Ann Surg Oncol DOI 10.1245/s10434-015-4556-6
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Salvage Esophagectomy After Definitive Chemoradiotherapy for Patients with Esophageal Squamous Cell Carcinoma: Who Really Benefits from this High-Risk Surgery? Masayuki Watanabe, MD, PhD, FACS, Shinji Mine, MD, Koujiro Nishida, MD, PhD, Kazuhiko Yamada, MD, PhD, Hironobu Shigaki, MD, PhD, Akira Matsumoto, MD, and Takeshi Sano, MD, PhD Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
ABSTRACT Purpose. The aim of this study was to identify good candidates for salvage esophagectomy after definitive chemoradiotherapy (dCRT), based on safety and survival. Methods. Sixty-three patients who underwent salvage esophagectomy, after dCRT, at the Cancer Institute Hospital, Tokyo, Japan, between 1988 and 2013, were retrospectively analyzed. Short-term outcomes were evaluated by reviewing postoperative complications, length of postoperative hospital stay, and mortality. Survival rates were calculated using the Kaplan–Meier method, and statistical significance was determined using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses of overall survival. Univariate logistic regression analysis was used to identify factors related to R0 resection. Results. Postoperative complications occurred in 41 patients (65.1 %), and the mortality rate was 7.9 %. Inhospital deaths did not occur among patients with less advanced tumors prior to dCRT (cT1–2 and cN0), or among those who had previously achieved a complete response (CR); the 3- and 5-year overall survival rates were 29.8 % and 15.0 %, respectively. Univariate analysis revealed that residual disease, tumor depth, dCRT response, lymph node metastasis, and time to relapse were significant
Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4556-6) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2015 First Received: 27 December 2014 M. Watanabe, MD, PhD, FACS e-mail: [email protected]
factors affecting overall survival. Multivariate analysis demonstrated that R0 resection and ypT0–2 tumors were significant, favorable prognostic factors in patients undergoing salvage esophagectomy. In addition, cT1–2 tumors, initially resectable tumors, ycT1–2 tumors, and relapse after CR were factors predicting R0 resection. Conclusions. Based on both short- and long-term outcomes, patients with pretreatment or preoperative T1–2 tumors and those with relapse after CR are good candidates for salvage esophagectomy.
Definitive chemoradiotherapy (dCRT) is a treatment modality that has the potential to cure patients of esophageal cancer. Squamous cell carcinoma, the predominant histologic type of esophageal cancer among Asian individuals, tends to respond especially well to dCRT. According to Japan Clinical Oncology Group studies, complete response (CR) was achieved following dCRT by 89 and 63 % of patients with stage I and stage II/III disease, respectively.1,2 Even in patients with T4 tumors and/ or M1 lymph node metastases, 33 % have been reported to achieve CRs.3 Despite the high CR rates, locoregional failure occurs in 40–60 % of patients who previously achieved CR.1–5 Salvage esophagectomy is almost the only method that offers any chance of long-term survival to patients with residual or relapsed tumors after dCRT.6 However, salvage esophagectomies are also associated with high rates of morbidity and mortality; morbidity rates are reported to range from 50 to 79 %,6–11 and in-hospital mortality is reported to be 6–22 %.6–16 Another problem associated with this surgery is its poor long-term outcomes, with 5-year survival rates of 0–33 %.6,8,9,12–15
M. Watanabe et al.
Although several authors have reported the prognostic factors for patients undergoing salvage esophagectomy, based on small case series,6,9,14,15 the subpopulation of individuals who really benefit from this high-risk surgery remains unclear. In this study, we retrospectively analyzed the short- and longterm outcomes of patients who underwent esophagectomy in our institute, after failed dCRT, to identify those who were good candidates for this type of surgery.
Kaplan–Meier method, and statistical significance was determined using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate overall survival analyses. Univariate logistic regression analysis was used to identify factors related to R0 resection.
METHODS
Patient Characteristics
Patients
A total of 58 males and 5 females (mean age 63 years) underwent salvage esophagectomies (see Table 1 for patient characteristics). Pretreatment evaluations revealed that 30 patients (47.6 %) had resectable tumors, and the remaining patients had unresectable tumors. CR to dCRT was achieved in 20 patients (31.7 %), and persistent tumors were observed in 43 patients (Table 1).
Between April 1988 and December 2013, a total of 63 patients underwent salvage esophagectomy at the Cancer Institute Hospital, Tokyo, Japan, and were included in this study. The Ethics Committees of the Cancer Institute Hospital approved this study and waived the need for informed consent for the study due to its retrospective nature.
RESULTS
Operative and Pathologic Findings Data Collection Hospital records were reviewed to determine patient age, sex, tumor location, staging, tumor resectability, radiation dose, response to dCRT, and pathology. Clinical and pathologic findings were classified according to the TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer (7th edition).17 Short-term outcomes were evaluated through a review of postoperative complications using the Clavien– Dindo classification,18 postoperative hospital stays, and mortality. Long-term outcomes were assessed based on overall survival from the day of the salvage esophagectomy to the date of death or the last known follow-up date.
The operative and pathologic findings of the patients are shown in electronic supplementary Table 1. Transthoracic esophagectomy was performed in 60 patients; 2 patients underwent transhiatal esophagectomy and 1 patient underwent transcervical esophagectomy. Three-, two-, and one-field lymphadenectomies were performed in 18, 41, and 4 patients, respectively. Type ypT0–2 and ypT3– 4 tumors were found in 25 (39.7 %) and 38 (60.3 %) patients, respectively; lymph node metastasis was observed in 24 cases (38.1 %). R0 resection was achieved in 46 patients (73.0 %), whereas R1 and R2 resections were performed in 4 and 13 patients, respectively. Short-Term Outcomes
Chemoradiotherapy Fifty-one patients underwent radiotherapy or chemoradiotherapy in our institute, while the remaining 12 patients had already received the treatment before referral to our hospital. Twelve patients were treated with radiation therapy alone and 51 underwent concurrent CRT. Radiation dose ranged from 50 to 70 Gy, and the median was 60 Gy. Chemotherapeutic regimens during dCRT were 5-fluorouracil plus cisplatin in 48 patients, cisplatin alone in 2 patients, and 5-fluorouracil alone in 1 patient.
