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Major colorectal cancer resection should not be denied to the elderly
EJSO 2002; 28: 661±666 doi:10.1053/ejso 2002.1265, available online at http://www.idealibrary.com on
1
Major colorectal cancer resection should not be denied to the elderly J. J. Smith, J. Lee, C. Burke, K. B. Contractor and P. M. Dawson Colorectal Surgical Unit, West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex TW7 6AF, UK
Aims: Adjuvant therapy after surgery for colorectal cancer is often denied to the elderly for various reasons. This study was to determine morbidity and mortality risk after surgery in the elderly and whether this is affected by adjuvant therapy. Methods: Data were collected prospectively and entered on a database for all patients undergoing resection of colorectal cancer between January 1994 and July 2000. A total of 304 patients were included, 65 aged 80 years and over. Results: There were 84 deaths, 21 (30%) in the over 80s, and 63 (26%) in the under 80s (P 0.51). The `in-hospital' mortality was 10.1% in the over 80s and 3.8% in the under 80s (P 0.056). In the over 80s the colon was more affected than the rectum (P 0.002). The over 80s were less likely to be offered adjuvant therapy, 7.2% vs 42.1% (P , 0.001). The 5 year survival (all-cause mortality) in the over 80s was 58.5% and 47.6% in the under 80s (P 0.25). Cox's regression analysis of all patients identified the following factors to be independently related to overall survival: age > 80 years, post-operative leak, increasing Dukes stage and distant recurrence of disease. Conclusion: This study has demonstrated that surgery should not be denied to elderly patients with colorectal cancer as despite a higher post-operative morbidity and mortality rate and with the absence of adjuvant therapy, favourable long-term outcome can be achieved by resectional surgery alone. # 2002 Published by Elsevier Science Ltd Key words: octogenarians; colorectal cancer; elderly; adjuvant therapy; post-operative complications; survival.
INTRODUCTION Data from the Office of National Statistics (ONS) place colorectal cancer as the third most common cause of cancer in men and women1 making up about 13% of all cancers in both men and women.2 Further data from the ONS available on their website (http:// www.ons.gov.uk) has shown how the population is getting older and living longer. A man aged 80 years today can expect to live until the age of 87 years and a woman to the age of 89 years. It has been predicted that the overall UK population will remain static over the next 15 years, although the number of people over 80 years of age will increase.3 As the incidence of colorectal cancer increases with age, it follows that one can expect Data from this manuscript have been presented at the European Conference on Cancer Strategies and Outcomes, Edinburgh, March 2001, and at the Association of Surgeons of Great Britain and Ireland, Birmingham, 2001. Correspondence to: Mr Jason Smith, Colorectal Surgical Unit, West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, TW7 6AF, UK. Tel: 44 20 8 565 5972; Fax: 44 20 8 565 5024; E-mail: [email protected] 1748±7983/02/$35.00
to see an increase in disease incidence over the next few years.4,5 There has been recent interest in the media on `ageism' where there is a perception that the elderly are not being given all the opportunities they should for treatment.6,7 This is especially true when the treatment involves major surgery with high morbidity and mortality. Eighty year olds can have another 10 years of life to look forward to, which would be cut short if they were not offered cancer resection, as the cancer will inevitably progress. Furthermore, delayed diagnosis of cancer in the elderly also makes the prognosis worse.8 The elderly are less likely to be screened for cancer prevention.9 Progression of colorectal cancer is slow in this group.10 Previous studies have suggested that elderly patients do not fare well after surgery for colorectal cancer, with high rates of emergency presentations, inoperability and peri-operative mortality.11±17 The slight improvement in overall survival over the last 50 years has been attributed to a reduction in peri-operative mortality.5 Survival in rectal cancers has improved by 2% in men and 4% in women despite a gradual increase in the number of new cases. According to the latest National Confident Enquiry in #
2002 Published by Elsevier Science Ltd
662 Post-Operative Deaths report of 2000, 70% of perioperative deaths occurred in patients aged between 70 and 100 years. This was against 64% of patients in the same age group in the 1990 results.18 It has also been shown that elderly patients are less likely to receive adjuvant therapy, owing to refusal by the patient18 or owing to reduction in the chemotherapy doses by the physician for fear of toxicity,19 often regardless of their general health,20±22 under the impression that toxicity outweighs the benefits.19 Although adjuvant therapy for colorectal carcinoma has been shown to improve overall survival and to prolong disease-free intervals,23 many elderly patients are not being offered this form of treatment18 despite the response in this group having been shown to be comparable with younger patients.24 The increasing media interest in `ageism' in health care prompted this analysis of outcome following surgery for colorectal carcinoma in the elderly. The aim of this study is to assess survival following surgery and whether outcome is affected by adjuvant therapy in octogenarians.
