of recurrence. If recurrence happens early, the indication of a second resection may be questioned. Few papers have specifically analyzed this issue and did not offer any conclusive data about indications and treatment schedules.13,14 Because of the large number of collected patients in a short and recent period, the present study offers a way to clarify controversial issues related to the management of patients with early recurrence. Theoretically, modern imaging, accurate surgical technique, and extensive adoption of perioperative chemotherapy should prevent early recurrence. In practice, early recurrence occurs in *10 % of patients. Hence, surgeons and oncologists
L. Vigano` et al.
(a) Overall survival (%) 1.0
0.8
0.6
0.4
Early recurrence resection Late recurrence resection
0.2
0
1
2
3
4
5
6
Years
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence resection
166
137
107
59
41
22
Late recurrence resection
606
530
371
229
137
85
(b) Overall survival (%) 1.0
0.8
0.6
0.4
Early recurrence resection Late recurrence resection
0.2
0
1
2
3
4
5
6
Years
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence resection
57
47
30
18
11
6
Late recurrence resection
304
239
155
91
50
22
FIG. 3 Overall survival after resection of early versus late recurrences: a hepatic-only recurrences; b extrahepatic recurrence (alone or in association with hepatic-only recurrences) (p = not significant for both)
who aggressively treat patients with CRLM frequently face this problem. Early recurrence is more common in patients with aggressive disease, such as those with synchronous and multiple metastases, or advanced T and N staging. The well-known prognostic impact of these parameters has been confirmed.20–22 The extension of surgical indications to more aggressive diseases implies an increased risk of early recurrence as long as adequate selection criteria to
identify patients who really benefit from surgery are lacking. Early recurrences were also related to some technical issues. A complete (R0) surgery is considered mandatory; however, a debate about the adequate width of the surgical margin is ongoing.23–26 A recent paper by de Haas et al. even denied that a 0-mm margin has a significant impact on OS, although recurrence risk was increased.27 The present study reaffirms the inadequacy of a 0-mm margin, which is
Recurrence After Colorectal Metastases Resection TABLE 2 Prognostic factors regarding overall survival after reresection to treat early recurrence Parameter
Univariate analysis p value
Multivariate analysis p value HR (95 % CI)
Patient and primary tumor characteristics Sex
NS
–
Age [ 70 years
NS
–
T3–4 stage
NS
–
N?
NS
–
Rectal tumor
NS
–
Synchronous metastases
NS
–
First liver resection data
Single metastasis
NS
–
[3 metastases
0.016
0.003
Metastases diameter [ 50 mm
NS
–
CEA [ 200 ng/dL
NS
–
Bilobar metastases
NS
–
Extrahepatic disease
NS
–
Type of hepatectomy (AR vs. NAR)
NS
–
Associated RFA
NS
–
Surgical margin (0 vs. [ 0 mm)
NS
–
–
2.387 (1.334–4.270)
Recurrence characteristics Single metastasis
NS
[3 metastases
NS
–
Diameter [ 50 mm
0.0005
0.0003 4.748 (2.045–11.027)
CEA [ 200 ng/dL
NS
–
After colorectal surgery (synchronous metastases excluded)
NS
–
Before first liver resection
NS
–
After first liver resection
NS
–
Before ER resection
0.021
0.028
Chemotherapy data
Oxaliplatin
NS
Irinotecan
NS
Associated bevacizumab
NS
0.529 (0.299–0.934)
Associated cetuximab NS [1 chemotherapy line NS [6 cycles
0.020
NS
Response (CR/PR vs. 0.014 SD/PD)
NS
After ER resection
NS
–
HR hazard ratio, NS not significant, ER early recurrence, CEA carcinoembryonic antigen, AR anatomic resection, NAR non-anatomic resection, RFA radiofrequency ablation, CR complete response, PR partial response, SD stable disease, PD disease progression
associated with an increased risk of early recurrence. Tumor re-growth at the lesion borders (‘dangerous halo’) or micrometastases might justify these data.25,28,29 An additional technical issue was the association of intraoperative radiofrequency ablation with liver surgery. Interstitial treatments are less effective than surgery in CRLM treatment.30,31 Even in association with surgery to ablate deeply located nodules, radiofrequency ablation has worse outcomes than resection alone.32 The present study confirmed these data. The distinction between recurrences at the surgical margin and true new hepatic nodules (data not available in the LMS database) will be helpful in future studies to further confirm the impact of surgical margin and interstitial treatments on early recurrence risk. Finally, the role of IOUS was emphasized. Several studies have shown that IOUS might detect additional hepatic lesions missed by preoperative imaging.33–36 In the present series, patients receiving IOUS had lower risk of hepatic early recurrence, suggesting a better completion of disease staging at surgery. The surgeon may strongly affect all of these technical issues. Finally, the impact of chemotherapy must be considered. Perioperative chemotherapy improves disease-free survival in resected patients.37 In the present study, preoperative chemotherapy per se did not reduce early recurrence risk. Differences were observed neither for different regimens nor for different targeted therapies. The response to chemotherapy was important, rather than the chemotherapy itself—the better the tumor response, the lower the early recurrence rate. The prognostic role of tumor response to preoperative chemotherapy was confirmed.15,38 On the other hand, adjuvant chemotherapy had a protective effect against early recurrence. Considering that even ad hoc randomized trials did not clarify the indications for adjuvant treatment,39,40 no recommendations can be formulated. In any case, adjuvant treatment reduced the early recurrence risk by one-third. The present results confirmed that cooperation between surgeons and oncologists is mandatory when treating CRLM patients, especially when aggressive indications are present. Lower survival was observed in patients with early recurrence than in patients with late recurrence. Delay of recurrence is a well-known prognostic factor.14,16,20,21 In any case, early recurrence should not be considered a ‘game over’ situation. Re-resection can be evaluated and should be scheduled whenever possible; it significantly improves outcome compared with non-surgical treatments, and achieves the same survival results as resection of late recurrences. These considerations were valid not only for hepatic-only recurrences, but also for extrahepatic deposits. Therefore, the concept of surgery as the standard treatment for recurrent metastases can be extended even to early recurrences.