Short-term outcomes after salvage esophagectomy are shown in Electronic Supplementary Table 2. The overall complication rate was 65.1 % and the mortality rate was 7.9 %. We compared the clinicopathological backgrounds between the groups, stratified according to the presence or absence of in-hospital mortality (Table 2), but a statistically significant factor relating to the occurrence of postoperative mortality was not evident. However, in-hospital mortality was never observed among the 20 patients with cT1–2 tumors, the 24 patients without nodal involvement before dCRT, or the 20 patients who achieved CR to dCRT.
Statistical Analysis Long-Term Outcomes All quantitative data are expressed as means ± one standard deviation. Statistical analyses were performed using the JMP 10 software program (SAS Institute, Cary, NC, USA). Survival rates were calculated using the
The 3- and 5-year overall survival rates of the 63 patients were 29.8 % and 15.0 %, respectively. Univariate analysis (Table 3) revealed that residual disease [R0;
Outcomes of Salvage Esophagectomy TABLE 1 Patient characteristics Variable Age at primary treatment [years; mean ± SD (range)]
63.0 ± 8.1 (45–83)
Sex
0.34, 95 % CI 0.141–0.792) were independent factors influencing overall survival. Survival curves for the patients, stratified by tumor depth and residual disease, are shown in Fig. 1a, b, respectively. Factors Predicting R0 Resection
Male
58 (92.1)
Female
5 (7.9)
Tumor location Upper
25 (39.7)
Middle Lower
29 (46.0) 9 (14.3)
cTa T1
10 (15.9)
T2
10 (15.9)
T3
22 (34.9)
T4
21 (33.3)
cNa
To identify the factors predicting R0 resection, before salvage esophagectomy, we performed a univariate logistic regression analysis (Table 4). The results indicated that tumor depth prior to surgery [ycT1–2; odds ratio (OR) 22.73, 95 % CI 4.090–427.906], tumor depth before dCRT (cT1–2; OR 11.26, 95 % CI 2.023–211.811), dCRT response (CR; OR 11.26, 95 % CI 2.023–211.811), and resectability before dCRT (resectable tumors; OR 6.63, 95 % CI 1.858–31.727) were factors related to R0 resection; however, we could not identify any independent factors predicting R0 resection.
Negative
24 (38.1)
Positive
39 (61.9)
DISCUSSION
M0
61 (96.8)
M1
2 (3.2)
In this study, we confirmed that salvage esophagectomy, after dCRT, was a high-risk surgery with a morbidity rate of 65.1 % and a mortality rate of 7.9 %. However, inhospital deaths were not observed among patients with less advanced tumors existing prior to dCRT (cT1–2 and cN0) or among those who had previously achieved a CR. R0 resection and ypT0–2 tumors were significant, favorable prognostic factors for patients who underwent salvage esophagectomy. In addition, cT1–2 tumors, initially resectable tumors, ycT1–2 tumors, and relapse after CR were factors predicting R0 resection. This study aimed to identify patients who were good candidates for salvage esophagectomy, and the results suggest that good candidates for this high-risk surgery are patients who can tolerate the high-risk surgery well and have the potential to achieve long-term survival. Therefore, we investigated the short-term outcomes to identify those factors affecting in-hospital mortality, and evaluated the long-term outcomes to clarify the prognostic factors, using one of the largest case-volume cohorts reported to date. We found that both the pretreatment tumor status and the response to dCRT may influence the in-hospital mortality rate. In our hospital, we have never experienced the in-hospital death of a patient with cT1–2 or cN0 tumors. During salvage esophagectomy, surgeons experience difficulty dissecting the indistinct planes between the tumor and the fibrotic masses within the irradiated tissue.19 In particular, tumors invading the adventitia, or those with lymph node metastases and extranodal spread, can cause fibrotic scars after dCRT, making the dissection challenging. In contrast, in patients with cT1–2 or cN0 tumors, indistinct planes are seldom encountered. Hence, this may
cMa
cStagea I
8 (12.7)
II III
13 (20.6) 16 (25.3)
IV
26 (41.3)
Resectabilitya Resectable
30 (47.6)
Unresectable
33 (52.4)
Radiation dose (Gy) 50 B dose \ 60
10 (15.9)
C60
53 (84.1)
Concurrent chemotherapy Present
51 (81.0)
Absent
12 (19.0)
Clinical response Complete
20 (31.7)
Incomplete
43 (68.3)
Data are expressed as n (%) unless otherwise indicated a
Diagnosed before definitive chemoradiotherapy
hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.088–0.374], pathologic tumor depth (ypT1/T2; HR 0.25, 95 % CI 0.124–0.484), dCRT response (CR; HR 0.34, 95 % CI 0.147–0.697), pathologic nodal status (ypN0; HR 0.51, 95 % CI 0.278–0.943), and time to relapse (every month; HR 0.93, 95 % CI 0.859–0.981) were significant factors affecting overall survival. Multivariate analysis (Table 3) demonstrated that residual disease (R0; HR 0.27, 95 % CI 0.115–0.614), and tumor depth (ypT1/T2; HR
M. Watanabe et al. TABLE 2 Clinicopathological backgrounds between the groups stratified according to presence or absence of in-hospital mortality Variables
Hospital mortality
p value
Absent (N = 58)
Present (N = 5)
63.3 ± 7.9 (45–83)
59.4 ± 10.5 (49–75)
0.31
Male
54 (93.1)
4 (80.0)
