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Impact of Comorbidities on the Outcomes of Older Patients Receiving Rectal Cancer Surgery
International Journal of Gerontology 6 (2012) 285e289
Contents lists available at SciVerse ScienceDirect
International Journal of Gerontology journal homepage: www.ijge-online.com
Original Article
Impact of Comorbidities on the Outcomes of Older Patients Receiving Rectal Cancer Surgeryq Hui-Ru Chang 1, 2, Shou-Chuan Shih 3, Fu-Man Lin 1, 4 * 1 Department of Medical Affairs, Mackay Memorial Hospital, 2 Institute of Health Policy and Management, National Taiwan University, 3 Superintendent Office, Mackay Memorial Hospital, 4 Institute of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan
a r t i c l e i n f o
s u m m a r y
Article history: Received 17 August 2011 Accepted 30 December 2011 Available online 28 September 2012
Background: The decision to perform surgery on older patients often presents as an ethical dilemma. The purpose of this study is to investigate the impact of comorbidities on the clinical outcomes of older rectal cancer surgery patients, with the goal of enabling healthcare professionals to evaluate the risk of surgery for the treatment of cancer in older patients with comorbid chronic disease. Methods: This study included 320 patients >60 years of age who were treated from 2004e2009 at a medical center in northern Taiwan. Logistic regression and Cox proportional hazards regression were used to determine if various chronic diseases (e.g., hypertension, diabetes, cardiovascular disease, cerebrovascular disease) increase the risk of in-hospital complications and 1-year mortality. Results: In the multivariate analysis, the risk of in-hospital complications for diabetic patients was 3.43 times that of nondiabetic patients (95% confidence interval [CI]: 1.13e10.37). For patients with cerebrovascular disease, the risk was 4.99 times that of those without cerebrovascular disease (95% CI: 1.30e19.07). In addition, patients 80 years of age demonstrated significantly higher 1-year mortality rates (HR ¼ 3.49, 95% CI:1.18e10.30). However, a history of hypertension, diabetes, cardiovascular disease, or cerebrovascular disease was not a significant predictor of 1-year mortality. Conclusion: Older patients with comorbidities are at a higher risk of in-hospital complications following rectal cancer surgery, whereas the presence of comorbidities did not show a significant adverse effect on 1-year mortality in the present study. We suggest using population-based data to establish effective therapeutic strategies for treating each comorbidity. Copyright Ó 2012, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: comorbidity, elderly, in-hospital complication, mortality, rectal cancer
1. Introduction Colorectal cancer is the second leading cause of death in developed countries among patients with malignancies1,2. During the past 20 years, the incidence of colorectal cancer in older patients has increased by over 70%3. Among the aging population, the total number of cases of colorectal cancer is increasing as well. Studies have demonstrated that age is a risk factor that affects surgical outcome, and surgery is infrequently offered to older cancer patients because of the increased risk of surgical morbidity and mortality4. Thus, the decision to perform surgery on older patients often presents as an ethical dilemma5. A number of studies have demonstrated that in highly functional elderly patients without comorbidities, postoperative clinical q All contributing authors declare no conflict of interest. * Correspondence to: Dr Fu-Man Lin, Number 92, Section 2, Zhongshan North Road, Zhongshan District, Taipei 10449, Taiwan. E-mail address: [email protected] (F.-M. Lin).
outcomes are similar to those of younger patients6,7; however, other research has shown that older cancer patients probably receive less curative treatment compared with younger patients8. The higher prevalence of chronic diseases in older patients may limit treatment choices; for example, patients with chronic diseases may not be candidates for surgery or chemotherapy9,10, and this influences the therapeutic outcome of cancer treatment. Furthermore, irrespective of whether or not surgery is permitted, chronic diseases also complicate surgery, increasing the risk of complications. Several studies have explored the impact of comorbidities on the surgical outcome of colorectal cancer, demonstrating that the risk of surgical complications and postoperative mortality are higher in patients with chronic obstructive pulmonary disease, deep vein thrombosis, neurological comorbidities, or cardiorespiratory comorbidities11,12. However, heterogeneity exists between colon cancer and rectal cancer, and their risk factors are different13. It has been suggested that investigations of colon or rectal cancer should be separated.
1873-9598/$ e see front matter Copyright Ó 2012, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.ijge.2012.05.006
286
To date, only a few studies have been conducted on the influence of comorbidities on the clinical outcomes of older rectal cancer patients9,14. Therefore, the aim of this study is to determine the impact of comorbidities on surgical complications and the mortality of older rectal cancer patients, with the hope of providing more information on surgical risk that could be used to evaluate patients with different chronic diseases. This is critical for surgical planning and therapy because the proper evaluation of the comorbid conditions and considerations of a treatment strategy could decrease the risk of surgical complications and mortality in older patients. 2. Methods The study included 320 patients >60 years of age who were treated for resected rectal cancer between 2004e2009 at a medical center in northern Taiwan. Data were retrieved from outpatient and inpatient claims data and the cancer registry. The outpatient and inpatient claims data included demographics, diagnoses, treatments, and medical expense records. The cancer registry data included the histological types of the treated tumors, treatment intensity, and survival status. The characteristics of the patients and surgical outcomes were retrieved from both databases. The comorbidities included in the present study were hypertension, diabetes, cardiovascular disease, and cerebrovascular disease, all which are common in Taiwan. The principal and secondary diagnoses in preoperative claims data were used to determine whether a patient had any of these diseases prior to surgery. The diagnosis of a comorbidity was defined according to the ICD-9 CM code for hypertension (401.XXe405.XX), diabetes (250.XX), cardiovascular disease (390.XXe398.XX, 411.XXe429.XX), and cerebrovascular disease (430.XXe438.XX). Abdominoperineal resection (APR), low anterior resection (LAR), and anterior resection (AR) are common types of resection. Only two categories of resection type were indicateddAPR or otherdin the present study. To specify the effects of chemotherapy on surgical outcome, we included only the claims data gathered before and 6 months after surgery in order to determine whether a patient underwent chemotherapy. Tumor stage was determined in accordance with the AJCC/UICC stage classification, and stage was grouped into early (Stages I-II) and advanced (Stages III-IV) for analyses. Tumor size was defined according to two levels, with a breakpoint value equal to the median of 4.5 mm. In addition, the demographic characteristics of patients at baseline were determined, including age and sex. Age was grouped into three categories (60e69, 70e79, and 80 years). Dekker et al indicated that older patients with colorectal cancer who survive the first year demonstrate the same rate of cancerrelated survival as younger patients. Therefore, the treatment of older patients with colorectal cancer should focus on perioperative care and the first postoperative year15. For this reason, the endpoints that were evaluated in the present study included inhospital complications and 1-year mortality after surgery. According the criteria of previous studies, we defined in-hospital complications as infections and other cardiovascular, respiratory, gastrointestinal, or urological complications16e18. Patients who developed any of these complications were classified as having an in-hospital complication. In order to avoid overestimating the incidence of complications, comorbidities that were present 1 month before surgery were excluded. Mortality is frequently used to measure the quality of surgery and has been used in numerous studies as a quality indicator of colorectal cancer surgery19e22. Similarly, we used mortality at 1 year postsurgery as a measurement of survival. Survival time, in days, was measured from the date of surgery to the date of death or last follow-up examination within 1 year postsurgery.
