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(Chest. 1999;116:466S-469S.)
© 1999 American College of Chest Physicians

Esophagectomy After Induction Chemoradiation*

Malcolm M. DeCamp, Jr, MD, FCCP; Scott J. Swanson, MD, FCCP and Michael T. Jaklitsch, MD, FCCP

* From the Department of Thoracic and Cardiovascular Surgery (Dr. DeCamp), The Cleveland Clinic Foundation, Cleveland, OH; and the Division of Thoracic Surgery (Drs. Swanson and Jaklitsch), Brigham & Women’s Hospital, Boston, MA.

Correspondence to: Malcolm M. DeCamp, MD, FCCP, The Cleveland Clinic Foundation, Department of Thoracic and Cardiovascular Surgery/F25, 9500 Euclid Ave, Cleveland, OH 44195


   Abstract
TOP
 Abstract
Introduction
 Single-Agent Therapy
 Rationale for Induction Therapy
 Surgery After Induction Therapy
 Conclusion
 References
 
The definition of a standard therapy for resectable esophageal cancer remains a clinical controversy. In the past decade, a variety of strategies have been developed in an attempt to improve local control and decrease the all too common problem of distant metastases. Preoperative treatment with radiotherapy or chemotherapy has been proved to be feasible, although neither strategy has resulted in improved survival rates. More recently, concurrent, neoadjuvant chemoradiation has been utilized with encouraging pathologic responses. Equally important is the recognition that such aggressive therapy does not lead to worse surgical outcomes. The evidence for the safety, feasibility, and efficacy of induction therapy followed by esophagectomy is presented in the context of developing a rational methodology to allow for the ongoing modification of standards of care in the management of this difficult disease.


   Introduction
TOP
 Abstract
 Introduction
Single-Agent Therapy
 Rationale for Induction Therapy
 Surgery After Induction Therapy
 Conclusion
 References
 
Esophageal cancer afflicts some 13,000 new patients in the United States each year. Despite advances in surgery, critical care, radiotherapy, and chemotherapy, over 11,000 patients will die of esophageal cancer annually.1 The disease represents 4% of newly diagnosed cancers in North America, with an incidence estimated to be between 5 and 10 cases per 100,000 population.2 3 Unfortunately, most North American patients still present with locally advanced (stage T3 and/or N1) disease.

In addition to its virulent biology, esophageal carcinoma is undergoing a major shift in its epidemiology. Traditionally, esophageal cancer has had an epidemoid histology and has been seen in patients with the usual risk factors for other aerodigestive tract carcinomas, specifically cigarette and alcohol abuse. Within North America and Europe there has been a 100% increase in the incidence of adenocarcinoma in the past decade3 4 5 (Fig 1 ). While the precise etiology of this shift in histology remains unknown, the disease now appears to more routinely affect younger, healthier patients. In addition, these patients generally have better nutritional states and preserved performance status and can likely tolerate more aggressive therapeutic strategies. The rising prevalence of adenocarcinoma that arises within or is associated with Barrett esophagus suggests a possible link to untreated or silent gastroesophageal reflux. This observation opens a potential avenue to define high-risk patients who would benefit from surveillance in order to achieve earlier detection.



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  		Figure 1. Variation in the histology of esophageal carcinomas reported by the tumor registry of the Cleveland Clinic Foundation from 1978 through 1993 (adapted from Kirby and Rice3 ).

 

   Single-Agent Therapy
TOP
 Abstract
 Introduction
 Single-Agent Therapy
Rationale for Induction Therapy
 Surgery After Induction Therapy
 Conclusion
 References
 
Advances in survival for patients with esophageal cancer are likely to arise from better individual modality therapy as well as from innovative combinations. In many institutions, complete surgical resection has been the "gold standard" against which newer strategies are compared. Over the past 30 years, the reported 5-year survival rates for patients undergoing esophagectomy have risen from an average of 10 to 15% to a high of 35% in selected series.6 7 8 The explanation for improvements in the outcome from surgery alone are multifactorial and include refinements in surgical technique, improved anesthesia and critical care management, and an emphasis on nutrition via enteral and/or parenteral routes. Despite these encouraging developments, Katlic and colleagues8 noted only an 11% 5-year survival rate in patients with locally advanced type N1 disease (stages IIB or III) who were treated over the last decade.

