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Benefits of repeated resections for liver and lung metastases from colorectal cancer
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Asian Journal of Surgery xxx (xxxx) xxx
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ORIGINAL ARTICLE
Benefits of repeated resections for liver and lung metastases from colorectal cancer Kwan Mo Yang a, In Ja Park b,*, Jong Lyul Lee b, Chan Wook Kim b, Yong Sik Yoon b, Seok-Byung Lim b, Chang Sik Yu b, Jin Cheon Kim b a Department of General Surgery, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Republic of Korea b Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
Received 16 October 2018; received in revised form 24 February 2019; accepted 4 March 2019
KEYWORDS Colorectal cancer; Metastasectomy; Oncologic outcome; Repeated resection
Summary Objective: We aimed to evaluate oncological outcomes after repeat metastasectomies in patients having undergone previous resections for colorectal cancer metastases. Methods: We examined 248 patients who underwent metastasectomies for lung and/or liver metastases at our center during a 7-year period, from January 2005 to December 2011. Recurrence-free survival 1 (RFS1) after the metastasectomy for the initial recurrence, recurrence-free survival 2 (RFS2) after the second, and recurrence-free survival 3 (RFS3) after the third repeated resections for recurrence were assessed. The overall survival (OS) rate after the first metastasectomy for the first recurrence (OS) was also assessed. Results: Sites of recurrence of the first metastasectomy were the liver, lung, and liver and lung in 115, 117, and 16 cases, respectively, and 133 patients had a second recurrence (133/248, 53.6%). Twenty-seven patients had a third recurrence (27/52, 51.9%), of whom 14 underwent a third metastasectomy. The 5-year and 10-year OS rates were 74.8% and 57.9%, respectively. The 1-year RFS1, RFS2, and RFS3 rates were 76%, 75%, and 39%, respectively. The hazard ratios for RFS were 1.142 and 2.590 for the first and second repeat surgeries, when compared to the first metastasectomy. The third metastasectomy showed significantly lower RFS than did the second metastasectomy. Conclusion: A second metastasectomy should be considered the optimal treatment for a second recurrence. However, careful considerations should be made before performing a third metastasectomy.
* Corresponding author. Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. Fax: þ82 2 2010 6701. E-mail address: [email protected] (I.J. Park). https://doi.org/10.1016/j.asjsur.2019.03.002 1015-9584/ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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K.M. Yang et al. ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Colorectal cancer (CRC) is the most common cancer of the gastrointestinal tract and the second most common cause of cancer-related deaths both in the United States and in Europe.1 About half of all patients with CRC develop distant metastases, as either synchronous metastases that are diagnosed at the time of initial cancer detection or as metachronous metastases diagnosed in the follow-up period.2 The surgical resection of metastases has been widely accepted and is considered a mainstay for patients with resectable liver or lung metastases. However, despite improvements in the overall survival (OS) rate with this treatment, recurrence remains common. The liver is the most common site for CRC recurrence. Synchronous liver metastases are present in about 15e20% of cases at the time of CRC diagnosis. Metachronous liver metastases occur in about 25e50% of cases, within 3 years after resection of the primary CRC.3 Liver resection is considered the standard management for patients with resectable liver metastases. Moreover, the curative resection of liver metastases has increased significantly and has led to long-term survival rates of up to 50%.3e5 However, despite the curative intent of liver metastasis resections, 60e70% of such patients develop recurrence within the first 2 years after the first metastasectomy.6,7 The second most common organ for distant metastases from primary CRC is the lung, and around 10e20% of patients develop pulmonary metastases.2 The 5-year survival rate of these patients, without surgery, is assumed to be below 5%. Similar to liver metastases, resections of pulmonary metastases have increased during the last decade, and 5-year survival rates of up to 68% have been observed after metastasis resections.8e10 Although several novel chemotherapeutic and biological agents have been developed, surgery is considered to be the most effective therapy for select patients with liver or lung metastases.5,9,11,12 However, the role of aggressive surgery among patients who present with recurrent metastases remains controversial. In this study, we aimed to evaluate the oncological outcomes after repeat metastasectomies in patients who were previously treated with liver or lung resections for CRC metastases.
2. Methods 2.1. Patients This study included 248 patients who underwent surgical resection with curative intent for metachronous-isolated lung and/or liver metastases, at the ASAN Medical Center, between January 2005 and December 2011. The inclusion
criteria for receiving a repeated resection were as follows: previous curative resection of the primary lesion, an achievable complete resection with clear margins, and absence of unresectable extrahepatic or extrapulmonary lesions. The second and third recurrences were treated under the same indications as the first recurrence. All operations were performed by specialized colorectal, hepatobiliary, and thoracic surgeons. The presence of extrahepatic or extrapulmonary metastases was considered as a contraindication for repeated resection. However, in patients with a solitary metastasis or metastasis that was limited to an organ, such as the primary (colorectal) local site, ovaries, local lymph nodes, celiac lymph nodes, para-aortic lymph nodes, adrenal glands, or peritoneum, with or without intrahepatic and/or pulmonary recurrence, we performed a repeated resection. In principle, radiofrequency ablation (RFA) for liver metastases and stereotactic radiosurgery for pulmonary metastases were not performed in patients with resectable metastasis, except for patients with a high-risk surgery or insufficient remnant liver or lung volume. After the repeated resection, postoperative chemotherapy was recommended, except for patients with poor performance or older age. The median follow-up duration was 66 months (range, 6e94 months). The following patient characteristics were analyzed: age, sex, primary tumor location, pathologic TNM stage, presence of lymphovascular invasion and/or perineural invasion, histologic differentiation, and metastasis type. After the first metastasectomy, 74% of the patients underwent postoperative chemotherapy (Table 1). After metastasectomy, patients were routinely followed up every 3 months, and the levels of serum carcinoembryonic antigen (CEA) were measured at every follow-up visit. Surveillance imaging, including abdominopelvic and chest computed tomography scans, was performed every 3 months, during the first 2 years of follow-up, and every 6 months thereafter, until the disease-free interval exceeded 5 years. The OS rate after the first metastasectomy for the first recurrence was defined as the interval from the date of the first metastasectomy to any-cause mortality or the date of the last follow-up (Fig. 1). The recurrence-free survival (RFS) after the surgical resection for the initial recurrence (RFS1) was defined as the interval from the date of the first metastasectomy to the recurrence from colorectal cancer or all-cause mortality, whichever occurred first. The RFS after the first (RFS2) and second (RFS3) repeated resections was defined as the time from the date of the first and second repeat surgeries, respectively. The primary endpoints for this study were survival and clinical recurrence. This study protocol was approved by the institutional review board of the Asan Medical Center (registration no:
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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Repeat metastasectomy from colorectal cancer
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Table 1 Demographic and clinical characteristics of the patients undergoing 1st metastasectomy. Variable Patient characteristics Gender, male Age, year Primary tumor characteristics Location of the primary tumor Colon/Rectum T Stage 1, 2 3, 4 N Stage Negative Positive Stage I II III Presence of lymphovascular invasion Perineural invasion Differentiation Well, moderate Poor, Mucinous Type of metastasis Lung Liver Both Follow-up, months CTx after the 1st metastasectomy, yes Capecitabine XELOX FOLFOX FOLFIRI Others XELOX, capecitabine-oxaliplatin; efluorouracileoxaliplatin; acidefluorouracileirinotecan.
