|Ahead of print publication
The age-adjusted Charlson comorbidity index is an independent prognostic factor in pancreatic cancer patients who receive curative resection followed by adjuvant chemotherapy
Toru Aoyama1, Naoto Yamamoto1, Mariko Kamiya1, Masaaki Murakawa1, Hiroshi Tamagawa1, Sho Sawazaki2, Masakatsu Numata2, Satoshi Kobayashi3, Makoto Ueno3, Manabu Morimoto3, Manabu Shiozawa4, Norio Yukawa2, Takashi Oshima2, Takaki Yoshikawa2, Yasushi Rino2, Munetaka Masuda2, Soichiro Morinaga1
1 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan; Department of Surgery, Yokohama City University, Yokohama, Kanagawa, Japan
2 Department of Surgery, Yokohama City University, Yokohama, Kanagawa, Japan
3 Department of Gastroenterology, Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
4 Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
Department of Surgery, Yokohama City University, 3-9 Fukura, Kanazawa.Ku, Yokohama 236-0004
Source of Support: None, Conflict of Interest: None
Background: We investigated the impact of the age-adjusted Charlson comorbidity index (ACCI) on the pancreatic cancer survival and recurrence after curative surgery followed by adjuvant chemotherapy.
Patients and Methods: This study included 155 patients who underwent curative surgery followed by adjuvant chemotherapy for pancreatic cancer between 2005 and 2014. The risk factors for the overall survival (OS) and recurrence-free survival (RFS) were identified.
Results: An ACCI of 8 was regarded as the optimum critical point of classification considering the 1-, 3- and 5-year survival rates. The OS rates at 3 and 5 years after surgery were 25.7% and 19.0% in the ACCI-low group, respectively, and 7.6% and 0% in the ACCI-high group, which amounted to a statistically significant difference (P = 0.019). The RFS rates at 3 and 5 years after surgery were 17.3% and 13.8% in the ACCI-low group, respectively, and 7.1% and 0% in the ACCI-high group, which amounted to a marginally statistically significant difference (P = 0.104). A multivariate analysis showed that the ACCI was a significant independent risk factor for both the OS and RFS.
Conclusions: The ACCI was a risk factor for the OS in patients who underwent curative surgery followed by adjuvant chemotherapy for pancreatic cancer. An effective plan is needed for determining the optimum surgical strategy according to the ACCI.
Keywords: Age-adjusted Charlson comorbidity index, pancreatic cancer, survival
|How to cite this URL:|
Aoyama T, Yamamoto N, Kamiya M, Murakawa M, Tamagawa H, Sawazaki S, Numata M, Kobayashi S, Ueno M, Morimoto M, Shiozawa M, Yukawa N, Oshima T, Yoshikawa T, Rino Y, Masuda M, Morinaga S. The age-adjusted Charlson comorbidity index is an independent prognostic factor in pancreatic cancer patients who receive curative resection followed by adjuvant chemotherapy. J Can Res Ther [Epub ahead of print] [cited 2020 Jul 13]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=257925
| > Introduction|| |
Pancreatic cancer, which has a 5-year survival rate of <5%, is a major cause of cancer death worldwide., Complete resection is essential for obtaining a cure in patients with pancreatic cancer. However, pancreatic cancer patients suffer recurrence, even after complete curative resection followed by adjuvant treatment., It is therefore important to identify the prognostic factors for pancreatic cancer to select candidates for more aggressive treatment.
Various clinic-pathological factors, including the tumor size, lymph node metastasis, resection margin status, and histological type, have been reported to be significant prognostic factors that can be used to predict the survival in patients with pancreatic cancer.,,, Several recent studies have shown that the presence of comorbidities and their severity affect the prognosis after surgery in pancreatic cancer. However, the optimum tools for comprehensively evaluating the various comorbid diseases in pancreatic cancer treatment have not been sufficiently established.