Primary radiotherapy has been used in some institutions as a definitive treatment for esophageal cancer. Surgical mortality rates approaching 30% lead to this nonoperative approach. Pearson9 reported a 17% overall survival rate for patients treated with radiotherapy alone, although other groups noted a consistent long-term survival rate at < 10% of treated patients. Relief of dysphagia and local control were good, but remote failure was common in these series.10

Chemotherapy as a single modality in the treatment of esophageal cancer is the least effective strategy. Though radiographic improvement can be seen in up to one half of patients, two or three cycles (6 to 12 weeks) of chemotherapy are required, relief of dysphasia is slow and/or incomplete, and survival is anecdotal. Unfortunately, there is no way to select "responders" prior to beginning therapy, leaving 50% of patients without a hope of benefit from therapy. Single-agent activity in this disease is modest (10 to 40%). Cisplatin and 5-fluorouracil (5-FU) are the most frequently utilized agents, although there is a growing interest in newer drugs such as paclitaxel. Combination therapy has been more promising with response rates between 50% and 70% for cisplatin-based doublets. Adding a third agent, such as a vinca alkaloid, bleomycin, or mitoguazone, has only fractionally improved response while almost universally worsening toxicity.11 The major utility of chemotherapy-alone investigations in the treatment of esophageal cancer has been to guide study designs for combined-modality trials and to identify active combinations of agents with acceptable toxicity profiles.


   Rationale for Induction Therapy
TOP
 Abstract
 Introduction
 Single-Agent Therapy
 Rationale for Induction Therapy
Surgery After Induction Therapy
 Conclusion
 References
 
Given that the majority of patients present with locally advanced disease, there is a need to have a treatment plan that can address both local and distant control and allow for durable palliation of dysphagia. The main focus of multimodality trials has been to improve survival while still allowing the safe resection of the primary tumor. For T4 lesions, preoperative therapy provides perhaps the only chance of enhancing operability.

As early as 1969, Goodner12 demonstrated that induction radiotherapy was feasible, and, in fact, its use enhanced resectability. Subsequent randomized studies have not confirmed this observation.13 14

In addition to its potential for enhancing resection rates, induction chemoradiotherapy has several theoretic advantages over primary surgery or postoperative chemoradiotherapy. Preoperative chemotherapy treatment should result in better drug delivery to the tumor as the local blood supply has not been disturbed by operative dissection. Distant control should be enhanced as remote micrometastases are treated early without having to wait for postsurgical recovery. Preoperative treatment allows for the identification of responders who may in turn benefit from additional postoperative therapy, allowing nonresponders to be spared the additional toxic therapy and identifying subgroups who would be better treated by other agents or modalities. Concurrent chemoradiation allows not only for the direct cytotoxic effect of the drugs but also takes advantage of the radiation-sensitizing properties of many chemotherapeutic agents, resulting in a synergistic tumoricidal effect within the radiation field. Finally, delivering radiation to the tumor bed preoperatively is potentially advantageous from a radiobiology viewpoint. The postoperative field is by definition ischemic and is likely to be hypoxic following radical resection. Tumor cell hypoxia is a well-described mechanism whereby cancers can become radioresistant. Practically speaking, it is more logical to irradiate diseased tissue that is to be resected than it is to treat the more healthy tissue that is present after surgery that is trying to heal.

Supporting these hypothetical arguments are the superior results of neoadjuvant chemoradiotherapy strategies with subsequent resection in other cancers of the aerodigestive tract. Squamous cell carcinoma of the head and neck has been effectively downstaged in 80 to 90% of cases with similar drug and radiation strategies.11 The same approach was successful in treating anal cancer in the 1970s and has been applied most recently to locally advanced non-small cell lung cancer and rectal cancer.


