Ann Surg Oncol (2015) 22:240–246 DOI 10.1245/s10434-014-3970-5
ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Clinical Significance of Surgical Resection for the Recurrence of Esophageal Cancer After Radical Esophagectomy Yukiharu Hiyoshi, MD, PhD1, Masaru Morita, MD, PhD, FACS1, Hiroyuki Kawano, MD1, Hajime Otsu, MD1, Koji Ando, MD, PhD1, Shuhei Ito, MD, PhD1, Yuji Miyamoto, MD, PhD2, Yasuo Sakamoto, MD, PhD2, Hiroshi Saeki, MD, PhD1, Eiji Oki, MD, PhD1, Tetsuo Ikeda, MD, PhD1, Hideo Baba, MD, PhD, FACS2, and Yoshihiko Maehara, MD, PhD, FACS1 1
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 2
ABSTRACT Background. This study aimed to clarify the clinical significance of surgical resection for recurrent lesions after esophagectomy for esophageal cancer. Methods. Recurrence was detected in 113 of 365 consecutive patients who underwent surgical resection for esophageal cancer, and some treatment was performed for recurrence in 100 of the 113 patients. The treatments were classified into two groups: chemotherapy and/or radiation with surgery (surgery group, n = 14) and chemotherapy and/or radiation without surgery (no surgery group, n = 86). The outcomes were retrospectively analyzed. Results. Of the 14 patients in the surgery group, 3 underwent repeated resection. Thus, a total of 22 resections were performed for these patients. The resected organs were the lymph nodes in nine patients, the lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, the liver in one patient, the brain in one patient, and the parotid gland in one patient. Among the 22 recurrent cases, 20 involved solitary lesions or multiple lesions located in a small resectable region. When the two groups were compared, the surgery group showed a more favorable prognosis in terms of both survival after esophagectomy (median survival time, 103.3 vs 23.1 months; p = 0.0060) and survival after initial recurrence (92.1 vs 12.2 months; p = 0.0057).
Ó Society of Surgical Oncology 2014 First Received: 24 May 2014; Published Online: 15 August 2014 M. Morita, MD, PhD, FACS e-mail: [email protected]
Conclusions. Multimodal treatment provides a significant benefit for patients with recurrence after esophagectomy for esophageal cancer. Surgical intervention should be aggressively included in the treatment strategy when the recurrent lesion is solitary or localized.
Esophageal cancer is a highly lethal disease and also one of the most common neoplasms. Recent advances in multimodal treatment, including endoscopic treatment, esophagectomy with three-field lymph node dissection, and definite chemoradiotherapy (CRT), have improved the prognosis of patients with esophageal cancer. Although the overall 5-year survival rate currently exceeds 50 %, recurrence still develops within 1 to 3 years after resection in more than half of these patients.1–7 We previously reported the characteristics and recurrence patterns after curative esophagecromy.8,9 In these reports, the recurrence patterns were classified as locoregional (54 %), hematogenous (36 %), or mixed type (10 %), and patients with recurrence treated by chemotherapy alone or multimodal therapy such as radiation or surgery combined with systemic chemotherapy, survived significantly longer than those with untreatable recurrence.9 However, the clinical significance of surgical treatment for recurrence was unclear in that study because only four patients underwent surgical resection for recurrent disease. Recent studies have demonstrated that surgical resection for recurrence of esophageal cancer could be an acceptable treatment that can improve the survival of patients with recurrence in the lymph nodes10–12 and lungs.13–15 We recently changed the indications for surgical resection to include patients with recurrence after esophageal
Surgical Resection for Recurrent Esophageal Cancer
cancer whose the lesions are solitary or localized. The number of patients treated with multimodal treatment, including surgery, for recurrence of esophageal cancer has increased. We therefore reviewed the recent clinical results of surgical resection for the recurrence of esophageal cancer after radical esophagectomy to determine whether surgery can improve the outcome for patients with recurrent disease. PATIENTS AND METHODS Patients Between 1998 and 2012, 365 Japanese patients consecutively underwent radical (R0) esophagectomy and reconstruction for esophageal cancer in the Department of Surgery and Science (Department of Surgery II) at Kyushu University. Positive lymph node metastasis was confirmed pathologically in 142 patients (38.9 %). The postoperative pathologies were classified as stage 0 in 33 patients, stage 1 in 67 patients, stage 2 in 148 patients, stage 3 in 109 patients, and stage 4 in 8 patients by the tumor-nodemetastasis (TNM) classification defined by the Union for International Cancer Control (UICC International Union Against Cancer, TNM Classification of Malignant Tumors, 7th edition). The patients with pathologically positive node metastasis were given postoperative chemotherapy. The study protocol and the patients’ informed consent statements were approved by the Institutional Review Board of Kyushu University Hospital. Follow-up Evaluation The patients were followed up at a minimum of 1-month intervals during the first year, at 3-month intervals until the fifth year, and on an annual basis thereafter. Recurrence was confirmed by clinical examinations including computed tomography (CT), ultrasonography, endoscopy, and [18F]-fluorodeoxyglucose–positron emission tomography CT (FDG-PET CT). Patients visited the outpatient clinic, and their tumor marker levels were measured every month for 2 years after surgery and every 3 months from 3 years until 5 years after surgery. Ultrasonography and CT scanning from the neck to the upper abdomen were performed at least twice a year for 3 years after surgery and then once each year from 4 years until 5 years after surgery. To these exams, FDGPET CT was added for some patients considered to be at high risk for recurrence and if recurrence was strongly suggested by another diagnostic method such as CT or elevated tumor marker levels. Endoscopy was performed
241
annually to detect anastomotic recurrence as well as second primary cancers, particularly in the head and neck. Surgical Indication and Procedure As a general rule, we performed surgical resection for recurrent esophageal cancer only when the recurrence was solitary or occurred in a localized field and the tumor was considered to be completely resectable. The recurrent tumors were completely resected, but prophylactic resection, such as radical neck dissection or lung lobectomy, was not performed. After surgery, adjuvant chemotherapy or prophylactic radiotherapy was performed in most cases. Statistical Analysis The association between the treatment for recurrence and the clinicopathologic factors was assessed using the v2 two-tailed test or Fisher’s exact test. Survival curves were plotted according to the Kaplan–Meier method, with the differences between two curves analyzed using the logrank test. All statistical analyses were performed using the Graphpad Prism software program, version 5.0 (Graphpad Software Inc, San Diego, CA, USA). A p value lower than 0.05 was considered significant. RESULTS Recurrences were recognized in 113 (31 %) of the 365 patients. Of the 113 patients, 13 received only best supportive care. We therefore analyzed 100 patients who underwent anticancer treatments for recurrence. Among these 100 patients, 14 underwent surgical resection in combination with chemotherapy, radiation therapy, or both for recurrence (surgery group). On the other hand, 86 patients were treated with chemotherapy, radiation therapy, or both without surgery (no surgery group). The median follow-up time after esophagectomy for these 100 patients was 20.8 months. Table 1 shows the clinical characteristics and treatments in the surgery group. Of the 14 patients, 3 underwent repeated resection for recurrent diseases (case 1: five times; case 2 and case 3: three times), and a total of 22 resections were performed in the 14 patients. The resected organs were lymph nodes in nine patients, lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, liver in one patient, brain in one patient, and parotid gland in one patient. Of the 22 recurrences, 4 (18.2 %) were treated with preoperative chemotherapy, and 18 (81.8 %) were treated with chemotherapy, radiation therapy, or both as adjuvant treatment.
