Journal of Surgical Oncology 2015;111:729–739
Influence of Age on Resection of Colorectal Liver Metastases THOMAS SCHMIDT, MD, PhD,1 MORITZ J. STROWITZKI, MD,1 CHRISTOPH REISSFELDER, MD,2 NUH N. RAHBARI, MD,2 HENRIK NIENHUESER, MD,1 THOMAS BRUCKNER, PhD,3* CHRISTOPH RAHA¨USER, cand. med. dent.,1 ULRICH KEPPLER, MD,1 MARTIN SCHNEIDER, MD,1 ¨ CHLER, MD,1 AND ALEXIS ULRICH, MD1 MARKUS W. BU 1 Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany 3 Department of Medical Biometry, University of Heidelberg, Heidelberg, Germany
2
Background and Objectives: Only limited data exist investigating the outcome of patients older than 75 years after resection of colorectal liver metastases (CLM). Therefore, the present study aims to evaluate clinical and oncological outcome of elderly patients. Methods: A cohort of 405 patients was divided into three age-groups: (1) 75 years of age. Patients’ data were prospectively collected and retrospectively analyzed. We performed survival analysis and added age-correction. Univariate and multivariate analysis was performed to determine independent prognostic risk factors. Results: The 5-year survival rate of the >75 years age-group was distinctly decreased, compared to the other age-groups. After age-correction, the 5-year survival rates and the survival curves increased to the greatest extent in patients older than 75 years. The MSKCC score proved to be a sufficient independent prognostic factor in the total patient cohort, patients 75 years (59.0%), compared to the proportion in the age group of 75 years age group, compared to the other age groups (75 years: 7.6% vs. other groups: 75
65–75
n
%
n
%
n
%
n
%
405 61.8 10.8
100.0
243 55.3 8.5
60.0
123 69.4 2.7
30.4
39 78.6 2.9
9.6
268 137
66.2 33.8
155 88
63.8 36.2
87 36
70.7 29.3
26 13
66.7 33.3
232 170 3
57.3 42.0 0.7
133 108 2
54.7 44.4 0.9
71 52 0
57.7 42.3 0.0
28 10 1
71.8 25.6 2.6
192 213
47.4 52.6
128 115
52.7 47.3
48 75
39.0 61.0
16 23
41.0 59.0
203 201 1
50.1 49.6 0.3
111 132 0
45.7 54.3 0.0
69 53 1
56.1 43.1 0.8
23 16 0
59.0 41.0 0.0
8 204 166 9 18
2.0 50.4 41.0 2.2 4.4
7 133 86 4 13
2.9 54.7 35.4 1.6 5.4
0 54 63 2 4
0.0 44.0 51.3 1.6 3.1
1 17 17 3 1
2.6 43.6 43.6 7.6 2.6
23 58 96 192 36
5.7 14.3 23.7 47.4 8.9
9 30 52 127 25
3.7 12.3 21.4 52.3 10.3
11 21 32 49 10
8.9 17.1 26.0 39.9 8.1
3 7 12 16 1
7.6 17.9 30.8 40.8 2.6
110 295
27.2 72.8
74 169
30.5 69.5
31 92
25.2 74.8
5 34
12.8 87.2
152 253
37.5 62.5
93 150
38.3 61.7
40 83
32.5 67.5
19 20
48.7 51.3
104 301 3.1 5.0 805.3 674.5
25.7 74.3
69 174 2.7 3.7 800.8 654.1
28.4 71.6
28 95 3.6 6.7 844.2 749.5
22.8 77.2
7 32 3.7 5.5 709.2 534.0
17.9 82.1
P-value
0.000 0.414
0.124
0.033
0.067
0.011
0.113
0.060
0.178
0.294
0.199 0.554
ASA, American Society of Anesthesiologists; ICU, Intensive Care Unit; UICC, Union for International Cancer Control. a Data are given as mean standard deviation. b Diagnosed before or within 3 months after resection of the primary tumor.