METHODS AND PATIENT SERIES A 55 variable database was constructed and analysed using SPSS (Statistical Package for Social Sciences, 10th edition, Chicago, IL) in which data from all patients undergoing resection for colorectal cancer under the care of one surgeon were prospectively collected between January 1994 and March 2001. Only patients undergoing resectional surgery were entered into the database. The database did not include patients that had non-operative treatment as the intent of the study was to determine the outcome of surgery with or without chemotherapy. The patients were not pre-selected in any way other than fitness to undergo a general anaesthetic. The intention of surgery in all cases was curative resection if at all possible; no difference in surgical approach was made between the under and over 80s. All patients were followed up at regular intervals in the outpatient department and the data entry endpoint for the patient was either last visit to outpatients or death. All patients were seen by a consultant medical oncologist for consideration of adjuvant therapy post resection regardless of Duke's or tumour, node and metastasis (TNM) staging. None of the currently running adjuvant therapy trials accepts patients over the age of 75 years. The decision to give adjuvant therapy was made by the consultant oncologist based on `biological' age and co-morbid risk factors; in particular, cardiovascular risk factors at any age precluded adjuvant therapy as the morbidity/mortality risk is too high. Major complications of surgery were defined as myocardial infarction, microbiologically proven chest infection, pulmonary embolism, deep venous
J. J. SMITH ET AL. thrombosis, systemic sepsis or anastomotic leak. Inhospital mortality was defined as death occurring during the first hospital episode during which the original resection had been performed. Cause of death either in hospital or post-discharge was identified and subclassified into cancer or non-cancer related as evident from post-mortem examination or death certificates. Patients over the age of 80 years were compared with those under 80 years of age. Statistical analysis was performed using the SPSS package. Spearman's and Pearson's correlation coefficients were used for non-parametric and parametric data respectively. Kaplan±Meier analysis was used to calculate survival characteristics with 2 and Fisher's exact tests for univariate comparison as appropriate. Backward stepwise linear regression was used to determine predictors of survival in the Cox model.
RESULTS The total number of patients in the study was 304 of which 65 (21.4%) were over 80 years old. The follow-up period for the over 80s was 0.2±74 months (median 12 months) and 0.2±80 months (median 21 months) for the under 80s. Demographic data relating to age and sex distribution and tumour characteristics are given in Table 1. The only significant difference between the two groups from these data is that it appears that the over 80 group had tumours that were predominantly colonic as opposed to rectal compared with the under 80s (P 0.002). Further analysis of this shows that almost half (49.3%) of the over 80s had tumours in a position that required a right hemicolectomy compared with only a quarter (24.3%) of the under 80s. As a consequence the under 80s had a higher anterior resection rate than the over 80s (37.4% vs 15.4%). The abdominoperineal resection rate was 5.8% in the over 80s and 8.9% in the under 80s, giving an overall rate of 8.2% for the unit. Of the 304 resections performed 35 were done as emergencies (12 in the over 80s and 23 in the under 80s). A Kaplan±Meier survival analysis on these patients demonstrates that (although the numbers are small) the survival rates are low as expected, 48.1% in the over 80s and 26.6% in the under 80s. On log-rank analysis this difference was not significant (P 0.1125). The major complication rate was higher in the over 80s (P , 0.001 ± Table 2). In-hospital mortality in the over 80s was also higher at 10.1% mainly as a result of the cardiorespiratory co-morbidity although the difference in mortality was not significant (P 0.056). It appears that the over 80s presented with earlier Duke's stage tumours than the under 80s (52.2% Duke's A or B compared with 42.6% in the under 80s ± Table 1). This was not significant on analysis and the TNM classification was almost identical.
TREATMENT OF COLORECTAL CANCER IN THE ELDERLY
663
Table 1 Demographics, pathology and curative procedure Over 80 years (n 69) Median age (range) Sex (M:F) Tumour site ± colon:rectum Mobile tumour Dukes stage
TNM classification
Under 80 years (n 235)
83 (80±93) 33:36 52:17 53.6% A 13.4% B 38.8% C 40.3% (D 7.5%)
68 (32±79) 129:106 132:103 63.8% A 9.1% B 33.5% C 43.5% (D 13.9%)
T1 T2 T3 T4
T1 T2 T3 T4
4.3% 23.2% 49.3% 23.2%
6.0% 20.5% 47.4% 26.1%
P NA 0.272 0.002 0.159 0.357
0.886
Differentiation
Well 5.8% Moderate 68.7% Poor 25.4%
Well 8.5% Moderate 75.7% Poor 15.7%
0.176
Curative procedure*
78.3%
72.3%
0.558
Table 2 Complications Over 80 years (n 69) In-hospital mortality Anastomotic leak rate Major complications Myocardial infarction Respiratory infection Wound infection rate
7 (10.1%) 5 (7.2%) 32 (46.4%) 5 (7.2%) 25 (36.2%) 5 (7.2%)
Longer-term differences in mortality also occur in both groups. In the over 80s Kaplan±Meier analysis (Fig. 1) has shown that 21 out of 69 (total) cases were dead at the end of follow-up (5 year survival 59%) and, in the under 80s, 67 of 235 (total) cases were dead at the end of follow-up (5 year survival 60%). The initial death rate is higher in the over 80s, but, at 5 years, survival is comparable and there is no significant difference between the two groups (P 0.19, log-rank test). For cancer-specific deaths (Fig. 2) there were 11 cases in the over 80s and 44 cases in the under 80s dying of their cancers. In the over 80s all the patients who died of their cancer were dead by 22 months and in the under 80s all the patients were dead by 65 months. This difference was significant with P 0.0312. When one analyses survival in the two groups comparing rectal with colonic cancers, differences in 5 year survival are more obvious. With respect to colonic cancers 15 of 50 patients had died by the end of followup in the over 80s (5 year survival 63%), and 47 of 129 in the under 80s (5 year survival 50%). This difference was not significant on log-rank analysis (P 0.78). With respect to rectal cancers the numbers are much smaller in the over 80s group as mentioned above. By the end of
Under 80 years (n 235) 9 17 53 6 21 12
(3.8%) (7.2%) (22.6%) (2.5%) (8.9%) (5.1%)
P 0.056 1.0 ,0.001 0.157 ,0.001 0.397
Figure 1 Survival curve (Kaplan±Meier) ± all-cause mortality.
