Surg Endosc DOI 10.1007/s00464-014-3753-x
and Other Interventional Techniques
Is minimally invasive esophagectomy beneficial to elderly patients with esophageal cancer? Jingpei Li • Yaxing Shen • Lijie Tan • Mingxiang Feng • Hao Wang • Yong Xi Qun Wang
•
Received: 26 February 2014 / Accepted: 11 July 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Open esophagectomy (OE) in elderly patients with esophageal cancer is hazardous due to high surgical mortality and limited survival. The aim of this study was to explore whether minimally invasive esophagectomy (MIE) has perioperative or long-term benefits in elderly patients with esophageal cancer compared with OE. Methods Between February 2005 and June 2013, 407 patients older than 70 years underwent esophagectomy for esophageal cancer, including 89 who received MIE and 318 who received OE. A retrospective pair-matched study was performed to compare 116 patients (58 pairs) who underwent either OE or MIE. Patients were matched by age, sex, comorbidity, tumor location, histology, TNM stage, and operative approach. Perioperative and long-term outcomes were compared between the two groups. Results The overall incidence of postoperative complications was significantly lower in the MIE group than in the OE group (37.9 vs. 60.3 %, P = 0.016), especially incidence of pulmonary complications (20.7 vs. 39.7 %, P = 0.026). The mean length of hospital stay was also significantly shorter (10 days [range 7–70] vs. 12 days
Jingpei Li, Yaxing Shen these authors contributed equally to this paper. J. Li Y. Shen L. Tan M. Feng (&) H. Wang Y. Xi Q. Wang Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China e-mail: [email protected] J. Li Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
[range 8–106], P = 0.032). The perioperative mortality rate trended lower in the MIE group but was not significantly different (3.4 vs. 8.6 %, P = 0.435). Kaplan–Meier analysis showed that the median disease-specific survival time in the MIE group was significantly longer than in the OE group ([27 months [range 1–82] vs. 24 months [range 1–99], P = 0.003). No difference was found in overall survival (39 ± 8.9 vs. 22 ± 3.4 months, P = 0.070). Conclusion In surgical management of elderly patients with esophageal cancer, MIE is associated with lower rates of morbidity and pulmonary complications as well as longer disease-specific survival time. Whether it provides benefit to patients’ long-term survival requires further research. Keywords Esophagectomy Minimally invasive surgery Esophageal cancer Elderly patients Survival
Esophagectomy for cancer is a major surgical procedure associated with high morbidity and mortality [1]. The risk may be more critical in elderly patients [2–4]. It is imperative to explore a safer approach to minimize morbidity and mortality of elderly patients. The technique of minimally invasive esophagectomy (MIE) for esophageal cancer has been shown to be associated with shorter hospital stay, decreased morbidity, and improved quality of life (QoL) and overall survival [1, 5– 8]. However, previous studies were mainly focused on the general population. Therefore, whether MIE could deliver similar perioperative or long-term benefits to elderly patients of esophageal cancer remains uncertain. The aim of this study was to analyze perioperative events and long-term survival in elderly patients who underwent MIE or open esophagectomy.
123
Surg Endosc
Patients and methods This study was approved by the Zhongshan Clinical Research Ethics Committee. Between February 2005 and June 2013, there were 2893 patients who underwent esophagectomy at Zhongshan Hospital of Fudan University, including 415 consecutive patients of esophageal cancer older than 70 years. Eight cases treated with OE who received neoadjuvant chemotherapy or chemoradiotherapy were excluded since no patients treated with MIE received neoadjuvant therapy. Since there were no patients treated with MIE who received surgery through the left thoracic approach, patients managed with open esophagectomy who underwent left thoracic esophagectomy were also excluded. Using the remaining historic cohort, a retrospective pair-matched study was performed to compare 116 patients (58 pairs) who underwent either open esophagectomy or MIE. Patients were matched by age, sex, comorbidities, tumor location, histology, and TNM stage. All patients were diagnosed with esophageal cancer by endoscopic biopsy. Preoperative staging was determined mainly by enhanced thoracic and abdominal computerized tomography. T1-3N0M0 esophageal cancer patients were selected as candidates for operation. Physical examination, standard laboratory tests, electrocardiograms, and lung function tests were performed in all patients.
