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Carcinoma of the Esophagus Part 2: Adjuvant Therapy

Carcinoma of the Esophagus Part 2: Adjuvant Therapy

ABSTRACT: The two general treatment approaches for esophagel cancer are primary treatment (surgical or nonsurgical) or adjuvant treatment (preoperative or postoperative). Due to differences in the patient populations selected for surgical or nonsurgical therapies, which may bias the results against nonsurgical therapy, it is difficult to determine the best treatment approach for this disease. The standard of care is either surgery alone or primary combined-modality therapy. Based on a nonrandomized comparison of the data from recent intergroup trials, the results of these two approaches are similar. For patients treated without surgery, the intergroup INT 0123 trial will determine whether higher doses of radiation are of benefit. No clear survival advantage has been seen with preoperative or postoperative adjuvant radiation therapy alone or chemotherapy alone. The randomized trials comparing preoperative combined-modality therapy vs surgery alone reveal encouraging results for the combination approach but need further confirmation. For patients treated with combined-modality therapy, the ideal regimen remains to be determined. Part 1 of this two-part review, which appeared in last month’s issue, centered on primary therapy for esophageal carcinoma. This part explores the rationale for and results of adjuvant therapy. [ONCOLOGY 13(10):1415-1427,1999]

Introduction

Two general approaches are used to treat
esophageal cancer: primary treatment (surgical or nonsurgical) or
adjuvant treatment (preoperative or postoperative). Primary
treatments include surgery alone, radiation therapy alone, and
radiation therapy plus chemotherapy (combined- modality therapy).
Adjuvant therapies include preoperative or postoperative radiation
therapy, preoperative chemotherapy, and preoperative
combined-modality therapy. The first part of this two-part review,
which appeared in last month’s issue, focused on primary therapy
for esophageal cancer. This second part examines the rationale for
and results of adjuvant therapy.

Adjuvant Radiation Therapy Without Chemotherapy

The rationale for using adjuvant radiation therapy is based on the
patterns of failure following potentially curative surgery in
patients with clinically resectable esophageal cancer. Unfortunately,
few surgical series have reported these data.

The rates of local failure in the surgical control arms from the
preoperative radiation therapy randomized trials of Mei et al[50] and
Gignoux et al[51] were 12% and 67%, respectively. Local failure rates
in the surgical control arm from the postoperative radiation therapy
randomized trial of Teniere et al[52] were 35% for patients with
negative locoregional lymph nodes and 38% for patients with positive nodes.

The surgical control arm of the intergroup INT 0113 trial provides a
modern, more relevant baseline for the results of surgery alone. As
discussed in part 1 of this article, the rate of local failure was
31% in patients with an R0 resection, and the total rate of local
failure (including the additional 30% of patients with persistent
disease) was 61%.

In summary, although the majority of patients with esophageal cancer
die of distant metastasis, the incidence of local failure following
surgery alone is high enough to examine the use of adjuvant radiation therapy.

Preoperative Radiation Therapy

Six randomized trials have assessed the value of preoperative
radiation therapy in patients with clinically resectable
disease.[16,50,51,53-55] The studies of Launois et al,[53] Gignoux et
al,[51] and Nygaard et al[16] were limited to patients with squamous
cell carcinoma. Arnott et al included patients with both squamous
cell carcinoma and adenocarcinoma.[54] The series of Huang et al[55]
and Mei et al[50] did not mention the histology.

Overall, preoperative radiation therapy did not increase the
resectability rate. Only two series reported local failure rates.
Although Mei and colleagues[50] found no difference in local failure,
Gignoux et al[51] did report a significant decrease in local failure
(46% vs 67%) in patients who received preoperative radiation therapy
compared with those treated with surgery alone.