H.-R. Chang et al.
Differences in the proportions of in-hospital complications among various patient characteristics were compared using the Chisquare test (or Fisher exact test, as appropriate), and differences in 1year mortality were compared using the log-rank test. The impact of comorbidities on surgical complications and 1-year mortality were analyzed using multiple logistic regression or Cox proportional hazards regression, respectively, after controlling for sex, age, tumor stage, tumor size, resection type, and chemotherapy. Each characteristic of a cancer patient is the result of a complex array of physiologic and molecular variations23. Different patient characteristics may influence surgical outcomes, and interactions between comorbidities and prognostic factors should be considered. For this reason, interaction terms were incorporated into the statistical model in order to determine the interactions between comorbidities, sex, age, and cancer stage. If the interaction was significant, subgroup analyses were further performed to determine the potential differential effects of the comorbidities across different subgroups of patients. The sample size of the present study was not large enough; however, we used the bootstrapping technique to obtain robust estimates (1000 repetitions) from the multivariate models. Statistical analyses were performed using SPSS software (version 17.0, SPSS Inc., Chicago, IL) and STATA software (version 10, StataCorp, College Station, TX). The two-sided tests defined statistical significance as p < 0.05. 3. Results In the present study, the in-hospital complication rate was 11.9% and the 1-year mortality rate was 11.3%. Table 1 shows the patient characteristics and surgical outcomes. There were 142 (44.4%) female and 178 (55.6%) male patients. One hundred and forty-five (45.3%) people were 60e69 years of age, 115 (35.9%) were 70e79 years, and 60 (18.8%) were 80 years. The number of patients with early-stage and advanced-stage cancer were 152 (47.5%) and 168 (52.5%), respectively. One hundred and seventy-nine patients (55.9%) had tumor sizes 45 mm, while 141 (44.1%) had tumors >45 mm. The percentages of patients who had hypertension, diabetes, cardiovascular disease, or cerebrovascular disease were 35.6%, 19.7%, 25%, and 8.1%, respectively. The in-hospital complication rate of patients with diabetes was 22.2%, which is significantly higher than the rate of 9.3% determined for patients without diabetes (p < 0.01). In addition, the in-hospital complication rate was significantly higher in patients with cerebrovascular disease compared with those without such diseases (34.6% vs. 9.9%, p < 0.001). One-year mortality was significantly associated age and tumor stage. One-year mortality was 21.7% among patients 80 years, higher than those aged 60e69 years (7.6%) and 70e79 years (10.4%). Patients with advanced-stage diseases demonstrated a higher 1-year mortality rate compared with those with early-stage diseases (17.9% vs. 3.9%, p < 0.001). Nevertheless, the development of in-hospital complications was not significantly associated with hypertension or cardiovascular disease, and 1-year mortality was not significantly associated with any comorbidity. The results of the risk factor analyses for in-hospital complications and 1-year mortality are shown in Table 2. The risk of developing complications among patients with diabetes or cerebrovascular diseases was significantly higher after controlling for sex, age, tumor stage, tumor size, chemotherapy, and resection type. The risk of developing in-hospital complications among diabetic patients was 3.43 times (95% confidence interval [CI]: 1.13e10.37) that of nondiabetic patients. In patients with cerebrovascular disease, the risk was 4.99 times (95% CI: 1.30e19.07) that of those without cerebrovascular disease. Furthermore, the mortality risk of patients 80 years was 3.49 times (95% CI:
Rectal Cancer Surgery Outcomes in Older Patients
287
Table 1 Characteristics of the patients and surgical outcomes. Study In-hospital P (c2 ) population complication rate (n ¼ 320)
(n ¼ 38)
1-year P (log-rank) mortality (n ¼ 36)
n (%)
%
Sex Female Male
%
142 (44.4) 178 (55.6)
14.8 9.6
0.150
10.6 11.8
0.712
Age (y) 60e69 y 70e79 y 80 y
145 (45.3) 115 (35.9) 60 (18.8)
9.7 10.4 20.0
0.096
7.6 10.4 21.7
0.014
Tumor stage Early 152 (47.5) Advanced 168 (52.5)
12.5 11.3
0.742
3.9 17.9
<0.001
Tumor size 45mm >45mm
179 (55.9) 141 (44.1)
10.1 14.2
0.257
9.5 13.5
0.289
Chemotherapy No 99 (30.9) Yes 221 (69.1)
9.1 13.1
0.303
9.1 12.2
0.468
Resection type Other 180 (56.3) APR 140 (43.8)
11.7 12.1
0.896
12.2 10.0
0.529
Hypertension No 206 (64.4) Yes 114 (35.6)
11.2 13.2
0.598
10.2 13.2
0.412
Diabetes No Yes
257 (80.3) 63 (19.7)
9.3 22.2
<0.01
11.3 11.1
0.968
Cardiovascular disease No 240 (75.0) Yes 80 (25.0)
10.0 17.5
0.073
9.6 16.3
0.105
Cerebrovascular disease No 294 (91.9) Yes 26 (8.1)
9.9 34.6
<0.001 10.9 15.4
0.468
APR ¼ abdominoperineal resection.
