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J Thorac Cardiovasc Surg 1998;116:545-553
© 1998 Mosby, Inc.

GENERAL THORACIC SURGERY

Surgery for esophageal cancer in elderly patients: The view from Nottingham

Nottingham, United Kingdom

From the Thoracic Surgery Unit, Nottingham City Hospital, Nottingham, United Kingdom.

Received for publication Jan 19, 1998. Revisions requested March 9, 1998; revisions received June 26, 1998. Accepted for publication June 29, 1998. Address for reprints: D. Beggs, FDS, FRCS, Consultant Thoracic Surgery, Nottingham City Hospital, Hucknall Rd, Nottingham NG5 1PB, United Kingdom.J Thorac Cardiovasc Surg 1998;116:545-53

	Abstract

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 
Objective: Our aim was to compare the outcome of esophageal resection for carcinoma in elderly patients (aged over 70 and over 80 years) with that of younger patients managed within a single specialist thoracic surgery unit.
Patients and methods: Between January 1987 and November 1997, 523 patients underwent esophagectomy for carcinoma in the Nottingham City Hospital Thoracic Surgery Unit. The patients were divided into 3 groups by age: group I, under 70 years (n = 337); group II, 70 to 79 years (n = 150), and group III, 80 to 86 years (n = 36). These groups were compared with regard to preoperative medical status, operability and resectability, complications, operative mortality, and long-term survival.
Results: Patients in groups II (6.0%) and III (2.8%) had fewer preexisting respiratory problems than patients in group I (12.5%), and the patients in group III had fewer preexisting cardiovascular problems (16.7%) than patients in groups I (25.2%) and II (32.7%). Although patients in group III were generally less likely to have operable lesions (64.3%), no significant differences in resectability rate were detected among the 3 groups (80.8%, 77.7%, and 80%). Elderly patients (groups II and III) had a higher incidence of overall (34% and 36.1%), respiratory (24.7% and 19.4%), and cardiovascular (7.3% and 11.1%) complications than those aged under 70 years (24.6%, 16.3%, and 2.1%, respectively). However, operative mortality (4.7%, 6.7%, and 5.6%) and 5-year survivals inclusive of operative mortality (25.1%, 21.2%, and 19.8%) were similar among the 3 groups.
Conclusions: Accumulated experience in all aspects of perioperative management may account for a low hospital mortality in elderly patients despite a greater operative risk. The survival benefit is similar to that in the younger age groups, enforcing the view that esophagectomy within specialist thoracic units can be safely offered (in appropriately selected patients) with acceptable long-term survival in all age groups.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 
In a society whose elderly population is growing, it is not surprising that the number of elderly patients referred to thoracic surgeons for esophagectomy is rising. The proportion of elderly patients (aged over 70 years) having an esophagectomy for carcinoma in our unit has steadily risen from 16.5% in 1987 to 43% in 1997 (² test for trend, P = .01) (Fig 1).