Univariate Prognostic Factors of Survival The median survival of all 405 patients after resection of CRC metastasis was 46.1 months (95% CI 40.1–52.0). To analyze whether prognostic factors for overall survival after metastasis resection are the same for the different age groups, we performed uni- and multivariate analysis. Univariate analysis for the whole study population revealed a significantly reduced survival for patients with a Memorial Sloan-Kettering Cancer Center (MSKCC) score >3 or surgical complications (Table III). The 3 was found to be an independent risk factor (P ¼ 0.016) (Fig. 4A). In patients in the 65–75 years age group, tumor localization, MSKCC score, time of metastasis and non-surgical complications were independent prognostic factors (Table IV and Fig. 4B–E). Interestingly, in the oldest group of patients >75 years, only localization of the primary tumor was an independent risk factor. However, the generally accepted MSKCC score did not show a prognostic significance (Table IV and Fig. 4F).
DISCUSSION The aim of the present study was to evaluate the clinical and oncological outcome of elderly patients after liver resection due to CLM. In a retrospective analysis of 405 patients with a mean age of 69.4 years and a median survival of 46.1 months, we could show that overall survival rates did not differ significantly between the different age groups: (1) 75 years of age.
The 5-year survival rates were markedly reduced in the oldest age group of >75 years compared to the younger age groups. However, we could provide data that, after age correction, 5-year survival rates increased to the highest extent in the >75 years age group, compared with the other groups. Furthermore, uni- and multivariate analysis revealed that, in all patients, MSKCC score >3 and surgical complications are independent risk factors for survival after liver resection. Of interest, in patients older than 75 years, MSKCC score did not prove to be a significant predictor of survival, but localization of the primary tumor did. To the best of our knowledge, this is the first study using age correction with the aid of population-based life tables to analyze the overall survival of patients undergoing liver resection due to CLM. Currently, various methods and programs for statistical computer software exist, such as the R package relsurv1, SAS1 and SPSS1, to calculate age-corrected survival rates, also called relative survival analysis [23–26]. All of these aim to overcome the limitations of another competing method, called cancer-specific survival analysis, which is most often used in controlled clinical trials to analyze survival of cancer
TABLE II. Survival Rates After 3- and 5-Years 75
65–75
3-year
5-year
3-year
5-year
3-year
5-year
3-year
5-year
66.1% 69.2%
37.9% 42.6%
66.2% 67.6%
40.3% 42.0%
66.3% 70.0%
39.0% 44.0%
64.5% 77.0%
23.3% 31.0%
Liver Resection and Age-correction
733
Fig. 2. Age-corrected survival plots (A–C; green lines) and observed overall survival plots (A–C; blue lines) of the 75 years (C) age groups.
patients [27]. In cancer-specific survival analysis, only deaths due to the specific cancer of interest are counted. The main limitation of cancerspecific survival analysis is the fact that it is highly susceptible to misclassify the cause of death especially in retrospective clinical studies [27]. However, in most cases the exact cause of death is not known and difficult to obtain from death certificates [28]. As a result, the estimation of cancer-specific survival of the analyzed patient cohort is biased. Moreover, in a retrospective analysis of 771 rectal cancer patients, Tarantino et al. could show that relative survival analysis is a feasible and more appropriate method to differentiate between cancer-related versus non-cancer-related deaths [26]. Relative survival analysis therefore defines the real impact of the investigated cancer more closely than cancer-specific survival analysis [26]. Journal of Surgical Oncology
Therefore, we used an SPSS1 Macro, which was first applied by Martus et al. in 1998 for survival analysis of 333 patients suffering from bladder cancer [23]. Depending on the age of the patients, Martus et al. could show that the 5-year survival rates increased by 10% to 15% after age correction. In our study, we observed an increase of 5-year survival rates by 1.7%–7.7% after age correction, depending on the different age groups. The observed difference in the extent of changes in 5-year survival rates between Martus et al. and our study is most probably due to the fact that the mean age of the patients analyzed by Martus et al. was about 5 years (male patients) to 8 years (female patients) higher, compared to our study. However, there are several advantages and disadvantages of the applied method for age correction of survival rates. One main limitation is the lack of comparability of the analyzed cohort compared to the external
