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Does Barrett's esophagus respond to chemoradiation therapy for adenocarcinoma of the esophagus?
ORIGINAL ARTICLE: Clinical Endoscopy
Does Barrett’s esophagus respond to chemoradiation therapy for adenocarcinoma of the esophagus? James S. Barthel, MD, Stephen T. Kucera, MD, James L. Lin, MD, Sarah E. Hoffe, MD, Jonathan R. Strosberg, MD, Irfan Ahmed, MD, Thomas J. Dilling, MD, Craig W. Stevens, MD, PhD Tampa, Florida, USA
Background: Adenocarcinoma of the esophagus is frequently associated with Barrett’s esophagus (BE). The response of esophageal adenocarcinoma to chemoradiation therapy is well described; however, the effect of chemoradiation on tumor-associated BE has not been specifically reported. Objective: To determine the response of tumor-associated BE to chemoradiation therapy. Design: Retrospective cohort study. Setting: A single National Cancer Institute Comprehensive Cancer Care Center experience. Patients: The study cohort consisted of 43 patients with stage I to IVA esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy and underwent either esophagectomy or surveillance at our institution. Main Outcome Measurement: The presence and extent of BE after chemoradiation therapy of esophageal adenocarcinoma associated with endoscopically documented pretreatment BE. Results: BE persisted after chemoradiation therapy in 93% (40/43) of cases (95% CI, 83%-99%). Twenty-seven patients received neoadjuvant chemoradiation therapy before esophagectomy. Persistent BE was detected in all 27 surgical specimens (100%). In 59% (16/27) of the cases, there was complete pathologic tumor response. Sixteen patients received definitive chemoradiation therapy. Persistent pretreatment BE was identified in 88% (14/16) by surveillance endoscopy (95% CI, 60%-98%). The mean length of BE before and after chemoradiation was 6.6 cm and 5.8 cm, respectively (P Z .38). Limitations: Retrospective design, small sample size, and single-site data collection. Conclusions: Chemoradiation therapy of esophageal adenocarcinoma does not eliminate tumor-associated BE, nor does it affect the length of the BE segment. (Gastrointest Endosc 2010;71:235-40.)
Copyright ª 2010 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.09.038
association with all stages of esophageal adenocarcinoma. Theisen et al7 reported that BE existed in 75% of patients with esophageal adenocarcinoma and that chemoradiation-induced tumor regression ‘‘unmasked’’ BE in an additional 22% as determined by restaging after therapy. Theisen et al did not comment on the response of BE to chemoradiation therapy in the 75% of patients with tumor-associated pretreatment BE. The majority of symptomatic esophageal cancer patients present with locoregional disease corresponding to American Joint Committee on Cancer (AJCC) stages II and III. Neoadjuvant chemoradiation therapy followed by esophagectomy (trimodality therapy) is the preferred approach for stage II and III esophageal cancer8 and can achieve 5-year survival rates of 33% to 39%.9-11
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Volume 71, No. 2 : 2010 GASTROINTESTINAL ENDOSCOPY 235
The incidence of esophageal adenocarcinoma is increasing by 4% to 10% per year and is increasing at a more rapid rate than any other malignant neoplasm in the United States and Western Europe.1-4 Barrett’s esophagus (BE) is the major risk factor for the development of esophageal adenocarcinoma5,6 and is frequently found in Abbreviations: AJCC, American Joint Committee on Cancer; BE, Barrett’s esophagus; cCR, complete clinical response; cPR, complete pathological response; IQR, interquartile range; PDT, photodynamic therapy. DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.
Barrett’s esophagus response to chemoradiation
Nonetheless, an increasing number of patients receive definitive chemoradiation therapy because of medical comorbidities that preclude surgery and because many patients refuse to undergo esophagectomy. Definitive chemoradiation therapy can achieve 5-year survival rates of 25% to 30% in stage II and III esophageal cancer.12,13 The response of tumor-associated BE to chemoradiation therapy for esophageal adenocarcinoma has not been specifically reported. There is an informal awareness among esophageal surgeons that neoadjuvant chemoradiation therapy does not produce regression of BE by the time esophagectomy is performed, and, therefore, esophageal surgeons typically adjust their resections to achieve a BE-free proximal margin. Medical and radiation oncologists who manage patients receiving definitive chemoradiation are less aware of this phenomenon. Because of the paucity of published information on the response of pretreatment tumor-associated BE to chemoradiation therapy for esophageal adenocarcinoma, we conducted a retrospective cohort study to determine the effect of chemoradiation therapy on pretreatment BE.
Barthel et al
Capsule Summary What is already known on this topic d
Barrett’s esophagus (BE) is frequently found with all stages of esophageal adenocarcinoma.
What this study adds to our knowledge d
d
In a retrospective cohort study of 43 patients with esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy, BE persisted in 93%. The mean length of BE before and after chemoradiation was unchanged.