Table 2 Results of multivariate analysis of the factors that influence surgical outcomes (calculated from 1000 bootstrap replications). In-hospital complication
1-year mortality
OR
95% CI
HR
95% CI
Sex (ref: female) Male
0.68
0.28e1.64
1.47
0.60e3.65
Age (ref: 60e69 y) 70e79 y 80 y
0.87 2.21
0.30e2.55 0.71e6.85
1.33 3.49*
0.50e3.56 1.18e10.30
Tumor stage (ref: early stage) Advanced stage 0.61
0.22e1.66
9.79
0.25e378.35
Tumor size (ref: 45 mm) >45 mm Chemotherapy
1.52 2.55
0.62e3.75 0.80e8.16
1.50 0.32
0.67e3.37 0.09e1.19
Resection type (ref: others) APR Hypertension Diabetes Cardiovascular disease Cerebrovascular disease
0.91 0.51 3.43* 1.21 4.99*
0.37e2.22 0.15e1.78 1.13e10.37 0.36e4.03 1.30e19.07
0.94 1.23 0.99 1.12 1.31
0.39e2.25 0.51e3.12 0.02e48.68 0.47e2.67 0.00e22,470.58
*p < 0.05. APR ¼ abdominoperineal resection.
1.18e10.30) that of patients aged 60e69 after controlling for prognostic factors, demonstrating a statistical level of significance. Nevertheless, the 1-year mortality rates of patients with hypertension, cardiovascular disease, or cerebrovascular disease were all greater than the rates of patients without these diseases, though these results were not statistically significant. Survival curveadjusted prognostic factors according to comorbidity are presented in Fig. 1. No significant comorbidity-associated differences were noted in the 1-year survival curve. Interaction terms were included in the multivariate analyses, which included 1000 bootstrap replications in order to determine the interaction effects of the comorbidities, sex, age, and cancer stage (data not shown). Interactions between comorbidities and sex, comorbidities and age, and comorbidities and tumor stage were not observed; therefore, further subgroup analyses were not performed. 4. Discussion After adjusting for other prognostic factors, the presence of diabetes or cerebrovascular disease significantly affected the risk of surgical complications among older patients undergoing surgical treatment for rectal cancer, whereas the presence of comorbidities did not demonstrate a significant adverse effect on 1-year mortality. Hyperglycemia impairs the immune system, thereby increasing the risk of infection and preventing normal wound healing24. Therefore, most previous studies on the postsurgical complications of diabetic patients treated using colorectal resection for the treatment of cancer are focused on infected surgical wounds. Diabetes mellitus has been shown to play a significant role in predisposing an individual to surgical site infections following colorectal resection25,26. Sehgal et al found that among diabetic patients who undergo colorectal cancer resection, higher than normal glucose levels are associated with a greater risk of developing surgical site infections. They concluded that diabetic patients who require a colectomy should have tightly controlled glucose levels, avoid the placement of drains, and receive prophylactic antibiotics for <24 hours26. Moreover, the study by Cong et al also confirmed that diabetes mellitus is a risk factor for anastomotic leakage following rectal surgery27. Few studies have evaluated the impact of cerebrovascular disease on postsurgical complications following colorectal cancer surgery. The study by Iancu et al reported that patients with cerebrovascular disease are at a greater risk for anastomotic leakage following colorectal cancer surgery28. A greater proportion of Asian patients have cerebral hemorrhages and intracranial vascular diseases than their Western counterparts; cerebrovascular disease has consistently been reported as the second most common cause of death in Taiwan, second only to malignancy29. Thus, the relationship between postsurgical care following treatment for rectal cancer and cerebrovascular treatment (such as antiplatelet or anticoagulant therapy) in older Asian patients warrants further investigations. Some studies have examined the relationship between surgical complications and comorbidities in older patients following resection for the treatment of colorectal cancer. Pedrazzani et al found that those with preexisting cardiovascular diseases demonstrate higher complication rates30. Janssen-Heijnen et al reported that postoperative morbidity is higher among those with reduced pulmonary function, cardiovascular disease, or neurological comorbidities9. In the present study, patients with diabetes or cerebrovascular disease were at increased risk of surgical complications, but those with hypertension or cardiovascular disease did not demonstrate increased risk. This discrepancy could be due to differences in the definitions of these conditions and the duration of the complications. If a complication was present before surgery, it was not considered a surgical complication in the present study;
288
H.-R. Chang et al.
1.00 No
0.98
Cumulative Survival
Cumulative Survival
1.00 Yes
0.96 0.94
No
0.98 0.96 0.94
0.92
0.92
0.90
0.90 0
100
200
300
Yes
400
0
100
Time in Days
200
1.00
400
1.00 No
0.98
Cumulative Survival
No
Cumulative Survival
300
Time in Days
Yes
0.96 0.94 0.92
0.98
Yes
0.96 0.94 0.92
0.90
0.90 0
100
200
300
400
0
Time in Days
100
200
300
400
Time in Days
Fig. 1. Survival curves of patients diagnosed with a comorbidity.
therefore, the incidence of surgical complications in this study was lower than those reported in other studies. The screening criteria for complications might also have led us to different results than other studies. Furthermore, the present study included complications that appeared only during the postsurgical period while the patient was hospitalized; however, previous studies used different definitions for the duration of complications, ranging from 1e3 months postsurgery or they used criteria that were the same as our study. Differences in the study designs that resulted in variations in the duration of the complications that were observed produced large differences in the incidences of postsurgical complications that were reported across different studies. In the present study, the 1-year mortality rates were greater in patients with hypertension, cerebrovascular disease, and cerebrovascular disease than patients without these diseases, but these differences did not achieve a statistical level of significance. Because the lower number of deaths due to the shorter postsurgical duration may have resulted in poor statistical reliability, Zaslavsky et al suggested using an extended duration of assessment in order to overcome this problem31. Previous studies on older patients with cancer have classified postsurgical survival as long-term or shortterm. Janssen-Heijnen et al used overall survival as a mortality measure, revealing that mortality risk is greater in older rectal surgery patients with cardiovascular disease, chronic obstructive pulmonary disease, diabetes, and hypertension9. Alves et al used in-hospital death as an endpoint, and only neurological comorbidities were classified as risk factors12. Nonetheless, these studies suggest that chronic disease could influence both short- and longterm survival. On the contrary, the impact of chronic disease on the mortality rate did not achieve a level of statistical significance in the present study. This may be due to the smaller sample size or the fact that patients in the study hospital were treated with an appropriate level of caution. Healthcare professionals might have been aware that the mortality of older patients with chronic disease may increase because of their poor health status, and thus they may have exercised more care when treating older patients.