follow-up six of 17 patients had died (5 year survival 53%) in the over 80s group compared with 20 of 106 patients in the under 80s group (5 year survival 77%). This difference again was not significant on log-rank analysis (P 0.1).
664
J. J. SMITH ET AL. Table 4 Linear regression model for the event `survival' Factor Age . 80 years Anastomotic leak Dukes stage Distant recurrence
Figure 2 Survival curve (Kaplan±Meier) ± cancer-specific mortality.
Table 3 Adjuvant therapy and survival data
Adjuvant therapy given Pre-operative DXT Post-operative DXT Post-operative chemotherapy 5 year survival rate
Over 80 years (n 69)
Under 80 years (n 235)
P
5 (7.2%) 0 2 (2.9%) 3 (4.3%)
98 (41.7%) 18 (7.7%) 61 (26%) 77 (32.8%)
,0.001 0.016 ,0.001 ,0.001
67.7%
71.6%
0.247
DXT, radiotherapy.
Octogenarians were less likely to receive adjuvant therapy compared with younger patients by a factor of 6 (Table 3, P , 0.001). The number of patients in the over 80s group receiving adjuvant therapy was very small (n 5), making further analysis unreliable. Three of these five patients had adjuvant chemotherapy and had died by the end of the study compared with 28 of 98 in the under 80s group. In order to determine the factors that significantly affect survival in patients undergoing major colorectal resection a Cox regression analysis of the entire database was performed giving the results shown in Table 4. The following factors were shown to be indicators of poor prognosis: age over 80, anastomotic leak, increasing Dukes stage and distant recurrence.
DISCUSSION It has been said that `treatment decisions in elderly patients should not be influenced by the chronological age of the patient'.25 One could argue that provided that
P
95% confidence interval
,0.001 ,0.001 ,0.001 ,0.001
0.093±0.512 0.035±0.512 1.563±4.304 2.274±14.039
it is safe to anaesthetize the patient age should be no barrier for major resection based on the results presented above. A large proportion of elderly patients survive for 5 years or more following colorectal cancer resection.26 A large systematic review of 35 000 elderly patients having colorectal resectional surgery has shown that elderly patients have an increased frequency of co-morbid conditions, were more likely to present with later stage disease, were more likely to undergo emergency surgery and were less likely to have curative surgery than their younger counterparts. The results of the somewhat smaller single-centre study described in this manuscript concur with the first point but none of the other points. It is well known that there is biological and regional variation in the epidemiology of colorectal malignancy, which may be evident here.27±30 Elderly patients were significantly more likely to have their tumours sited in the colon than the rectum (P 0.002). This is comparable with other reported series, which state that the majority of tumours in this group (i.e. >80 years) are sited in the right colon (40%).31,32 In the study described above there was no significant difference in the overall 5 year survival between the two groups. In-hospital mortality and crude 5 year survival are better (only just) for patients under 80 but not significantly so. It is unclear why there is a sudden accelerated death rate in the over 80s within the first 6±8 months after surgery; further analysis of the data has failed to suggest a reason. It is likely to be due to the higher cardiorespiratory risk factors in this group, but the numbers are too small to make this a meaningful assumption. Survival after colonic surgery appears to be better in the over 80s (63% compared with 50%) and is probably as a result of a predominance of right-sided lesions. However, as the over 80s also have higher cardiorespiratory risk factors it is not clear from these data why 5 year survival is better, although not significantly so. Survival after rectal cancer surgery appears to be worse in the over 80s (53% compared with 77%), again not significantly so. However, the number of over 80s in this group is small (17), making it difficult to draw meaningful conclusions. One quite subjective area in Table 1 is that of `curative procedure'. All patients both curative and palliative were included in this study. The operating surgeon defined
TREATMENT OF COLORECTAL CANCER IN THE ELDERLY `curative' at the time of surgery based on the operative findings and whether it was felt that all macroscopic evidence of tumour was removed. Later histological analysis of the resected specimen showed good agreement between the surgeons' decisions about curative procedure and the Dukes staging of the tumour (rs ÿ 0.54, P , 0.001). Of all of the cases thought not to be curative by the surgeon (79 cases) only one of them proved to be a Dukes A tumour and only two were classified as T1 on the TNM system. The use of adjuvant therapy in elderly patients is often said to be restricted because of general poor health or dose-related toxicity resulting in suboptimal treatment.18±22,33 A more recent study, however, has cast doubt on this assumption and has shown that elderly patients with good pre-treatment performance status tolerate adjuvant and palliative chemotherapy as well as younger patients.24 In a previous study, using a standard 5-fluorouracil and levamisole regimen, patients over the age of 75 years had