   Surgery After Induction Therapy
TOP
 Abstract
 Introduction
 Single-Agent Therapy
 Rationale for Induction Therapy
 Surgery After Induction Therapy
Conclusion
 References
 
Is It Safe?
Before induction therapy can be adopted as the standard of care for esophageal cancer it must be demonstrated to be safe, effective, and, finally, superior to simpler regimes. The systematic use of preoperative therapy has been reported since the 1980s. In three prospective studies13 14 15 involving a total of 522 patients who received between 33 and 60 Gy of external-beam radiotherapy prior to esophagectomy. In each trial, there was no increase in preoperative mortality or morbidity in the radiotherapy-plus-surgery group (Table 1 ). Unfortunately, there was no demonstrated survival benefit for preoperative radiotherapy at any of these doses.


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  		Table 1. Randomized Trials of Single-Modality Induction Therapy Followed by Esophagectomy vs Esophagectomy Alone*

 
Chemotherapy prior to resection also has been demonstrated to be safe and feasible in prospective series. Roth et al,16 reporting for the MD Anderson group, described their experience with 39 patients, some of whom had no increase in surgical mortality or morbidity when receiving combined modality therapy of two cycles of cisplatin, vindesine, and bleomycin (n = 19), compared with others who underwent surgery alone (n = 20). In an interim report of Intergroup Trial 0113, Kelsen et al17 confirmed these findings in a larger (N = 444), multi-institutional setting. Patients receiving cisplatin and 5-FU experienced the same induction treatment-related mortality and morbidity as those patients having primary resection as their only treatment. Despite this element of safety, there was no survival benefit to favor the routine use of induction chemotherapy.

Given that induction radiation and induction chemotherapy are at least safe, it is only logical to investigate the safety of combining these strategies in an effort to enhance survival. Forastierre and colleagues18 from the University of Michigan reported on 43 patients who were given concurrent cisplatin and 5-FU along with vinblastine with 45 Gy of radiation and subsequent transhiatal esophagectomy. Their reported treatment-related mortality and morbidity was no different from that of their own historical control subjects who had similar histology and had been operated on by the same surgeons. Walsh et al19 confirm this phase II experience with their prospective randomized phase III trial that involved two cycles of chemotherapy with concurrent radiation (45 Gy) vs resection alone. The surgical outcomes were similar between the two treatment groups.

Is It Effective?
There are at least three ways to judge the efficacy of induction therapy prior to esophagectomy. The definitive measure is to document enhanced survival, which requires at least 36 months of follow-up. Earlier indicators of benefit would be traditional response rates and pathologic response rates. Gignoux and Bosset20 reported 70 to 80% radiographic response rates to induction chemoradiation in their pilot experience in the mid 1980s. Subsequently, several independent investigators (Table 2 ) have found that 25 to 30% of patients receiving two cycles of combination chemotherapy with concurrent radiotherapy to at least 45 Gy have had no residual carcinoma in their resected specimens.18 19 21 22 23 24 25 26 These pathologic complete responses (PCRs) have been associated with survival benefits as high as 50% in 3 years. Unfortunately, there are no established pretreatment characteristics to define who is likely to be in the PCR group. An advantage of induction therapy followed by resection is the pathologic assessment of response to preoperative treatment. This is certainly more precise than radiographic response because a specific surgical-pathologic TNM assessment is known. In the setting of aggressive pretreatment staging (CT scanning, MRI, endoscopic ultrasound, thoracoscopy, laparoscopy), it is then possible to assess the degree of true pathologic downstaging attributable to induction therapy. In addition to the reported 29% PCR rate for induction therapy, Adelstein et al23 found that 50% of patients were downstaged. As pathologic response is unlikely to be an "all-or-none" event, the degree of downstaging should correlate with incremental improvement in survival.


