Japanese Journal of Clinical Oncology Advance Access originally published online on June 8, 2006
Japanese Journal of Clinical Oncology 2006 36(6):368-375; doi:10.1093/jjco/hyl027
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© 2006 Foundation for Promotion of Cancer Research
Short Time to Recurrence After Hepatic Resection Correlates with Poor Prognosis in Colorectal Hepatic Metastasis
Department of Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
For reprints and all correspondence: Shinichiro Takahashi, M.D., Department of Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan. E-mail: shtakaha{at}east.ncc.go.jp
Received November 22, 2005; accepted February 26, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Early recurrence is a major problem after hepatic resection of colorectal hepatic metastasis (CHM). Our aim was to investigate the relationship between time to recurrence after CHM resection and overall survival.
Methods: A retrospective analysis was performed for 101 consecutive patients who underwent hepatic resection for CHM and have been followed more than 5 years.
Results: Among 101 patients, 82 (81%) had a recurrence. Overall survival of patients with recurrence within 6 months after CHM resection was significantly worse than that of patients with recurrence after more than 6 months (P < 0.01). Overall survival was poorer when time to recurrence was shorter. One of the reasons for poor prognosis of patients with recurrence within 6 months was that only a few patients could undergo a second resection for recurrence after CHM resection. Histological type, including poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor, bilobar metastases, microscopic positive surgical margin and carcinoembryonic antigen (CEA) above 15 ng/ml had predictive value for decreased recurrence-free survival after CHM resection.
Conclusion: Short time to recurrence after CHM resection correlates with a poor prognosis. Histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor might be a predictor for early recurrence after CHM resection.
Key Words: colorectal cancer • hepatic metastasis • resection • recurrence
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Hepatic resection is currently the only potentially curative treatment for colorectal hepatic metastasis (CHM) (1–6). However, frequent recurrence is a major problem after surgery, with 80–85% of patients experiencing a recurrence (2,3,6). Thus, reduction of recurrence is necessary to improve prognosis after CHM resection.
A correlation between a short time to recurrence after resection of the primary tumor and poor prognosis after resection of recurrence has been demonstrated in colorectal cancer (2,5), breast cancer (7), hepatocellular carcinoma (8) and renal cell carcinoma (9). In CHM, however, the correlation between time to recurrence after resection for CHM and prognosis is still obscure. The relation between time to recurrence after resection and prognosis is complicated in CHM because many recurrences after CHM resection can be resected, and resection sometimes contributes to long-term survival (10–12).
This study was conducted to determine the correlation between time to recurrence after CHM resection and prognosis by scrutinizing recurrence after CHM resection, which may suggest the best timing for adjuvant chemotherapy and elucidate whether time to recurrence can be a surrogate endpoint for adjuvant study in resectable CHM. We also compared clinicopathological factors and time to recurrence to find out preoperative predictive factors for early recurrence.
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PATIENTS AND METHODS |
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PATIENT POPULATION
A total of 101 patients who had undergone hepatic resection for CHM at the National Cancer Center Hospital East between September 1992 and January 2000 and have been followed precisely for more than 5 years were examined retrospectively. The patients consisted of 56 (55%) men and 45 (45%) women, ranging in age from 23 to 78 years (mean, 60 years). None of the patients had received adjuvant chemotherapy after primary colorectal resection.
The criteria for hepatectomy were as follows: metastatic lesions were confined to the liver and all lesions could be resected using oncologic principles while preserving liver function. Extended lobectomy plus partial resections were considered as the upper limit of hepatectomy that could be performed safely, and trisegmentectomy was applied only when the volume of the residual liver was deemed to be abundant. Neither the number of metastatic tumors nor tumor size, in themselves, excluded patients from hepatectomy.
No patient received adjuvant therapy after CHM resection.
SURGICAL PROCEDURE
After laparotomy, a careful search was performed for local recurrences, extrahepatic metastases and peritoneal dissemination in the abdominal cavity. Any suspicious lesions were examined by biopsy. If the regional lymph nodes (hepatoduodenal or peripancreatic lymph nodes) were positive, dissection of the regional lymph nodes was performed. Intraoperative bimanual liver palpation and ultrasonography were performed to confirm tumor location and size of the lesions in all patients; all resections were ultrasound-guided procedures. Hepatic resection was performed with tumor-free resection margins using the forceps fracture method under inflow occlusion (Pringle's maneuver).