Gender Male Female Localization Colon Rectum Colon and Rectum Liver metastases at diagnosis Timing of development Synchronousa Metachronous No. of metastases 1 >1 ASA I II III IV UICC stadium of primary tumor I II III IV Preoperative chemotherapy Yes No Type of liver resection Minor (< 3 segments) Major (> 3 segments) Postoperative chemotherapy Yes No MSKCC clinical risk score 75 years age group. This is in line with studies performed by Tarantino et al. [26]. In addition, other studies also showed that liver resection due to CLM can be safely performed in elderly patients and that age has no influence on patient survival even after repeated liver resection [10,11,17,29–31]. However, many of these studies investigated the overall survival of patients older than 70 years, whereas the present study compared the overall survival of three age groups: 75 years. In contrast, Mizuguchi et al. provided evidence that age seems to be a clinical risk factor for patient outcome after liver surgery in specific subpopulations [32]. The systematic review and meta-analysis of this group could show that young patients with CLM have a 2.7 times lower mortality compared to the mortality of elderly patients [32]. This is most probably due to the fact that age correction was not performed in any of these studies and therefore the true effect of cancer-related deaths vs non-cancer-related deaths on patients’ mortality can not be appropriately estimated. In a retrospective analysis of 281 patients who underwent liver resection due to CLM, Reissfelder et al. showed that only MSKCC and Iwatsuki scores were able to predict the overall survival of patients [18]. Comparable to the aforementioned observations of Reissfelder et al., the present study shows that MSKCC score is a sufficient prognostic factor for survival. It should be noted that this was only the case in patients younger than 75 years. However, multivariate analysis revealed localization of the primary tumor within the rectum to be an independent risk factor for survival of patients older than 75 years. According to Stillwell et al., studies that investigated the influence of primary tumor inconsistently classified the primary tumor site and therefore are difficult to be compared [33]. However, there seems to be evidence that patients with CLM due to rightsided colon cancer have a worse prognosis compared to patients with liver metastasis from left-sided colon or rectal cancer [34,35]. In line with these findings, Sourrouille et al. observed that patients with combined pulmonary and hepatic metastases due to rectal tumor had an impaired disease-free survival after resection of metastases [36]. The patient cohort in this study, however, was very small and significant effects on overall survival by localization of the primary tumor could not be seen. Of note, in the present study, localization of primary tumor did not prove to be a significant predictor of survival in the whole study population.
CONCLUSIONS In conclusion, liver resection due to CRC remains a safe and promising treatment option, even for patients older than 75 years. Prognostic factors, such as MSKCC score that truly predict outcome of younger patients, are not useful in patients older than 75 years. It is therefore necessary that more clinical studies with elderly patients are performed to determine the role of further risk factors and clinical predictors for overall survival in these patients.
ACKNOWLEDGMENTS Our grateful thanks to Prof. Dr. rer. nat. Peter Martus, Managing Director of the Institute for Clinical Epidemiology and Applied Journal of Surgical Oncology
Biometry at the University of Tübingen, for providing the SPSS Macro for age correction of survival rates.
REFERENCES 1. Siegel R,Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 2. Taylor I: Liver metastases from colorectal cancer: lessons from past and present clinical studies. Br J Surg 1996;83:456–460. 3. Morris EJA, Forman D, Thomas JD, et al.: Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 2010;97:1110–1118. 4. Rees M, Tekkis PP, Welsh FKS, et al.: Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008;247: 125–135. 5. Reissfelder C, Rahbari NN, Bejarano LU, et al.: Comparison of various surgical approaches for extensive bilateral colorectal liver metastases. Langenbecks Arch Surg 2014;399:481–491. 6. Nordlinger B, Sorbye H, Glimelius B, et al.: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. The Lancet 2008;371:1007–1016. 7. Vauthey J-N, Pawlik TM, Ribero D, et al.: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065–2072. 8. Gomez D, Malik HZ, Bonney GK, et al.: Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis. Br J Surg 2007;94:1395–1402. 9. Reissfelder C, Brand K, Sobiegalla J, et al.: Chemotherapyassociated liver injury and its influence on outcome after resection of colorectal liver metastases. Surgery 2014;155:245–254. 10. Petrowsky H, Clavien P-A: Should we deny surgery for malignant hepato-pancreatico-biliary tumors to elderly patients?. World J Surg 2005;29:1093–1100. 11. Zacharias T, Jaeck D, Oussoultzoglou E, et al.: First and repeat resection of colorectal liver metastases in elderly patients. Ann Surg 2004;240:858–865. 12. Fong Y, Fortner J, Sun RL, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309–318. 13. Fortner JG, Silva JS, Golbey RB, et al.: Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I. Treatment by hepatic resection. Ann Surg 1984;199:306–316. 14. Adam R, Frilling A, Elias D, et al.: Liver resection of colorectal metastases in elderly patients. Br J Surg 2010;97:366–376. 15. Koruda MJ, Sheldon GF:: Surgery in the aged. Adv Surg 1991;24:293–331. 16. Cooper GS, Yuan Z, Landefeld CS, et al.: A national populationbased study of incidence of colorectal cancer and age. Implications for screening in older Americans. Cancer 1995;75:775–781. 17. Kulik U, Framke T, Grosshennig A, et al.: Liver resection of colorectal liver metastases in elderly patients. World J Surg 2011;35:2063–2072. 18. Reissfelder C, Rahbari NN, Koch M, et al.: Validation of prognostic scoring systems for patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol 2009;16: 3279–3288. 19. Reissfelder C, Rahbari NN, Koch M, et al.: Postoperative course and clinical significance of biochemical blood tests following hepatic resection. Br J Surg 2011;98:836–844. 20. Rahbari NN, Koch M, Zimmermann JB, et al.: Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial. Ann Surg 2011;253:1102–1110. 21. Rahbari NN, Reissfelder C, Koch M, et al.: The predictive value of postoperative clinical risk scores for outcome after hepatic
Liver Resection and Age-correction
22.
