Accomplishments in 2008 in the Management of Esophageal Cancer

SUMMARY

1. Overview of the Disease Process

   1. Incidence

   2. Prognostic or Predictive Factors

2. Current General Therapy Standards

   1. Surgery

   2. Combined Treatment Modalities

3. Accomplishments in 2008

   1. Therapy

   2. Biomarkers & Basic Science

4. What Needs to be Done

   1. Applications of the Accomplishments

   2. Controversies and Disagreements

   3. Special Populations

5. Future Directions

   1. Comments on Research

      Obstacles to Progress

I. OVERVIEW OF THE DISEASE PROCESS

I-A. Incidence

Worldwide, esophageal cancer is ranked in the top ten of the most common malignancies. It is estimated that 16,470 new patients were diagnosed with esophageal cancer and 14,280 died from the disease in the United States in 2008.¹ Squamous cell carcinoma remains the most common histology worldwide. Rapid increases in the incidence of adenocarcinoma of the esophagus have been reported in the United States and Europe over the past two decades, with rates highest among white males. The incidence of adenocarcinoma has surpassed that of squamous cell carcinoma in these countries.²

Data from population-based cancer registries in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program showed that adenocarcinoma incidence rates rose from 1975 through 2004 among white men and women in all stage and age groups. The incidence of adenocarcinoma among white men increased 463%, from 1.01 per 100,000 person-years in 1975–1979 to 5.69 per 100,000 person-years in 2000 – 2004, regardless of stage and age. A similar rapid increase was also observed among white women, with an increased incidence of 335%, from 0.17 per 100,000 person-years to 0.74 per 100,000 personyears. The authors conclude that the stage and age independence of the rates indicates that these increases are likely to be real and not an artifact of heightened surveillance and earlier diagnosis.³

Barrett’s esophagus develops in 5% to 20% of patients with gastroesophageal reflux disease and predisposes to esophageal adenocarcinoma. Adenocarcinoma arising in Barrett’s esophagus accounts for a substantial portion of intrathoracic esophageal malignancies today. A recent meta-analysis including 47 studies reported an estimated cancer incidence in Barrett’s esophagus of 4.1–6.1/1,000 person-years.⁴

I-B. Prognostic or Predictive Factors

It is now accepted that the prognosis for patients who undergo curative surgical resection but receive no neoadjuvant therapy correlates most strongly with the achievement of complete tumor resection (R0), the depth of tumor infiltration, and the presence of lymph node metastasis. It has also been suggested that the number of metastatic lymph nodes and the location of lymph nodes may influence the survival of patients who undergo surgery alone.⁵

Positron emission tomography (PET) imaging to assess response during and after neoadjuvant therapy may have prognostic significance in esophageal cancer.⁶ Results from the German MUNICON trial indicated that PET may be a valuable tool with which to discriminate responders from non-responders, and would thus allow earlier referral of nonresponders to an alternate therapy, prior to undergoing the full course of chemoradiation or surgery. The results suggested the feasibility of a PET-guided treatment algorithm for esophageal cancer.⁷ In patients who receive neoadjuvant therapy and undergo subsequent surgery, pathologic response to neoadjuvant treatment is a surrogate marker for treatment efficacy, which may predict survival and thus may help to identify patients at high risk of recurrence.⁸

II. CURRENT GENERAL THERAPY STANDARDS

II-A. Surgery

An analysis from the National Data Base including 12,246 patients with esophageal cancer confirmed the strong association for perioperative mortality (6.1% vs. 10.9%), 5-year overall survival (30.4% vs. 20.7%), and 5-year survival corrected for perioperative death (32.4% vs. 23.3%) for patients treated in high- and low-volume centers. A significant number of deaths could potentially be avoided by focusing quality improvement initiatives on factors such as completeness of resection, multimodality utilizations, and clinical trial participation.⁹