The study was approved by both the Moffitt Cancer Center Scientific Review Committee and the University of South Florida Biomedical Institutional Review Board. We reviewed the medical records of 137 patients referred for chemoradiation as treatment for esophageal adenocarcinoma between January 1, 2000, and January 1, 2009, at the Moffitt Cancer Center. A total of 94 patients were excluded (Fig. 1). Forty-one patients were excluded because they did not have BE associated with their adenocarcinoma pretreatment. The absence of BE was confirmed both endoscopically and histologically through review of pretreatment staging endoscopy and surgical pathology reports. Nineteen patients deferred surveillance endoscopy after chemoradiation and were therefore excluded. Eleven patients underwent primary esophagectomy for clinical stage I cancer after consultation with medical, radiation, and surgical oncology. Surveillance endoscopy was not performed in a total of 23 patients who received palliative chemoradiation for stage IVB esophageal adenocarcinoma. Our population cohort was therefore composed of 43 patients with clinical stage I to IVA esophageal adenocarcinoma associated with BE receiving treatment with curative intent. All patients underwent pretreatment clinical staging including EUS at our institution. All patients had either esophagectomy in conjunction with trimodality therapy or at least one surveillance endoscopy after definitive chemoradiation therapy. Esophagectomy was performed within 6 to 8 weeks after neoadjuvant chemoradiation therapy. Staging endoscopy and related pathology reports
were reviewed to obtain a pretreatment description of the BE segment as well as the tumor histology and stage. Oncology treatment records were reviewed to determine dose and duration of chemotherapeutic regimens. Radiation oncology treatment records and films were reviewed to obtain radiation technique and the size of the treatment field. Two radiation oncologists reviewed the actual treatment simulation and port films to determine the anatomic extent of irradiated esophageal tissue. A reference system was created by marking the carina on each film and designating this point as equivalent to 25 cm from the incisors. By using the scale on the films, the superior and inferior treatment margins as equivalent to the distance from the incisors were then measured and noted. This allowed data to be collected from each case verifying the extent of actual tissue within the irradiated field. Esophagectomy pathology reports were reviewed in patients receiving trimodality therapy to determine whether BE was present in resection specimens and to assess the completeness of resection with respect to BE persisting after neoadjuvant chemoradiation therapy. Surveillance endoscopy and coinciding mucosal biopsy pathology reports were used to assess the effect of definitive chemoradiation therapy on pretreatment BE. BE was defined as columnar-lined epithelium in the tubular esophagus visible above the gastroesophageal junction in association with histologic evidence of specialized intestinal metaplasia.14 The BE segment length was measured as the maximum length of contiguous columnar epithelium. Because the intent of surveillance endoscopy was detection of residual tumor, as many as 6 biopsy specimens were obtained from the area of the previous or persistent tumor and adjacent mucosa and not necessarily throughout the length of visible BE. In consultation with the Moffitt Cancer Center Biomedical Statistics Group, the R statistical package, version 2.6.0 (www.r-project.org) was used to generate descriptive statistics and confidence intervals and to compare pre- and posttreatment mean lengths of BE by using a 2-tailed paired t test. Statistical significance was defined as P! .05.
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METHODS
Barthel et al
Barrett’s esophagus response to chemoradiation
TABLE 1. American Joint Committee on Cancer clinical stages of patients receiving either neoadjuvant chemoradiation before esophagectomy or definitive chemoradiation therapy AJCC clinical stage
Neoadjuvant chemoradiation
Definitive chemoradiation
I
1
2
IIA
0
1
IIB
7
6
III
16
4
3
3
IVA
AJCC, American Joint Committee on Cancer.
The study cohort was composed of 43 patients with an age range of 44 to 88 years and a mean age of 67 years. There were 38 men and 5 women. Esophageal cancer pretreatment AJCC clinical stages were as follow: 3 patients had stage I disease, 14 had stage II disease, 20 had stage III disease, and 6 patients had stage IVA disease (Table 1). At the time of initial staging EUS, the median length of BE was 6.0 cm (interquartile range [IQR] 4.5-8.5 cm). BE was documented in 41 (95%) of 43 patients (95% CI, 83%-99%) after neoadjuvant or definitive chemoradiation therapy based on surgical specimens or endoscopic findings. Radiation techniques used for both neoadjuvant and definitive chemoradiation therapy included compensatorbased intensity-modulated radiation therapy, 2- and 3dimensional conformal, and tomotherapy with a median dose of 50.4 Gy of radiation. Thirteen patients were treated with 2-dimensional conformal radiation therapy, 21 with 3dimensional conformal radiation therapy, 8 with compensator-based intensity-modulated radiation therapy, and 1 with tomotherapy. The median length of esophagus included in the radiation field was 13.0 cm (IQR 11.0-15.5 cm). Concurrent chemotherapy consisted typically of cisplatin combined with 5-fluorouracil or irinotecan. All patients receiving neoadjuvant chemotherapy received 2 cycles of cisplatin and 5-fluorouracil. Patients receiving definitive
chemotherapy received an additional 2 cycles of cisplatin and 5-fluorouracil or cisplatin and irinotecan. Twenty-seven of 43 patients received neoadjuvant chemoradiation before esophagectomy. The median pretreatment AJCC clinical stage was III (Table 1). The median time to esophagectomy from completion of chemoradiation was 60 days (IQR 58-61 days). In all 27 (100%) cases, BE was detected in the surgical specimens. Among these patients, 16 (59%) had a complete pathologic response (cPR), defined as absence of microscopically detectable cancer in the esophagectomy specimen. BE persisted despite cPR in all cases. In 96% (26/27) of patients, the proximal surgical margin was found to be free of BE. Postesophagectomy endoscopic surveillance in the patient whose surgical margin was not free of BE revealed a short segment (!3 cm) of residual, nondysplastic Barrett’s epithelium. The median pretreatment AJCC clinical stage was II for the 16 patients who received definitive chemoradiation therapy with curative intent (Table 1). Persistent BE was identified in 14 (88%) of 16 patients (95% CI, 60%-98%) at either initial posttreatment endoscopy or on subsequent surveillance endoscopy. The median time to initial posttreatment endoscopy was 59 days (IQR 37-90 days), with all patients undergoing initial surveillance endoscopy within 105 days of completion of chemoradiation therapy. Among the 14 patients with documented BE after definitive chemoradiation therapy, the median time from completion of therapy to the last surveillance endoscopy performed was 196 days (IQR 91-267 days). Surveillance endoscopy 6 months and beyond detected 100% of cases with reappearance of endoscopically visible columnarlined esophagus above the gastroesophageal junction coinciding with intestinal metaplasia on biopsy sample histology (Fig. 2B). The mean pretreatment BE segment length was 6.6 cm, and the mean posttreatment BE segment length was 5.8 cm in these patients. The 0.8 cm (95% CI, 1.1 to 2.8 cm) difference in mean BE segment length was not statistically significant (P Z .38).