View larger version (59K): [in this window] [in a new window]   Fig. 1. Percentage of patients older than 70 years having esophagectomy.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 
Between January 1987 and November 1997, 686 patients with carcinoma of the esophagus or gastroesophageal junction were evaluated with a view to performing esophagectomy. Thirty-one patients (4.5%) were believed to be unsuitable for surgery on medical grounds and the remaining 655 (95.5%) had a surgical exploration. In 523 patients (79.8%) esophageal resection was accomplished. These 523 patients were divided into 3 groups by age: group I, under 70 years; group II, 70 to 79 years; and group III, 80 to 86 years. (Demographic details and age distributions are shown in Table I and Fig 2). These groups were compared with regard to their preoperative fitness, operability and resectability rates, tumor characteristics and pathologic features, type of operation, length of hospital stay, prevalence of postoperative complications, operative mortality, and 5-year survival.Preoperative evaluation was by means of physical examination, hematologic and biochemical investigations, chest x-ray radiography, barium meal, abdominal ultrasound, and esophagogastroscopy. Bone scan was performed if indicated. Major airways involvement by tumor was excluded where appropriate by bronchoscopy.Computed tomographic scan was not routinely performed because experience in this unit showed it to be a poor means of assessing both mediastinal tumor extent and lymph node status. ⁸ Our experience with endoscopic ultrasound, although brief, was soon abandoned as, apparently, providing no benefit. Its value is currently being reassessed in the light of experience of other units. Spirometry, capillary blood gas analysis, and electrocardiography were routine. Exercise tests were carried out in all patients above the age of 70 years, in those with lung volumes of less than 60% of predicted value for age and height, or in those with significant ischemic changes on the electrocardiogram.Patients were considered eligible for a surgical exploration if they had no evidence of metastatic disease on screening tests and appeared to have adequate cardiorespiratory reserve. In general, patients more than 70 years old were very unlikely to qualify for an operation if they had a forced expiratory volume in 1 second of less than 50% of the predicted value for weight and height, vital capacity of less than 50% predicted, or if they were unable to complete stage I of the Bruce protocol (in the absence of musculoskeletal disorder) on exercise testing owing to symptoms or signs of myocardial ischemia or desaturation on exercise.All operations were performed by the same team of three thoracic surgeons who used similar surgical techniques and uniform perioperative management.Extensive mediastinal dissection was routinely carried out and included all periesophageal tissues with the subcarinal, paratracheal and parahiatal lymph nodes, both parietal pleurae overlying the esophagus, and the aortic adventitia. In the abdomen the lymph nodes from the left gastric artery pedicle were routinely excised, flush ligation of the left gastric pedicle being achieved by application of a vascular stapler (TLV-30 Auto Suture UK, Division of United States Surgical Corporation, Norwalk, Conn).After the operation, all patients were transferred to the intensive care unit for a short period to allow elective removal of the endotracheal tube before their return to the ward. Postoperative analgesia was initially provided by means of continuous infusion of a local anesthetic (bupivacaine) and an opioid (fentanyl) mixture through an epidural catheter. Parenteral or enteral nutrition was not used. Barium swallow was carried out on the seventh postoperative day to check for anastomotic integrity before the commencement of oral feeding. Preoperative chemotherapy or radiotherapy was not given in view of the conflicting evidence of its benefit. ⁹Operative mortality includes all in-hospital deaths plus any death occurring after the patient was discharged from the hospital within 30 days of the operation.

View larger version (58K): [in this window] [in a new window]   Fig. 2. Age distribution per decade of life.

Survival time was calculated from the time of the operation until death or until the end of the study period. Relevant information was obtained from the patients' medical records, the patients' general practitioners, and the Thoracic Surgery Audit Database.

Statistics
Survival distribution was calculated by means of the product-limit method of Kaplan and Meier and includes operative mortality and all causes of death. In univariate analysis, survival curves were compared with log-rank test and proportions with the ² test or Fisher's exact test as appropriate. Further comparisons between each pair of groups were made only if the overall P value was less than .05. A P value of less than .05 was used as guide to statistical significance. Multivariate adjustment for preoperative medical problems (risk factors) involved Cox proportional hazards and logistic regression analysis. Nonparametric tests were used to make between-group comparisons for the continuous variables length of tumor and length of hospital stay because of the non-normality of their distributions. All statistical analyses were done with the use of the statistical package SPSS PC (version 7.5) (SPSS Inc, Chicago, Ill).

	Results

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 
Fitness for operation, operability, and resectability
Among those patients who were initially evaluated (n = 686), a significantly higher proportion of octogenarians (19.6%) were considered to be medically unfit for an operation than was the case in patients aged from 70 to 79 (4.9%) and under 70 years (2.3%), as shown in Table II. As a result, the operability rate (defined as the proportion of the patients who underwent a resection among those who were initially evaluated with a view to esophagectomy) was significantly lower in group III (64.3%) than in groups I (78.9%) and II (73.9%) (P = .03, ²). The resectability rate, however (defined as the proportion of the patients who underwent a resection among those who underwent surgical exploration) was similar (77.7%-80.8%) among all 3 groups.

Respiratory complications (pulmonary infection, respiratory failure, and adult respiratory distress syndrome) were the major causes of death in groups I and II, with anastomotic leaks being an important cause of death in the first 2 groups and the only apparent cause of death in the patients aged over 80 years. Cardiovascular events (myocardial infarction, ventricular tachyarrhythmias, pulmonary embolism, and stroke) accounted for 5 deaths in groups I and II (Table VIII).

Median hospital stay was increased marginally with age group (12, 13, and 13.5 days, respectively; Table VIII).

