Originally published as JCO Early Release 10.1200/JCO.2005.12.911 on March 21 2005

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Carcinoma of the Esophagus: Is Biology Screaming in My Deaf Ears?

The University of Texas M.D. Anderson Cancer Center, Houston, TX

Carcinoma of the esophagus is rampant in many parts of the world, accounting for up to 600,000 new cases per year. In the West, adenocarcinoma has been on the rise. There are obvious associations with increased body mass, gastroesophageal reflux, and smoking,^1,2 whereas the role of over-the-counter acid suppressants remains uncertain. Progression of Barrett's metaplasia to adenocarcinoma adds another intriguing twist to the formula. Although adenocarcinoma still predominantly afflicts white men, recently a similar trend has been observed in black men,³ and adenocarcinoma seems to be increasing in white women as well. Increasingly, the gastroesophageal junction is involved with adenocarcinoma of the esophagus or proximal stomach, posing special intellectual and practical challenges. Lifestyle, especially when it includes tobacco and alcohol abuse associated with poor nutrition, has been linked to squamous cell carcinoma in the West. Adenocarcinoma has intrigued us initially by primarily afflicting white men, but it may turn out to be a lifestyle-related cancer after all.

Localized esophageal cancer is a virulent malignancy and is often diagnosed when patients have enlarged regional lymph nodes and a deeply penetrated primary. Despite many efforts to improve treatment, there has been little change in the 5-year overall survival (OS) rates, which have remained under 20% for decades. The morbidity associated with therapy delivers a devastating blow to the patient's quality of life, particularly if an extensive resection is performed. Off-protocol preoperative chemoradiotherapy is popularly prescribed in academic and nonacademic centers, without convincing data to justify its use. One popular argument for this practice is that preoperative chemoradiotherapy provides a window of opportunity for the appearance of metastasis before surgery; another argument is that it often serves as a stress test before surgery for the group of patients harboring significant comorbid conditions. After stating these arguments, it is clear that the value of preoperative approaches in the treatment of carcinoma of the esophagus remains questionable and needs to be resolved.

It is also clear that patients who achieve a pathologic complete response (pCR) after preoperative therapy survive longer than those who do not. One question is are these patients living longer because they achieved a pCR because of preoperative therapy or would they have done just as well if they had no preoperative therapy? How can we possibly answer this conundrum, knowing that, to date, none of the well-conducted randomized trials (there are not many) of preoperative chemoradiotherapy has succeeded in prolonging OS? Are we increasing the fraction of patients who achieve a pCR (and is their survival also being prolonged) as a result of preoperative therapy? Maybe, but the number of these additional pCR patients is too small to influence trial results. Can we learn more by unraveling some of the mysteries of the clinical biology of localized esophageal cancer? The following report certainly provides a basis for it.

In this issue of the Journal of Clinical Oncology, Berger et al⁴ present their data on 171 patients with localized carcinoma of the esophagus who were seen over a 9-year period. It turned out to be a favorable population, with the majority of patients (> 65%) having a node-negative clinical stage (IIB or less). Of these patients, 131 underwent chemoradiotherapy followed by surgical resection. Cisplatin-fluorouracil–based chemotherapy was used, and the median radiation dose was 45 Gy. The median follow-up time at this review was rather short, just 14 months. The authors correlated pathologic response with OS and disease-free survival. A pCR was observed in 42 (32%) of the 131 patients, and some degree of response was observed in an additional 10%. The 5-year OS rate for the entire cohort was 26%, and the median survival time was 33 months. For patients who achieved a pCR, however, the 5-year OS rate was 48%, and the median survival time was 50 months. Ten percent of the patients who had some pathologic response did better than those who had no response. The 30-day postoperative mortality rate was 5%. The authors, after comparing treatment results with their surgical cohort of 40 patients, suggest that preoperative chemoradiotherapy did not significantly prolong survival compared with surgery alone. What is new in this report? Not only this is a painstaking effort, it helps us to reflect back on what we have achieved with this strategy and suggests that it may be time to pause!

