Gen Thorac Cardiovasc Surg (2014) 62:531–540 DOI 10.1007/s11748-014-0458-y
CURRENT TOPICS REVIEW ARTICLE
Perioperative therapy for esophageal cancer Makoto Yamasaki • Hiroshi Miyata • Yasuhiro Miyazaki • Tsuyoshi Takahashi • Yukinori Kurokawa • Kiyokazu Nakajima Shuji Takiguchi • Masaki Mori • Yuichiro Doki
•
Received: 15 January 2014 / Published online: 29 July 2014 Ó The Japanese Association for Thoracic Surgery 2014
Abstract Traditionally, surgery is considered the best treatment for esophageal cancer in terms of locoregional control and long-term survival, but survival after surgery alone for locally advanced esophageal cancer is not satisfactory. A multidisciplinary approach that includes surgery, radiotherapy, and chemotherapy, alone or in combination, has been developed to improve the prognosis. Multiple clinical trials have addressed the preferred treatment strategy, such as neoadjuvant or adjuvant and chemotherapy, radiotherapy, or chemoradiotherapy, in managing locally advanced esophageal cancer. In this review, we provide an update on treatment strategies for locally advanced esophageal cancers. Recent studies indicate that neoadjuvant chemoradiotherapy or chemotherapy has a survival benefit over surgery alone in this patient group. Neoadjuvant chemoradiotherapy is an accepted standard of care in the United States while neoadjuvant chemotherapy is regarded as standard treatment in Japan and the United Kingdom. The standard treatment differs among countries because two large randomized controlled trials that evaluated the effectiveness of neoadjuvant chemotherapy reported conflicting results and no trial has made a comparison between neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy directly. Future trials in locally advanced esophageal cancer should focus on
This review was submitted at the invitation of the editorial committee. M. Yamasaki (&) H. Miyata Y. Miyazaki T. Takahashi Y. Kurokawa K. Nakajima S. Takiguchi M. Mori Y. Doki Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2 Yamadaoka, Suita, Osaka 565-0879, Japan e-mail: [email protected]
identifying the optimum strategy and its regimen and aim to minimize treatment toxicities and effects on quality of life. Keywords Esophageal cancer Adjuvant therapy Neoadjuvant therapy Chemotherapy Radiotherapy
Introduction Esophageal cancer is the eighth most frequently diagnosed cancer and the sixth leading cause of cancer deaths worldwide and is among the most aggressive and fatal malignancies [1]. In Japan, esophageal cancer is the eighth most common and seventh leading cause of cancer deaths, with an estimated 21,600 new cases and 11,700 deaths in 2008 [2]. Surgery has been considered the standard treatment for patients with resectable esophageal cancer; however, the long-term survival with surgery alone remains poor, and the 5-year survival rate is only 15–52 %, even from locoregional disease, regardless of the development of surgical techniques and perioperative care [3–5]. To prolong survival time of patients with resectable esophageal cancer, multidisciplinary management including radiotherapy and chemotherapy alone or in combination, as well as surgery, has been developed. Multiple clinical trials have addressed the preferred treatment strategy, such as neoadjuvant or adjuvant and chemotherapy, radiotherapy, or chemoradiotherapy, in managing locally advanced esophageal cancer. This article reviews the results of recent clinical trials for esophageal cancer treatment with the addition of chemotherapy and chemoradiotherapy to the surgical management of resectable disease.
123
532
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Table 1 Randomized controlled trials of adjuvant radiotherapy and adjuvant chemotherapy versus surgery alone for esophageal cancer Reference
Histology
Treatment schedule
RT (Gy)
CT
Kunath et al. [6]
SCC
S ? RT
50–55
–
S
–
–
21
6
Teniere et al. [7]
SCC
S ? RT
45–55
–
102
18
Fok et al. [8]
SCC
Zieren et al. [9]
SCC
Xiao et al. [10]
SCC
Pouliquen et al. [11]
SCC
Ando et al. [12]
SCC
Ando et al. [5]
SCC
n
23
MS (months)
5-year OS (%)
9
19
S
–
–
119
18
19
S ? RT
45–53
–
42
11
10
S
–
–
39
22
16
S ? RT
56
–
33
14
23a
S
–
–
35
13
22a
S ? RT
50–60
–
220
S
–
–
275
S ? CT
–
Cisplatin ? fluorouracil
52
13
S
–
–
68
14
41
p value
Surgical procedure
NS
Transhiatal and left thoracotomy
NS
Transhiatal or right thoracotomy
NS
Ivor-Lewis or transhiatal
NS
McKeown: 8/transhiatal: 25 McKeown: 8/transhiatal: 27
NS
McKeown or left thoracotomy
NS
NR
NS
Right thoracotomy
NS
Right thoracotomy
32
S ? CT
–
Cisplatin ? vindesine
100
57
48
S
–
–
105
47
45
S ? CT
–
Cisplatin ? fluorouracil
120
61
S
–
–
122
52
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, S surgery, NS not significant, NR not reported a
3-year overall survival
Adjuvant therapy Adjuvant radiotherapy Adjuvant radiotherapy has been evaluated in five studies [6–10] (Table 1). A meta-analysis of these phase III trials showed no significant difference in survival following adjuvant radiotherapy compared with surgery alone, but the rate of local recurrence with radiotherapy was lower in three of the trials [7, 8, 10]. Teniere et al. [7] showed a significant decrease in locoregional recurrence in a subgroup of patients with pN0 disease after curative surgery and who had adjuvant radiotherapy. Xiao et al. [10] showed a significant survival benefit with adjuvant radiotherapy for pN1 and stage III patients, with an improvement in 5-year overall survival from 13.1 to 35.1 % (p = 0.003). Some trials, however, noted that this benefit was achieved at the expense of increased morbidity [7, 8]. These studies indicated that only selected locally advanced esophageal cancer patients are likely to benefit from adjuvant radiotherapy. Adjuvant chemotherapy Three phase III trials have evaluated adjuvant chemotherapy and surgery compared with surgery alone [5, 11, 12]
123
(Table 1). None of these trials reported a statistical difference in overall survival. The most recent trial conducted in Japan (Japan Clinical Oncology Group, JCOG9204) showed that the disease-free survival rate at 5 year favored the adjuvant chemotherapy arm compared with surgery alone (55 vs 45 %, p = 0.037), although there was no significant difference in overall survival at 5 years (61 vs 52 %, p = 0.13). Adjuvant chemoradiotherapy The National Comprehensive Cancer Network recommends adjuvant chemoradiotherapy for stage II and III esophageal cancer, especially adenocarcinoma, although no randomized phase III trials in patients with esophageal cancer have evaluated adjuvant chemoradiotherapy compared with surgery alone. This recommendation is based on a randomized phase III trial for adenocarcinoma of the stomach and gastroesophageal junction that showed that the median overall survival rate in the adjuvant chemoradiotherapy group was significantly higher than in the group receiving surgery alone (36 vs 27 months, p = 0.005) [13]. A phase II randomized trial of 45 patients compared adjuvant chemotherapy with adjuvant chemoradiotherapy after curative resection of esophageal cancer [14] and yielded no significant difference in 5-year overall survival
Gen Thorac Cardiovasc Surg (2014) 62:531–540
533
Table 2 Randomized controlled trials of neoadjuvant radiotherapy versus surgery alone for esophageal cancer Reference
Histology
Treatment schedule
RT (Gy)
CT
Launois et al. [15]
SCC
RT ? S
40
–
S
–
–
Gignoux et al. [16]
SCC
RT ? S S
33 –
– –
Wang et al. [17]
SCC
RT ? S
40
–
S
–
RT ? S
Arnott et al. [18]
Nygaard [19]
AC: 114/SCC: 56/other: 6
SCC
n
MS (months)
5-year OS (%)
p value
Surgical procedure
Surgical complication (number of patients)
5
10
NS
Left thoracotomy
Deaths, 14
57
8
12
106 102
12 12
11 10
NS
NR
Deaths, 6 Deaths, 8
104
35
NS
NR
Perioperative deaths, 5; leaks, 1
–
102
30
20
–
90
8
9
S
–
–
86
8
17
RT ? S
35
–
48
21
S
–
–
41
9
67
Deaths, 11
Perioperative deaths, 5; leaks, 5 NS
Left thoracotomy
Postoperative deaths, 10; respiratory, 10 Postoperative deaths, 8; respiratory, 5
NS
Ivor-Lewis
Postoperative deaths, 4; respiratory, 5; leaks, 2 Postoperative deaths, 5; respiratory, 5; leaks, 2
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, S surgery, NS not significant, NR not reported
between the two (38 vs 50 %, respectively, p = 0.97); however, this study was limited by a small sample size. Recent trials have focused on neoadjuvant therapy rather than adjuvant therapy, not only because of the negative results of most trials of adjuvant radiotherapy, chemotherapy, and chemoradiotherapy but also because of difficulties in adequately administering chemotherapy and/or radiotherapy promptly after surgery.
