Seminars in Oncology
Volume 36, Issue 6 , Pages 493-497, December 2009

Squamous Cell Carcinoma of the Esophagus: Treat With How Many Modalities?

Article Outline

 

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com. I look forward to a lively discussion.

Gloria J. Morris, MD, PhD

Current Clinical Practice Feature Editor

The American Cancer Society reported 16,400 new diagnoses of esophageal cancer for 2008, and 14,300 deaths, reflecting a poor cure rate, and the predominant late stage of presentation. The relative incidence of squamous cell carcinomas to adenocarcinomas has shown a significant change, with a decline in squamous cell incidence in all race and gender groups, while adenocarcinomas have shown a fivefold rise.1 In contrast to the literature on treatment of esophageal cancer until the late 1980s, which reported results for patients with predominantly squamous cell carcinomas, the newest clinical studies report on patients with adenocarcinoma versus squamous cell cancers in a 4:1 to 5:1 ratio. Heterogeneity of staging practices, surgical technique, and analysis of results by histology leaves ambiguity as to the optimal combination of treatment modalities in this disease and whether similar practices will give similar results for both histologies. A case of squamous cell carcinoma of the distal esophagus is discussed below to highlight these issues in light of current data.

Back to Article Outline

The Problem 

A 55-year-old Polish man had persistent complaints of chest pain for the previous year, sufficient to undergo a normal cardiac catheterization 3 months before diagnosis. He had a 40 pack-year smoking history and possible excessive alcohol intake on weekends. He had no weight loss. After he reported dysphagia for everything but pureed foods, a computed tomography (CT) scan of the chest was ordered. The CT scan showed enlarged subcarinal lymph nodes, and thickening of the distal 8 cm of esophagus, with a maximum transverse diameter of 4.5 cm. Biopsy by esophagogastroduodenoscopy (EGD) revealed invasive moderately differentiated squamous cell carcinoma. Multiple small lymph nodes seen in the right retrocrural space and the left periaortic chain, as well as the subcarinal lymph nodes on CT, did not exhibit significant 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG)-glucose uptake on the staging positron emission tomography (PET)/CT study. The PET-positive esophageal mass, which started 2 cm below the carina, did not involve the gastric cardia. A single 1-cm lymph node in the left paratracheal location was FDG-avid with a standardized uptake value of 5.8 (Figure 1). Magnetic resonance imaging (MRI) of the brain was negative. The patient's past medical history is negative for any illnesses or surgeries. He is scheduled to receive consultation from thoracic surgery, medical oncology, and radiation oncology.

Back to Article Outline

Medical Oncologist's Opinion 

This is a 45-year-old patient with apparently localized squamous cell carcinoma of the esophagus. On the staging PET/CT scan, only the esophageal mass and one paratracheal lymph node showed significant FDG uptake. To complete the workup, we would perform an endoscopic ultrasound for assessment of tumor-node-metastasis (TNM) status and to ensure resectability. Squamous cell histology is much less common than adenocarcinoma, but both histologies are most typically treated in the United States with preoperative chemoradiation followed by surgery. The patient would be evaluated by physicians from Thoracic Surgery, Radiation Oncology, and Medical Oncology, and then his case would be discussed by the Thoracic Tumor Board so that the pathology and scans could be reviewed in the group setting. Since the patient seems to be fairly healthy and is relatively young, there is no reason to think that he would not be able to tolerate trimodality therapy.

Numerous randomized trials have been performed to test the concept of preoperative chemoradiation versus surgery alone, and three meta-analyses of these trials showed a survival benefit to preoperative chemoradiation.2, 3, 4 The choice of drugs used in the chemoradiation regimen varies among institutions. The most commonly used chemotherapy agents that have some activity in esophageal cancer include cisplatin, oxaliplatin, 5-fluorouracil, capecitabine, paclitaxel, docetaxel, and irinotecan. Most often, the preoperative regimen includes two or three agents. While targeted agents such as cetuximab and bevacizumab are currently being studied in clinical trials, we would not use these agents in the neoadjuvant setting outside of a trial. One of the most commonly used preoperative chemotherapy regimens is cisplatin plus 5-fluorouracil, delivered in two cycles concurrently with radiation therapy. At our institution, we sometimes give the 5-fluorouracil as a very-low-dose continuous infusion throughout radiation to try to maximize the drug's radiosensitizing properties. Examples of other possible chemotherapy combinations include cisplatin and irinotecan, cisplatin and paclitaxel, or oxaliplatin and 5-fluorouracil.

After completion of chemoradiation, we give the patient a 3- to 4-week rest, and then proceed with a transhiatal esophagectomy. We always include surgery as part of the treatment plan because the typical complete pathologic response rate after chemoradiation is 25%, and resection of residual disease is important. We are a referral center with highly experienced thoracic surgeons who frequently perform this operation; patients undergoing esophagectomy should be treated in a center where a fair volume of this disease is seen.