increased hospitalization rates, early reduction of dosages and a higher drop-out rate than patients under 70 years.34 The study by Newcombe and Carbone suggests that elderly patients were less likely to receive or accept adjuvant therapy and were less likely to be referred for a specialist opinion.35 It would be better to adjust the doses in this age group according to biological rather than chronological age.10 Despite histological evidence that 47.8% of the over 80s had Dukes stage C or D, only five of the elderly patients received adjuvant therapy compared with 98 of the younger patients; all patients, however, regardless of stage were referred for an oncological opinion. The absence of adjuvant therapy in the elderly group did not appear to affect overall long-term survival, although the numbers are small. Resectional surgery in elderly patients with colorectal cancer is justified in other studies because it has been shown that old age per se is not an independent risk factor for surgery, although it is an independent risk factor for short-term survival.14,36,37 The patient population described in the study was similar to previous reports. The data analysis from this cohort of patients is consistent with previously reported studies.10,12,15,16,31,37 From the Cox regression analysis it was seen that age over 80 years was a risk factor for survival. However, the 5 year survival rates for the two groups are similar. In hospital mortality is higher in the over 80s, but if you can get the patient through the operative procedure and immediate post-operative phase then the long-term outcome is comparable with that for their younger counterparts.
CONCLUSION Although the major complication was significantly higher in the elderly, the 5 year survival was comparable
665
between the two groups. This study has demonstrated that surgery should not be denied to elderly patients with colorectal cancer as despite a higher post-operative morbidity and mortality rate and with the absence of adjuvant therapy, favourable long-term outcome can be achieved by resectional surgery alone.
REFERENCES 1. Office of National Statistics. Cancer Survival 1991±1998. Office of National Statistics, 2000; 120: 31.3.2000. 2. Office of National Statistics. Cancer Statistics ± England and Wales. London: HMSO, 1994. 3. OPCS. Mortality Statistics: England and Wales. Series DH2, no. 10. London: HMSO, 1984. 4. Kashtan H, Werbin N, Wasserman I. Colorectal cancer in patients over 70 years old. Isr J Med Sci 1992; 28: 861±4. 5. Ohman U. Decreased operative mortality from colorectal cancer but unchanged treatment results during 30±50 years. Larkartidningren 1982; 79: 1001±4. 6. BBC News. NHS ageism row sparks action. BBC News Online 13 April 2000. 7. BBC News. Inquiry sought into NHS ageism. BBC News Online 6 August 2000. 8. Young CJ, Sweeney JL, Hunter A. Implications of delayed diagnosis in colorectal cancer. Aust NZ J Surg 2000; 70: 635±8. 9. Stults BM. Preventative cancer for the elderly. Front Radiat Ther Oncol 1986; 20: 182±91. 10. Tomoda H, Tsujitani, Furusawa M. Surgery for colorectal cancer in elderly patients ± a comparison with younger adult patients. Jpn J Surg 1988; 18: 397±402. 11. Brown SC, Abraham JS, Walsh S, Sykes PA. Risk factors and operative mortality in surgery for colorectal cancer. Ann R Coll Surg Engl 1991; 73: 269±72. 12. Irvin TT. Prognosis of colorectal cancer in the elderly. Br J Surg 1988; 75: 419±21. 13. Clarke DN, Jones PF, Needham CD. Outcome in colorectal cancer: seven year study of a population. Br Med J 2001; 280: 431±5. 14. Kingston RD, Jeacock J, Walsh S, Keeling F. The outcome of colorectal cancer in the eldery: a twelve year review from the Trafford Database. Eur J Surg Oncol 1995; 21: 514±16. 15. Hernanz de la Fuente F, Revuelta Alvarez S, Del Castillo Diego J. Colorectal cancer in elderly patients: postoperative mortality and survival. Rev Esp Enferm Dig 1984; 84: 17±21. 16. Lindmark G, Pahlman L, Enbald P, Glimelius B. Surgery for colorectal cancer in elderly patients. Acta Chir Scand 1998; 154: 659±63. 17. Waldron RP, Donavan IA, Drumm J, Mottram SN, Tedman S. Emergency presentation and mortality from colorectal cancer in the elderly. Br J Surg 1986; 73: 214±16. 18. Mahomey T, Kuo YH, Topilow A, Davis JM. Stage III colon cancers: why adjuvant chemotherapy is not offered to elderly patients. Arch Surg 2000; 135: 182±5. 19. Freyer G, Maire P, Ardiet C, Tranchard B, Droz JP. Cytotoxic chemotherapy in elderly patients: present and future. Bull Cancer 1995; 82: 531±40. 20. Mor V, Masterson Allen S, Goldberg RJ. Relationship between age at diagnosis and treatment of cancer patients. J Am Geriatr Soc 1985; 33: 585±9. 21. Samet J, Hunt WC, Key C. Choice of cancer therapy varies with age of patient. J Am Med Assoc 1986; 255: 3385±90. 22. Mantel N, Haenszel W. Statistical aspect of data from retrospective studies. J Natl Cancer Inst 1959; 22: 719±48. 23. Vershraegren CF, Padzur. Medical management of colorectal carcinomas. Tumori 1994; 80: 1±11. 24. Popescu RA, Norman A, Ross PJ, Parikh B, Cunningham D. Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 1999; 17: 2412±18. 25. Staudacher C, Chiappa A, Zbar AP, Bertani E, Biella F. Curative resection for colorectal cancer in the elderly. Prognostic factors and five-year follow-up. Ann Ital Chir 2000; 71: 491±6.
