Ann Surg Oncol (2010) 17:1159–1167 DOI 10.1245/s10434-009-0862-1
ORIGINAL ARTICLE – THORACIC ONCOLOGY
Pathologic Response after Neoadjuvant Therapy is the Major Determinant of Survival in Patients with Esophageal Cancer Kenneth L. Meredith1, Jill M. Weber1, Kiran K. Turaga1, Erin M. Siegel2, Jim McLoughlin3, Sarah Hoffe4, Melis Marcovalerio5, Nilay Shah1, Scott Kelley6, and Richard Karl1 Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL; 2Department of Cancer Prevention and Control, Moffitt Cancer Center, Tampa, FL; 3Department of Surgery, Medical College of Georgia, Augusta, GA; 4 Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL; 5Department of Surgery, New York Presbyterian Veterans Administration, New York, NY; 6Department of Surgery, Watson Clinic, Lakeland, FL 1
ABSTRACT Background. Esophageal cancer remains a malignancy with high morbidity and mortality despite improvements to diagnosis, staging, chemotherapy, radiation, and surgery. Neoadjuvant therapy (NT) may improve oncologic outcome in many patients, however the degree to which patients benefit remains unclear. We examined the relationship between pathologic response to NT and magnitude of benefit in patients with esophageal cancer. Methods. Using a comprehensive esophageal cancer database, we identified patients who underwent esophagectomy between 1994 and 2008. Pathologic response was denoted as complete (pCR), partial (pPR), and nonresponse (NR). Clinical and pathologic data were compared using Fisher’s exact and chi-square when appropriate, while Kaplan–Meier estimates were used for survival analysis. Results. We identified 347 patients who underwent esophagectomy, and 262 (75.5%) were treated with NT. The median age was 66 years (28–86 years) with median follow-up of 20 months (1–177 months). There were 106 (40.5%) patients exhibiting pCR, 95 (36.3%) with pPR, and 61 (23.3%) with NR. The rate of R0 resections was higher amongst pCR (100%) compared with 94.7% in pPR (P = 0.02) and 87.5% in NR (P = 0.0007). There were 15 (14.2%) recurrences in pCR, 22 (23.7%) in pPR, and 17 (28.8%) in NR (P = 0.04). Patients achieving pCR had 5-year disease-free survival (DFS) and overall survival (OS) of 52% and 52%, respectively, compared with 36% Ó Society of Surgical Oncology 2010 First Received: 15 April 2009; Published Online: 6 February 2010 K. L. Meredith e-mail:
[email protected]
and 38% in pPR and 22% and 19% in NR (P \ 0.0001, P \ 0.0001). Conclusions. Esophageal cancer patients frequently succumb to their disease. However, patients treated with neoadjuvant therapy who achieve pCR have a higher rate of R0 resections, fewer recurrences, and improved 5-year OS and DFS.