Several issues must be considered. A review of the results of preoperative chemoradiotherapy administered to 828 patients with localized esophageal cancer who were enrolled onto 18 trials since 1993 shows a median pCR rate of 27% (range, 6% to 51%).⁵ For the entire group, the 5-year OS rate was 34%, but for the pCR patients, it was 64%. Remarkably, the 3-year and 5-year OS rates were similar for the entire group and the pCR group. This could suggest that a 3-year benchmark for prospective studies may be useful in speeding up the interpretation and application of future trials. The 5-year OS rate for 69 pCR patients who were treated at The University of Texas M.D. Anderson Cancer Center was 65%, and a higher proportion of stage II patients than stage III patients achieved a pCR.⁵ As Berger et al⁴ have concluded, preoperative chemoradiotherapy is not very effective and may have reached its highest potential. This may be because we have become such experts in identifying a study population through the use of extensive and sophisticated staging procedures, and then, we administer empirically chosen, complex (but still homogeneous) therapy to all patients in a trial, while forgetting that cancers (even in well-defined stage groups) are often heterogeneous. We always end up with disparate patient outcomes that clinical or treatment parameters can rarely explain. So how do we get to the bottom of this? Clinical biology can certainly teach us one of the lessons.

When we are facing an untreated patient with localized carcinoma of the esophagus, we have no inkling of whether that patient will be cured, relapse locally, develop metastases, or live for a relatively long time or for only a short time. Should we not be able to reliably predict the outcome before any treatment is administered? Yes, but we have not even begun to develop a process that will prove practical in the future. However, we are learning more about the clinical biology of esophageal cancer. For example, the clinical stage has a low predictive value in terms of patient outcome even if preoperative therapy is not administered; however, if preoperative therapy is administered, the OS and disease-free survival are reliably predicted by the surgical pathologic stage.^6,7 Thus, the posttherapy pathologic stage, especially after preoperative chemoradiotherapy, provides an early surrogate benchmark to further speed up comparative trials. It also provides a useful outcome prediction tool for communicating with patients, relatives, and colleagues.

Additionally, the degree of pathologic response correlates with the rate of local-regional relapse, metastasis-free survival, event-free survival, and the speed at which metastases appear (Rohatgi et al, submitted for publication). Clinical biology continues to speak loudly and clearly. In one study, in patients who had presurgery endoscopic biopsies after chemoradiotherapy, a correlation was found between a positive biopsy and positive lymph nodes in the surgical specimen.⁸ Also, presurgery node positivity (by endoscopic ultrasonography) correlated with OS.⁹ Thus, at every intervention, it may be possible to predict the outcome (and reconsider our original plan). With improving understanding of clinical biology, we might be able to better select patients for appropriate (but still homogenous) therapies until molecular determinants are incorporated to improve the selection and treatment processes substantially.

Preoperative chemoradiotherapy for carcinoma of the esophagus reveals its true clinical biology. Post-therapy pathology is the earliest and most reliable determinant of patients' outcomes. With cocktails of various chemoradiotherapy agents, we are not yet altering the clinical biology in a significant way. Is it time to slow down the development of homogeneous approaches to heterogeneous cancers? Yes. We should divert more resources to developing new strategies to reduce empiricism by developing treatments that are patient specific and cancer specific, improving patient outcome, reducing morbidity, increasing convenience, and ultimately preserving the esophagus without jeopardizing its function.

Author's Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Jaffer A. Ajani, Aventis, Sanofi. Research Funding: Jaffer A. Ajani, Aventis, NS Pharma, Taiho, Sanofi. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

REFERENCES

1. Wild CP, Hardie LJ: Reflux, Barrett's oesophagus and adenocarcinoma: Burning questions. Nat Rev Cancer 3:676-684, 2003[CrossRef][Medline]

2. Engel LS, Chow WH, Vaughan TL, et al: Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst 95:1404-1413, 2003[Abstract/Free Full Text]

3. Devesa SS, Blot WJ, Fraumeni JF: Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 83:2049-2053, 1998[CrossRef][Medline]

4. Berger AC, Farma J, Scott WJ, et al: Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol 23:4330-4337, 2005[Abstract/Free Full Text]

5. Rohatgi P, Swisher SG, Correa AM, et al: Prediction of pathologic complete response after preoperative chemoradiotherapy in carcinoma of the esophagus and outcome after pathologic complete response. Cancer (in press)

6. Chiriec LR, Swisher SG, Ajani JA, et al: Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer (in press)

7. Gibson M, Burtness B, Heath E, et al: Effect of neoadjuvant chemoradiotherapy on pathologic stage and survival in patients with locally advanced esophageal cancer. Proc Am Soc Clin Oncol 23:320, 2004 (abstr 4032)

8. Yang O, Cleary KR, Yao J, et al: Significance of post-chemoradiation biopsy in predicting residual esophageal carcinoma in the surgical specimen. Dis Esophagus 17:38-43, 2004[Medline]

9. Agarwal B, Swisher SG, Ajani, et al: Endoscopic ultrasound after preoperative chemoradiation can help identify patients who benefit maximally after surgical esophageal resection. Am J Gastroenterol 99:1258-1266, 2004[CrossRef][Medline]

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