0.35
Female
4 (6.9)
1 (20.0)
Age, years (range) Sex
Location Upper
23 (39.7)
1 (20.0)
Middle Lower
26 (44.8) 9 (15.5)
3 (60.0) 1 (20.0)
T1/2
20 (34.5)
0
T3/4
38 (65.5)
5 (100)
Negative
24 (41.4)
0
Positive
34 (58.6)
5 (100)
Resectable
30 (51.7)
3 (60.0)
Unresectable
28 (48.3)
2 (40.0)
20 (34.5)
0
0.69
cT before dCRT 0.17
cN before dCRT 0.15
Resectability 1.00
Response to dCRT Complete Incomplete
0.17
38 (65.5)
5 (100)
Length from CRT to surgery (months)
10.5 ± 14.3
7.4 ± 4.6
0.32
ycT T1/2
27 (46.6)
1 (20.0)
0.37
T3/4
31 (53.5)
4 (80.0)
Negative
30 (51.7)
1 (20.0)
Positive
28 (48.3)
4 (80.0)
Operation time (min)
500 ± 129
403 ± 175
0.061
Blood loss (g)
617 ± 496
359 ± 184
0.13
ycN 0.35
Data are expressed as n (%) or mean ± one standard deviation dCRT definitive chemoradiotherapy
be why pretreatment tumor status influences the mortality rate. Although the reason why the response to dCRT affects the in-hospital death rate remains unclear, patients with early-stage disease tend to achieve CR, and the longer interval between dCRT completion and surgery may decrease the risk of postoperative events. Similarly, Hofstetter indicated that the latent period between the completion of radiation and surgical resection may affect the extent of small-vessel radiation damage and potentially jeopardize stomach viability.20 We demonstrated that R0 resection and pT0–2 tumors were independent, favorable prognostic factors after salvage esophagectomy. Several other authors have also investigated the prognostic factors for patients undergoing salvage esophagectomy. Swisher et al. performed a univariate analysis for survival among 13 patients and
revealed that improved survival was associated with early tumor pathologic stage (T1N0, T2N0), prolonged time to relapse, and R0 resection.6 Miyata et al. found that pretreatment T and N status, pathological T stage, and operative curability were significant prognostic factors, based on a univariate analysis of 33 patients.14 Morita et al. performed multivariate analysis for survival among 27 patients and revealed that incomplete resection was an independent, unfavorable prognostic factor.21 Wang et al. reported the results of a multivariate analysis involving 104 patients, and stated that CR, R0 resection, pathologic N and M tumor categories, and total mediastinal dissection with more than 15 dissected nodes were independent prognostic factors.22 Thus, these reports suggest that similar results were obtained among the researchers and that there seems to be a consensus that R0 resection is
Outcomes of Salvage Esophagectomy TABLE 3 Univariate and multivariate analysis of salvage esophagectomy prognostic factors Variable
Reference
Univariate analysis
Multivariate analysis
HR
95 % CI
p value
0.99
0.954–1.026
0.57
HR
95 % CI
p value
0.61
0.290–1.274
0.19
Age
Every year
Sex
Male
Female
0.59
0.211–2.486
0.42
Location
Lower
Upper or middle
0.62
0.231–1.365
0.25
Resectability
Resectable
Unresectable
0.60
0.337–1.068
0.083
cT
T1/T2
T3/T4
0.70
0.374–1.278
0.25
cN
N0
Positive
0.71
0.384–1.288
0.27
Response to dCRT
Complete
Incomplete
0.34
0.147–0.697
0.0024
0.99
0.363–2.831
0.99
Time to relapse
Every month
0.93
0.859–0.981
0.0016
0.94
0.846–1.006
0.081
Operation time
Every minute
1.00
1.001–1.001
0.26
Blood loss
Every 1 g
1.00
1.000–1.001
0.38
No. of dissected nodes
Every node
0.99
0.981–1.006
0.33
No. of metastatic nodes
Every node
1.09
0.992–1.182
0.069
1.05
0.919–1.172
0.45
ypT
T1/T2
T3/T4
0.25
0.124–0.484
\0.0001
0.34
0.141–0.792
0.013
ypN
N0
Positive
0.51
0.278–0.943
0.032
0.89
0.368–2.081
0.79
Residual disease
R0
R1/R2
0.18
0.088–0.374
\0.0001
0.27
0.115–0.614
0.021
HR hazard ratio, CI confidence interval, dCRT definitive chemoradiotherapy
necessary to achieve long-term survival after salvage esophagectomy. Therefore, we next investigated the preoperative factors predicting R0 resection, and found that ycT1–2 tumors, cT1–2 tumors, dCRT response, and the presence of initially resectable tumors were significant factors in the univariate analysis. Interestingly, some of these factors overlapped with factors influencing the safety of the surgery. Although independent predictive factors were not identified for R0 resection, selection of good candidates for salvage surgery, based on these factors, will still be possible. In this study, a regimen of 5-fluorouracil plus cisplatin was used for dCRT in many cases. Although this
P < 0.0001
80 ypT0-2
60 40
ypT3
20 0
No. at risk
(B)
100
Overall survival (%)
Overall survival (%)
(A)
regimen still remains a standard worldwide, studies to establish new regimens to improve treatment effect or to reduce toxicity are in progress. Carboplatin plus paclitaxel has been reported to show comparable effects, with lower toxicity compared with 5-fluorouracil plus cisplatin, as both dCRT 23 and preoperative CRT.24 A phase II study of dCRT with docetaxel, cisplatin, and 5-fluorouracil demonstrated a high CR rate of 52.4 %, although this regimen frequently caused myelosuppression and esophagitis.25 Development of novel regimens may improve curability or decrease mortality of salvage esophagectomy, and will hopefully reduce the need for high-risk surgery.