CLINICAL FOLLOW-UP
After hepatic resection, patients were closely followed up with diagnostic imaging (chest X-ray and abdominal CT every 3 months, measurement of serum carcinoembryonic antigen (CEA) levels every month and annual colonoscopy to detect tumor recurrence) up to 5years. After 5 years patients were followed up every 6 months or annually.
MORPHOLOGIC INVESTIGATIONS
The resected colorectal specimens and hepatic specimens were fixed in 10% phosphate-buffered formalin and cut at intervals of 5 mm and 10 mm, respectively, and then embedded in paraffin. Serial sections of 3 µm thickness were stained with hematoxylin and eosin for morphologic examination. Histological diagnosis was performed according to the World Health Organization intestinal tumor classification (13).
STATISTICAL ANALYSIS
The chi-square test and student t-test were used to compare data (Dukes' stage, primary location, positive regional lymph node, size of tumor, number of tumors, synchronous/metachronous, tumor distribution and ratio of recurrence) between subgroups based on time to recurrence. Mann–Whitney's U-test was used to compare preoperative serum CEA level between subgroups. Analyses of survival were performed using the Kaplan–Meier method (14), and differences between the curves were tested using the log-rank test. The log-rank test was also used to examine the significance of associations between survival curves and CEA cutoff values of 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100 and 200 ng/ml.
Factors related to survival were analyzed with the Cox proportional hazards regression model (15). A P-value of <0.05 was considered statistically significant.
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RESULTS |
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SURGICAL RESECTIONS
Partial resection was performed on 47 patients, subsegmentectomy on 9, segmentectomy on 25, lobectomy on 11, extended lobectomy on 6 and trisegmentectomy on 3 according to Couinaud's anatomical classification (16). A microscopic positive surgical margin was observed in 14 patients. There was no perioperative mortality. Twenty-one complications were observed: 7 cases of biliary leak; 6 cases of intra-abdominal abscess; 4 cases of wound infection; and 1 case each of liver failure, ileus, lung abscess and urinary tract infection.
SURVIVAL AFTER CHM RESECTION
The overall 5-year Kaplan–Meier survival rate after hepatic resection for CHM was 42%, with a median survival of 34 months (Fig. 1A). Recurrence-free 1-, 3- and 5-year survival rates were 43, 23 and 21%, with a median recurrence-free survival of 9 months (Fig. 1B). The median follow-up duration of survivors was 87 months.
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RECURRENCES AFTER CHM RESECTION (FIG.2)
Among the 101 patients who underwent CHM resection, 82 (81%) developed recurrences. Locations of recurrences were as follows: liver in 36 patients, lung in 17, both liver and lung in 9, lymph node in 6, peritoneum and local recurrence in 4 each, brain and adrenal gland in 2 each, and ovary and bone in 1 each. Thirty-seven recurrences (45%) occurred within 6 months after hepatic resection and 72 recurrences (88%) occurred within 2 years. The ratio of hepatic recurrences to total recurrences was significantly higher in 1st–12th month than that after 12th month from CHM resection (P = 0.01). The ratio of pulmonary recurrence and that of recurrence in organs other than the liver and lung were significantly higher after 24th month (P < 0.05) and in 13th–24th month (P < 0.05) from CHM resection, respectively, than those in the other period. Of the 82 patients with recurrence after hepatic resection 36 received re-resection. Re-resection could be performed in only 10 of 24 patients (42%) whose recurrence occurred in the liver or lung within 6 months after hepatic resection, whereas re-resection could be performed in 22 of 29 patients (76%) whose recurrence occurred in the liver or lung more than 6 months later (P = 0.01). Of the remaining 46 patients, 33 received systemic chemotherapy, 7 received hepatic arterial infusion, 2 received radiation therapy and 4 received best supportive care.
CLINICOPATHOLOGICAL FEATURES ACCORDING TO TIME TO RECURRENCE
Table 1 summarizes the primary and metastatic tumor characteristics. Patients were classified into three subgroups according to time to recurrence after hepatic resection as follows: no recurrence, recurrence within 6 months and recurrence after more than 6 months. There were no significant differences in primary tumor characteristics between the three subgroups. All patients in the no recurrence group had a primary tumor that was classified as a well- or moderately differentiated carcinoma.
