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* From the Department Thoracic Surgery, University Hospital Gasthuisberg, Leuven, Belgium.
Correspondence to: Tony Lerut, Department of Thoracic Surgery, University Hospital Gasthuisberg, Herestraat 49, Leuven, Belgium 3000
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Abstract |
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30%. Until now, there has been no proven
benefit from combined neoadjuvant treatment modalities using
chemotherapy or chemoradiotherapy except for the subset of patients
showing a complete response at pathologic examination. Further research
should focus on new chemotherapeutic agents and the development of
molecular markers that allow better identification of candidates for
multimodality regimens. |
Introduction |
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TOPAbstractIntroductionReferences |
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Besides these geographical changes, a major shift in the histologic type of tumors seems to have occurred both in the United States and in Europe, resulting in a sharp increase in adenocarcinoma of the esophagus and GEJ.3 Whereas an association with smoking and alcohol abuse is generally accepted for esophageal carcinoma, there seems to be a strong correlation between reflux,4 Barrett metaplasia, and dietary factors (eg, fat) in adenocarcinoma.5 Although generally considered relatively uncommon, esophageal cancer ranks ninth as cause of death and sixth as cause of cancer death worldwide.
Indeed, most patients present themselves with an advanced stage of disease as the main symptom, dysphagia, may not become apparent until two thirds of the esophageal lumen has been obliterated. Many patients may not seek medical attention until severe dysphagia has occurred. As a result, a majority of patients will have involved local/regional or distant, multiple lymph node metastases, or even organ metastases, at the time of diagnosis.
Esophageal obstruction may result in weight loss, regurgitation, and
pulmonary damage, which, together with tobacco and alcohol abuse,
results in poor general physical condition. Moreover, esophageal
neoplasms typically occur in the older age group with typical peak
incidence between 65 and 70 years of age. In the Western hemisphere,
with its increasing life expectancy, 
20% of esophageal carcinomas
occur in patients who are > 70 years of age. All these factors
naturally will have a negative impact on morbidity and mortality,
whatever therapeutic regimen is chosen. A major literature review by
Earlam and Cunha-Melo6
7
in 1980 reported a 29% mortality
rate and a 5-year survival rate of as little as 4% after surgery for
esophageal cancer. This research set a negative attitude for many years
to follow.
Another literature review by Mueller et al8 in 1990 reversed this negative attitude, as 5-year survival figures had increased substantially by up to 20%, illustrating very well the major role surgeons have played in the treatment of this disease. Lowered postoperative mortality rates and increased radicality at the time of surgery are believed to be the main factors responsible for the better 5-year survival rates, which vary between 25% and 40% in recent reports.9 10 11 12 13
A survey among seven European surgeons with proven clinical experience and scientific interest in the field was recently performed by Peracchia, MD, PhD (personal communication, December 1998) analyzing the data of 6,146 surgical patients. The data show a decrease in the postoperative hospital mortality rate from 14.1% (range, 12 to 15%) before 1980 down to 5.7% (range, 1.4 to 10%) between 1984 and 1989.
Along with these surgical improvements, much attention also has been paid to the standardization and refinement of oncologic surgical techniques. Today, there is general agreement on the necessity of a so-called R0 resection (ie, a complete macroscopic and microscopic removal of tumor as the basic requirement in the surgery with curative intent for carcinoma of the esophagus and GEJ).5 14 There is still a great controversy as to the extent of the resection15 16 and the type of surgical access (ie, transthoracic, left- or right-sided, or transhiatal resection. Irrespective of the access route, there is, however, a growing consensus about the need for a wide peritumoral dissection, including the removal of all peritumoral tissue in the mediastinum. Many medical centers advocate an en bloc resection that includes the surrounding mediastinal pleura, the azygos vein, the thoracic duct, and, for some authors, also the pericardium.10 17
A number of reports, especially those from Japanese groups, are focusing on the value of extended lymphadenectomy both in the mediastinum and in the superior abdominal compartment (two-field lymphadenectomy). A number of authors think that adding bilateral cervical lymphadenectomy (three-field lymphadenectomy) is essential, especially in supracarcinal tumors.9
The value of lymphadenectomy is threefold. It definitely adds to an improved pathologic staging. Although there is no definitive proof, because of the lack of randomized studies, there is emerging evidence that extensive lymphadenectomy improves prolonged disease-free survival times and cure rates through better control of local/regional recurrence, which probably results in better control of distant metastases. As a result, even in advanced stage III disease 5-year survival rates of around 20% can be obtained after an R0 resection.10 14
In the previously mentioned survey by Peracchia, the overall 5-year survival rate after R0 resection increased from 17.5% before 1980 to 31.5% between 1984 and 1989 and to 38.5% since 1990. Nevertheless, the majority of the patients present in an advanced stage at the time of diagnosis, which jeopardizes the chances for a complete R0 resection and, thus, for a cure. Consequently, neoadjuvant and combined modality therapy have become focuses of interest in the effort to prolong survival and to reduce recurrence rates. Preoperative radiotherapy was studied in the early 1980s, but a benefit in outcome compared to surgery alone could not be shown.18 19 20 21
The expected benefits of preoperative systemic therapy (ie, chemotherapy) are the preoperative elimination of potential systemic micrometastases in patients with both local/regional and locally advanced tumors and the lowering of the stage of the primary tumor. Such a regimen should increase the R0 resection rate in patients with locally advanced tumors and in patients with tumors at unfavorable locations and should reduce the rate of local and distant recurrences, thereby increasing the chances for long-term survival.