ypT4 0
1
0Y
1Y
3 2 4 Years after surgery 2Y
3Y
5Y
P < 0.0001
80 60 R0
40 R2
20 0
R1
0
1
No. at risk
0Y
1Y
2Y
3Y
4Y
5Y
46
31
18
14
9
6
5
4Y
100
3 2 4 Years after surgery
5
ypT0-2
24
21
14
11
6
6
R0
ypT3
19
10
5
4
4
1
R1
4
4
0
0
0
0
0
R2
13
2
0
0
0
0
ypT4
19
5
2
0
0
FIG. 1 Overall survival, stratified by a pathologic tumor depth and b residual tumor. Significantly better survivals were observed in patients with ypT0–2 tumors, and in those with R0 resection
M. Watanabe et al. TABLE 4 Univariate analysis of R0 resection predictive factors Variables
Reference
Univariate analysis HR
95 % CI
p value
Age
Every year
1.04
0.973–1.127
0.23
Location
Lower
Upper/middle
2.05
0.464–8.365
0.33
Resectability
Resectable
Unresectable
6.63
1.858–31.727
0.0071
cT
T1/T2
T3/T4
cN
Negative
Positive
Response to dCRT
Complete
Incomplete
Interval before surgery ycT
Every month T1/T2
T3/T4
ycN
Negative
Positive
11.26
2.023–211.811
0.0031
0.752–9.938
0.15
11.26
2.023–211.811
0.0031
1.04 22.74
0.987–1.156 4.098–427.906
0.28 \0.0001
3.12
0.985–11.165
0.053
2.50
HR hazard ratio, CI confidence interval, dCRT definitive chemoradiotherapy
There are several limitations to this study. First, this was a retrospective study conducted at a single institute. Salvage esophagectomy is a high-risk surgery that can be performed only by experienced surgeons in high-volume centers. Moreover, even in high-volume esophageal surgery centers, the number of cases is still limited. Thus, this salvage esophagectomy study includes one of the largest number of cases reported to date. However, to establish evidence for such rare and difficult situations, data collection across multiple, high-volume centers is needed. Second, the selection of good candidates for salvage surgery may carry a risk that patients who do not meet the criteria will lose the chance of being cured. As a matter of course, all patients who present with persistent or recurrent locoregional disease, after dCRT, and who do not have evidence of systemic disease, are candidates for salvage resection.21 Thus, the indications for surgery should be decided by the patients, in conjunction with their surgeons, on the basis of adequate, informed consent, including the risk/benefit balance. CONCLUSIONS Salvage esophagectomies can be performed safely in patients with less advanced cancers (cT1–2 and cN0 tumors) and in those who have previously achieved a CR following dCRT. Pathologic T stage (T0–2) and R0 resection are independent, favorable prognostic factors. Based on both short- and long-term outcomes, patients with pretreatment or preoperative T1–2 tumors, and those who have relapsed after CR, are good candidates for salvage esophagectomy. DISCLOSURE Masayuki Watanabe, Shinji Mine, Koujiro Nishida, Kazuhiko Yamada, Hironobu Shigaki, Akira Matsumoto, and Takeshi Sano have no disclosure to declare.
REFERENCES 1. Kato H, Sato A, Fukuda H, et al. A phase II trial of chemoradiotherapy for stage I esophageal squamous cell carcinoma: Japan Clinical Oncology Group study (JCOG9708). Jpn J Clin Oncol. 2009;39:638–43. 2. Kato K, Muro K, Manashi K, et al. Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for stage II-III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906). Int J Radiat Oncol Biol Phys. 2011;81:684–90. 3. Ohtsu A, Baku N, Muro K, et al. Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. J Clin Oncol. 1999;17:2915–21. 4. Yamamoto S, Ishihara R, Motoori M, et al. Comparison between definitive chemoradiotherapy and esophagectomy in patients with clinical stage I esophageal squamous cell carcinoma. Am J Gastroenterol. 2011;106:1048–54. 5. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer. Long-term follow-up of a prospective randomized trial (RTOG 85-01). JAMA. 1999;281: 1623–7. 6. Swisher SG, Wynn P, Putnam JB, et al. Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radiotherapy. J Thorac Cardiovasc Surg. 2002;123:175–83. 7. Smithers BM, Cullinan M, Thomas JM, et al. Outcomes from salvage esophagectomy post definitive chemoradiotherapy compared with resection following preoperative neoadjuvant chemoradiotherapy. Dis Esophagus. 2007;20:471–7. 8. Meunier B, Raoul J, LePrise E, et al. Salvage esophagectomy after unsuccessful curative chemoradiotherapy for squamous cell cancer of the esophagus. Dig Surg. 1998;15:224–6. 9. Tomimaru Y, Yano M, Takachi K, et al. Factors affecting prognosis of patients with esophageal cancer undergoing salvage surgery after definitive chemoradiotherapy. J Surg Oncol. 2006; 93:422–8. 10. Oki E, Morita M, Kakeji Y, et al. Salvage esophagectomy after definitive chemoradiotherapy for esophageal cancer. Dis Esophagus. 2007;20:301–4. 11. Nishimura M, Daiko H, Yoshida J, Nagai K. Salvage esophagectomy following definitive chemoradiotherapy. Gen Thorac Cardiovasc Surg. 2007;55:461–5. 12. Nakamura T, Hayahsi K, Ota M, et al. Salvage esophagectomy after definitive chemotherapy and radiotherapy for advanced esophageal cancer. Am J Surg. 2004;188:261–6.