All patients received a combination of epidural and general anesthesia before the operation. The operative technique of MIE has been described elsewhere [9–11]. The procedure of open esophagectomy was performed in a manner similar to MIE. Patients were retained overnight in the surgical intensive care unit (ICU) on continuous telemetry before being returned to the dedicated thoracic surgical ward on the first postoperative day. Follow-up data were collected from a patient research database. Adjuvant chemotherapy was delivered to those who had lymph node metastasis with generally good performance. Patients were seen in the outpatient department every 3 months for the first postoperative year, every 4–5 months for the next 2 years, and then annually for 10 years. Telephone follow-up was conducted with those patients who ceased to come to the clinic regularly. Data concerning deceased patients were also collected through telephone follow-up. Follow-up was measured in months from the time of operation until death or end of follow-up. Perioperative mortality was categorized as disease-specific death in survival analysis. Death by any other cause was scored as end of follow-up. The follow-up was evaluated in September 2013 and was completed for all included patients. Differences between the MIE and open esophagectomy groups were assessed using the Wilcoxon rank sum test for continuous variables, the Chi square or Fisher exact tests for categorical variables, and the Kaplan–Meier method for survival time. For all calculations, a P value of \0.05 was
Table 1 Patient characteristics of all Patients Characteristic
MIE (n = 89)
OE (n = 318)
P
Age
73 (70–83)
73 (70–85)
0.478
Sex (male/female)
66/23
227/91
0.606
Comorbidity, n (%) Tumor location
21 (23.6 %)
57 (18.0 %)
0.230 0.543
Upper, n (%)
7 (7.9 %)
18 (5.7 %)
Middle, n (%)
65 (73.0 %)
225 (70.8 %)
Lower, n (%)
17 (19.1 %)
75 (23.6 %)
Squamous carcinoma
82 (92.1 %)
285 (89.6 %)
Adenocarcinoma
2 (2.2 %)
17 (5.3 %)
Other
5 (5.6 %)
16 (5.0 %)
1
21 (23.6 %)
34 (10.7 %)
2
43 (48.3 %)
158 (49.7 %)
3
25 (28.1 %)
126 (39.6 %)
Cervical-right thoracic–abdominal esophagectomy
86 (96.6 %)
32 (10.1 %)
Right thoracic–abdominal esophagectomy
3 (3.4 %)
63 (19.8 %)
Left thoracic esophagectomy
0 (0.0 %)
223 (54.8 %)
Histology
0.466
TNM stage
0.004
Operative approach
123
0.000
Surg Endosc Table 2 Perioperative results of all patients Type, n (%)
MIE (n = 89)
Length of stay (range), days
12 (7–70)
Readmission to ICU, n (%)
Table 3 Patient Characteristics of the pair-matched population OE (n = 318)
P
Characteristic Age
72 (70–79)
72 (70–85)
0.514
Sex (male/female)
44/14
44/14
1.000
13 (22.4 %)
13 (22.4 %)
1.000
6 (10.3 %)
10 (17.2 %)
8 (9.0 %)
59 (18.6 %)
0.031
Comorbidity, n (%)
137 (43.1 %)
0.228
Tumor location
Mortality
3 (3.4 %)
16 (5.0 %)
0.710
Upper, n (%)
0.514
15 (16.9 %)
76 (23.9 %)
0.159
Middle, n (%)
44 (75.9 %)
42 (72.4 %)
Pneumoniaa
7 (7.9 %)
48 (15.1 %)
0.078
Lower, n (%)
8 (13.8 %)
6 (10.3 %)
Pleural effusion req. drainage
6 (6.7 %)
18 (5.7 %)
0.702
58 (100.0 %)
58 (100.0 %)
ARDS
1 (1.1 %)
7 (2.2 %)
0.829
Pulmonary embolusb
1 (1.1 %)
3 (0.9 %)
0.649
Cardiovascular complications
P
0.951
32 (36.0 %)
Squamous carcinoma TNM stage
1.000 0.886
1
4 (6.9 %)
3 (5.2 %)
2 3
31 (53.4 %) 23 (39.7 %)
30 (51.7 %) 25 (43.1 %)
8 (9.0 %)
31 (9.7 %)
0.830
Atrial fibrillation
7 (7.9 %)
29 (9.1 %)
0.713
Myocardial infarction
1 (1.1 %)
2 (0.6 %)
0.827
21 (23.6 %)
50 (15.7 %)
0.084
Table 4 Perioperative results of the matched population
19 (21.3 %) 2 (2.2 %)
45 (14.2 %) 5 (1.6 %)
0.100 0.977
Type, n (%)
MIE (n = 58)
OE (n = 58)
P
Length of stay (range), days
10 (7–70)
18 (20.2 %)
49 (15.4 %)
0.279
Readmission to ICU, n (%)
Wound infection
3 (3.4 %)
13 (4.1 %)
0.999
Chylothorax
1 (1.1 %)
6 (1.9 %)
0.977
Gastrointestinal complications Anastomotic leak Delayed gastric emptying Other Hoarseness
a
Pneumonia was defined by clinical and radiographic criteria, including armpit-temperature [38.5 °C, WBC [ 10 9 109/L, positive sputum culture, and patchy shadow in X-ray
b
OE (n = 58)
12 (7–254)
Morbidity Pulmonary complications
MIE (n = 58)
Pulmonary embolus was diagnosed by ultrasonic cardiogram
considered to be significant. Statistical computations and plotting were performed using SPSS software, version 19.0 (SPSS, Chicago, IL).