Neoadjuvant therapy Neoadjuvant radiotherapy Several randomized trials have evaluated neoadjuvant radiotherapy compared with surgery alone in esophageal cancer [15–19] (Table 2). The results indicated no statistically significant difference in overall survival with neoadjuvant radiotherapy compared with surgery alone. Nygaard et al. [19] showed that preoperative irradiation has a beneficial effect on 3-year overall survival; however, that finding was based on comparing patients not receiving radiotherapy with those receiving either radiotherapy or chemoradiotherapy. Meta-analysis of randomized trials showed no significant difference in survival between neoadjuvant radiotherapy and surgery alone [20]. A neoadjuvant radiation treatment strategy is currently not recommended in locally advanced esophageal cancer patients.
Neoadjuvant chemotherapy Several randomized trials have compared neoadjuvant chemotherapy with surgery alone for the treatment of locally advanced esophageal cancer [3, 19, 21–27] (Table 3). Of the nine trials, three showed that neoadjuvant chemotherapy had improved the prognosis compared with surgery alone [3, 24, 27], but six showed no survival benefit to neoadjuvant chemotherapy [19, 21–23, 25, 26]. These randomized trials were conducted using various regimens such as cisplatin, fluorouracil (5-FU), bleomycin, vindesine, and their combinations and were underpowered to evaluate a difference in survival between neoadjuvant chemotherapy and surgery alone. Two larger randomized trials that evaluated neoadjuvant chemotherapy with cisplatin and 5-FU (FP) for locally advanced esophageal cancer also yielded conflicting results. One trial was Radiation Therapy Oncology Group trial 8911 (US Inter Group 113), in which 452 patients with locally advanced esophageal cancer were randomly assigned to three cycles of neoadjuvant and postoperative chemotherapy or to surgery alone [25]. That trial yielded no significant differences in median survival between patients who received both neoadjuvant and adjuvant chemotherapy and those who underwent surgery alone: 14.9 and 16.1 months, respectively (p = 0.53). Another trial, the UK Medical Research Council (MRC) OE02 trial, involved 802 patients with resectable esophageal cancer who were randomized to two groups: those who received two cycles of neoadjuvant
123
123
CT ? S
S
SCC
SCC
SCC
SCC
AC: 120/SCC: 103
AC: 124/SCC: 110
Mainpang et al. [22]
Law et al. [23]
Boonstra et al. [24]
Kelsen et al. [25]
CT ? S
S
AC: 265/SCC: 123/others: 12
AC: 268/SCC: 124/others: 22
–
–
–
S
Allum et al. [3]
–
–
CT ? S
SCC
Ancona et al. [26]
–
S
–
–
–
S
CT ? S
–
CT ? S
– –
CT ? S
S
– –
CT ? S
S
–
S
Schlag et al. [21]
–
RT (Gy)
CT ? S
SCC
Nygaard et al. [19]
Treatment schedule
Histology
Reference
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? etoposide
–
Cisplatin ? fluorouracil
–
Bleomycin ? vindesine ? cisplatin
–
Cisplatin ? fluorouracil
–
Bleomycin ? cisplatin
CT
84
85
73
74
22
24
24
22
41
44
402
400
47
47
227
213
n
13
17
24
25
16
15
12
16
13
17
17
17
6
7
7
7
MS (months)
34
43
22
34
20
19
17
26
13
40
36
31
9
3
5-year OS (%)
Table 3 Randomized controlled trials of neoadjuvant chemotherapy versus surgery alone for esophageal cancer
\0.01
NS
NS
0.03
NS
NS
NS
NS
p value
NR
McKeown
Ivor-Lewis or transhiatal or left thoracotomy
McKeown: 11/transhiatal: 58/others: 13
McKeown: 9/transhiatal: 55/others: 12
Ivor-Lewis: 42/transhiatal: 7/others: 20
Ivor-Lewis: 45/transhiatal: 4/others: 11
Ivor-Lewis
Ivor-Lewis or McKeown
Ivor-Lewis
Surgical procedure
Deaths, 40; Respiratory, 58; Infection, 32; anastomotic, 26; cardiac, 15; other, 30
Deaths, 2; respiratory, 8; leak, 1; cardiac, 2; sepsis, 3 Deaths, 36; respiratory, 56; infection, 21; anastomotic, 23; cardiac, 14; other, 32
Deaths, 1; respiratory, 8; leak, 2; cardiac, 1; sepsis, 3
Deaths, 13; major complication, 57; minor complication, 67
Deaths, 10; major complication, 53, minor complication, 49
Respiratory, 8; leak, 9; bleeding, 2; vocal-cord, 12; cardiac, 3
Respiratory, 17**; leak, 8; bleeding, 3; vocal-cord, 10; cardiac, 3
Perioperative deaths, 6; respiratory, 11; cardiac, 18; wound infection, 7
Perioperative deaths, 5; leaks, 3; respiratory, 10; cardiac, 20; wound infection, 4
Not reported
Not reported
Not reported
Not reported
Postoperative deaths, 5; respiratory, 5; leaks, 2
Postoperative deaths, 6; respiratory, 3; leaks, 3; hematologic, 1; alopecia, 1
Surgical complication (number of patients)
534 Gen Thorac Cardiovasc Surg (2014) 62:531–540
Neoadjuvant chemoradiotherapy
** p = 0.041
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, S surgery, NS not significant, NR not reported
24 111 – – S
535
chemotherapy and those who underwent surgery alone [3]. In that trial, overall survival was comparatively prolonged in the neoadjuvant chemotherapy group, with a median survival of 16.8 months vs 13.3 months in the surgeryalone group. In an update of this trial, the survival benefit was maintained, with a hazard ratio (HR) of 0.84 [95 % confidence interval (CI), 0.72–0.98, p = 0.03]. In Japan, the JCOG9907 trial comparing adjuvant and neoadjuvant chemotherapy was reported, in which 330 patients with locally advanced esophageal cancer were randomized to undergo surgery followed or preceded by chemotherapy consisting of FP chemotherapy [28]. In that trial, 5-year overall survival in neoadjuvant chemotherapy group was superior to that of adjuvant chemotherapy (55 vs 43 %, respectively, p = 0.04). Prior to the JCOG9907 trial, the JCOG9204 trial compared adjuvant chemotherapy with surgery alone and identified no significant difference in overall survival. From these data, the JCOG9907 results implied that neoadjuvant chemotherapy is more beneficial than surgery alone. A recent meta-analysis comparing survival after neoadjuvant chemotherapy or surgery alone in nine randomized trials (total of 1,981 patients) for resectable esophageal cancer found strong evidence of a survival benefit to neoadjuvant chemotherapy over surgery alone [29]. The pooled HR for all-cause mortality for neoadjuvant chemotherapy was 0.87 (0.79–0.96, p = 0.005), which corresponds to an absolute survival difference of 5.1 % at 2 years. Therefore, neoadjuvant chemotherapy is currently regarded as the standard treatment in Japan and the United Kingdom.
Mortality, 5; morbidity, 21 Ivor-Lewis: 44/transhiatal: 10/gastrectomy: 44/other: 1
Mortality, 5; morbidity, 28 Ivor-Lewis: 43/transhiatal: 10/gastrectomy: 46/other: 1 0.02 38 113 Cisplatin ? fluorouracil – AC Ychou et al. [27]
CT ? S
Histology Reference
Table 3 continued
Treatment schedule
RT (Gy)
CT
n
MS (months)
5-year OS (%)
p value
Surgical procedure
Surgical complication (number of patients)
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Several randomized trials have evaluated neoadjuvant concurrent chemoradiotherapy compared with surgery alone in esophageal cancer [30–37] (Table 4). These trials showed conflicting results regarding neoadjuvant chemoradiotherapy. Walsh et al. [30] reported the first randomized study to evaluate the role of neoadjuvant chemoradiotherapy, finding that neoadjuvant chemoradiotherapy (cisplatin/5-FU/40 Gy) followed by surgery improved 3-year survival (32 vs 6 %, p = 0.01) and median survival (16 vs 11 months, p = 0.01) compared with surgery alone. However, this trial was criticized for a lack of appropriate staging, premature closure, and an unusually poor survival rate in the surgery alone arm. In the Cancer and Leukemia Group B 9781 (CALGB9781) trial (cisplatin/5-FU/50.4 Gy), 5-year overall survival was significantly improved from 16 to 39 % in patients who received neoadjuvant chemoradiotherapy compared with those who underwent surgery alone [35]. However, that trial ultimately enrolled only 56 of the planned 475 patients
123
536
because of slow recruitment. On the other hand, another three trials reported no survival benefit with the addition of chemoradiotherapy with cisplatin and 5-FU regimens [33, 34, 36]. Recently, a phase III randomized trial (CROSS study) of neoadjuvant chemoradiotherapy (carboplatin/ paclitaxel/41.4 Gy) reported that neoadjuvant chemoradiotherapy improved 3-year overall survival compared with surgery alone (59 vs. 48 %, respectively), with a median survival of 49 months in the chemoradiotherapy compared with 26 months with surgery alone [37]. A recent updated meta-analysis of 12 randomized trials compared neoadjuvant chemoradiotherapy with surgery alone [29]. The HR for all-cause mortality with neoadjuvant chemoradiotherapy was 0.78 (95 % CI 0.70–0.88, p \ 0.0001). Thus, neoadjuvant chemoradiotherapy is currently an accepted standard of care in the United States. Neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy Two trials evaluated the survival benefits of neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy [38, 39], but both closed prematurely and were consequently underpowered to detect a significant survival advantage. A recent meta-analysis also compared neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy and identified no statistically significant difference in overall survival between neoadjuvant chemoradiotherapy and chemotherapy (HR 0.88, 95 % CI 0.76–1.01, p = 0.07) [29]. Surgical treatment Multiple surgical options exist for performing esophagectomy for esophageal cancer. In Western countries, the most common approaches are the Ivor-Lewis (right thoracotomy and laparotomy) esophagectomy and the transhiatal esophagectomy, whereas in Japan the most common approaches are the McKeown technique (right thoracotomy followed by laparotomy and neck incision with cervical anastomosis) and its modified procedure which adds to cervical lymphadenectomy, so-called three-field lymphadenectomy. A generally accepted consensus on surgical approach is not reached yet. Actually the various surgical procedures, right side transthoracic (Ivor-Lewis and McKeown), transhiatal, left side transthoracic approaches and so on, are inconsistently adopted as above-mentioned studies have shown (Tables 1, 2, 3, 4). Some prospective studies that evaluated surgical procedure for esophageal cancer, which had compared transthoracic esophagectomy with transhiatal esophagectomy, reported conflicting results [40–43]. A meta-analysis demonstrated no difference between the two groups in 5-year survival, however, lymphadenectomy and reported
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surgical quality were suboptimal in both groups and the transthoracic group had significantly more advanced cancer [44]. A recent review article recommends that the transthoracic esophagectomy should be performed in esophageal cancer [45]. The surgical procedure should be consistently adopted in the future trial. Surgical complications reported in the reviewed studies are shown in Tables 2, 3 and 4. There is wide variation in postoperative morbidity and mortality rates among trials. Although two trials reported that neoadjuvant chemotherapy and chemoradiotherapy lead to a significant increase in pulmonary complication and postoperative death compared with surgery alone, respectively [24, 31], there was no difference in the incidence and type of postoperative complication between the presence and absence of neoadjuvant therapy, and the types of therapeutic modality in most other trials. However, these results should be interpreted with caution, because surgical procedure and the extent of lymphadenectomy were inconsistently performed and the criteria of complication were not mentioned in these trials. Recently, Hirao et al. [46] reported that preoperative chemotherapy did not increase the risk of complication or hospital mortality after surgery for advanced thoracic oesophageal cancer in that context. In the future, we should re-examine the influence of neoadjuvant therapy on postoperative morbidity and mortality, and the long-term complication, including quality of life.