L. Vigano` et al.
Once again, the problem of patient selection plays a pivotal role in the outcome. Patient selection is even more important considering that an early recurrence after liver surgery occurred; a new recurrence after re-resection would clearly demonstrate the uselessness of treatment. The present study helps to define a treatment protocol. It may be preferred to schedule re-resection after a new chemotherapy line, thus allowing patient selection and control of rapidly progressing disease. In fact, patients with preoperative treatment experienced better survival. The role of response to chemotherapy could not be confirmed in the multivariate analysis, and was likely masked by the surgeon’s selection criteria of patients to be re-resected. Of course, the results of this study should be validated prospectively on a separate patient cohort, and the impact of chemotherapy is difficult to evaluate outside of a clinical trial. The administration of preoperative treatment to more advanced patients might hide its beneficial effect. At the same time, the protective effect of adjuvant chemotherapy might be related to a delay in recurrence or a delay in diagnosis due to a different follow-up schedule. Nevertheless, owing to the large number of patients, a significant contribution of chemotherapy to early recurrence reduction is strongly suggested, and the administration of chemotherapy before early recurrence resection can be reasonably recommended to select the good candidates.
4.
5.
6.
7.
8.
9.
10.
11.
12.
CONCLUSIONS Early recurrence occurs in *10 % of patients undergoing liver resection for CRLM. Its risk is increased in cases of aggressive disease, poor preoperative disease control, and non-optimal surgical treatment (0-mm margin; associated intraoperative radiofrequency ablation). IOUS reduces the hepatic early recurrence rate. Although early recurrence negatively affects prognosis, re-resection has the potential to restore better survival. Chemotherapy is advocated before early recurrence resection to adequately select good candidates and to control rapidly progressive disease. DISCLOSURE
13.
14.
15.
16.
The authors have no conflicts of interest to declare. 17.
REFERENCES 18. 1. Adam R, De Gramont A, Figueras J, et al. The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus. Oncologist. 2012; 17(10):1225–1239. 2. Kopetz S, Chang GJ, Overman MJ, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–3683. 3. Wieser M, Sauerland S, Arnold D, Schmiegel W, ReinacherSchick A. Peri-operative chemotherapy for the treatment of resectable liver metastases from colorectal cancer: a systematic
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review and meta-analysis of randomized trials. BMC Cancer. 2010;10:309. House MG, Ito H, Go¨nen M, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg. 2010;210(5):744–752. Vigano` L, Russolillo N, Ferrero A, Langella S, Sperti E, Capussotti L. Evolution of long-term outcome of liver resection for colorectal metastases: analysis of actual 5-year survival rates over two decades. Ann Surg Oncol. 2012;19(6):2035–2044. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg. 2009;250(3):440–448. Tanaka K, Shimada H, Ueda M, Matsuo K, Endo I, Togo S. Long-term characteristics of 5-year survivors after liver resection for colorectal metastases. Ann Surg Oncol. 2007;14(4): 1336–1346. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575–4580. Vigano` L, Ferrero A, Lo Tesoriere R, Capussotti L. Liver surgery for colorectal metastases: results after 10 years of follow-up. Long-term survivors, late recurrences, and prognostic role of morbidity. Ann Surg Oncol. 2008;15(9):2458–2464. Adam R, Pascal G, Azoulay D, Tanaka K, Castaing D, Bismuth H. Liver resection for colorectal metastases: the third hepatectomy. Ann Surg. 2003;238(6):871–883. Petrowsky H, Gonen M, Jarnagin W, et al. Second liver resections are safe and effective treatment for recurrent hepatic metastases from colorectal cancer: a bi-institutional analysis. Ann Surg. 2002;235(6):863–871. Imamura H, Kawasaki S, Miyagawa S, Ikegami T, Kitamura H, Shimada R. Aggressive surgical approach to recurrent tumors after hepatectomy for metastatic spread of colorectal cancer to the liver. Surgery. 2000;127(5):528–535. Malik HZ, Gomez D, Wong V, et al. Predictors of early disease recurrence following hepatic resection for colorectal cancer metastasis. Eur J Surg Oncol. 2007;33(8):1003–1009. Kaibori M, Iwamoto Y, Ishizaki M, et al. Predictors and outcome of early recurrence after resection of hepatic metastases from colorectal cancer. Langenbecks Arch Surg. 2012; 397(3): 373–381. Vigano` L, Capussotti L, Barroso E, et al. Progression while receiving preoperative chemotherapy should not be an absolute contraindication to liver resection for colorectal metastases. Ann Surg Oncol. 2012;19(9):2786–2796. Takahashi S, Konishi M, Nakagohri T, Gotohda N, Saito N, Kinoshita T. Short time to recurrence after hepatic resection correlates with poor prognosis in colorectal hepatic metastasis. Jpn J Clin Oncol. 2006;36(6):368–375. Greene FL, American Joint Committee on Cancer. American Cancer Society. AJCC cancer staging manual. 6th ed. New York: Springer; 2002. World Health Organization. Handbook for reporting results of cancer treatment. WHO offset publication no. 48-. Geneva: World Health Organization; 1979. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–216. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer. 1996;77:1254–1262.