Susan Urba, MD

Professor of Internal Medicine

Division of Hematology/Oncology

University of Michigan Comprehensive Cancer Center

Ann Arbor, MI

Back to Article Outline

Surgical Oncologist's Opinion 

This is a difficult problem of a mid-distal esophageal squamous cell carcinoma, which is not as common as it once used to be in this country. The development of squamous cell carcinoma of the esophagus and its relationship to alcohol and smoking is thought to be due to chronic irritation of the tissue rather than exposure of the distal esophagus to gastric contents, which results in the typical adenocarcinoma seen most frequently in the United States. Squamous cell carcinomas result in a different set of concerns for both preoperative evaluation and intraoperative planning.

This patient, with subcarinal nodes, paratracheal nodes, and a mass just below the carina, requires a more in-depth preoperative evaluation than would a patient with a simple distal adenocarcinoma. Tumors at the carinal level, especially those with a significant bulky mass of 4.5 cm, may invade surrounding structures in the mediastinum as well as the tracheobronchial tree. As CT imaging is not sufficiently sensitive to eliminate this possibility prior to surgery, it is imperative that all tumors of the esophagus within 3 to 5 cm of the carina be evaluated with bronchoscopy to prove that there is no tracheal or bronchial involvement, particularly on the left side, where the tumor can invade the left mainstem bronchus with or without symptoms. Careful evaluation of the chest CT will alert the surgeon as to whether important vascular structures from the heart or the aorta may be of concern intraoperatively.

Biopsy of the PET-positive paratracheal lymph node to confirm involvement, usually by endoscopic ultrasound (EUS), would lead to a recommendation that the patient undergo neoadjuvant therapy. Nutritional support during neoadjuvant therapy would be a serious priority, since the patient is already limited in his ability to achieve oral intake. It is always our preference for patients to receive enteral nutrition either per os, or when this is not possible, via a laparoscopically placed surgical feeding tube in the jejunum, to preserve the stomach as a conduit. The latter is rarely required in our experience. We have never used total parenteral nutrition as a method of nutritional support due to a number of factors such as infection, expense, and the risk of villous atrophy complicating postoperative feeding.

With respect to operative intervention, it is our preference to perform another intraoperative bronchoscopy prior to resection, to prove that the tumor has not progressed, and an esophagoscopy to assess distance and size. Tumor invasion and/or post-treatment effect to the mediastinum may make the preferred transhiatal esophagectomy difficult, if not impossible. All nodal stations are addressed either with direct vision or palpation of the mediastinum during the transhiatal portion of the operation, and node sampling is carried out.

If the tumor is closely approximated to the airway and not frankly invading, the resection can still take place, but one must be very vigilant of reactive bronchorrhea, which may complicate the postoperative course.

Our typical postoperative care begins with extubation in the operating room and return to the general care floor. The patient's nasogastric tube, chest tubes, and drains are removed on the third postoperative day, and jejunostomy tube feedings are started. Patients are discharged on day 5 and kept strictly without oral intake (NPO) for an additional 10 days, while on continuous tube feedings. They are then started on clear liquids for 3 days, and a soft mushy diet after that. They return to our offices in 1 month to have their J-tube removed. Using this approach, we have had no postoperative leaks in over 2 years; however, approximately 10% of patients require dilatation therapy at least once postoperatively.

While one can argue against the benefit of preoperative chemoradiation, it is my feeling that once there is evidence of nodal involvement, surgical intervention, while very good at treating local disease, is not adequate to provide maximal survival and control of distant disease.

Mark Iannettoni, MD

Ehrenhaft Professor of Cardiothoracic Surgery

Head, Department of Cardiothoracic Surgery

Surgical Director of the UI Heart and Vascular Center

Department of Cardiothoracic Surgery

University of Iowa Hospitals and Clinics

Iowa City, IA

Back to Article Outline

Radiation Oncologists' Opinion 

The patient presents with a locally advanced squamous cell cancer of the mid-esophagus with no evidence of metastatic disease seen on his PET/CT scan. Esophageal cancer treatment regimens and outcomes are closely associated with stage. Thus, an accurate staging workup is required to determine if the appropriate course of action should include definitive chemoradiation versus neoadjuvant chemoradiation followed by surgical resection (trimodality therapy).

EUS has a pivotal role in staging his locoregional disease extent. Primarily, EUS can aid the determination of the extent of invasion of his primary tumor to determine resectability. Furthermore, EUS-guided fine-needle aspiration can sample suspicious nodes to determine the extent of nodal involvement.