Outcomes of Salvage Esophagectomy 13. Chao YK, Chan SC, Chang HK, et al. Salvage surgery after failed chemoradiotherapy in squamous cell carcinoma of the esophagus. Eur J Surg Oncol. 2009;35:289–94. 14. Miyata H, Yamasaki M, Takiguchi S, et al. Salvage esophagectomy after definitive chemoradiotherapy for thoracic esophageal cancer. J Surg Oncol. 2009;100:442–6. 15. Takeuchi H, Saikawa Y, Oyama T, et al. Factors influencing the long-term survival in patients with esophageal cancer who underwent esophagectomy after chemoradiotherapy. World J Surg. 2010;34:277–84. 16. Wilson KS, Wilson AG, Dewar GJ. Curative treatment for esophageal cancer: Vancouver Island Cancer Center experience from 1993 to 1998. Can J Gastroenterol. 2002;16:361–8. 17. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumors. 7th ed. Oxford: Wiley-Blackwell; 2010. 18. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of survey. Ann Surg. 2004;240:205–13. 19. Tachimori Y. Salvage esophagectomy after definitive chemoradiotherapy. Gen Thorac Cardiovasc Surg. 2009;57:71–8. 20. Hofstetter WL. Salvage esophagectomy. J Thorac Dis. 2014;6: S341–9.
21. Morita M, Kumashiro R, Hisamatsu Y, et al. Clinical significance of salvage esophagectomy for remnant or recurrent cancer following definitive chemoradiotherapy. J Gastroenterol. 2011;46: 1284–91. 22. Wang S, Tachimori Y, Hokamura N, et al. Prognostic analysis of salvage esophagectomy after definitive chemoradiotherapy for esophageal squamous cell carcinoma: the importance of lymphadenectomy. J Thorac Cardiovasc Surg. 2014;147:1805–11. 23. Honing J, Smit JK, Muijis CT, et al. A comparison of carboplatin and paclitaxel with cisplatin and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients. Ann Oncol. 2014; 25:638–43. 24. van Hagen P, Hulschof MCCM, van Lanschot JJB, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84. 25. Higuchi K, Komori S, Tanabe S, et al. Definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer: a phase 2 trial (KDOG 0501-P2). Int J Radiat Oncol Biol Phys. 2014;89:872–9.
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Salvage Esophagectomy After Definitive Chemoradiotherapy for Patients with Esophageal Squamous Cell Carcinoma: Who Really Benefits from this High-Risk Surgery? Masayuki Watanabe, MD, PhD, FACS, Shinji Mine, MD, Koujiro Nishida, MD, PhD, Kazuhiko Yamada, MD, PhD, Hironobu Shigaki, MD, PhD, Akira Matsumoto, MD, and Takeshi Sano, MD, PhD Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
ABSTRACT Purpose. The aim of this study was to identify good candidates for salvage esophagectomy after definitive chemoradiotherapy (dCRT), based on safety and survival. Methods. Sixty-three patients who underwent salvage esophagectomy, after dCRT, at the Cancer Institute Hospital, Tokyo, Japan, between 1988 and 2013, were retrospectively analyzed. Short-term outcomes were evaluated by reviewing postoperative complications, length of postoperative hospital stay, and mortality. Survival rates were calculated using the Kaplan–Meier method, and statistical significance was determined using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses of overall survival. Univariate logistic regression analysis was used to identify factors related to R0 resection. Results. Postoperative complications occurred in 41 patients (65.1 %), and the mortality rate was 7.9 %. Inhospital deaths did not occur among patients with less advanced tumors prior to dCRT (cT1–2 and cN0), or among those who had previously achieved a complete response (CR); the 3- and 5-year overall survival rates were 29.8 % and 15.0 %, respectively. Univariate analysis revealed that residual disease, tumor depth, dCRT response, lymph node metastasis, and time to relapse were significant
Electronic supplementary material The online version of this article (doi:10.1245/s10434-015-4556-6) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2015 First Received: 27 December 2014 M. Watanabe, MD, PhD, FACS e-mail: [email protected]
factors affecting overall survival. Multivariate analysis demonstrated that R0 resection and ypT0–2 tumors were significant, favorable prognostic factors in patients undergoing salvage esophagectomy. In addition, cT1–2 tumors, initially resectable tumors, ycT1–2 tumors, and relapse after CR were factors predicting R0 resection. Conclusions. Based on both short- and long-term outcomes, patients with pretreatment or preoperative T1–2 tumors and those with relapse after CR are good candidates for salvage esophagectomy.
Definitive chemoradiotherapy (dCRT) is a treatment modality that has the potential to cure patients of esophageal cancer. Squamous cell carcinoma, the predominant histologic type of esophageal cancer among Asian individuals, tends to respond especially well to dCRT. According to Japan Clinical Oncology Group studies, complete response (CR) was achieved following dCRT by 89 and 63 % of patients with stage I and stage II/III disease, respectively.1,2 Even in patients with T4 tumors and/ or M1 lymph node metastases, 33 % have been reported to achieve CRs.3 Despite the high CR rates, locoregional failure occurs in 40–60 % of patients who previously achieved CR.1–5 Salvage esophagectomy is almost the only method that offers any chance of long-term survival to patients with residual or relapsed tumors after dCRT.6 However, salvage esophagectomies are also associated with high rates of morbidity and mortality; morbidity rates are reported to range from 50 to 79 %,6–11 and in-hospital mortality is reported to be 6–22 %.6–16 Another problem associated with this surgery is its poor long-term outcomes, with 5-year survival rates of 0–33 %.6,8,9,12–15
M. Watanabe et al.
Although several authors have reported the prognostic factors for patients undergoing salvage esophagectomy, based on small case series,6,9,14,15 the subpopulation of individuals who really benefit from this high-risk surgery remains unclear. In this study, we retrospectively analyzed the short- and longterm outcomes of patients who underwent esophagectomy in our institute, after failed dCRT, to identify those who were good candidates for this type of surgery.