155 (62.5%) 56 (29e82)
97 (39.1%)/151 (60.9%) 44 (17.7%) 204 (82.3%) 121 (48.8%) 127 (51.2%) 32 (12.9%) 89 (25.9%) 127 (51.2%) 65 (26.2%) 61 (24.6%) 237 (95.6%) 11 (4.4%) 127 (26.2%) 121 16 73 (13e140) 197 (79.4%) 52 77 31 21 16
(21.0%) (31.0%) (12.5%) (8.5%) (6.4%)
FOLFOX, FOLFIRI,
folinic
acidfolinic
S2017-2218-0001), in accordance with the Declaration of Helsinki.
2.2. Statistical analysis Survival curves were generated using the KaplaneMeier method, and the differences between curves were evaluated using the log-rank test. With regard to comparison of the RFS, patients who underwent first, second, and third metastasectomy were considered as the independent groups eligible for the analysis. Multivariate analyses for survival included the variables that showed statistical significance in the log-rank test and were performed using the Cox proportional hazards model, with a 95% confidence interval (CI), to assess the risk factors associated with overall survival. Statistical significance was defined as p < 0.05, and all analyses were performed using the SPSS software version 21 (IBM Corp., Armonk, NY).
3. Results Of the 248 patients who underwent a first metastasectomy for hepatic and/or pulmonary metastases, 54% developed a second recurrence. Of these patients, 52 underwent a second metastasectomy, and 52% of these patients developed a third recurrence. Of these 27 patients, 14 underwent a third metastasectomy, 71% of whom developed a fourth recurrence (Fig. 1). The initial sites of recurrence after surgery were the liver group (n Z 115), lung group (n Z 117), and liver/lung group (n Z 16). Among the 133 patients who had recurrence after the first metastasectomy, 81 patients underwent nonsurgical treatment. Among them, 6 patients had bone or brain metastasis, 37 (46%) patients had multiple site metastasis or peritoneal seeding, 23 patients had lung metastasis, 13 patients had liver metastasis, and 2 patients had local recurrence. Among the 23 patients with pulmonary metastasis, 11 patients had multiple recurrences in both lobes, 8 patients underwent radiation therapy, and 4 patients refused further treatment. Among the 13 patients with hepatic recurrence, 7 patients had multiple recurrences in both lobes, 4 patients underwent radiation therapy, and 2 patients refused further treatment. Two patients who had local recurrence refused pelvic exenteration. There was no statistically significant difference in the 5year OS and RFS rates between the liver group, lung group, and liver and lung group. The 5-year OS rates were 65.7% in the liver group, 81.8% in the lung group, and 71.2% in the liver and lung group (p Z 0.602). The 3-year RFS rates were 47.8% in the liver group, 51.2% in the lung group, and 25% in the liver and lung group (p Z 0.149). The profile of the patients who were included in this study is shown in Table 2. Fifty-two and 14 patients underwent a second metastasectomy for a second recurrence and a third metastasectomy for a third recurrence, respectively. The most common repeated resection site was the lung, where the majority of tumors that underwent repeated resections were isolated single lesions. The most common type of metastasectomy was a wedge resection for lung metastasis and a partial hepatectomy for liver metastasis. Postoperative complications were classified according to the Clavien-Dindo Classification system. Severe complications occurred in one out of 52 patients after the second metastasectomy and in one out of 14 patients after the third metastasectomy. There were no lifethreatening complications or death from any repeat surgery. Overall recurrence rates were 51% and 77% in the first and third metastasectomy groups, respectively.
3.1. Overall survival (OS) rate after first metastasectomy Relapse occurred in 133 patients after the first metastasectomy, and a second metastasectomy was performed in 52 patients. The results were classified according to the following subgroups: 5-year and 10-year OS rates in the second metastasectomy group (n Z 52) were 82% and 39%, and that of the subgroup with nonsurgical treatment on second recurrence were 36% and 23% (Fig. 2A, p < 0.001), respectively. The sequential outcomes of the patients are
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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K.M. Yang et al. OS
1st metastasectomy for 1st recurrence (n=248) (Lung 117, Liver 115, Both 16) RFS1
2nd
Recurrence (n=133)
(Liver 31, Lung 58, Liver & lung 8, Others 36; MulƟple 22, LR 5, Bone 5, Brain 2, thyroid 1, ovary 1)
Non-surgical Treatment (n=81)
2nd metastasectomy (n=52)
(Liver 14, Lung 24, Liver & lung 5, Others 38; MulƟple sites 29, Bone 5, LR3, Brain 1)
(Liver 12, Lung 31, Liver & lung 2, Others 7; DLNs 3, LR 2, thyroid 1, ovary 1) RFS2
3rd Recurrence (n=27) (Liver 5, Lung 13, Liver & lung 2, Others 7; LR 2, DLNs 3, adrenal 1, bone 1)
Non-surgical Treatment (n=13)
3rd metastasectomy (n=14)
(Liver 3, Lung 3,
(Liver 2, Lung 9, Liver & lung 1, adrenal 1, LR 1)
Others 7; MulƟple 3, LR 2, bone 1, brain 1) RFS3
4th Recurrence (n=10) (Liver 2, Lung 5, MulƟple 2, Brain 1)
Figure 1 Study workflow profile. Multiple sites include peritoneal seeding. LR; local recurrence, DLNs; distant lymph node metastasis.
shown in Fig. 1. Of the 248 patients who underwent a first metastasectomy, 133 (133/248, 54%) developed a second recurrence, of whom 52 (39%) underwent a second metastasectomy. Of the 52 patients who underwent a third metastasectomy, 27 (27/52, 52%) developed a third recurrence, of whom 14 (47%) underwent a third metastasectomy. Of the 14 patients who underwent a third metastasectomy, 10 (71%) developed a fourth recurrence. Among the 248 patients who underwent first metastasectomy, 197 (79.4%) underwent adjuvant chemotherapy. Because almost 80% of patients underwent chemotherapy, it was difficult to compare these patients to those who did not undergo chemotherapy. The 3-year RFS rates and 5-year OS rates were not significantly different between patients who underwent adjuvant chemotherapy and those who did not undergo chemotherapy (54.2% vs. 48.5%, p Z 0.736; 75.4% vs. 43.4%, p Z 0.732).
3.2. OS and RFS rates after initial and repeat metastasectomies The 5-year and 10-year OS rates were 74.8% and 57.6%, respectively (Fig. 2B). The 1-year RFS1, RFS2, and RFS3 rates were 76%, 75%, and 39%, respectively. The hazard ratios (HRs) for RFS2 and RFS3 were 1.142 and 2.590,
respectively (p Z 0.028, Fig. 2C). There were no statistically significant differences in RFS between the patients who underwent a first metastasectomy and those who underwent a second metastasectomy; however, those who underwent a third metastasectomy showed a significantly lower RFS rate than to those who underwent only a single repeated resection (p Z 0.028).
