Ann Surg Oncol DOI 10.1245/s10434-014-3577-x

ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY

Chemotherapy and Targeted Therapy for Patients with Initially Unresectable Colorectal Liver Metastases, Focusing on Conversion Hepatectomy and Long-Term Survival Toru Beppu, MD, PhD, FACS1,2, Yuji Miyamoto, MD, PhD2, Yasuo Sakamoto, MD,PhD1,2, Katsunori Imai, MD, PhD2, Hidetoshi Nitta, MD, PhD2, Hiromitsu Hayashi, MD, PhD2, Akira Chikamoto, MD2, Masayuki Watanabe, MD, PhD, FACS2, Takatoshi Ishiko, MD, PhD2, and Hideo Baba, MD, PhD, FACS2 1

Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto, Japan; 2Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan

ABSTRACT Background. Eight years have passed since the introduction of chemotherapy (chemo) and targeted therapy regimens for colorectal liver metastases (CRLM). This study aimed to clarify the effectiveness of chemo and targeted therapy in facilitating conversion hepatectomy and improving long-term survival in Japanese patients with CRLM. Methods. A total of 199 patients with CRLM were treated between May 2005 and August 2012. Initial therapies for these patients included straightforward hepatic resection (n = 48; 24 %), induction chemotherapy (n = 148; 74 %), and radiofrequency ablation (n = 3; 2 %). Results. In 56 of 137 patients (40.1 %) with initially unresectable CRLM, 7.5 courses of chemo and targeted therapy downsized and converted tumors to resectable tumors. The 5-year cumulative overall survival (OS) rate and the median survival time were significantly higher for the resectable CRLM than for the unresectable CRLM (54.6 vs. 5.3 % and 77.3 vs. 21.3 months, respectively; P \ .0001). Multivariate analysis revealed that conversion hepatectomy (hazard ratio [HR] 0.19; P \ .001) and

Toru Beppu and Yuji Miyamoto are equal contributors.

Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3577-x) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 22 October 2013 T. Beppu, MD, PhD, FACS e-mail: [email protected]

responder to chemo and targeted therapy (HR 0.46; P \ .01) were independent prognostic factors for OS. Multivariate analysis also revealed that left-sided colon or rectal cancer (odds ratio [OR] 8.4; P \ .05), H1/H2 metastases (OR 7.3; P \ .05), no extrahepatic metastases (OR 52.6; P \ .001), and responder to chemo and targeted therapy (OR 6.1; P \ .05) were significant predictors of conversion hepatectomy. Conclusions. A chemo and targeted therapy can facilitate conversion hepatectomy and allow for an excellent prognosis in patients with initially unresectable CRLM.

Liver resection is the standard procedure as well as the only curative treatment for colorectal liver metastases (CRLM), unfortunately the initial resection rates are reported to be \25 %.1,2 The goals of therapy for patients with CRLM are dependent on the initial resectability of the metastases, and patients may be categorized depending on whether the metastases are initially resectable, marginally resectable, or unresectable.3 The introduction of oncosurgical approaches and the combined use of targeted agents with chemotherapy (chemo) had resulted in a new strategy for the management of CRLM.4 When marked tumor shrinkage results after induction chemotherapy, unresectable CRLM may be rendered resectable. This is called conversion therapy, and for such patients, a favorable long-term prognosis can be expected after hepatic resection with curative intent.5 The 5-year survival rate after complete resection for patients with liver-limited CRLM is reported to be 40–50 %.6,7 The Japanese social insurance system included oxaliplatin in colorectal cancer treatment in May 2005. We have already reported that oxaliplatin plus fluorouracil and

