Among the epiphenomena in Western clinical oncology that have occurred in the past 3 decades, including the decreasing incidences of rectal and distal gastric cancers, the most intriguing and most important has been the marked increasing incidence of adenocarcinoma of the esophagus (ACE) along with the concurrent declining incidence of squamous cell esophageal cancer (SCCE).1 Thus, as eligibility for recent US trials for patients with esophageal cancer restrict entry to either ACE patients or SCCE patients to achieve adequate statistical power for select therapeutic end points, most cooperative group trials have developed phase II trials for patients with ACE. Within the United States over the past 20 years, very few trials have been developed or reported for patients with SCCE. Thus, SCCE has become a de-facto orphan cancer.
Nevertheless, in the Middle East, Africa, and Asia, and parts of Europe, SCCE dominates the esophageal cancer landscape. World-wide rates are highest in Northern China, South Africa, Turkey, and Iran.2 In the United States, the black population has a five-fold higher incidence of SCCE than the white population. While the rate of SCCE has been steadily decreasing in among blacks in the United States, 83% percent of blacks with esophageal cancer present with SCCE.3
Despite clear differences in incidence and etiology, ACE and SCCE share important risk factors, most notably smoking and alcohol consumption. The best known and accepted risk factors for SCCE include a constellation of factors at the population, individual, and cellular level, including though not limited to race, socioeconomic class, diets low in fruits in vegetables, achalasia, systemic sclerosis, previous esophageal stricture, and a prior history of squamous cell tumors of the head and neck or lung. In China, risk factors are similar but also include diets high in N-nitroso compounds, fungal toxins, diets low in selenium and zinc, highly salted meats, and diets with low intake of vitamins A and C and the consumption of very hot beverages. Recent evidence also shows that in certain regions of the world (China, South Africa, and South America), human papilloma virus (HPV) infection may predispose to SCCE.4,5
Progress has also been made in identifying the molecular alterations that lead to esophageal cancers. These include functional losses of tumor suppressor genes, Rb, p53 and p16. For the most part, these functional losses are induced by loss of heterozygosity (LOH) and, to a lesser degree, by methylation changes or by mutational changes in these genes that inhibit apoptosis or act as breaks at crucial phases within the cell cycle.6 Cyclins, especially cyclin D1 and cyclin E, are almost always upregulated in esophageal cancers. 7
Mutations in erbB-2 have been recognized, and recently, a successful trial targeting erbB-2 with trastuzumab for patients with gastric and GE junction adenocarcinomas has been reported.8 Notwithstanding this report, as our general knowledge regarding these and many other molecular changes within esophageal cancers has dramatically increased, there has been little progress in identifying specific molecular profiles that reliably correlate with prognosis and/or response prediction for either ACE or SCCE. Indeed, several of the molecular alterations mentioned above appear common to both esophageal histologies.
Although efforts have been made to find and treat early SCCE by identifying them with lugol's iodine, well over 90% of SCCE patients present with symptoms of dysphagia, odynophagia, significant weight loss, and nutritional depletion. SCCE patients tend to harbor tumors in the mid esophagus, where invasion through the esophageal wall can cause a tracheoesophageal fistula. At the time of diagnosis, close to 40% of SCCE patients have clinically visible distant metastases, and almost all patients presenting with symptoms invariably have occult metastatic disease.9 In terms of therapy, few Western experts doubt the value of trimodality therapy, including surgery, for patients with clinical stage II or stage III ACE. Although reports from prospective randomized trials have suggested that surgery may not increase survival after chemotherapy and radiotherapy for patients with SCCE,10,11 a recent presentation at 2010 Annual Meeting of the American Society of Clinical Oncology (ASCO) makes a strong case for trimodality therapy for patients with SCCE.12
In this issue of Gastrointestinal Cancer Research, Rossman et al have published results of the Eastern Cooperative Group trial E2298.13 These investigators combined their accrual forces with investigators in South Africa in a phase II trial to determine the effect of docetaxel and carboplatin for patients with incurable and measurable SCCE. Accrual goals were modest—35 patients. Even so, the trial's first patient went on study in July 1999 and the last of 33 patients (six were later declared ineligible) began therapy a little over 2 years later, in August 2001. Approximately, half the 33 patients were black. By itself, the length of time to complete the trial is a testament to the declining incidence of SCCE in the United States. The investigators employed standard eligibility criteria, standard dose reduction criteria, and standard response definitions. The primary study end point was response rate with secondary end points including toxicity, time to progression, and overall survival, with the study statistically powered for a true response rate of at least 30% via two-stage design. The doublet to be tested, docetaxel 75 mg/m2 and carboplatin AUC 6, is a well recognized combination that has been an anchor for patients with non-small-cell lung cancer.14 It is therefore disappointing that the investigators reported one patient (3%) with a complete clinical response and only four patients (13%) with partial responses. Although the estimated median survival was 6.7 months, and 4 of 5 responders were black, the investigators declared the trial a failure as they were aiming for a response rate of 30% or more.
Considering the time span of approximately 15 years from conception to publication, perhaps it is unfair to find fault with the design and execution of this trial. However, even in 1999, the doublet of carboplatin and docetaxel was not considered an exciting or innovative combination. Platinum compounds and taxanes had been tested for patients with advanced esophageal cancer, with one publication coming out a year prior to the initiation of the Eastern Cooperative Oncology Group (ECOG) 2298 study.15 Furthermore, the doses tested by ECOG investigators would most likely preclude combining the carboplatin and docetaxel with concomitant radiotherapy for potentially curative patients. Efforts to define intratumoral markers for sensitivity or resistance to the doublet were not part of the trial design. An 18% rate of ineligibility (most of which was due to inability to document lesions) is, by most standards, unacceptable.
So, why does a negative trial, completed almost a decade ago, deserve publication and then further discussion in the form of an editorial? In my opinion, this trial is important because it went against the grain to target an underserved, and generally an impoverished population afflicted with a tumor that is rarely curable. It was among the first trials by a cooperative group to recognize the importance of separating treatments for ACE and SCEE. Also, the initiation and completion of an international cancer trial sponsored by a major cooperative group in the United States is both noteworthy and praiseworthy. We certainly need more international trials.
Also, it bears noting that it is difficult to find editors willing to publish the results of negative studies, the editors of GCR (and I am not one of them) should be congratulated for their willingness to publish a so-called “negative trial” on a topic that receives little current attention.16 At a time when cooperative groups sponsored by the National Cancer Institute are being criticized for closing trials for lack of accrual17 and at a time when poor accrual forced the Southwest Oncology Group (SWOG) to close S0414, a study offering a clinical trial to patients with potentially curable SCCE (Charles R. Thomas, personal communication, 2010), it is important to note the achievement of these investigators and point again to the need for further clinical trials focused on SCCE. In an age in which we tout globalism, SCCE remains a global scourge, for which efforts at prevention and treatment based on further understanding of macro (population and individual) and micro (cellular) level contributions is warranted.