Kaplan–Meier method, and statistical significance was determined using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate overall survival analyses. Univariate logistic regression analysis was used to identify factors related to R0 resection.
METHODS
Patient Characteristics
Patients
A total of 58 males and 5 females (mean age 63 years) underwent salvage esophagectomies (see Table 1 for patient characteristics). Pretreatment evaluations revealed that 30 patients (47.6 %) had resectable tumors, and the remaining patients had unresectable tumors. CR to dCRT was achieved in 20 patients (31.7 %), and persistent tumors were observed in 43 patients (Table 1).
Between April 1988 and December 2013, a total of 63 patients underwent salvage esophagectomy at the Cancer Institute Hospital, Tokyo, Japan, and were included in this study. The Ethics Committees of the Cancer Institute Hospital approved this study and waived the need for informed consent for the study due to its retrospective nature.
RESULTS
Operative and Pathologic Findings Data Collection Hospital records were reviewed to determine patient age, sex, tumor location, staging, tumor resectability, radiation dose, response to dCRT, and pathology. Clinical and pathologic findings were classified according to the TNM classification of the Union for International Cancer Control and the American Joint Committee on Cancer (7th edition).17 Short-term outcomes were evaluated through a review of postoperative complications using the Clavien– Dindo classification,18 postoperative hospital stays, and mortality. Long-term outcomes were assessed based on overall survival from the day of the salvage esophagectomy to the date of death or the last known follow-up date.
The operative and pathologic findings of the patients are shown in electronic supplementary Table 1. Transthoracic esophagectomy was performed in 60 patients; 2 patients underwent transhiatal esophagectomy and 1 patient underwent transcervical esophagectomy. Three-, two-, and one-field lymphadenectomies were performed in 18, 41, and 4 patients, respectively. Type ypT0–2 and ypT3– 4 tumors were found in 25 (39.7 %) and 38 (60.3 %) patients, respectively; lymph node metastasis was observed in 24 cases (38.1 %). R0 resection was achieved in 46 patients (73.0 %), whereas R1 and R2 resections were performed in 4 and 13 patients, respectively. Short-Term Outcomes
Chemoradiotherapy Fifty-one patients underwent radiotherapy or chemoradiotherapy in our institute, while the remaining 12 patients had already received the treatment before referral to our hospital. Twelve patients were treated with radiation therapy alone and 51 underwent concurrent CRT. Radiation dose ranged from 50 to 70 Gy, and the median was 60 Gy. Chemotherapeutic regimens during dCRT were 5-fluorouracil plus cisplatin in 48 patients, cisplatin alone in 2 patients, and 5-fluorouracil alone in 1 patient.
Short-term outcomes after salvage esophagectomy are shown in Electronic Supplementary Table 2. The overall complication rate was 65.1 % and the mortality rate was 7.9 %. We compared the clinicopathological backgrounds between the groups, stratified according to the presence or absence of in-hospital mortality (Table 2), but a statistically significant factor relating to the occurrence of postoperative mortality was not evident. However, in-hospital mortality was never observed among the 20 patients with cT1–2 tumors, the 24 patients without nodal involvement before dCRT, or the 20 patients who achieved CR to dCRT.
Statistical Analysis Long-Term Outcomes All quantitative data are expressed as means ± one standard deviation. Statistical analyses were performed using the JMP 10 software program (SAS Institute, Cary, NC, USA). Survival rates were calculated using the
The 3- and 5-year overall survival rates of the 63 patients were 29.8 % and 15.0 %, respectively. Univariate analysis (Table 3) revealed that residual disease [R0;
Outcomes of Salvage Esophagectomy TABLE 1 Patient characteristics Variable Age at primary treatment [years; mean ± SD (range)]
63.0 ± 8.1 (45–83)
Sex
0.34, 95 % CI 0.141–0.792) were independent factors influencing overall survival. Survival curves for the patients, stratified by tumor depth and residual disease, are shown in Fig. 1a, b, respectively. Factors Predicting R0 Resection
Male
58 (92.1)
Female
5 (7.9)
Tumor location Upper
25 (39.7)
Middle Lower
29 (46.0) 9 (14.3)
cTa T1
10 (15.9)
T2
10 (15.9)
T3
22 (34.9)
T4
21 (33.3)
cNa
To identify the factors predicting R0 resection, before salvage esophagectomy, we performed a univariate logistic regression analysis (Table 4). The results indicated that tumor depth prior to surgery [ycT1–2; odds ratio (OR) 22.73, 95 % CI 4.090–427.906], tumor depth before dCRT (cT1–2; OR 11.26, 95 % CI 2.023–211.811), dCRT response (CR; OR 11.26, 95 % CI 2.023–211.811), and resectability before dCRT (resectable tumors; OR 6.63, 95 % CI 1.858–31.727) were factors related to R0 resection; however, we could not identify any independent factors predicting R0 resection.