12 (8–106)
0.032
4 (6.9 %)
12 (20.7 %)
0.031
Morbidity
22 (37.9 %)
35 (60.3 %)
0.016
Mortality
2 (3.4 %)
5 (8.6 %)
0.435
12 (20.7 %) 7 (12.1 %)
23 (39.7 %) 16 (27.6 %)
0.026 0.036
3 (5.2 %)
5 (8.6 %)
0.714
Pulmonary complications Pneumonia Pleural effusion req. drainage ARDS
1 (1.7 %)
2 (3.4 %)
1.000
Pulmonary embolus
1 (1.7 %)
0 (0.0 %)
1.000
4 (6.9 %)
5 (8.6 %)
1.000
Atrial fibrillation
4 (6.9 %)
4 (6.9 %)
0.714
Myocardial infarction
0 (0.0 %)
1 (1.7 %)
1.000
17 (29.3 %)
10 (17.2 %)
0.124
10 (17.2 %)
6 (10.3 %)
0.281
0 (0.0 %)
4 (6.9 %)
0.127
14 (24.1 %) 1 (1.7 %)
8 (13.8 %) 5 (8.6 %)
0.155 0.208
1 (1.7 %)
1 (1.7 %)
0.476
Cardiovascular complications
Gastrointestinal complications
Results
Anastomotic leak Delayed gastric emptying
No patients were converted to open procedures and all patients in both groups received R0 dissection. Patients and tumor demographics are listed in Table 1. Since patients with severe comorbidities were excluded from surgery, comorbidities in Table 1 consisted of controllable or uneventful hypertension, diabetes mellitus, arrhythmia, cerebral infarction, etc. The tumors in the OE group were significantly more advanced than those in the MIE group. There were significantly more instances of application of the left thoracic approach in the OE group. The perioperative results are shown in Table 2. Rates of readmission to the ICU in the MIE group were significantly lower than that in the OE group (9.0 vs. 18.6 %, p = 0.031). No significant difference was found in length of hospital stay or the rates of morbidity and mortality. There were 19 (19/ 407, 4.7 %) perioperative deaths. Ten patients died of
Other complications Hoarseness Wound infection Chylothorax
pneumonia, four of severe anastomotic leak or gastric necrosis, two of pulmonary embolus, two of myocardial infarction, and one of acute respiratory distress syndrome (ARDS). After matching for age, sex, comorbidity, tumor location, histology, TNM stage, and operative approach (Table 3), 116 patients (58 receiving open esophagectomy and 58 receiving MIE) were eligible for analysis. The perioperative results are given in Table 4. The length of hospital stay in the MIE group was significantly shorter
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Surg Endosc
Fig. 1 Disease-specific survival time of the pair-matched population
rates of other complications between the two groups did not reach statistical significance. Seven patients received adjuvant chemotherapy in the MIE group compared to five patients in the OE group. No patient received adjuvant radiotherapy in MIE, while two patients received radiotherapy in the OE group due to recurrence of cervical lymph nodes. Among the general population, there were 193 patients (47.4 %) who ceased to report to the out-patient clinic regularly. After repeated attempts at telephone follow-up, there were still 142 censored patients (34.9 %) that we failed to reach. Among the pair-matched population, 13 patients (22.4 %) were lost to follow up in the MIE group and 21 patients (36.2 %) in the OE group. The median duration of follow-up was 27 months (range 1–99). Fewer than half of the patients in the MIE group died. Thus, the median disease-specific survival time (including postoperative deaths) in the MIE group was greater than the median duration of follow-up and was also significantly longer than that in the OE group ([27 months [range 1–82] vs. 24 months [range 1–99], P = 0.003) (Fig. 1). There was no difference in overall survival between the two groups (39 ± 8.9 vs. 22 ± 3.4 months, P = 0.070) (Fig. 2).
Discussion
Fig. 2 Overall survival of the pair-matched population
than that in the OE group (10 days [range 7–70] vs. 12 days [range 8–106], P = 0.032). Readmission to the ICU in the MIE group occurred at a significantly lower rate than in the OE group (6.9 vs. 20.7 %, P = 0.031). The complication rate in the MIE group was significantly lower than that in the OE group (37.9 vs. 60.3 %, P = 0.016). The pulmonary complication rate in the MIE group was significantly lower than that in the OE group (20.7 vs. 39.7 %, P = 0.026), especially the incidence of pneumonia (12.1 vs. 27.6 %, P = 0.036). Differences in incidence
123
Shorter length of hospital stay, fewer pulmonary complications, lower rates of morbidity, and longer disease-specific survival time were recorded among elderly patients treated with MIE in this pair-matched study. Previous studies in large series of esophageal cancer patients showed that advanced age is a significant risk factor for surgical mortality [2, 3]. However, Jougon [12] compared a series of 89 patients older than 70 years with a group of patients younger than 70 years and suggested that esophagectomy could be performed in selected elderly patients with acceptable morbidity (24.7 %) and mortality (7.8 %). In Japan, Fang and his colleagues [13] reported that esophagectomy with 3-field lymph node dissection could be carried out safely in patients over 70 years, with an in-hospital mortality of approximately 7.6 % in their series of 240 patients older than 70 years vs. 3.3 % for patients younger than 70 years. Although many studies are optimistic about esophagectomy performed in elderly patients [14–16], there are still some concerns among thoracic surgeons and patients with respect to generally high perioperative mortality (7.6–11.6 %) [12, 13, 17]. Abunasra and his colleagues [18] reported that pulmonary complications accounted for 51.4 % (19/37) of in-hospital deaths, especially pulmonary infections (17/37,46.0 %). As was seen in our series, there
Surg Endosc