Incidence of esophageal cancer has steadily increased in the Western world, and it often portends a dismal prognosis even in patients undergoing curative resection.1–4 In 2008, there were 16,470 patients diagnosed with esophageal cancer in the United States and 14,280 deaths from the disease.5 Overall 5-year survival for disease localized to the esophagus is 34%, while survival for all stages is much lower at 16%. Surgery has been the mainstay of treatment for esophageal cancer; however, the outcome for patients treated with surgery alone remains poor.6–8 More aggressive surgical approaches to esophagectomy including extended lymphadenectomy have failed to demonstrate a survival benefit in several randomized trials.9,10 However, others have demonstrated reduced local recurrences and survival advantage for patients who underwent radical surgery.11 In an attempt to improve outcome, a variety of protocols have been investigated including a neoadjuvant approach with systemic chemotherapy or radiation therapy for localized esophageal cancer.1,12–20 However the optimal treatment regimen to be given preoperatively remains to be determined. Several trials have demonstrated a benefit in overall survival and recurrence-free survival in patients treated with neoadjuvant chemotherapy [5-fluorouracil (5-FU) and cisplatin], while other trials have failed to
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reproduce these benefits.12,21 Other drugs used in combination with 5-FU such as carboplatin and paclitaxel that improved outcomes have not demonstrated superiority over FU and cisplatin.22 There has been substantial interest in whether the use of trimodality therapy would be superior to surgery alone. The addition of external-beam radiation to systemic chemotherapy has further increased rates of complete pathologic response and shown improvements in overall survival.23 However, this benefit from trimodality therapy was not reproduced in several trials.20,24,25 Potential explanations for the lack of benefit illustrated in these trials are heterogeneity of the patient populations and nonstratification of survival by pathologic response to therapy. The recently published longterm results of the Cancer and Leukemia Group B (CALGB) 9781 trial found 39% 5-year survival in those patients receiving trimodality therapy compared with 16% in patients treated with surgery alone (P = 0.02).26 Complete pathologic response was noted in 40% of patients treated with this regimen; however, the small study population precluded additional survival analysis by pathologic response. In addition to potentially improving survival, neoadjuvant therapy may decrease local recurrence and facilitate R0 resection. Moreover, pathologic response to neoadjuvant therapy may predict tumor sensitivity and give insight into tumor biology for adjuvant chemotherapy if needed or therapies for local or distant recurrences. The effect of neoadjuvant therapy on pathological response has been studied mostly as a secondary hypothesis in well-designed clinical trials, in which there has been a dramatic survival benefit in patients with significant partial or complete pathological response.27–29 However, the dose–response characteristic and potential effect of neoadjuvant chemotherapy on surgical margins remain inadequately studied. The present study was undertaken to assess the impact of neoadjuvant chemotherapy and radiation on survival in patients with resectable esophageal cancer, to identify clinicopathological variables that predict overall survival and disease-free survival following neoadjuvant therapy, and to identify the potential impact of therapy on surgical outcomes. PATIENTS AND METHODS A query was performed from our comprehensive esophageal cancer database consisting of all patients who underwent esophagectomy at H. Lee Moffitt Cancer Center between June 1994 and January 2008. We sought to identify a cohort of patients who were treated with neoadjuvant therapy or surgery alone (SA) without neoadjuvant therapy. Variables collected in the database include demographics, Charlson index comorbidities, risk
K. L. Meredith et al.
factor history, family history, preoperative symptoms, tumor stage and histopathologic variables, survival, and recurrence data. Currently 541 patient charts have been abstracted and were available for this study. Data from the esophageal database were collected solely by experienced clinicians. Data were entered into a secure web-based dataentry system and uploaded into an Access database by a data analyst. Ambiguities in any data points were discussed by the committee, researched, reviewed, and corrected. Data entry quality was monitored, with 33% of all cases being re-reviewed for accuracy. Inclusion criteria for this study included all patients with diagnosis of esophageal adenocarcinoma (AC) or squamous cell carcinoma (SCC) and all patients in whom response to neoadjuvant therapy was recorded. Additionally, a comparison group of patients with stage II or greater who would have been candidates for NT but who were treated with surgery alone was identified. Patients with high-grade dysplasia, esophagectomy for benign esophageal disease, or unknown postoperative stage were excluded. It is our practice that all patients undergo endoscopic ultrasound (EUS), computed tomography (CT) scans of the chest, abdomen, and pelvis in addition to positron emission tomography (PET) for accurate staging prior to consideration of neoadjuvant therapy or surgery. Surgery All operations were performed with curative intent and included removal of the primary tumor en bloc with its draining lymph nodes. Esophagogastrectomy was defined as resection of the proximal stomach and thoracic esophagus with esophagogastric anastomosis in the chest (Ivor– Lewis approach) or transabdominal esophagectomy with anastomosis in the neck (transhiatal approach). Minimally invasive esophagectomy (MIE) via transhiatal technique was performed on select patients. The choice of operation was based on the site of the primary tumor and surgeon preference. Resections were defined as curative (R0) when all gross disease was removed with negative margins. Incomplete (R1) resections were defined as positive surgical margins or tumor \ 1 mm from any margin. Procedure-related mortality was defined as death in hospital or within 30 days of operation. Neoadjuvant Therapy The decision to treat patients with combined-modality therapy and the neoadjuvant regimen administered was determined by multidisciplinary tumor board discussions, tumor histology and stage, patient ability to tolerate therapy, and in accordance with National Comprehensive Cancer
Neoadjuvant Therapy for Esophageal Cancer
Network (NCCN) guidelines. Patients treated with neoadjuvant therapy at Moffitt Cancer Center receive 75 mg/m2 cisplatin intravenously on days 1 and 28 followed by 225 mg/m2/day 5-fluorouracil given by continuous infusion on days 1–5 in addition to 50.4 Gy of radiation delivered by external-beam radiation. Patients who underwent stereotactic-based radiation therapy received treatment to a clinical target volume defined as 5 cm superior and inferior to the tumor margin with a 2 cm radial margin.