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In terms of characteristics of the metastatic tumor, the number of tumors was significantly less (P < 0.01) and unilobar distribution was seen significantly more frequently (P < 0.01) in the no recurrence group compared with the other subgroups.
SURVIVAL ACCORDING TO TIME TO RECURRENCE
Kaplan–Meier curves for overall survival after CHM resection according to time to recurrence in patients who developed recurrences are shown in Fig. 3A. Patients were divided into four subgroups according to time to recurrence after hepatic resection as follows: within 6 months, 7th–12th month, 13th–24th month and after 24th month. Overall survival of patients with recurrence within 6 months after resection was significantly worse than that of patients with recurrence in 7th–12th month (P = 0.04), that of patients with recurrence in 13th–24th month (P < 0.01) and that of patients with recurrence after 24th month (P < 0.01). Overall 5-year survival rate in patients who developed recurrence within 6 months after hepatic resection was only 10% with a median survival of 26 months. Overall survival was poorer when time to recurrence was shorter.
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Figure 3B shows overall survival after recurrence according to time to recurrence. Overall survival after recurrence of patients with recurrence within 6 months after resection was still worse than that of patients with recurrence in 13th–24th month (P < 0.04) and that of patients with recurrence after 24th month (P < 0.03). Overall survival after recurrence of patients with recurrence in 7th–12th month after resection seemed to be better than that of patients with recurrence within 6 months, but the difference was not significant (P = 0.14). Survival after recurrence tended to be poorer when time to recurrence was shorter. Overall survival after recurrence of patients with recurrence within 6 months after resection was significantly worse than that of patients with recurrence in more than 6 months (P < 0.01).
CORRELATION BETWEEN CLINICOPATHOLOGICAL FACTORS AND RECURRENCE-FREE SURVIVAL
To find prognostic factors for recurrence-free survival after CHM resection, correlations between clinicopathological factors and recurrence-free survival were analyzed (Table 2). Histological type of tumor, including poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor (P < 0.01) (Fig. 4), two or more hepatic tumors (P < 0.01), bilobar distribution (P < 0.01), microscopic positive surgical margin (P = 0.03) and CEA level before hepatic resection above 15 ng/ml (P = 0.04) were significantly associated with poor recurrence-free survival.
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We examined the independent predictive value of the aforementioned factors in recurrence-free survival. Data were analyzed using a Cox regression model (Table 3). Histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor [P < 0.01; relative risk (RR) = 5.16; 95% confidence interval (CI), 2.10–12.69], bilobar metastases (P = 0.04; RR = 2.73; 95% CI, 1.03–7.27), microscopic positive surgical margin (P = 0.03; RR = 2.25; 95% CI, 1.11–4.59) and CEA level above 15 ng/ml (P = 0.02; RR = 1.96; 95% CI, 1.09–3.55) had a predictive value for decreased recurrence-free survival after CHM resection. Median disease-free survivals and 1-year recurrence rates of patients with the aforementioned factors were 4.6, 5.6, 5.0 and 8.4 months and 100, 70, 79 and 65%, respectively.
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Histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor and CEA level above 15 ng/ml were also the poor prognostic factors for overall survival (data not shown).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The goal of this study was to assess the correlation between time to recurrence after CHM resection and prognosis. Results showed that prognosis of patients with recurrence within 6 months after resection was significantly worse than that of patients with recurrence after more than 6 months. Our findings indicate that short time to recurrence after CHM resection correlates with a poor prognosis.
The main reason for poor prognosis of patients with recurrence within 6 months was that only a few patients could undergo a second resection for recurrence after CHM resection. Most patients who could not undergo a second resection had extensive disease such as hepatic or pulmonary recurrence with much tumor burden, recurrence involving multiple organs, or distant metastases outside liver and lung that were not suitable for resection. In this series, re-resection rates of recurrence in the remnant liver and lung were relatively low (42 and 40%, respectively) when recurrences were observed within 6 months after CHM resection, whereas they were high (76 and 75%, respectively) when recurrences were observed more than 6 months after resection.