Discussion The treatment strategy for resectable esophageal cancer has undergone a considerable evolution over the past three decades. Many clinical trials have evaluated different modalities for managing locoregional cancer. Based on the trials and meta-analyses for locally advanced esophageal cancer described here, neoadjuvant therapy has been recommended over surgery alone worldwide. However, countries differ in neoadjuvant treatment as the recommended modality. Most patients with resectable esophageal cancer currently receive neoadjuvant chemotherapy in United Kingdom and Japan, based on the MAGIC [47], the MRC [3], the JCOG9204 [5], and JCOG9907 [28] trials; however, neoadjuvant chemoradiotherapy has been recommended for these patients in the United States because the results of the Radiation Therapy Oncology Group trial 8911 suggested that neoadjuvant chemotherapy was not beneficial in improving prognosis over surgery alone [25]. Thus, randomized trials directly comparing neoadjuvant chemoradiotherapy and chemotherapy are warranted. Such a comparison is currently being explored in Japan in the JCOG1109 (UMIN000009482, NExT study) trial. This trial consists of three-arm structure, which is designed to compare not only neoadjuvant chemotherapy using
CRT ? S
S
SCC
AC: 38/SCC: 12
AC: 37/SCC: 13
Urba et al. [32]
Mariette et al. [36]
45 –
CRT ? S
–
50.4
–
35
S
S
AC: 19/SCC: 7
AC/SCC
CRT ? S
AC: 23/SCC: 7
S
AC: 78/SCC: 50/other: 0
Tepper et al. [35]
CRT ? S
AC: 80/SCC: 45/other: 3
–
S
Burmeister et al. [34]
45
–
CRT ? S
SCC
Lee et al. [33]
–
S 45
37
CRT ? S
–
S
Bosset et al. [31]
40
RT (Gy)
CRT ? S
AC
Walsh et al. [30]
Treatment schedule
Histology
Reference
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Fluorouracil ? vindesine ? cisplatin
–
Cisplatin
–
Cisplatin ? fluorouracil
CT
98
97
26
30
128
128
50
51
50
50
139
143
55
58
n
44
32
21
54
19
22
27
28
17.6
16.9
19
19
11
16
MS (months)
55
49
16
39
13
17
41
49
16a
30a
9
7
NS
\0.01
NS
NS
NS
NS
0.01
32a
6a
p value
5-year OS (%)
Table 4 Randomized controlled trials of neoadjuvant chemoradiotherapy versus surgery alone for esophageal cancer
–
McKeown: 8/Ivor-Lewis: 30/transhiatal: 6/left thoracotomy: 1
McKeown or Ivor-Lewis: 105/other: 5
McKeown or Ivor-Lewis: 98/other: 7
Ivor-Lewis: 35/McKeown: 11
Ivor-Lewis: 30/McKeown: 5
Transhiatal
McKeown: 12/Ivor-Lewis: 22/left thoracotomy: 17/transhiatal: 2/other: 2 McKeown/Ivor-Lewis
McKeown: 13/Ivor-Lewis: 21/left thoracotomy: 15/transhiatal: 0/other: 2
Surgical procedure
Mortality, 1; morbidity, 49
Mortality, 7; morbidity, 44
Deaths 1; respiratory, 4; leak, 0; cardiac, 1
Deaths, 0; respiratory, 2; leak, 2, tracheoesophageal fistula, 2
Deaths, 6; respiratory, 36; leak, 6; cardiac, 14
Deaths, 5; respiratory, 25; leak, 6; cardiac, 15
Deaths, 1; respiratory, 5; vocal cord palsy, 3; stricture, 8
Deaths, 1; respiratory, 1; vocal cord palsy, 4; stricture, 5
Perioperative deaths, 2; leaks, 4 wound dehiscence, 1
Perioperative deaths, 1; leak, 7
Postoperative deaths, 5; sepsis, 2
Deaths, 2; respiratory, 32; leaks, 2; cardiac, 13; other, 3 Postoperative deaths, 17**; respiratory failure, 6; sepsis, 7
Deaths, 3; respiratory, 28; leaks, 2; cardiac, 14; other, 4
Surgical complication (number of patients)
Gen Thorac Cardiovasc Surg (2014) 62:531–540 537
123
123
3-year overall survival
** p = 0.012
a
48 26 188 – S
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, CRT chemoradiotherapy, S surgery, NS not significant
Transhiatal or McKeown 0.011 59 49 175 Paclitaxel ? carboplatin 41.4
AC: 134/SCC: 41 AC: 141/SCC: 43 van Hagen et al. [37]
CRT ? S
Surgical procedure p value 5-year OS (%) MS (months) n CT RT (Gy) Treatment schedule Histology Reference
Table 4 continued
Deaths, 6; respiratory, 78; leak, 36; cardiac, 36; other, 22 Deaths, 8; respiratory, 82; leak, 48; cardiac, 31; other, 23
Gen Thorac Cardiovasc Surg (2014) 62:531–540
Surgical complication (number of patients)
538
cisplatin and 5-FU regarded as standard treatment in Japan with neoadjuvant chemoradiotherapy widely accepted in Western countries, but also neoadjuvant chemotherapy and chemoradiotherapy as standard treatment arm with novel neoadjuvant chemotherapy using Docetaxel plus cisplatin and 5-FU as more intensified regimen. Future trials should investigate further the use and combinations of novel chemotherapeutic agents and novel radiation technology to improve on current survival rates. Taxanes such as docetaxel and paclitaxel were recently reported as powerful anticancer agents for a variety of cancers. In gastric cancer and head and neck cancers, three large randomized trials [48–50] compared chemotherapy using docetaxel plus cisplatin and 5-FU or cisplatin and 5-FU. Both studies demonstrated that the addition of docetaxel significantly improved progression-free survival and overall survival compared with the standard regimens of cisplatin and 5-FU. Cisplatin and 5-FU plus docetaxel have also demonstrated active in patients with locally advanced or metastatic esophageal cancer [51]. Neoadjuvant treatment with docetaxel, cisplatin, 5-FU, and radiation in locally advanced esophageal cancer was also investigated in a Phase II study [52]. pCR (pathological complete remission) was found in 47 % (35 of 74), and median survival of all 74 patients was 55 months. A recent multicenter phase III randomized trial (the CROSS study) reported that neoadjuvant chemoradiotherapy with carboplatin and paclitaxel improved overall survival compared with surgery alone in patients with resectable esophageal or gastroesophageal junction cancers [37]. Median survival was 49 months in the chemoradiotherapy arm compared with 26 months in the surgery arm. Currently, several phase II or III trials are investigating new chemotherapy combinations or new combination partners for radiation in the neoadjuvant setting. These regimens are paclitaxel/carboplatin (NCT01404156), oxaliplatin/leucovorin/5-FU/bevacizumab (NCT01212822), paclitaxel/carboplatin/trastuzumab (monoclonal antibody against ErbB-2)/radiation (NCT01196390), navelbine/cisplatin/radiation (NCT01216527) and docetaxel/cisplatin/ cetuximab (monoclonal antibody against EGFR)/radiation (NCT01107639). Several other phase III trials not mentioned here are now recruiting patients to investigate new chemotherapy combinations and molecular-targeting compounds as combination partners, such as S-1/cisplatin; S-1/paclitaxel and 5-FU/leucovorin/oxaliplatin/docetaxel; and trastuzumab, lapatinib (dual EGFR and ErbB-2 tyrosine kinase inhibitor), and cetuximab in far advanced or metastatic disease as first-line treatment. Furthermore, improvement of radiation is another focus of current research. Proton-beam therapy and intensity-modulated radiation therapy are both forms of radiation therapy designed to focus on the regions of the tumor (maximal therapeutic
Gen Thorac Cardiovasc Surg (2014) 62:531–540
effect) while the dose to the surrounding normal critical structures can be minimized (minimum side effect). Studies of new anticancer agents and improved radiation technology for esophageal cancer have just begun, and their clinical applications will be anticipated in the future. Several questions still need to be answered to optimize treatment strategies. One is the histologic heterogeneity of esophageal cancer. The majority of the previous trials targeted squamous cell carcinoma, which in Western countries is currently the less common histologic type compared with adenocarcinoma. Another is the relevance of tumor staging, for which current standard modalities such as positron emission tomography or endoscopic ultrasonography are not adopted in clinical trials. Furthermore, the chemotherapy regimens and the method and area of irradiation have not been established, although newer agents and their regimens have shown promising results. Future trials in locally advanced esophageal cancer should focus on identification of the optimum strategy and its regimen and should aim to minimize treatment toxicities and effects on quality of life. In addition, they should attempt to identify those patients who are most likely to benefit from certain treatment modalities. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. 2. Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H, The Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2007: a study of 21 population-based cancer registries for the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2013;43(3):328–336. 3. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Longterm results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009;27(30):5062–7. 4. Rutega˚rd M, Charonis K, Lu Y, Lagergren P, Lagergren J, Rouvelas I. Population-based esophageal cancer survival after resection without neoadjuvant therapy: an update. Surgery. 2012;152(5):903–10. 5. Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study—JCOG9204. J Clin Oncol. 2003;21:4592–6. 6. Kunath U, Fischer P. Radical nature and life expectancy in the surgical treatment of esophageal and cardial carcinoma. Dtsch Med Wochenschr. 1984;109:450–3. 7. Te´nie`re P, Hay JM, Fingerhut A, Fagniez PL. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet. 1991;173:123–30.