1161 TABLE 1 Patient and tumor characteristics Characteristic
N
N%
287
82.7
60
17.3
Upper third
2
0.6
Middle third
24
6.9
Lower third
227
65.4
89
25.6
5
1.5
301 46
86.7 13.3
1
0.3
IIA
74
21.3
IIB
61
17.6
III
164
47.3
IV
13
3.7
Unknown
34
9.8
Gender Male Female Site
Pathological Definitions
GE junction
Esophagectomy specimens were evaluated by routine hematoxylin and eosin staining. Board-certified pathologists who specialize in gastrointestinal malignancies reviewed all specimens. Tumor stage was assessed by the pathologist and classified according to the sixth edition of the tumor–node– metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) for esophageal cancer.30 Complete pathologic response (pCR) was defined as absence of histological evidence of neoplasia, gross tumor or individual cells in the resected esophageal specimen by light microscopy but not immunohistochemical stains. Partial pathologic response (pPR) was defined as a change in T or N stage from preoperative endoscopic ultrasound (EUS) or greater than 50% reduction in size of tumor compared preand postoperatively. Nonresponders (NR) were defined as those with no change in tumor stage when comparing preoperative (EUS) and postoperative pathologic stage.
Histology
Statistical Analysis
cell carcinoma (n = 46) of the esophagus. The median age for the entire cohort was 64 years (range 28–86 years) and the median follow-up was 20 months (1–177 months). There were 287 (83%) males and 60 (17%) females. There were 135 (38.9%) patients with stage II tumors, of which 74 (55%) were stage IIa and 61 (45%) were stage IIb tumors. Stage III tumors were present in 164 (47.3%) of patients. Preoperative tumor stage was unknown in 34 (9.8%) of patients. Tumors were most often located in the lower third or gastroesophageal junction (n = 316) compared with the upper third (n = 2) or mid-esophagus (n = 24). The majority of patients treated were Caucasian (n = 329, 94.8%) compared with other ethnic backgrounds (n = 18, 5.2%). Two hundred sixty-two patients (75.5%) were treated with neoadjuvant therapy, whereas 85 (24.5%) patients were treated with SA. Among those proceeding to SA, 68 were stage II and 17 were stage III.