T. Beppu et al.

leucovorin (FOLFOX) is a feasible and safe systemic chemotherapy that results in a high conversion rate of 37 % and an excellent midterm survival in patients with initially unresectable CRLM.8 In past reports, conversion hepatectomy was emphasized to achieve long survival in patients with initially unresectable CRLM.9–11 Recently, a systematic review concerning downsizing chemotherapy and rescue liver surgery for initially unresectable CRLM demonstrated a treatment response rate of 64 % (range 43– 79 %).12 The modern chemotherapy regimens allowed downsizing of CRLM, leading to curative (R0) resection in 436 of 1,886 patients (23.1 %). The median survival time (MST) was 45 months (range, 36–60 months) and the recurrence-free survival rate was 19 %. These results were obtained by a combination of irinotecan and oxaliplatinbased regimens with or without targeted agents.12–15 In this era of modern chemotherapy, we evaluated the effectiveness of a chemo and targeted therapy regimen in facilitating conversion hepatectomy and improving longterm survival in Japanese patients with initially unresectable CRLM and elucidated the predictive factors for conversion of tumors from unresectable to resectable in this patient population.

PATIENTS AND METHODS Between May 2005 and August 2012, a total of 199 CRLM patients were treated at the Department of Gastroenterological Surgery, Kumamoto University Hospital, Kumamoto, Japan. Initial therapies for the patients included straightforward hepatectomy (n = 48; 24 %), induction chemotherapy (n = 148; 74 %), and radiofrequency ablation (RFA; n = 3; 2 %). Patients who underwent hepatectomy or RFA first, continued chemotherapy at the other hospitals, or visited our department halfway through treatment were excluded. Finally, 137 patients with initially unresectable CRLM treated with chemo and targeted therapies were enrolled. The term unresectable was used to designate initially unresectable CRLM, and marginally resectable CRLM, or concomitant extrahepatic metastases. The definitions of unresectable CRLM included: extensive liver involvement (more than six liver segments involved, 65 % liver invasion or all three hepatic veins or Glissonean pedicles involved), unresectable extrahepatic metastases, major liver insufficiency, and patients unfit for or declining surgery.4 Marginally resectable CRLM included oncologically nonresectable CRLM (i.e., five or more CRLM), concomitant resectable extrahepatic metastases, and with a risk of noncurative resection. The CRLM patients in this study were divided into H-factor categories (H1, H2, or H3) according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR): H1, B4 metastases, with the largest

diameter being B5 cm; H2, lesions other than H1 or H3; and H3, C5 metastases, with the largest diameter being C5 cm.16 Tumor response rates were calculated using the response evaluation criteria in solid tumors (RECIST) criteria 1.1.17 Therapeutic Strategy

8

Briefly, when patients were diagnosed with initially resectable and liver-only metastases, they underwent hepatic resection with six courses of adjuvant FOLFOX chemotherapy.18 For patients diagnosed with unresectable CRLM, induction chemotherapy was initiated. As first-line cytotoxic drugs, we selected oxaliplatin-containing regimens, namely FOLFOX, capecitabine and oxaliplatin (XELOX), or S-1 plus oxaliplatin (SOX). From 2007, bevacizumab was combined with chemotherapy. Cetuximab and panitumumab [anti-epidermal growth factor receptor (EGFR) antibody] were introduced in 2008 and 2010, respectively, for limited patients with wild-type KRAS mutations. When curative hepatic resection became possible, hepatic resection with or without RFA was immediately performed.19 Unresectable patients were treated continuously with various chemotherapeutic regimens, including irinotecan plus fluorouracil and leucovorin (FOLFIRI), partially with targeted agents. The eligibility criteria for this study were: age\85 years, normal organ function, and histologically proven colorectal cancer. The Institutional Review Board of the Kumamoto University approved this clinical study. Hepatic Resection A multidisciplinary team, which included specialists in hepatic surgery, decided on resectability. The type of hepatic resection was based on the results of preoperative diagnostic imaging, intraoperative ultrasound, and careful attention to liver function. Hepatic resection was performed using a CUSA aspiration system (Valley Lab Inc., Boulder, CO) and soft coagulation devices (VIO 300D BiClamp model; ERBE, Elektromedizin, GmbH, Germany).20 If necessary, intermittent cessation of hepatic flow was achieved. All detectable lesions were resected to achieve R0 resection; however, metastatic nodules measuring \2 cm, particularly those located deeper in the liver, were subjected to RFA.19 Statistical Analysis Data are expressed as medians and interquartile ranges. The Mann–Whitney U test and v2 test were used to compare between groups and compare proportions between groups, respectively. Overall survival (OS) curves were estimated using the Kaplan–Meier method and analyzed using the log-