539 8. Fok M, Sham JS, Choy D, Cheng SW, Wong J. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery. 1993;113:138–47. 9. Zieren HU, Mu¨ller JM, Jacobi CA, Pichlmaier H, Mu¨ller RP, Staar S. Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg. 1995;19:444–9. 10. Xiao ZF, Yang ZY, Liang J, Miao YJ, Wang M, Yin WB, et al. Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients. Ann Thorac Surg. 2003;75:331–6. 11. Pouliquen X, Levard H, Hay JM, McGee K, Fingerhut A, Langlois-Zantin O. 5-Fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus. A multicenter randomized trial. French Associations for Surgical Research. Ann Surg. 1996;223:127–33. 12. Ando N, Iizuka T, Kakegawa T, Lsono K, Watanabe H, Lde H, et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg. 1997;114:205–9. 13. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345(10): 725–30. 14. Tachibana M, Yoshimura H, Kinugasa S, Shibakita M, Dhar DK, Ueda S, et al. Postoperative chemotherapy vs chemoradiotherapy for thoracic esophageal cancer: a prospective randomized clinical trial. Eur J Surg Oncol. 2003;29(7):580–7. 15. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet. 1981;153:690–2. 16. Gignoux M, Roussel A, Paillot B, Gillet M, Schlag P, Favre JP, et al. The value of preoperative radiotherapy in esophageal cancer: results of a study by the EORTC. World J Surg. 1987;11:426–32. 17. Wang M, Gu XZ, Yin WB, Huang GJ, Wang LJ, Zhang DW. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients. Int J Radiat Oncol Biol Phys. 1989;16:325–7. 18. Arnott SJ, Duncan W, Kerr GR, Walbaum PR, Cameron E, Jack WJ, et al. Low dose preoperative radiotherapy for carcinoma of the oesophagus: results of a randomized clinical trial. Radiother Oncol. 1992;24:108–13. 19. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg. 1992;16:1104–9 discussion 1110. 20. Arnott SJ, Duncan W, Gignoux M, Girling DJ, Hansen HS, Launois B, et al. Preoperative radiotherapy for esophageal carcinoma. Cochrane Database Syst Rev. 2005;4:CD001799. 21. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg. 1992;127:1446–50. 22. Maipang T, Vasinanukorn P, Petpichetchian C, Chamroonkul S, Geater A, Chansawwaang S, et al. Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol. 1994;56:191–7. 23. Law S, Fok M, Chow S, Chu KM, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg. 1997;114:210–7.
123
540 24. Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, et al. Chemotherapy followed by surgery versus surgery alone in patients with oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011;11:181. 25. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Radiation Therapy Oncology Group, USA Intergroup, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007;25:3719–25. 26. Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001;91:2165–74. 27. Ychou M, Boige V, Pignon JP, Conroy T, Bouche´ O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29:1715–21. 28. Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19(1):68–74. 29. Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–92. 30. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335(7):462–7. 31. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997;337:161–7. 32. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19(2):305–13. 33. Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004;15:947–54. 34. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005;6:659–68. 35. Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26:1086–92. 36. Mariette C, Seitz JF, Maillard E. Impact of neoadjuvant chemoradiation in localized esophageal cancer: results of a randomized, controlled phase III trial. FFCD 9901 (abstract 8000). In: Proceedings of the 35th ESMO Congress. Milan, 2010. 37. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84. 38. Burmeister BH, Thomas JM, Burmeister EA, Walpole ET, Harvey JA, Thomson DB, et al. Is concurrent radiation therapy
123
Gen Thorac Cardiovasc Surg (2014) 62:531–540
39.
40.
41.
42.
43.
44.
45. 46.
47.
48.
49.
50.
51.
52.
required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Eur J Cancer. 2011;47(3):354–60. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, RieraKnorrenschild J, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009;27(6):851–6. Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1662–9. Omloo JM, Lagarde SM, Hulscher JB, Reitsma JB, Fockens P, van Dekken H, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/ distal esophagus: five-year survival of a randomized clinical trial. Ann Surg. 2007;246(6):992–1000. Yekebas EF, Schurr PG, Kaifi JT, Link BC, Kutup A, Mann O, et al. Effectiveness of radical en-bloc-esophagectomy compared to transhiatal esophagectomy in squamous cell cancer of the esophagus is influenced by nodal micrometastases. J Surg Oncol. 2006;93(7):541–9. Horstmann O, Verreet PR, Becker H, Ohmann C, Ro¨her HD. Transhiatal oesophagectomy compared with transthoracic resection and systematic lymphadenectomy for the treatment of oesophageal cancer. Eur J Surg. 1995;161(8):557–67. Boshier PR, Anderson O, Hanna GB. Transthoracic versus transhiatal esophagectomy for the treatment of esophagogastric cancer: a meta-analysis. Ann Surg. 2011;254(6):894–906. Uzunoglu FG, Reeh M, Kutup A, Izbicki JR. Surgery of esophageal cancer. Langenbecks Arch Surg. 2013;398(2):189–93. Hirao M, Ando N, Tsujinaka T, Udagawa H, Yano M, Yamana H, et al. Influence of preoperative chemotherapy for advanced thoracic oesophageal squamous cell carcinoma on perioperative complications. Br J Surg. 2011;98(12):1735–41. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, V325 Study Group, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, EORTC 24971/TAX 323 Study Group, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–704. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, TAX 324 Study Group, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–15. Yamasaki M, Miyata H, Tanaka K, Shiraishi O, Motoori M, Peng YF, et al. Multicenter phase I/II study of docetaxel, cisplatin and fluorouracil combination chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the esophagus. Oncology. 2011;80(5–6):307–13. Pasini F, de Manzoni G, Zanoni A, Grandinetti A, Capirci C, Pavarana M, et al. Neoadjuvant therapy with weekly docetaxel and cisplatin, 5-fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long-lasting pathological complete response: a phase 2 study. Cancer. 2013;119(5):939–45.