were two in-hospital deaths (one from pneumonia and one from myocardial infarction) in patients undergoing MIE vs. five deaths (three from pneumonia, one from severe gastric necrosis, and one from pulmonary embolus) in patients undergoing open esophagectomy. Hence, minimizing pulmonary complications is a shortcut to lowering the mortality rate. The results from a recent randomized controlled trial showed that MIE is generally advantageous over open esophagectomy in terms of a reduced rate of pulmonary infection [5]. Furthermore, combined with our previous experience [6, 10, 11], applying this minimally invasive approach to elderly patients might harvest the benefits of reduced pulmonary complications, or even lower perioperative mortality rates. Indeed, with comparable comorbidity, there were fewer pulmonary complications and shorter length of hospital stay in the MIE group compared with the OE group (Table 3, 4). The analysis of disease-specific survival time in matched patients found a significant intergroup difference. We considered that there might be multiple reasons accounting for the survival benefit among elderly patients. Chiefly, elderly patients in the MIE group suffered significantly fewer postoperative complications, and even promising better QoL [6], which in turn might provide a survival benefit due to fast recovery and better general condition. Furthermore, MIE is more costly than open esophagectomy [19]. Though there are no directly supportive data, in our experience, this leads to patient selection such that the proportion of higher economic classes is greater in patients treated with MIE than that in those treated with open esophagectomy. Low economic class might potentially compromise postoperative care, general follow-up, and even adjuvant therapy. Possibly as a result of this phenomenon, partially due to insufficient adjuvant chemotherapy, nontumorous deaths and the high rates of censored patients, no significant difference in overall survival was noted in elderly patients in the MIE or OE groups (P = 0.070). However, there are also several limitations to our study. First, the decision whether the patient underwent open or MIE was determined by multiple factors, for instance, economic and educational background of patients and available time and willingness of different surgeons for different patients. Since this was a retrospective study, certain defects of this study were uncontrollable, such as the exact proportion of the above factors. Previously, the common approach for esophageal cancer within our department was open esophagectomy through left or right thoracic approach. It was not until May, 2004 that we started applying MIE for this malignant disease. After slowly accumulating nearly 50 patients of clinical Stage I esophageal cancer, surgeons of our thoracic department have gradually passed their learning curve by February,
2005, when we began to enroll patients treated with both open and MIE in this study. Hence, by pair-matching patients, we have attempted to eliminate selection bias as rigorously as possible outside of the setting of a randomized, prospective study. Second, though the attrition rate for follow-up was high, there would be minor impact on significance of the result if it was randomized attrition which was confirmed by our further statistical analysis between the patients who still stayed in follow-up or out of follow-up of each group. Additionally, in our practice, those who had several comorbidities or poor performance status were generally excluded from surgery by surgeons, patients, or patients’ relatives. Hence, the occurrence of comorbidities in both populations (21/89, 23.6 % vs. 57/318, 18.0 %, P = 0.230) was relatively lower than in previous reported series [15, 17, 20].
Conclusions Compared with traditional open esophagectomy, successful utilization of MIE for esophagectomy of esophageal carcinoma is associated with a reduced incidence of pulmonary complications and a longer survival time in elderly patients. In conclusion, a minimally invasive approach to esophageal cancer resection may be preferred in elderly patients, although further investigations are needed to confirm this conclusion. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 81370587). Disclosure Jingpei Li, Yaxing Shen, Lijie Tan, Mingxiang Feng, Hao Wang, Yong Xi, and Qun Wang declare no conflict of interest.
References 1. Luketich JD, Pennathur A, Awais O, Levy RM, Keeley S, Shende M et al (2012) Outcomes after minimally invasive esophagectomy: review of over 1000 patients. Ann Surg 256:95–103 2. Moskovitz AH, Rizk NP, Venkatraman E, Bains MS, Flores RM, Park BJ et al (2006) Mortality increases for octogenarians undergoing esophagogastrectomy for esophageal cancer. Ann Thorac Surg 82:2031–2036 3. Morita M, Otsu H, Kawano H, Kumashiro R, Taketani K, Kimura Y et al (2013) Advances in esophageal surgery in elderly patients with thoracic esophageal cancer. Anticancer Res 33:1641–1647 4. Kinugasa S, Tachibana M, Yoshimura H, Dhar DK, Shibakita M, Ohno S et al (2001) Esophageal resection in elderly esophageal carcinoma patients: improvement in postoperative complications. Ann Thorac Surg 71:414–418 5. Biere SS, van Berge HM, Maas KW, Bonavina L, Rosman C, Garcia JR et al (2012) Minimally invasive versus open oesophagectomy for patients with oesophageal cancer: a multicentre, open-label, randomised controlled trial. Lancet 379:1887–1892 6. Wang H, Feng M, Tan L, Wang Q (2010) Comparison of the short-term quality of life in patients with esophageal cancer after