3.3. Multivariate analysis of OS rate after first metastasectomy In the multivariate analysis, unresectable lesion (HR Z 43.517; 95% CI, 12.249e142.927; p < 0.001) and RFS < 6 months (HR Z 1.965, 95% CI: 1.075e3.594, p Z 0.028) were the significant risk factors for OS. Resected number of metastases >1, resected number of organs, TNM stage of the primary tumor, location of the primary tumor, preoperative serum CEA levels (>6 ng/mL), and presence of lymphovascular or perineural invasion had no statistically significant association with OS1 (see Table 3).
4. Discussion Approximately 50e60% and 10e20% of patients who undergo curative resections for CRC will develop liver and
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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Repeat metastasectomy from colorectal cancer Table 2
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Profile of the repeat resections.
Variable
Resection organ site, n (%) Lung only Liver only Lung and liver Liver or lung and others Others only Resected tumor number (lung), n 1 2e3 4 Resected tumor number (liver), n 1 2e3 4 Type of pulmonary resection, n (%) Wedge resection Lobectomy Type of hepatic resection, n (%) Partial hepatectomy Segmentectomy/Sectionectomy Resectability (R0/R1/R2) Complications (Clavien-Dindo), n Grade I/II Grade IIIa/IIIb Grade IVa/IVb Grade V Overall recurrence rates, % 3-year recurrence-free survival rate (%) 5-year overall survival rate (%)
1st metastasectomy
2nd metastasectomy
3rd metastasectomy
(n Z 248)
(n Z 52)
(n Z 14)
117 (47%) 115 (46%) 16 (7%)
31 (60%) 11 (21%) 2 (4%) 1 (2%) 7 (13%)
9 1 1 1 2
91 (78%) 21 (20%) 1 (2%)
24 (77%) 5 (16%) 2 (6%)
7 (78%) 2 (22%) 0 (0%)
86 (73%) 25 (22%) 6 (5%)
11 (79%) 2 (14%) 1 (7%)
2 (67%) 1 (33%) 0 (0%)
113 (84%) 22 (16%)
29 (87.9%) 4 (12.1%)
7 (78%) 2 (22%)
76 (65%) 41 (35%) 234/14/0
9 (64.3%) 5 (35.7%) 46/4/2
2 (67%) 1 (33%) 13/0/1
7/4 0/0 0/0 0/0 53.6% 49.5% 74.8%
2/1 1/0 0/0 0/0 51.9% 41.4% 62.4%
1/1 1/0 0/0 0/0 71.4% 19.6% 45.6%
P-value
0.347 (65%) (7%) (7%) (7%) (14%) 0.738
0.757
0.415
0.559
0.758
lung metastases, respectively.2,3 Although resections for recurrent liver or lung metastases with curative intent may result in greater long-term survival, recurrence was common after initial metastasectomy.3e6,8 Patients with limited-recurrent liver or lung metastases that are considered for repeated resections have favorable outcomes.5,9,11,12 However, controversies remain when metastases are found concomitantly in both organs or develop in other organs. Until recently, resection for metastatic CRC has mostly been performed in patients with isolated hepatic or pulmonary metastases. Since the liver and lung are the most common sites of metastasis, surgery might be indicated for patients with limited liver-only or lung-only metastases, while a systemic treatment might be more suitable for patients with liver metastases and extrahepatic disease or concurrent lung metastasis. However, recent studies have demonstrated that the resection of liver metastases and limited-resectable concurrent extrahepatic disease can result in higher long-term survival.13e18 Indeed, surgical managements in patients with both hepatic and pulmonary metastases has shown survival benefits that are comparable to those of hepatic or pulmonary metastasectomies.19,20 Therefore, the presence of extrahepatic disease and concurrent hepatic and pulmonary metastases should no longer be considered an absolute contraindication for curative
surgery. In our study, if a resection was possible, then we performed a metastasectomy, even if the metastases developed in both the liver and lungs or the liver with concurrent extrahepatic disease. Furthermore, if there were extrahepatic or extrapulmonary metastases after the first metastasectomy, we performed metastasectomies in cases with a solitary metastasis or a metastasis that was limited to a single organ. Indeed, we tried to analyze the liver and lung together, even though these are different entities. It is meaningful to know the oncologic outcomes for both organs because the liver and lung are the most common sites for colorectal cancer metastasis. Our study demonstrated that repeat metastasectomies in patients who underwent previous liver and/or lung resections for CRC metastases can be performed safely, and good long-term survival can be achieved in select patients. There were no statistically significant differences in OS1 and OS2 (74.8% vs. 62.4%, p Z 0.207) or in OS2 and OS3 (62.4% vs. 45.6%, p Z 0.207) rates. This observation suggests that the survival benefits of repeat metastasectomies for recurrent metastases are consistent, regardless of the number of previous metastasectomies. Repeated resections of recurrences may lead to good long-term survival; however, recurrence remains common. Many reports have demonstrated that 60e70% of patients develop recurrence within the first 2 years after an initial
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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Figure 2 (A) Overall survival (OS) rates in the subgroup with second metastasectomy and the subgroup with nonsurgical treatment on second recurrence. (B) OS rate after the first metastasectomy. (C) Recurrence-free survival (RFS) rate after the first metastasectomy, second metastasectomy, and third metastasectomy.