CURRENT TOPICS REVIEW ARTICLE
Perioperative therapy for esophageal cancer Makoto Yamasaki • Hiroshi Miyata • Yasuhiro Miyazaki • Tsuyoshi Takahashi • Yukinori Kurokawa • Kiyokazu Nakajima Shuji Takiguchi • Masaki Mori • Yuichiro Doki
•
Received: 15 January 2014 / Published online: 29 July 2014 Ó The Japanese Association for Thoracic Surgery 2014
Abstract Traditionally, surgery is considered the best treatment for esophageal cancer in terms of locoregional control and long-term survival, but survival after surgery alone for locally advanced esophageal cancer is not satisfactory. A multidisciplinary approach that includes surgery, radiotherapy, and chemotherapy, alone or in combination, has been developed to improve the prognosis. Multiple clinical trials have addressed the preferred treatment strategy, such as neoadjuvant or adjuvant and chemotherapy, radiotherapy, or chemoradiotherapy, in managing locally advanced esophageal cancer. In this review, we provide an update on treatment strategies for locally advanced esophageal cancers. Recent studies indicate that neoadjuvant chemoradiotherapy or chemotherapy has a survival benefit over surgery alone in this patient group. Neoadjuvant chemoradiotherapy is an accepted standard of care in the United States while neoadjuvant chemotherapy is regarded as standard treatment in Japan and the United Kingdom. The standard treatment differs among countries because two large randomized controlled trials that evaluated the effectiveness of neoadjuvant chemotherapy reported conflicting results and no trial has made a comparison between neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy directly. Future trials in locally advanced esophageal cancer should focus on
This review was submitted at the invitation of the editorial committee. M. Yamasaki (&) H. Miyata Y. Miyazaki T. Takahashi Y. Kurokawa K. Nakajima S. Takiguchi M. Mori Y. Doki Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2 Yamadaoka, Suita, Osaka 565-0879, Japan e-mail: [email protected]
identifying the optimum strategy and its regimen and aim to minimize treatment toxicities and effects on quality of life. Keywords Esophageal cancer Adjuvant therapy Neoadjuvant therapy Chemotherapy Radiotherapy
Introduction Esophageal cancer is the eighth most frequently diagnosed cancer and the sixth leading cause of cancer deaths worldwide and is among the most aggressive and fatal malignancies [1]. In Japan, esophageal cancer is the eighth most common and seventh leading cause of cancer deaths, with an estimated 21,600 new cases and 11,700 deaths in 2008 [2]. Surgery has been considered the standard treatment for patients with resectable esophageal cancer; however, the long-term survival with surgery alone remains poor, and the 5-year survival rate is only 15–52 %, even from locoregional disease, regardless of the development of surgical techniques and perioperative care [3–5]. To prolong survival time of patients with resectable esophageal cancer, multidisciplinary management including radiotherapy and chemotherapy alone or in combination, as well as surgery, has been developed. Multiple clinical trials have addressed the preferred treatment strategy, such as neoadjuvant or adjuvant and chemotherapy, radiotherapy, or chemoradiotherapy, in managing locally advanced esophageal cancer. This article reviews the results of recent clinical trials for esophageal cancer treatment with the addition of chemotherapy and chemoradiotherapy to the surgical management of resectable disease.
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Gen Thorac Cardiovasc Surg (2014) 62:531–540
Table 1 Randomized controlled trials of adjuvant radiotherapy and adjuvant chemotherapy versus surgery alone for esophageal cancer Reference
Histology
Treatment schedule
RT (Gy)
CT
Kunath et al. [6]
SCC
S ? RT
50–55
–
S
–
–
21
6
Teniere et al. [7]
SCC
S ? RT
45–55
–
102
18
Fok et al. [8]
SCC
Zieren et al. [9]
SCC
Xiao et al. [10]
SCC
Pouliquen et al. [11]
SCC
Ando et al. [12]
SCC
Ando et al. [5]
SCC
n
23
MS (months)
5-year OS (%)
9
19
S
–
–
119
18
19
S ? RT
45–53
–
42
11
10
S
–
–
39
22
16
S ? RT
56
–
33
14
23a
S
–
–
35
13
22a
S ? RT
50–60
–
220
S
–
–
275
S ? CT
–
Cisplatin ? fluorouracil
52
13
S
–
–
68
14
41
p value
Surgical procedure
NS
Transhiatal and left thoracotomy
NS
Transhiatal or right thoracotomy
NS
Ivor-Lewis or transhiatal
NS
McKeown: 8/transhiatal: 25 McKeown: 8/transhiatal: 27
NS
McKeown or left thoracotomy
NS
NR
NS
Right thoracotomy
NS
Right thoracotomy
32
S ? CT
–
Cisplatin ? vindesine
100
57
48
S
–
–
105
47
45
S ? CT
–
Cisplatin ? fluorouracil
120
61
S
–
–
122
52
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, S surgery, NS not significant, NR not reported a
3-year overall survival
Adjuvant therapy Adjuvant radiotherapy Adjuvant radiotherapy has been evaluated in five studies [6–10] (Table 1). A meta-analysis of these phase III trials showed no significant difference in survival following adjuvant radiotherapy compared with surgery alone, but the rate of local recurrence with radiotherapy was lower in three of the trials [7, 8, 10]. Teniere et al. [7] showed a significant decrease in locoregional recurrence in a subgroup of patients with pN0 disease after curative surgery and who had adjuvant radiotherapy. Xiao et al. [10] showed a significant survival benefit with adjuvant radiotherapy for pN1 and stage III patients, with an improvement in 5-year overall survival from 13.1 to 35.1 % (p = 0.003). Some trials, however, noted that this benefit was achieved at the expense of increased morbidity [7, 8]. These studies indicated that only selected locally advanced esophageal cancer patients are likely to benefit from adjuvant radiotherapy. Adjuvant chemotherapy Three phase III trials have evaluated adjuvant chemotherapy and surgery compared with surgery alone [5, 11, 12]
123
(Table 1). None of these trials reported a statistical difference in overall survival. The most recent trial conducted in Japan (Japan Clinical Oncology Group, JCOG9204) showed that the disease-free survival rate at 5 year favored the adjuvant chemotherapy arm compared with surgery alone (55 vs 45 %, p = 0.037), although there was no significant difference in overall survival at 5 years (61 vs 52 %, p = 0.13). Adjuvant chemoradiotherapy The National Comprehensive Cancer Network recommends adjuvant chemoradiotherapy for stage II and III esophageal cancer, especially adenocarcinoma, although no randomized phase III trials in patients with esophageal cancer have evaluated adjuvant chemoradiotherapy compared with surgery alone. This recommendation is based on a randomized phase III trial for adenocarcinoma of the stomach and gastroesophageal junction that showed that the median overall survival rate in the adjuvant chemoradiotherapy group was significantly higher than in the group receiving surgery alone (36 vs 27 months, p = 0.005) [13]. A phase II randomized trial of 45 patients compared adjuvant chemotherapy with adjuvant chemoradiotherapy after curative resection of esophageal cancer [14] and yielded no significant difference in 5-year overall survival
Gen Thorac Cardiovasc Surg (2014) 62:531–540
533
Table 2 Randomized controlled trials of neoadjuvant radiotherapy versus surgery alone for esophageal cancer Reference
Histology
Treatment schedule
RT (Gy)
CT
Launois et al. [15]
SCC
RT ? S
40
–
S
–
–
Gignoux et al. [16]
SCC
RT ? S S
33 –
– –
Wang et al. [17]
SCC
RT ? S
40
–
S
–
RT ? S
Arnott et al. [18]
Nygaard [19]
AC: 114/SCC: 56/other: 6
SCC
n
MS (months)
5-year OS (%)
p value
Surgical procedure
Surgical complication (number of patients)
5
10
NS
Left thoracotomy
Deaths, 14
57
8
12
106 102
12 12
11 10
NS
NR
Deaths, 6 Deaths, 8
104
35
NS
NR
Perioperative deaths, 5; leaks, 1
–
102
30
20
–
90
8
9
S
–
–
86
8
17
RT ? S
35
–
48
21
S
–
–
41
9
67
Deaths, 11
Perioperative deaths, 5; leaks, 5 NS
Left thoracotomy
Postoperative deaths, 10; respiratory, 10 Postoperative deaths, 8; respiratory, 5
NS
Ivor-Lewis
Postoperative deaths, 4; respiratory, 5; leaks, 2 Postoperative deaths, 5; respiratory, 5; leaks, 2
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, S surgery, NS not significant, NR not reported
between the two (38 vs 50 %, respectively, p = 0.97); however, this study was limited by a small sample size. Recent trials have focused on neoadjuvant therapy rather than adjuvant therapy, not only because of the negative results of most trials of adjuvant radiotherapy, chemotherapy, and chemoradiotherapy but also because of difficulties in adequately administering chemotherapy and/or radiotherapy promptly after surgery.
Neoadjuvant therapy Neoadjuvant radiotherapy Several randomized trials have evaluated neoadjuvant radiotherapy compared with surgery alone in esophageal cancer [15–19] (Table 2). The results indicated no statistically significant difference in overall survival with neoadjuvant radiotherapy compared with surgery alone. Nygaard et al. [19] showed that preoperative irradiation has a beneficial effect on 3-year overall survival; however, that finding was based on comparing patients not receiving radiotherapy with those receiving either radiotherapy or chemoradiotherapy. Meta-analysis of randomized trials showed no significant difference in survival between neoadjuvant radiotherapy and surgery alone [20]. A neoadjuvant radiation treatment strategy is currently not recommended in locally advanced esophageal cancer patients.