The Charlson comorbidity index (CCI) was first proposed by Charlson et al. in 1987 and has been extensively used to evaluate the impact of comorbidity in a variety of cancers and noncancer conditions. The CCI is a prognostic taxonomy that was initially developed to account for the influence of patients' adverse medical conditions in longitudinal studies and is useful for prognostic prediction by weighing and scoring each comorbidity disease. The age-adjusted CCI (ACCI) incorporates the age of the patient as a correction variable in the final CCI, and several studies have shown that it is a useful tool for predicting both the short- and long-term outcomes in various cancers.,,
In the present study, we investigated whether or not the overall survival (OS) and recurrence-free survival (RFS) were affected by the ACCI of pancreatic cancer patients who underwent curative surgery followed by adjuvant chemotherapy.
| > Patients and Methods|| |
The study participants were selected from the medical records of consecutive patients who underwent surgery for pancreatic cancer at the Kanagawa Cancer Center from 2005 to 2014. The inclusion criteria were as follows: (1) patients with a common pathological type of pancreatic cancer (according to UICC TNM 7th edition); (2) patients in whom curative resection was successful as the initial treatment for pancreatic cancer and who received gemcitabine or S-1 adjuvant chemotherapy; (3) patients without synchronous or metachronous malignancies; and (4) the patients who collected the details of the comorbidity records. The resected specimens were examined histopathologically and staged according to the UICC TNM 7th edition. Patients with other pancreatic and periampullary neoplasms, such as intraductal papillary mucinous neoplasms, cystadenocarcinoma, and endocrine tumors, were excluded from the present study.
All the operations were performed by four surgeons from the pancreatic unit. All pancreatic surgeries were performed in accordance with standardized procedures that have been described elsewhere.,,, In brief, in cases of pancreaticoduodenectomy (PD), we performed subtotal stomach-preserving PD as the standard procedure. The lymph node groups that were resected en bloc included the anterior pancreatic duodenal lymph nodes, the posterior pancreatic duodenal lymph nodes, nodes in the lower hepatoduodenal ligament, and nodes along the right lateral aspect of the superior mesenteric artery and vein. In cases of distal pancreatectomy, lymph node dissection was performed in the region of the celiac trunk and the superior mesenteric artery and vein, as well as behind the pancreas along the left side of the renal vein and the left adrenal gland.
Treatment with gemcitabine was initiated within 8 weeks after surgery. The patients received a weekly dose of 1000 mg/m2 for 3 weeks, followed by 1 week of rest. S-1 chemotherapy was started within 10 weeks after surgery. The patients received 40 mg of S-1 per square meter of body-surface area twice a day for 4 weeks, followed by 2 weeks of rest as 1 course (6-week schedule) or 2 weeks followed by 1 week of rest as 1 course (3-week schedule). All of the patients in the present study received either gemcitabine or S-1 treatment for 6 months.
Definition of postoperative surgical complications
Postoperative surgical complications of Grade 2–5 according to the Clavien-Dindo classification were retrospectively determined from the patient's records.
Patients were followed up at outpatient clinics. Hematological tests and physical examinations were performed at least every 3 months for 5 years. In the patients who received adjuvant chemotherapy, hematological tests and physical examinations were performed at least every 2 weeks during adjuvant chemotherapy, and at least every 3 months for 5 years after the patients finished adjuvant chemotherapy. The carcinoembryonic antigen and carbohydrate antigen 19-9 tumor marker levels were checked at least every 3 months for 5 years. Patients underwent a CT examination every 3 months during the first 3 years after surgery, and then every 6 months until 5 years after surgery.
Measurement of the age-adjusted Charlson comorbidity index
We used the comorbidity index developed by Charlson et al. to quantify baseline comorbidities. Information on preexisting comorbidities that were present before the pancreatic cancer surgery was obtained from the medical records. The index is a weighted measure that incorporates 19 different medical categories, each of which is weighted according to its potential impact on mortality. The final score of each patient was calculated by taking all comorbid conditions into account. The ACCI was calculated with additional points added for age (1 point added for each decade over 40 years of age).