liver or lung resection.6,7,21 The most common recurrence sites after liver or lung resection were the liver and lungs. Yokata et al reported that following initial pulmonary resections (n Z 76), recurrences developed in the lungs (n Z 37), liver (n Z 12), and other organs (n Z 11).22 Among these patient, 37 underwent metastasectomies, with 22 undergoing pulmonary resections, 11 hepatic resections, and two resections at other sites. After metastasectomy, the 3-year OS rate was 84.1% for the surgery group and 38.9% for the chemotherapy group (p < 0.001). Bellier et al21 reported that out of the 46 patients who underwent hepatic or pulmonary resections for initial recurrences, 35 (76.1%) experienced lung and/or liver relapse. Among these patients, 14 out of the 22 (63.3%) patients with recurrent liver metastasis could undergo repeat metastasectomies, in addition to 11 of the 24 patients (45.8%) with recurrent pulmonary metastases. In our study, the distribution of first metastasectomy sites was as follows: liver, 115 patients; lungs, 117 patients; and liver and lungs, 16 patients. After the first metastasectomy, 133 patients developed a second recurrence (53.6%), among whom 95 patients (95/133, 71.4%) had liver or lung metastases and 38 (28.6%) had metastases at other sites, which primarily included peritoneal seeding. Of the 95 patients who had liver or lung metastases, 46 (46/95,
48.4%) patients underwent a first repeat metastasectomy, while only seven patients (7/38, 18.4%) with recurrences at other sites underwent repeat metastasectomies. In select patients, repeated resections can provide good OS rate with acceptable mortalities for both liver5,11,21 and pulmonary metastases.9,12 Therefore, despite the high recurrence rate, surgery provides a promising strategy for the treatment of isolated recurrences. Although the majority of patients in this study who underwent repeated resections had prolonged survivals, a third or even fourth resection should be considered carefully. Several previous studies have reported the outcomes of repeated hepatic and pulmonary resections, with good long-term survival rates that are consistent with our results.21,23 However, the recurrence rates in our series were significantly higher after the third metastasectomy. Recurrence rates after the first metastasectomy, second metastasectomy, and third metastasectomy were 54% (133/ 248), 52% (27/52), and 71% (10/14), respectively. The HR for RFS for the first and second repeat surgery was 1.142 and 2.590, respectively, in comparison with that of the first metastasectomy. Third metastasectomy showed significantly lower RFS rate compared to second metastasectomy (p Z 0.028). Although repeat metastasectomies may provide prolonged survival, recurrence rates after a third
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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Table 3 Univariate and multivariate analyses of factors associated with overall survival after the initial resection for the first recurrence. Variables
Univariate P-value
Initial recurrence pattern Recurrence free Resectable recurrence Unresectable recurrence Recurrence free interval after initial resection 6 months <6 months Resected tumor number of initial recurrence 1 >1 Resected organ number of initial recurrence 1 >1 Tumor location (primary tumor) Colon Rectum Stage (primary tumor) I II III Preoperative CEA (ng/mL), >6 Presence of lymphovascular invasion (primary tumor), yes Presence of perineural invasion (primary tumor), yes
metastasectomy were significantly higher. Of the 14 patients who underwent third metastasectomy, five died or had recurrences within 6 months, and eight died or had recurrences within 12 months. Therefore, third metastasectomy should be carefully considered. Several factors have been found to correlate with survival after the resection of hepatic or pulmonary metastases, such as the number of metastases, tumor size, presence of extrahepatic or pulmonary metastases, serum CEA levels, and N stage of the primary tumor.17,18,22 In our present study, the multivariate analysis revealed that an unresectable lesion and an RFS <6 months were significant risk factors for overall survival after a first metastasectomy. Elias et al15 reported that the total number of metastases, regardless of location, showed a stronger prognostic effect than the sites of the metastases, with 5-year survival rates of 38% in patients with 1e3 metastases, 29% in patients with 4e6 metastases, and 18% in patients with less than six metastases (p Z 0.002). In our study, metastasectomies were performed even when the metastases were found in the extrahepatic or extrapulmonary regions. Most patients had single metastasis (>70%), and no patients who underwent metastasectomies had more than four metastatic lesions. This may be an important factor in explaining the relatively high OS rate that was observed in our present study. In our study, only one patient had severe morbidity (grade III, according to the Clavien-Dindo classification) after the first and third metastasectomy. Therefore, repeated resections should be a part of a multidisciplinary management in specialized centers, where the incidences
Multivariate HR
95% CI
<0.001*
P-value <0.001*
1.000 12.094 43.517
3.533e41.403 12.249e142.927
1.000 1.965
1.075e3.594
0.042* 0.028*
0.439
0.869
0.927
0.201
0.328 0.857
of operative complications would be expected to be reasonable. Our findings suggest that the frequency (about 70%) of parenchyma-saving resections (partial hepatectomy or pulmonary wedge resection) appears to increase the likelihood of a subsequent effective repeated resection. Radiofrequency ablation is considered to be an alternative treatment in certain indications for patients not suitable to undergo surgical resection. Accordingly, the proportion of nonsurgical treatments, such as RFA or stereotactic body radiation therapy, has been increasing in our hospital. A previous study demonstrated that hepatic resection should be preferred for the treatment of liver metastasis, whereas RFA might be considered as a reasonable alternative for solitary hepatic metastases <3 cm in diameter.23 However, because the purpose of this study was to evaluate the oncologic outcomes of surgical treatment, the method of treatment was limited to surgery. In this study, among the 117 patients who underwent first metastasectomy for liver metastasis, 70 had multiple metastases or large metastases >3 cm in diameter. Recently, biologic agents that selectively target proteins altered in cancer cells have been developed. In particular, both inhibitors of the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) have shown to improve the efficacy of the available chemotherapeutic regimens.24 However, in the present study, only 7 patients received bevacizumab after the first metastasectomy. Because the use of target agent in Korea was not active during the research period, there are restrictions according to strict Korean government health insurance reimbursement policy.
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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8 The limitations of this study included the retrospective nature of the data analysis and the highly selective patient population. The patients in this study likely had favorable tumor biology and were good surgical candidates; hence, these results may not be reflective of the general population of patients with metastatic CRC. Despite this limitation, our survival estimates are still valuable, since this study is one of the largest series to date concerning patients who have undergone both lung and liver resections for metastatic CRC. In conclusion, repeated resections may improve longterm survival. We report that a second metastasectomy should be considered as the optimal treatment strategy for a second recurrence in patients with recurrent disease after an initial hepatic or pulmonary resection. However, careful consideration should be made before performing a third metastasectomy.
Conflict of interest statement The authors have no conflicts of interest, financial or otherwise.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.asjsur.2019.03.002.
References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5e29. 2. Labianca R, Beretta GD, Kildani B, et al. Colon cancer. Crit Rev Oncol Hematol. 2010;74:106e133. 3. Lochan R, White SA, Manas DM. Liver resection for colorectal liver metastasis. Surg Oncol. 2007;16:33e45. 4. Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247:125e135. 5. Nanji S, Tsang ME, Wei X, Booth CM. Outcomes after repeat hepatic resection for recurrent metastatic colorectal cancer: a population-based study. Am J Surg. 2017;213:1053e1059. 6. 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;250:440e448. 7. Saiura A, Yamamoto J, Hasegawa K, et al. Liver resection for multiple colorectal liver metastases with surgery up-front approach: bi-institutional analysis of 736 consecutive cases. World J Surg. 2012;36:2171e2178.