64
42
62
65
64
62
65
72
44
69 50
73
4
5
6
7
8
9
10
11
12 13
14
T1bN2M0
T3N2M0 T3N2M0
T3N0M0
T3N0M0
T3N0M0
T4aN0M0
T1bN0M0
T3N1M0
T1bN0M0
T3N2M0
T1bN1M0
Neck LN Neck LN Right Lung Right Lung
74.2 11.5 12.4 31.3
65.9
15.8
4.5 10.4
4.6
9.3
6.9
5.5
11.9
12.2
LN resection
Neck LN
Brain Neck LN
Left Lung
Local
Chemo
None
None None
None
None
None
None
None
Resection & reconstruction
Left parotid grand resection
Partial hepatectomy
Neck dissection
Resection & reconstruction
Neck dissection
Resection of brain tumor Neck dissection
Partial pulmonary resection
None
None Chemo
None
None
None
None
None
Chemo
Chemo
Bilateral partial pulmonary None resection with chest wall resection
Partial pulmonary resection
Partial pulmonary resection
Neck dissection Neck dissection
Partial pulmonary resection with chest wall resection
Partial pulmonary resection
Lung & hip subcutaneous Hip tumor resection
Local
Left parotid grand
Liver
Neck LN & bone
Bilateral lung & chest wall invasion
Right lung & chest wall invasion
52.7
21.7
Left lung
41.3
LN resection
LN resection
CRT
Chemo CRT
None
RT
Chemo
Chemo
CRT
Chemo
Chemo
Chemo
None
CRT
CRT CRT
RT
Chemo
RT
None
None
Chemo
CRT
Postop
76.9
41.8
41.9
83.3
17.8
27.8
15.3
17.0
Alive
23.1
Died of disease 7.7 Alive 18.6
Alive
Alive
Died of disease 16.6
Alive
Alive
Died of disease 35.3
Alive
Died of other cause
Alive
Alive
a
Age at esophagectomy
7.3
3.1 8.2
10.7
7.7
9.7
12.3
15.9
23.1
11.0
20.1
30.4
42.0
92.1
Survival after Survival primary surgery after (months) recurrence (months)
Died of disease 103.3
Prognosis
TNM tumor-node-metastasis, Preop preoperatively, Postop, postoperatively, CRT chemoradiotherapy, LN lymph node, RT radiation therapy, Chemo chemotherapy
M
M M
F
F
M
M
M
M
M
M
F
T2N0M0
Right axillary LN
3
M
76.4
67
Right axillary LN
63.4
None
2
Right axillary LN
58.6
LN resection
None
Right chest wall Right axillary LN
11.2 23.2
Tumor resection
T2N3M0
57
1
M
Preop
Other treatments
Surgery for recurrence
Case Age Gender TNM Time to Site of recurrence (years)a classification recurrence of primary (months) lesion
TABLE 1 Characteristics of the patients who underwent surgical resection for recurrences after radical esophagectomy