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Figure 1. Outline of patient selection and reasons for exclusion.
RESULTS
Barrett’s esophagus response to chemoradiation
Barthel et al
TABLE 2. Summary of endoscopic surveillance findings in patients receiving definitive chemoradiation therapy Endoscopic and histopathologic findings
No. patients
No BE, inflammatory changes only
2
Nondysplastic BE þ cCR
2
BE with LGD þ cCR
3
BE with HGD þ cCR
4
BE þ residual tumor
5
BE, Barrett’s esophagus; cCR, complete clinical response; LGD, low-grade dysplasia; HGD, high-grade dysplasia.
We confirmed persistent BE after chemoradiation therapy in 95% of our patient cohort. Subgroup analysis revealed persistent BE in 100% of esophagectomy
specimens from patients receiving trimodality therapy and in 88% of patients treated with definitive chemoradiation therapy. In all instances, the radiation field significantly overlapped the length of the BE segment. We compared the mean length of BE segments in patients before and after definitive chemoradiation therapy and found that there was no statistically significant change in segment length in response to therapy. Chemoradiation therapy of esophageal adenocarcinoma does not eliminate pretreatment tumor-associated BE, nor does it significantly affect the length of the pretreatment BE segment. BE is known to recur in the esophageal remnant after esophagectomy.15-18 BE appearance after esophagectomy seems to be a time-related phenomenon because of chronic free reflux of gastric contents across an appropriately patent gastroesophageal anastomosis.19 Wolfsen et al20 observed an 18% prevalence of BE among 48 patients who underwent esophagectomy for Barrett dysplasia or localized adenocarcinoma. The median time after esophagectomy to diagnosis was 42 months. In our patients, BE was present in either an esophagectomy specimen or endoscopic mucosal biopsy samples within 2 to 6 months after completion of either neoadjuvant or definitive chemoradiation therapy. The reappearance of BE in our patients seemed to coincide with the resolution of therapy-related acute mucosal inflammation. The observed temporal relationships do not support a reflux-related recurrence of BE, but rather suggest the persistence of pretreatment tumor-associated BE. The origins of primary site recurrences of esophageal adenocarcinoma in patients who initially undergo complete response to chemoradiation therapy may be related to therapy-resistant or protected cell populations.21 We observed 95% persistence of BE after chemoradiation therapy. Among patients treated with definitive chemoradiation who achieved a cCR, surveillance endoscopy revealed BE and dysplasia in 78%. Our observations suggest that many recurrences of adenocarcinoma after cCR induced by definitive chemoradiation therapy actually represent metachronous cancers arising in persistent dysplastic BE.
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Figure 2. Endoscopic findings after chemoradiation therapy for adenocarcinoma of the esophagus. A, Radiation esophagitis and stricturing of the distal esophagus shortly after completion of chemoradiation therapy. B, Persistent BE several months after chemoradiation therapy.
Two patients did not have BE identified on posttreatment surveillance endoscopy. Circumferential exudate, erythema, and ulceration were observed in the region of the previous cancer and BE in these patients (Fig. 2A). No biopsy specimens were obtained in these cases. The time from completion of chemoradiation to initial endoscopy in these 2 patients was 33 and 37 days. Unfortunately, they did not undergo subsequent endoscopic surveillance. Overall, the complete clinical response (cCR) rate for patients treated with definitive chemoradiation was 56% (9/16) and was comparable with the 59% cPR observed in the 27 patients who received neoadjuvant chemoradiation therapy. Among the patients who achieved a cCR with definitive chemoradiation, surveillance endoscopy revealed BE complicated by dysplasia in 78% (7/9) of cases (Table 2).