Palliation of the dysphagia
Besides an attempt at cure, palliation of dysphagia is also important. Good palliation of dysphagia was achieved in 413 patients (79.0%). In all, 112 patients had symptoms of dysphagia after they were discharged from the hospital and required 1 to 4 dilatations: 76 patients (22.6%) in group I, 30 patients (20.0%) in group II, and 6 patients (16.7%) in group III. In 37 of these patients, anastomotic tumor recurrence was documented 3 to 50 months after the operation.

The exact incidence of malignant anastomotic recurrence is rather difficult to assess, because often patients die of distant metastases and generalized disease away from the hospital. The same seems to be true for the very important issue of postesophagectomy quality of life, the evaluation of which requires specifically designed and executed studies, which are clearly beyond the scope of this report.

Survival
The overall 5-year survival including postoperative mortality and all causes of death was 23.8% (median 19 months, 95% CI 16.4-21.6 months). Five-year survival was higher in group I (25.1%, median 19 months, CI 15.8-22.2) and group II (21.2%, median 20 months, CI 15.1-24.9) than in group III (19.8%, median 20 months, CI 11-29 months), but not significantly so (Fig 3). Neither preexisting respiratory disease nor preexisting cardiovascular disease was a significant predictor of survival (log-rank test, P = .4 for both), and differences in survival between age groups remained nonsignificant after adjusting in multivariate analysis for preexisting disease (P_trend = .35).

View larger version (18K): [in this window] [in a new window]   Fig. 3. Actuarial survival for all patients and for patients in groups I, II, and III (P = .88).

View larger version (15K): [in this window] [in a new window]   Fig. 4. Actuarial survival for patients having a curative (R0) or noncurative (R1-2) resection (P < .0001).

View larger version (21K): [in this window] [in a new window]   Fig. 5. Actuarial survival for each group of patients having a curative (R0) or noncurative (R1-2) resection (P = .0003).

	Discussion

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 
There are no scientifically established criteria to define the term elderly, which is being used arbitrarily in assessing the outcome after operations in patients more than 70 years old. ^1-5 The proportion of septuagenarians in our series (35.6%) (Fig 2) is higher than the 29.8%, ¹ 22%, ⁴ and 16.5% ⁵ previously reported by other authors.

Inasmuch as the number of patients with carcinoma of the esophagus or cardia being referred at advanced age is rising, both the referring physician and the thoracic surgeon need to meet the challenge. A conservative approach, often adopted by many physicians and surgeons in the treatment of elderly patients with esophageal carcinoma, is based, first, on the fear of increased operative mortality and, second, on the perception that these patients have a potentially short life span. However, as shown here and reported elsewhere, ⁵ high operative mortality is not necessarily the case. Furthermore, the average life expectancy in the United Kingdom is 74 years for men and 79 years for women, ¹⁰with the average life expectancy for octogenarians for men and women being 5.9 and 7.5 years, respectively. ¹¹ Although forms of treatment other than surgery, such as chemotherapy, radiotherapy, intubation, and laser therapy, can be considered, they are essentially palliative. We would agree with others ¹² that the feasibility of esophageal resection in elderly patients depends partly on the anticipated benefits. In this respect, surgery seems to offer the only real hope for cure and the best form of palliation with acceptable long-term quality of life. ¹³ We therefore favor early surgical exploration of all eligible patients, being prepared to attempt complete resection in patients with locally advanced but resectable disease.

An improvement in the preoperative staging with reduction of the nonresectability rate (20% in this series) is of course highly desirable, and in this respect refinements in endoscopic ultrasonography and the development of thoracoscopic-laparoscopic staging methods appear to be promising. ¹⁴

The resection rate in our series was similar in all 3 groups, but the percentage of those who were refused an operation on medical grounds rose with age. In octogenarians this was 19.6% (Table II). Despite this precaution, the elderly patients had more postoperative complications than their younger counterparts (Table VII). The 34.0% postoperative complication rate in group II is higher than the 24.7% reported by Jougon and associates ⁵ but compares favorably with postoperative complication rates of over 50% reported for septuagenarians by other authors. ^2,4 The 36.1% complication rate in our octogenarians is similar to that reported by Adam and colleagues. ⁶

The operative mortality was, however, kept low in all 3 age groups. The 6.7% operative mortality in group II is lower than the recently reported 7.8% ⁵ and compares favorably with operative mortality rates of 13% to 21% reported earlier, also for septuagenarians. ^1-4,15 The 5.6% operative mortality in patients in group III compares favorably with operative mortality rates of 10% to 13% reported for octogenarians from other centers. ^6,7

The similar survival in the 3 groups (Fig 3) stresses the point that the disease itself and not the patient age is the limiting factor for long-term survival after esophageal resection for carcinoma.