242 Y. Hiyoshi et al.
Surgical Resection for Recurrent Esophageal Cancer
Among the 22 recurrences, 20 were solitary lesions or multiple lesions located in a small resectable area. On the other hand, two cases (cases 5 and 9) involved multiple lesions located in different areas. In case 5, recurrences of cancer the neck lymph node and bone both developed. After systemic chemotherapy (docetaxel, cisplatin, and 5-FU; six courses), the bone metastasis became undetectable by FDG-PET, and resection of the metastatic neck lymph node was performed. In case 9, recurrence had developed in the right lung and the subcutaneous hip region. Because the hip lesion caused pain, the lesion was resected as palliative surgery, and systemic chemotherapy for the lung metastasis was performed after resection. The lymph node recurrences were seen in the axilla and neck, and the mean number of metastases was 3.3 (range, 1–8). In terms of survival, the patients with solitary-node recurrence (cases 3, 5, and 14) did not differ significantly from those with multiple-node metastases (cases 1, 2, and 13) (Kaplan–Meier analysis, data not shown). Regarding hematogenous recurrences, in case 4, bilateral lung metastases were resected synchronously. In case 6, a solitary liver metastasis was resected after systemic chemotherapy. However, lung and lymph node recurrence developed after the surgery. In case 12, the patient showed impaired consciousness and convulsions caused by solitary brain tumor recurrence, and the tumor was resected during an emergency surgery. However, multiple recurrences in the lung, kidney, and lymph node developed soon after surgery. Regarding local recurrence, in cases 8 and 10, resection for local recurrence around the anastomosis and reconstruction with a free jejunal graft were performed. Table 2 shows a comparison of the clinicopathologic findings and the type of recurrence between the groups (patients with or without surgery). The type of recurrence was classified into three patterns (loco-regional, hematogenous, and mixed type), with the latter defined as lymphatic recurrence concomitant with hematogenous recurrence, as reported previously.8 Comparison of the surgery and no surgery groups showed no significant differences in age, gender, pathologic findings of the primary esophageal cancer, interval between esophagectomy and recurrence, or the type of recurrence. Figure 1 shows the results from the Kaplan–Meier analysis of the recurrence-free survival after esophagectomy. The median recurrence-free survival time was 11.4 months in the surgery group and 8.5 months in the no surgery group. The log-rank test showed no significant differences in the recurrence-free survival between the two groups. Figure 2 shows the results of the Kaplan–Meier analysis for the cancer-specific survival both after esophagectomy (Fig. 2a) and after the initial recurrence (Fig. 2b). For the surgery and no surgery groups, the respective median survival times after esophagectomy were 103.3 and
243 TABLE 2 Comparison of the clinicopathologic findings between the two groups stratified by treatment for recurrence Factors
No surgery groupa (n = 86)
Surgery groupb (n = 14)
p value
62.5 (37–85)
65.5 (44–75)
NS
79/7
11/3
NS
30/56
6/8
NS
31/55
7/7
NS
10.0 (1.0–49.7)
11.4 (4.5–65.9)
NS
51/22/13
6/7/1
NS
Age at recurrence Median: years (range) Gender Male/female Pathologic findings of primary esophageal cancer Depth of invasion T1-2/T3-4 Lymph node metastasis N–/N? Time of recurrence Median: months (range) Type of recurrence Loco-regional/ hematogenous/mixed a
Patients treated with chemotherapy and/or radiation and surgery
b
Patients treated with chemotherapy and/or radiation without surgery
NS not significant
23.1 months, and the median survival times after initial recurrence were 92.1 and 12.2 months. The surgery group showed a more favorable prognosis in terms of both survival after esophagectomy and survival after initial recurrence according to the log-rank test. DISCUSSION Increasing evidence supports the efficacy of CRT in the treatment of primary esophageal cancer.16,17 On the other hand, the response to CRT is low for recurrent esophageal cancer, and complete remissions are few.18 However, because surgical treatment is indicated for only a small number of patients who show localized tumor recurrence, radiation, chemotherapy, or both still are generally used in many unresectable cases. We have aggressively indicated salvage resection followed by chemotherapy, radiation therapy, or both for cases of localized recurrence. In the current retrospective study, we evaluated the clinical significance of surgical resection for the recurrence of esophageal cancer after radical esophagectomy. Among 100 patients who underwent some treatment(s) for recurrence of esophageal cancer, a total of 22 recurrent lesions in 14 patients were surgically resected. Both the survival after esophagectomy and the survival after initial recurrence were significantly better in the surgery group than in the group treated with chemotherapy, radiotherapy, or both.
244
Y. Hiyoshi et al.
The comparison between the two groups was performed with the understanding that there was an enormous selection bias. For example, 12 (86 %) of the 14 patients in the surgery group underwent surgical resection for recurrence more recently (2009–2012). Thus, the improved prognosis after surgical resection may have been due not only to the survival advantage associated with resection for recurrent disease but also to recent advances in multimodal treatment, such as chemotherapy or radiotherapy. However, consistent with our results, some previous reports have demonstrated surgical resection to be an acceptable treatment that could improve the survival of patients with a recurrence of esophageal cancer. With regard to lymph node recurrence, Motoyama et al.10 demonstrated that the outcomes of recurrent esophageal cancers localized to the neck lymph nodes were better than those seen with other lymph node recurrence patterns, and salvage resection followed by chemoradiotherapy seems to be indicated for those patients. Yano et al.11 demonstrated that the number of relapsed cervical nodes (solitary/multiple) was a significant prognostic factor and concluded that a solitary