Neoadjuvant chemotherapy Several randomized trials have compared neoadjuvant chemotherapy with surgery alone for the treatment of locally advanced esophageal cancer [3, 19, 21–27] (Table 3). Of the nine trials, three showed that neoadjuvant chemotherapy had improved the prognosis compared with surgery alone [3, 24, 27], but six showed no survival benefit to neoadjuvant chemotherapy [19, 21–23, 25, 26]. These randomized trials were conducted using various regimens such as cisplatin, fluorouracil (5-FU), bleomycin, vindesine, and their combinations and were underpowered to evaluate a difference in survival between neoadjuvant chemotherapy and surgery alone. Two larger randomized trials that evaluated neoadjuvant chemotherapy with cisplatin and 5-FU (FP) for locally advanced esophageal cancer also yielded conflicting results. One trial was Radiation Therapy Oncology Group trial 8911 (US Inter Group 113), in which 452 patients with locally advanced esophageal cancer were randomly assigned to three cycles of neoadjuvant and postoperative chemotherapy or to surgery alone [25]. That trial yielded no significant differences in median survival between patients who received both neoadjuvant and adjuvant chemotherapy and those who underwent surgery alone: 14.9 and 16.1 months, respectively (p = 0.53). Another trial, the UK Medical Research Council (MRC) OE02 trial, involved 802 patients with resectable esophageal cancer who were randomized to two groups: those who received two cycles of neoadjuvant
123
123
CT ? S
S
SCC
SCC
SCC
SCC
AC: 120/SCC: 103
AC: 124/SCC: 110
Mainpang et al. [22]
Law et al. [23]
Boonstra et al. [24]
Kelsen et al. [25]
CT ? S
S
AC: 265/SCC: 123/others: 12
AC: 268/SCC: 124/others: 22
–
–
–
S
Allum et al. [3]
–
–
CT ? S
SCC
Ancona et al. [26]
–
S
–
–
–
S
CT ? S
–
CT ? S
– –
CT ? S
S
– –
CT ? S
S
–
S
Schlag et al. [21]
–
RT (Gy)
CT ? S
SCC
Nygaard et al. [19]
Treatment schedule
Histology
Reference
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? etoposide
–
Cisplatin ? fluorouracil
–
Bleomycin ? vindesine ? cisplatin
–
Cisplatin ? fluorouracil
–
Bleomycin ? cisplatin
CT
84
85
73
74
22
24
24
22
41
44
402
400
47
47
227
213
n
13
17
24
25
16
15
12
16
13
17
17
17
6
7
7
7
MS (months)
34
43
22
34
20
19
17
26
13
40
36
31
9
3
5-year OS (%)
Table 3 Randomized controlled trials of neoadjuvant chemotherapy versus surgery alone for esophageal cancer
\0.01
NS
NS
0.03
NS
NS
NS
NS
p value
NR
McKeown
Ivor-Lewis or transhiatal or left thoracotomy
McKeown: 11/transhiatal: 58/others: 13
McKeown: 9/transhiatal: 55/others: 12
Ivor-Lewis: 42/transhiatal: 7/others: 20
Ivor-Lewis: 45/transhiatal: 4/others: 11
Ivor-Lewis
Ivor-Lewis or McKeown
Ivor-Lewis
Surgical procedure
Deaths, 40; Respiratory, 58; Infection, 32; anastomotic, 26; cardiac, 15; other, 30
Deaths, 2; respiratory, 8; leak, 1; cardiac, 2; sepsis, 3 Deaths, 36; respiratory, 56; infection, 21; anastomotic, 23; cardiac, 14; other, 32
Deaths, 1; respiratory, 8; leak, 2; cardiac, 1; sepsis, 3
Deaths, 13; major complication, 57; minor complication, 67
Deaths, 10; major complication, 53, minor complication, 49
Respiratory, 8; leak, 9; bleeding, 2; vocal-cord, 12; cardiac, 3
Respiratory, 17**; leak, 8; bleeding, 3; vocal-cord, 10; cardiac, 3
Perioperative deaths, 6; respiratory, 11; cardiac, 18; wound infection, 7
Perioperative deaths, 5; leaks, 3; respiratory, 10; cardiac, 20; wound infection, 4
Not reported
Not reported
Not reported
Not reported
Postoperative deaths, 5; respiratory, 5; leaks, 2
Postoperative deaths, 6; respiratory, 3; leaks, 3; hematologic, 1; alopecia, 1
Surgical complication (number of patients)
534 Gen Thorac Cardiovasc Surg (2014) 62:531–540
Neoadjuvant chemoradiotherapy
** p = 0.041
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, S surgery, NS not significant, NR not reported
24 111 – – S
535
chemotherapy and those who underwent surgery alone [3]. In that trial, overall survival was comparatively prolonged in the neoadjuvant chemotherapy group, with a median survival of 16.8 months vs 13.3 months in the surgeryalone group. In an update of this trial, the survival benefit was maintained, with a hazard ratio (HR) of 0.84 [95 % confidence interval (CI), 0.72–0.98, p = 0.03]. In Japan, the JCOG9907 trial comparing adjuvant and neoadjuvant chemotherapy was reported, in which 330 patients with locally advanced esophageal cancer were randomized to undergo surgery followed or preceded by chemotherapy consisting of FP chemotherapy [28]. In that trial, 5-year overall survival in neoadjuvant chemotherapy group was superior to that of adjuvant chemotherapy (55 vs 43 %, respectively, p = 0.04). Prior to the JCOG9907 trial, the JCOG9204 trial compared adjuvant chemotherapy with surgery alone and identified no significant difference in overall survival. From these data, the JCOG9907 results implied that neoadjuvant chemotherapy is more beneficial than surgery alone. A recent meta-analysis comparing survival after neoadjuvant chemotherapy or surgery alone in nine randomized trials (total of 1,981 patients) for resectable esophageal cancer found strong evidence of a survival benefit to neoadjuvant chemotherapy over surgery alone [29]. The pooled HR for all-cause mortality for neoadjuvant chemotherapy was 0.87 (0.79–0.96, p = 0.005), which corresponds to an absolute survival difference of 5.1 % at 2 years. Therefore, neoadjuvant chemotherapy is currently regarded as the standard treatment in Japan and the United Kingdom.
Mortality, 5; morbidity, 21 Ivor-Lewis: 44/transhiatal: 10/gastrectomy: 44/other: 1
Mortality, 5; morbidity, 28 Ivor-Lewis: 43/transhiatal: 10/gastrectomy: 46/other: 1 0.02 38 113 Cisplatin ? fluorouracil – AC Ychou et al. [27]
CT ? S
Histology Reference
Table 3 continued
Treatment schedule
RT (Gy)
CT
n
MS (months)
5-year OS (%)
p value
Surgical procedure
Surgical complication (number of patients)
Gen Thorac Cardiovasc Surg (2014) 62:531–540
Several randomized trials have evaluated neoadjuvant concurrent chemoradiotherapy compared with surgery alone in esophageal cancer [30–37] (Table 4). These trials showed conflicting results regarding neoadjuvant chemoradiotherapy. Walsh et al. [30] reported the first randomized study to evaluate the role of neoadjuvant chemoradiotherapy, finding that neoadjuvant chemoradiotherapy (cisplatin/5-FU/40 Gy) followed by surgery improved 3-year survival (32 vs 6 %, p = 0.01) and median survival (16 vs 11 months, p = 0.01) compared with surgery alone. However, this trial was criticized for a lack of appropriate staging, premature closure, and an unusually poor survival rate in the surgery alone arm. In the Cancer and Leukemia Group B 9781 (CALGB9781) trial (cisplatin/5-FU/50.4 Gy), 5-year overall survival was significantly improved from 16 to 39 % in patients who received neoadjuvant chemoradiotherapy compared with those who underwent surgery alone [35]. However, that trial ultimately enrolled only 56 of the planned 475 patients
123
536
because of slow recruitment. On the other hand, another three trials reported no survival benefit with the addition of chemoradiotherapy with cisplatin and 5-FU regimens [33, 34, 36]. Recently, a phase III randomized trial (CROSS study) of neoadjuvant chemoradiotherapy (carboplatin/ paclitaxel/41.4 Gy) reported that neoadjuvant chemoradiotherapy improved 3-year overall survival compared with surgery alone (59 vs. 48 %, respectively), with a median survival of 49 months in the chemoradiotherapy compared with 26 months with surgery alone [37]. A recent updated meta-analysis of 12 randomized trials compared neoadjuvant chemoradiotherapy with surgery alone [29]. The HR for all-cause mortality with neoadjuvant chemoradiotherapy was 0.78 (95 % CI 0.70–0.88, p \ 0.0001). Thus, neoadjuvant chemoradiotherapy is currently an accepted standard of care in the United States. Neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy Two trials evaluated the survival benefits of neoadjuvant chemoradiotherapy compared with neoadjuvant chemotherapy [38, 39], but both closed prematurely and were consequently underpowered to detect a significant survival advantage. A recent meta-analysis also compared neoadjuvant chemoradiotherapy with neoadjuvant chemotherapy and identified no statistically significant difference in overall survival between neoadjuvant chemoradiotherapy and chemotherapy (HR 0.88, 95 % CI 0.76–1.01, p = 0.07) [29]. Surgical treatment Multiple surgical options exist for performing esophagectomy for esophageal cancer. In Western countries, the most common approaches are the Ivor-Lewis (right thoracotomy and laparotomy) esophagectomy and the transhiatal esophagectomy, whereas in Japan the most common approaches are the McKeown technique (right thoracotomy followed by laparotomy and neck incision with cervical anastomosis) and its modified procedure which adds to cervical lymphadenectomy, so-called three-field lymphadenectomy. A generally accepted consensus on surgical approach is not reached yet. Actually the various surgical procedures, right side transthoracic (Ivor-Lewis and McKeown), transhiatal, left side transthoracic approaches and so on, are inconsistently adopted as above-mentioned studies have shown (Tables 1, 2, 3, 4). Some prospective studies that evaluated surgical procedure for esophageal cancer, which had compared transthoracic esophagectomy with transhiatal esophagectomy, reported conflicting results [40–43]. A meta-analysis demonstrated no difference between the two groups in 5-year survival, however, lymphadenectomy and reported
123
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surgical quality were suboptimal in both groups and the transthoracic group had significantly more advanced cancer [44]. A recent review article recommends that the transthoracic esophagectomy should be performed in esophageal cancer [45]. The surgical procedure should be consistently adopted in the future trial. Surgical complications reported in the reviewed studies are shown in Tables 2, 3 and 4. There is wide variation in postoperative morbidity and mortality rates among trials. Although two trials reported that neoadjuvant chemotherapy and chemoradiotherapy lead to a significant increase in pulmonary complication and postoperative death compared with surgery alone, respectively [24, 31], there was no difference in the incidence and type of postoperative complication between the presence and absence of neoadjuvant therapy, and the types of therapeutic modality in most other trials. However, these results should be interpreted with caution, because surgical procedure and the extent of lymphadenectomy were inconsistently performed and the criteria of complication were not mentioned in these trials. Recently, Hirao et al. [46] reported that preoperative chemotherapy did not increase the risk of complication or hospital mortality after surgery for advanced thoracic oesophageal cancer in that context. In the future, we should re-examine the influence of neoadjuvant therapy on postoperative morbidity and mortality, and the long-term complication, including quality of life.