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subtotal esophagectomy via video-assisted thoracoscopic or open surgery. Dis Esophagus 23:408–414 Smithers BM, Gotley DC, Martin I, Thomas JM (2007) Comparison of the outcomes between open and minimally invasive esophagectomy. Ann Surg 245:232–240 Nagpal K, Ahmed K, Vats A, Yakoub D, James D, Ashrafian H et al (2010) Is minimally invasive surgery beneficial in the management of esophageal cancer? a meta-analysis. Surg Endosc 24:1621–1629 Shen Y, Feng M, Khan MA, Wang H, Tan L, Wang Q (2014) A simple method minimizes chylothorax after minimally invasive esophagectomy. J Am Coll Surg 218:108–112 Shen Y, Zhang Y, Tan L, Feng M, Wang H, Khan MA et al (2012) Extensive mediastinal lymphadenectomy during minimally invasive esophagectomy: optimal results from a single center. J Gastrointest Surg 16:715–721 Feng M, Shen Y, Wang H, Tan L, Zhang Y, Khan MA et al (2012) Thoracolaparoscopic esophagectomy: is the prone position a safe alternative to the decubitus position? J Am Coll Surg 214:838–844 Jougon JB, Ballester M, Duffy J, Dubrez J, Delaisement C, Velly JF et al (1997) Esophagectomy for cancer in the patient aged 70 years and older. Ann Thorac Surg 63:1423–1427 Fang W, Igaki H, Tachimori Y, Sato H, Daiko H, Kato H (2001) Three-field lymph node dissection for esophageal cancer in elderly patients over 70 years of age. Ann Thorac Surg 72:867–871
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14. Pultrum BB, Bosch DJ, Nijsten MW, Rodgers MG, Groen H, Slaets JP et al (2010) Extended esophagectomy in elderly patients with esophageal cancer: minor effect of age alone in determining the postoperative course and survival. Ann Surg Oncol 17:1572–1580 15. Yang HX, Ling L, Zhang X, Lin P, Rong TH, Fu JH (2010) Outcome of elderly patients with oesophageal squamous cell carcinoma after surgery. Br J Surg 97:862–867 16. Mariette C, Piessen G (2012) Is advanced age still a contraindication to surgery for esophageal cancer? J Visc Surg 149:e163–e164 17. Cijs TM, Verhoef C, Steyerberg EW, Koppert LB, Tran TC, Wijnhoven BP et al (2010) Outcome of esophagectomy for cancer in elderly patients. Ann Thorac Surg 90:900–907 18. Abunasra H, Lewis S, Beggs L, Duffy J, Beggs D, Morgan E (2005) Predictors of operative death after oesophagectomy for carcinoma. Br J Surg 92:1029–1033 19. Dhamija A, Dhamija A, Hancock J, McCloskey B, Kim AW, Detterbeck FC et al (2014) Minimally invasive oesophagectomy more expensive than open despite shorter length of stay. Eur J Cardiothorac Surg. doi:10.1093/ejcts/ezt482 20. Ma JY, Wu Z, Wang Y, Zhao YF, Liu LX, Kou YL et al (2006) Clinicopathologic characteristics of esophagectomy for esophageal carcinoma in elderly patients. World J Gastroenterol 12:1296–1299
and Other Interventional Techniques
Is minimally invasive esophagectomy beneficial to elderly patients with esophageal cancer? Jingpei Li • Yaxing Shen • Lijie Tan • Mingxiang Feng • Hao Wang • Yong Xi Qun Wang
•
Received: 26 February 2014 / Accepted: 11 July 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Open esophagectomy (OE) in elderly patients with esophageal cancer is hazardous due to high surgical mortality and limited survival. The aim of this study was to explore whether minimally invasive esophagectomy (MIE) has perioperative or long-term benefits in elderly patients with esophageal cancer compared with OE. Methods Between February 2005 and June 2013, 407 patients older than 70 years underwent esophagectomy for esophageal cancer, including 89 who received MIE and 318 who received OE. A retrospective pair-matched study was performed to compare 116 patients (58 pairs) who underwent either OE or MIE. Patients were matched by age, sex, comorbidity, tumor location, histology, TNM stage, and operative approach. Perioperative and long-term outcomes were compared between the two groups. Results The overall incidence of postoperative complications was significantly lower in the MIE group than in the OE group (37.9 vs. 60.3 %, P = 0.016), especially incidence of pulmonary complications (20.7 vs. 39.7 %, P = 0.026). The mean length of hospital stay was also significantly shorter (10 days [range 7–70] vs. 12 days
Jingpei Li, Yaxing Shen these authors contributed equally to this paper. J. Li Y. Shen L. Tan M. Feng (&) H. Wang Y. Xi Q. Wang Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China e-mail: [email protected] J. Li Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
[range 8–106], P = 0.032). The perioperative mortality rate trended lower in the MIE group but was not significantly different (3.4 vs. 8.6 %, P = 0.435). Kaplan–Meier analysis showed that the median disease-specific survival time in the MIE group was significantly longer than in the OE group ([27 months [range 1–82] vs. 24 months [range 1–99], P = 0.003). No difference was found in overall survival (39 ± 8.9 vs. 22 ± 3.4 months, P = 0.070). Conclusion In surgical management of elderly patients with esophageal cancer, MIE is associated with lower rates of morbidity and pulmonary complications as well as longer disease-specific survival time. Whether it provides benefit to patients’ long-term survival requires further research. Keywords Esophagectomy Minimally invasive surgery Esophageal cancer Elderly patients Survival
Esophagectomy for cancer is a major surgical procedure associated with high morbidity and mortality [1]. The risk may be more critical in elderly patients [2–4]. It is imperative to explore a safer approach to minimize morbidity and mortality of elderly patients. The technique of minimally invasive esophagectomy (MIE) for esophageal cancer has been shown to be associated with shorter hospital stay, decreased morbidity, and improved quality of life (QoL) and overall survival [1, 5– 8]. However, previous studies were mainly focused on the general population. Therefore, whether MIE could deliver similar perioperative or long-term benefits to elderly patients of esophageal cancer remains uncertain. The aim of this study was to analyze perioperative events and long-term survival in elderly patients who underwent MIE or open esophagectomy.