Clinical and pathologic data were compared using the chi-squared or Fisher’s exact tests when appropriate to test for differences in frequency across all groups. Mean differences were examined by response for continuous data using analysis of variance (ANOVA). All statistical tests performed were two-sided and declared at the 5% significance level. Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan–Meier method, with differences in survival rates assessed using the log-rank test to determine univariate significance. Statistical analyses were performed by using SE STATA (Stata Statistical Software, release 9.0; Stata Corp., College Station, TX). RESULTS
Cardia Adenocarcinoma Squamous cell carcinoma Stage I
Grade Well differentiated
25
7.2
Moderately differentiated
130
37.5
Poorly differentiated
103
29.7
81
23.3
8
2.3
GX: unspecified Unknown GE gastroesophageal
Demographics Surgical Outcomes The clinical and pathological characteristics of the patients are listed in Table 1. We identified 347 (64%) patients of 541 with adenocarcinoma (n = 301) or squamous
The 30-day mortality was 2.6% (n = 9) for all patients undergoing esophagectomy. The operations performed are
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Survival and Pathologic Response
TABLE 2 Surgical and pathologic characteristics Demographic
N
N%
241
69.5
32
9.2
Minimally invasive TH
48
13.8
Other
26
7.5
262
75.5
85
24.5
106
40.4
95 61
36.3 23.3
Procedure Transthoracic Transhiatal
Treatment type Neoadjuvant therapy Surgery alone Response to therapy Complete response Partial response No response TH transhiatal
listed in Table 2. The majority of patients (n = 241, 69.5%) were treated by transthoracic esophagectomy. The open transhiatal approach was performed in 32 (9.4%) patients, and minimally invasive transhiatal esophagectomy was performed in 48 (14%) of patients. Three-field esophagectomy or thoracoabdominal approaches were performed in 26 (7.5%). The major complications were: pulmonary aspiration/pneumonia (16.6%), wound infections (6.8%), leak (5.7%) (open 4.3%, MIE 8.6%; P = 0.16), stricture 14.3%, and cardiac 0.3%. There were no differences in the complication profiles between patients treated with neoadjuvant therapy and those proceeding to SA (P = 0.62). There were no differences in the mean number of nodes harvested between those treated with the open techniques (8.5 ± 5.6) compared with those treated with the minimally invasive technique (8.9 ± 5.3; P = 0.6) or the rate of R0 resections (94.2%) in the open group versus in the MIE group (97.9%; P = 0.49). Margin status was not recorded in 22 (6.3%) patients. The overall rate of R0 resection was 94.7% in patients undergoing esophagectomy.
The 5-year overall and disease-free survival for the entire cohort of patients were 42.2% and 42.1%, with median survival of 36 months (0–156 months) and DFS of 31 months (3–156 months). A decrease in OS and DFS was noted with increasing stage (Figs. 1, 2). When examining the impact of neoadjuvant therapy on OS, DFS, recurrences, and R0 resections, by pathologic response, we demonstrated no difference in 5-year OS among those receiving NT (39.4%) compared with patients who did not receive NT (46.3%) (P = 0.057). However, the impact of pathologic response predicted improvements in OS and DFS. Patients achieving complete pathologic response had significantly improved 5-year OS and disease-free survival (52% and 52%) compared with pPR (36% and 38%) or NR (22% and 19%) (P \ 0.0001 and P \ 0.0001, respectively) (Figs. 3, 4). The median survival was 66 months
Overall Survival
0.8
Stage I Stage II Stage III Stage IV
0.6
p < 0.0001
1.0
0.4
0.2
0
12
24
36
48
60
72
84
96
108
Months FIG. 1 Stage-specific overall survival
Disease-Free Survival
Neoadjuvant Therapy and Pathologic Response
1.0
Amongst the 347 patients who underwent esophagectomy, 262 (75.5%) were treated with neoadjuvant therapy. Response to NT therapy (pCR or pPR) was noted in 201 (76.7%) patients. There were no differences in the response rates between patients with AC and SCC (P = 0.32). Complete pathologic response was achieved in 106 (40.4%), pPR in 95 (36.3%), and NR in 61 (23.3%) of patients. Ninetytwo (40.4%) patients with AC achieved pCR, compared with 14 (41.2%) patients with SCC (P = 0.56). Similar trends were noted in pPR (AC, n = 86, 37.7% versus SCC, n = 9, 26.5%; P = 0.25), and NR (AC, n = 50, 21.9% versus SCC, n = 11, 32.4%; P = 0.19).