23. 24. 25. 26.
27. 28. 29.
resection: a validation analysis in 807 patients. Ann Surg Oncol 2011;18:3640–3649. Rahbari NN, Elbers H, Koch M, et al.: Clamp-crushing versus stapler hepatectomy for transection of the parenchyma in elective hepatic resection (CRUNSH)–a randomized controlled trial (NCT01049607). BMC Surg 2011;11:22. Martus P, Birkenhake S, Sauer R: The age correction of survival probabilities in cancer studies. Strahlenther Onkol 1998;174:1–6. Pohar M, Stare J: Making relative survival analysis relatively easy. Comput Biol Med 2007;37:1741–1749. Brenner H, Gefeller O, Hakulinen T: A computer program for period analysis of cancer patient survival. Eur J Cancer 2002;38:690–695. Tarantino I, Achermann P, Güller U, et al.: Relative survival is an adequate estimate of cancer-specific survival: baseline mortalityadjusted 10-year survival of 771 rectal cancer patients. Ann Surg Oncol 2013;20:3877–3884. Sarfati D, Blakely T, Pearce N: Measuring cancer survival in populations: relative survival vs cancer-specific survival. Int J Epidemiol 2010;39:598–610. James DS, Bull AD: Information on death certificates: cause for concern?. J Clin Pathol 1996;49:213–216. De Liguori Carino, van Leeuwen N, Ghaneh BL, et al.: Liver resection for colorectal liver metastases in older patients. Crit Rev Oncol Hematol 2008;67:273–278.
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30. Cook EJ, Welsh FKS, Chandrakumaran K, et al.: Resection of colorectal liver metastases in the elderly: does age matter. Colorectal Dis 2012;14:1210–1216. 31. Mastoraki A, Tsakali A, Papanikolaou IS, et al.: Outcome following major hepatic resection in the elderly patients. Clin Res Hepatol Gastroenterol 2014;38:462–466. 32. Mizuguchi T, Kawamoto M, Meguro M, et al.: The impact of aging on morbidity and mortality after liver resection: a systematic review and meta-analysis. Surg Today 2014;DOI:10.1007/s00595– 014-0863-y 33. Stillwell AP, Ho Y-H, Veitch C: Systematic review of prognostic factors related to overall survival in patients with stage IV colorectal cancer and unresectable metastases. World J Surg 2011;35:684–692. 34. Bajwa A, Blunt N, Vyas S, et al.: Primary tumour resection and survival in the palliative management of metastatic colorectal cancer. Eur J Surg Oncol 2009;35:164–167. 35. Chafai N, Chan CLH, Bokey EL, et al.: What factors influence survival in patients with unresected synchronous liver metastases after resection of colorectal cancer?. Colorectal Dis 2005;7: 176–181. 36. Sourrouille I, Mordant P, Maggiori L, et al.: Long-term survival after hepatic and pulmonary resection of colorectal cancer metastases. J Surg Oncol 2013;108:220–224.