123
Surg Endosc
Patients and methods This study was approved by the Zhongshan Clinical Research Ethics Committee. Between February 2005 and June 2013, there were 2893 patients who underwent esophagectomy at Zhongshan Hospital of Fudan University, including 415 consecutive patients of esophageal cancer older than 70 years. Eight cases treated with OE who received neoadjuvant chemotherapy or chemoradiotherapy were excluded since no patients treated with MIE received neoadjuvant therapy. Since there were no patients treated with MIE who received surgery through the left thoracic approach, patients managed with open esophagectomy who underwent left thoracic esophagectomy were also excluded. Using the remaining historic cohort, a retrospective pair-matched study was performed to compare 116 patients (58 pairs) who underwent either open esophagectomy or MIE. Patients were matched by age, sex, comorbidities, tumor location, histology, and TNM stage. All patients were diagnosed with esophageal cancer by endoscopic biopsy. Preoperative staging was determined mainly by enhanced thoracic and abdominal computerized tomography. T1-3N0M0 esophageal cancer patients were selected as candidates for operation. Physical examination, standard laboratory tests, electrocardiograms, and lung function tests were performed in all patients.
All patients received a combination of epidural and general anesthesia before the operation. The operative technique of MIE has been described elsewhere [9–11]. The procedure of open esophagectomy was performed in a manner similar to MIE. Patients were retained overnight in the surgical intensive care unit (ICU) on continuous telemetry before being returned to the dedicated thoracic surgical ward on the first postoperative day. Follow-up data were collected from a patient research database. Adjuvant chemotherapy was delivered to those who had lymph node metastasis with generally good performance. Patients were seen in the outpatient department every 3 months for the first postoperative year, every 4–5 months for the next 2 years, and then annually for 10 years. Telephone follow-up was conducted with those patients who ceased to come to the clinic regularly. Data concerning deceased patients were also collected through telephone follow-up. Follow-up was measured in months from the time of operation until death or end of follow-up. Perioperative mortality was categorized as disease-specific death in survival analysis. Death by any other cause was scored as end of follow-up. The follow-up was evaluated in September 2013 and was completed for all included patients. Differences between the MIE and open esophagectomy groups were assessed using the Wilcoxon rank sum test for continuous variables, the Chi square or Fisher exact tests for categorical variables, and the Kaplan–Meier method for survival time. For all calculations, a P value of \0.05 was
Table 1 Patient characteristics of all Patients Characteristic
MIE (n = 89)
OE (n = 318)
P
Age
73 (70–83)
73 (70–85)
0.478
Sex (male/female)
66/23
227/91
0.606
Comorbidity, n (%) Tumor location
21 (23.6 %)
57 (18.0 %)
0.230 0.543
Upper, n (%)
7 (7.9 %)
18 (5.7 %)
Middle, n (%)
65 (73.0 %)
225 (70.8 %)
Lower, n (%)
17 (19.1 %)
75 (23.6 %)
Squamous carcinoma
82 (92.1 %)
285 (89.6 %)
Adenocarcinoma
2 (2.2 %)
17 (5.3 %)
Other
5 (5.6 %)
16 (5.0 %)
1
21 (23.6 %)
34 (10.7 %)
2
43 (48.3 %)
158 (49.7 %)
3
25 (28.1 %)
126 (39.6 %)
Cervical-right thoracic–abdominal esophagectomy
86 (96.6 %)
32 (10.1 %)
Right thoracic–abdominal esophagectomy
3 (3.4 %)
63 (19.8 %)
Left thoracic esophagectomy
0 (0.0 %)
223 (54.8 %)
Histology
0.466
TNM stage
0.004
Operative approach
123
0.000
Surg Endosc Table 2 Perioperative results of all patients Type, n (%)
MIE (n = 89)
Length of stay (range), days
12 (7–70)
Readmission to ICU, n (%)
Table 3 Patient Characteristics of the pair-matched population OE (n = 318)
P
Characteristic Age
72 (70–79)
72 (70–85)
0.514
Sex (male/female)
44/14
44/14
1.000
13 (22.4 %)
13 (22.4 %)
1.000
6 (10.3 %)
10 (17.2 %)
8 (9.0 %)
59 (18.6 %)
0.031
Comorbidity, n (%)
137 (43.1 %)
0.228
Tumor location
Mortality
3 (3.4 %)
16 (5.0 %)
0.710
Upper, n (%)
0.514
15 (16.9 %)
76 (23.9 %)
0.159
Middle, n (%)
44 (75.9 %)
42 (72.4 %)
Pneumoniaa
7 (7.9 %)
48 (15.1 %)
0.078
Lower, n (%)
8 (13.8 %)
6 (10.3 %)
Pleural effusion req. drainage
6 (6.7 %)
18 (5.7 %)
0.702
58 (100.0 %)
58 (100.0 %)
ARDS
1 (1.1 %)
7 (2.2 %)
0.829
Pulmonary embolusb
1 (1.1 %)
3 (0.9 %)
0.649
Cardiovascular complications
P
0.951
32 (36.0 %)
Squamous carcinoma TNM stage
1.000 0.886
1
4 (6.9 %)
3 (5.2 %)
2 3
31 (53.4 %) 23 (39.7 %)
30 (51.7 %) 25 (43.1 %)
8 (9.0 %)
31 (9.7 %)
0.830
Atrial fibrillation
7 (7.9 %)
29 (9.1 %)
0.713
Myocardial infarction
1 (1.1 %)
2 (0.6 %)
0.827
21 (23.6 %)
50 (15.7 %)
0.084
Table 4 Perioperative results of the matched population
19 (21.3 %) 2 (2.2 %)
45 (14.2 %) 5 (1.6 %)
0.100 0.977
Type, n (%)
MIE (n = 58)
OE (n = 58)
P
Length of stay (range), days
10 (7–70)
18 (20.2 %)
49 (15.4 %)
0.279
Readmission to ICU, n (%)
Wound infection
3 (3.4 %)
13 (4.1 %)
0.999
Chylothorax
1 (1.1 %)
6 (1.9 %)
0.977
Gastrointestinal complications Anastomotic leak Delayed gastric emptying Other Hoarseness
a
Pneumonia was defined by clinical and radiographic criteria, including armpit-temperature [38.5 °C, WBC [ 10 9 109/L, positive sputum culture, and patchy shadow in X-ray
b
OE (n = 58)
12 (7–254)
Morbidity Pulmonary complications
MIE (n = 58)
Pulmonary embolus was diagnosed by ultrasonic cardiogram
considered to be significant. Statistical computations and plotting were performed using SPSS software, version 19.0 (SPSS, Chicago, IL).