K.M. Yang et al. 8. Pfannschmidt J, Hoffmann H, Dienemann H. Reported outcome factors for pulmonary resection in metastatic colorectal cancer. J Thorac Oncol. 2010;5:S172eS178. 9. Sponholz S, Schirren M, Baldes N, Oguzhan S, Schirren J. Repeat resection for recurrent pulmonary metastasis of colorectal cancer. Langenbeck’s Arch Surg. 2017;402:77e85. 10. Wiegering A, Riegel J, Wagner J, et al. The impact of pulmonary metastasectomy in patients with previously resected colorectal cancer liver metastases. PLoS One. 2017;12:e0173933. 11. Oba M, Hasegawa K, Shindoh J, et al. Survival benefit of repeat resection of successive recurrences after the initial hepatic resection for colorectal liver metastases. Surgery. 2016;159: 632e640. 12. Hishida T, Tsuboi M, Okumura T, et al. Does repeated lung resection provide long-term survival for recurrent pulmonary metastases of colorectal cancer? Results of a retrospective Japanese Multicenter study. Ann Thorac Surg. 2017;103:399e405. 13. Leung U, Gonen M, Allen PJ, et al. Colorectal cancer liver metastases and concurrent extrahepatic disease treated with resection. Ann Surg. 2017;265:158e165. 14. Elias D, Sideris L, Pocard M, et al. Results of R0 resection for colorectal liver metastases associated with extrahepatic disease. Ann Surg Oncol. 2004;11:274e280. 15. Elias D, Liberale G, Vernerey D, et al. Hepatic and extrahepatic colorectal metastases: when resectable, their localization does not matter, but their total number has a prognostic effect. Ann Surg Oncol. 2005;12:900e909. 16. Adam R, de Haas RJ, Wicherts DA, et al. Concomitant extrahepatic disease in patients with colorectal liver metastases: when is there a place for surgery? Ann Surg. 2011;253:349e359. 17. Carpizo DR, D’Angelica M. Liver resection for metastatic colorectal cancer in the presence of extrahepatic disease. Lancet Oncol. 2009;10:801e809. 18. Elias D, Ouellet JF, Bellon N, Pignon JP, Pocard M, Lasser P. Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg. 2003;90:567e574. 19. Limmer S, Oevermann E, Killaitis C, Kujath P, Hoffmann M, Bruch HP. Sequential surgical resection of hepatic and pulmonary metastases from colorectal cancer. Langenbeck’s Arch Surg. 2010;395:1129e1138. 20. Shah SA, Haddad R, Al-Sukhni W, et al. Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma. J Am Coll Surg. 2006;202:468e475. 21. Bellier J, De Wolf J, Hebbar M, et al. Repeated resections of hepatic and pulmonary metastases from colorectal cancer provide long-term survival. World J Surg. 2018;42:1171e1179. 22. Kanemitsu Y, Kato T, Komori K, Fukui T, Mitsudomi T. Validation of a nomogram for predicting overall survival after resection of pulmonary metastases from colorectal cancer at a single center. World J Surg. 2010;34:2973e2978. 23. Lee BC, Lee HG, Park IJ, et al. The role of radiofrequency ablation for treatment of metachronous isolated hepatic metastasis from colorectal cancer. Medicine (Baltim). 2016;95:e4999. 24. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI, and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol. 2009;20:1842e1847.
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ORIGINAL ARTICLE
Benefits of repeated resections for liver and lung metastases from colorectal cancer Kwan Mo Yang a, In Ja Park b,*, Jong Lyul Lee b, Chan Wook Kim b, Yong Sik Yoon b, Seok-Byung Lim b, Chang Sik Yu b, Jin Cheon Kim b a Department of General Surgery, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Republic of Korea b Department of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
Received 16 October 2018; received in revised form 24 February 2019; accepted 4 March 2019
KEYWORDS Colorectal cancer; Metastasectomy; Oncologic outcome; Repeated resection
Summary Objective: We aimed to evaluate oncological outcomes after repeat metastasectomies in patients having undergone previous resections for colorectal cancer metastases. Methods: We examined 248 patients who underwent metastasectomies for lung and/or liver metastases at our center during a 7-year period, from January 2005 to December 2011. Recurrence-free survival 1 (RFS1) after the metastasectomy for the initial recurrence, recurrence-free survival 2 (RFS2) after the second, and recurrence-free survival 3 (RFS3) after the third repeated resections for recurrence were assessed. The overall survival (OS) rate after the first metastasectomy for the first recurrence (OS) was also assessed. Results: Sites of recurrence of the first metastasectomy were the liver, lung, and liver and lung in 115, 117, and 16 cases, respectively, and 133 patients had a second recurrence (133/248, 53.6%). Twenty-seven patients had a third recurrence (27/52, 51.9%), of whom 14 underwent a third metastasectomy. The 5-year and 10-year OS rates were 74.8% and 57.9%, respectively. The 1-year RFS1, RFS2, and RFS3 rates were 76%, 75%, and 39%, respectively. The hazard ratios for RFS were 1.142 and 2.590 for the first and second repeat surgeries, when compared to the first metastasectomy. The third metastasectomy showed significantly lower RFS than did the second metastasectomy. Conclusion: A second metastasectomy should be considered the optimal treatment for a second recurrence. However, careful considerations should be made before performing a third metastasectomy.
* Corresponding author. Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro, 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. Fax: þ82 2 2010 6701. E-mail address: [email protected] (I.J. Park). https://doi.org/10.1016/j.asjsur.2019.03.002 1015-9584/ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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K.M. Yang et al. ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Colorectal cancer (CRC) is the most common cancer of the gastrointestinal tract and the second most common cause of cancer-related deaths both in the United States and in Europe.1 About half of all patients with CRC develop distant metastases, as either synchronous metastases that are diagnosed at the time of initial cancer detection or as metachronous metastases diagnosed in the follow-up period.2 The surgical resection of metastases has been widely accepted and is considered a mainstay for patients with resectable liver or lung metastases. However, despite improvements in the overall survival (OS) rate with this treatment, recurrence remains common. The liver is the most common site for CRC recurrence. Synchronous liver metastases are present in about 15e20% of cases at the time of CRC diagnosis. Metachronous liver metastases occur in about 25e50% of cases, within 3 years after resection of the primary CRC.3 Liver resection is considered the standard management for patients with resectable liver metastases. Moreover, the curative resection of liver metastases has increased significantly and has led to long-term survival rates of up to 50%.3e5 However, despite the curative intent of liver metastasis resections, 60e70% of such patients develop recurrence within the first 2 years after the first metastasectomy.6,7 The second most common organ for distant metastases from primary CRC is the lung, and around 10e20% of patients develop pulmonary metastases.2 The 5-year survival rate of these patients, without surgery, is assumed to be below 5%. Similar to liver metastases, resections of pulmonary metastases have increased during the last decade, and 5-year survival rates of up to 68% have been observed after metastasis resections.8e10 Although several novel chemotherapeutic and biological agents have been developed, surgery is considered to be the most effective therapy for select patients with liver or lung metastases.5,9,11,12 However, the role of aggressive surgery among patients who present with recurrent metastases remains controversial. In this study, we aimed to evaluate the oncological outcomes after repeat metastasectomies in patients who were previously treated with liver or lung resections for CRC metastases.