666 26. Surgery for colorectal cancer in elderly patients: a systematic review. Colorectal Cancer Collaborative Group. Lancet 2000; 356: 968±74. 27. Terry P, Giovannucci E, Michels KB, et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst 2001; 93: 525±33. 28. Bell RA, Shelton BJ, Paskett ED. Colorectal cancer screening in North Carolina: associations with diabetes mellitus and demographic and health characteristics. Prevent Med 2001; 32: 163±7. 29. Gonzalez EC, Roetzheim RG, Ferrante JM, Campbell R. Predictors of proximal vs. distal colorectal cancers. Dis Colon Rectum 2001; 44: 251±8. 30. Hemminki K, Lonnstedt I, Vaittinen P, Lichtenstein P. Estimation of genetic and environmental components in colorectal and lung cancer and melanoma. Genet Epidemiol 2001; 20: 107±16. 31. Kemppainen M, Raiha I, Rajala T, Souranda L. Characteristics of colorectal cancer in elderly patients. Gerontology 1993; 39: 222±7.
J. J. SMITH ET AL. 32. Arai T, Takubo K, Sawabe M, Esaki Y. Pathologic characteristics of colorectal cancer in the elderly: a retrospective study of 947 surgical cases. J Clin Gastroenterol 2000; 31: 67±72. 33. Conti JA, Christman K. Cancer chemotherapy in the elderly. J Clin Gastroenterol 1995; 21: 65±71. 34. Brower M, Asbury R, Krammer Z. Adjuvant therapy for colorectal cancer in the elderly: population based experience. ASCO Proc 1993; 12: 195. 35. Newcomb PA, Carbone PP. Cancer treatment and age: patient perspectives. J Natl Cancer Inst 1993; 85: 1580±4. 36. Hessman O, Bergkvist L. Colorectal cancer in patients over 75 years of age determines outcome. Eur J Surg Oncol 1997; 23: 13±19. 37. Agarwal N, Leighton L, Mandile MA, Cayten CG. Outcomes of colorectal cancer in patients age 80 years and older. Am J Gastroenterol 1990; 85: 1096±101 Accepted for publication 23 January 2002
1
Major colorectal cancer resection should not be denied to the elderly J. J. Smith, J. Lee, C. Burke, K. B. Contractor and P. M. Dawson Colorectal Surgical Unit, West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex TW7 6AF, UK
Aims: Adjuvant therapy after surgery for colorectal cancer is often denied to the elderly for various reasons. This study was to determine morbidity and mortality risk after surgery in the elderly and whether this is affected by adjuvant therapy. Methods: Data were collected prospectively and entered on a database for all patients undergoing resection of colorectal cancer between January 1994 and July 2000. A total of 304 patients were included, 65 aged 80 years and over. Results: There were 84 deaths, 21 (30%) in the over 80s, and 63 (26%) in the under 80s (P 0.51). The `in-hospital' mortality was 10.1% in the over 80s and 3.8% in the under 80s (P 0.056). In the over 80s the colon was more affected than the rectum (P 0.002). The over 80s were less likely to be offered adjuvant therapy, 7.2% vs 42.1% (P , 0.001). The 5 year survival (all-cause mortality) in the over 80s was 58.5% and 47.6% in the under 80s (P 0.25). Cox's regression analysis of all patients identified the following factors to be independently related to overall survival: age > 80 years, post-operative leak, increasing Dukes stage and distant recurrence of disease. Conclusion: This study has demonstrated that surgery should not be denied to elderly patients with colorectal cancer as despite a higher post-operative morbidity and mortality rate and with the absence of adjuvant therapy, favourable long-term outcome can be achieved by resectional surgery alone. # 2002 Published by Elsevier Science Ltd Key words: octogenarians; colorectal cancer; elderly; adjuvant therapy; post-operative complications; survival.