Patients with lymph node metastases have a poorer prognosis than those with negative nodes. Debate still exists regarding two-field vs. three-field lymphadenectomy for esophageal cancer. One large study including 2,303 esophageal cancer patients from nine international centers who underwent R0 resection without preoperative treatment showed that the number of lymph nodes removed is an independent predictor of survival after esophagectomy. To maximize this survival benefit, a minimum of 23 lymph nodes should be removed.⁵ The 5-year results of a randomized trial comparing a limited transhiatal esophagectomy with an extended transthoracic approach in esophageal adenocarcinoma patients showed no survival differences. Patients with one to eight positive lymph nodes in the resection specimen may benefit from the more aggressive approach.¹⁰

The application of minimally invasive esophagectomy (MIE) continues to evolve. A study of 104 patients who underwent laparoscopic/thoracoscopic Ivor Lewis resection showed it is a technically feasible procedure with acceptable postoperative morbidity of 27.9%, leakage rate of 9.6%, and mortality of 2.9%. The mean number of lymph nodes harvested was 13.8. Further studies are required to evaluate the extent of lymphadenectomy and oncologic outcome of MIE.¹¹

Salvage esophagectomy after chemoradiotherapy has been demonstrated to be feasible but challenging due to fibrotic tissue from radiation. It provides a potential survival benefit with increased operative morbidity and mortality. Given that long-term survival with a fair quality of life can be achieved, such treatment should be considered for carefully selected patients at experienced centers.^12,13

II-B. Combined Treatment Modalities

There is an emerging consensus that either chemoradiotherapy or chemotherapy should be added to the surgical treatment of esophageal cancer staged T3 or N1.¹⁴ The possible superiority of neoadjuvant chemoradiotherapy over neoadjuvant chemotherapy alone has been suggested in a randomized trial by the German Esophageal Cancer Study Group.¹⁵ Recent meta-analyses also support the efficacy of concurrent chemoradiation in the neoadjuvant setting with a potentially greater benefit from neoadjuvant chemoradiotherapy than neoadjuvant chemotherapy alone.^16,17

In the United States, neoadjuvant chemoradiotherapy has been the most widely used treatment approach for localized esophageal cancer. For patients with squamous carcinoma of the esophagus, definitive chemoradiotherapy is an option, especially for tumors in the proximal esophagus. For patients with gastroesophageal junction (GEJ) adenocarcinoma, there are data to support use of adjuvant chemoradiotherapy from the Intergroup (INT)-0116 trial, and perioperative chemotherapy from the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial.^18,19

III. ACCOMPLISHMENTS IN 2008

III-A. Therapy

The Cancer and Leukemia Group B (CALGB) 9781 trial compared survival and response of trimodality therapy vs. surgery alone in patients with esophageal cancer. Patients were randomly assigned to receive esophagectomy with node dissection alone; or cisplatin 100 mg/m² and fluorouracil 1,000 mg/m²/d for 4 days during weeks 1 and 5 concurrent with radiotherapy (50.4 Gy), followed by surgery.²⁰ Treatment was generally well tolerated. No increase in perioperative mortality was shown in the neoadjuvant therapy group, and pathologic complete response rate was 40%. In an intent-to-treat analysis, median survival was 4.48 vs. 1.79 years favoring trimodality therapy (P = .002). Results of this study, despite closing early as a result of poor accrual, suggest a survival benefit for trimodality therapy compared with surgery alone (5-year survival, 39% vs. 16%, respectively).²⁰

A survival benefit was also demonstrated in a recent large, individual patient data-based meta-analysis of nine randomized trials involving neoadjuvant chemoradiotherapy. Pooled results, presented by Thirion et al at the 2008 American Society of Therapeutic Radiology and Oncology (ASTRO) meeting, found an 18% reduction in the overall hazard of death (95% CI: 0.72– 0.93; P = .002), translating into a 5-year absolute benefit of 7% (from 18% to 25%) in favor of trimodality therapy over surgery alone.¹⁷