In our study, age did not significantly affect the rate of inhospital complications among older rectal cancer surgical patients, but age did significantly influence the 1-year mortality: the 1-year mortality risks of patients aged 70e79 years and >80 years were 1.33 and 3.48 times the risk for those aged 60e69 years, respectively. The International Society for Geriatric Oncology defines old age as >70 years. Using this definition, Kesisoglou et al found that patients >70 years of age demonstrate higher morbidity and mortality rates. This observation is probably the result of these patients having a poor overall health status3. Most previous studies on postsurgical mortality in elderly colorectal cancer patients define elderly as >80 years. It has been established that “age” is a risk factor of early postsurgical mortality, and that short-term postsurgical mortality is significantly greater in older patients32,33. The life expectancy of a patient who does not undergo surgery cannot be predicted, but pain, poor general health, and complications caused by tumor obstruction are all factors that diminish the patient’s quality of life if the tumor is not removed. Therefore, by minimizing the operative risk and ensuring careful intraoperative and postoperative monitoring, surgical treatment of rectal cancer can be considered in geriatric patients34. This study has two limitations. First, because data were collected only from the study hospital, this study lacked information on the development of comorbidities. The progression of a comorbidity could have induced poor health status and affected morbidity or mortality; therefore, the effects of comorbidities on surgical outcomes cannot be exactly estimated. Second, treatment intensity and disease severity would similarly have been underestimated because of data limitations. 4. Conclusions Healthcare professionals are facing an inevitable increase in the number of older cancer patients. Whether or not to perform surgery on an older patient should be carefully considered, especially when surgery remains as the most effective therapy. This
Rectal Cancer Surgery Outcomes in Older Patients
study indicates that, although comorbidities can affect in-hospital complications, 1-year postsurgery mortality was unaffected. Although we strictly controlled for cancer stage, presurgical comorbidities, and other prognostic factors, selection bias still exists, as in previous studies, because our samples were derived from only one hospital. Therefore, we recommend that future research use population-based data in order to establish effective therapeutic strategies for the treatment of specific comorbidities. Moreover, although we found that comorbidities affect in-hospital complications, our study population consisted of only older patients. Thus, we recommend comparisons between older and younger groups in order to determine whether this effect occurs only in older patients. Furthermore, in order to understand survival differences, we propose comparing the clinical outcomes of older patients who have undergone surgery against the outcomes of older patients who have not.
References 1. Boyle P, Langman JS. ABC of colorectal cancer: epidemiology. BMJ. 2000;321:805e808. 2. Howard RA, Freedman DM, Park Y, et al. Physical activity, sedentary behavior, and the risk of colon and rectal cancer in the NIH-AARP Diet and Health Study. Cancer Causes Control. 2008;19:939e953. 3. Kesisoglou I, Pliakos I, Sapalidis K, et al. Emergency treatment of complicated colorectal cancer in the elderly. Should the surgical procedure be influenced by the factor ‘age’? Eur J Cancer Care (Engl). 2010;19:820e826. 4. Cicerchia M, Ceci M, Locatelli C, et al. Geriatric syndromes in peri-operative elderly cancer patients. Surg Oncol. 2010;19:131e139. 5. Ramesh HS, Pope D, Gennari R, et al. Optimising surgical management of elderly cancer patients. World J Surg Oncol. 2005;3:17. 6. Sawada S, Komori E, Nogami N, et al. Advanced age is not correlated with either short-term or long-term postoperative results in lung cancer patients in good clinical condition. Chest. 2005;128:1557e1563. 7. Vironen JH, Sainio P, Husa AI, et al. Complications and survival after surgery for rectal cancer in patients younger than and aged 75 years or older. Dis Colon Rectum. 2004;47:1225e1231. 8. Audisio RA, Bozzetti F, Gennari R, et al. The surgical management of elderly cancer patients; recommendations of the SIOG surgical task force. Eur J Cancer. 2004;40:926e938. 9. Janssen-Heijnen ML, Maas HA, Houterman S, et al. Comorbidity in older surgical cancer patients: influence on patient care and outcome. Eur J Cancer. 2007;43:2179e2193. 10. Muss HB, Biganzoli L, Sargent DJ, et al. Therapy in the elderly: making the right decision. J Clin Oncol. 2007;25:1870e1875. 11. Lemmens VE, Janssen-Heijnen ML, Houterman S, et al. Which comorbid conditions predict complications after surgery for colorectal cancer? World J Surg. 2007;31:192e199. 12. Alves A, Panis Y, Mathieu P, et al. Postoperative mortality and morbidity in French patients undergoing colorectal surgery: results of a prospective multicenter study. Arch Surg. 2005;140:278e283. discussion 284.