Evaluations and statistical analyses
The significance of correlations between the ACCI and clinic-pathological parameters was determined using Fisher's exact test or the Chi-square test. The OS was defined as the period between surgery and death. The RFS was defined as the period between surgery and recurrence or death, whichever came first. The data of the patients who did not experience an event were censored on the date of the final observation. The OS and RFS were evaluated by univariate and multivariate analyses. The OS and RES curves were calculated using the Kaplan–Meier method and compared by the log-rank test. A Cox proportional hazards model was used to perform the univariate and multivariate survival analyses. P < 0.05 were considered to indicate statistical significance. The survival data were obtained from hospital records or from the city registry system. The SPSS software program (v11.0 J Win; SPSS, Chicago, IL, USA) was used for all of the statistical analyses. This study was approved by the IRB of the Kanagawa Cancer Center.
| > Results|| |
We evaluated 155 patients in the present study. The patients' ages ranged from 30 to 84 years (median: 66 years); 86 patients were male, and 69 were female. The median follow-up period was 60.6 months (range: 8.7–138 months). Thirty-six patients received distal pancreatic surgery, 107 received PD, and 12 total pancreatic resection. The median length of the operation was 504 min (range: 140–1195 min). The median blood loss was 1130 ml (range: 30–10175 ml). The median number of harvested lymph nodes was 30 (range: 1–92).
The OS stratified by each clinical factor was compared by the log-rank test, and a statistically significant difference was observed in the T factor with a marginally significant difference observed in lymph node metastasis and the ACCI [Table 1]. An ACCI of 8 was regarded as the optimum critical point of classification considering the 1-, 3- and 5-year survival rates.
|Table 1: Comparison of survival rates stratified by patient characteristics|
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Each clinicopathological factor was categorized as shown in [Table 2] and analyzed for prognostic significance. The univariate analyses for the OS showed that the ACCI was a significant prognostic factor. The ACCI was thus selected for the final multivariate analysis model. The OS rates at 3 and 5 years after surgery were 25.7% and 19.0% in the ACCI-low group, respectively, and 7.6% and 0% in the ACCI-high group. The OS curves are shown in [Figure 1].
|Table 2: Uni and Multivariate Cox proportional hazards analysis of clinico pathological factors for overall survival|
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|Figure 1: A comparison of the overall survival in the patients with an age-adjusted Charlson comorbidity index ≥8 and those with an age-adjusted Charlson comorbidity index ≤7|
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The univariate analyses for the RFS showed that the ACCI was a marginally significant prognostic factor. The ACCI was thus selected for the final multivariate analysis model [Table 3]. The RFS rates at 3 and 5 years after surgery were 17.3% and 13.8% in the ACCI-low group, respectively, and 7.1% and 0% in the ACCI-high group. The RFS curves are shown in [Figure 2].
|Table 3: Uni and multivariate cox proportional hazards analysis of clinico pathological factors for recurrence free survival|
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|Figure 2: A comparison of the recurrence-free survival in the patients with an age-adjusted Charlson comorbidity index ≥8 and those with an age-adjusted Charlson comorbidity index ≤7|
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On comparing the patients' demographic and clinical characteristics between the ACCI ≤7- and ≥8-point groups, the incidence of patients who received adjuvant chemotherapy and the incidence of postoperative infectious complications were significantly different between the two groups. The incidence of patients who received adjuvant chemotherapy was 52.4% in the ACCI ≥8-point group and 30.6% in the ACCI ≤7-point group (P = 0.049). The incidence of postoperative infectious complications was 33.3% in the ACCI ≥8-point group and 11.9% in the ACCI ≤7-point group (P = 0.010).
| > Discussion|| |
The present study examined whether or not the ACCI was associated with a poorer OS and RFS in pancreatic cancer patients who underwent curative surgery followed by adjuvant chemotherapy. Our findings clearly indicated that the ACCI was an independent risk factor for both the OS and RFS. Furthermore, the present study results suggested that the ACCI was closely related to the incidence of postoperative surgical complications. Therefore, the ACCI might have some clinical significance for pancreatic cancer patients who undergo radical surgery and effective adjuvant chemotherapy.