The Radiation Therapy Oncology Group (RTOG) 0113 trial compared two nonsurgical approaches using induction chemotherapy followed by definitive chemoradiotherapy in patients with localized esophageal cancer. Patients were treated with radiotherapy plus fluorouracil, cisplatin, and paclitaxel vs. radiotherapy plus paclitaxel and cisplatin. Results did not meet the 66% 1-year survival mark of patients in the RTOG 9504 trial. Both arms resulted in an unacceptably high level of morbidity. These findings suggest that fluorouracil-based regimens should continue to be used routinely in the treatment of localized esophageal cancer.²¹

In the Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (REAL-2) study, reported by Cunningham et al in New England Journal of Medicine,²² patients were randomly assigned to receive one of four triple therapies: epirubicin and cisplatin plus either fluorouracil (ECF) or capecitabine (ECX); or epirubicin and oxaliplatin plus either fluorouracil (EOF) or capecitabine (EOX). After 1 year of therapy, overall survival duration was better with EOX than with ECF (11.2 vs. 9.9 mo; hazard ratio for death, 0.80; 95% CI: 0.66 to 0.97; P = .02). Progression-free survival and response rates did not differ significantly among the regimens. The group receiving oxaliplatin showed lower incidence of grade 3–4 neutropenia, alopecia, renal toxicity, and thromboembolism compared with the cisplatin group, although cisplatin-treated patients experienced diarrhea and neuropathy more frequently. Study results showed that alternative regimens to ECF, substituting capecitabine for fluorouracil and oxaliplatin for cisplatin, are at least as effective and have equivalent survival rates as ECF for treating patients with advanced GEJ cancer.²²

III-B. Biomarkers & Basic Science

There is ongoing research to identify markers that are predictive for response, prognostic, or both in esophageal cancers. Because up to 70% of esophageal cancers are locally advanced at the time of diagnosis and preoperative therapy is an accepted choice for these tumors, markers to predict response pre-therapeutically are needed to avoid administering toxic and expensive therapy to patients who are unlikely to benefit. In contrast to PET-based treatment algorithms,^7,23 no prospectively tested tumor- or patient-related biomarkers are yet available for routine clinical use. A recent proteomic analysis revealed four cellular stress response-associated proteins and a number of cytoskeleton proteins whose pre-therapeutic abundance was significantly different between responders and nonresponders. Immunohistochemistry and gene expression analysis confirmed these data, showing a significant association between low HSP27 expression and non-response to neoadjuvant chemotherapy in adenocarcinoma of distal esophagus type I (AEG I) with a PET-based regimen.²⁴ Significant work needs to be done before predictive markers are routinely incorporated in clinical practice.

IV. WHAT NEEDS TO BE DONE?

IV-A. Applications of the Accomplishments

The results of CALGB 9781 and recent meta-analyses continue to support use of neoadjuvant multimodality therapy. Use of this approach has been increasing, particularly among US physicians. From the surgical point of view, a proper lymphadenectomy, harvesting an adequate number of lymph nodes, should be performed to improve long-term patient survival, whereas the surgical approach seems to be less important. Data from the REAL-2 trial have shown feasibility with promising clinical activity when substituting intravenous 5-fluorouracil with oral fluoropyrimidine. This will substantially increase the convenience of fluoropyrimidine-based regimens for patients with advanced disease.

IV-B. Controversies and Disagreements

Prospective data support the efficacy of chemoradiation or chemotherapy alone in a neoadjuvant setting. There is a paucity of randomized data directly comparing these approaches, including induction chemotherapy followed by chemoradiation. The role of adjuvant chemotherapy following curative resection remains unclear. Many investigators consider GEJ tumors to be a separate disease entity and treat it differently from esophageal and gastric cancers, but limited data are available to provide guidance for proper management.

Definitive chemoradiotherapy is an accepted treatment option for squamous esophageal cancer. The survival benefit of the addition of surgery is less clear, although the addition of surgery improves local tumor control. It is crucial to work toward identifying which patients may benefit from trimodality therapy. There is no trial of neoadjuvant therapy that includes cT2N0 adenocarcinoma patients, nor is such a trial likely to be conducted given the present knowledge. The cT2N0 adenocarcinomas are uncommon but should be considered cautiously given the limited available data.