0.8
Stage I Stage II Stage III Stage IV
0.6
p < 0.0001
0.4
0.2
0
12
24
36
48
60
72
Months FIG. 2 Stage-specific disease-free survival
84
96
108
Neoadjuvant Therapy for Esophageal Cancer
1163 Overall Survival
Overall Survival Complete response Partial response No response p = 0.0001
1.0
0.8
1.0
Surgery alone No response
0.8
p < 0.0001
0.6
0.6
0.4
0.4
0.2
0.2
0
12
24
36
48
60
72
84
96
0
108
12
24
36
48
60
72
84
96
108
Months
Months
FIG. 3 Overall survival by pathologic response to neoadjuvant treatment
FIG. 5 Overall survival of nonresponders and surgery-alone groups
Disease-Free Survival
Disease-Free Survival Complete response Partial response No response p = 0.0001
1.0
0.8
1.0
Surgery alone No response
0.8
p < 0.0001
0.6
0.6
0.4
0.4
0.2
0.2
0
12
24
36
48
60
72
84
96
108
0
12
24
36
48
60
72
84
96
108
Months
Months
FIG. 4 Disease-free survival by pathologic response to neoadjuvant treatment
FIG. 6 Disease-free survival of nonresponders and surgery-alone groups
(2–156 months) in patients with pCR, 32 months (2– 98 months) in those with pPR, and 16 months (2– 102 months) in those with NR. Patients with NR fared worse in terms of 5-year OS and DFS than those treated with SA (45.9% and 46.3%) (P \ 0.0001 and P \ 0.0001) (Figs. 5, 6). Additionally, patients achieving pCR were more likely to have R0 (n = 106, 100%) resection compared with pPR (n = 90, 94.7%; P = 0.02), NR (n = 54, 87.5%; P = 0.0007), and SA (n = 78, 91.8%; P = 0.002). We sought to determine histologic influence on pathologic response and survival. Patients with AC who achieved pCR again demonstrated superior 5-year survival of 52.1% compared with 38.8% in pPR and 23.5% in NR (P = 0.0002). Improvements in 5-year DFS were also noted in the pCR (52.4%) group compared with other treatment groups (39.9% in pPR and 21.1% in NR; P \ 0.0001). Patients with SCC did not demonstrate
similar benefits in terms of OS (44.1% in pCR, 50% in NR; P = 0.94) or DFS (45.7% in pCR, 33.7% in NR; P = 0.93) as seen in patients with AC. Small numbers limited analysis of patients with SCC and partial response to neoadjuvant therapy. Stage-specific analysis was performed to identify any potential benefit amongst groups treated with neoadjuvant therapy. Of the 135 patients with stage II esophageal cancer, 68 (50.3%) were treated with neoadjuvant therapy. There were 31 (46.3%) patients achieving pCR, 19 (28.4%) with pPR, and 17 (25.4%) with NR. Patients achieving pCR exhibited 5-year OS and DFS of 63% and 61%, respectively, compared with 51% and 51% for pPR and 22% and 8% in those who were deemed NR. There was an improvement in survival (P = 0.037) and disease-free survival (P = 0.0007) noted in patients with pathologic complete response to therapy compared with those who did
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K. L. Meredith et al. Overall Survival
Overall Survival 1.0
Complete response No response
1.0
Complete response No response
0.8
p = 0.037
0.8
p = 0.0052
0.6
0.6
0.4
0.4
0.2
0.2
0
12
24
36
48
60
72
84
96
0
108
12
24
36
48
60
72
84
96
108
Months
Months
FIG. 7 Overall survival by pathologic response to neoadjuvant treatment in patients with stage II esophageal cancer
FIG. 9 Overall survival by pathologic response to neoadjuvant treatment in patients with stage III esophageal cancer
Disease-Free Survival
Disease-Free Survival
1.0
Complete response No response
1.0
Complete response No response
0.8
p = 0.0007
0.8
p = 0.035
0.6
0.6
0.4
0.4
0.2
0.2
0
12
24
36
48
60
72
84
96
108
0
12
24
36
48
60
72
84
96
108
Months
Months
FIG. 8 Disease-free survival by pathologic response to neoadjuvant treatment in patients with stage II esophageal cancer
FIG. 10 Disease-free survival by pathologic response to neoadjuvant treatment in patients with stage III esophageal cancer