DISCUSSION
Barthel et al
Barrett’s esophagus response to chemoradiation
Endoscopic ablation is effective in eliminating BE in patients with no history of esophageal adenocarcinoma and therefore may be useful in the nonsurgical management of persistent pretreatment BE. Currently available endoscopic large-area ablation therapies include photodynamic therapy (PDT), radiofrequency ablation, and cryoablation. Overholt et al22 reported complete elimination of BE in 52% of patients receiving PDT compared with 7% of patients receiving omeprazole alone. The PDT-induced squamous neoepithelialization was subsequently shown to be lasting and to result in a 50% reduction in adenocarcinoma occurrence over a 5-year period.23 Unfortunately, attempts to use PDT as salvage therapy in patients with recurrent adenocarcinoma after definitive chemoradiation therapy have resulted in high rates of severe stricture and esophageal perforations.24-26 These problems may limit the use of PDT ablation in the management of tumor-associated persistent pretreatment BE. However, newer endoscopic ablation therapies hold promise and warrant investigation. Shaheen et al27 recently reported that balloon-based radiofrequency ablation achieved elimination of BE in 77.4% of patients compared with 2.3% of patients who received sham ablation. Fleischer et al28 provided prospective observational evidence supporting the durability of radiofrequencyinduced squamous neoepithelialization. Endoscopic radiofrequency ablation has not been used as salvage therapy in patients with primary site recurrences after definitive chemoradiation therapy for esophageal adenocarcinoma, and therefore its safety in the radiated esophagus is unknown. Johnston et al29 reported a small case series of successful BE ablation using liquid nitrogen spray cryoablation. Preliminary30,31 and circumstantial evidence32 suggests that cryoablation may be less prone to produce esophageal stricture than other forms of ablation therapy. The limitations of our study include retrospective design, small sample size, and single-site data collection. We realize that these limitations may have created biases that influenced the observed rate of persistence of pretreatment tumor-associated BE. Nonetheless, we observed a 95% rate of persistent BE after chemoradiation in our patients. We suspect that a 100% BE persistence rate was not detected because of excessively short endoscopic followup intervals in 3 patients. In conclusion, we have provided strong evidence that chemoradiation as neoadjuvant or definitive therapy for esophageal cancer does not eliminate or significantly alter the length of pretreatment tumor-associated BE. Our observations suggest that surveillance for persistent BE should begin 6 months after completion of definitive chemoradiation therapy. To prevent growth of metachronous tumors, patients with persistent BE should be considered for subsequent endoscopic ablation or esophagectomy as their individual situation permits. We agree with Wolfsen et al20 that surveillance endoscopy in patients who undergo trimodality therapy is also warranted to ensure that all
pretreatment BE was removed at esophagectomy. Patients with persistent BE in the esophageal remnant should be considered for endoscopic ablation. Addressing posttherapy BE may be a simple way to improve 5-year survival rates among patients with adenocarcinoma of the esophagus. Further research to confirm our observations is warranted.
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REFERENCES 1. Blot WJ, Devesa SS, Fraumeni JF Jr. Continuing climb in rates of esophageal adenocarcinoma: an update. JAMA 1993;270:1320. 2. Lepage C, Rachet B, Jooste V, et al. Continuing rapid increase in esophageal adenocarcinoma in England and Wales. Am J Gastroenterol 2008;103:2694-9. 3. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993;104:510-3. 4. Powell J, McConkey CC. The rising trend in oesophageal adenocarcinoma and gastric cardia. Eur J Cancer Prev 1992;1:265-9. 5. Cameron AJ, Ott BJ, Payne WS. The incidence of adenocarcinoma in columnarlined (Barrett’s) esophagus. N Engl J Med 1985;313:857-9. 6. Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barrett’s esophagus: a prospective study of 170 patients followed 4.8 years. Am J Gastroenterol 1997;92:212-5. 7. Theisen J, Stein HJ, Dittler HJ, et al. Preoperative chemotherapy unmasks underlying Barrett’s mucosa in patients with adenocarcinoma of the distal esophagus. Surg Endosc 2002;16:671-3. 8. Ajani J, Bekaii-Saab T, D’Amico TA, et al. Esophageal cancer clinical practice guidelines. J Natl Compr Canc Netw 2006;4:328-47. 9. Berger AC, Farma J, Scott WJ, et al. Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 2005;23:4330-7. 10. Donahue JM, Nichols FC, Li Z, et al. Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg 2009;87:392-8, discussion 8–9. 11. Tepper J, Krasna MJ, Niedzwiecki D, 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. 12. al-Sarraf M, Martz K, Herskovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997;15:277-84. 13. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA 1999;281:1623-7. 14. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett’s esophagus. Am J Gastroenterol 2008;103:788-97. 15. Hamilton SR, Yardley JH. Regnerative of cardiac type mucosa and acquisition of Barrett mucosa after esophagogastrostomy. Gastroenterology 1977;72:669-75. 16. Lindahl H, Rintala R, Sariola H, et al. Cervical Barrett’s esophagus: a common complication of gastric tube reconstruction. J Pediatr Surg 1990;25:446-8. 17. Oberg S, Johansson J, Wenner J, et al. Metaplastic columnar mucosa in the cervical esophagus after esophagectomy. Ann Surg 2002;235: 338-45. 18. Gutschow C, Collard JM, Romagnoli R, et al. Denervated stomach as an esophageal substitute recovers intraluminal acidity with time. Ann Surg 2001;233:509-14. 19. O’Riordan JM, Tucker ON, Byrne PJ, et al. Factors influencing the development of Barrett’s epithelium in the esophageal remnant postesophagectomy. Am J Gastroenterol 2004;99:205-11.
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20. Wolfsen HC, Hemminger LL, DeVault KR. Recurrent Barrett’s esophagus and adenocarcinoma after esophagectomy. BMC Gastroenterol 2004;4:18. 21. Zhang HY, Spechler SJ, Souza RF. Esophageal adenocarcinoma arising in Barrett esophagus. Cancer Lett 2009;275:170-7. 22. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488-98. 23. Overholt BF, Wang KK, Burdick JS, et al. Five-year efficacy and safety of photodynamic therapy with photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc 2007;66:460-8. 24. Lecleire S, Di Fiore F, Antonietti M, et al. Nonoperable patients with superficial esophageal cancer treated by photodynamic therapy after chemoradiotherapy have more severe complications than patients treated in primary intent. Am J Gastroenterol 2008;103:2215-9. 25. Wolfsen HC. Salvage photodynamic therapy by using porfimer sodium after chemoradiation therapy: a Western viewpoint. Gastrointest Endosc 2006;63:195, author reply 196. 26. Yano T, Muto M, Minashi K, et al. Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer. Gastrointest Endosc 2005;62:31-6. 27. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009;360:2277-88. 28. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic ablation of Barrett’s esophagus: a multicenter study with 2.5-year follow-up. Gastrointest Endosc 2008;68:867-76.