In addition to EUS, laparoscopy and thoracoscopy also have been used to more accurately stage regional lymph nodes, and to detect occult intraperitoneal metastases. If the celiac lymph nodes in this patient were found to be positive, he would have M1b disease, which would preclude him from receiving trimodality therapy. Accurate staging of esophageal cancer using these methods is paramount to ensure that aggressive curative treatment strategies are only used for patients with a locoregional disease burden. Cancer and Leukemia Group B (CALGB) 9380 was a prospective trial examining the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer; this trial found that noninvasive imaging using CT, MRI, or EUS incorrectly staged 50%, 40%, and 30% of patients, respectively.5

The standard treatment for locally advanced esophageal cancer remains definitive chemoradiation. The landmark Radiation Therapy Oncology Group (RTOG) trial 85-10 randomized patients between treatment with radiation alone (64 Gy) or concurrent chemotherapy (two cycles of cisplatin/5-fluorouracil) and radiation (50 Gy) followed by two cycles of adjuvant chemotherapy.6 After a minimum follow-up of 5 years, the median survival was 9.3 months in the radiation alone arm versus 14.1 months in those treated with combined modality therapy. The 5-year survival rate was 26% for those who received combination therapy compared to 0% for those treated with radiation alone.

In patients with squamous cell cancer of the esophagus treated initially with chemoradiotherapy, the added benefit of surgical resection is controversial. Definitive chemoradiotherapy is associated with a 25% overall survival rate at 5 years in patients with squamous cell cancer, which is similar to results seen in other trimodality trials. Two trials compared definitive chemoradiotherapy to neoadjuvant chemoradiation followed by surgical resection in squamous cell cancer of the esophagus. The first study randomized 172 patients with squamous cell cancer of the esophagus to induction chemotherapy and concurrent chemoradiation followed by surgical resection versus definitive chemoradiation.7 The patients who underwent surgery had a significant improvement in local control at 2 years of 64% versus 41%. Median survival was similar between the two arms at 16.4 months in the surgery arm and 14.9 months in the chemoradiation alone arm. The second study, by the Fédération Francophone de Cancérologie Digestive, FFCD 9102, randomized 444 patients (89% had squamous cell cancer) with at least a partial response to neoadjuvant chemoradiation, proceeding to surgical resection versus continuing chemoradiotherapy.8 Median survivals were similar between the two groups: 17.7 months in the surgery arm and 19.3 months in the chemoradiation arm. Patients who underwent surgery had significantly lower rates of locoregional recurrence: 34% versus 43% for those who underwent definitive chemoradiation. Both of these trials suggest that the addition of surgery to patients who undergo chemoradiation results in improved locoregional control.

Taking these studies together, we can make several conclusions regarding the optimal management of our patient with a mid-thoracic esophageal squamous cell cancer. His staging workup should be completed with an EUS, and a diagnostic laparoscopy to determine the extent of his nodal involvement, placing attention on the status of celiac node involvement.

Assuming he is found to have no evidence of metastatic disease, he could undergo definitive chemoradiation, which cures a proportion of patients; however, it is associated with an unacceptably high rate of locoregional failure. Therefore, his optimal management would include surgical resection following neoadjuvant chemoradiation.

Mohan Suntharalingam, MD

Marlene and Stuart Greenebaum Professor of Radiation Oncology

Vice Chair, Radiation Oncology

University of Maryland Marlene and Stuart Greenebaum Cancer Center

Baltimore, MD

Matthew Koshy, MD

Resident

Department of Radiation Oncology

University of Maryland Marlene and Stuart Greenebaum Cancer Center

Baltimore, MD

Back to Article Outline

Summary and Assessment 

This patient's locally advanced disease warrants aggressive staging with EUS and bronchoscopy to assess the extent of involvement of local structures that may affect the feasibility of surgery. Following this, trimodality therapy, with chemotherapy, radiation, and surgery, has the potential advantages of earlier treatment of micrometastasis, less seeding during surgery, and potential downstaging of the tumor at the time of resection. Agents favored for chemotherapy include 5-fluorouracil, cisplatin, and paclitaxel, given neoadjuvantly, or in concert with radiation as preoperative adjuvants.

Preoperative restaging has three areas of potential impact on patient management. Identification of responders from nonresponders to adjuvant therapy, such as with CT or EUS, would direct selection of further systemic therapy and avoid futile treatment regimens. Identification of nonresponders would also suggest that surgery play a more urgent role if disease is still potentially resectable. PET/CT and/or bronchoscopy/thoracoscopy gives further anatomical information on disease extent and evaluate resectability. A recent retrospective review of one institution's series of 61 esophageal cancer patients staged with PET/CT concluded that, while PET/CT can indicate response of locoregional disease to adjuvant therapy, there was no relationship between decrease of the elevated PET standardized uptake value in presumed tumor areas and disease-free survival, overall survival, or local control.9 Lastly, a recent analysis of prognostic factors in patients with esophageal cancers concluded that even when pathological response is complete, initial clinical stage is independently correlated with survival and risk of local recurrence, arguing that there might be few patients with T3–4 or N1 disease who should be spared surgery.10