Recurrence After Colorectal Metastases Resection 21. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–321. 22. Ribero D, Vigano` L, Amisano M, Capussotti L. Prognostic factors after resection of colorectal liver metastases: from morphology to biology. Future Oncol. 2013;9(1):45–57. 23. Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241(5):715–722. 24. Are C, Gonen M, Zazzali K, et al. The impact of margins on outcome after hepatic resection for colorectal metastases. Ann Surg. 2007;246(2):295–300. 25. Kokudo N, Miki Y, Sugai S, et al. Genetic and histological assessment of surgical margins in resected liver metastases from colorectal carcinoma: minimum surgical margins for successful resection. Arch Surg. 2002;137(7):833–840. 26. Nuzzo G, Giuliante F, Ardito F, et al. Influence of surgical margin on type of recurrence after liver resection for colorectal metastases: a single-center experience. Surgery. 2008;143(3): 384–393. 27. de Haas RJ, Wicherts DA, Flores E, Azoulay D, Castaing D, Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008; 248(4):626–637. 28. Mentha G, Terraz S, Morel P, et al. Dangerous halo after neoadjuvant chemotherapy and two-step hepatectomy for colorectal liver metastases. Br J Surg. 2009;96(1):95–103. 29. Vigano` L, Capussotti L, De Rosa G, Oulhaci De Saussure W, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response and micrometastases on long-term survival. Ann Surg. 2013;258(5):731–740. 30. Cirocchi R, Trastulli S, Boselli C, et al. Radiofrequency ablation in the treatment of liver metastases from colorectal cancer. Cochrane Database Syst Rev. 2012;6:CD006317. 31. Wong SL, Mangu PB, Choti MA, et al. American Society of Clinical Oncology 2009 clinical evidence review on
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radiofrequency ablation of hepatic metastases from colorectal cancer. J Clin Oncol. 2010;28(3):493–508. Abdalla EK, Vauthey JN, Ellis LM, et al. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg. 2004;239(6):818–825. van Vledder MG, Pawlik TM, Munireddy S, Hamper U, de Jong MC, Choti MA. Factors determining the sensitivity of intraoperative ultrasonography in detecting colorectal liver metastases in the modern era. Ann Surg Oncol. 2010;17(10):2756–2763. Torzilli G, Botea F, Procopio F, et al. Use of contrast-enhanced intraoperative ultrasonography during liver surgery for colorectal cancer liver metastases: its impact on operative outcome. Analysis of a prospective cohort study. Eur J Cancer Suppl. 2008;6(11):16–23. Sietses C, Meijerink MR, Meijer S, van den Tol MP. The impact of intraoperative ultrasonography on the surgical treatment of patients with colorectal liver metastases. Surg Endosc. 2010; 24(8):1917–1922. Vigano` L, Ferrero A, Amisano M, Russolillo N, Capussotti L. Comparison of laparoscopic and open intraoperative ultrasonography for staging liver tumours. Br J Surg. 2013;100(4):535–542. 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. Adam R, Pascal G, Castaing D, et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg. 2004;240(6):1052–1061. Portier G, Elias D, Bouche O, et al. Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial. J Clin Oncol. 2006;24:4976–4982. Mitry E, Fields A, Bleiberg H, et al. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a meta-analysis of two randomized trials. J Clin Oncol. 2008; 26:4906–4911.
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Early Recurrence After Liver Resection for Colorectal Metastases: Risk Factors, Prognosis, and Treatment. A LiverMetSurvey-Based Study of 6,025 Patients Luca Vigano`, MD1, Lorenzo Capussotti, MD1, Re´al Lapointe, MD, FCRSC2, Eduardo Barroso, MD3, Catherine Hubert, MD4, Felice Giuliante, MD5, Jan N. M. Ijzermans, MD, PhD6, Darius F. Mirza, MD, FRCS7, Dominique Elias, MD, PhD8, and Rene´ Adam, MD, PhD9 Department of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Turin, Italy; 2Department of Surgery, Hepatobiliary and Pancreatic Surgery Division, University of Montreal, Montreal, QC, Canada; 3Department of HPB Surgery and Transplantation, Curry Cabral Hospital, Lisbon, Portugal; 4Unit of HPB Surgery, Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium; 5Department of Surgery, Hepatobiliary Unit, Catholic University of the Sacred Heart School of Medicine, Rome, Italy; 6Department of Transplantation and Hepatobiliary Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands; 7Liver Unit, Queen Elizabeth Hospital, Birmingham, UK; 8Department of Surgery, Institute Gustave Roussy, Villejuif, France; 9Centre He´pato-Biliaire, AP-HP Hoˆpital Paul Brousse, Villejuif, France 1
ABSTRACT Purpose. The aims of this study were to assess the risk of early recurrence after liver resection for colorectal metastases (CRLM) and its prognostic value; identify early recurrence predictive factors; clarify the effect of perioperative chemotherapy on its occurrence; and elucidate the best early recurrence management. Methods. Patients of the LiverMetSurvey registry who underwent complete liver resection (R0/R1) between 1998 and 2009 were reviewed. Early recurrence was defined as any recurrence that occurred within 6 months after resection. Results. A total of 6,025 patients were included; 2,734 (45.4 %) had recurrence, including 639 (10.6 %) early recurrences. Early recurrence was mainly hepatic (59.5 vs. 54.4 % for late recurrences; p = 0.023). Independent risk factors of early recurrence were: T3–4 primary tumor (p = 0.0002); synchronous CRLM (p = 0.0001); [3 CRLM (p \ 0.0001); 0-mm margin liver resection (p = 0.003); and associated intraoperative radiofrequency ablation (p = 0.0005). Response to preoperative chemotherapy (complete/partial) and administration of adjuvant
Ó Society of Surgical Oncology 2013 First Received: 22 July 2013 L. Vigano`, MD e-mail: [email protected]
chemotherapy reduced early recurrence risk (p = 0.003 and p \ 0.0001, respectively). Intraoperative ultrasonography reduced hepatic early recurrence rate (p = 0.025). Early recurrence negatively affected prognosis: 5-year survival 26.9 versus 49.4 % for the late recurrence group (p \ 0.0001, median follow-up 34.4 months). Overall, 234 (36.6 %) patients with early recurrence underwent reresection. These patients had survival rates higher than non-re-resected patients (5-year survival 47.2 vs. 8.9 %; p \ 0.0001) and similar to re-resected patients for late recurrence (48.7 %). Chemotherapy before early recurrence resection improved later survival (5-year survival 61.5 vs. 43.7 %; p = 0.028). Conclusions. Early recurrence risk is enhanced for extensive disease after poor preoperative disease control and inadequate surgical treatment, but is reduced after adjuvant chemotherapy. Although early recurrence negatively affects prognosis, re-resection may restore better survival. Chemotherapy before early recurrence resection is advocated.