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  		Table 2. PCR Rates for Induction Chemoradiotherapy*

 
Is It Better?
Concurrent chemoradiation prior to resection has a definite salutary effect on many tumors and does not engender increased operative risk. Unfortunately, there are no preoperative predictors of who truly benefits. Symptom relief, radiologic response, repeat endoscopic biopsy, or endoscopic ultrasound appearance have not been predictive of pathologic response to induction therapy.23 In order to justify such intensive preoperative therapy, a survival benefit in a randomized comparison with resection alone is called for. In their 2-year interim analysis, Urba and colleagues,27 from Michigan, reported equivalent survival when 100 patients were randomized between trimodality therapy or surgery alone. With additional follow-up, these investigators found borderline statistical superiority for the group treated with trimodal therapy at 3 years (log rank, p = 0.07; Cox regression value, 0.04).24 The only other published prospective randomized series comes from Ireland where 113 patients were randomized to induction chemoradiation plus resection vs primary esophagectomy. With 3 years of follow-up, there was a highly significant survival advantage (p = 0.01) for the group treated with neoadjuvant therapy.19 Despite this impressive result, the trial has been criticized because the resection-alone group had surprisingly poor outcomes when compared with other contemporary primary surgical series.

Such observations and criticisms form the basis of intergroup trial C9781, a phase III multi-institutional comparison of induction chemoradiation followed by resection vs surgery alone. This trial should accrue some 500 patients and will require 3 years of follow-up to confirm or refute the observations of Walsh et al.19


   Conclusion
TOP
 Abstract
 Introduction
 Single-Agent Therapy
 Rationale for Induction Therapy
 Surgery After Induction Therapy
 Conclusion
References
 
Over the past two decades, surgery to resect carcinoma of the esophagus has clearly become a safer enterprise. Despite this improvement in technique, the overall survival rate for carcinoma of the esophagus has remained essentially unchanged. While the incidence of squamous cell carcinoma of the esophagus remains stable, there is an alarming increase in the recognition of adenocarcinomas of the distal esophagus and gastroesophageal junction. Based on this, there is a real need to improve the outlook for patients who develop this disease. Induction chemoradiotherapy has been successfully applied in selected patients with this disease and has been clearly demonstrated to be both feasible and, in small series, effective. Future mandates will include the need to explore new agents and new combinations of agents to improve the pathologic complete response rate as well as the downstaging rate, which, in turn, should lead to enhanced survival. Disease-free survival remains the "gold standard" for assessing the efficacy of combined-modality treatment protocols in the management of esophageal cancer. Changing the standard of care for this disease will require well-constructed randomized trials to define optimal treatment strategies. As physicians treating this devastating disease, it is our responsibility to develop an investigational agenda providing the best possible care for our patients while at the same time evaluating promising new drugs and treatment strategies, thus, modifying the emerging standards of care based on solid clinical investigation.


   Footnotes
 
Abbreviations: 5-FU = 5-fluorouracil; PCR = pathologic complete response


   References
TOP
 Abstract
 Introduction
 Single-Agent Therapy
 Rationale for Induction Therapy
 Surgery After Induction Therapy
 Conclusion
 References
 