The 21.2% 5-year survival in group II compares favorably with 5-year survivals of 19% and 13.5% reported in septuagenarians by other authors, ^1,5 and the 19.8% 5-year survival in group III also compares favorably with a 17% survival reported by Adam and associates ⁶ in their series of 31 octogenarians. Although the survival figures quoted here leave much to be desired, sadly the bulk of the evidence currently available suggests that use of neoadjuvant treatment confers no overall survival benefit beyond that achieved so far by surgery alone. ^16-18 Thus it seems that routine use of such treatment with its associated toxicity is currently not justified. ^9,19 The practice is unusual in the United Kingdom.

It has been suggested that the transhiatal approach for esophagectomy is less invasive ²⁰ and its use would have been associated with reduced postoperative morbidity and mortality, but this has not been proven. ^21,22 Regarding elderly patients, Naunheim and associates ² have reported similar mortality and morbidity figures in patients treated with a transhiatal or transthoracic approach in their series of 38 septuagenarians.

Our experience also suggests that thoracotomy is as safe in the septuagenarians and octogenarians as in the younger age patients. Only 5 of 186 patients in this series over 70 years old had a transhiatal resection and none over 80 years (Table V). In addition, the low operative mortality observed in all 3 age groups (Table VIII) shows that selected elderly patients can tolerate with somewhat increased morbidity an extensive mediastinal dissection as well as the younger patients.

Although the competent performance of the operation itself is very important, ²³ we do not believe that the type of surgical approach used is an important factor affecting the immediate postoperative outcome. We would emphasize instead the need for effective analgesia, the provision of vigorous physiotherapy, and the prompt treatment of pulmonary infection, arrhythmias, and other complications as soon as they occur.

It would appear that the immediate postoperative outcome after esophagectomy depends heavily on the adoption of a coordinated multidisciplinary approach and teamwork in all aspects of perioperative management of the often debilitated elderly patients with esophageal cancer. This is perhaps more efficiently achieved within specialist units with experience in the management of thoracic problems.

	Conclusions

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 
Despite careful patient selection, postoperative complications tend to occur more frequently in elderly patients. Early recognition and effective treatment of such complications in a unit managing large numbers of patients with esophageal cancer, with more than one third of them being over 70 years of age, seems to account for a low operative mortality and short hospital stay in both septuagenarians and octogenarians. By applying a thoracotomy-based operative approach with extensive mediastinal dissection, regardless of age, we were able to observe 5-year survivals of 20% or more in all age groups. These data support the view that esophageal resection for carcinoma within specialist thoracic units is feasible and wholly appropriate for all reasonably fit patients, regardless of age.

	Acknowledgments

 
We are indebted to Lynda Beggs, Thoracic Surgery Audit Officer at Nottingham City Hospital, for assistance with the collection of data and the manuscript. Thanks are also due to Andrea Venn, MSc, Medical Statistician, Department of Respiratory Medicine, University of Nottingham, for carrying out the statistical analyses and interpretation of the data.

	References

Top Abstract Introduction Patients and methods Results Discussion Conclusions References

 

1. Keeling P, Gillen P, Hennessy TP. Oesophageal resection in the elderly. Ann R Coll Surg Eng 1988;70:34-7. [Medline]
   
2. Naunheim KS, Hanosh J, Zwischenberger J, et al. Esophagectomy in septuagenarian. Ann Thorac Surg 1993;56:880-4. [Abstract]
   
3. Muehrcke DD, Kaplan DK, Donnelly RJ. Oesophagogastrectomy in patients over 70. Thorax 1989;44:141-5. [Abstract/Free Full Text]
   
4. Sugimashi K, Matsuzaki K, Matsuura H, Kuwano H, Ueo H, Inokuchi K. Evaluation of the surgical treatment of the oesophagus in the elderly: 20 years' experience. Br J Surg 1985;72:28-30. [Medline]
   
5. Jougon JB, Ballester M, Duffy J, et al. Esophagectomy for cancer in the patient aged 70 years and older. Ann Thorac Surg 1997;63:1423-7. [Abstract/Free Full Text]
   
6. Adam DJ, Craig SR, Sang CTM, Cameron EWJ, Walker WS. Esophagectomy for carcinoma in the octogenarian. Ann Thorac Surg 1996;61:190-4.
   