Liver resection is the gold-standard treatment for colorectal liver metastases (CRLM). Combined with chemotherapy, complete resection achieves 5-year survival rates of up to 60 %.1–5 Despite these excellent results, recurrence-free survival rates are lower and many surviving patients experience recurrence.6–9 Approximately 60 % of patients will develop recurrence during follow-up, the majority within the first
L. Vigano` et al.
2 years.6 Aggressive treatment of recurrence, including chemotherapy and re-resection when feasible, has been adopted worldwide for both hepatic and extrahepatic disease in selected patients.10–12 Survival results after recurrence resection are similar to those after the first hepatectomy provided that complete resection is performed.10–12 The benefit of surgery may be questioned in patients with early recurrence after liver resection. To date, management of early recurrences is not well-defined, and questions of whether re-resection should be performed and whether preoperative chemotherapy should be added are open for discussion.13,14 The aims of the present study were to depict the incidence of early recurrence and analyze the outcome of patients with early recurrence in a large, multicentric setting; to identify predictive factors of early recurrence; and to evaluate the outcome of re-resection of early recurrence, either with or without preoperative chemotherapy. METHODS Data Collection LiverMetSurvey (LMS; www.livermetsurvey.org) is a prospective international registry of patients undergoing surgery for CRLM. The registry characteristics have been reported previously.15 In brief, data concerning the characteristics of the primary tumor and metastases, liver resection, perioperative treatments, recurrence, and survival are entered into the registry, using a standardized questionnaire completed online. Data about recurrence include its site, date of appearance, and treatment. Data quality control is assessed by online queries and offline requests. Follow-up data are updated online by each center, with a global review by the data manager every 6 months. Study Design Patients undergoing liver resection between January 1998 and June 2009 were included. A minimum follow-up of 6 months was mandatory for all patients. Patients with a follow-up \6 months, or with an incomplete resection (R2 resection) or a two-stage hepatectomy were excluded from the present analysis. Patients with operative mortality (noncancer-related 90-day mortality) were also excluded. Follow-up was updated to 31 December 2011.
within 6 months after liver resection have the poorest outcome. According to these data, early recurrence was defined as any recurrence occurring within 6 months after liver resection. The same time interval was adopted by Malik et al.13 in their study about early recurrences after liver resection for CRLM. Patient characteristics and details of surgical treatment and perioperative chemotherapy were analyzed to identify predictive factors of early recurrence. Primary tumor was staged according to the 6th edition of the TNM staging system for colorectal cancer17. The carcinoembryonic antigen (CEA) value and the characteristics of metastases, including number and diameter, were registered at the time of diagnosis. Synchronous metastases were defined as liver metastases diagnosed before colorectal resection or at the time of surgery. Response to chemotherapy was classified according to WHO criteria,18 which present an absolute agreement with RECIST criteria.19 In case of multiple chemotherapy lines, the response to the last regimen was considered. Overall survival (OS) for early and late recurrence groups were computed and compared. The OS after early recurrence resection was analyzed and compared with the OS of untreated early recurrences and the OS after resection of late recurrences. The analyses of OS after recurrence only included patients with at least a 6-month follow-up after recurrence. Statistical Analysis Categorical variables were compared using the v2 test. A multivariate analysis was performed using a logistic regression model to identify independent factors associated with early recurrence. The Kaplan–Meier method was used to estimate survival probabilities, which were compared using the Log-rank test. A multivariate analysis was performed using a Cox proportional hazard model to identify independent prognostic factors of OS after early recurrence resection. A p value B 0.05 was considered statistically significant. Multivariate analysis was completed for factors with a p value B 0.10 upon univariate analysis. RESULTS As of December 2011, 16,779 patients have been registered in the LMS database by 235 centers in 63 countries. The present study included 6,025 patients who had onestage liver resection between January 1998 and June 2009, complete surgery, and no 90-day mortality.