IV-C. Special Populations

With regard to elderly patients, especially those > 80 years of age, the clinical outcomes and indications for esophagectomy have not been clearly defined. Morita et al²⁵ and Takeno et al²⁶ recently reported a similar incidence of surgical complications in patients older and younger than 80 years of age. Both studies suggested that elective esophagectomy can be performed safely in high-volume centers, at least in selected elderly patients who have no or few coexisting medical problems. With recent developments in surgical techniques and perioperative management, an esophagectomy can be considered as a viable treatment option in this patient population, especially when a curative resection can be expected preoperatively.

V. FUTURE DIRECTIONS

V-A. Comments on Research

Significant tumor heterogeneity exists among patients with esophageal and GEJ cancers. Therefore, individualized treatment strategies are warranted on the basis of each patient’s recurrence risk. Currently, there is no validated predictive marker available to assess response to neoadjuvant therapy; PET scans appear promising for that purpose and need to be further explored. Future advances in therapy for this disease will require exploiting combinations including new biologic agents.²⁷ Several key clinical trials are investigating this approach (Table 1).

Table 1.

Key phase III trials in esophageal cancer.

Trial Name	Stage	Status	Schema
NCT00655876 RTOG 0436 (US)	T1N1, T2-4Nx, M1a	Recruiting	Cisplatin + paclitaxel + RT +/− cetuximab
NCT00509561 WCTU-SCOPE-1 (UK)	I-III	Recruiting	Cisplatin + capecitabine + RT +/− cetuximab
NCT00686114 Shixiu-1 (China)	I-IVA	Approved— not yet active	Cisplatin + paclitaxel + RT +/− erlotinib
NCT00041262 MRC-OE05 (UK)	II–III	Recruiting	Cisplatin + 5-FU +/− epirubicin → surgery
NCT00861094 (France)	Any T, N0 or N1, M0 or M1a	Recruiting	RT + oxaliplatin + leucovorin vs. RT + cisplatin + 5-FU
NCT00047112 (France)	T1-2, N0-1, M0 or T3, N0, M0	Ongoing	RT + 5-FU + cisplatin → surgery vs. surgery
NCT00587600 (US)	Barrett’s > 1 cm	Completed	Photodynamic therapy vs. no treatment
NCT00193882 TROG 03.01 (Australia)	Advanced disease not suitable for definitive treatment	Recruiting	Palliation of dysphagia: RT + cisplatin + 5-FU vs. RT
NCT00653107 (Norway)	Dysphagia	Approved— not yet active	Stent + brachytherapy vs. brachytherapy
NCT00002884 (France)	T1-4 (tumor < 7 cm, nodes located < 3 cm from tumor)	Ongoing	RT + cisplatin + 5-FU +/− brachytherapy

Abbreviations: 5-FU = 5-fluorouracil; MRC-OE05 = Medical Research Council- Oesophageal 05; RT = radiotherapy; RTOG = Radiation Therapy Oncology Group; TROG = Trans-Tasman Radiation Oncology Group; WCTU-SCOPE = Wales Cancer Trials Unit- Study of Chemotherapy in Oesophageal Cancer Plus or Minus Erbitux.

V-B. Obstacles to Progress

The challenge is therefore to determine which patients will benefit most from multimodality therapy. There is currently no accurate predictive marker for patients who are to receive neoadjuvant treatment. The emerging role of PET in early response prediction after neoadjuvant therapy needs further validation. The available data suggest that there may be differences in the optimal therapies for GEJ cancers versus esophageal cancers. The current American Joint Committee on Cancer (AJCC) staging system does not provide adequate prognostic estimates for patients with esophageal and GEJ cancers who receive multimodality treatment. An update is warranted based on neoadjuvant therapy response and better classification of these tumors.²⁸