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Management of Esophageal Cancer

Management of Esophageal Cancer

ABSTRACT: The standard approaches of surgery or radiotherapy cure only a minority of patients with esophageal cancer. Because of these poor results and the frequent systemic pattern of recurrences, combined-modality therapy employing chemotherapy has been extensively studied. Preoperative chemotherapy, both alone and given concurrently with radiation, has not shown a significant impact on survival and remains investigational. Concurrent chemoradiation as definitive therapy is an alternative to surgery for localized disease. Paclitaxel and vinorelbine have significant activity as single agents in metastatic disease. Paclitaxel is currently under investigation in combination therapy for metastatic disease, as a radiosensitizer for locally advanced disease, and as preoperative therapy. For palliation of locally advanced esophageal cancer, a variety of endoscopic techniques are available to relieve dysphagia. Laboratory studies have identified growth factor pathways and tumor-suppressor genes as potential new pharmacologic targets. [ONCOLOGY 10(9):1385-1402, 1996]

Introduction

In 1995, 12,100 new cases of esophageal cancer were diagnosed
in the United States, and the vast majority, 10,900 patients,
will die of the disease.[1] Esophageal cancer represents 2% of
American cancer deaths and 9% of deaths due to gastrointestinal
cancer.[1] In Western countries, there is a clear association
between the development of squamous cell carcinoma of the esophagus
and the abuse of tobacco and alcohol.[2] Although esophageal squamous
cell cancer remains relatively uncommon in the United States,
it is a leading worldwide cause of cancer, with a particularly
high incidence observed in northern China, the Caspian Littoral,
and the Transkei province of South Africa.

Adenocarcinoma of the esophagus, which in the past represented
only a small proportion of cases of esophageal cancer, is rapidly
overtaking squamous cell carcinoma as the predominant disease
histology in the United States and currently represents half of
newly diagnosed cases. Indeed, esophageal adenocarcinoma poses
a potentially daunting health care problem, with cases increasing
at an annual rate exceeding that of any other malignancy, including
malignant melanoma.[3] Although Barrett's esophagus is one established
premalignant precursor of esophageal adenocarcinoma, the factors
responsible for the rapid rise in the incidence of adenocarcinoma
have yet to be determined. Recent epidemiologic studies have implicated
obesity[4] and tobacco abuse[5] as potential risk factors for
the development of adenocarcinoma of the esophagus. The epidemiologic
factors responsible for the geographic variability in the incidence
of esophageal squamous cell cancer, including potential dietary
and environmental carcinogens, also remain indeterminate.

Surgical Management

The prognosis for patients with esophageal cancer treated with
the standard approaches of surgery or radiation therapy is poor.
The poor prognosis for patients with locally advanced esophageal
carcinoma is compounded by poor patient tolerance of therapy,
given the comorbid cardiac, hepatic, and pulmonary diseases that
accompany long-standing alcohol and tobacco abuse. The largest
retrospective series of patients treated with either surgery alone
or radiotherapy alone, reviewed by Earlam and Cunha-Melo, reported
equally poor 5-year survival rates of 4% for surgery alone and
6% for radiotherapy alone.[6,7] In this early surgical review,
the operative mortality for patients treated surgically was a
sobering 29%. This significant operative mortality has fueled
an ongoing debate regarding the relative efficacy of surgery and
radiation therapy for treating local disease, although more recent
surgical series from single institutions have reported an operative
mortality of 5% to 15% for esophagectomy, with Muller et al citing
an overall rate of 12.5% in a review of the surgical literature.[8]

Optimal Surgical Approach

The optimal surgical approach in the local management of esophageal
cancer has been vigorously debated. Of all esophageal surgical
procedures, a laparotomy is performed first, to mobilize the stomach
or colon to reconstitute the upper gastrointestinal tract. One
standard approach, the Ivor Lewis esophagectomy, employs a separate
right thoracotomy for resection of the esophageal tumor, dissection
of regional lymph nodes, and intrathoracic gastroesophageal reanastomosis.

The use of thoracotomy in surgery for esophageal cancer has been
advocated because it allows direct visualization of the mediastinal
contents. Another approach, transhiatal esophagectomy, avoids
thoracotomy and employs an abdominal approach to resect the esophageal
tumor and to dissect mediastinal lymph nodes; it achieves gastroesophageal
reanastomosis via a cervical incision. Proponents of transhiatal
esophagectomy argue that this approach reduces operative morbidity
and mortality. Surgical series, however, have indicated comparable
operative morbidity and mortality whether or not a thoracotomy
is performed, and critics of the transhiatal approach argue that
an adequate mediastinal dissection cannot be performed without
a thoracotomy, particularly for proximal or mid-thoracic esophageal
lesions.[9]

At the other end of the spectrum, even more radical surgical approaches
have been advocated, involving either en bloc resection of the
mediastinal contents[10] or a three-field lymph node dissection
involving resection of the cervical and abdominal lymph nodes
in addition to the traditional mediastinal lymph node dissection.[11]
Although proponents of more radical surgical approaches contend
that greater local control may lead to an improvement in survival,
this is achieved at the potential cost of higher surgical morbidity
and mortality.[12] The optimal surgical management of a locally
advanced esophageal lesion remains to be established. However,
regardless of the approach taken, ultimately, the majority of
patients treated with surgery are destined to die of recurrent
disease.