Parameters Studied Patient Characteristics and Chemotherapy Details In 2006, Takahashi et al.16 showed that time to recurrence after liver resection for CRLM correlates with prognosis and that patients with disease recurrence
Among the 6,025 patients, CRLM were synchronous to the primary tumor in 3,015 (50.0 %) patients; [3 metastases
Recurrence After Colorectal Metastases Resection
(synchronous or metachronous) were noted in 1,046 (17.4 %) patients, and metastases [50 mm were observed in 1,103 (18.3 %) patients. Associated extrahepatic disease was present in 417 (6.9 %) patients, and was pulmonary in one-third of patients (n = 139). Preoperative staging included hepatic magnetic resonance imaging (MRI) in 37.8 % of patients, and positron emission tomography/computed tomography (PET– CT) in 35.2 % of patients. A total of 4,682 patients (77.7 %) had intraoperative hepatic ultrasonography (IOUS). In total, 2,249 (37.3 %) patients had chemotherapy before liver resection. Of these, chemotherapy was ‘conversion’ type in 587 initially unresectable patients. The last chemotherapy regimen included oxaliplatin in 1,086 (48.3 %) patients, irinotecan in 546 (24.3 %) patients, and both agents in 134 (6.0 %) patients. Bevacizumab was administered in 382 (17.0 %) patients and cetuximab was administered in 127 (5.6 %) patients. Preoperative chemotherapy included [6 cycles in 829 (36.9 %) patients, and at least two lines in 331 (14.7 %) patients. The tumor response to the last chemotherapy line before surgery was complete response (CR) in 75 (3.8 %) patients, partial response (PR) in 1,318 (66.9 %) patients, stable disease (SD) in 435 (22.1 %) patients, and disease progression (PD) in 143 (7.2 %) patients. In all, 2,820 (46.8 %) patients received adjuvant chemotherapy (median 6 cycles).
Considering technical data, early recurrence risk was decreased among patients undergoing anatomic resections (9.6 vs. 12.0 %; p \ 0.0001) and increased among patients who had intraoperative radiofrequency ablation associated with resection (18.3 vs. 9.9 %; p \ 0.0001), patients with a 0-mm liver resection margin (17.4 vs. 10.5 %; p \ 0.0001), and patients requiring perioperative blood transfusions (12.8 vs. 10.3 %; p = 0.026). The results of univariate analysis are summarized in Table 1. Chemotherapy and Early Recurrence Risk The early recurrence rate was not reduced by preoperative chemotherapy overall; however, it was associated with the tumor response to treatment. Early recurrence rate was 5.3 % in patients with CR, 14.2 % in patients with PR, 19.3 % in patients with SD, and 23.1 % in patients with PD (p \ 0.0001). The risk of early recurrence was increased among patients with [6 cycles of chemotherapy (20.7 vs. 11.9 %; p \ 0.0001) and among those receiving at least two chemotherapy lines (21.5 vs. 14.0 %; p \ 0.0001). Chemotherapy regimen and targeted therapies did not affect early recurrence risk. Early recurrence was reduced among patients who received adjuvant chemotherapy (9.4 vs. 14.5 %; p \ 0.0001).
Recurrences Recurrences were noted in 2,734 (45.4 %) patients, including 639 (10.6 %; 23.4 % of recurrences) early recurrences (B6 months after liver resection). Hepatic recurrences were more common in the early recurrence group than in the late recurrence group (59.5 vs. 54.4 %; p = 0.023), while extrahepatic recurrences were more common in the late recurrence group (33.6 vs. 27.4 %; p = 0.003). Hepatic?extrahepatic recurrences were similar in the two groups. Patient Characteristics and Early Recurrence Risk The risk of early recurrence was increased among patients with advanced T stage (T3–4, 11.5 % vs. T0–2, 6.9 %; p = 0.0002), node-positive primary tumor (11.8 vs. 8.9 %; p = 0.001), synchronous metastases (13.4 vs. 7.8 %; p \ 0.001), [3 liver deposits (17.1 vs. 9.1 %; p \ 0.0001), bilobar lesions (15.0 vs. 8.9 %; p \ 0.0001), and CEA value [ 200 ng/dL (16.2 vs. 10.6 %; p = 0.006). Patients resectable at diagnosis had early recurrence in 9.8 % of cases versus 17.4 % of initially unresectable cases (p \ 0.0001). Preoperative hepatic MRI and PET-CT did not reduce early recurrence risk (10.7 % if MRI vs. 10.7 % if not; p = not significant; 11.8 % if PET-CT vs. 11.3 % if not; p = not significant). In patients without extrahepatic disease, IOUS lowered the risk of early hepatic recurrence (5.2 vs. 7.2 %; p = 0.025).
Multivariate Analysis of Factors Associated with Early Recurrence At multivariate analysis (Table 1), the response to preoperative chemotherapy (CR/PR vs. SD/PD) and the administration of adjuvant chemotherapy were independent protective factors against early recurrence [p = 0.003, odds ratio (OR) 0.588; and p \ 0.0001, OR 0.430, respectively]. Five independent risk factors of early recurrence were identified: T3–4 stage of the primary tumor (p = 0.0002, OR 2.017); synchronous CRLM (p = 0.0001, OR 1.579); [3 liver metastases (p \ 0.0001, OR 1.835); 0-mm margin of liver resection (p = 0.003, OR 1.564); and intraoperative radiofrequency ablation associated with liver resection (p = 0.0005, OR 1.768). A separate multivariate analysis was performed focusing on patients with hepatic early recurrence (patients with extrahepatic recurrence were excluded). The same independent risk factors were identified. Patient Outcome After a median follow-up of 34.4 months, 3-, 5- and 10-year OS rates were 69.8, 52.3, and 34.8 %, respectively (median survival 65.4 months). Survival was decreased in patients with early recurrence: 5-year OS was 26.9 vs. 49.4 % in the late recurrence group (p \ 0.0001; Fig. 1).