29. Johnston MH, Eastone JA, Horwhat JD, et al. Cryoablation of Barrett’s esophagus: a pilot study. Gastrointest Endosc 2005;62:842-8. 30. Cash BD, Johnston LR, Johnston MH. Cryospray ablation (CSA) in the palliative treatment of squamous cell carcinoma of the esophagus. World J Surg Oncol 2007;5:34. 31. Dumot JA, Greenwald BD. Argon plasma coagulation, bipolar cautery, and cryotherapy: ABC’s of ablative techniques. Endoscopy 2008;40: 1026-32. 32. Evonich RF 3rd, Nori DM, Haines DE. A randomized trial comparing effects of radiofrequency and cryoablation on the structural integrity of esophageal tissue. J Interv Card Electrophysiol 2007;19:77-83.
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Received July 4, 2009. Accepted September 25, 2009. Current affiliations: Departments of Gastrointestinal Oncology (J.S.B., J.L.L., J.R.S.) and Radiation Oncology (S.E.H., I.A., T.J.D., C.W.S.), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, Department of Medicine (S.T.K.), University of South Florida College of Medicine, Tampa, Florida, USA. Presented at the 2009 Gastrointestinal Cancers Symposium, January 1315, San Francisco, California. Reprint requests: James S. Barthel, MD, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Does Barrett’s esophagus respond to chemoradiation therapy for adenocarcinoma of the esophagus? James S. Barthel, MD, Stephen T. Kucera, MD, James L. Lin, MD, Sarah E. Hoffe, MD, Jonathan R. Strosberg, MD, Irfan Ahmed, MD, Thomas J. Dilling, MD, Craig W. Stevens, MD, PhD Tampa, Florida, USA
Background: Adenocarcinoma of the esophagus is frequently associated with Barrett’s esophagus (BE). The response of esophageal adenocarcinoma to chemoradiation therapy is well described; however, the effect of chemoradiation on tumor-associated BE has not been specifically reported. Objective: To determine the response of tumor-associated BE to chemoradiation therapy. Design: Retrospective cohort study. Setting: A single National Cancer Institute Comprehensive Cancer Care Center experience. Patients: The study cohort consisted of 43 patients with stage I to IVA esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy and underwent either esophagectomy or surveillance at our institution. Main Outcome Measurement: The presence and extent of BE after chemoradiation therapy of esophageal adenocarcinoma associated with endoscopically documented pretreatment BE. Results: BE persisted after chemoradiation therapy in 93% (40/43) of cases (95% CI, 83%-99%). Twenty-seven patients received neoadjuvant chemoradiation therapy before esophagectomy. Persistent BE was detected in all 27 surgical specimens (100%). In 59% (16/27) of the cases, there was complete pathologic tumor response. Sixteen patients received definitive chemoradiation therapy. Persistent pretreatment BE was identified in 88% (14/16) by surveillance endoscopy (95% CI, 60%-98%). The mean length of BE before and after chemoradiation was 6.6 cm and 5.8 cm, respectively (P Z .38). Limitations: Retrospective design, small sample size, and single-site data collection. Conclusions: Chemoradiation therapy of esophageal adenocarcinoma does not eliminate tumor-associated BE, nor does it affect the length of the BE segment. (Gastrointest Endosc 2010;71:235-40.)
Copyright ª 2010 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 doi:10.1016/j.gie.2009.09.038
association with all stages of esophageal adenocarcinoma. Theisen et al7 reported that BE existed in 75% of patients with esophageal adenocarcinoma and that chemoradiation-induced tumor regression ‘‘unmasked’’ BE in an additional 22% as determined by restaging after therapy. Theisen et al did not comment on the response of BE to chemoradiation therapy in the 75% of patients with tumor-associated pretreatment BE. The majority of symptomatic esophageal cancer patients present with locoregional disease corresponding to American Joint Committee on Cancer (AJCC) stages II and III. Neoadjuvant chemoradiation therapy followed by esophagectomy (trimodality therapy) is the preferred approach for stage II and III esophageal cancer8 and can achieve 5-year survival rates of 33% to 39%.9-11
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Volume 71, No. 2 : 2010 GASTROINTESTINAL ENDOSCOPY 235
The incidence of esophageal adenocarcinoma is increasing by 4% to 10% per year and is increasing at a more rapid rate than any other malignant neoplasm in the United States and Western Europe.1-4 Barrett’s esophagus (BE) is the major risk factor for the development of esophageal adenocarcinoma5,6 and is frequently found in Abbreviations: AJCC, American Joint Committee on Cancer; BE, Barrett’s esophagus; cCR, complete clinical response; cPR, complete pathological response; IQR, interquartile range; PDT, photodynamic therapy. DISCLOSURE: All authors disclosed no financial relationships relevant to this publication.
Barrett’s esophagus response to chemoradiation
Nonetheless, an increasing number of patients receive definitive chemoradiation therapy because of medical comorbidities that preclude surgery and because many patients refuse to undergo esophagectomy. Definitive chemoradiation therapy can achieve 5-year survival rates of 25% to 30% in stage II and III esophageal cancer.12,13 The response of tumor-associated BE to chemoradiation therapy for esophageal adenocarcinoma has not been specifically reported. There is an informal awareness among esophageal surgeons that neoadjuvant chemoradiation therapy does not produce regression of BE by the time esophagectomy is performed, and, therefore, esophageal surgeons typically adjust their resections to achieve a BE-free proximal margin. Medical and radiation oncologists who manage patients receiving definitive chemoradiation are less aware of this phenomenon. Because of the paucity of published information on the response of pretreatment tumor-associated BE to chemoradiation therapy for esophageal adenocarcinoma, we conducted a retrospective cohort study to determine the effect of chemoradiation therapy on pretreatment BE.