Recurrence free survival (%)
100 Surgery
(n=14)
No surgery (n=86)
80 60
NS
40 20 0 0
40
20
60
Time after esophagectomy (months) FIG. 1 Results of the Kaplan–Meier analysis of recurrence-free survival after esophagectomy
A 100
Surgery No surgery
nodal recurrence could be a candidate for surgical resection. The treatment outcome of resection for lymph node recurrence in the mediastinum or abdomen also was reported.12 Our results additionally indicate that surgical resection may be one of the treatment options for either solitary or localized node metastases. Metachronous pulmonary metastasis from esophageal cancer is seen in 17.5 to 41.4 % of the cases with hematogenous recurrence, and it is one of the main recurrence patterns.5,6,19 With regard to colorectal cancer, surgical intervention for metachronous pulmonary metastasis has been reported by several authors and is widely accepted.20 The treatment outcome of surgical resection for lung metastasis of esophageal cancer also has been evaluated in some recent studies. For example, Ichikawa et al.13 retrospectively analyzed 23 consecutive patients who underwent surgical resection for metachronous pulmonary metastasis of esophageal cancer. The median survival time was 28.7 months, and extrapulmonary metastasis as the initial recurrence site was an unfavorable prognostic factor. Similarly, studies have demonstrated that solitary pulmonary metastasis might be a good candidate for surgical resection, thus resulting in a favorable prognosis.14,15 In the current study, six partial pulmonary resections were performed for metastatic esophageal cancer in four patients. Importantly, two patients (patients 2 and 3) underwent repeated pulmonary resections for metachronous disease, and patient 4 underwent synchronous bilateral resection for bilateral lung metastases. Three of these four patients still were alive at the last follow-up evaluation (1 patient had died of another disease), and the mean survival time after esophagectomy was 45.6 months (range, 15.3–83.3 months). These findings may demonstrate that not only solitary lung metastasis but also bilateral lesions and metachronous multiple lesions can be candidates for surgical resection. Because previous operations generally result in the formation of fibrous adhesions to the surrounding tissue,
B 100 80
(n=14)
60 40 20
(n=86)
P=0.0060 0
Survival (%)
Survival (%)
80
Surgery No surgery
60
(n=14)
40 20
(n=86)
P=0.0057 0
0
20
40
Time after esophagectomy (months)
60
0
20
40
60
Time after initial recurrence (months)
FIG. 2 Results of the Kaplan–Meier analysis of cancer-specific survival. a Survival after esophagectomy. b Survival after initial recurrence
Surgical Resection for Recurrent Esophageal Cancer
the surgical approach for local recurrence after radical esophagectomy usually is difficult, and CRT tends to be clinically applied for such patients. In such cases, salvage surgery for patients with a good performance status or chemotherapy alone is considered to be the treatment for local recurrence, but the risk of salvage surgery still is extremely high.21–23 In the current study, two patients who had been treated with CRT for primary esophageal cancer underwent resection of local recurrence followed by reconstruction using a free jejunal graft, and both patients still are alive without recurrence at this writing (respective survival times, 17.0 and 17.8 months). As reported previously, salvage surgery with free jejunal transfer is considered to be safe for patients previously treated with definitive CRT ([50 Gy) or radical esophagectomy.24,25 The microvascular anastomosis was safely applied with no critical postoperative complications.26 Although surgical resection for recurrent esophageal cancer in the lymph nodes and lungs seems to have the potential to improve the prognosis, few reports have systematically demonstrated the prognostic advantages of surgical resection for other hematogenous recurrences, such as those to the liver, bone, and brain. In the current study, two patients underwent resection for liver recurrence and brain recurrence, respectively. Although the recurrent lesions were solitary in both cases, the patients died of multiple recurrences in other organs. The prognostic advantage of surgical resection for such lesions is still unclear at this writing. The advances in imaging modalities such as endoscopy, CT, and FDG-PET have enabled the detection of recurrent esophageal cancer at an early stage, so the opportunities to treat small solitary recurrences are expected to be increasing. In particular, FDG-PET has advantages because it can be used to detect recurrent disease in the whole body with high sensitivity.27 On the other hand, systemic chemotherapy currently is regarded as one of the most effective treatments for esophageal cancer. Although fluorouracil and cisplatin (FP) combination therapy has become a standard choice,28,29 many studies have reported that taxanes have significant activity in patients with advanced and metastatic esophageal cancer.30–32 Such novel effective chemotherapy might lead to the downstaging of unresectable recurrence of esophageal cancer, allowing more patients to be candidates for surgical resection. Taken together with the findings of previous studies, the results of this study suggest that a favorable outcome can be expected for selected patients with solitary or localized recurrence of esophageal cancer, especially for those with lymph node and lung recurrence. We believe that surgical intervention as a part of multimodal treatment for solitary or localized recurrence of esophageal cancer for patients
245
with a good performance status is acceptable and may have prognostic advantages. CONFLICT OF INTEREST
There are no conflicts of interest.