L. Vigano` et al. TABLE 1 Univariate and multivariate analysis of factors associated with occurrence of early recurrence after resection of colorectal liver metastases Parameter (n)
Early recurrence [n (%)]
Univariate analysis
Multivariate analysis— whole series (n = 6,025)
Multivariate analysis— patients with preop CTx (n = 2,249)
p value
p value
p value
NS
–
–
0.014
NS
NS
T3-4 vs. T0-2 0.005
0.0002
0.001
NS
NS
NS
–
–
\0.0001
0.0001
\0.0001
NS
\0.0001
\0.0001
NS
–
–
NS
–
–
0.006
NS
NS
253 (15.0) 383 (8.9)
\0.0001
NS
NS
Yes (4,794)
470 (9.8)
\0.0001
NS
NS
No (707)
123 (17.4)
OR (95 % CI)
OR (95 % CI)
Patient characteristics Sex Male (3,689)
372 (10.1)
Female (2,336)
267 (11.4)
Age, years [70 (1,530)
137 (9.0)
B70 (4,480)
502 (11.2)
Primary tumor characteristics T stage 0 (19) 1 (90)
2 (10.5) 4 (4.4)
2 (617)
44 (7.1)
3 (3,465)
395 (11.4)
4 (847)
101 (11.9)
2.017 (1.388–2.930)
0.002
2.614 (1.427–4.787)
N status Negative (1,918)
170 (8.9)
Positive (3,139)
374 (11.8)
Rectal tumor Yes (1,998)
225 (11.3)
No (3,791)
407 (10.7)
Liver metastases characteristics Synchronous metastases Yes (3,015)
405 (13.4)
No (2,982)
234 (7.8)
Single metastasis Yes (2,880) No (2,937)
231 (8.0)
1.579 (1.251–1.991)
NS
NS
384 (13.1)
[3 metastases Yes (1,046)
179 (17.1)
No (4,771)
436 (9.1)
1.835 (1.415–2.380)
0.0001
Metastases diameter [ 50 mm Yes (1,103)
125 (11.3)
No (4,142)
431 (10.4)
Metastases diameter [ 100 mm Yes (197)
20 (10.2)
No (5,048)
536 (10.6)
CEA [ 200 ng/dL Yes (253)
41 (16.2)
No (3,404)
361 (10.6)
Bilobar metastases Yes (1,686) No (4,310) Resectability at diagnosis
1.953 (1.388–2.748)
Recurrence After Colorectal Metastases Resection TABLE 1 continued Parameter (n)
Early Univariate recurrence analysis [n (%)]
Multivariate analysis— whole series (n = 6,025)
Multivariate analysis— patients with preop CTx (n = 2,249)
p value
p value
p value
NS
–
–
NS
NS
OR (95 % CI)
OR (95 % CI)
Extrahepatic disease Yes (417)
52 (12.5)
No (5,608)
587 (10.5)
Surgical procedures and operative outcome Type of hepatectomy AR (2,837)
271 (9.6) \0.0001
NAR (1,636)
197 (12.0)
AR ? NAR (1,298)
161 (12.4)
Associated intraoperative radiofrequency ablation 85 (18.3) \0.0001 547 (9.9)
0.0005
Yes (112)
10 (8.9)
–
No (5,508)
580 (10.5)
Yes (464) No (5,498)
1.768 (1.282–2.439) 0.030
1.610 (1.046–2.478)
Laparoscopic resection NS
–
Surgical margin 0 mm (602)
105 (17.4) \0.0001
[0 mm (4,079)
430 (10.5)
0.003
1.564 (1.163–2.104) 0.047
Blood transfusion Yes (946)
121 (12.8) 0.026
No (3,644)
374 (10.3)
NS
NS
–
–
Chemotherapy After colorectal surgery (synchronous metastases excluded) Yes (1,614)
137 (8.5)
No (1,064)
82 (7.7)
NS
Before liver resection Yes (2,249)
339 (15.1) \0.0001
No (3,345)
286 (8.6)
NS
Last chemotherapy regimen Oxaliplatin (1,086)
159 (14.6) NS
Irinotecan (546)
89 (16.3)
Oxaliplatin?irinotecan (134)
29 (21.6)
Other (297)
52 (17.5)
–
Associated bevacizumab Yes (382)
62 (16.2)
No (1,682)
264 (15.7)
NS
–
26 (20.5) NS 301 (15.5)
–
Yes (331)
71 (21.5) \0.0001
NS
No (1,918)
268 (14.0)
Associated cetuximab Yes (127) No (1,937) [1 line
[6 cycles Yes (829)
172 (20.7) \0.0001
No (1,036)
123 (11.9)
NS
1.477 (1.005–2.171)
L. Vigano` et al. TABLE 1 continued Parameter (n)
Early Univariate recurrence analysis [n (%)] p value
Multivariate analysis— whole series (n = 6,025)
Multivariate analysis— patients with preop CTx (n = 2,249)
p value
p value
OR (95 % CI)
OR (95 % CI)
[6 cycles at the last line Yes (655)
130 (19.8) \0.0001
No (1,202)
161 (13.4)
NS
Response CR (75)
4 (5.3)
PR (1,318)
187 (14.2)
SD (435)
84 (19.3)
PD (143)
33 (23.1)
CR/PR vs. SD/PD \ 0.0001
0.003
0.588 (0.412–0.835)
After liver resection Yes (2,820)
264 (9.4) \0.0001
No (1,982)
287 (14.5)
\0.0001 0.451 (0.360–0.563) \0.0001 0.430 (0.312–0.592)
Preop preoperative, CTx chemotherapy, OR odds ratio, NS not significant, CEA carcinoembryonic antigen, AR anatomic resection, NAR nonanatomic resection, CR complete response, PR partial response, SD stable disease, PD disease progression
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence
639
478
262
130
73
42
Late recurrence
2095
2006
1595
1054
638
366
FIG. 1 Overall survival of patients with early recurrence versus those with late recurrence (p \ 0.0001)
Early Recurrence Treatment A total of 234 (36.6 %) patients with early recurrence underwent re-resection; this re-resection rate was lower than in
patients with late recurrence (47.2 %; p \ 0.0001). This difference was observed for all recurrence sites (hepatic: 46.6 vs. 60.1 %, p \ 0.0001; extrahepatic: 29.8 vs. 37.2 %, p = 0.042; hepatic?extrahepatic: 7.1 vs. 19.5 %, p = 0.004).
