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Editorial |
Department of Digestive and Oncological Surgery, University Hospital C. Huriez, Centre Hospitalier Régional Universitaire, Place de Verdun, 59037 Lille, France
Correspondence: Address correspondence and reprint requests to: Christophe Mariette, MD, PhD; E-mail: c-mariette{at}chru-lille.fr.
The question of which treatment approach is the most appropriate regarding esophageal cancer is much debated. Because the number of well-controlled randomized trials is small, efforts to resolve this controversy have been mostly unsuccessful.
Resection is still the standard treatment for patients with localized esophageal cancer and no medical contraindications to surgery. Recent multi-institutional randomized trials have documented resectability rates of 54% to 69% and operative mortality and morbidity rates of 4% to 10% and 26% to 41%, respectively, with 5-year survival rates from 15% to 24% for patients undergoing surgery alone.1–3
These results prompted a reevaluation of the role of surgical resection for esophageal cancer. High rates of objective tumor response with neoadjuvant treatment suggest that surgery may now be considered as an adjuvant treatment. This view has been reinforced by trial results indicating that the proportion of patients who survive beyond 5 years after chemoradiotherapy (CRT) without surgery is comparable to that reported in some series of surgery alone.4 As a consequence, many investigators and clinicians have begun to question the necessity of surgical intervention.
PREOPERATIVE COMBINED-MODALITY TREATMENT
Comparing preoperative radiotherapy (RT) with immediate surgery, none of the randomized trials has shown a survival benefit for combined therapy. The results of trials exploring the addition of chemotherapy (CT) to resection are conflicting. Regarding the two large multi-institutional randomized trials of preoperative CT versus a surgical control,1,3 only one1 noted a significant median and 3-year survival benefit for patients who underwent CT. Consequently, we are still left with inexplicable disparate outcomes in these two trials, and, therefore, the worth of preoperative CT remains questionable. If preoperative CT is beneficial for esophageal cancer, such a benefit is small.
Recognition of the need for improved locoregional control and the fact that most patients die of distant disease have prompted many investigators to explore preoperative CRT in an attempt to improve outcome. The two large multi-institutional randomized trials2,5 failed to show any survival advantage of preoperative CRT. Only one randomized study6 showed a survival benefit with combined-modality therapy, but this study has been mostly criticized. Consequently, despite the widespread use of preoperative CRT, the absence of benefit reported in phase III trials means that this approach should be considered investigational. A consistent finding in these trials is that 25% of patients treated with induction CRT have no residual tumor in samples of resected tissue after esophagectomy. One would intuitively conclude that this group of patients does not require surgery, because it is difficult to understand how esophagectomy offers additional benefit in this setting, but in that case evidence-based data are lacking.
DEFINITIVE CRT
The traditional role of surgery in the management of esophageal cancer has further been challenged by the results of three phase III trials examining the usefulness of definitive CRT.4,7,8 Comparing CRT with RT alone,4 it seems that CRT is superior to RT, with 26% of patients alive at 5 years in the combined-modality group compared with no patients who received RT alone. However, persistent or recurrent local disease was present in approximately 40% of patients treated with CRT; this suggests that if surgery were also used, survival would be improved further. Moreover, mainly localized tumors were included with survival rates far lower than the 59% at 5 years reported with surgery alone.9
Two large multi-institutional randomized trials of preoperative CRT plus surgery versus definitive CRT alone have been conducted that included locally advanced esophageal carcinomas. Stahl et al.7 showed overall survival to be equivalent between the two treatment groups. Treatment-related mortality and local progression–free survival were significantly higher in the surgery group. Patients with a tumor response had a probability of surviving 3 years of >50%, regardless of the treatment group, whereas the outcome of nonresponders was generally poor. Moreover, 3-year survival increased to 32% in non-responding patients who underwent complete tumor resection after CRT.
Bedenne et al.,8 among 455 patients who began CRT, randomized 259 patients with tumoral response to surgery or continuation of CRT. No difference was noted for 2-year survival between the two groups, although the 3-month mortality was significantly higher (9% vs. 1%; P = .002) in patients who underwent surgery. However, patients in the surgery arm had many fewer esophageal stents or dilatations.
These results again challenge the role of surgery as a mandatory therapeutic intervention for all patients with carcinoma of the esophagus. Nevertheless, this does not mean that there is no role for surgery in these patients. The question raised is what patients will benefit from surgery. From these results, it seems that a tumor response to induction treatment may identify a group of patients with a good prognosis whether surgery is performed or not.
CONCLUSIONS
The treatment of esophageal cancer will undoubtedly continue to evolve as improvements in technology, combined with a greater understanding of the genomics and biology of tumors and better-defined and effective therapeutic interventions. The role of surgery is likely to change over time, but it will probably continue as a primary or secondary treatment modality for a substantial number of patients with esophageal cancer.
In patients with confined disease, resection can be curative, and the acceptable outcome achieved by surgeons who are experienced at esophagectomy is unlikely to be challenged by other forms of therapy. For patients with locally advanced disease who undergo CRT, studies suggest that surgery may no longer be recommended as a routine treatment in responding patients. However, for patients who have residual disease in situ at the completion of treatment, common sense dictates that surgery should be beneficial in achieving a long-term disease-free state. Finally, surgery should be proposed to nonresponding patients who are likely to benefit from a complete resection.
Unfortunately, at present, we are unable to accurately select the patients who require some kind of therapeutic intervention and those for whom particular treatments should be avoided. However, it is likely that in the near future, we will be able to establish a genetic fingerprint for each individual patient that will dictate the most effective therapeutic strategy in each setting.
Received for publication August 17, 2005. Accepted for publication October 4, 2005.
REFERENCES
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