Influence of Age on Resection of Colorectal Liver Metastases THOMAS SCHMIDT, MD, PhD,1 MORITZ J. STROWITZKI, MD,1 CHRISTOPH REISSFELDER, MD,2 NUH N. RAHBARI, MD,2 HENRIK NIENHUESER, MD,1 THOMAS BRUCKNER, PhD,3* CHRISTOPH RAHA¨USER, cand. med. dent.,1 ULRICH KEPPLER, MD,1 MARTIN SCHNEIDER, MD,1 ¨ CHLER, MD,1 AND ALEXIS ULRICH, MD1 MARKUS W. BU 1 Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany 3 Department of Medical Biometry, University of Heidelberg, Heidelberg, Germany
2
Background and Objectives: Only limited data exist investigating the outcome of patients older than 75 years after resection of colorectal liver metastases (CLM). Therefore, the present study aims to evaluate clinical and oncological outcome of elderly patients. Methods: A cohort of 405 patients was divided into three age-groups: (1) 75 years of age. Patients’ data were prospectively collected and retrospectively analyzed. We performed survival analysis and added age-correction. Univariate and multivariate analysis was performed to determine independent prognostic risk factors. Results: The 5-year survival rate of the >75 years age-group was distinctly decreased, compared to the other age-groups. After age-correction, the 5-year survival rates and the survival curves increased to the greatest extent in patients older than 75 years. The MSKCC score proved to be a sufficient independent prognostic factor in the total patient cohort, patients 75 years (59.0%), compared to the proportion in the age group of 75 years age group, compared to the other age groups (75 years: 7.6% vs. other groups: 75
65–75
n
%
n
%
n
%
n
%
405 61.8 10.8
100.0
243 55.3 8.5
60.0
123 69.4 2.7
30.4
39 78.6 2.9
9.6
268 137
66.2 33.8
155 88
63.8 36.2
87 36
70.7 29.3
26 13
66.7 33.3
232 170 3
57.3 42.0 0.7
133 108 2
54.7 44.4 0.9
71 52 0
57.7 42.3 0.0
28 10 1
71.8 25.6 2.6
192 213
47.4 52.6
128 115
52.7 47.3
48 75
39.0 61.0
16 23
41.0 59.0
203 201 1
50.1 49.6 0.3
111 132 0
45.7 54.3 0.0
69 53 1
56.1 43.1 0.8
23 16 0
59.0 41.0 0.0
8 204 166 9 18
2.0 50.4 41.0 2.2 4.4
7 133 86 4 13
2.9 54.7 35.4 1.6 5.4
0 54 63 2 4
0.0 44.0 51.3 1.6 3.1
1 17 17 3 1
2.6 43.6 43.6 7.6 2.6
23 58 96 192 36
5.7 14.3 23.7 47.4 8.9
9 30 52 127 25
3.7 12.3 21.4 52.3 10.3
11 21 32 49 10
8.9 17.1 26.0 39.9 8.1
3 7 12 16 1
7.6 17.9 30.8 40.8 2.6
110 295
27.2 72.8
74 169
30.5 69.5
31 92
25.2 74.8
5 34
12.8 87.2
152 253
37.5 62.5
93 150
38.3 61.7
40 83
32.5 67.5
19 20
48.7 51.3
104 301 3.1 5.0 805.3 674.5
25.7 74.3
69 174 2.7 3.7 800.8 654.1
28.4 71.6
28 95 3.6 6.7 844.2 749.5
22.8 77.2
7 32 3.7 5.5 709.2 534.0
17.9 82.1
P-value
0.000 0.414
0.124
0.033
0.067
0.011
0.113
0.060
0.178
0.294
0.199 0.554
ASA, American Society of Anesthesiologists; ICU, Intensive Care Unit; UICC, Union for International Cancer Control. a Data are given as mean standard deviation. b Diagnosed before or within 3 months after resection of the primary tumor.
Univariate Prognostic Factors of Survival The median survival of all 405 patients after resection of CRC metastasis was 46.1 months (95% CI 40.1–52.0). To analyze whether prognostic factors for overall survival after metastasis resection are the same for the different age groups, we performed uni- and multivariate analysis. Univariate analysis for the whole study population revealed a significantly reduced survival for patients with a Memorial Sloan-Kettering Cancer Center (MSKCC) score >3 or surgical complications (Table III). The 3 was found to be an independent risk factor (P ¼ 0.016) (Fig. 4A). In patients in the 65–75 years age group, tumor localization, MSKCC score, time of metastasis and non-surgical complications were independent prognostic factors (Table IV and Fig. 4B–E). Interestingly, in the oldest group of patients >75 years, only localization of the primary tumor was an independent risk factor. However, the generally accepted MSKCC score did not show a prognostic significance (Table IV and Fig. 4F).