2. Methods 2.1. Patients This study included 248 patients who underwent surgical resection with curative intent for metachronous-isolated lung and/or liver metastases, at the ASAN Medical Center, between January 2005 and December 2011. The inclusion
criteria for receiving a repeated resection were as follows: previous curative resection of the primary lesion, an achievable complete resection with clear margins, and absence of unresectable extrahepatic or extrapulmonary lesions. The second and third recurrences were treated under the same indications as the first recurrence. All operations were performed by specialized colorectal, hepatobiliary, and thoracic surgeons. The presence of extrahepatic or extrapulmonary metastases was considered as a contraindication for repeated resection. However, in patients with a solitary metastasis or metastasis that was limited to an organ, such as the primary (colorectal) local site, ovaries, local lymph nodes, celiac lymph nodes, para-aortic lymph nodes, adrenal glands, or peritoneum, with or without intrahepatic and/or pulmonary recurrence, we performed a repeated resection. In principle, radiofrequency ablation (RFA) for liver metastases and stereotactic radiosurgery for pulmonary metastases were not performed in patients with resectable metastasis, except for patients with a high-risk surgery or insufficient remnant liver or lung volume. After the repeated resection, postoperative chemotherapy was recommended, except for patients with poor performance or older age. The median follow-up duration was 66 months (range, 6e94 months). The following patient characteristics were analyzed: age, sex, primary tumor location, pathologic TNM stage, presence of lymphovascular invasion and/or perineural invasion, histologic differentiation, and metastasis type. After the first metastasectomy, 74% of the patients underwent postoperative chemotherapy (Table 1). After metastasectomy, patients were routinely followed up every 3 months, and the levels of serum carcinoembryonic antigen (CEA) were measured at every follow-up visit. Surveillance imaging, including abdominopelvic and chest computed tomography scans, was performed every 3 months, during the first 2 years of follow-up, and every 6 months thereafter, until the disease-free interval exceeded 5 years. The OS rate after the first metastasectomy for the first recurrence was defined as the interval from the date of the first metastasectomy to any-cause mortality or the date of the last follow-up (Fig. 1). The recurrence-free survival (RFS) after the surgical resection for the initial recurrence (RFS1) was defined as the interval from the date of the first metastasectomy to the recurrence from colorectal cancer or all-cause mortality, whichever occurred first. The RFS after the first (RFS2) and second (RFS3) repeated resections was defined as the time from the date of the first and second repeat surgeries, respectively. The primary endpoints for this study were survival and clinical recurrence. This study protocol was approved by the institutional review board of the Asan Medical Center (registration no:
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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Table 1 Demographic and clinical characteristics of the patients undergoing 1st metastasectomy. Variable Patient characteristics Gender, male Age, year Primary tumor characteristics Location of the primary tumor Colon/Rectum T Stage 1, 2 3, 4 N Stage Negative Positive Stage I II III Presence of lymphovascular invasion Perineural invasion Differentiation Well, moderate Poor, Mucinous Type of metastasis Lung Liver Both Follow-up, months CTx after the 1st metastasectomy, yes Capecitabine XELOX FOLFOX FOLFIRI Others XELOX, capecitabine-oxaliplatin; efluorouracileoxaliplatin; acidefluorouracileirinotecan.
155 (62.5%) 56 (29e82)
97 (39.1%)/151 (60.9%) 44 (17.7%) 204 (82.3%) 121 (48.8%) 127 (51.2%) 32 (12.9%) 89 (25.9%) 127 (51.2%) 65 (26.2%) 61 (24.6%) 237 (95.6%) 11 (4.4%) 127 (26.2%) 121 16 73 (13e140) 197 (79.4%) 52 77 31 21 16
(21.0%) (31.0%) (12.5%) (8.5%) (6.4%)
FOLFOX, FOLFIRI,
folinic
acidfolinic
S2017-2218-0001), in accordance with the Declaration of Helsinki.
2.2. Statistical analysis Survival curves were generated using the KaplaneMeier method, and the differences between curves were evaluated using the log-rank test. With regard to comparison of the RFS, patients who underwent first, second, and third metastasectomy were considered as the independent groups eligible for the analysis. Multivariate analyses for survival included the variables that showed statistical significance in the log-rank test and were performed using the Cox proportional hazards model, with a 95% confidence interval (CI), to assess the risk factors associated with overall survival. Statistical significance was defined as p < 0.05, and all analyses were performed using the SPSS software version 21 (IBM Corp., Armonk, NY).
3. Results Of the 248 patients who underwent a first metastasectomy for hepatic and/or pulmonary metastases, 54% developed a second recurrence. Of these patients, 52 underwent a second metastasectomy, and 52% of these patients developed a third recurrence. Of these 27 patients, 14 underwent a third metastasectomy, 71% of whom developed a fourth recurrence (Fig. 1). The initial sites of recurrence after surgery were the liver group (n Z 115), lung group (n Z 117), and liver/lung group (n Z 16). Among the 133 patients who had recurrence after the first metastasectomy, 81 patients underwent nonsurgical treatment. Among them, 6 patients had bone or brain metastasis, 37 (46%) patients had multiple site metastasis or peritoneal seeding, 23 patients had lung metastasis, 13 patients had liver metastasis, and 2 patients had local recurrence. Among the 23 patients with pulmonary metastasis, 11 patients had multiple recurrences in both lobes, 8 patients underwent radiation therapy, and 4 patients refused further treatment. Among the 13 patients with hepatic recurrence, 7 patients had multiple recurrences in both lobes, 4 patients underwent radiation therapy, and 2 patients refused further treatment. Two patients who had local recurrence refused pelvic exenteration. There was no statistically significant difference in the 5year OS and RFS rates between the liver group, lung group, and liver and lung group. The 5-year OS rates were 65.7% in the liver group, 81.8% in the lung group, and 71.2% in the liver and lung group (p Z 0.602). The 3-year RFS rates were 47.8% in the liver group, 51.2% in the lung group, and 25% in the liver and lung group (p Z 0.149). The profile of the patients who were included in this study is shown in Table 2. Fifty-two and 14 patients underwent a second metastasectomy for a second recurrence and a third metastasectomy for a third recurrence, respectively. The most common repeated resection site was the lung, where the majority of tumors that underwent repeated resections were isolated single lesions. The most common type of metastasectomy was a wedge resection for lung metastasis and a partial hepatectomy for liver metastasis. Postoperative complications were classified according to the Clavien-Dindo Classification system. Severe complications occurred in one out of 52 patients after the second metastasectomy and in one out of 14 patients after the third metastasectomy. There were no lifethreatening complications or death from any repeat surgery. Overall recurrence rates were 51% and 77% in the first and third metastasectomy groups, respectively.
3.1. Overall survival (OS) rate after first metastasectomy Relapse occurred in 133 patients after the first metastasectomy, and a second metastasectomy was performed in 52 patients. The results were classified according to the following subgroups: 5-year and 10-year OS rates in the second metastasectomy group (n Z 52) were 82% and 39%, and that of the subgroup with nonsurgical treatment on second recurrence were 36% and 23% (Fig. 2A, p < 0.001), respectively. The sequential outcomes of the patients are
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K.M. Yang et al. OS
1st metastasectomy for 1st recurrence (n=248) (Lung 117, Liver 115, Both 16) RFS1
2nd
Recurrence (n=133)
(Liver 31, Lung 58, Liver & lung 8, Others 36; MulƟple 22, LR 5, Bone 5, Brain 2, thyroid 1, ovary 1)
Non-surgical Treatment (n=81)
2nd metastasectomy (n=52)
(Liver 14, Lung 24, Liver & lung 5, Others 38; MulƟple sites 29, Bone 5, LR3, Brain 1)
(Liver 12, Lung 31, Liver & lung 2, Others 7; DLNs 3, LR 2, thyroid 1, ovary 1) RFS2
3rd Recurrence (n=27) (Liver 5, Lung 13, Liver & lung 2, Others 7; LR 2, DLNs 3, adrenal 1, bone 1)
Non-surgical Treatment (n=13)
3rd metastasectomy (n=14)
(Liver 3, Lung 3,
(Liver 2, Lung 9, Liver & lung 1, adrenal 1, LR 1)
Others 7; MulƟple 3, LR 2, bone 1, brain 1) RFS3
4th Recurrence (n=10) (Liver 2, Lung 5, MulƟple 2, Brain 1)
Figure 1 Study workflow profile. Multiple sites include peritoneal seeding. LR; local recurrence, DLNs; distant lymph node metastasis.