Discussion The treatment strategy for resectable esophageal cancer has undergone a considerable evolution over the past three decades. Many clinical trials have evaluated different modalities for managing locoregional cancer. Based on the trials and meta-analyses for locally advanced esophageal cancer described here, neoadjuvant therapy has been recommended over surgery alone worldwide. However, countries differ in neoadjuvant treatment as the recommended modality. Most patients with resectable esophageal cancer currently receive neoadjuvant chemotherapy in United Kingdom and Japan, based on the MAGIC [47], the MRC [3], the JCOG9204 [5], and JCOG9907 [28] trials; however, neoadjuvant chemoradiotherapy has been recommended for these patients in the United States because the results of the Radiation Therapy Oncology Group trial 8911 suggested that neoadjuvant chemotherapy was not beneficial in improving prognosis over surgery alone [25]. Thus, randomized trials directly comparing neoadjuvant chemoradiotherapy and chemotherapy are warranted. Such a comparison is currently being explored in Japan in the JCOG1109 (UMIN000009482, NExT study) trial. This trial consists of three-arm structure, which is designed to compare not only neoadjuvant chemotherapy using
CRT ? S
S
SCC
AC: 38/SCC: 12
AC: 37/SCC: 13
Urba et al. [32]
Mariette et al. [36]
45 –
CRT ? S
–
50.4
–
35
S
S
AC: 19/SCC: 7
AC/SCC
CRT ? S
AC: 23/SCC: 7
S
AC: 78/SCC: 50/other: 0
Tepper et al. [35]
CRT ? S
AC: 80/SCC: 45/other: 3
–
S
Burmeister et al. [34]
45
–
CRT ? S
SCC
Lee et al. [33]
–
S 45
37
CRT ? S
–
S
Bosset et al. [31]
40
RT (Gy)
CRT ? S
AC
Walsh et al. [30]
Treatment schedule
Histology
Reference
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Cisplatin ? fluorouracil
–
Fluorouracil ? vindesine ? cisplatin
–
Cisplatin
–
Cisplatin ? fluorouracil
CT
98
97
26
30
128
128
50
51
50
50
139
143
55
58
n
44
32
21
54
19
22
27
28
17.6
16.9
19
19
11
16
MS (months)
55
49
16
39
13
17
41
49
16a
30a
9
7
NS
\0.01
NS
NS
NS
NS
0.01
32a
6a
p value
5-year OS (%)
Table 4 Randomized controlled trials of neoadjuvant chemoradiotherapy versus surgery alone for esophageal cancer
–
McKeown: 8/Ivor-Lewis: 30/transhiatal: 6/left thoracotomy: 1
McKeown or Ivor-Lewis: 105/other: 5
McKeown or Ivor-Lewis: 98/other: 7
Ivor-Lewis: 35/McKeown: 11
Ivor-Lewis: 30/McKeown: 5
Transhiatal
McKeown: 12/Ivor-Lewis: 22/left thoracotomy: 17/transhiatal: 2/other: 2 McKeown/Ivor-Lewis
McKeown: 13/Ivor-Lewis: 21/left thoracotomy: 15/transhiatal: 0/other: 2
Surgical procedure
Mortality, 1; morbidity, 49
Mortality, 7; morbidity, 44
Deaths 1; respiratory, 4; leak, 0; cardiac, 1
Deaths, 0; respiratory, 2; leak, 2, tracheoesophageal fistula, 2
Deaths, 6; respiratory, 36; leak, 6; cardiac, 14
Deaths, 5; respiratory, 25; leak, 6; cardiac, 15
Deaths, 1; respiratory, 5; vocal cord palsy, 3; stricture, 8
Deaths, 1; respiratory, 1; vocal cord palsy, 4; stricture, 5
Perioperative deaths, 2; leaks, 4 wound dehiscence, 1
Perioperative deaths, 1; leak, 7
Postoperative deaths, 5; sepsis, 2
Deaths, 2; respiratory, 32; leaks, 2; cardiac, 13; other, 3 Postoperative deaths, 17**; respiratory failure, 6; sepsis, 7
Deaths, 3; respiratory, 28; leaks, 2; cardiac, 14; other, 4
Surgical complication (number of patients)
Gen Thorac Cardiovasc Surg (2014) 62:531–540 537
123
123
3-year overall survival
** p = 0.012
a
48 26 188 – S
RT radiotherapy, CT chemotherapy, MS median survival, OS overall survival, CRT chemoradiotherapy, S surgery, NS not significant
Transhiatal or McKeown 0.011 59 49 175 Paclitaxel ? carboplatin 41.4
AC: 134/SCC: 41 AC: 141/SCC: 43 van Hagen et al. [37]
CRT ? S
Surgical procedure p value 5-year OS (%) MS (months) n CT RT (Gy) Treatment schedule Histology Reference
Table 4 continued
Deaths, 6; respiratory, 78; leak, 36; cardiac, 36; other, 22 Deaths, 8; respiratory, 82; leak, 48; cardiac, 31; other, 23
Gen Thorac Cardiovasc Surg (2014) 62:531–540
Surgical complication (number of patients)
538
cisplatin and 5-FU regarded as standard treatment in Japan with neoadjuvant chemoradiotherapy widely accepted in Western countries, but also neoadjuvant chemotherapy and chemoradiotherapy as standard treatment arm with novel neoadjuvant chemotherapy using Docetaxel plus cisplatin and 5-FU as more intensified regimen. Future trials should investigate further the use and combinations of novel chemotherapeutic agents and novel radiation technology to improve on current survival rates. Taxanes such as docetaxel and paclitaxel were recently reported as powerful anticancer agents for a variety of cancers. In gastric cancer and head and neck cancers, three large randomized trials [48–50] compared chemotherapy using docetaxel plus cisplatin and 5-FU or cisplatin and 5-FU. Both studies demonstrated that the addition of docetaxel significantly improved progression-free survival and overall survival compared with the standard regimens of cisplatin and 5-FU. Cisplatin and 5-FU plus docetaxel have also demonstrated active in patients with locally advanced or metastatic esophageal cancer [51]. Neoadjuvant treatment with docetaxel, cisplatin, 5-FU, and radiation in locally advanced esophageal cancer was also investigated in a Phase II study [52]. pCR (pathological complete remission) was found in 47 % (35 of 74), and median survival of all 74 patients was 55 months. A recent multicenter phase III randomized trial (the CROSS study) reported that neoadjuvant chemoradiotherapy with carboplatin and paclitaxel improved overall survival compared with surgery alone in patients with resectable esophageal or gastroesophageal junction cancers [37]. Median survival was 49 months in the chemoradiotherapy arm compared with 26 months in the surgery arm. Currently, several phase II or III trials are investigating new chemotherapy combinations or new combination partners for radiation in the neoadjuvant setting. These regimens are paclitaxel/carboplatin (NCT01404156), oxaliplatin/leucovorin/5-FU/bevacizumab (NCT01212822), paclitaxel/carboplatin/trastuzumab (monoclonal antibody against ErbB-2)/radiation (NCT01196390), navelbine/cisplatin/radiation (NCT01216527) and docetaxel/cisplatin/ cetuximab (monoclonal antibody against EGFR)/radiation (NCT01107639). Several other phase III trials not mentioned here are now recruiting patients to investigate new chemotherapy combinations and molecular-targeting compounds as combination partners, such as S-1/cisplatin; S-1/paclitaxel and 5-FU/leucovorin/oxaliplatin/docetaxel; and trastuzumab, lapatinib (dual EGFR and ErbB-2 tyrosine kinase inhibitor), and cetuximab in far advanced or metastatic disease as first-line treatment. Furthermore, improvement of radiation is another focus of current research. Proton-beam therapy and intensity-modulated radiation therapy are both forms of radiation therapy designed to focus on the regions of the tumor (maximal therapeutic
Gen Thorac Cardiovasc Surg (2014) 62:531–540
effect) while the dose to the surrounding normal critical structures can be minimized (minimum side effect). Studies of new anticancer agents and improved radiation technology for esophageal cancer have just begun, and their clinical applications will be anticipated in the future. Several questions still need to be answered to optimize treatment strategies. One is the histologic heterogeneity of esophageal cancer. The majority of the previous trials targeted squamous cell carcinoma, which in Western countries is currently the less common histologic type compared with adenocarcinoma. Another is the relevance of tumor staging, for which current standard modalities such as positron emission tomography or endoscopic ultrasonography are not adopted in clinical trials. Furthermore, the chemotherapy regimens and the method and area of irradiation have not been established, although newer agents and their regimens have shown promising results. Future trials in locally advanced esophageal cancer should focus on identification of the optimum strategy and its regimen and should aim to minimize treatment toxicities and effects on quality of life. In addition, they should attempt to identify those patients who are most likely to benefit from certain treatment modalities. Conflict of interest interest exists.