not respond (Figs. 7, 8). The median survival among groups was 30 months (2–102 months) in NR, 78 months (6–156 months) in pPR, and not reached in pCR. Amongst the 164 patients with stage III esophageal cancer, 147 (89.6%) were treated with neoadjuvant therapy. There were 53 (36.1%) patients who achieved pCR, 60 (40.1%) who achieved pPR, and 34 (23.1%) who were deemed NR. The 5-year overall and disease-free survival in patients achieving pCR was 50.4% and 50.1%, respectively, compared with 38.9% and 40.4% in pPR and 24.1% and 26.7% in NR. The improvement in OS and DFS that was seen in stage II patients was also demonstrated in stage III patients who achieved pCR with NT compared with NR (P = 0.0052, P = 0.035) (Figs. 9, 10). The median OS in the pCR, pPR, and NR groups was 68 months (1– 108 months), 30 months (1–98 months), and 12 months (2–90 months), respectively.
Recurrences There were 82 (23.6%) recurrences, with median time to recurrence of 11 months (1.5–68 months). Local recurrence was noted in 6 (1.7%) patients, regional nodal recurrence in 10 (2.9%), and systemic progression in 64 (18.4%). Systemic recurrences were reported in liver (n = 6), lung (n = 1), bone (n = 11), brain (n = 10) and other sites (n = 26). Recurrence site data was not recorded for 12 (3.5%) patients. Stage-specific recurrence analysis demonstrated 23 (17%) recurrences in patients with stage II and 41 (25%) recurrences in patients with stage III esophageal cancer. Five patients (38.5%) with stage IVa disease developed recurrence. Upon further investigation of the impact of pathologic response on recurrence, we found 15 (14.2%) recurrences in patients with pathologic complete response, 22 (23.7%)
Neoadjuvant Therapy for Esophageal Cancer
in patients with pPR, and 17 (28.8%) in patients deemed NR. Patients who achieved pCR were less likely to experience recurrence than patients with pPR or those who did not respond to neoadjuvant therapy (P = 0.04). Furthermore there were no differences in recurrence between those treated with surgery alone (n = 16, 19%) compared with NR (P = 0.22). These recurrence patterns were independent of histology. Patients with AC were as likely to exhibit recurrence (n = 71, 23.8%) as were those with SCC (n = 11, 22.5%) (P = 0.67). Adjuvant Chemotherapy Overall, there were 65 (21.24%) patients who were treated with adjuvant chemotherapy, of whom 34 had received neoadjuvant therapy. No differences were noted between histology and treatment with adjuvant chemotherapy. Patients with AC (n = 59, 19.6%) were as likely to receive adjuvant therapy as were those with SCC (n = 6, 13%; P = 0.40). The 5-year OS and DFS in treated patients were 43% and 43%, respectively, compared with 46% and 48% in those who were not. The use of adjuvant therapy had no impact on OS or DFS, even in patients receiving neoadjuvant therapy (P = 0.25 and P = 0.24). DISCUSSION In our series of 347 patients with locally advanced esophageal cancer we found that overall and disease-free survival were correlated with degree of pathologic response to neoadjuvant therapy. This is consistent with data published from previous trials as well as a recent experience from Chirieac et al. in which post-neoadjuvanttherapy staging was significantly associated with overall survival and disease-free survival.27 We also report the association of neoadjuvant therapy with R0 resection. This has significant implications and adds evidence for the benefit of neoadjuvant therapy. In our study, 40.4% of patients achieved complete response, which is equal to or greater than results of published series.22,28,29 However, even patients who achieved partial pathologic response demonstrated superior diseasefree and overall survival, and this could be used as a post hoc staging system for survival prognostication, as recommended by Chirieac and colleagues.27 The effect on overall survival persisted regardless of stage. Stage II esophageal cancer patients who exhibited pathologic complete response had 63% 5-year survival, compared with 50.4% in patients with stage III disease and pCR, and this was substantially better than all other treatment groups in both stages. Burmeister et al.’s prospective randomized trial with neoadjuvant chemoradiation found a lack of