289 13. Wei EK, Giovannucci E, Wu K, Rosner B, et al. Comparison of risk factors for colon and rectal cancer. Int J Cancer. 2004;108:433e442. 14. Shahir MA, Lemmens VE, van de Poll-Franse LV, et al. Elderly patients with rectal cancer have a higher risk of treatment-related complications and a poorer prognosis than younger patients: a population-based study. Eur J Cancer. 2006;42:3015e3021. 15. Dekker JW, van den Broek CB, Bastiaannet E, et al. Importance of the first postoperative year in the prognosis of elderly colorectal cancer patients. Ann Surg Oncol. 2011;18:1533e1539. 16. Longo WE, Virgo KS, Johnson FE, et al. Outcome after proctectomy for rectal cancer in Department of Veterans Affairs Hospitals: a report from the National Surgical Quality Improvement Program. Ann Surg. 1998;228:64e70. 17. Zaheer S, Pemberton JH, Farouk R, et al. Surgical treatment of adenocarcinoma of the rectum. Ann Surg. 1998;227:800e811. 18. Lehnert T, Methner M, Pollok A, et al. Multivisceral resection for locally advanced primary colon and rectal cancer: an analysis of prognostic factors in 201 patients. Ann Surg. 2002;235:217e225. 19. Dobie SA, Baldwin LM, Dominitz JA, et al. Completion of therapy by Medicare patients with stage III colon cancer. J Natl Cancer Inst. 2006;98:610e619. 20. Heriot AG, Tekkis PP, Smith JJ, et al. Prediction of postoperative mortality in elderly patients with colorectal cancer. Dis Colon Rectum. 2006;49:816e824. 21. Khan MR, Bari H, Raza SA. Early postoperative outcome after curative colorectal cancer surgery. Singapore Med J. 2011;52:195e200. 22. Stillwell AP, Buettner PG, Siu SK, et al. Predictors of postoperative mortality, morbidity, and long-term survival after palliative resection in patients with colorectal cancer. Dis Colon Rectum. 2011;54:535e544. 23. Pal SK, Hurria A. Impact of age, sex, and comorbidity on cancer therapy and disease progression. J Clin Oncol. 2010;28:4086e4093. 24. Blondet JJ, Beilman GJ. Glycemic control and prevention of perioperative infection. Curr Opin Crit Care. 2007;13:421e427. 25. McConnell YJ, Johnson PM, Porter GA. Surgical site infections following colorectal surgery in patients with diabetes: association with postoperative hyperglycemia. J Gastrointest Surg. 2009;13:508e515. 26. Sehgal R, Berg A, Figueroa R, et al. Risk factors for surgical site infections after colorectal resection in diabetic patients. J Am Coll Surg. 2011;212:29e34. 27. Cong ZJ, Fu CG, Wang HT, et al. Influencing factors of symptomatic anastomotic leakage after anterior resection of the rectum for cancer. World J Surg. 2009;33:1292e1297. 28. Iancu C, Mocan LC, Todea-Iancu D, et al. Host-related predictive factors for anastomotic leakage following large bowel resections for colorectal cancer. J Gastrointestin Liver Dis. 2008;17:299e303. 29. Huang ZS, Chiang TL, Lee TK. Stroke prevalence in Taiwan: findings from the 1994 National Health Interview Survey. Stroke. 1997;28:1579e1584. 30. Pedrazzani C, Cerullo G, De Marco G, et al. Impact of age-related comorbidity on results of colorectal cancer surgery. World J Gastroenterol. 2009;15: 5706e5711. 31. Zheng H, Zhang W, Ayanian JZ, et al. Profiling hospitals by survival of patients with colorectal cancer. Health Serv Res. 2011;46:729e746. 32. Marusch F, Koch A, Schmidt U, et al. The impact of the risk factor "age" on the early postoperative results of surgery for colorectal carcinoma and its significance for perioperative management. World J Surg. 2005;29:1013e1021. discussion 1021e2. 33. Kunitake H, Zingmond DS, Ryoo J, et al. Caring for octogenarian and nonagenarian patients with colorectal cancer: what should our standards and expectations be? Dis Colon Rectum. 2010;53:735e743. 34. Lemmens VE, Janssen-Heijnen ML, Verheij CD, et al. Co-morbidity leads to altered treatment and worse survival of elderly patients with colorectal cancer. Br J Surg. 2005;92:615e623.
Contents lists available at SciVerse ScienceDirect
International Journal of Gerontology journal homepage: www.ijge-online.com
Original Article
Impact of Comorbidities on the Outcomes of Older Patients Receiving Rectal Cancer Surgeryq Hui-Ru Chang 1, 2, Shou-Chuan Shih 3, Fu-Man Lin 1, 4 * 1 Department of Medical Affairs, Mackay Memorial Hospital, 2 Institute of Health Policy and Management, National Taiwan University, 3 Superintendent Office, Mackay Memorial Hospital, 4 Institute of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan
a r t i c l e i n f o
s u m m a r y
Article history: Received 17 August 2011 Accepted 30 December 2011 Available online 28 September 2012
Background: The decision to perform surgery on older patients often presents as an ethical dilemma. The purpose of this study is to investigate the impact of comorbidities on the clinical outcomes of older rectal cancer surgery patients, with the goal of enabling healthcare professionals to evaluate the risk of surgery for the treatment of cancer in older patients with comorbid chronic disease. Methods: This study included 320 patients >60 years of age who were treated from 2004e2009 at a medical center in northern Taiwan. Logistic regression and Cox proportional hazards regression were used to determine if various chronic diseases (e.g., hypertension, diabetes, cardiovascular disease, cerebrovascular disease) increase the risk of in-hospital complications and 1-year mortality. Results: In the multivariate analysis, the risk of in-hospital complications for diabetic patients was 3.43 times that of nondiabetic patients (95% confidence interval [CI]: 1.13e10.37). For patients with cerebrovascular disease, the risk was 4.99 times that of those without cerebrovascular disease (95% CI: 1.30e19.07). In addition, patients 80 years of age demonstrated significantly higher 1-year mortality rates (HR ¼ 3.49, 95% CI:1.18e10.30). However, a history of hypertension, diabetes, cardiovascular disease, or cerebrovascular disease was not a significant predictor of 1-year mortality. Conclusion: Older patients with comorbidities are at a higher risk of in-hospital complications following rectal cancer surgery, whereas the presence of comorbidities did not show a significant adverse effect on 1-year mortality in the present study. We suggest using population-based data to establish effective therapeutic strategies for treating each comorbidity. Copyright Ó 2012, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: comorbidity, elderly, in-hospital complication, mortality, rectal cancer
1. Introduction Colorectal cancer is the second leading cause of death in developed countries among patients with malignancies1,2. During the past 20 years, the incidence of colorectal cancer in older patients has increased by over 70%3. Among the aging population, the total number of cases of colorectal cancer is increasing as well. Studies have demonstrated that age is a risk factor that affects surgical outcome, and surgery is infrequently offered to older cancer patients because of the increased risk of surgical morbidity and mortality4. Thus, the decision to perform surgery on older patients often presents as an ethical dilemma5. A number of studies have demonstrated that in highly functional elderly patients without comorbidities, postoperative clinical q All contributing authors declare no conflict of interest. * Correspondence to: Dr Fu-Man Lin, Number 92, Section 2, Zhongshan North Road, Zhongshan District, Taipei 10449, Taiwan. E-mail address: [email protected] (F.-M. Lin).