Barthel et al
Capsule Summary What is already known on this topic d
Barrett’s esophagus (BE) is frequently found with all stages of esophageal adenocarcinoma.
What this study adds to our knowledge d
d
In a retrospective cohort study of 43 patients with esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy, BE persisted in 93%. The mean length of BE before and after chemoradiation was unchanged.
The study was approved by both the Moffitt Cancer Center Scientific Review Committee and the University of South Florida Biomedical Institutional Review Board. We reviewed the medical records of 137 patients referred for chemoradiation as treatment for esophageal adenocarcinoma between January 1, 2000, and January 1, 2009, at the Moffitt Cancer Center. A total of 94 patients were excluded (Fig. 1). Forty-one patients were excluded because they did not have BE associated with their adenocarcinoma pretreatment. The absence of BE was confirmed both endoscopically and histologically through review of pretreatment staging endoscopy and surgical pathology reports. Nineteen patients deferred surveillance endoscopy after chemoradiation and were therefore excluded. Eleven patients underwent primary esophagectomy for clinical stage I cancer after consultation with medical, radiation, and surgical oncology. Surveillance endoscopy was not performed in a total of 23 patients who received palliative chemoradiation for stage IVB esophageal adenocarcinoma. Our population cohort was therefore composed of 43 patients with clinical stage I to IVA esophageal adenocarcinoma associated with BE receiving treatment with curative intent. All patients underwent pretreatment clinical staging including EUS at our institution. All patients had either esophagectomy in conjunction with trimodality therapy or at least one surveillance endoscopy after definitive chemoradiation therapy. Esophagectomy was performed within 6 to 8 weeks after neoadjuvant chemoradiation therapy. Staging endoscopy and related pathology reports
were reviewed to obtain a pretreatment description of the BE segment as well as the tumor histology and stage. Oncology treatment records were reviewed to determine dose and duration of chemotherapeutic regimens. Radiation oncology treatment records and films were reviewed to obtain radiation technique and the size of the treatment field. Two radiation oncologists reviewed the actual treatment simulation and port films to determine the anatomic extent of irradiated esophageal tissue. A reference system was created by marking the carina on each film and designating this point as equivalent to 25 cm from the incisors. By using the scale on the films, the superior and inferior treatment margins as equivalent to the distance from the incisors were then measured and noted. This allowed data to be collected from each case verifying the extent of actual tissue within the irradiated field. Esophagectomy pathology reports were reviewed in patients receiving trimodality therapy to determine whether BE was present in resection specimens and to assess the completeness of resection with respect to BE persisting after neoadjuvant chemoradiation therapy. Surveillance endoscopy and coinciding mucosal biopsy pathology reports were used to assess the effect of definitive chemoradiation therapy on pretreatment BE. BE was defined as columnar-lined epithelium in the tubular esophagus visible above the gastroesophageal junction in association with histologic evidence of specialized intestinal metaplasia.14 The BE segment length was measured as the maximum length of contiguous columnar epithelium. Because the intent of surveillance endoscopy was detection of residual tumor, as many as 6 biopsy specimens were obtained from the area of the previous or persistent tumor and adjacent mucosa and not necessarily throughout the length of visible BE. In consultation with the Moffitt Cancer Center Biomedical Statistics Group, the R statistical package, version 2.6.0 (www.r-project.org) was used to generate descriptive statistics and confidence intervals and to compare pre- and posttreatment mean lengths of BE by using a 2-tailed paired t test. Statistical significance was defined as P! .05.
236 GASTROINTESTINAL ENDOSCOPY Volume 71, No. 2 : 2010
www.giejournal.org
METHODS
Barthel et al
Barrett’s esophagus response to chemoradiation
TABLE 1. American Joint Committee on Cancer clinical stages of patients receiving either neoadjuvant chemoradiation before esophagectomy or definitive chemoradiation therapy AJCC clinical stage
Neoadjuvant chemoradiation
Definitive chemoradiation
I
1
2
IIA
0
1
IIB
7
6
III
16
4
3
3
IVA
AJCC, American Joint Committee on Cancer.