Chemotherapy and Targeted Therapy for CRLM

rank test. To determine the independent relationship between preoperative variables and conversion hepatectomy, univariate and stepwise multivariate logistic regression analyses were performed. Univariate Cox proportional hazards models of all potential baseline predictors were built to compute hazard ratio (HRs) and their 95 % confident intervals (95 % CIs). A multivariate Cox proportional hazards model was used for multivariate analysis. The JMP statistical software package (SAS Institute, Inc., Cary, NC) was used for all statistical analyses. A P value of \.05 was considered statistically significant. RESULTS In 56 of 137 patients (40.9 %) with initially unresectable CRLM, tumors were downsized and converted to resectable tumors. There was no patient who was not resected in spite of becoming resectable. We made efforts to resect all tumors even a combination of radiofrequency ablation. The clinical characteristics of these 56 patients are summarized in Table 1. The conversion rate in patients with overall and liver-only metastases were 41 % (56 of 137) and 68.5 % (50 of 73), respectively. A total of 9 % of patients with liver plus extrahepatic metastases (6 of 64) were converted. They included lung plus liver metastases in five patients and paraaortic lymph node metastases plus liver in 1. Out of these three lung metastases and one para-aortic lymph node metastasis were resected. The remaining one lung metastasis vanished, and the other showed long-term stable disease. A median of 7.5 (range, 5–8) and an average of 8.6 courses of chemo and targeted therapy was required to downsize and convert the tumors in these 56 patients. The mean size of maximal liver metastasis was downsized from 50 ± 31 to 32 ± 4 mm. The 137 patients with initially unresectable CRLM were divided into two groups: finally resectable and finally unresectable (Table 2). The number of tumors and extrahepatic and lymph node metastases from the primary site was less, while the serum carcinoembryonic antigen level and H category were lower in the resected patients than in the nonresected patients. Oxaliplatin-based regimens were used as first-line chemotherapy in 98 % of resected patients and 83 % of nonresected patients. Bevacizumab and anti-EGFR antibody were administered to 36 and 7 % of the total number of patients, respectively. Tumor response rates were 64 % among the resectable patients and 38 % among the unresectable patients. Long-Term Survival and Prognostic Factors in Patients with Resectable CRLM In the resectable CRLM, the 5-year cumulative OS rate was 54.6 % and the MST was 77.3 months; values were

TABLE 1 Clinical characteristics of 56 patients with initially unresectable CRLM downsized to be resectable after chemotherapy Characteristic

Data (n = 56)

Age, year (range)a

63 (33–81)

Gender (male:female)

35:21

Synchronous:metachronous

42:14

Liver only:liver ? extrahepatic

50:6

Number of liver metastases (range)a

3 (1–36)

Maximal liver metastases, mm (range)a

35 (2.5–310)

Chemotherapy:chemotherapy ? targeted agents Cycles of chemo and targeted therapy (range)a

32:24 7.5 (5–38)

Type of hepatectomy (major:segmental: partial)

20:13:23

RFA (combined:noncombined)

13:43

RFA radiofrequency ablation a

Data are represented as median value (range)