Causes of Treatment Failure

The failure of standard surgical or radiation-based therapy, even
in patients with disease clinically limited to the locoregional
area prior to treatment, is due to both locoregional failure and
early systemic dissemination of disease. Autopsy series verify
the frequent systemic nature of squamous cell carcinoma, even
at or shortly after the initial presentation.[13] Despite the
brief duration of illness for these patients, the majority were
found to have evidence of distant metastatic disease, often in
association with locally recurrent or persistent disease, at autopsy.
Adenocarcinoma of the distal esophagus or gastroesophageal junction
appears to have a natural history of disease similar to that of
squamous cell esophageal carcinoma, with equally poor survival
after surgical therapy due to a combination of local and systemic
disease recurrence.[14] The clear need to address the early systemic
spread of esophageal carcinoma with systemic treatment has led
to the incorporation of chemotherapy into combined-modality therapy
employing surgery and radiation therapy.

Neoadjuvant Chemotherapy

Clinical trials of systemic chemotherapy administered preoperatively
for esophageal cancer, also termed neoadjuvant or primary chemotherapy,
have been undertaken largely because of the poor results achieved
with conventional surgery or radiation therapy and the frequent
systemic pattern of disease recurrence. Such combined-modality
trials employing chemotherapy have taken one of three different
approaches: chemotherapy followed by a planned surgical procedure,
chemotherapy given concurrently with radiation therapy followed
by surgery, and chemotherapy and radiation therapy without subsequent
surgical intervention.

The rationale, both preclinical and clinical, for neoadjuvant
chemotherapy has been reviewed.[15] For patients with esophageal
cancer, the approach of preoperative chemotherapy offers several
potential clinical benefits, including enhancing resectability
by downstaging the primary tumor. Another potential advantage
is the assessment of the response to preoperative chemotherapy
directly in the primary tumor, making the end point of adjuvant
therapy more precise by identifying patients who respond to chemotherapy
and who might therefore benefit from further chemotherapy postoperatively.
Administering chemotherapy early in the course of disease also
has the advantage of treating subclinical but established micrometastatic
disease, when chemotherapy is likely to have its greatest impact,
given the limited effectiveness of systemic therapy for clinically
apparent metastatic disease. A disadvantage of preoperative chemotherapy
is the delay in achieving local control of disease.

The rationale for concomitant chemotherapy and radiation has also
been reviewed.[16] Concurrent chemoradiotherapy potentially allows
for the achievement of enhanced local tumor control, as well as
the simultaneous treatment of systemic micrometastases.

Although a neoadjuvant, combined-modality approach to esophageal
cancer should be reserved for patients at high risk of death due
to disease recurrence, most US patients present with high-risk
transmural (T3) or lymph node-positive (N1) disease and are therefore
candidates for neoadjuvant therapy. Use of the recently available
technique of endoscopic ultrasonography may provide greater ability
to stage locoregional disease in the esophagus, particularly the
degree of local tumor extension by T-stage and the detection of
regional node involvement.[17] Evaluation by endoscopic ultrasonography
is increasingly being used in clinical trials for staging and
evaluating response, but assessing response by endoscopic ultrasonography
should still be considered investigational.

Preoperative Chemotherapy Followed by Surgery

The use of preoperative chemotherapy for locally advanced esophageal
carcinoma has been the subject of numerous clinical trials. Most
studies have been single-arm, phase II trials evaluating preoperative
chemotherapy in one to up to six cycles followed by a definitive
surgical procedure. In early trials, patients with T3 or node-positive
disease went on to undergo postoperative radiotherapy. However,
in more recent trials, radiotherapy has not been added preoperatively
or postoperatively, because randomized clinical trials have failed
to show a survival benefit resulting from the addition of radiotherapy
to surgery (discussed below). Also, in these more recent trials,
chemotherapy has been performed both preoperatively and postoperatively.
The results of selected phase II trials of preoperative chemotherapy
for esophageal cancer are summarized in Table 1.

Phase II Trials--Virtually all preoperative chemotherapy
trials for esophageal cancer have employed cisplatin (Platinol)-based
combination chemotherapy. Although earlier trials treated squamous
cell carcinoma, with the increased incidence of adenocarcinoma,
both histologies have been treated on preoperative protocols.
Early trials combined bleomycin (Blenoxane) with cisplatin and
other agents, but the pulmonary toxicity associated with bleomycin
and the marginal antitumor activity observed with the combination
of bleomycin and cisplatin in preoperative therapy prompted trials
of other cisplatin-based combinations. In these trials, major
antitumor responses were seen in up to 50% to 60% of patients,
with pathologic complete responses in up to 11% of patients. Most
patients were operable after preoperative chemotherapy, with an
operative mortality ranging from 0% to 24%. Median survival ranged
from only 8 to 28 months.