The study cohort was composed of 43 patients with an age range of 44 to 88 years and a mean age of 67 years. There were 38 men and 5 women. Esophageal cancer pretreatment AJCC clinical stages were as follow: 3 patients had stage I disease, 14 had stage II disease, 20 had stage III disease, and 6 patients had stage IVA disease (Table 1). At the time of initial staging EUS, the median length of BE was 6.0 cm (interquartile range [IQR] 4.5-8.5 cm). BE was documented in 41 (95%) of 43 patients (95% CI, 83%-99%) after neoadjuvant or definitive chemoradiation therapy based on surgical specimens or endoscopic findings. Radiation techniques used for both neoadjuvant and definitive chemoradiation therapy included compensatorbased intensity-modulated radiation therapy, 2- and 3dimensional conformal, and tomotherapy with a median dose of 50.4 Gy of radiation. Thirteen patients were treated with 2-dimensional conformal radiation therapy, 21 with 3dimensional conformal radiation therapy, 8 with compensator-based intensity-modulated radiation therapy, and 1 with tomotherapy. The median length of esophagus included in the radiation field was 13.0 cm (IQR 11.0-15.5 cm). Concurrent chemotherapy consisted typically of cisplatin combined with 5-fluorouracil or irinotecan. All patients receiving neoadjuvant chemotherapy received 2 cycles of cisplatin and 5-fluorouracil. Patients receiving definitive
chemotherapy received an additional 2 cycles of cisplatin and 5-fluorouracil or cisplatin and irinotecan. Twenty-seven of 43 patients received neoadjuvant chemoradiation before esophagectomy. The median pretreatment AJCC clinical stage was III (Table 1). The median time to esophagectomy from completion of chemoradiation was 60 days (IQR 58-61 days). In all 27 (100%) cases, BE was detected in the surgical specimens. Among these patients, 16 (59%) had a complete pathologic response (cPR), defined as absence of microscopically detectable cancer in the esophagectomy specimen. BE persisted despite cPR in all cases. In 96% (26/27) of patients, the proximal surgical margin was found to be free of BE. Postesophagectomy endoscopic surveillance in the patient whose surgical margin was not free of BE revealed a short segment (!3 cm) of residual, nondysplastic Barrett’s epithelium. The median pretreatment AJCC clinical stage was II for the 16 patients who received definitive chemoradiation therapy with curative intent (Table 1). Persistent BE was identified in 14 (88%) of 16 patients (95% CI, 60%-98%) at either initial posttreatment endoscopy or on subsequent surveillance endoscopy. The median time to initial posttreatment endoscopy was 59 days (IQR 37-90 days), with all patients undergoing initial surveillance endoscopy within 105 days of completion of chemoradiation therapy. Among the 14 patients with documented BE after definitive chemoradiation therapy, the median time from completion of therapy to the last surveillance endoscopy performed was 196 days (IQR 91-267 days). Surveillance endoscopy 6 months and beyond detected 100% of cases with reappearance of endoscopically visible columnarlined esophagus above the gastroesophageal junction coinciding with intestinal metaplasia on biopsy sample histology (Fig. 2B). The mean pretreatment BE segment length was 6.6 cm, and the mean posttreatment BE segment length was 5.8 cm in these patients. The 0.8 cm (95% CI, 1.1 to 2.8 cm) difference in mean BE segment length was not statistically significant (P Z .38).
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Figure 1. Outline of patient selection and reasons for exclusion.
RESULTS
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Barthel et al
TABLE 2. Summary of endoscopic surveillance findings in patients receiving definitive chemoradiation therapy Endoscopic and histopathologic findings
No. patients
No BE, inflammatory changes only
2
Nondysplastic BE þ cCR
2
BE with LGD þ cCR
3
BE with HGD þ cCR
4
BE þ residual tumor
5
BE, Barrett’s esophagus; cCR, complete clinical response; LGD, low-grade dysplasia; HGD, high-grade dysplasia.
We confirmed persistent BE after chemoradiation therapy in 95% of our patient cohort. Subgroup analysis revealed persistent BE in 100% of esophagectomy
specimens from patients receiving trimodality therapy and in 88% of patients treated with definitive chemoradiation therapy. In all instances, the radiation field significantly overlapped the length of the BE segment. We compared the mean length of BE segments in patients before and after definitive chemoradiation therapy and found that there was no statistically significant change in segment length in response to therapy. Chemoradiation therapy of esophageal adenocarcinoma does not eliminate pretreatment tumor-associated BE, nor does it significantly affect the length of the pretreatment BE segment. BE is known to recur in the esophageal remnant after esophagectomy.15-18 BE appearance after esophagectomy seems to be a time-related phenomenon because of chronic free reflux of gastric contents across an appropriately patent gastroesophageal anastomosis.19 Wolfsen et al20 observed an 18% prevalence of BE among 48 patients who underwent esophagectomy for Barrett dysplasia or localized adenocarcinoma. The median time after esophagectomy to diagnosis was 42 months. In our patients, BE was present in either an esophagectomy specimen or endoscopic mucosal biopsy samples within 2 to 6 months after completion of either neoadjuvant or definitive chemoradiation therapy. The reappearance of BE in our patients seemed to coincide with the resolution of therapy-related acute mucosal inflammation. The observed temporal relationships do not support a reflux-related recurrence of BE, but rather suggest the persistence of pretreatment tumor-associated BE. The origins of primary site recurrences of esophageal adenocarcinoma in patients who initially undergo complete response to chemoradiation therapy may be related to therapy-resistant or protected cell populations.21 We observed 95% persistence of BE after chemoradiation therapy. Among patients treated with definitive chemoradiation who achieved a cCR, surveillance endoscopy revealed BE and dysplasia in 78%. Our observations suggest that many recurrences of adenocarcinoma after cCR induced by definitive chemoradiation therapy actually represent metachronous cancers arising in persistent dysplastic BE.
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Figure 2. Endoscopic findings after chemoradiation therapy for adenocarcinoma of the esophagus. A, Radiation esophagitis and stricturing of the distal esophagus shortly after completion of chemoradiation therapy. B, Persistent BE several months after chemoradiation therapy.
Two patients did not have BE identified on posttreatment surveillance endoscopy. Circumferential exudate, erythema, and ulceration were observed in the region of the previous cancer and BE in these patients (Fig. 2A). No biopsy specimens were obtained in these cases. The time from completion of chemoradiation to initial endoscopy in these 2 patients was 33 and 37 days. Unfortunately, they did not undergo subsequent endoscopic surveillance. Overall, the complete clinical response (cCR) rate for patients treated with definitive chemoradiation was 56% (9/16) and was comparable with the 59% cPR observed in the 27 patients who received neoadjuvant chemoradiation therapy. Among the patients who achieved a cCR with definitive chemoradiation, surveillance endoscopy revealed BE complicated by dysplasia in 78% (7/9) of cases (Table 2).