significantly higher than those (5.3 % and 21.3 months) for the unresectable CRLM, respectively (P \ .0001; Fig. 1). The median (range) observation time was 21.8 months (1.1–78.3 months). The 5-year cumulative OS rate (limited to the converted CRLM patients without extrahepatic disease) was 47.4 % and the MST was 55.8 months; values were significantly higher than those (0 % and 21.4 months) for the unresectable CRLM, respectively (P \ .0001; Supplementary Fig. 1). In contrast, 5-year cumulative OS and MST were similar for converted patients with or without concomitant extrahepatic disease. The 5-year cumulative OS rate and the MST in patients treated with hepatectomy and hepatectomy plus RFA were 50.1 % and 77.3 months and 68.2 % and not reached, respectively. The values were equivalent in the two groups (Supplementary Fig. 2). Multivariate analysis revealed that conversion hepatectomy (HR 0.19; P \ .001) and response to chemo and targeted therapy (HR 0.46; P \ .01) were independent prognostic factors for OS (Table 3). Predictive Factors for Conversion Hepatectomy After Chemo and Targeted Therapy Multivariate analysis revealed that left-sided colon/rectal origin (OR 8.4; P \ .05), H1/H2 CRLM (OR 7.3; P \ .05), absence of extrahepatic metastases (OR 52.6; P \ .001), and response to chemo and targeted therapy (OR 6.1; P \ .05) were significant predictors of conversion after chemo and targeted therapy (Table 4). We evaluated the conversion rates according to the number of favorable factors for conversion. The conversion rates are 0 % for none (n = 3), 7.7 % for 1 (n = 26), 17.5 % for 2 (n = 40), 52.3 % for 3 (n = 44), and 100 % for 4 (n = 24) (P \ .001).

T. Beppu et al. TABLE 2 Clinical characteristics of 137 initially unresectable CRLM patients treated with induction chemotherapy Variables

Hepatectomy (?) N = 56

Age (range)a

Hepatectomy (-) % Percent (%)

63 (33–81)

N = 81

P value Percent (%)

66 (34–82)

.121

Gender

.335

Male

35

64

57

70

Female

21

36

24

30

Right colon

9

16

28

35

Left colon Rectum

24 23

43 41

27 26

33 32

M0

50

89

21

26

M1

6

11

60

74

N0

22

39

17

21

N1

16

29

41

51

N2

18

32

23

28

Primary tumor site

.057

\.001

Extrahepatic metastases

Lymph node metastases

.019

Serum CEA level (ng/mL [range])a

19.4 (0–2428.8)

68.4 (1.1–7,255.0)

.056

Timing of liver metastases

.195

Synchronous

42

75

68

84

Metachronous

14

25

13

16

Number of liver metastases (range)

a

Maximal size of liver metastases (range)a Degree of liver metastases H1

3 (1–36)

10 (1–30)

35 (2.5–310)

50 (3–150)

\.001 .385 .001

20

36

22

27

H2

28

50

23

28

H3

8

14

36

44

Oxaliplatin base

55

98

67

83

Irinotecan base

1

2

7

9

5FU base

0

0

4

5

HAI

0

0

3

4

Combined

20

36

29

36

Noncombined

36

64

52

64

First-line chemotherapy cytotoxic agents

.039

Bevacizumab

.992

Anti-EGFR antibody

.751

Combined

4

7

7

9

Noncombined

52

93

74

91

Preoperative serum CEA (ng/mL [range])a

5.1 (1.0–327.8)

Overall response CR

0

0

1

1

PR

36

64

31

38

SD

15

27

23

28

PD

1

2

11

14

NE

4

7

15

19

.020

CEA carcinoembryonic antigen, HAI hepatic arterial infusion, CR complete response, PR partial response, SD stable disease, PD progressive disease, NE not evaluated a

Data are represented as median value (range)

Chemotherapy and Targeted Therapy for CRLM Overall survival 1.0

0.8

0.6

0.4

0.2

0

12

24 36 48 Observation period (months)

60

72

FIG. 1 Comparison of the cumulative overall survival (OS) rates between patients with finally resectableand finally unresectable colorectal liver metastases (CRLM). Blue line resectable CRLM (n = 56); red line unresectable CRLM (n = 81). In the resectable and unresectable CRLM, the 5-year cumulative OS rate and the MST were 54.6 % and 77.3 months, and 5.3 % and 21.3 months. The values of resectable CRLM were significantly higher than those of unresectable CRLM (P \ 0.0001)