outcomes are similar to those of younger patients6,7; however, other research has shown that older cancer patients probably receive less curative treatment compared with younger patients8. The higher prevalence of chronic diseases in older patients may limit treatment choices; for example, patients with chronic diseases may not be candidates for surgery or chemotherapy9,10, and this influences the therapeutic outcome of cancer treatment. Furthermore, irrespective of whether or not surgery is permitted, chronic diseases also complicate surgery, increasing the risk of complications. Several studies have explored the impact of comorbidities on the surgical outcome of colorectal cancer, demonstrating that the risk of surgical complications and postoperative mortality are higher in patients with chronic obstructive pulmonary disease, deep vein thrombosis, neurological comorbidities, or cardiorespiratory comorbidities11,12. However, heterogeneity exists between colon cancer and rectal cancer, and their risk factors are different13. It has been suggested that investigations of colon or rectal cancer should be separated.
1873-9598/$ e see front matter Copyright Ó 2012, Taiwan Society of Geriatric Emergency & Critical Care Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.ijge.2012.05.006
286
To date, only a few studies have been conducted on the influence of comorbidities on the clinical outcomes of older rectal cancer patients9,14. Therefore, the aim of this study is to determine the impact of comorbidities on surgical complications and the mortality of older rectal cancer patients, with the hope of providing more information on surgical risk that could be used to evaluate patients with different chronic diseases. This is critical for surgical planning and therapy because the proper evaluation of the comorbid conditions and considerations of a treatment strategy could decrease the risk of surgical complications and mortality in older patients. 2. Methods The study included 320 patients >60 years of age who were treated for resected rectal cancer between 2004e2009 at a medical center in northern Taiwan. Data were retrieved from outpatient and inpatient claims data and the cancer registry. The outpatient and inpatient claims data included demographics, diagnoses, treatments, and medical expense records. The cancer registry data included the histological types of the treated tumors, treatment intensity, and survival status. The characteristics of the patients and surgical outcomes were retrieved from both databases. The comorbidities included in the present study were hypertension, diabetes, cardiovascular disease, and cerebrovascular disease, all which are common in Taiwan. The principal and secondary diagnoses in preoperative claims data were used to determine whether a patient had any of these diseases prior to surgery. The diagnosis of a comorbidity was defined according to the ICD-9 CM code for hypertension (401.XXe405.XX), diabetes (250.XX), cardiovascular disease (390.XXe398.XX, 411.XXe429.XX), and cerebrovascular disease (430.XXe438.XX). Abdominoperineal resection (APR), low anterior resection (LAR), and anterior resection (AR) are common types of resection. Only two categories of resection type were indicateddAPR or otherdin the present study. To specify the effects of chemotherapy on surgical outcome, we included only the claims data gathered before and 6 months after surgery in order to determine whether a patient underwent chemotherapy. Tumor stage was determined in accordance with the AJCC/UICC stage classification, and stage was grouped into early (Stages I-II) and advanced (Stages III-IV) for analyses. Tumor size was defined according to two levels, with a breakpoint value equal to the median of 4.5 mm. In addition, the demographic characteristics of patients at baseline were determined, including age and sex. Age was grouped into three categories (60e69, 70e79, and 80 years). Dekker et al indicated that older patients with colorectal cancer who survive the first year demonstrate the same rate of cancerrelated survival as younger patients. Therefore, the treatment of older patients with colorectal cancer should focus on perioperative care and the first postoperative year15. For this reason, the endpoints that were evaluated in the present study included inhospital complications and 1-year mortality after surgery. According the criteria of previous studies, we defined in-hospital complications as infections and other cardiovascular, respiratory, gastrointestinal, or urological complications16e18. Patients who developed any of these complications were classified as having an in-hospital complication. In order to avoid overestimating the incidence of complications, comorbidities that were present 1 month before surgery were excluded. Mortality is frequently used to measure the quality of surgery and has been used in numerous studies as a quality indicator of colorectal cancer surgery19e22. Similarly, we used mortality at 1 year postsurgery as a measurement of survival. Survival time, in days, was measured from the date of surgery to the date of death or last follow-up examination within 1 year postsurgery.
H.-R. Chang et al.