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benefit in terms of overall survival in patients receiving neoadjuvant therapy.14 However a recent meta-analysis demonstrated a 13% absolute survival benefit at 2 years, with results seen in both major histological subtypes.15 Neither of these studies included evaluation of extent of pathological response, nor was the aforementioned trial powered for subgroup analysis. We also found that R0 resection was achieved in 94.6% of our patients, but this was highly dependent on treatment group and pathologic response to neoadjuvant therapy. As expected all patients with pCR had R0 resection; however, as the degree of pathologic response decreased, or if the patient proceeded straight to surgery, then likelihood of R0 resection also decreased. This increase in curative resection with pathologic response has also been demonstrated by Pennathur et al., who reported an 81% margin-negative resection rate among those receiving neoadjuvant chemoradiation.19 The increased rate of R0 resections has also been described to a lesser extent in patients undergoing neoadjuvant chemotherapy without radiation. The Medical Research Council Oesophageal Cancer Working Group (MRC) found a 60% R0 resection rate among those treated with systemic 5-FU/cisplatin neoadjuvantly compared with 54% in the surgery-alone arm, which translated into an improvement in overall survival.31 Kelsen and colleagues, in the RTOG 8911/Intergroup 113 trial comparing neoadjuvant chemotherapy and surgery alone, demonstrated no overall survival benefit and a margin-negative resection rate of 62% with operative mortality of 6%.17 However patients who had R1 resection had worse overall survival than those who underwent complete resection. The longterm results of the RTOG 8911/Intergroup 113 trial corroborated its initial benefits of R0 resection yet failed to show an improvement in survival compared with the similarly designed MRC trial.21 Several trials in esophageal cancer investigating the neoadjuvant approach have failed to demonstrate survival benefits. Criticisms of these well-designed clinical trials include their heterogeneous patient populations and nonstratification of patients by pathologic response. Subgroup analysis by pathological response in these trials may further clarify survival benefits in margin-negative patients, since we believe that pathological response is independently associated with disease-free survival after adjusting for margin status. Methods for prediction of pathological response based on radiographic response have yielded disappointing results. Luketich et al. reported that the sensitivity of positron emission tomography (PET) scan for detection of persistent disease, although better than for computed tomography (CT) scan, was still only 69%, while specificity was 94%.32 In a more promising study, Weber and
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colleagues reported 93% sensitivity and 95% specificity of PET scan for detection of response to therapy.33 In our own series of 81 patients we found sensitivity of 61.8%, specificity of 43.8%, and positive and negative predictive values of 70% and 35%, respectively. Unfortunately, the overall accuracy of PET for prediction of complete response was only 54%.34 While some authors have suggested potentially avoiding surgery after neoadjuvant therapy, adequate follow-up is lacking and recurrence rates are higher when esophagectomy is omitted.35,36 Until we are better at predicting which patients truly have complete response to neoadjuvant therapy and have longer follow-up data on definitive therapy, surgery should be recommended to those who are medically fit to undergo esophagectomy. We are currently investigating markers to predict pathological response to neoadjuvant therapy. This would enable us to prognosticate patients better and perhaps identify patients who may be nonresponders. As we have demonstrated, patients undergoing neoadjuvant therapy who are deemed nonresponders fared worse in survival, stage for stage, than all other treatment groups. Identifying this subgroup of patients with esophageal cancer would potentially avoid neoadjuvant therapy in 23.3% of patients who would not benefit from such an approach. This would allow for surgical treatment or potential alternative regimens to be initiated earlier. Until such an approach is feasible we must continue to rely on histopathological examination