DISCUSSION A total of 56 of 137 patients with initially unresectable CRLM (41 %) could undergo hepatic resection after 7.5 courses of chemo and targeted therapy. R0 resection was accomplished in 77 % of the resected patients. The conversion rate in this study was relatively high compared with previously reported conversion rates of 12.5–45 %.9–12, 21,22 This may be explained by 3 reasons. First, this study included marginally resectable patients primarily for clinical trial purposes. These patients were enrolled in the clinical trial for CRLM with H2 or H3; 4 patients with initially resectable lesions were treated with neoadjuvant chemotherapy first. Second, liver surgeons mainly decided the indications for hepatic resection. Finally, RFA was permitted in patients with tumors that were unresectable with hepatectomy alone. A previous study reported that resectability was more frequently determined by liver surgeons than by multidisciplinary teams comprising no gastrointestinal specialists.23 We have reported the utility of RFA with concomitant use of hepatectomy for CRLM measuring B2 cm during the chemo-effective period, and the utility was confirmed again in this study.19 With the advent of effective modern chemotherapy, R1 resection currently provides survival benefits similar to those of R0 resection.24 Although RFA-combination hepatectomy is not R0 resection, OS were similar hepatectomy alone and RFA-combination.19

A standard resectability criterion is necessary to better understand the role of induction chemotherapy.12 OncoSurg group (4) revealed that the relative contraindications for hepatectomy included multiple or bilobar metastases, large tumors, Dukes stage C (or poorly differentiated) primary tumors, synchronous metastases, disease in elderly patients, or a resection margin of \1 cm. Unresectable extrahepatic metastases and portal lymph node involvement remained absolute contraindications. It is relatively difficult to clearly distinguish initially resectable lesions from initially unresectable lesions. Currently, from an oncological viewpoint, perioperative chemotherapy is recommended even if the lesions are anatomically resectable.25 In the era of effective chemo and targeted therapy, liver surgeons, including us, tend to select induction chemotherapy followed by hepatic resection for marginally resectable patients with CRLM. We have completed a phase II clinical trial for the Kyushu Study Group of Clinical Cancer (KSCC) 0802; hepatic resection following first-line mFOLFOX6 chemotherapy with bevacizumab for liver-limited CRLM.26 In this multicenter trial, calculation of conversion rate was determined to be problematic because defining initially and finally resectable CRLM was impossible. Therefore, we determined the primary endpoint to be resectability of H2 and H3 CRLM. As an additional observational study, five surgeons individually reviewed the conversion rate in completely unresectable CRLM patients by blind evaluation of diagnostic prechemotherapy and postchemotherapy images referring to the CELIM study.27 In the current study, we clearly identified four independent predictive factors for conversion hepatectomy after chemo and targeted therapy: left-sided colon or rectal cancer (OR 8.4), H1/H2 liver metastases (OR 7.3), absence of extrahepatic metastases (OR 51.6), and response to chemo and targeted therapy (OR 6.1). Unfortunately, the concomitant use of biologic agents was not a predictive factor. Conversion rates and MST in chemotherapy alone (n = 49) and chemo and targeted therapy (n = 88) were equivalent: 40.9 and 40.8 % (P = .992) and 25.2 months and not reached (P = .087) in the two groups, respectively. Right-sided colon cancer has a stronger tendency for hepatic recurrence after colorectal resection compared with left-sided colon cancer.28 Furthermore, it was reported that the proportion of patients with poorly differentiated adenocarcinoma or mucinous carcinoma, distant nodal involvement, and histological venous invasion was significantly higher among patients with right-sided colon cancer than left-sided colon cancer.29 These may be the reasons for a lower conversion rate in patients with right-sided colon cancer. According to the number of favorable factors for conversion, the conversion rates are 0 % for no favorable factors, 7.7 % for 1, 17.5 % for 2, 52.3 % for 3, and

T. Beppu et al. TABLE 3 Independent prognostic factors to predict overall survival using Cox proportional hazards model Factors

N

MST (M)