The clinical impact of the ACCI in pancreatic cancer has been reported in previous reports. For example, Asano et al. evaluated the prognostic value of the Charlson age comorbidity index (CACI) in 379 pancreatic cancer patients who underwent R0 or R1 resection. The authors classified the patients into CACI-low and CACI-high groups by setting 4 as the cutoff value for the CACI. They found that the OS rates at 1, 3, and 5 years after surgery were 71%, 17%, and 8% in the CACI-low group, respectively, and 53%, 14%, and 4% in the CACI-high group. The OS rate was significantly higher in the CACI-low group than in the CACI-high group. They also showed that the CACI was an independent factor associated with a worse OS (hazard ratio of 1.43, 95% confidence interval [CI], 1.05–1.96) in a multivariate analysis using the Cox regression model. Similar hazard ratios and 95% CIs have been observed in other studies. Therefore, the ACCI has some clinical influence on the pancreatic cancer survival.
There are several possible reasons why the ACCI affects the OS and RFS of pancreatic cancer patients. One possible reason is that the ACCI might be associated with the incidence of postoperative surgical complications. Indeed, the incidence of postoperative infectious complications was higher in the ACCI-high group than in the ACCI-low group in our study. Recent studies have shown that the development of postoperative complications reduces the patient survival or increases the risk of disease recurrence in various types of malignancies.,,,,,,,, Previously, we investigated the impact of postoperative complications on the pancreatic cancer survival and recurrence after curative surgery. This study included 164 patients who underwent curative surgery for pancreatic cancer between 2005 and 2014. The patients were classified into those with postoperative complications (C group) and those without postoperative complications (NC group). The RFS rate at 5 years after surgery was 10.6% in the C group patients and 21.0% in the NC group patients. In addition, the RFS tended to be worse in the C group than in the NC group (P = 0.1756). The OS rate at 5 years after surgery was 7.4% in the C group and 22.8% in the NC group, which was significantly different (P = 0.0189). A multivariate analysis showed that postoperative complications were significant independent risk factors for the OS and marginally significant risk factors for the RFS. Similar results were obtained in other reports. A second possible reason for this association is that the ACCI might be associated with the incidence of postoperative adjuvant chemotherapy. In the present study, the incidence of patients who received postoperative adjuvant chemotherapy was higher in the ACCI-low group than in the ACCI-high group. Similar results were observed in the previous study. As mentioned above, Asano et al. showed that the incidence of patients receiving chemotherapy, including postoperative adjuvant chemotherapy, was higher in the low-CACI group than in the high-CACI group (87% vs. 69%, P < 0.0001). The outcomes of patients with pancreatic cancer have gradually been improved by effective adjuvant chemotherapies, such as gemcitabine or S-1., A third possible reason is that the patients in the ACCI-low group might have had some characteristics that led to decreased host immunity against the tumor. However, the optimum mechanism of host immunity remains unclear. Further studies focusing on this issue are thus needed.
Special attention is required when interpreting the current results, as the present study is associated with several potential limitations. First, the present study was a retrospective analysis performed in a single institution. We cannot deny the possibility that our findings were observed by chance. Second, there was a selection bias in the patients in this series. Surgeons often avoid performing pancreatectomy in some patients, as the procedure is associated with high rates of morbidity and mortality (40%–60% and 1%–1.5%, respectively). Thus, the fact that some patients in this study received pancreatectomy at all may in and of itself be considered a potential bias. In addition, our hospital is a specialized cancer center. Given these limitations, the results must be confirmed in another cohort or in a prospective multicenter-study.
| > Conclusions|| |
The OS and RFS of the pancreatic cancer patients who underwent curative resection followed by adjuvant chemotherapy differed significantly based on the ACCI. It is necessary to develop the effective plan of the surgical strategy according to the ACCI.
This work was supported, in part, by the nongovernmental organization Yokohama Surgical Research Group and Takeda Medical Foundation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A, et al.
Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016;388:73-85.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011;378:607-20.
Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J, et al.
1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg 2006;10:1199-210.
Moon HJ, An JY, Heo JS, Choi SH, Joh JW, Kim YI, et al.
Predicting survival after surgical resection for pancreatic ductal adenocarcinoma. Pancreas 2006;32:37-43.