12 (8–106)
0.032
4 (6.9 %)
12 (20.7 %)
0.031
Morbidity
22 (37.9 %)
35 (60.3 %)
0.016
Mortality
2 (3.4 %)
5 (8.6 %)
0.435
12 (20.7 %) 7 (12.1 %)
23 (39.7 %) 16 (27.6 %)
0.026 0.036
3 (5.2 %)
5 (8.6 %)
0.714
Pulmonary complications Pneumonia Pleural effusion req. drainage ARDS
1 (1.7 %)
2 (3.4 %)
1.000
Pulmonary embolus
1 (1.7 %)
0 (0.0 %)
1.000
4 (6.9 %)
5 (8.6 %)
1.000
Atrial fibrillation
4 (6.9 %)
4 (6.9 %)
0.714
Myocardial infarction
0 (0.0 %)
1 (1.7 %)
1.000
17 (29.3 %)
10 (17.2 %)
0.124
10 (17.2 %)
6 (10.3 %)
0.281
0 (0.0 %)
4 (6.9 %)
0.127
14 (24.1 %) 1 (1.7 %)
8 (13.8 %) 5 (8.6 %)
0.155 0.208
1 (1.7 %)
1 (1.7 %)
0.476
Cardiovascular complications
Gastrointestinal complications
Results
Anastomotic leak Delayed gastric emptying
No patients were converted to open procedures and all patients in both groups received R0 dissection. Patients and tumor demographics are listed in Table 1. Since patients with severe comorbidities were excluded from surgery, comorbidities in Table 1 consisted of controllable or uneventful hypertension, diabetes mellitus, arrhythmia, cerebral infarction, etc. The tumors in the OE group were significantly more advanced than those in the MIE group. There were significantly more instances of application of the left thoracic approach in the OE group. The perioperative results are shown in Table 2. Rates of readmission to the ICU in the MIE group were significantly lower than that in the OE group (9.0 vs. 18.6 %, p = 0.031). No significant difference was found in length of hospital stay or the rates of morbidity and mortality. There were 19 (19/ 407, 4.7 %) perioperative deaths. Ten patients died of
Other complications Hoarseness Wound infection Chylothorax
pneumonia, four of severe anastomotic leak or gastric necrosis, two of pulmonary embolus, two of myocardial infarction, and one of acute respiratory distress syndrome (ARDS). After matching for age, sex, comorbidity, tumor location, histology, TNM stage, and operative approach (Table 3), 116 patients (58 receiving open esophagectomy and 58 receiving MIE) were eligible for analysis. The perioperative results are given in Table 4. The length of hospital stay in the MIE group was significantly shorter
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Fig. 1 Disease-specific survival time of the pair-matched population
rates of other complications between the two groups did not reach statistical significance. Seven patients received adjuvant chemotherapy in the MIE group compared to five patients in the OE group. No patient received adjuvant radiotherapy in MIE, while two patients received radiotherapy in the OE group due to recurrence of cervical lymph nodes. Among the general population, there were 193 patients (47.4 %) who ceased to report to the out-patient clinic regularly. After repeated attempts at telephone follow-up, there were still 142 censored patients (34.9 %) that we failed to reach. Among the pair-matched population, 13 patients (22.4 %) were lost to follow up in the MIE group and 21 patients (36.2 %) in the OE group. The median duration of follow-up was 27 months (range 1–99). Fewer than half of the patients in the MIE group died. Thus, the median disease-specific survival time (including postoperative deaths) in the MIE group was greater than the median duration of follow-up and was also significantly longer than that in the OE group ([27 months [range 1–82] vs. 24 months [range 1–99], P = 0.003) (Fig. 1). There was no difference in overall survival between the two groups (39 ± 8.9 vs. 22 ± 3.4 months, P = 0.070) (Fig. 2).