REFERENCES 1. Akiyama H, Tsurumaru M, Kawamura T, Ono Y. Principles of surgical treatment for carcinoma of the esophagus: analysis of lymph node involvement. Ann Surg. 1981;194:438–46. 2. Matthews HR, Powell DJ, McConkey CC. Effect of surgical experience on the results of resection for oesophageal carcinoma. Br J Surg. 1986;73:621–3. 3. Skinner DB, Little AG, Ferguson MK, Soriano A, Staszak VM. Selection of operation for esophageal cancer based on staging. Ann Surg. 1986;204:391–401. 4. Dresner SM, Griffin SM. Pattern of recurrence following radical oesophagectomy with two-field lymphadenectomy. Br J Surg. 2000;87:1426–33. 5. Hulscher JB, van Sandick JW, Tijssen JG, Obertop H, van Lanschot JJ. The recurrence pattern of esophageal carcinoma after transhiatal resection. J Am Coll Surg. 2000;191:143–8. 6. Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T, Hatakeyama K. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg. 2004;198:205–11. 7. Morita M, Yoshida R, Ikeda K, et al. Advances in esophageal cancer surgery in Japan: an analysis of 1,000 consecutive patients treated at a single institute. Surgery. 2008;143:499–508. 8. Morita M, Kuwano H, Ohno S, Furusawa M, Sugimachi K. Characteristics and sequence of the recurrent patterns after curative esophagectomy for squamous cell carcinoma. Surgery. 1994;116:1–7. 9. Sugiyama M, Morita M, Yoshida R, et al. Patterns and time of recurrence after complete resection of esophageal cancer. Surg Today. 2012;42:752–8. 10. Motoyama S, Kitamura M, Saito R, Maruyama K, Okuyama M, Ogawa J. Outcome and treatment strategy for mid- and lowerthoracic esophageal cancer recurring locally in the lymph nodes of the neck. World J Surg. 2006;30:191–8. 11. Yano M, Takachi K, Doki Y, et al. Prognosis of patients who develop cervical lymph node recurrence following curative resection for thoracic esophageal cancer. Dis Esophagus. 2006;19: 73–7. 12. Nakamura T, Ota M, Narumiya K, et al. Multimodal treatment for lymph node recurrence of esophageal carcinoma after curative resection. Ann Surg Oncol. 2008;15:2451–7. 13. Ichikawa H, Kosugi S, Nakagawa S, et al. Operative treatment for metachronous pulmonary metastasis from esophageal carcinoma. Surgery. 2011;149:164–70. 14. Takemura M, Sakurai K, Takii M, Yoshida K. Metachronous pulmonary metastasis after radical esophagectomy for esophageal cancer: prognosis and outcome. J Cardiothorac Surg. 2012;7: 103. 15. Chen F, Sato K, Sakai H, et al. Pulmonary resection for metastasis from esophageal carcinoma. Interact Cardiovasc Thorac Surg. 2008;7:809–12. 16. Hironaka S, Ohtsu A, Boku N, et al. Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T(2-3)N(any) M(0) squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 2003;57:425–33. 17. Law S, Kwong DL, Kwok KF, et al. Improvement in treatment results and long-term survival of patients with esophageal cancer:
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Y. Hiyoshi et al. impact of chemoradiation and change in treatment strategy. Ann Surg. 2003;238:339–47; discussion 347–338. Shimada H, Kitabayashi H, Nabeya Y, et al. Treatment response and prognosis of patients after recurrence of esophageal cancer. Surgery. 2003;133:24–31. Chen G, Wang Z, Liu XY, Liu FY. Recurrence pattern of squamous cell carcinoma in the middle thoracic esophagus after modified Ivor-Lewis esophagectomy. World J Surg. 2007;31: 1107–14. Pfannschmidt J, Dienemann H, Hoffmann H. Surgical resection of pulmonary metastases from colorectal cancer: a systematic review of published series. Ann Thorac Surg. 2007;84:324–38. Oki E, Morita M, Kakeji Y, et al. Salvage esophagectomy after definitive chemoradiotherapy for esophageal cancer. Dis Esophagus. 2007;20:301–4. 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. Morita M, Kumashiro R, Hisamatsu Y, et al. Clinical significance of salvage esophagectomy for remnant or recurrent cancer following definitive chemoradiotherapy. J Gastroentero. 2011;46:1284–91. Kadota H, Fukushima J, Nakashima T, et al. Comparison of salvage and planned pharyngolaryngectomy with jejunal transfer for hypopharyngeal carcinoma after chemoradiotherapy. Laryngoscope. 2010;120:1103–8. Ida S, Morita M, Hiyoshi Y, et al. Surgical resection of hypopharynx and cervical esophageal cancer with a history of
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ORIGINAL ARTICLE – GASTROINTESTINAL ONCOLOGY
Clinical Significance of Surgical Resection for the Recurrence of Esophageal Cancer After Radical Esophagectomy Yukiharu Hiyoshi, MD, PhD1, Masaru Morita, MD, PhD, FACS1, Hiroyuki Kawano, MD1, Hajime Otsu, MD1, Koji Ando, MD, PhD1, Shuhei Ito, MD, PhD1, Yuji Miyamoto, MD, PhD2, Yasuo Sakamoto, MD, PhD2, Hiroshi Saeki, MD, PhD1, Eiji Oki, MD, PhD1, Tetsuo Ikeda, MD, PhD1, Hideo Baba, MD, PhD, FACS2, and Yoshihiko Maehara, MD, PhD, FACS1 1
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan 2
ABSTRACT Background. This study aimed to clarify the clinical significance of surgical resection for recurrent lesions after esophagectomy for esophageal cancer. Methods. Recurrence was detected in 113 of 365 consecutive patients who underwent surgical resection for esophageal cancer, and some treatment was performed for recurrence in 100 of the 113 patients. The treatments were classified into two groups: chemotherapy and/or radiation with surgery (surgery group, n = 14) and chemotherapy and/or radiation without surgery (no surgery group, n = 86). The outcomes were retrospectively analyzed. Results. Of the 14 patients in the surgery group, 3 underwent repeated resection. Thus, a total of 22 resections were performed for these patients. The resected organs were the lymph nodes in nine patients, the lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, the liver in one patient, the brain in one patient, and the parotid gland in one patient. Among the 22 recurrent cases, 20 involved solitary lesions or multiple lesions located in a small resectable region. When the two groups were compared, the surgery group showed a more favorable prognosis in terms of both survival after esophagectomy (median survival time, 103.3 vs 23.1 months; p = 0.0060) and survival after initial recurrence (92.1 vs 12.2 months; p = 0.0057).
Ó Society of Surgical Oncology 2014 First Received: 24 May 2014; Published Online: 15 August 2014 M. Morita, MD, PhD, FACS e-mail: [email protected]
Conclusions. Multimodal treatment provides a significant benefit for patients with recurrence after esophagectomy for esophageal cancer. Surgical intervention should be aggressively included in the treatment strategy when the recurrent lesion is solitary or localized.