7. Kuwano H, Morita M, Baba K, at al. Surgical treatment of esophageal carcinoma in patients eighty years of age and older. J Surg Oncol 1993;52:36-9. [Medline]
   
8. Markland CG, Manhire A, Davis P, Beggs D, Morgan WE, Salama FD. The role of computing tomography in assessing the operability of oesophageal carcinoma. Eur J Cardiothorac Surg 1989;3:33-6. [Abstract]
   
9. Lerut T. Oesophageal carcinoma-Past and present studies. Eur J Surg Oncol 1996;22:317-25. [Medline]
   
10. Raleigh V, Kiri VA. Difference in life expectancy in various areas in England. J Epidemiol Comm Health 1997;51:649-58. [Abstract/Free Full Text]
    
11. Registrar General Scotland. Annual report 1993. Edinburgh: Her Majesty's Stationery Office; 1994.
    
12. Reed CE. Who should undergo esophagectomy? Ann Thorac Surg 1997;63:1225-6. [Free Full Text]
    
13. McLarty AJ, Deschamps C, Trastek VF, Allen MS, Pairolero PC, Harmsen WS. Esophageal resection for cancer of the esophagus: long-term function and quality of life. Ann Thorac Surg 1997;63:1568-72. [Abstract/Free Full Text]
    
14. Krasna MJ, Flowers JL, Attar S, McLaughlin J. Combined thoracoscopic/laparoscopic staging of esophageal cancer. J Thorac Cardiovasc Surg 1996;111:800-7. [Abstract/Free Full Text]
    
15. Yamanaka H, Hiramatsu Y, Kawaguchi Y, Kohima Y, Hioki K, Yamamoto M. Surgical treatment for poor-risk patients with carcinoma of the esophagus. Jpn J Surg 1991;21:178-83. [Medline]
    
16. Ando N, Iizuka T, Kakagawa T, Isono K, Watanabe H, Ide H, et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group study. J Thorac Cardiovasc Surg 1997;114:205-9. [Abstract/Free Full Text]
    
17. Law S, Fok M, Chow S, Chu K, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg 1997;114:210-7. [Abstract/Free Full Text]
    
18. Bosset J, Gignoux M, Triboulet J, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161-7. [Abstract/Free Full Text]
    
19. Skinner DB. Editorial on combined therapy for squamous cell carcinoma of the esophagus. J Thorac Cardiovasc Surg 1997;114:203-4. [Free Full Text]
    
20. Orringer MB. Transhiatal esophagectomy without thoracotomy for carcinoma of the thoracic esophagus. Ann Surg 1984;200:282-7. [Medline]
    
21. Goldminc M, Maddern G, LePrise E, Meunier B, Campion JP, Launois B. Oesophagectomy by transhiatal approach or thoracotomy: a prospective randomised trial. Br J Surg 1993;80:367-70. [Medline]
    
22. Hagen JA, Peters JH, DeMeester TR. Superiority of extended en bloc esophagogastrectomy for carcinoma of the lower esophagus and cardia. J Thorac Cardiovasc Surg 1993;106:850-9. [Abstract]
    
23. Matthews HR, Powell DJ, McConkey CC. Effect of surgical experience on the results of resection for oesophageal carcinoma. Br J Surg 1986;76:621-3.
    
24. American Joint Committee on Cancer. Esophagus. In: Beahrs OH, Henson DE, Hutter RVP, Kennedy BJ, editors. Manual for staging of cancer. 4th ed. Philadelphia. Lippincott: 1992. p. 57-61.
    

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alexiou, C. Articles by Morgan, W. E. Search for Related Content PubMed PubMed Citation Articles by Alexiou, C. Articles by Morgan, W. E.