INTRODUCTION Data from the Office of National Statistics (ONS) place colorectal cancer as the third most common cause of cancer in men and women1 making up about 13% of all cancers in both men and women.2 Further data from the ONS available on their website (http:// www.ons.gov.uk) has shown how the population is getting older and living longer. A man aged 80 years today can expect to live until the age of 87 years and a woman to the age of 89 years. It has been predicted that the overall UK population will remain static over the next 15 years, although the number of people over 80 years of age will increase.3 As the incidence of colorectal cancer increases with age, it follows that one can expect Data from this manuscript have been presented at the European Conference on Cancer Strategies and Outcomes, Edinburgh, March 2001, and at the Association of Surgeons of Great Britain and Ireland, Birmingham, 2001. Correspondence to: Mr Jason Smith, Colorectal Surgical Unit, West Middlesex University Hospital, Twickenham Road, Isleworth, Middlesex, TW7 6AF, UK. Tel: 44 20 8 565 5972; Fax: 44 20 8 565 5024; E-mail: [email protected] 1748±7983/02/$35.00
to see an increase in disease incidence over the next few years.4,5 There has been recent interest in the media on `ageism' where there is a perception that the elderly are not being given all the opportunities they should for treatment.6,7 This is especially true when the treatment involves major surgery with high morbidity and mortality. Eighty year olds can have another 10 years of life to look forward to, which would be cut short if they were not offered cancer resection, as the cancer will inevitably progress. Furthermore, delayed diagnosis of cancer in the elderly also makes the prognosis worse.8 The elderly are less likely to be screened for cancer prevention.9 Progression of colorectal cancer is slow in this group.10 Previous studies have suggested that elderly patients do not fare well after surgery for colorectal cancer, with high rates of emergency presentations, inoperability and peri-operative mortality.11±17 The slight improvement in overall survival over the last 50 years has been attributed to a reduction in peri-operative mortality.5 Survival in rectal cancers has improved by 2% in men and 4% in women despite a gradual increase in the number of new cases. According to the latest National Confident Enquiry in #
2002 Published by Elsevier Science Ltd
662 Post-Operative Deaths report of 2000, 70% of perioperative deaths occurred in patients aged between 70 and 100 years. This was against 64% of patients in the same age group in the 1990 results.18 It has also been shown that elderly patients are less likely to receive adjuvant therapy, owing to refusal by the patient18 or owing to reduction in the chemotherapy doses by the physician for fear of toxicity,19 often regardless of their general health,20±22 under the impression that toxicity outweighs the benefits.19 Although adjuvant therapy for colorectal carcinoma has been shown to improve overall survival and to prolong disease-free intervals,23 many elderly patients are not being offered this form of treatment18 despite the response in this group having been shown to be comparable with younger patients.24 The increasing media interest in `ageism' in health care prompted this analysis of outcome following surgery for colorectal carcinoma in the elderly. The aim of this study is to assess survival following surgery and whether outcome is affected by adjuvant therapy in octogenarians.
METHODS AND PATIENT SERIES A 55 variable database was constructed and analysed using SPSS (Statistical Package for Social Sciences, 10th edition, Chicago, IL) in which data from all patients undergoing resection for colorectal cancer under the care of one surgeon were prospectively collected between January 1994 and March 2001. Only patients undergoing resectional surgery were entered into the database. The database did not include patients that had non-operative treatment as the intent of the study was to determine the outcome of surgery with or without chemotherapy. The patients were not pre-selected in any way other than fitness to undergo a general anaesthetic. The intention of surgery in all cases was curative resection if at all possible; no difference in surgical approach was made between the under and over 80s. All patients were followed up at regular intervals in the outpatient department and the data entry endpoint for the patient was either last visit to outpatients or death. All patients were seen by a consultant medical oncologist for consideration of adjuvant therapy post resection regardless of Duke's or tumour, node and metastasis (TNM) staging. None of the currently running adjuvant therapy trials accepts patients over the age of 75 years. The decision to give adjuvant therapy was made by the consultant oncologist based on `biological' age and co-morbid risk factors; in particular, cardiovascular risk factors at any age precluded adjuvant therapy as the morbidity/mortality risk is too high. Major complications of surgery were defined as myocardial infarction, microbiologically proven chest infection, pulmonary embolism, deep venous
J. J. SMITH ET AL. thrombosis, systemic sepsis or anastomotic leak. Inhospital mortality was defined as death occurring during the first hospital episode during which the original resection had been performed. Cause of death either in hospital or post-discharge was identified and subclassified into cancer or non-cancer related as evident from post-mortem examination or death certificates. Patients over the age of 80 years were compared with those under 80 years of age. Statistical analysis was performed using the SPSS package. Spearman's and Pearson's correlation coefficients were used for non-parametric and parametric data respectively. Kaplan±Meier analysis was used to calculate survival characteristics with 2 and Fisher's exact tests for univariate comparison as appropriate. Backward stepwise linear regression was used to determine predictors of survival in the Cox model.