shown in Fig. 1. Of the 248 patients who underwent a first metastasectomy, 133 (133/248, 54%) developed a second recurrence, of whom 52 (39%) underwent a second metastasectomy. Of the 52 patients who underwent a third metastasectomy, 27 (27/52, 52%) developed a third recurrence, of whom 14 (47%) underwent a third metastasectomy. Of the 14 patients who underwent a third metastasectomy, 10 (71%) developed a fourth recurrence. Among the 248 patients who underwent first metastasectomy, 197 (79.4%) underwent adjuvant chemotherapy. Because almost 80% of patients underwent chemotherapy, it was difficult to compare these patients to those who did not undergo chemotherapy. The 3-year RFS rates and 5-year OS rates were not significantly different between patients who underwent adjuvant chemotherapy and those who did not undergo chemotherapy (54.2% vs. 48.5%, p Z 0.736; 75.4% vs. 43.4%, p Z 0.732).
3.2. OS and RFS rates after initial and repeat metastasectomies The 5-year and 10-year OS rates were 74.8% and 57.6%, respectively (Fig. 2B). The 1-year RFS1, RFS2, and RFS3 rates were 76%, 75%, and 39%, respectively. The hazard ratios (HRs) for RFS2 and RFS3 were 1.142 and 2.590,
respectively (p Z 0.028, Fig. 2C). There were no statistically significant differences in RFS between the patients who underwent a first metastasectomy and those who underwent a second metastasectomy; however, those who underwent a third metastasectomy showed a significantly lower RFS rate than to those who underwent only a single repeated resection (p Z 0.028).
3.3. Multivariate analysis of OS rate after first metastasectomy In the multivariate analysis, unresectable lesion (HR Z 43.517; 95% CI, 12.249e142.927; p < 0.001) and RFS < 6 months (HR Z 1.965, 95% CI: 1.075e3.594, p Z 0.028) were the significant risk factors for OS. Resected number of metastases >1, resected number of organs, TNM stage of the primary tumor, location of the primary tumor, preoperative serum CEA levels (>6 ng/mL), and presence of lymphovascular or perineural invasion had no statistically significant association with OS1 (see Table 3).
4. Discussion Approximately 50e60% and 10e20% of patients who undergo curative resections for CRC will develop liver and
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
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Profile of the repeat resections.
Variable
Resection organ site, n (%) Lung only Liver only Lung and liver Liver or lung and others Others only Resected tumor number (lung), n 1 2e3 4 Resected tumor number (liver), n 1 2e3 4 Type of pulmonary resection, n (%) Wedge resection Lobectomy Type of hepatic resection, n (%) Partial hepatectomy Segmentectomy/Sectionectomy Resectability (R0/R1/R2) Complications (Clavien-Dindo), n Grade I/II Grade IIIa/IIIb Grade IVa/IVb Grade V Overall recurrence rates, % 3-year recurrence-free survival rate (%) 5-year overall survival rate (%)
1st metastasectomy
2nd metastasectomy
3rd metastasectomy
(n Z 248)
(n Z 52)
(n Z 14)
117 (47%) 115 (46%) 16 (7%)
31 (60%) 11 (21%) 2 (4%) 1 (2%) 7 (13%)
9 1 1 1 2
91 (78%) 21 (20%) 1 (2%)
24 (77%) 5 (16%) 2 (6%)
7 (78%) 2 (22%) 0 (0%)
86 (73%) 25 (22%) 6 (5%)
11 (79%) 2 (14%) 1 (7%)
2 (67%) 1 (33%) 0 (0%)
113 (84%) 22 (16%)
29 (87.9%) 4 (12.1%)
7 (78%) 2 (22%)
76 (65%) 41 (35%) 234/14/0
9 (64.3%) 5 (35.7%) 46/4/2
2 (67%) 1 (33%) 13/0/1
7/4 0/0 0/0 0/0 53.6% 49.5% 74.8%
2/1 1/0 0/0 0/0 51.9% 41.4% 62.4%
1/1 1/0 0/0 0/0 71.4% 19.6% 45.6%
P-value
0.347 (65%) (7%) (7%) (7%) (14%) 0.738
0.757
0.415
0.559
0.758
lung metastases, respectively.2,3 Although resections for recurrent liver or lung metastases with curative intent may result in greater long-term survival, recurrence was common after initial metastasectomy.3e6,8 Patients with limited-recurrent liver or lung metastases that are considered for repeated resections have favorable outcomes.5,9,11,12 However, controversies remain when metastases are found concomitantly in both organs or develop in other organs. Until recently, resection for metastatic CRC has mostly been performed in patients with isolated hepatic or pulmonary metastases. Since the liver and lung are the most common sites of metastasis, surgery might be indicated for patients with limited liver-only or lung-only metastases, while a systemic treatment might be more suitable for patients with liver metastases and extrahepatic disease or concurrent lung metastasis. However, recent studies have demonstrated that the resection of liver metastases and limited-resectable concurrent extrahepatic disease can result in higher long-term survival.13e18 Indeed, surgical managements in patients with both hepatic and pulmonary metastases has shown survival benefits that are comparable to those of hepatic or pulmonary metastasectomies.19,20 Therefore, the presence of extrahepatic disease and concurrent hepatic and pulmonary metastases should no longer be considered an absolute contraindication for curative
surgery. In our study, if a resection was possible, then we performed a metastasectomy, even if the metastases developed in both the liver and lungs or the liver with concurrent extrahepatic disease. Furthermore, if there were extrahepatic or extrapulmonary metastases after the first metastasectomy, we performed metastasectomies in cases with a solitary metastasis or a metastasis that was limited to a single organ. Indeed, we tried to analyze the liver and lung together, even though these are different entities. It is meaningful to know the oncologic outcomes for both organs because the liver and lung are the most common sites for colorectal cancer metastasis. Our study demonstrated that repeat metastasectomies in patients who underwent previous liver and/or lung resections for CRC metastases can be performed safely, and good long-term survival can be achieved in select patients. There were no statistically significant differences in OS1 and OS2 (74.8% vs. 62.4%, p Z 0.207) or in OS2 and OS3 (62.4% vs. 45.6%, p Z 0.207) rates. This observation suggests that the survival benefits of repeat metastasectomies for recurrent metastases are consistent, regardless of the number of previous metastasectomies. Repeated resections of recurrences may lead to good long-term survival; however, recurrence remains common. Many reports have demonstrated that 60e70% of patients develop recurrence within the first 2 years after an initial
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Figure 2 (A) Overall survival (OS) rates in the subgroup with second metastasectomy and the subgroup with nonsurgical treatment on second recurrence. (B) OS rate after the first metastasectomy. (C) Recurrence-free survival (RFS) rate after the first metastasectomy, second metastasectomy, and third metastasectomy.