Discussion
Fig. 2 Overall survival of the pair-matched population
than that in the OE group (10 days [range 7–70] vs. 12 days [range 8–106], P = 0.032). Readmission to the ICU in the MIE group occurred at a significantly lower rate than in the OE group (6.9 vs. 20.7 %, P = 0.031). The complication rate in the MIE group was significantly lower than that in the OE group (37.9 vs. 60.3 %, P = 0.016). The pulmonary complication rate in the MIE group was significantly lower than that in the OE group (20.7 vs. 39.7 %, P = 0.026), especially the incidence of pneumonia (12.1 vs. 27.6 %, P = 0.036). Differences in incidence
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Shorter length of hospital stay, fewer pulmonary complications, lower rates of morbidity, and longer disease-specific survival time were recorded among elderly patients treated with MIE in this pair-matched study. Previous studies in large series of esophageal cancer patients showed that advanced age is a significant risk factor for surgical mortality [2, 3]. However, Jougon [12] compared a series of 89 patients older than 70 years with a group of patients younger than 70 years and suggested that esophagectomy could be performed in selected elderly patients with acceptable morbidity (24.7 %) and mortality (7.8 %). In Japan, Fang and his colleagues [13] reported that esophagectomy with 3-field lymph node dissection could be carried out safely in patients over 70 years, with an in-hospital mortality of approximately 7.6 % in their series of 240 patients older than 70 years vs. 3.3 % for patients younger than 70 years. Although many studies are optimistic about esophagectomy performed in elderly patients [14–16], there are still some concerns among thoracic surgeons and patients with respect to generally high perioperative mortality (7.6–11.6 %) [12, 13, 17]. Abunasra and his colleagues [18] reported that pulmonary complications accounted for 51.4 % (19/37) of in-hospital deaths, especially pulmonary infections (17/37,46.0 %). As was seen in our series, there
Surg Endosc
were two in-hospital deaths (one from pneumonia and one from myocardial infarction) in patients undergoing MIE vs. five deaths (three from pneumonia, one from severe gastric necrosis, and one from pulmonary embolus) in patients undergoing open esophagectomy. Hence, minimizing pulmonary complications is a shortcut to lowering the mortality rate. The results from a recent randomized controlled trial showed that MIE is generally advantageous over open esophagectomy in terms of a reduced rate of pulmonary infection [5]. Furthermore, combined with our previous experience [6, 10, 11], applying this minimally invasive approach to elderly patients might harvest the benefits of reduced pulmonary complications, or even lower perioperative mortality rates. Indeed, with comparable comorbidity, there were fewer pulmonary complications and shorter length of hospital stay in the MIE group compared with the OE group (Table 3, 4). The analysis of disease-specific survival time in matched patients found a significant intergroup difference. We considered that there might be multiple reasons accounting for the survival benefit among elderly patients. Chiefly, elderly patients in the MIE group suffered significantly fewer postoperative complications, and even promising better QoL [6], which in turn might provide a survival benefit due to fast recovery and better general condition. Furthermore, MIE is more costly than open esophagectomy [19]. Though there are no directly supportive data, in our experience, this leads to patient selection such that the proportion of higher economic classes is greater in patients treated with MIE than that in those treated with open esophagectomy. Low economic class might potentially compromise postoperative care, general follow-up, and even adjuvant therapy. Possibly as a result of this phenomenon, partially due to insufficient adjuvant chemotherapy, nontumorous deaths and the high rates of censored patients, no significant difference in overall survival was noted in elderly patients in the MIE or OE groups (P = 0.070). However, there are also several limitations to our study. First, the decision whether the patient underwent open or MIE was determined by multiple factors, for instance, economic and educational background of patients and available time and willingness of different surgeons for different patients. Since this was a retrospective study, certain defects of this study were uncontrollable, such as the exact proportion of the above factors. Previously, the common approach for esophageal cancer within our department was open esophagectomy through left or right thoracic approach. It was not until May, 2004 that we started applying MIE for this malignant disease. After slowly accumulating nearly 50 patients of clinical Stage I esophageal cancer, surgeons of our thoracic department have gradually passed their learning curve by February,
2005, when we began to enroll patients treated with both open and MIE in this study. Hence, by pair-matching patients, we have attempted to eliminate selection bias as rigorously as possible outside of the setting of a randomized, prospective study. Second, though the attrition rate for follow-up was high, there would be minor impact on significance of the result if it was randomized attrition which was confirmed by our further statistical analysis between the patients who still stayed in follow-up or out of follow-up of each group. Additionally, in our practice, those who had several comorbidities or poor performance status were generally excluded from surgery by surgeons, patients, or patients’ relatives. Hence, the occurrence of comorbidities in both populations (21/89, 23.6 % vs. 57/318, 18.0 %, P = 0.230) was relatively lower than in previous reported series [15, 17, 20].
Conclusions Compared with traditional open esophagectomy, successful utilization of MIE for esophagectomy of esophageal carcinoma is associated with a reduced incidence of pulmonary complications and a longer survival time in elderly patients. In conclusion, a minimally invasive approach to esophageal cancer resection may be preferred in elderly patients, although further investigations are needed to confirm this conclusion. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 81370587). Disclosure Jingpei Li, Yaxing Shen, Lijie Tan, Mingxiang Feng, Hao Wang, Yong Xi, and Qun Wang declare no conflict of interest.
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