The authors have declared that no conflict of
References 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. 2. Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H, The Japan Cancer Surveillance Research Group. Cancer incidence and incidence rates in Japan in 2007: a study of 21 population-based cancer registries for the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2013;43(3):328–336. 3. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE. Longterm results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer. J Clin Oncol. 2009;27(30):5062–7. 4. Rutega˚rd M, Charonis K, Lu Y, Lagergren P, Lagergren J, Rouvelas I. Population-based esophageal cancer survival after resection without neoadjuvant therapy: an update. Surgery. 2012;152(5):903–10. 5. Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study—JCOG9204. J Clin Oncol. 2003;21:4592–6. 6. Kunath U, Fischer P. Radical nature and life expectancy in the surgical treatment of esophageal and cardial carcinoma. Dtsch Med Wochenschr. 1984;109:450–3. 7. Te´nie`re P, Hay JM, Fingerhut A, Fagniez PL. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet. 1991;173:123–30.
539 8. Fok M, Sham JS, Choy D, Cheng SW, Wong J. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery. 1993;113:138–47. 9. Zieren HU, Mu¨ller JM, Jacobi CA, Pichlmaier H, Mu¨ller RP, Staar S. Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg. 1995;19:444–9. 10. Xiao ZF, Yang ZY, Liang J, Miao YJ, Wang M, Yin WB, et al. Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients. Ann Thorac Surg. 2003;75:331–6. 11. Pouliquen X, Levard H, Hay JM, McGee K, Fingerhut A, Langlois-Zantin O. 5-Fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus. A multicenter randomized trial. French Associations for Surgical Research. Ann Surg. 1996;223:127–33. 12. Ando N, Iizuka T, Kakegawa T, Lsono K, Watanabe H, Lde H, et al. A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: the Japan Clinical Oncology Group Study. J Thorac Cardiovasc Surg. 1997;114:205–9. 13. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345(10): 725–30. 14. Tachibana M, Yoshimura H, Kinugasa S, Shibakita M, Dhar DK, Ueda S, et al. Postoperative chemotherapy vs chemoradiotherapy for thoracic esophageal cancer: a prospective randomized clinical trial. Eur J Surg Oncol. 2003;29(7):580–7. 15. Launois B, Delarue D, Campion JP, Kerbaol M. Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet. 1981;153:690–2. 16. Gignoux M, Roussel A, Paillot B, Gillet M, Schlag P, Favre JP, et al. The value of preoperative radiotherapy in esophageal cancer: results of a study by the EORTC. World J Surg. 1987;11:426–32. 17. Wang M, Gu XZ, Yin WB, Huang GJ, Wang LJ, Zhang DW. Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: report on 206 patients. Int J Radiat Oncol Biol Phys. 1989;16:325–7. 18. Arnott SJ, Duncan W, Kerr GR, Walbaum PR, Cameron E, Jack WJ, et al. Low dose preoperative radiotherapy for carcinoma of the oesophagus: results of a randomized clinical trial. Radiother Oncol. 1992;24:108–13. 19. Nygaard K, Hagen S, Hansen HS, Hatlevoll R, Hultborn R, Jakobsen A, et al. Pre-operative radiotherapy prolongs survival in operable esophageal carcinoma: a randomized, multicenter study of pre-operative radiotherapy and chemotherapy. The second Scandinavian trial in esophageal cancer. World J Surg. 1992;16:1104–9 discussion 1110. 20. Arnott SJ, Duncan W, Gignoux M, Girling DJ, Hansen HS, Launois B, et al. Preoperative radiotherapy for esophageal carcinoma. Cochrane Database Syst Rev. 2005;4:CD001799. 21. Schlag PM. Randomized trial of preoperative chemotherapy for squamous cell cancer of the esophagus. The Chirurgische Arbeitsgemeinschaft Fuer Onkologie der Deutschen Gesellschaft Fuer Chirurgie Study Group. Arch Surg. 1992;127:1446–50. 22. Maipang T, Vasinanukorn P, Petpichetchian C, Chamroonkul S, Geater A, Chansawwaang S, et al. Induction chemotherapy in the treatment of patients with carcinoma of the esophagus. J Surg Oncol. 1994;56:191–7. 23. Law S, Fok M, Chow S, Chu KM, Wong J. Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus: a prospective randomized trial. J Thorac Cardiovasc Surg. 1997;114:210–7.
123
540 24. Boonstra JJ, Kok TC, Wijnhoven BP, van Heijl M, van Berge Henegouwen MI, Ten Kate FJ, et al. Chemotherapy followed by surgery versus surgery alone in patients with oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial. BMC Cancer. 2011;11:181. 25. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, Radiation Therapy Oncology Group, USA Intergroup, et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol. 2007;25:3719–25. 26. Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001;91:2165–74. 27. Ychou M, Boige V, Pignon JP, Conroy T, Bouche´ O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29:1715–21. 28. Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol. 2012;19(1):68–74. 29. Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–92. 30. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335(7):462–7. 31. Bosset JF, Gignoux M, Triboulet JP, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med. 1997;337:161–7. 32. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19(2):305–13. 33. Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol. 2004;15:947–54. 34. Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ, Devitt P, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial. Lancet Oncol. 2005;6:659–68. 35. Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26:1086–92. 36. Mariette C, Seitz JF, Maillard E. Impact of neoadjuvant chemoradiation in localized esophageal cancer: results of a randomized, controlled phase III trial. FFCD 9901 (abstract 8000). In: Proceedings of the 35th ESMO Congress. Milan, 2010. 37. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074–84. 38. Burmeister BH, Thomas JM, Burmeister EA, Walpole ET, Harvey JA, Thomson DB, et al. Is concurrent radiation therapy
123
Gen Thorac Cardiovasc Surg (2014) 62:531–540
39.
40.
41.
42.
43.
44.
45. 46.
47.
48.
49.
50.
51.
52.
required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial. Eur J Cancer. 2011;47(3):354–60. Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, RieraKnorrenschild J, et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009;27(6):851–6. Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1662–9. Omloo JM, Lagarde SM, Hulscher JB, Reitsma JB, Fockens P, van Dekken H, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/ distal esophagus: five-year survival of a randomized clinical trial. Ann Surg. 2007;246(6):992–1000. Yekebas EF, Schurr PG, Kaifi JT, Link BC, Kutup A, Mann O, et al. Effectiveness of radical en-bloc-esophagectomy compared to transhiatal esophagectomy in squamous cell cancer of the esophagus is influenced by nodal micrometastases. J Surg Oncol. 2006;93(7):541–9. Horstmann O, Verreet PR, Becker H, Ohmann C, Ro¨her HD. Transhiatal oesophagectomy compared with transthoracic resection and systematic lymphadenectomy for the treatment of oesophageal cancer. Eur J Surg. 1995;161(8):557–67. Boshier PR, Anderson O, Hanna GB. Transthoracic versus transhiatal esophagectomy for the treatment of esophagogastric cancer: a meta-analysis. Ann Surg. 2011;254(6):894–906. Uzunoglu FG, Reeh M, Kutup A, Izbicki JR. Surgery of esophageal cancer. Langenbecks Arch Surg. 2013;398(2):189–93. Hirao M, Ando N, Tsujinaka T, Udagawa H, Yano M, Yamana H, et al. Influence of preoperative chemotherapy for advanced thoracic oesophageal squamous cell carcinoma on perioperative complications. Br J Surg. 2011;98(12):1735–41. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355(1):11–20. Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, V325 Study Group, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol. 2006;24(31):4991–7. Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, EORTC 24971/TAX 323 Study Group, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695–704. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, TAX 324 Study Group, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705–15. Yamasaki M, Miyata H, Tanaka K, Shiraishi O, Motoori M, Peng YF, et al. Multicenter phase I/II study of docetaxel, cisplatin and fluorouracil combination chemotherapy in patients with advanced or recurrent squamous cell carcinoma of the esophagus. Oncology. 2011;80(5–6):307–13. Pasini F, de Manzoni G, Zanoni A, Grandinetti A, Capirci C, Pavarana M, et al. Neoadjuvant therapy with weekly docetaxel and cisplatin, 5-fluorouracil continuous infusion, and concurrent radiotherapy in patients with locally advanced esophageal cancer produced a high percentage of long-lasting pathological complete response: a phase 2 study. Cancer. 2013;119(5):939–45.