Most studies dealing with neoadjuvant chemotherapy are based on combinations that contain cisplatin, which seem to be well tolerated without increasing the postoperative mortality or morbidity rates. Response rates are ranging between 25% and 50%.22 23 24 25 However, no definite conclusions could be obtained from these studies because of conflicting results, even in the most recent large-scale randomized trials. Kok et al26 reported an 18.5-month median survival time in the chemotherapy-plus-surgery arm of the study vs an 11-month median survival time in the surgery-alone arm. On the contrary, the intergroup 113 trial could not show any benefit at all either for the histologic or TNM subgroup or in overall median survival time (16 months) between the two arms of the study.27 As a result, much attention has been focused on chemoradiotherapy as a neodadjuvant treatment modality.
The potential activity of chemotherapy against occult micrometastases as well as the radiosensitizing properties of some chemotherapeutic agents form the basis for the chemoradiotherapy combination in potentially resectable or locally advanced carcinoma. In potentially resectable carcinomas, it seems that neither the possibility of R0 resection nor survival rates are significantly influenced by these regimens compared to surgery alone.28 29 30 In locally advanced disease, however, the potential benefit of the regimens becomes more evident, with a substantial number of patients having the stage of their disease lowered and becoming eligible for complete resection.31 32 33 34 In about 15 to 20% of these patients, a complete tumor sterilization has been found during a pathologic examination after surgery.
There is, however, no indication today that these neoadjuvant regimens are influencing the overall cure rates. Probably, increased cure rates are to be expected in the subset of patients showing a complete remission, but this results awaits further confirmation. Indeed, several studies report 3-year survival rates as high as 100% in this particular group.
Unfortunately, until now no indicators have been available to predict which subset of patients is most likely to show a complete response. Other patients will show a resistance to the neoadjuvant regimens, losing their chances for any treatment form with a curative option due to tumor progression. The especially high incidence of local/regional recurrence due to remaining viable tumor, which is often difficult to detect at the time of restaging of the disease, contraindicates chemoradiotherapy without subsequent operation.35 36 37 38 39 From the data available in literature, the need for better systemic agents is evident.
Recently, two agents with activity in esophageal cancer have been identified: paclitaxel and campothecan irinothecan. These agents seem to have more impact in controlling distant metastases than the classic cisplatin-based regimens.40
Another major focus of research is on the development of molecular markers to allow better selection of patients for chemotherapy regimens.41 42 As the development of these markers progresses, surgery remains the standard of care, and the results of newer treatment modalities should be compared to the surgical outcomes obtained in centers with proven clinical experience and scientific interest.43
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Footnotes |
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References |
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m, R, Lindgren, A, et al (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal carcinoma. N Engl J Med 340,825-831This article has been cited by other articles:
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  X. Wu, J. Gu, T.-T. Wu, S. G. Swisher, Z. Liao, A. M. Correa, J. Liu, C. J. Etzel, C. I. Amos, M. Huang, et al. Genetic Variations in Radiation and Chemotherapy Drug Action Pathways Predict Clinical Outcomes in Esophageal Cancer J. Clin. Oncol., August 10, 2006; 24(23): 3789 - 3798. [Abstract] [Full Text] [PDF]
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 K S Nair, R Naidoo, and R Chetty Expression of cell adhesion molecules in oesophageal carcinoma and its prognostic value J. Clin. Pathol., April 1, 2005; 58(4): 343 - 351. [Abstract] [Full Text] [PDF]
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 S. Mattioli, F. D'Ovidio, P. Tazzari, V. Pilotti, N. Daddi, G. Bandini, M. Piccioli, and S. Pileri Iliac crest biopsy versus rib segment resection for the detection of bone marrow isolated tumor cells from lung and esophageal cancer Eur. J. Cardiothorac. Surg., May 1, 2001; 19(5): 576 - 579. [Abstract] [Full Text] [PDF]
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