The poor outcomes following surgical resection alone and definitive chemoradiation alone led investigators to employ trimodality therapy consisting of neoadjuvant chemoradiation followed by esophagectomy to improve outcomes. Two trials examined neoadjuvant chemoradiation followed by surgery versus surgery alone. Walsh et al randomized 113 patients with esophageal adenocarcinoma to surgery alone versus neoadjuvant chemoradiation consisting of two courses of 5-fluorouracil and cisplatin administered during radiation therapy followed by surgery.11 Neoadjuvant treatment was associated with a significantly longer median survival of 16 months versus 11 months, and 3-year survival (32% v 6%). Urba et al randomized 100 patients with localized esophageal or gastro-esophageal cancer to surgery alone versus neoadjuvant chemoradiation with cisplatin, 5-fluorouracil, and vinblastine administered with radiation therapy followed by surgery. Neither the difference in median survival (16.9 months v 17.6 months) nor that in 3-year overall survival (30% v 16%) in the trimodality and surgery arms, respectively, was statistically significant.12

Local control is only one part of the efforts to obtain cure for esophageal cancer patients. High death rates clearly reflect a need for treatments that control distant disease. Current trials of the RTOG include a phase II trial studying paclitaxel-based chemoradiation with and without 5-fluorouracil, a phase III trial comparing paclitaxel/cisplatin with and without the targeted agent (cetuximab), and a third study that uses paclitaxel-based induction chemotherapy followed by concurrent chemoradiation with selective surgical salvage for resectable locoregionally advanced esophageal cancer. The initial report of this latter study presents an estimated 1-year survival of 72% and an estimated disease-free survival of 39% with one postoperative death out of 18 surgical procedures.13 It will be interesting to see if subgroup analyses of these trial data find differences in outcome based on histology.

Recent contributions to the literature on the subject of multimodality therapy include studies limited to patients having one of the two esophageal cancer histologies. The meta-analysis by Fiorica et al concluded that adenocarcinoma patients benefited from multimodality therapy to a greater extent than squamous cell patients.4 Some recent trials of multimodality treatment found a greater survival, response rate, and progression-free survival for squamous cell cancers, while others found the opposite. Some series suggest that squamous cell cancers have a significantly higher risk of operative morbidity than for adenocarcinomas, while clinical trials vary in their reporting of whether neoadjuvant therapy as a whole increases surgical morbidity. Understanding of these potential differences in outcome can improve the chances that the chosen therapy will deliver maximum benefit relative to risk. Whether a patient is diagnosed in a major academic center, or a community oncology setting, treatment of esophageal cancer remains a complex task worthy of early and ongoing multidisciplinary collaboration by the best minds available.

Back to Article Outline

References 

  1. Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol. 2007;17:2–9
  2. Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J. Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol. 2007;8:226–234
  3. Urschel JD, Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer. Am J Surg. 2003;185:538–543
  4. Fiorica F, Di Bona D, Schepis F, Licata A, Shahied L, Venturi A, et al. Preoperative chemoradiotherapy for oesophageal cancer: a systematic review and meta-analysis. Gut. 2004;53:925–930
  5. Krasna MJ, Jiao X. Thoracoscopic and laparoscopic staging for esophageal cancer. Semin Thorac Cardiovasc Surg. 2000;12:186–194
  6. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992;326:1593–1598
  7. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–2317
  8. Bedenne L, Michel P, Bouche O, Milan C, Mariette C, Conroy T, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160–1168
  9. Monzajeb AM, Farmer MR, Mattern M, Mebea A, Levine EA, Geisinger KR, et al. Patterns of failure for esophageal cancer patients optimally staged with F-18-FDG-PET and observed after chemo-radiotherapy. Int J Radiat Oncol Biol Phys. 2007;69(Suppl):S274
  10. Kim MK, Cho KJ, Park SI, Kim YH, Kim JH, Song HY, et al. Initial stage affects survival even after complete pathologic remission is achieved in locally advanced esophageal cancer: analysis of 70 patients with pathologic major response after preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2009;75:115–121
  11. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–467
  12. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19:305–313
  13. Swisher S, Winter K, Komaki R, Ajani J, Wu T, Hofstetter W, et al. A phase II study of a paclitaxel based chemoradiation regimen with selective surgical salvage for resectable locoregionally advanced esophageal cancer: initial reporting of RTOG 0246. Int J Radiat Oncol Biol Phys. 2007;60(Suppl):S106

PII: S0093-7754(09)00164-X

doi:10.1053/j.seminoncol.2009.09.002

Seminars in Oncology
Volume 36, Issue 6 , Pages 493-497, December 2009

Article Tools

* Image Usage & Resolution