Kelsen et al[18] reported long-term follow-up of a single trial
of 34 patients with squamous cell carcinoma treated preoperatively
with the combination of cisplatin, vindesine, and bleomycin. In
this study, survival was encouraging, with 18% of patients alive
and free of disease at 5 years and no recurrences occurring after
3.5 years, representing a doubling of survival compared with historic
surgical controls.[18]

The combination of cisplatin and 5-fluorouracil (5-FU), given
by continuous infusion for 4 to 5 days, has also been extensively
studied in preoperative chemotherapy trials. Major responses have
been observed in 40% to 60% of patients, with pathologic complete
responses in up to 11% of patients; the majority of patients had
resectable disease after preoperative treatment, with an acceptable
operative mortality. Subsequent trials for both esophageal squamous
cell cancer and adenocarcinoma combining cisplatin with etoposide

(VePesid) and 5-FU, leucovorin and 5-FU, or doxorubicin and etoposide
have noted similar response proportions, rates of resectability,
operative mortality, and survival comparable to those of 5-FU
and cisplatin alone.[19-21] Toxicity in these trials, mainly mucositis,
myelosuppression, and nephrotoxicity, has been substantial but
tolerable.

Overall, preoperative treatment with cisplatin-based combination
chemotherapy achieves a major response in 50% of patients, with
occasional pathologic complete responses. The use of preoperative
chemotherapy appears to be safe, with no demonstrable adverse
effect on surgical outcome. However, the overall survival of patients
treated with preoperative chemotherapy has been disappointing,
with a median survival ranging from 10 to 28 months in larger
series, although a trend toward improved survival has been suggested
in these trials.

The duration of chemotherapy delivered in preoperative chemotherapy
trials has also undergone evolution. Although earlier trials administered
only one to two cycles of chemotherapy preoperatively without
subsequent postoperative therapy, more recent trials have given
up to three or more cycles of preoperative therapy and two or
three cycles of postoperative chemotherapy. The treatment outcome
of earlier and more recent trials may not be directly comparable,
particularly with regard to the impact of additional cycles of
systemic therapy on systemic recurrence.

Phase III Trials--The role of preoperative chemotherapy
in the treatment of locoregional esophageal carcinoma can be clearly
defined only in the context of random-assignment trials with a
surgery-only control arm. Four small, randomized trials comparing
surgery alone with preoperative chemotherapy followed by surgery
have been published, and a fifth trial compared preoperative chemotherapy
with preoperative radiotherapy (Table 1). Roth et al[22] randomized
patients to receive preoperative chemotherapy with cisplatin,
bleomycin, and vindesine vs surgery alone. Reporting in abstract
form only, Schlag[23] randomly assigned patients to undergo surgery
alone or to re- ceive three cycles of preoperative chemotherapy
with 5-FU and cisplatin. Nygaard et al[24] randomized patients
to receive surgery alone, preoperative chemotherapy with cisplatin
and bleomycin, preoperative radiotherapy, or preoperative treatment
with sequential chemotherapy and radiotherapy. LePrise et al compared
surgery alone with sequential preoperative chemotherapy as well
as cisplatin and 5-FU and radiotherapy to a dose of 6,000 cGy,
given in two split courses.[25] None of these small, randomized
trials demonstrated a survival advantage for preoperative chemotherapy.

In the study by Roth et al,[22] the subgroup of patients who responded
to chemotherapy showed a trend toward improved survival, compared
with surgical controls, that nearly reached statistical significance.
A prognostic factor analysis identified percentage of weight loss
prior to diagnosis and objective response to chemotherapy as predictive
of long-term survival. No survival benefit was conveyed by preoperative
chemotherapy in the study by Nygaard et al[24] and the patients
with the poorest survival at 3 years (3%) received preoperative
chemotherapy.

Kelsen et al[18] randomly assigned 96 patients to receive treatment
with either preoperative high-dose radiotherapy, 5,500 cGy delivered
over 5.5 to 6.0 weeks by a multifield technique, or preoperative
chemotherapy with cisplatin, vindesine, and bleomycin. In this
trial, a survival comparison between the two treatment groups
could not be made because the trial design permitted a postoperative
crossover to the other treatment modality, and most patients received
both chemotherapy and radiation therapy. The actuarial survival
rate observed for all patients was 20% at 5 years, which was superior
to that of historic controls, with the subgroup of responders
to either chemotherapy or radiotherapy showing a trend toward
improved survival.

At present, for patients treated surgically, surgery alone remains
the standard of care, and the use of preoperative chemotherapy
outside an investigational setting cannot be recommended. A conclusive
evaluation of preoperative chemotherapy using the best currently
available combination chemotherapy regimen awaits the completion
of ongoing, random-assignment clinical trials. A national intergroup
trial (Intergroup Trial 113) randomizing patients to receive three
preoperative and two postoperative chemotherapy cycles with cisplatin
and 5-FU vs surgery alone has now been completed, and data analysis
of this trial is under way.

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