Univariate analysis

Multivariate analysis

HR

95 % CI

P value

HR

95 % CI

P value

0.235–0.648

\.001

0.788

0.431–1.442

.44

0.551–1.853

.972

0.259–0.798

.006

0.093–0.406

\.001

No. of liver metastasesa B5

71

49.4

0.394

C6

66

23.5

1

1

Extrahepatic metastases Negative

73

31.9

0.56

Positive

64

22.9

1

68

44.6

0.408

50

22.9

1

Resectable

56

77.3

0.183

Unresectable

81

21.3

1

Overall response CR ? PR SD ? PD

0.342–0.910

.02

1.011 1

0.237–0.695

.001

0.455 1

Hepatectomy 0.097–0.328

\.001

0.194 1

MST median survival time, HR hazard ratio, 95 % CI 95 % confidential interval, CR complete response, PR partial response, SD stable disease, PD progressive disease a

Cutoff is a median value of five metastases

100 % for 4 (P \ .001). Patients with 0 or 1 favorable factor for conversion might be treated with reference to group III in ESMO guideline.3 Prognosis is significantly poorer in patients categorized as H2 and H3 than in those categorized as H1.30 Our study group demonstrated that largest diameter, C5 cm, was the independent predictive factor for a high recurrence rate, while C5 metastases was the strongest independent predictive factor for a high recurrence rate and a poor prognosis.31 In the current study, we identified that H3 status was a negative predictor of conversion. Interestingly, absence of extrahepatic metastases was an independent predictor of conversion; however, it was not a prognostic factor for OS. Among the patients with initially unresectable CRLM, 6 (9 %) and 50 (68 %) with and without extrahepatic metastases, respectively, underwent resection (P \ .001). The MST was 22.9 months in 64 patients with extrahepatic metastases and 31.9 months in 73 patients without (P = .02). In fact, among patients with finally unresectable CRLM, MST was comparable among those with and without extrahepatic metastases (20.6 and 21.4 months, respectively). It is speculated that the prognosis of patients with initially unresectable CRLM accompanied by extrahepatic metastases is improving. In this study, an objective response was observed in 49.6 % patients after chemo and targeted therapy. The response rate in patients who underwent liver resection was greater than that in patients who did not (64.3 vs. 38.3 %). A positive correlation was demonstrated between the response rate and resection rate in CRLM patients with liver-limited metastases as well as those with concomitant extrahepatic disease.32 To provide a potentially curative option for patients

with unresectable CRLM, there is a clear requirement for effective conversion treatment that yields high tumor response rates, eventually facilitating hepatectomy. The most suitable treatment regimen to achieve resectability remains difficult to ascertain; however, oxaliplatin has been frequently used as a cytotoxic agent in first-line chemotherapy for achieving conversion of initially unresectable CRLM in 3 phase II and 2 phase III studies.11,14,33–35 The regimens used in these studies included FOLFOX, XELOX, and triplets. In our study, usage rate of oxaliplatin was extremely high, while the rate of targeted drugs was still low; therefore, it seemed impossible to compare the results with those of other regimens. There was no significant difference in OS between patients with S1-combined therapies (n = 19) and without those (n = 88) (24.5 vs 30.4 months, P = .338), respectively. However, conversion rate was significantly lower in patients with S-1 than that in patients without S-1 (10.5 vs. 45.8 %; P = .004). Mean favorable conversion factors were similar (2.37 vs. 2.45; P = .672) in patients with and without S-1, respectively. In the NO16966 trial, patients with metastatic colorectal cancer were randomly assigned to XELOX versus FOLFOX-4 followed by bevacizumab versus placebo. Response rates were similar in both arms.36 Cetuximab combined with FOLFOX or FOLFIRI for patients with unresectable liver-only CRLM demonstrated high response rates of 68 and 57 %, respectively, and resectability rates of 38 and 30 %, respectively.27 Cetuximab plus chronomodulated 5FU, leucovorin, irinotecan, and oxaliplatin in patients with unresectable liver-only CRLM yielded a high response rate of 79 % and a conversion rate of 60 %.37 A recent meta-analysis of chemotherapy using anti-EGFR antibody agents for patients with liver-limited CRLM accompanied by wild-type

Chemotherapy and Targeted Therapy for CRLM TABLE 4 Predictive factors for conversion hepatectomy using univariate and stepwise multivariate logistic regression Factors