liver or lung resection.6,7,21 The most common recurrence sites after liver or lung resection were the liver and lungs. Yokata et al reported that following initial pulmonary resections (n Z 76), recurrences developed in the lungs (n Z 37), liver (n Z 12), and other organs (n Z 11).22 Among these patient, 37 underwent metastasectomies, with 22 undergoing pulmonary resections, 11 hepatic resections, and two resections at other sites. After metastasectomy, the 3-year OS rate was 84.1% for the surgery group and 38.9% for the chemotherapy group (p < 0.001). Bellier et al21 reported that out of the 46 patients who underwent hepatic or pulmonary resections for initial recurrences, 35 (76.1%) experienced lung and/or liver relapse. Among these patients, 14 out of the 22 (63.3%) patients with recurrent liver metastasis could undergo repeat metastasectomies, in addition to 11 of the 24 patients (45.8%) with recurrent pulmonary metastases. In our study, the distribution of first metastasectomy sites was as follows: liver, 115 patients; lungs, 117 patients; and liver and lungs, 16 patients. After the first metastasectomy, 133 patients developed a second recurrence (53.6%), among whom 95 patients (95/133, 71.4%) had liver or lung metastases and 38 (28.6%) had metastases at other sites, which primarily included peritoneal seeding. Of the 95 patients who had liver or lung metastases, 46 (46/95,
48.4%) patients underwent a first repeat metastasectomy, while only seven patients (7/38, 18.4%) with recurrences at other sites underwent repeat metastasectomies. In select patients, repeated resections can provide good OS rate with acceptable mortalities for both liver5,11,21 and pulmonary metastases.9,12 Therefore, despite the high recurrence rate, surgery provides a promising strategy for the treatment of isolated recurrences. Although the majority of patients in this study who underwent repeated resections had prolonged survivals, a third or even fourth resection should be considered carefully. Several previous studies have reported the outcomes of repeated hepatic and pulmonary resections, with good long-term survival rates that are consistent with our results.21,23 However, the recurrence rates in our series were significantly higher after the third metastasectomy. Recurrence rates after the first metastasectomy, second metastasectomy, and third metastasectomy were 54% (133/ 248), 52% (27/52), and 71% (10/14), respectively. The HR for RFS for the first and second repeat surgery was 1.142 and 2.590, respectively, in comparison with that of the first metastasectomy. Third metastasectomy showed significantly lower RFS rate compared to second metastasectomy (p Z 0.028). Although repeat metastasectomies may provide prolonged survival, recurrence rates after a third
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Table 3 Univariate and multivariate analyses of factors associated with overall survival after the initial resection for the first recurrence. Variables
Univariate P-value
Initial recurrence pattern Recurrence free Resectable recurrence Unresectable recurrence Recurrence free interval after initial resection 6 months <6 months Resected tumor number of initial recurrence 1 >1 Resected organ number of initial recurrence 1 >1 Tumor location (primary tumor) Colon Rectum Stage (primary tumor) I II III Preoperative CEA (ng/mL), >6 Presence of lymphovascular invasion (primary tumor), yes Presence of perineural invasion (primary tumor), yes
metastasectomy were significantly higher. Of the 14 patients who underwent third metastasectomy, five died or had recurrences within 6 months, and eight died or had recurrences within 12 months. Therefore, third metastasectomy should be carefully considered. Several factors have been found to correlate with survival after the resection of hepatic or pulmonary metastases, such as the number of metastases, tumor size, presence of extrahepatic or pulmonary metastases, serum CEA levels, and N stage of the primary tumor.17,18,22 In our present study, the multivariate analysis revealed that an unresectable lesion and an RFS <6 months were significant risk factors for overall survival after a first metastasectomy. Elias et al15 reported that the total number of metastases, regardless of location, showed a stronger prognostic effect than the sites of the metastases, with 5-year survival rates of 38% in patients with 1e3 metastases, 29% in patients with 4e6 metastases, and 18% in patients with less than six metastases (p Z 0.002). In our study, metastasectomies were performed even when the metastases were found in the extrahepatic or extrapulmonary regions. Most patients had single metastasis (>70%), and no patients who underwent metastasectomies had more than four metastatic lesions. This may be an important factor in explaining the relatively high OS rate that was observed in our present study. In our study, only one patient had severe morbidity (grade III, according to the Clavien-Dindo classification) after the first and third metastasectomy. Therefore, repeated resections should be a part of a multidisciplinary management in specialized centers, where the incidences
Multivariate HR
95% CI
<0.001*
P-value <0.001*
1.000 12.094 43.517
3.533e41.403 12.249e142.927
1.000 1.965
1.075e3.594
0.042* 0.028*
0.439
0.869
0.927
0.201
0.328 0.857
of operative complications would be expected to be reasonable. Our findings suggest that the frequency (about 70%) of parenchyma-saving resections (partial hepatectomy or pulmonary wedge resection) appears to increase the likelihood of a subsequent effective repeated resection. Radiofrequency ablation is considered to be an alternative treatment in certain indications for patients not suitable to undergo surgical resection. Accordingly, the proportion of nonsurgical treatments, such as RFA or stereotactic body radiation therapy, has been increasing in our hospital. A previous study demonstrated that hepatic resection should be preferred for the treatment of liver metastasis, whereas RFA might be considered as a reasonable alternative for solitary hepatic metastases <3 cm in diameter.23 However, because the purpose of this study was to evaluate the oncologic outcomes of surgical treatment, the method of treatment was limited to surgery. In this study, among the 117 patients who underwent first metastasectomy for liver metastasis, 70 had multiple metastases or large metastases >3 cm in diameter. Recently, biologic agents that selectively target proteins altered in cancer cells have been developed. In particular, both inhibitors of the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) have shown to improve the efficacy of the available chemotherapeutic regimens.24 However, in the present study, only 7 patients received bevacizumab after the first metastasectomy. Because the use of target agent in Korea was not active during the research period, there are restrictions according to strict Korean government health insurance reimbursement policy.
Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002
+
MODEL
8 The limitations of this study included the retrospective nature of the data analysis and the highly selective patient population. The patients in this study likely had favorable tumor biology and were good surgical candidates; hence, these results may not be reflective of the general population of patients with metastatic CRC. Despite this limitation, our survival estimates are still valuable, since this study is one of the largest series to date concerning patients who have undergone both lung and liver resections for metastatic CRC. In conclusion, repeated resections may improve longterm survival. We report that a second metastasectomy should be considered as the optimal treatment strategy for a second recurrence in patients with recurrent disease after an initial hepatic or pulmonary resection. However, careful consideration should be made before performing a third metastasectomy.
Conflict of interest statement The authors have no conflicts of interest, financial or otherwise.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.asjsur.2019.03.002.
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Please cite this article as: Yang KM et al., Benefits of repeated resections for liver and lung metastases from colorectal cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.03.002