Recurrence After Colorectal Metastases Resection
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence resection
223
184
137
77
52
28
No early recurrence resection
354
204
81
23
14
6
FIG. 2 Overall survival of patients with resected early recurrence versus those with unresected early recurrence (p \ 0.0001)
In the early recurrence group, re-resected patients had higher OS than non-re-resected patients (Fig. 2). After a median follow-up after recurrence of 24.3 months, 5-year OS was 47.2 % in re-resected patients versus 8.9 % in unresected patients (p \ 0.0001). The same results were observed regarding both hepatic recurrences (5-year OS 51.3 vs. 8.3 %; p \ 0.0001) and extrahepatic/hepatic? extrahepatic recurrences (35.7 vs. 10.4 %; p \ 0.0001). Early recurrence resection achieved OS results similar to those achieved after late recurrence resection, both considering hepatic recurrences (5-year OS 51.3 vs. 48.7 %; p = not significant; Fig. 3a) and extrahepatic/hepatic?extrahepatic recurrences (5-year OS 35.7 vs. 45.0 %; p = not significant; Fig. 3b). Prognostic Factors After Early Recurrence Resection The administration of chemotherapy before early recurrence resection improved survival (5-year OS 61.5 vs. 43.7 %; p = 0.021), as did the response to preoperative chemotherapy (5-year OS CR/PR 63.0 vs. SD/PD 46.5 %; p = 0.014). Multivariate analysis confirmed the positive prognostic role of chemotherapy administration before recurrence resection [p = 0.028, hazard ratio (HR) 0.529], but did not confirm the prognostic role of response to chemotherapy. Two additional negative prognostic factors were identified at multivariate analysis: [3 liver
metastases at first liver resection (5-year OS 3.7 vs. 32.5 %; p = 0.003; HR 2.387) and recurrence diameter [ 50 mm (5-year OS 0 vs. 20 %; p = 0.0003; HR 4.748). The results of uni- and multivariate analysis are summarized in Table 2. DISCUSSION Liver resection in association with perioperative chemotherapy increases the survival of patients with CRLM.1–3 Despite the reported excellent outcomes,1–5 recurrence after resection is common and may occur in up to 60 % of patients.6 Re-resection is indicated whenever feasible because it achieves results similar to the first liver resection.10–12 However, these recommendations do not consider the timing of recurrence. If recurrence happens early, the indication of a second resection may be questioned. Few papers have specifically analyzed this issue and did not offer any conclusive data about indications and treatment schedules.13,14 Because of the large number of collected patients in a short and recent period, the present study offers a way to clarify controversial issues related to the management of patients with early recurrence. Theoretically, modern imaging, accurate surgical technique, and extensive adoption of perioperative chemotherapy should prevent early recurrence. In practice, early recurrence occurs in *10 % of patients. Hence, surgeons and oncologists
L. Vigano` et al.
(a) Overall survival (%) 1.0
0.8
0.6
0.4
Early recurrence resection Late recurrence resection
0.2
0
1
2
3
4
5
6
Years
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence resection
166
137
107
59
41
22
Late recurrence resection
606
530
371
229
137
85
(b) Overall survival (%) 1.0
0.8
0.6
0.4
Early recurrence resection Late recurrence resection
0.2
0
1
2
3
4
5
6
Years
Patients at risk
Total
1 year
2 years
3 years
4 years
5 years
Early recurrence resection
57
47
30
18
11
6
Late recurrence resection
304
239
155
91
50
22
FIG. 3 Overall survival after resection of early versus late recurrences: a hepatic-only recurrences; b extrahepatic recurrence (alone or in association with hepatic-only recurrences) (p = not significant for both)
who aggressively treat patients with CRLM frequently face this problem. Early recurrence is more common in patients with aggressive disease, such as those with synchronous and multiple metastases, or advanced T and N staging. The well-known prognostic impact of these parameters has been confirmed.20–22 The extension of surgical indications to more aggressive diseases implies an increased risk of early recurrence as long as adequate selection criteria to
identify patients who really benefit from surgery are lacking. Early recurrences were also related to some technical issues. A complete (R0) surgery is considered mandatory; however, a debate about the adequate width of the surgical margin is ongoing.23–26 A recent paper by de Haas et al. even denied that a 0-mm margin has a significant impact on OS, although recurrence risk was increased.27 The present study reaffirms the inadequacy of a 0-mm margin, which is
Recurrence After Colorectal Metastases Resection TABLE 2 Prognostic factors regarding overall survival after reresection to treat early recurrence Parameter
Univariate analysis p value
Multivariate analysis p value HR (95 % CI)
Patient and primary tumor characteristics Sex
NS
–
Age [ 70 years
NS
–
T3–4 stage
NS
–
N?