Esophageal cancer is a highly lethal disease and also one of the most common neoplasms. Recent advances in multimodal treatment, including endoscopic treatment, esophagectomy with three-field lymph node dissection, and definite chemoradiotherapy (CRT), have improved the prognosis of patients with esophageal cancer. Although the overall 5-year survival rate currently exceeds 50 %, recurrence still develops within 1 to 3 years after resection in more than half of these patients.1–7 We previously reported the characteristics and recurrence patterns after curative esophagecromy.8,9 In these reports, the recurrence patterns were classified as locoregional (54 %), hematogenous (36 %), or mixed type (10 %), and patients with recurrence treated by chemotherapy alone or multimodal therapy such as radiation or surgery combined with systemic chemotherapy, survived significantly longer than those with untreatable recurrence.9 However, the clinical significance of surgical treatment for recurrence was unclear in that study because only four patients underwent surgical resection for recurrent disease. Recent studies have demonstrated that surgical resection for recurrence of esophageal cancer could be an acceptable treatment that can improve the survival of patients with recurrence in the lymph nodes10–12 and lungs.13–15 We recently changed the indications for surgical resection to include patients with recurrence after esophageal
Surgical Resection for Recurrent Esophageal Cancer
cancer whose the lesions are solitary or localized. The number of patients treated with multimodal treatment, including surgery, for recurrence of esophageal cancer has increased. We therefore reviewed the recent clinical results of surgical resection for the recurrence of esophageal cancer after radical esophagectomy to determine whether surgery can improve the outcome for patients with recurrent disease. PATIENTS AND METHODS Patients Between 1998 and 2012, 365 Japanese patients consecutively underwent radical (R0) esophagectomy and reconstruction for esophageal cancer in the Department of Surgery and Science (Department of Surgery II) at Kyushu University. Positive lymph node metastasis was confirmed pathologically in 142 patients (38.9 %). The postoperative pathologies were classified as stage 0 in 33 patients, stage 1 in 67 patients, stage 2 in 148 patients, stage 3 in 109 patients, and stage 4 in 8 patients by the tumor-nodemetastasis (TNM) classification defined by the Union for International Cancer Control (UICC International Union Against Cancer, TNM Classification of Malignant Tumors, 7th edition). The patients with pathologically positive node metastasis were given postoperative chemotherapy. The study protocol and the patients’ informed consent statements were approved by the Institutional Review Board of Kyushu University Hospital. Follow-up Evaluation The patients were followed up at a minimum of 1-month intervals during the first year, at 3-month intervals until the fifth year, and on an annual basis thereafter. Recurrence was confirmed by clinical examinations including computed tomography (CT), ultrasonography, endoscopy, and [18F]-fluorodeoxyglucose–positron emission tomography CT (FDG-PET CT). Patients visited the outpatient clinic, and their tumor marker levels were measured every month for 2 years after surgery and every 3 months from 3 years until 5 years after surgery. Ultrasonography and CT scanning from the neck to the upper abdomen were performed at least twice a year for 3 years after surgery and then once each year from 4 years until 5 years after surgery. To these exams, FDGPET CT was added for some patients considered to be at high risk for recurrence and if recurrence was strongly suggested by another diagnostic method such as CT or elevated tumor marker levels. Endoscopy was performed
241
annually to detect anastomotic recurrence as well as second primary cancers, particularly in the head and neck. Surgical Indication and Procedure As a general rule, we performed surgical resection for recurrent esophageal cancer only when the recurrence was solitary or occurred in a localized field and the tumor was considered to be completely resectable. The recurrent tumors were completely resected, but prophylactic resection, such as radical neck dissection or lung lobectomy, was not performed. After surgery, adjuvant chemotherapy or prophylactic radiotherapy was performed in most cases. Statistical Analysis The association between the treatment for recurrence and the clinicopathologic factors was assessed using the v2 two-tailed test or Fisher’s exact test. Survival curves were plotted according to the Kaplan–Meier method, with the differences between two curves analyzed using the logrank test. All statistical analyses were performed using the Graphpad Prism software program, version 5.0 (Graphpad Software Inc, San Diego, CA, USA). A p value lower than 0.05 was considered significant. RESULTS Recurrences were recognized in 113 (31 %) of the 365 patients. Of the 113 patients, 13 received only best supportive care. We therefore analyzed 100 patients who underwent anticancer treatments for recurrence. Among these 100 patients, 14 underwent surgical resection in combination with chemotherapy, radiation therapy, or both for recurrence (surgery group). On the other hand, 86 patients were treated with chemotherapy, radiation therapy, or both without surgery (no surgery group). The median follow-up time after esophagectomy for these 100 patients was 20.8 months. Table 1 shows the clinical characteristics and treatments in the surgery group. Of the 14 patients, 3 underwent repeated resection for recurrent diseases (case 1: five times; case 2 and case 3: three times), and a total of 22 resections were performed in the 14 patients. The resected organs were lymph nodes in nine patients, lungs in six patients, local recurrence in two patients, subcutaneous recurrence in two patients, liver in one patient, brain in one patient, and parotid gland in one patient. Of the 22 recurrences, 4 (18.2 %) were treated with preoperative chemotherapy, and 18 (81.8 %) were treated with chemotherapy, radiation therapy, or both as adjuvant treatment.
64
42
62
65
64
62
65
72
44
69 50
73
4
5
6
7
8
9
10
11
12 13
14
T1bN2M0
T3N2M0 T3N2M0
T3N0M0
T3N0M0
T3N0M0
T4aN0M0
T1bN0M0
T3N1M0
T1bN0M0
T3N2M0
T1bN1M0
Neck LN Neck LN Right Lung Right Lung
74.2 11.5 12.4 31.3
65.9
15.8
4.5 10.4
4.6
9.3
6.9
5.5
11.9
12.2
LN resection
Neck LN
Brain Neck LN
Left Lung
Local
Chemo
None
None None
None
None
None
None
None
Resection & reconstruction
Left parotid grand resection
Partial hepatectomy
Neck dissection
Resection & reconstruction
Neck dissection
Resection of brain tumor Neck dissection
Partial pulmonary resection
None
None Chemo
None
None
None
None
None
Chemo
Chemo
Bilateral partial pulmonary None resection with chest wall resection
Partial pulmonary resection
Partial pulmonary resection
Neck dissection Neck dissection
Partial pulmonary resection with chest wall resection
Partial pulmonary resection
Lung & hip subcutaneous Hip tumor resection
Local
Left parotid grand
Liver
Neck LN & bone
Bilateral lung & chest wall invasion
Right lung & chest wall invasion
52.7
21.7
Left lung
41.3
LN resection
LN resection
CRT
Chemo CRT
None
RT
Chemo
Chemo
CRT
Chemo
Chemo
Chemo
None
CRT
CRT CRT
RT
Chemo
RT
None
None
Chemo
CRT
Postop
76.9
41.8
41.9
83.3
17.8
27.8
15.3
17.0
Alive
23.1
Died of disease 7.7 Alive 18.6
Alive
Alive
Died of disease 16.6
Alive
Alive
Died of disease 35.3
Alive
Died of other cause
Alive
Alive
a
Age at esophagectomy
7.3
3.1 8.2
10.7
7.7
9.7
12.3
15.9
23.1
11.0
20.1
30.4
42.0
92.1
Survival after Survival primary surgery after (months) recurrence (months)
Died of disease 103.3
Prognosis
TNM tumor-node-metastasis, Preop preoperatively, Postop, postoperatively, CRT chemoradiotherapy, LN lymph node, RT radiation therapy, Chemo chemotherapy
M
M M
F
F
M
M
M
M
M
M
F
T2N0M0
Right axillary LN
3
M
76.4
67
Right axillary LN
63.4
None
2
Right axillary LN
58.6
LN resection
None
Right chest wall Right axillary LN
11.2 23.2
Tumor resection
T2N3M0
57
1
M
Preop
Other treatments
Surgery for recurrence
Case Age Gender TNM Time to Site of recurrence (years)a classification recurrence of primary (months) lesion
TABLE 1 Characteristics of the patients who underwent surgical resection for recurrences after radical esophagectomy