Univariate analysis OR

Multivariate analysis

95 % CI

P value

OR

1.219–6.744

.014

8.370

0.745–4.111

.199

1.692

95 % CI

P value

1.420–69.800

.018

0.337–9.397

.523

Primary tumor site Right

1

Left/rectum

2.759

1

Timing of liver metastases Synchronous

1

Metachronous

1.744

LN metastases Positive Negative Serum CEA level

1

1

1

2.436

1.148–5.258

.02

2.156

0.485–10.243

.312

1.000

0.999–1.000

.07

0.999

0.998–1.000

.213

2.100–12.120

\.001

7.251

1.680–38.827

.007

8.452–60.920

\.001

51.612

11.512–355.269

\.001

1.129–5.206

.023

6.067

1.578–29.763

.008

0.486–2.024

.992

0.787

0.158–3.785

.763

0.077–17.601

.927

Degree of metastases H3

1

H1/H2

4.800

1

Extrahepatic metastases M1

1

M0

21.014

1

Overall response SD/PD

1

CR/PR

2.391

1

Bevacizumab Noncombined Combined Anti-EGFR antibody

1 0.996

Noncombined

1

Combined

0.813

1

1 0.204–2.835

.750

1.134

H-factor categories according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) OR odds ratio, 95 % CI 95 % confidential interval, LN lymph node, CEA carcinoembryonic antigen, CR complete response, PR partial response, SD stable disease, PD progressive disease, EGFR epidermal growth factor receptor

KRAS mutations demonstrated an increase in not only response rate but also R0 resection rate.38 Therefore, a combination of oxaliplatin-based chemotherapy and antiEGFR antibody agents may be the most effective approach for achieving conversion in limited patients with wild-type KRAS mutations. The 5-year OS rate (54.6 %) and MST (77.3 months) were significantly higher for the 56 resectable patients than in the unresectable patients (5.3 % and 21.3 months, respectively) in our study (Fig. 1). Independent prognostic factors for OS were conversion hepatectomy (HR 0.19) and responder to chemo and targeted therapy (HR 0.46). HR of conversion hepatectomy is similar in previous FOLFOX study and in this study; 0.21 and 0.19.8 A current metaanalysis demonstrated an excellent 5-year OS rate of 52– 73 % and MST of 36–60 months for patients with initially unresectable CRLM that was converted to resectable CRLM after modern chemotherapy.12 In addition, the innovative approach demonstrated a disease-free survival

rate of 16 % (24 of 148) after a minimum 5-year follow-up; these patients were all considered to be cured.11 Since early recurrence after conversion hepatectomy is an important matter, we additionally analyzed early recurred patients in this study. A total of 19 patients recurred within 6 months; however MST was 30.4 months in these patients (Supplementary Fig. 3). MST was superior compared with 21.3 M of unresectable patients; therefore, it might be unnecessary to define these patients out of hepatic resection. The selection of chemotherapy after conversion hepatectomy remains an unresolved issue. The addition of targeted agents had no proven impact in an adjuvant setting after curative resection of colon cancer.39 Effective preoperative chemotherapy regimens, limited to patients receiving conversion hepatectomy, are occasionally continued if adverse events are tolerable. In our study, the adjuvant therapies after hepatectomy were performed using same regimen of preoperative chemotherapy alone in 23 patients (41 %) even for the patients who received chemo and

T. Beppu et al.

targeted therapy. MST was similar: 77.3 and 49.4 months (P = .845) in patients with and without adjuvant chemotherapy, respectively. In conclusion, the chemo and targeted therapy described in our study can facilitate conversion hepatectomy and improve prognosis in patients with initially unresectable CRLM, particularly in those who respond to chemo and targeted therapy.

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Chemotherapy and targeted therapy for patients with initially unresectable colorectal liver metastases, focusing on conversion hepatectomy and long-term survival.

Eight years have passed since the introduction of chemotherapy (chemo) and targeted therapy regimens for colorectal liver metastases (CRLM). This stud...
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