  1. Parker, SL, Tong, T, Bolden, S, et al (1996) Cancer statistics, 1996. CA Cancer J Clin 46,5-27[Abstract]
  2. Schottenfeld, D (1984) Epidemiology of cancer of the esophagus. Semin Oncol 11,92-100[ISI][Medline]
  3. Kirby, TJ, Rice, TW (1994) The epidemiology of esophageal carcinoma: the changing face of a disease. Chest Surg Clin N Am 4,217-225[Medline]
  4. Alpern, HD, Buell, C, Olson, J (1989) Increasing percentage of adenocarcinoma in primary carcinoma of the esophagus [letter]. Am J Gastroenterol 84,574[ISI][Medline]
  5. Blot, WJ, Devesa, SS, Kueller, RW, et al (1991) Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 265,1287-1289[Abstract]
  6. Mannell, A (1982) Carcinoma of the esophagus. Curr Probl Surg 19,553-647[Medline]
  7. Mansour, KA, Downey, RS (1989) Esophageal carcinoma: surgery without preoperative adjuvant chemotherapy. Ann Thorac Surg 48,201-204[Abstract]
  8. Katlic, MR, Wilkins, EW, Jr, Guillolte, (1990) Three decades of treatment of esophageal squamous carcinoma at the Massachusetts General Hospital. J Thorac Cardiovasc Surg 99,929-938[Abstract]
  9. Pearson, JG (1981) Radiotherapy for esophageal carcinoma. World J Surg 5,489-497[CrossRef][Medline]
  10. Petrovich, Z, Langholz, B, Formenti, S, et al (1991) Management of carcinoma of the esophagus: the role of radiotherapy. Am J Clin Oncol 14,80-86[ISI][Medline]
  11. Forastiere, AA, Heitmiller, RF, Kleinberg, L (1997) Multimodality therapy for esophageal cancer. Chest 112,195S-200S[Medline]
  12. Goodner, JT (1969) Surgical and radiation treatment of cancer of the thoracic esophagus. AJR Am J Roentgenol 105,523-528[Free Full Text]
  13. Launois, B, Delarue, D, Campion, JP, et al (1981) Preoperative radiotherapy for carcinoma of the esophagus. Surg Gynecol Obstet 153,690-692[ISI][Medline]
  14. Gignoux, M, Buyse, M, Segol, P, et al (1982) Radiotherapie preoperatoire du cancer de l’oesophage. Acta Chir Belg 81,373-379
  15. Wang, M, Gu, XZ, Yin, WB, et al (1989) Randomized clinical trial on the combination of preoperative irradiation and surgery in the treatment of esophageal carcinoma: a report on 206 patients. Int J Radiat Oncol Biol Phys 16,325-327[ISI][Medline]
  16. Roth, JA, Pass, HI, Flanagan, MM, et al (1988) Randomized clinical trail of preoperative and postoperative adjuvant chemotherapy with cisplatin, vindesine, and bleomycin for carcinoma of the esophagus. J Thorac Cardiovasc Surg 96,242-248[Abstract]
  17. Kelson, DP, Ginsberg, R, Pajak, TF, et al (1998) Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339,1979-1984[Abstract/Free Full Text]
  18. Forastiere, AA, Orringer, MB, Perez–Tamayo, C, et al (1993) Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for carcinoma of the esophagus: final results. J Clin Oncol 11,1118-1123[Abstract/Free Full Text]
  19. Walsh, TN, Noonan, N, Hollywood, D, et al (1996) A randomized trial of multimodality therapy versus surgery for esophageal adenocarcinoma. N Engl J Med 335,462-467[Abstract/Free Full Text]
  20. Gignoux, M, Bosset, JF (1989) Adjuvant therapy for resectable oesophageal cancer: results of a pilot study. Anticancer Res 9,1023-1024[ISI][Medline]
  21. Poplin, E, Fleming, T, Leichman, L, et al (1987) Combined therapies for squamous cell carcinoma of the esophagus, a Southwest Oncology Group (SWOG 8037). J Clin Oncol 5,622-628[Abstract/Free Full Text]
  22. Naunheim, KS, Petrosku, PJ, Roy, TS, et al (1995) Multimodality therapy for adenocarcinoma of the esophagus. Ann Thorac Surg 59,1085-1091[Abstract/Free Full Text]
  23. Adelstein, DJ, Rice, TW, Becker, M, et al (1997) Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma. Cancer 80,1011-1020[CrossRef][ISI][Medline]
  24. Urba, S, Orringer, M, Turrisi, A, et al (1997) A randomized trial comparing surgery to preoperative concomitant chemoradiation plus surgery in patients with resectable esophageal cancer: updated analysis [abstract]. Proc Am Soc Clin Oncol 16,277
  25. Forastiere, AA, Heitmiller, RF, Lee, DJ, et al (1997) Intensive chemoradiation followed by esophagectomy for squamous cell and adenocarcinoma of the esophagus. Cancer J Sci Am 3,144-152[ISI][Medline]
  26. Jones, DR, Detterbeck, FC, Egan, TM, et al (1997) Induction chemoradiiotherapy followed by esophagectomy in patients with carcinoma of the esophagus. Ann Thorac Surg 64,185-191[Abstract/Free Full Text]
  27. Urba, S, Orringer, M, Turrisi, A, et al (1995) A randomized trial comparing transhiatal esophagectomy (THE) to pre-operative concurrent chemoradiation (CT/XRT) followed by esophagectomy in loco-regional esophageal carcinoma [abstract]. Proc Am Soc Clin Oncol 14,199



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