Negative
24 (38.1)
Positive
39 (61.9)
DISCUSSION
M0
61 (96.8)
M1
2 (3.2)
In this study, we confirmed that salvage esophagectomy, after dCRT, was a high-risk surgery with a morbidity rate of 65.1 % and a mortality rate of 7.9 %. However, inhospital deaths were not observed among patients with less advanced tumors existing prior to dCRT (cT1–2 and cN0) or among those who had previously achieved a CR. R0 resection and ypT0–2 tumors were significant, favorable prognostic factors for patients who underwent salvage esophagectomy. In addition, cT1–2 tumors, initially resectable tumors, ycT1–2 tumors, and relapse after CR were factors predicting R0 resection. This study aimed to identify patients who were good candidates for salvage esophagectomy, and the results suggest that good candidates for this high-risk surgery are patients who can tolerate the high-risk surgery well and have the potential to achieve long-term survival. Therefore, we investigated the short-term outcomes to identify those factors affecting in-hospital mortality, and evaluated the long-term outcomes to clarify the prognostic factors, using one of the largest case-volume cohorts reported to date. We found that both the pretreatment tumor status and the response to dCRT may influence the in-hospital mortality rate. In our hospital, we have never experienced the in-hospital death of a patient with cT1–2 or cN0 tumors. During salvage esophagectomy, surgeons experience difficulty dissecting the indistinct planes between the tumor and the fibrotic masses within the irradiated tissue.19 In particular, tumors invading the adventitia, or those with lymph node metastases and extranodal spread, can cause fibrotic scars after dCRT, making the dissection challenging. In contrast, in patients with cT1–2 or cN0 tumors, indistinct planes are seldom encountered. Hence, this may
cMa
cStagea I
8 (12.7)
II III
13 (20.6) 16 (25.3)
IV
26 (41.3)
Resectabilitya Resectable
30 (47.6)
Unresectable
33 (52.4)
Radiation dose (Gy) 50 B dose \ 60
10 (15.9)
C60
53 (84.1)
Concurrent chemotherapy Present
51 (81.0)
Absent
12 (19.0)
Clinical response Complete
20 (31.7)
Incomplete
43 (68.3)
Data are expressed as n (%) unless otherwise indicated a
Diagnosed before definitive chemoradiotherapy
hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.088–0.374], pathologic tumor depth (ypT1/T2; HR 0.25, 95 % CI 0.124–0.484), dCRT response (CR; HR 0.34, 95 % CI 0.147–0.697), pathologic nodal status (ypN0; HR 0.51, 95 % CI 0.278–0.943), and time to relapse (every month; HR 0.93, 95 % CI 0.859–0.981) were significant factors affecting overall survival. Multivariate analysis (Table 3) demonstrated that residual disease (R0; HR 0.27, 95 % CI 0.115–0.614), and tumor depth (ypT1/T2; HR
M. Watanabe et al. TABLE 2 Clinicopathological backgrounds between the groups stratified according to presence or absence of in-hospital mortality Variables
Hospital mortality
p value
Absent (N = 58)
Present (N = 5)
63.3 ± 7.9 (45–83)
59.4 ± 10.5 (49–75)
0.31
Male
54 (93.1)
4 (80.0)
0.35
Female
4 (6.9)
1 (20.0)
Age, years (range) Sex
Location Upper
23 (39.7)
1 (20.0)
Middle Lower
26 (44.8) 9 (15.5)
3 (60.0) 1 (20.0)
T1/2
20 (34.5)
0
T3/4
38 (65.5)
5 (100)
Negative
24 (41.4)
0
Positive
34 (58.6)
5 (100)
Resectable
30 (51.7)
3 (60.0)
Unresectable
28 (48.3)
2 (40.0)
20 (34.5)
0
0.69
cT before dCRT 0.17
cN before dCRT 0.15
Resectability 1.00
Response to dCRT Complete Incomplete
0.17
38 (65.5)
5 (100)
Length from CRT to surgery (months)
10.5 ± 14.3
7.4 ± 4.6
0.32
ycT T1/2
27 (46.6)
1 (20.0)
0.37
T3/4
31 (53.5)
4 (80.0)
Negative
30 (51.7)
1 (20.0)
Positive
28 (48.3)
4 (80.0)
Operation time (min)
500 ± 129
403 ± 175
0.061
Blood loss (g)
617 ± 496
359 ± 184
0.13
ycN 0.35
Data are expressed as n (%) or mean ± one standard deviation dCRT definitive chemoradiotherapy
be why pretreatment tumor status influences the mortality rate. Although the reason why the response to dCRT affects the in-hospital death rate remains unclear, patients with early-stage disease tend to achieve CR, and the longer interval between dCRT completion and surgery may decrease the risk of postoperative events. Similarly, Hofstetter indicated that the latent period between the completion of radiation and surgical resection may affect the extent of small-vessel radiation damage and potentially jeopardize stomach viability.20 We demonstrated that R0 resection and pT0–2 tumors were independent, favorable prognostic factors after salvage esophagectomy. Several other authors have also investigated the prognostic factors for patients undergoing salvage esophagectomy. Swisher et al. performed a univariate analysis for survival among 13 patients and
revealed that improved survival was associated with early tumor pathologic stage (T1N0, T2N0), prolonged time to relapse, and R0 resection.6 Miyata et al. found that pretreatment T and N status, pathological T stage, and operative curability were significant prognostic factors, based on a univariate analysis of 33 patients.14 Morita et al. performed multivariate analysis for survival among 27 patients and revealed that incomplete resection was an independent, unfavorable prognostic factor.21 Wang et al. reported the results of a multivariate analysis involving 104 patients, and stated that CR, R0 resection, pathologic N and M tumor categories, and total mediastinal dissection with more than 15 dissected nodes were independent prognostic factors.22 Thus, these reports suggest that similar results were obtained among the researchers and that there seems to be a consensus that R0 resection is