Differences in the proportions of in-hospital complications among various patient characteristics were compared using the Chisquare test (or Fisher exact test, as appropriate), and differences in 1year mortality were compared using the log-rank test. The impact of comorbidities on surgical complications and 1-year mortality were analyzed using multiple logistic regression or Cox proportional hazards regression, respectively, after controlling for sex, age, tumor stage, tumor size, resection type, and chemotherapy. Each characteristic of a cancer patient is the result of a complex array of physiologic and molecular variations23. Different patient characteristics may influence surgical outcomes, and interactions between comorbidities and prognostic factors should be considered. For this reason, interaction terms were incorporated into the statistical model in order to determine the interactions between comorbidities, sex, age, and cancer stage. If the interaction was significant, subgroup analyses were further performed to determine the potential differential effects of the comorbidities across different subgroups of patients. The sample size of the present study was not large enough; however, we used the bootstrapping technique to obtain robust estimates (1000 repetitions) from the multivariate models. Statistical analyses were performed using SPSS software (version 17.0, SPSS Inc., Chicago, IL) and STATA software (version 10, StataCorp, College Station, TX). The two-sided tests defined statistical significance as p < 0.05. 3. Results In the present study, the in-hospital complication rate was 11.9% and the 1-year mortality rate was 11.3%. Table 1 shows the patient characteristics and surgical outcomes. There were 142 (44.4%) female and 178 (55.6%) male patients. One hundred and forty-five (45.3%) people were 60e69 years of age, 115 (35.9%) were 70e79 years, and 60 (18.8%) were 80 years. The number of patients with early-stage and advanced-stage cancer were 152 (47.5%) and 168 (52.5%), respectively. One hundred and seventy-nine patients (55.9%) had tumor sizes 45 mm, while 141 (44.1%) had tumors >45 mm. The percentages of patients who had hypertension, diabetes, cardiovascular disease, or cerebrovascular disease were 35.6%, 19.7%, 25%, and 8.1%, respectively. The in-hospital complication rate of patients with diabetes was 22.2%, which is significantly higher than the rate of 9.3% determined for patients without diabetes (p < 0.01). In addition, the in-hospital complication rate was significantly higher in patients with cerebrovascular disease compared with those without such diseases (34.6% vs. 9.9%, p < 0.001). One-year mortality was significantly associated age and tumor stage. One-year mortality was 21.7% among patients 80 years, higher than those aged 60e69 years (7.6%) and 70e79 years (10.4%). Patients with advanced-stage diseases demonstrated a higher 1-year mortality rate compared with those with early-stage diseases (17.9% vs. 3.9%, p < 0.001). Nevertheless, the development of in-hospital complications was not significantly associated with hypertension or cardiovascular disease, and 1-year mortality was not significantly associated with any comorbidity. The results of the risk factor analyses for in-hospital complications and 1-year mortality are shown in Table 2. The risk of developing complications among patients with diabetes or cerebrovascular diseases was significantly higher after controlling for sex, age, tumor stage, tumor size, chemotherapy, and resection type. The risk of developing in-hospital complications among diabetic patients was 3.43 times (95% confidence interval [CI]: 1.13e10.37) that of nondiabetic patients. In patients with cerebrovascular disease, the risk was 4.99 times (95% CI: 1.30e19.07) that of those without cerebrovascular disease. Furthermore, the mortality risk of patients 80 years was 3.49 times (95% CI:
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Table 1 Characteristics of the patients and surgical outcomes. Study In-hospital P (c2 ) population complication rate (n ¼ 320)
(n ¼ 38)
1-year P (log-rank) mortality (n ¼ 36)
n (%)
%
Sex Female Male
%
142 (44.4) 178 (55.6)
14.8 9.6
0.150
10.6 11.8
0.712
Age (y) 60e69 y 70e79 y 80 y
145 (45.3) 115 (35.9) 60 (18.8)
9.7 10.4 20.0
0.096
7.6 10.4 21.7
0.014
Tumor stage Early 152 (47.5) Advanced 168 (52.5)
12.5 11.3
0.742
3.9 17.9
<0.001
Tumor size 45mm >45mm
179 (55.9) 141 (44.1)
10.1 14.2
0.257
9.5 13.5
0.289
Chemotherapy No 99 (30.9) Yes 221 (69.1)
9.1 13.1
0.303
9.1 12.2
0.468
Resection type Other 180 (56.3) APR 140 (43.8)
11.7 12.1
0.896
12.2 10.0
0.529
Hypertension No 206 (64.4) Yes 114 (35.6)
11.2 13.2
0.598
10.2 13.2
0.412
Diabetes No Yes
257 (80.3) 63 (19.7)
9.3 22.2
<0.01
11.3 11.1
0.968
Cardiovascular disease No 240 (75.0) Yes 80 (25.0)
10.0 17.5
0.073
9.6 16.3
0.105
Cerebrovascular disease No 294 (91.9) Yes 26 (8.1)
9.9 34.6
<0.001 10.9 15.4
0.468
APR ¼ abdominoperineal resection.
Table 2 Results of multivariate analysis of the factors that influence surgical outcomes (calculated from 1000 bootstrap replications). In-hospital complication
1-year mortality
OR
95% CI
HR
95% CI
Sex (ref: female) Male
0.68
0.28e1.64
1.47
0.60e3.65
Age (ref: 60e69 y) 70e79 y 80 y
0.87 2.21
0.30e2.55 0.71e6.85
1.33 3.49*
0.50e3.56 1.18e10.30
Tumor stage (ref: early stage) Advanced stage 0.61
0.22e1.66
9.79
0.25e378.35
Tumor size (ref: 45 mm) >45 mm Chemotherapy
1.52 2.55
0.62e3.75 0.80e8.16
1.50 0.32
0.67e3.37 0.09e1.19
Resection type (ref: others) APR Hypertension Diabetes Cardiovascular disease Cerebrovascular disease
0.91 0.51 3.43* 1.21 4.99*
0.37e2.22 0.15e1.78 1.13e10.37 0.36e4.03 1.30e19.07
0.94 1.23 0.99 1.12 1.31
0.39e2.25 0.51e3.12 0.02e48.68 0.47e2.67 0.00e22,470.58
*p < 0.05. APR ¼ abdominoperineal resection.
1.18e10.30) that of patients aged 60e69 after controlling for prognostic factors, demonstrating a statistical level of significance. Nevertheless, the 1-year mortality rates of patients with hypertension, cardiovascular disease, or cerebrovascular disease were all greater than the rates of patients without these diseases, though these results were not statistically significant. Survival curveadjusted prognostic factors according to comorbidity are presented in Fig. 1. No significant comorbidity-associated differences were noted in the 1-year survival curve. Interaction terms were included in the multivariate analyses, which included 1000 bootstrap replications in order to determine the interaction effects of the comorbidities, sex, age, and cancer stage (data not shown). Interactions between comorbidities and sex, comorbidities and age, and comorbidities and tumor stage were not observed; therefore, further subgroup analyses were not performed. 4. Discussion After adjusting for other prognostic factors, the presence of diabetes or cerebrovascular disease significantly affected the risk of surgical complications among older patients undergoing surgical treatment for rectal cancer, whereas the presence of comorbidities did not demonstrate a significant adverse effect on 1-year mortality. Hyperglycemia impairs the immune system, thereby increasing the risk of infection and preventing normal wound healing24. Therefore, most previous studies on the postsurgical complications of diabetic patients treated using colorectal resection for the treatment of cancer are focused on infected surgical wounds. Diabetes mellitus has been shown to play a significant role in predisposing an individual to surgical site infections following colorectal resection25,26. Sehgal et al found that among diabetic patients who undergo colorectal cancer resection, higher than normal glucose levels are associated with a greater risk of developing surgical site infections. They concluded that diabetic patients who require a colectomy should have tightly controlled glucose levels, avoid the placement of drains, and receive prophylactic antibiotics for <24 hours26. Moreover, the study by Cong et al also confirmed that diabetes mellitus is a risk factor for anastomotic leakage following rectal surgery27. Few studies have evaluated the impact of cerebrovascular disease on postsurgical complications following colorectal cancer surgery. The study by Iancu et al reported that patients with cerebrovascular disease are at a greater risk for anastomotic leakage following colorectal cancer surgery28. A greater proportion of Asian patients have cerebral hemorrhages and intracranial vascular diseases than their Western counterparts; cerebrovascular disease has consistently been reported as the second most common cause of death in Taiwan, second only to malignancy29. Thus, the relationship between postsurgical care following treatment for rectal cancer and cerebrovascular treatment (such as antiplatelet or anticoagulant therapy) in older Asian patients warrants further investigations. Some studies have examined the relationship between surgical complications and comorbidities in older patients following resection for the treatment of colorectal cancer. Pedrazzani et al found that those with preexisting cardiovascular diseases demonstrate higher complication rates30. Janssen-Heijnen et al reported that postoperative morbidity is higher among those with reduced pulmonary function, cardiovascular disease, or neurological comorbidities9. In the present study, patients with diabetes or cerebrovascular disease were at increased risk of surgical complications, but those with hypertension or cardiovascular disease did not demonstrate increased risk. This discrepancy could be due to differences in the definitions of these conditions and the duration of the complications. If a complication was present before surgery, it was not considered a surgical complication in the present study;
288
H.-R. Chang et al.