Tumor doubling time is correlated with prognosis in various cancers (17–20). In CHM, it has been reported that short tumor doubling time is a poor prognostic factor for both overall and disease-free survival (21). Short time to recurrence represents short tumor doubling time. Those results are in accord with those of the present study.
Our results suggest that recurrence-free survival can be a surrogate endpoint for adjuvant trial in resectable CHM. Moreover, recurrence within 6 months should be a major target for additional chemotherapy because of a great number and the poor prognosis of these patients. Theoretically, if we can determine which patients will have a recurrence with short recurrence-free survival, we could identify which ones would possibly benefit from neoadjuvant chemotherapy. Adam et al. (22) showed efficacy of neoadjuvant chemotherapy for CHM patients with four or more tumors regardless of initially resectable or not, as long as objective tumor response or stabilization was achieved by chemotherapy, and demonstrated the possibility of neoadjuvant chemotherapy for resectable CHM. However, neoadjuvant chemotherapy sometimes causes chemotherapy-associated steatohepatitis which may increase operative morbidity (23,24); then, neoadjuvant chemotherapy should be recommended for high-risk patients for recurrence.
In the present study, histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor, bilobar metastases, microscopic positive surgical margin and CEA above 15 ng/ml were the independent prognostic factors for poor recurrence-free survival. Especially, histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor exhibited the strongest power for predicting early recurrence because all patients with the factor had recurred within 10 months. Then, histological type of poorly differentiated signet ring cell or mucinous adenocarcinoma in the primary tumor, which was not considered in other large studies (2,5), should be considered as one of the preoperative predictors of early recurrence after CHM resection. Patients with the factor are recommended to receive neoadjuvant chemotherapy. Bilobar metastases and CEA above 15 ng/ml were also prognostic factors for recurrence; however, long-term recurrence-free survival was achieved in some patients with the factors. Neoadjuvant chemotherapy for patients with either of the factors is controversial. In addition, considering the correlation between positive surgical margin and early recurrence, hepatic surgeons should pay much attention to keep negative surgical margin during hepatic dissection in order to prevent early recurrence.
In a retrospective analysis of consecutive 1001 CHM patients by Fong et al. (5), poor prognostic factors for recurrence after CHM resection were positive surgical margin, extrahepatic disease, node-positive primary, less than 12 months of disease-free interval from the primary resection, 2 or more tumors, tumor size >5 cm and CEA >200 ng/ml. The aforementioned prognostic factors for recurrence were also predictors of poor overall survival, and the fact was consistent with the concept of our results that short time to recurrence correlated with poor survival. Fong et al. proposed a scoring system using five poor prognostic factors and insisted that the scoring system was useful in choosing adjuvant therapy.
The difference between our results and those of Fong's might be partly due to patients' background and the number of patients examined. In the present study, patients with extrahepatic disease were excluded because CHM with extrahepatic disease was totally different from pure CHM considering pathways of metastases. Moreover, none of the patients had received adjuvant chemotherapy after primary colorectal resection or CHM resection. However, the possibility that not all of Fong's predictors could be validated well because of relatively small population of our study cannot be ruled out.
In the present study, patients were followed and examined precisely at least for 5 years in order to elucidate complete profile of recurrence, and then median follow-up of survivors was 87 months. This study has clarified frequencies of the recurrences after CHM resection in liver, lung and other organs respectively according to time to recurrence and also clarified the resection-rates for those recurrences. On the result of the present study, the organ where recurrence had occurred most frequently and the resection-rate for the recurrences differed according to time to recurrence after CHM resection. Frequency of hepatic recurrence decreased rapidly after 2 years of CHM resection; however, that of pulmonary recurrence was not low even more than 2 years after CHM resection. A periodical checkup by chest XP or chest CT adding to abdominal examination is recommended for 5 years at least.
In conclusion, short time to recurrence after CHM resection correlates with a poor prognosis. This result provides grounds for proposal that an effective neoadjuvant chemotherapy and a system using the clinicopathological factors and pharmacogenetics which identify best candidates for the neoadjuvant chemotherapy are needed in order to reduce early recurrence. Histological type of primary tumor might be a strong predictor for early recurrence after CHM resection.
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References |
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