DISCUSSION The aim of the present study was to evaluate the clinical and oncological outcome of elderly patients after liver resection due to CLM. In a retrospective analysis of 405 patients with a mean age of 69.4 years and a median survival of 46.1 months, we could show that overall survival rates did not differ significantly between the different age groups: (1) 75 years of age.
The 5-year survival rates were markedly reduced in the oldest age group of >75 years compared to the younger age groups. However, we could provide data that, after age correction, 5-year survival rates increased to the highest extent in the >75 years age group, compared with the other groups. Furthermore, uni- and multivariate analysis revealed that, in all patients, MSKCC score >3 and surgical complications are independent risk factors for survival after liver resection. Of interest, in patients older than 75 years, MSKCC score did not prove to be a significant predictor of survival, but localization of the primary tumor did. To the best of our knowledge, this is the first study using age correction with the aid of population-based life tables to analyze the overall survival of patients undergoing liver resection due to CLM. Currently, various methods and programs for statistical computer software exist, such as the R package relsurv1, SAS1 and SPSS1, to calculate age-corrected survival rates, also called relative survival analysis [23–26]. All of these aim to overcome the limitations of another competing method, called cancer-specific survival analysis, which is most often used in controlled clinical trials to analyze survival of cancer
TABLE II. Survival Rates After 3- and 5-Years 75
65–75
3-year
5-year
3-year
5-year
3-year
5-year
3-year
5-year
66.1% 69.2%
37.9% 42.6%
66.2% 67.6%
40.3% 42.0%
66.3% 70.0%
39.0% 44.0%
64.5% 77.0%
23.3% 31.0%
Liver Resection and Age-correction
733
Fig. 2. Age-corrected survival plots (A–C; green lines) and observed overall survival plots (A–C; blue lines) of the 75 years (C) age groups.
patients [27]. In cancer-specific survival analysis, only deaths due to the specific cancer of interest are counted. The main limitation of cancerspecific survival analysis is the fact that it is highly susceptible to misclassify the cause of death especially in retrospective clinical studies [27]. However, in most cases the exact cause of death is not known and difficult to obtain from death certificates [28]. As a result, the estimation of cancer-specific survival of the analyzed patient cohort is biased. Moreover, in a retrospective analysis of 771 rectal cancer patients, Tarantino et al. could show that relative survival analysis is a feasible and more appropriate method to differentiate between cancer-related versus non-cancer-related deaths [26]. Relative survival analysis therefore defines the real impact of the investigated cancer more closely than cancer-specific survival analysis [26]. Journal of Surgical Oncology
Therefore, we used an SPSS1 Macro, which was first applied by Martus et al. in 1998 for survival analysis of 333 patients suffering from bladder cancer [23]. Depending on the age of the patients, Martus et al. could show that the 5-year survival rates increased by 10% to 15% after age correction. In our study, we observed an increase of 5-year survival rates by 1.7%–7.7% after age correction, depending on the different age groups. The observed difference in the extent of changes in 5-year survival rates between Martus et al. and our study is most probably due to the fact that the mean age of the patients analyzed by Martus et al. was about 5 years (male patients) to 8 years (female patients) higher, compared to our study. However, there are several advantages and disadvantages of the applied method for age correction of survival rates. One main limitation is the lack of comparability of the analyzed cohort compared to the external