DISCUSSION
Barthel et al
Barrett’s esophagus response to chemoradiation
Endoscopic ablation is effective in eliminating BE in patients with no history of esophageal adenocarcinoma and therefore may be useful in the nonsurgical management of persistent pretreatment BE. Currently available endoscopic large-area ablation therapies include photodynamic therapy (PDT), radiofrequency ablation, and cryoablation. Overholt et al22 reported complete elimination of BE in 52% of patients receiving PDT compared with 7% of patients receiving omeprazole alone. The PDT-induced squamous neoepithelialization was subsequently shown to be lasting and to result in a 50% reduction in adenocarcinoma occurrence over a 5-year period.23 Unfortunately, attempts to use PDT as salvage therapy in patients with recurrent adenocarcinoma after definitive chemoradiation therapy have resulted in high rates of severe stricture and esophageal perforations.24-26 These problems may limit the use of PDT ablation in the management of tumor-associated persistent pretreatment BE. However, newer endoscopic ablation therapies hold promise and warrant investigation. Shaheen et al27 recently reported that balloon-based radiofrequency ablation achieved elimination of BE in 77.4% of patients compared with 2.3% of patients who received sham ablation. Fleischer et al28 provided prospective observational evidence supporting the durability of radiofrequencyinduced squamous neoepithelialization. Endoscopic radiofrequency ablation has not been used as salvage therapy in patients with primary site recurrences after definitive chemoradiation therapy for esophageal adenocarcinoma, and therefore its safety in the radiated esophagus is unknown. Johnston et al29 reported a small case series of successful BE ablation using liquid nitrogen spray cryoablation. Preliminary30,31 and circumstantial evidence32 suggests that cryoablation may be less prone to produce esophageal stricture than other forms of ablation therapy. The limitations of our study include retrospective design, small sample size, and single-site data collection. We realize that these limitations may have created biases that influenced the observed rate of persistence of pretreatment tumor-associated BE. Nonetheless, we observed a 95% rate of persistent BE after chemoradiation in our patients. We suspect that a 100% BE persistence rate was not detected because of excessively short endoscopic followup intervals in 3 patients. In conclusion, we have provided strong evidence that chemoradiation as neoadjuvant or definitive therapy for esophageal cancer does not eliminate or significantly alter the length of pretreatment tumor-associated BE. Our observations suggest that surveillance for persistent BE should begin 6 months after completion of definitive chemoradiation therapy. To prevent growth of metachronous tumors, patients with persistent BE should be considered for subsequent endoscopic ablation or esophagectomy as their individual situation permits. We agree with Wolfsen et al20 that surveillance endoscopy in patients who undergo trimodality therapy is also warranted to ensure that all
pretreatment BE was removed at esophagectomy. Patients with persistent BE in the esophageal remnant should be considered for endoscopic ablation. Addressing posttherapy BE may be a simple way to improve 5-year survival rates among patients with adenocarcinoma of the esophagus. Further research to confirm our observations is warranted.
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20. Wolfsen HC, Hemminger LL, DeVault KR. Recurrent Barrett’s esophagus and adenocarcinoma after esophagectomy. BMC Gastroenterol 2004;4:18. 21. Zhang HY, Spechler SJ, Souza RF. Esophageal adenocarcinoma arising in Barrett esophagus. Cancer Lett 2009;275:170-7. 22. Overholt BF, Lightdale CJ, Wang KK, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005;62:488-98. 23. Overholt BF, Wang KK, Burdick JS, et al. Five-year efficacy and safety of photodynamic therapy with photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc 2007;66:460-8. 24. Lecleire S, Di Fiore F, Antonietti M, et al. Nonoperable patients with superficial esophageal cancer treated by photodynamic therapy after chemoradiotherapy have more severe complications than patients treated in primary intent. Am J Gastroenterol 2008;103:2215-9. 25. Wolfsen HC. Salvage photodynamic therapy by using porfimer sodium after chemoradiation therapy: a Western viewpoint. Gastrointest Endosc 2006;63:195, author reply 196. 26. Yano T, Muto M, Minashi K, et al. Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer. Gastrointest Endosc 2005;62:31-6. 27. Shaheen NJ, Sharma P, Overholt BF, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med 2009;360:2277-88. 28. Fleischer DE, Overholt BF, Sharma VK, et al. Endoscopic ablation of Barrett’s esophagus: a multicenter study with 2.5-year follow-up. Gastrointest Endosc 2008;68:867-76.
29. Johnston MH, Eastone JA, Horwhat JD, et al. Cryoablation of Barrett’s esophagus: a pilot study. Gastrointest Endosc 2005;62:842-8. 30. Cash BD, Johnston LR, Johnston MH. Cryospray ablation (CSA) in the palliative treatment of squamous cell carcinoma of the esophagus. World J Surg Oncol 2007;5:34. 31. Dumot JA, Greenwald BD. Argon plasma coagulation, bipolar cautery, and cryotherapy: ABC’s of ablative techniques. Endoscopy 2008;40: 1026-32. 32. Evonich RF 3rd, Nori DM, Haines DE. A randomized trial comparing effects of radiofrequency and cryoablation on the structural integrity of esophageal tissue. J Interv Card Electrophysiol 2007;19:77-83.
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Received July 4, 2009. Accepted September 25, 2009. Current affiliations: Departments of Gastrointestinal Oncology (J.S.B., J.L.L., J.R.S.) and Radiation Oncology (S.E.H., I.A., T.J.D., C.W.S.), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, Department of Medicine (S.T.K.), University of South Florida College of Medicine, Tampa, Florida, USA. Presented at the 2009 Gastrointestinal Cancers Symposium, January 1315, San Francisco, California. Reprint requests: James S. Barthel, MD, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.