RESULTS The total number of patients in the study was 304 of which 65 (21.4%) were over 80 years old. The follow-up period for the over 80s was 0.2±74 months (median 12 months) and 0.2±80 months (median 21 months) for the under 80s. Demographic data relating to age and sex distribution and tumour characteristics are given in Table 1. The only significant difference between the two groups from these data is that it appears that the over 80 group had tumours that were predominantly colonic as opposed to rectal compared with the under 80s (P 0.002). Further analysis of this shows that almost half (49.3%) of the over 80s had tumours in a position that required a right hemicolectomy compared with only a quarter (24.3%) of the under 80s. As a consequence the under 80s had a higher anterior resection rate than the over 80s (37.4% vs 15.4%). The abdominoperineal resection rate was 5.8% in the over 80s and 8.9% in the under 80s, giving an overall rate of 8.2% for the unit. Of the 304 resections performed 35 were done as emergencies (12 in the over 80s and 23 in the under 80s). A Kaplan±Meier survival analysis on these patients demonstrates that (although the numbers are small) the survival rates are low as expected, 48.1% in the over 80s and 26.6% in the under 80s. On log-rank analysis this difference was not significant (P 0.1125). The major complication rate was higher in the over 80s (P , 0.001 ± Table 2). In-hospital mortality in the over 80s was also higher at 10.1% mainly as a result of the cardiorespiratory co-morbidity although the difference in mortality was not significant (P 0.056). It appears that the over 80s presented with earlier Duke's stage tumours than the under 80s (52.2% Duke's A or B compared with 42.6% in the under 80s ± Table 1). This was not significant on analysis and the TNM classification was almost identical.
TREATMENT OF COLORECTAL CANCER IN THE ELDERLY
663
Table 1 Demographics, pathology and curative procedure Over 80 years (n 69) Median age (range) Sex (M:F) Tumour site ± colon:rectum Mobile tumour Dukes stage
TNM classification
Under 80 years (n 235)
83 (80±93) 33:36 52:17 53.6% A 13.4% B 38.8% C 40.3% (D 7.5%)
68 (32±79) 129:106 132:103 63.8% A 9.1% B 33.5% C 43.5% (D 13.9%)
T1 T2 T3 T4
T1 T2 T3 T4
4.3% 23.2% 49.3% 23.2%
6.0% 20.5% 47.4% 26.1%
P NA 0.272 0.002 0.159 0.357
0.886
Differentiation
Well 5.8% Moderate 68.7% Poor 25.4%
Well 8.5% Moderate 75.7% Poor 15.7%
0.176
Curative procedure*
78.3%
72.3%
0.558
Table 2 Complications Over 80 years (n 69) In-hospital mortality Anastomotic leak rate Major complications Myocardial infarction Respiratory infection Wound infection rate
7 (10.1%) 5 (7.2%) 32 (46.4%) 5 (7.2%) 25 (36.2%) 5 (7.2%)
Longer-term differences in mortality also occur in both groups. In the over 80s Kaplan±Meier analysis (Fig. 1) has shown that 21 out of 69 (total) cases were dead at the end of follow-up (5 year survival 59%) and, in the under 80s, 67 of 235 (total) cases were dead at the end of follow-up (5 year survival 60%). The initial death rate is higher in the over 80s, but, at 5 years, survival is comparable and there is no significant difference between the two groups (P 0.19, log-rank test). For cancer-specific deaths (Fig. 2) there were 11 cases in the over 80s and 44 cases in the under 80s dying of their cancers. In the over 80s all the patients who died of their cancer were dead by 22 months and in the under 80s all the patients were dead by 65 months. This difference was significant with P 0.0312. When one analyses survival in the two groups comparing rectal with colonic cancers, differences in 5 year survival are more obvious. With respect to colonic cancers 15 of 50 patients had died by the end of followup in the over 80s (5 year survival 63%), and 47 of 129 in the under 80s (5 year survival 50%). This difference was not significant on log-rank analysis (P 0.78). With respect to rectal cancers the numbers are much smaller in the over 80s group as mentioned above. By the end of
Under 80 years (n 235) 9 17 53 6 21 12
(3.8%) (7.2%) (22.6%) (2.5%) (8.9%) (5.1%)
P 0.056 1.0 ,0.001 0.157 ,0.001 0.397
Figure 1 Survival curve (Kaplan±Meier) ± all-cause mortality.
follow-up six of 17 patients had died (5 year survival 53%) in the over 80s group compared with 20 of 106 patients in the under 80s group (5 year survival 77%). This difference again was not significant on log-rank analysis (P 0.1).
664
J. J. SMITH ET AL. Table 4 Linear regression model for the event `survival' Factor Age . 80 years Anastomotic leak Dukes stage Distant recurrence
Figure 2 Survival curve (Kaplan±Meier) ± cancer-specific mortality.
Table 3 Adjuvant therapy and survival data
Adjuvant therapy given Pre-operative DXT Post-operative DXT Post-operative chemotherapy 5 year survival rate
Over 80 years (n 69)
Under 80 years (n 235)
P
5 (7.2%) 0 2 (2.9%) 3 (4.3%)
98 (41.7%) 18 (7.7%) 61 (26%) 77 (32.8%)
,0.001 0.016 ,0.001 ,0.001
67.7%
71.6%
0.247
DXT, radiotherapy.