Gender Male Female Localization Colon Rectum Colon and Rectum Liver metastases at diagnosis Timing of development Synchronousa Metachronous No. of metastases 1 >1 ASA I II III IV UICC stadium of primary tumor I II III IV Preoperative chemotherapy Yes No Type of liver resection Minor (< 3 segments) Major (> 3 segments) Postoperative chemotherapy Yes No MSKCC clinical risk score 75 years age group. This is in line with studies performed by Tarantino et al. [26]. In addition, other studies also showed that liver resection due to CLM can be safely performed in elderly patients and that age has no influence on patient survival even after repeated liver resection [10,11,17,29–31]. However, many of these studies investigated the overall survival of patients older than 70 years, whereas the present study compared the overall survival of three age groups: 75 years. In contrast, Mizuguchi et al. provided evidence that age seems to be a clinical risk factor for patient outcome after liver surgery in specific subpopulations [32]. The systematic review and meta-analysis of this group could show that young patients with CLM have a 2.7 times lower mortality compared to the mortality of elderly patients [32]. This is most probably due to the fact that age correction was not performed in any of these studies and therefore the true effect of cancer-related deaths vs non-cancer-related deaths on patients’ mortality can not be appropriately estimated. In a retrospective analysis of 281 patients who underwent liver resection due to CLM, Reissfelder et al. showed that only MSKCC and Iwatsuki scores were able to predict the overall survival of patients [18]. Comparable to the aforementioned observations of Reissfelder et al., the present study shows that MSKCC score is a sufficient prognostic factor for survival. It should be noted that this was only the case in patients younger than 75 years. However, multivariate analysis revealed localization of the primary tumor within the rectum to be an independent risk factor for survival of patients older than 75 years. According to Stillwell et al., studies that investigated the influence of primary tumor inconsistently classified the primary tumor site and therefore are difficult to be compared [33]. However, there seems to be evidence that patients with CLM due to rightsided colon cancer have a worse prognosis compared to patients with liver metastasis from left-sided colon or rectal cancer [34,35]. In line with these findings, Sourrouille et al. observed that patients with combined pulmonary and hepatic metastases due to rectal tumor had an impaired disease-free survival after resection of metastases [36]. The patient cohort in this study, however, was very small and significant effects on overall survival by localization of the primary tumor could not be seen. Of note, in the present study, localization of primary tumor did not prove to be a significant predictor of survival in the whole study population.
CONCLUSIONS In conclusion, liver resection due to CRC remains a safe and promising treatment option, even for patients older than 75 years. Prognostic factors, such as MSKCC score that truly predict outcome of younger patients, are not useful in patients older than 75 years. It is therefore necessary that more clinical studies with elderly patients are performed to determine the role of further risk factors and clinical predictors for overall survival in these patients.
ACKNOWLEDGMENTS Our grateful thanks to Prof. Dr. rer. nat. Peter Martus, Managing Director of the Institute for Clinical Epidemiology and Applied Journal of Surgical Oncology
Biometry at the University of Tübingen, for providing the SPSS Macro for age correction of survival rates.
REFERENCES 1. Siegel R,Naishadham D, Jemal A: Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29. 2. Taylor I: Liver metastases from colorectal cancer: lessons from past and present clinical studies. Br J Surg 1996;83:456–460. 3. Morris EJA, Forman D, Thomas JD, et al.: Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 2010;97:1110–1118. 4. Rees M, Tekkis PP, Welsh FKS, et al.: Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg 2008;247: 125–135. 5. Reissfelder C, Rahbari NN, Bejarano LU, et al.: Comparison of various surgical approaches for extensive bilateral colorectal liver metastases. Langenbecks Arch Surg 2014;399:481–491. 6. Nordlinger B, Sorbye H, Glimelius B, et al.: Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. The Lancet 2008;371:1007–1016. 7. Vauthey J-N, Pawlik TM, Ribero D, et al.: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065–2072. 8. Gomez D, Malik HZ, Bonney GK, et al.: Steatosis predicts postoperative morbidity following hepatic resection for colorectal metastasis. Br J Surg 2007;94:1395–1402. 9. Reissfelder C, Brand K, Sobiegalla J, et al.: Chemotherapyassociated liver injury and its influence on outcome after resection of colorectal liver metastases. Surgery 2014;155:245–254. 