242 Y. Hiyoshi et al.
Surgical Resection for Recurrent Esophageal Cancer
Among the 22 recurrences, 20 were solitary lesions or multiple lesions located in a small resectable area. On the other hand, two cases (cases 5 and 9) involved multiple lesions located in different areas. In case 5, recurrences of cancer the neck lymph node and bone both developed. After systemic chemotherapy (docetaxel, cisplatin, and 5-FU; six courses), the bone metastasis became undetectable by FDG-PET, and resection of the metastatic neck lymph node was performed. In case 9, recurrence had developed in the right lung and the subcutaneous hip region. Because the hip lesion caused pain, the lesion was resected as palliative surgery, and systemic chemotherapy for the lung metastasis was performed after resection. The lymph node recurrences were seen in the axilla and neck, and the mean number of metastases was 3.3 (range, 1–8). In terms of survival, the patients with solitary-node recurrence (cases 3, 5, and 14) did not differ significantly from those with multiple-node metastases (cases 1, 2, and 13) (Kaplan–Meier analysis, data not shown). Regarding hematogenous recurrences, in case 4, bilateral lung metastases were resected synchronously. In case 6, a solitary liver metastasis was resected after systemic chemotherapy. However, lung and lymph node recurrence developed after the surgery. In case 12, the patient showed impaired consciousness and convulsions caused by solitary brain tumor recurrence, and the tumor was resected during an emergency surgery. However, multiple recurrences in the lung, kidney, and lymph node developed soon after surgery. Regarding local recurrence, in cases 8 and 10, resection for local recurrence around the anastomosis and reconstruction with a free jejunal graft were performed. Table 2 shows a comparison of the clinicopathologic findings and the type of recurrence between the groups (patients with or without surgery). The type of recurrence was classified into three patterns (loco-regional, hematogenous, and mixed type), with the latter defined as lymphatic recurrence concomitant with hematogenous recurrence, as reported previously.8 Comparison of the surgery and no surgery groups showed no significant differences in age, gender, pathologic findings of the primary esophageal cancer, interval between esophagectomy and recurrence, or the type of recurrence. Figure 1 shows the results from the Kaplan–Meier analysis of the recurrence-free survival after esophagectomy. The median recurrence-free survival time was 11.4 months in the surgery group and 8.5 months in the no surgery group. The log-rank test showed no significant differences in the recurrence-free survival between the two groups. Figure 2 shows the results of the Kaplan–Meier analysis for the cancer-specific survival both after esophagectomy (Fig. 2a) and after the initial recurrence (Fig. 2b). For the surgery and no surgery groups, the respective median survival times after esophagectomy were 103.3 and
243 TABLE 2 Comparison of the clinicopathologic findings between the two groups stratified by treatment for recurrence Factors
No surgery groupa (n = 86)
Surgery groupb (n = 14)
p value
62.5 (37–85)
65.5 (44–75)
NS
79/7
11/3
NS
30/56
6/8
NS
31/55
7/7
NS
10.0 (1.0–49.7)
11.4 (4.5–65.9)
NS
51/22/13
6/7/1
NS
Age at recurrence Median: years (range) Gender Male/female Pathologic findings of primary esophageal cancer Depth of invasion T1-2/T3-4 Lymph node metastasis N–/N? Time of recurrence Median: months (range) Type of recurrence Loco-regional/ hematogenous/mixed a
Patients treated with chemotherapy and/or radiation and surgery
b
Patients treated with chemotherapy and/or radiation without surgery
NS not significant
23.1 months, and the median survival times after initial recurrence were 92.1 and 12.2 months. The surgery group showed a more favorable prognosis in terms of both survival after esophagectomy and survival after initial recurrence according to the log-rank test. DISCUSSION Increasing evidence supports the efficacy of CRT in the treatment of primary esophageal cancer.16,17 On the other hand, the response to CRT is low for recurrent esophageal cancer, and complete remissions are few.18 However, because surgical treatment is indicated for only a small number of patients who show localized tumor recurrence, radiation, chemotherapy, or both still are generally used in many unresectable cases. We have aggressively indicated salvage resection followed by chemotherapy, radiation therapy, or both for cases of localized recurrence. In the current retrospective study, we evaluated the clinical significance of surgical resection for the recurrence of esophageal cancer after radical esophagectomy. Among 100 patients who underwent some treatment(s) for recurrence of esophageal cancer, a total of 22 recurrent lesions in 14 patients were surgically resected. Both the survival after esophagectomy and the survival after initial recurrence were significantly better in the surgery group than in the group treated with chemotherapy, radiotherapy, or both.