NS
–
Rectal tumor
NS
–
Synchronous metastases
NS
–
First liver resection data
Single metastasis
NS
–
[3 metastases
0.016
0.003
Metastases diameter [ 50 mm
NS
–
CEA [ 200 ng/dL
NS
–
Bilobar metastases
NS
–
Extrahepatic disease
NS
–
Type of hepatectomy (AR vs. NAR)
NS
–
Associated RFA
NS
–
Surgical margin (0 vs. [ 0 mm)
NS
–
–
2.387 (1.334–4.270)
Recurrence characteristics Single metastasis
NS
[3 metastases
NS
–
Diameter [ 50 mm
0.0005
0.0003 4.748 (2.045–11.027)
CEA [ 200 ng/dL
NS
–
After colorectal surgery (synchronous metastases excluded)
NS
–
Before first liver resection
NS
–
After first liver resection
NS
–
Before ER resection
0.021
0.028
Chemotherapy data
Oxaliplatin
NS
Irinotecan
NS
Associated bevacizumab
NS
0.529 (0.299–0.934)
Associated cetuximab NS [1 chemotherapy line NS [6 cycles
0.020
NS
Response (CR/PR vs. 0.014 SD/PD)
NS
After ER resection
NS
–
HR hazard ratio, NS not significant, ER early recurrence, CEA carcinoembryonic antigen, AR anatomic resection, NAR non-anatomic resection, RFA radiofrequency ablation, CR complete response, PR partial response, SD stable disease, PD disease progression
associated with an increased risk of early recurrence. Tumor re-growth at the lesion borders (‘dangerous halo’) or micrometastases might justify these data.25,28,29 An additional technical issue was the association of intraoperative radiofrequency ablation with liver surgery. Interstitial treatments are less effective than surgery in CRLM treatment.30,31 Even in association with surgery to ablate deeply located nodules, radiofrequency ablation has worse outcomes than resection alone.32 The present study confirmed these data. The distinction between recurrences at the surgical margin and true new hepatic nodules (data not available in the LMS database) will be helpful in future studies to further confirm the impact of surgical margin and interstitial treatments on early recurrence risk. Finally, the role of IOUS was emphasized. Several studies have shown that IOUS might detect additional hepatic lesions missed by preoperative imaging.33–36 In the present series, patients receiving IOUS had lower risk of hepatic early recurrence, suggesting a better completion of disease staging at surgery. The surgeon may strongly affect all of these technical issues. Finally, the impact of chemotherapy must be considered. Perioperative chemotherapy improves disease-free survival in resected patients.37 In the present study, preoperative chemotherapy per se did not reduce early recurrence risk. Differences were observed neither for different regimens nor for different targeted therapies. The response to chemotherapy was important, rather than the chemotherapy itself—the better the tumor response, the lower the early recurrence rate. The prognostic role of tumor response to preoperative chemotherapy was confirmed.15,38 On the other hand, adjuvant chemotherapy had a protective effect against early recurrence. Considering that even ad hoc randomized trials did not clarify the indications for adjuvant treatment,39,40 no recommendations can be formulated. In any case, adjuvant treatment reduced the early recurrence risk by one-third. The present results confirmed that cooperation between surgeons and oncologists is mandatory when treating CRLM patients, especially when aggressive indications are present. Lower survival was observed in patients with early recurrence than in patients with late recurrence. Delay of recurrence is a well-known prognostic factor.14,16,20,21 In any case, early recurrence should not be considered a ‘game over’ situation. Re-resection can be evaluated and should be scheduled whenever possible; it significantly improves outcome compared with non-surgical treatments, and achieves the same survival results as resection of late recurrences. These considerations were valid not only for hepatic-only recurrences, but also for extrahepatic deposits. Therefore, the concept of surgery as the standard treatment for recurrent metastases can be extended even to early recurrences.
L. Vigano` et al.
Once again, the problem of patient selection plays a pivotal role in the outcome. Patient selection is even more important considering that an early recurrence after liver surgery occurred; a new recurrence after re-resection would clearly demonstrate the uselessness of treatment. The present study helps to define a treatment protocol. It may be preferred to schedule re-resection after a new chemotherapy line, thus allowing patient selection and control of rapidly progressing disease. In fact, patients with preoperative treatment experienced better survival. The role of response to chemotherapy could not be confirmed in the multivariate analysis, and was likely masked by the surgeon’s selection criteria of patients to be re-resected. Of course, the results of this study should be validated prospectively on a separate patient cohort, and the impact of chemotherapy is difficult to evaluate outside of a clinical trial. The administration of preoperative treatment to more advanced patients might hide its beneficial effect. At the same time, the protective effect of adjuvant chemotherapy might be related to a delay in recurrence or a delay in diagnosis due to a different follow-up schedule. Nevertheless, owing to the large number of patients, a significant contribution of chemotherapy to early recurrence reduction is strongly suggested, and the administration of chemotherapy before early recurrence resection can be reasonably recommended to select the good candidates.
4.
5.
6.
7.
8.
9.
10.
11.
12.
CONCLUSIONS Early recurrence occurs in *10 % of patients undergoing liver resection for CRLM. Its risk is increased in cases of aggressive disease, poor preoperative disease control, and non-optimal surgical treatment (0-mm margin; associated intraoperative radiofrequency ablation). IOUS reduces the hepatic early recurrence rate. Although early recurrence negatively affects prognosis, re-resection has the potential to restore better survival. Chemotherapy is advocated before early recurrence resection to adequately select good candidates and to control rapidly progressive disease. DISCLOSURE
13.
14.
15.
16.
The authors have no conflicts of interest to declare. 17.
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