Octogenarians were less likely to receive adjuvant therapy compared with younger patients by a factor of 6 (Table 3, P , 0.001). The number of patients in the over 80s group receiving adjuvant therapy was very small (n 5), making further analysis unreliable. Three of these five patients had adjuvant chemotherapy and had died by the end of the study compared with 28 of 98 in the under 80s group. In order to determine the factors that significantly affect survival in patients undergoing major colorectal resection a Cox regression analysis of the entire database was performed giving the results shown in Table 4. The following factors were shown to be indicators of poor prognosis: age over 80, anastomotic leak, increasing Dukes stage and distant recurrence.
DISCUSSION It has been said that `treatment decisions in elderly patients should not be influenced by the chronological age of the patient'.25 One could argue that provided that
P
95% confidence interval
,0.001 ,0.001 ,0.001 ,0.001
0.093±0.512 0.035±0.512 1.563±4.304 2.274±14.039
it is safe to anaesthetize the patient age should be no barrier for major resection based on the results presented above. A large proportion of elderly patients survive for 5 years or more following colorectal cancer resection.26 A large systematic review of 35 000 elderly patients having colorectal resectional surgery has shown that elderly patients have an increased frequency of co-morbid conditions, were more likely to present with later stage disease, were more likely to undergo emergency surgery and were less likely to have curative surgery than their younger counterparts. The results of the somewhat smaller single-centre study described in this manuscript concur with the first point but none of the other points. It is well known that there is biological and regional variation in the epidemiology of colorectal malignancy, which may be evident here.27±30 Elderly patients were significantly more likely to have their tumours sited in the colon than the rectum (P 0.002). This is comparable with other reported series, which state that the majority of tumours in this group (i.e. >80 years) are sited in the right colon (40%).31,32 In the study described above there was no significant difference in the overall 5 year survival between the two groups. In-hospital mortality and crude 5 year survival are better (only just) for patients under 80 but not significantly so. It is unclear why there is a sudden accelerated death rate in the over 80s within the first 6±8 months after surgery; further analysis of the data has failed to suggest a reason. It is likely to be due to the higher cardiorespiratory risk factors in this group, but the numbers are too small to make this a meaningful assumption. Survival after colonic surgery appears to be better in the over 80s (63% compared with 50%) and is probably as a result of a predominance of right-sided lesions. However, as the over 80s also have higher cardiorespiratory risk factors it is not clear from these data why 5 year survival is better, although not significantly so. Survival after rectal cancer surgery appears to be worse in the over 80s (53% compared with 77%), again not significantly so. However, the number of over 80s in this group is small (17), making it difficult to draw meaningful conclusions. One quite subjective area in Table 1 is that of `curative procedure'. All patients both curative and palliative were included in this study. The operating surgeon defined
TREATMENT OF COLORECTAL CANCER IN THE ELDERLY `curative' at the time of surgery based on the operative findings and whether it was felt that all macroscopic evidence of tumour was removed. Later histological analysis of the resected specimen showed good agreement between the surgeons' decisions about curative procedure and the Dukes staging of the tumour (rs ÿ 0.54, P , 0.001). Of all of the cases thought not to be curative by the surgeon (79 cases) only one of them proved to be a Dukes A tumour and only two were classified as T1 on the TNM system. The use of adjuvant therapy in elderly patients is often said to be restricted because of general poor health or dose-related toxicity resulting in suboptimal treatment.18±22,33 A more recent study, however, has cast doubt on this assumption and has shown that elderly patients with good pre-treatment performance status tolerate adjuvant and palliative chemotherapy as well as younger patients.24 In a previous study, using a standard 5-fluorouracil and levamisole regimen, patients over the age of 75 years had increased hospitalization rates, early reduction of dosages and a higher drop-out rate than patients under 70 years.34 The study by Newcombe and Carbone suggests that elderly patients were less likely to receive or accept adjuvant therapy and were less likely to be referred for a specialist opinion.35 It would be better to adjust the doses in this age group according to biological rather than chronological age.10 Despite histological evidence that 47.8% of the over 80s had Dukes stage C or D, only five of the elderly patients received adjuvant therapy compared with 98 of the younger patients; all patients, however, regardless of stage were referred for an oncological opinion. The absence of adjuvant therapy in the elderly group did not appear to affect overall long-term survival, although the numbers are small. Resectional surgery in elderly patients with colorectal cancer is justified in other studies because it has been shown that old age per se is not an independent risk factor for surgery, although it is an independent risk factor for short-term survival.14,36,37 The patient population described in the study was similar to previous reports. The data analysis from this cohort of patients is consistent with previously reported studies.10,12,15,16,31,37 From the Cox regression analysis it was seen that age over 80 years was a risk factor for survival. However, the 5 year survival rates for the two groups are similar. In hospital mortality is higher in the over 80s, but if you can get the patient through the operative procedure and immediate post-operative phase then the long-term outcome is comparable with that for their younger counterparts.
CONCLUSION Although the major complication was significantly higher in the elderly, the 5 year survival was comparable
665
between the two groups. This study has demonstrated that surgery should not be denied to elderly patients with colorectal cancer as despite a higher post-operative morbidity and mortality rate and with the absence of adjuvant therapy, favourable long-term outcome can be achieved by resectional surgery alone.
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