244
Y. Hiyoshi et al.
The comparison between the two groups was performed with the understanding that there was an enormous selection bias. For example, 12 (86 %) of the 14 patients in the surgery group underwent surgical resection for recurrence more recently (2009–2012). Thus, the improved prognosis after surgical resection may have been due not only to the survival advantage associated with resection for recurrent disease but also to recent advances in multimodal treatment, such as chemotherapy or radiotherapy. However, consistent with our results, some previous reports have demonstrated surgical resection to be an acceptable treatment that could improve the survival of patients with a recurrence of esophageal cancer. With regard to lymph node recurrence, Motoyama et al.10 demonstrated that the outcomes of recurrent esophageal cancers localized to the neck lymph nodes were better than those seen with other lymph node recurrence patterns, and salvage resection followed by chemoradiotherapy seems to be indicated for those patients. Yano et al.11 demonstrated that the number of relapsed cervical nodes (solitary/multiple) was a significant prognostic factor and concluded that a solitary
Recurrence free survival (%)
100 Surgery
(n=14)
No surgery (n=86)
80 60
NS
40 20 0 0
40
20
60
Time after esophagectomy (months) FIG. 1 Results of the Kaplan–Meier analysis of recurrence-free survival after esophagectomy
A 100
Surgery No surgery
nodal recurrence could be a candidate for surgical resection. The treatment outcome of resection for lymph node recurrence in the mediastinum or abdomen also was reported.12 Our results additionally indicate that surgical resection may be one of the treatment options for either solitary or localized node metastases. Metachronous pulmonary metastasis from esophageal cancer is seen in 17.5 to 41.4 % of the cases with hematogenous recurrence, and it is one of the main recurrence patterns.5,6,19 With regard to colorectal cancer, surgical intervention for metachronous pulmonary metastasis has been reported by several authors and is widely accepted.20 The treatment outcome of surgical resection for lung metastasis of esophageal cancer also has been evaluated in some recent studies. For example, Ichikawa et al.13 retrospectively analyzed 23 consecutive patients who underwent surgical resection for metachronous pulmonary metastasis of esophageal cancer. The median survival time was 28.7 months, and extrapulmonary metastasis as the initial recurrence site was an unfavorable prognostic factor. Similarly, studies have demonstrated that solitary pulmonary metastasis might be a good candidate for surgical resection, thus resulting in a favorable prognosis.14,15 In the current study, six partial pulmonary resections were performed for metastatic esophageal cancer in four patients. Importantly, two patients (patients 2 and 3) underwent repeated pulmonary resections for metachronous disease, and patient 4 underwent synchronous bilateral resection for bilateral lung metastases. Three of these four patients still were alive at the last follow-up evaluation (1 patient had died of another disease), and the mean survival time after esophagectomy was 45.6 months (range, 15.3–83.3 months). These findings may demonstrate that not only solitary lung metastasis but also bilateral lesions and metachronous multiple lesions can be candidates for surgical resection. Because previous operations generally result in the formation of fibrous adhesions to the surrounding tissue,
B 100 80
(n=14)
60 40 20
(n=86)
P=0.0060 0
Survival (%)
Survival (%)
80
Surgery No surgery
60
(n=14)
40 20
(n=86)
P=0.0057 0
0
20
40
Time after esophagectomy (months)
60
0
20
40
60
Time after initial recurrence (months)
FIG. 2 Results of the Kaplan–Meier analysis of cancer-specific survival. a Survival after esophagectomy. b Survival after initial recurrence
Surgical Resection for Recurrent Esophageal Cancer
the surgical approach for local recurrence after radical esophagectomy usually is difficult, and CRT tends to be clinically applied for such patients. In such cases, salvage surgery for patients with a good performance status or chemotherapy alone is considered to be the treatment for local recurrence, but the risk of salvage surgery still is extremely high.21–23 In the current study, two patients who had been treated with CRT for primary esophageal cancer underwent resection of local recurrence followed by reconstruction using a free jejunal graft, and both patients still are alive without recurrence at this writing (respective survival times, 17.0 and 17.8 months). As reported previously, salvage surgery with free jejunal transfer is considered to be safe for patients previously treated with definitive CRT ([50 Gy) or radical esophagectomy.24,25 The microvascular anastomosis was safely applied with no critical postoperative complications.26 Although surgical resection for recurrent esophageal cancer in the lymph nodes and lungs seems to have the potential to improve the prognosis, few reports have systematically demonstrated the prognostic advantages of surgical resection for other hematogenous recurrences, such as those to the liver, bone, and brain. In the current study, two patients underwent resection for liver recurrence and brain recurrence, respectively. Although the recurrent lesions were solitary in both cases, the patients died of multiple recurrences in other organs. The prognostic advantage of surgical resection for such lesions is still unclear at this writing. The advances in imaging modalities such as endoscopy, CT, and FDG-PET have enabled the detection of recurrent esophageal cancer at an early stage, so the opportunities to treat small solitary recurrences are expected to be increasing. In particular, FDG-PET has advantages because it can be used to detect recurrent disease in the whole body with high sensitivity.27 On the other hand, systemic chemotherapy currently is regarded as one of the most effective treatments for esophageal cancer. Although fluorouracil and cisplatin (FP) combination therapy has become a standard choice,28,29 many studies have reported that taxanes have significant activity in patients with advanced and metastatic esophageal cancer.30–32 Such novel effective chemotherapy might lead to the downstaging of unresectable recurrence of esophageal cancer, allowing more patients to be candidates for surgical resection. Taken together with the findings of previous studies, the results of this study suggest that a favorable outcome can be expected for selected patients with solitary or localized recurrence of esophageal cancer, especially for those with lymph node and lung recurrence. We believe that surgical intervention as a part of multimodal treatment for solitary or localized recurrence of esophageal cancer for patients
245
with a good performance status is acceptable and may have prognostic advantages. CONFLICT OF INTEREST
There are no conflicts of interest.
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