10. Petrowsky H, Clavien P-A: Should we deny surgery for malignant hepato-pancreatico-biliary tumors to elderly patients?. World J Surg 2005;29:1093–1100. 11. Zacharias T, Jaeck D, Oussoultzoglou E, et al.: First and repeat resection of colorectal liver metastases in elderly patients. Ann Surg 2004;240:858–865. 12. Fong Y, Fortner J, Sun RL, et al.: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309–318. 13. Fortner JG, Silva JS, Golbey RB, et al.: Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. I. Treatment by hepatic resection. Ann Surg 1984;199:306–316. 14. Adam R, Frilling A, Elias D, et al.: Liver resection of colorectal metastases in elderly patients. Br J Surg 2010;97:366–376. 15. Koruda MJ, Sheldon GF:: Surgery in the aged. Adv Surg 1991;24:293–331. 16. Cooper GS, Yuan Z, Landefeld CS, et al.: A national populationbased study of incidence of colorectal cancer and age. Implications for screening in older Americans. Cancer 1995;75:775–781. 17. Kulik U, Framke T, Grosshennig A, et al.: Liver resection of colorectal liver metastases in elderly patients. World J Surg 2011;35:2063–2072. 18. Reissfelder C, Rahbari NN, Koch M, et al.: Validation of prognostic scoring systems for patients undergoing resection of colorectal cancer liver metastases. Ann Surg Oncol 2009;16: 3279–3288. 19. Reissfelder C, Rahbari NN, Koch M, et al.: Postoperative course and clinical significance of biochemical blood tests following hepatic resection. Br J Surg 2011;98:836–844. 20. Rahbari NN, Koch M, Zimmermann JB, et al.: Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: a randomized controlled trial. Ann Surg 2011;253:1102–1110. 21. Rahbari NN, Reissfelder C, Koch M, et al.: The predictive value of postoperative clinical risk scores for outcome after hepatic
Liver Resection and Age-correction
22.
23. 24. 25. 26.
27. 28. 29.
resection: a validation analysis in 807 patients. Ann Surg Oncol 2011;18:3640–3649. Rahbari NN, Elbers H, Koch M, et al.: Clamp-crushing versus stapler hepatectomy for transection of the parenchyma in elective hepatic resection (CRUNSH)–a randomized controlled trial (NCT01049607). BMC Surg 2011;11:22. Martus P, Birkenhake S, Sauer R: The age correction of survival probabilities in cancer studies. Strahlenther Onkol 1998;174:1–6. Pohar M, Stare J: Making relative survival analysis relatively easy. Comput Biol Med 2007;37:1741–1749. Brenner H, Gefeller O, Hakulinen T: A computer program for period analysis of cancer patient survival. Eur J Cancer 2002;38:690–695. Tarantino I, Achermann P, Güller U, et al.: Relative survival is an adequate estimate of cancer-specific survival: baseline mortalityadjusted 10-year survival of 771 rectal cancer patients. Ann Surg Oncol 2013;20:3877–3884. Sarfati D, Blakely T, Pearce N: Measuring cancer survival in populations: relative survival vs cancer-specific survival. Int J Epidemiol 2010;39:598–610. James DS, Bull AD: Information on death certificates: cause for concern?. J Clin Pathol 1996;49:213–216. De Liguori Carino, van Leeuwen N, Ghaneh BL, et al.: Liver resection for colorectal liver metastases in older patients. Crit Rev Oncol Hematol 2008;67:273–278.
Journal of Surgical Oncology
739
30. Cook EJ, Welsh FKS, Chandrakumaran K, et al.: Resection of colorectal liver metastases in the elderly: does age matter. Colorectal Dis 2012;14:1210–1216. 31. Mastoraki A, Tsakali A, Papanikolaou IS, et al.: Outcome following major hepatic resection in the elderly patients. Clin Res Hepatol Gastroenterol 2014;38:462–466. 32. Mizuguchi T, Kawamoto M, Meguro M, et al.: The impact of aging on morbidity and mortality after liver resection: a systematic review and meta-analysis. Surg Today 2014;DOI:10.1007/s00595– 014-0863-y 33. Stillwell AP, Ho Y-H, Veitch C: Systematic review of prognostic factors related to overall survival in patients with stage IV colorectal cancer and unresectable metastases. World J Surg 2011;35:684–692. 34. Bajwa A, Blunt N, Vyas S, et al.: Primary tumour resection and survival in the palliative management of metastatic colorectal cancer. Eur J Surg Oncol 2009;35:164–167. 35. Chafai N, Chan CLH, Bokey EL, et al.: What factors influence survival in patients with unresected synchronous liver metastases after resection of colorectal cancer?. Colorectal Dis 2005;7: 176–181. 36. Sourrouille I, Mordant P, Maggiori L, et al.: Long-term survival after hepatic and pulmonary resection of colorectal cancer metastases. J Surg Oncol 2013;108:220–224.