of the resected specimen to determine the degree of pathologic response to neoadjuvant therapy and identify any potential survival advantages. Our study does suffer from the limitations of a retrospective study and heterogeneity of therapy over the 14-year period. However, with the exception of our approach to lymph node examination, our pathological review of the primary tumor has remained constant over the years, and since we follow a protocol-based regimen we believe this introduces only limited nondirectional bias. While the number of lymph nodes harvested in our study is lower than in other series, the majority of our patients underwent neoadjuvant therapy and many specimens were examined prior to specialized techniques such as ‘‘fat clearing’’ and ‘‘bread loafing’’ of the specimen now considered to be standard. Additionally, caution must be used in the interpretation of the nonresponders and surgery-alone group comparison. The surgery-alone cohort had higher numbers of patients with stage II esophageal cancer with respect to the nonresponders, who included higher numbers of patients with stage III disease. We recognize that this stage migration could potentially bias results. Therefore, additional stagespecific comparisons are needed in these treatment groups to further clarify any potential survival benefit. Finally, we observed no survival differences between those receiving
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adjuvant chemotherapy and those who did not. However, this additional therapy is usually offered to patients considered at higher risk for relapse and who may experience worse outcomes regardless. Since there is no standardization as to when adjuvant therapy is to be given, this is also subject to bias. CONCLUSIONS Patients with esophageal cancer frequently succumb to their disease. Neoadjuvant therapy is an important adjunct in the treatment of patients with locally advanced esophageal cancer. While this approach may improve outcome in the majority of patients, it has not been shown to consistently benefit all patients in several well-designed prospective clinical trials. Heterogeneous patient populations, lack of uniform consensus on the type of therapy to be given, and varying degree of pathologic response may play an important role in explaining the results from these pivotal negative trials. Analysis based on pathologic stratification not only yields important information about tumor biology but also gives insight into tumor chemo- and radiation sensitivity. We have demonstrated that degree of pathological response is the most important predictor of overall and disease-free survival in patients undergoing neoadjuvant therapy. Moreover, patients who achieve pathologic complete response to neoadjuvant therapy have the greatest chance of prolonged survival, irrespective of stage. This improvement in survival declines with the degree of pathologic response to neoadjuvant therapy. Future studies and perhaps staging should include pathologic response classification to enable better estimates of prognosis in patients with esophageal cancer who undergo neoadjuvant therapy prior to esophagectomy. REFERENCES 1. Reynolds JV, Muldoon C, Hollywood D, et al. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg. 2007;245(5):707–16. 2. Lagergren J. Adenocarcinoma of oesophagus: what exactly is the size of the problem and who is at risk? Gut . 2005;54(Suppl 1):i1–5. 3. Law S, Wong J. What is appropriate treatment for carcinoma of the thoracic esophagus? World J Surg 2001;25(2):189–95. 4. Pera M, Manterola C, Vidal O, Grande L. Epidemiology of esophageal adenocarcinoma. J Surg Oncol. 2005;92(3):151–9. 5. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. 6. Earlam R, Cunha-Melo JR. Oesophageal squamous cell carcinoma: I. A critical review of surgery. Br J Surg. 1980;67(6):381–90. 7. Muller JM, Erasmi H, Stelzner M, et al. Surgical therapy of oesophageal carcinoma. Br J Surg. 1990;77(8):845–57. 8. Wu PC, Posner MC, Wu PC, Posner MC. The role of surgery in the management of oesophageal cancer. Lancet Oncol. 2003;4(8):481–8.
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