Kuhlmann KF, de Castro SM, Wesseling JG, ten Kate FJ, Offerhaus GJ, Busch OR, et al.
Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 2004;40:549-58.
Lim JE, Chien MW, Earle CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: A population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74-85.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373-83.
Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol 1994;47:1245-51.
Wu CC, Hsu TW, Chang CM, Yu CH, Lee CC. Age-adjusted Charlson comorbidity index scores as predictor of survival in colorectal cancer patients who underwent surgical resection and chemoradiation. Medicine (Baltimore) 2015;94:e431.
Tian Y, Jian Z, Xu B, Liu H. Age-adjusted Charlson comorbidity index score as predictor of survival of patients with digestive system cancer who have undergone surgical resection. Oncotarget 2017;8:79453-61.
Büchler MW, Friess H, Wagner M, Kulli C, Wagener V, Z'Graggen K, et al.
Pancreatic fistula after pancreatic head resection. Br J Surg 2000;87:883-9.
Wagner M, Z'graggen K, Vagianos CE, Redaelli CA, Holzinger F, Sadowski C, et al.
Pylorus-preserving total pancreatectomy. Early and late results. Dig Surg 2001;18:188-95.
Andrén-Sandberg A, Wagner M, Tihanyi T, Löfgren P, Friess H. Technical aspects of left-sided pancreatic resection for cancer. Dig Surg 1999;16:305-12.
Seiler CA, Wagner M, Sadowski C, Kulli C, Büchler MW. Randomized prospective trial of pylorus-preserving vs. classic duodenopancreatectomy (Whipple procedure): Initial clinical results. J Gastrointest Surg 2000;4:443-52.
Murakawa M, Aoyama T, Asari M, Katayama Y, Yamaoku K, Kanazawa A, et al.
The short- and long-term outcomes of radical antegrade modular pancreatosplenectomy for adenocarcinoma of the body and tail of the pancreas. BMC Surg 2015;15:120.
Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, et al.
Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet 2016;388:248-57.
Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, et al.
Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 2007;297:267-77.
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13.
Asano T, Yamada S, Fujii T, Yabusaki N, Nakayama G, Sugimoto H, et al.
The Charlson age comorbidity index predicts prognosis in patients with resected pancreatic cancer. Int J Surg 2017;39:169-75.
Lagarde SM, de Boer JD, ten Kate FJ, Busch OR, Obertop H, van Lanschot JJ, et al.
Postoperative complications after esophagectomy for adenocarcinoma of the esophagus are related to timing of death due to recurrence. Ann Surg 2008;247:71-6.
Mynster T, Christensen IJ, Moesgaard F, Nielsen HJ. Effects of the combination of blood transfusion and postoperative infectious complications on prognosis after surgery for colorectal cancer. Danish RANX05 colorectal cancer study group. Br J Surg 2000;87:1553-62.
Tokunaga M, Tanizawa Y, Bando E, Kawamura T, Terashima M. Poor survival rate in patients with postoperative intra-abdominal infectious complications following curative gastrectomy for gastric cancer. Ann Surg Oncol 2013;20:1575-83.
Tsujimoto H, Ichikura T, Ono S, Sugasawa H, Hiraki S, Sakamoto N, et al.
Impact of postoperative infection on long-term survival after potentially curative resection for gastric cancer. Ann Surg Oncol 2009;16:311-8.
Miki C, Tanaka K, Inoue Y, Araki T, Ohi M, Mohri Y, et al.
Perioperative host-tumor inflammatory interactions: A potential trigger for disease recurrence following a curative resection for colorectal cancer. Surg Today 2008;38:579-84.
McArdle CS, McMillan DC, Hole DJ. Impact of anastomotic leakage on long-term survival of patients undergoing curative resection for colorectal cancer. Br J Surg 2005;92:1150-4.
Aoyama T, Murakawa M, Katayama Y, Yamaoku K, Kanazawa A, Higuchi A,et al
. Impact of postoperative complications on survival and recurrence in pancreatic cancer. Anticancer Res 2015;35:2401-9.
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[Table 1], [Table 2], [Table 3]