1.00 No
0.98
Cumulative Survival
Cumulative Survival
1.00 Yes
0.96 0.94
No
0.98 0.96 0.94
0.92
0.92
0.90
0.90 0
100
200
300
Yes
400
0
100
Time in Days
200
1.00
400
1.00 No
0.98
Cumulative Survival
No
Cumulative Survival
300
Time in Days
Yes
0.96 0.94 0.92
0.98
Yes
0.96 0.94 0.92
0.90
0.90 0
100
200
300
400
0
Time in Days
100
200
300
400
Time in Days
Fig. 1. Survival curves of patients diagnosed with a comorbidity.
therefore, the incidence of surgical complications in this study was lower than those reported in other studies. The screening criteria for complications might also have led us to different results than other studies. Furthermore, the present study included complications that appeared only during the postsurgical period while the patient was hospitalized; however, previous studies used different definitions for the duration of complications, ranging from 1e3 months postsurgery or they used criteria that were the same as our study. Differences in the study designs that resulted in variations in the duration of the complications that were observed produced large differences in the incidences of postsurgical complications that were reported across different studies. In the present study, the 1-year mortality rates were greater in patients with hypertension, cerebrovascular disease, and cerebrovascular disease than patients without these diseases, but these differences did not achieve a statistical level of significance. Because the lower number of deaths due to the shorter postsurgical duration may have resulted in poor statistical reliability, Zaslavsky et al suggested using an extended duration of assessment in order to overcome this problem31. Previous studies on older patients with cancer have classified postsurgical survival as long-term or shortterm. Janssen-Heijnen et al used overall survival as a mortality measure, revealing that mortality risk is greater in older rectal surgery patients with cardiovascular disease, chronic obstructive pulmonary disease, diabetes, and hypertension9. Alves et al used in-hospital death as an endpoint, and only neurological comorbidities were classified as risk factors12. Nonetheless, these studies suggest that chronic disease could influence both short- and longterm survival. On the contrary, the impact of chronic disease on the mortality rate did not achieve a level of statistical significance in the present study. This may be due to the smaller sample size or the fact that patients in the study hospital were treated with an appropriate level of caution. Healthcare professionals might have been aware that the mortality of older patients with chronic disease may increase because of their poor health status, and thus they may have exercised more care when treating older patients.
In our study, age did not significantly affect the rate of inhospital complications among older rectal cancer surgical patients, but age did significantly influence the 1-year mortality: the 1-year mortality risks of patients aged 70e79 years and >80 years were 1.33 and 3.48 times the risk for those aged 60e69 years, respectively. The International Society for Geriatric Oncology defines old age as >70 years. Using this definition, Kesisoglou et al found that patients >70 years of age demonstrate higher morbidity and mortality rates. This observation is probably the result of these patients having a poor overall health status3. Most previous studies on postsurgical mortality in elderly colorectal cancer patients define elderly as >80 years. It has been established that “age” is a risk factor of early postsurgical mortality, and that short-term postsurgical mortality is significantly greater in older patients32,33. The life expectancy of a patient who does not undergo surgery cannot be predicted, but pain, poor general health, and complications caused by tumor obstruction are all factors that diminish the patient’s quality of life if the tumor is not removed. Therefore, by minimizing the operative risk and ensuring careful intraoperative and postoperative monitoring, surgical treatment of rectal cancer can be considered in geriatric patients34. This study has two limitations. First, because data were collected only from the study hospital, this study lacked information on the development of comorbidities. The progression of a comorbidity could have induced poor health status and affected morbidity or mortality; therefore, the effects of comorbidities on surgical outcomes cannot be exactly estimated. Second, treatment intensity and disease severity would similarly have been underestimated because of data limitations. 4. Conclusions Healthcare professionals are facing an inevitable increase in the number of older cancer patients. Whether or not to perform surgery on an older patient should be carefully considered, especially when surgery remains as the most effective therapy. This
Rectal Cancer Surgery Outcomes in Older Patients
study indicates that, although comorbidities can affect in-hospital complications, 1-year postsurgery mortality was unaffected. Although we strictly controlled for cancer stage, presurgical comorbidities, and other prognostic factors, selection bias still exists, as in previous studies, because our samples were derived from only one hospital. Therefore, we recommend that future research use population-based data in order to establish effective therapeutic strategies for the treatment of specific comorbidities. Moreover, although we found that comorbidities affect in-hospital complications, our study population consisted of only older patients. Thus, we recommend comparisons between older and younger groups in order to determine whether this effect occurs only in older patients. Furthermore, in order to understand survival differences, we propose comparing the clinical outcomes of older patients who have undergone surgery against the outcomes of older patients who have not.
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