Outcomes of Salvage Esophagectomy TABLE 3 Univariate and multivariate analysis of salvage esophagectomy prognostic factors Variable
Reference
Univariate analysis
Multivariate analysis
HR
95 % CI
p value
0.99
0.954–1.026
0.57
HR
95 % CI
p value
0.61
0.290–1.274
0.19
Age
Every year
Sex
Male
Female
0.59
0.211–2.486
0.42
Location
Lower
Upper or middle
0.62
0.231–1.365
0.25
Resectability
Resectable
Unresectable
0.60
0.337–1.068
0.083
cT
T1/T2
T3/T4
0.70
0.374–1.278
0.25
cN
N0
Positive
0.71
0.384–1.288
0.27
Response to dCRT
Complete
Incomplete
0.34
0.147–0.697
0.0024
0.99
0.363–2.831
0.99
Time to relapse
Every month
0.93
0.859–0.981
0.0016
0.94
0.846–1.006
0.081
Operation time
Every minute
1.00
1.001–1.001
0.26
Blood loss
Every 1 g
1.00
1.000–1.001
0.38
No. of dissected nodes
Every node
0.99
0.981–1.006
0.33
No. of metastatic nodes
Every node
1.09
0.992–1.182
0.069
1.05
0.919–1.172
0.45
ypT
T1/T2
T3/T4
0.25
0.124–0.484
\0.0001
0.34
0.141–0.792
0.013
ypN
N0
Positive
0.51
0.278–0.943
0.032
0.89
0.368–2.081
0.79
Residual disease
R0
R1/R2
0.18
0.088–0.374
\0.0001
0.27
0.115–0.614
0.021
HR hazard ratio, CI confidence interval, dCRT definitive chemoradiotherapy
necessary to achieve long-term survival after salvage esophagectomy. Therefore, we next investigated the preoperative factors predicting R0 resection, and found that ycT1–2 tumors, cT1–2 tumors, dCRT response, and the presence of initially resectable tumors were significant factors in the univariate analysis. Interestingly, some of these factors overlapped with factors influencing the safety of the surgery. Although independent predictive factors were not identified for R0 resection, selection of good candidates for salvage surgery, based on these factors, will still be possible. In this study, a regimen of 5-fluorouracil plus cisplatin was used for dCRT in many cases. Although this
P < 0.0001
80 ypT0-2
60 40
ypT3
20 0
No. at risk
(B)
100
Overall survival (%)
Overall survival (%)
(A)
regimen still remains a standard worldwide, studies to establish new regimens to improve treatment effect or to reduce toxicity are in progress. Carboplatin plus paclitaxel has been reported to show comparable effects, with lower toxicity compared with 5-fluorouracil plus cisplatin, as both dCRT 23 and preoperative CRT.24 A phase II study of dCRT with docetaxel, cisplatin, and 5-fluorouracil demonstrated a high CR rate of 52.4 %, although this regimen frequently caused myelosuppression and esophagitis.25 Development of novel regimens may improve curability or decrease mortality of salvage esophagectomy, and will hopefully reduce the need for high-risk surgery.
ypT4 0
1
0Y
1Y
3 2 4 Years after surgery 2Y
3Y
5Y
P < 0.0001
80 60 R0
40 R2
20 0
R1
0
1
No. at risk
0Y
1Y
2Y
3Y
4Y
5Y
46
31
18
14
9
6
5
4Y
100
3 2 4 Years after surgery
5
ypT0-2
24
21
14
11
6
6
R0
ypT3
19
10
5
4
4
1
R1
4
4
0
0
0
0
0
R2
13
2
0
0
0
0
ypT4
19
5
2
0
0
FIG. 1 Overall survival, stratified by a pathologic tumor depth and b residual tumor. Significantly better survivals were observed in patients with ypT0–2 tumors, and in those with R0 resection
M. Watanabe et al. TABLE 4 Univariate analysis of R0 resection predictive factors Variables
Reference
Univariate analysis HR
95 % CI
p value
Age
Every year
1.04
0.973–1.127
0.23
Location
Lower
Upper/middle
2.05
0.464–8.365
0.33
Resectability
Resectable
Unresectable
6.63
1.858–31.727
0.0071
cT
T1/T2
T3/T4
cN
Negative
Positive
Response to dCRT
Complete
Incomplete
Interval before surgery ycT
Every month T1/T2
T3/T4
ycN
Negative
Positive
11.26
2.023–211.811
0.0031
0.752–9.938
0.15
11.26
2.023–211.811
0.0031
1.04 22.74
0.987–1.156 4.098–427.906
0.28 \0.0001
3.12
0.985–11.165
0.053
2.50
HR hazard ratio, CI confidence interval, dCRT definitive chemoradiotherapy
There are several limitations to this study. First, this was a retrospective study conducted at a single institute. Salvage esophagectomy is a high-risk surgery that can be performed only by experienced surgeons in high-volume centers. Moreover, even in high-volume esophageal surgery centers, the number of cases is still limited. Thus, this salvage esophagectomy study includes one of the largest number of cases reported to date. However, to establish evidence for such rare and difficult situations, data collection across multiple, high-volume centers is needed. Second, the selection of good candidates for salvage surgery may carry a risk that patients who do not meet the criteria will lose the chance of being cured. As a matter of course, all patients who present with persistent or recurrent locoregional disease, after dCRT, and who do not have evidence of systemic disease, are candidates for salvage resection.21 Thus, the indications for surgery should be decided by the patients, in conjunction with their surgeons, on the basis of adequate, informed consent, including the risk/benefit balance. CONCLUSIONS Salvage esophagectomies can be performed safely in patients with less advanced cancers (cT1–2 and cN0 tumors) and in those who have previously achieved a CR following dCRT. Pathologic T stage (T0–2) and R0 resection are independent, favorable prognostic factors. Based on both short- and long-term outcomes, patients with pretreatment or preoperative T1–2 tumors, and those who have relapsed after CR, are good candidates for salvage esophagectomy. DISCLOSURE Masayuki Watanabe, Shinji Mine, Koujiro Nishida, Kazuhiko Yamada, Hironobu Shigaki, Akira Matsumoto, and Takeshi Sano have no disclosure to declare.
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