Two series showed an improvement in survival. The study by Nygaard
and associates was a four-arm trial in which patients were randomized
to chemotherapy (cisplatin (Platinol)/bleomycin (Blenoxane) × 2
cycles), radiation therapy, combined-modality therapy, or surgery
alone.[16] Patients who received preoperative radiation therapy (with
or without chemotherapy) demonstrated a significant improvement in
overall 3-year survival rate compared with those who did not receive
radiation (18% vs 5%; P = .009). Of the 48 patients given
preoperative radiation therapy without chemotherapy, 20% were alive
at 3 years; however, this benefit did not reach statistical
significance. Therefore, this was not a pure radiation study, and the
benefit may have been due, in part, to the chemotherapy.

Huang et al reported a similar improvement in survival in patients
who received preoperative radiation therapy vs those who did not
undergo such therapy (46% vs 25%); however, a statistical analysis
was not performed.[55] A recent meta-analysis from the Oesphageal
Cancer Collaborative Group also showed no clear evidence of a
survival advantage with preoperative radiation.[56]

There have been many criticisms of the randomized trials of
preoperative radiation therapy. For example, conventional doses of
radiation therapy were not used. Also, none of these trials allowed
an adequate interval between the completion of radiation therapy and
surgery. In general, a 4- to 6-week interval is recommended. The use
of these unconventional techniques precludes a meaningful analysis of
radiation-related morbidity from being performed.

In summary, since only two of the six series of preoperative
radiation therapy have reported local failure rates, it is difficult
to draw firm conclusions regarding the influence of this therapy on
local control. Two series have reported an improvement in survival;
in one of these studies, half of the patients received chemotherapy,
and the other series did not perform a statistical analysis. Four of
the six series found no advantage of preoperative radiation with
respect to overall survival. Nonrandomized trials from Yadava et
al[57] and Sugimachi and associates[58] also report no survival benefit.

Thus, based on the available randomized, albeit limited, trials,
preoperative radiation therapy does not appear to significantly
decrease local failure or improve survival.

Postoperative Radiation Therapy

Nonrandomized trials have reported encouraging results with
postoperative radiation therapy. For example, in a study by Kasai et
al, patients with lymph node–negative disease had a 5-year
survival rate of 88%.[59] Yamamoto et al reported a 2-year local
control rate of 94% in node-positive patients.[60]

Only two randomized trials have been published that were limited to
patients treated in the adjuvant setting. Teniere and colleagues[52]
reported 221 patients with squamous cell esophageal carcinoma
randomized to surgery alone or surgery plus postoperative radiation
therapy (4,500 to 5,500 cGy at 180 cGy/fraction). With a minimum
follow-up of 3 years, postoperative radiation had no significant
impact on survival.

The second randomized trial, by Fok et al,[61] included patients with
squamous cell carcinoma and adenocarcinoma. It should be emphasized
that patients with both curative and palliative resections were
included in this series. Although the total dose of radiation was
conventional, the dose per fraction (350 cGy/fraction) was not. The
addition of postoperative radiation therapy did not significantly
decrease local or distant failure or improve median survival.

Postoperative radiation therapy is sometimes recommended for patients
with positive locoregional lymph nodes. Although the data from
Teniere et al[52] support the use of postoperative radiation therapy
for decreasing local failure, the benefit was limited to patients
with negative lymph nodes. In this subset of patients, postoperative
radiation therapy decreased the local failure rate from 35% to 10%.
There was no significant effect of postoperative radiation in
patients with positive nodes.

In summary, although the limited available data suggest that adjuvant
postoperative radiation therapy may decrease local failure in
node-negative patients, it has no impact on overall survival. The
only established role for postoperative radiation therapy is in
patients with positive margins. In patients selected for treatment
with postoperative radiation, based on the positive survival results
from combined-modality therapy trials, such as Radiation Therapy
Oncology Group (RTOG) 85-01, it is reasonable to combine systemic
chemotherapy with radiation.[5,6]

Preoperative Chemotherapy

Given the advantage in local control and survival when systemic
chemotherapy is added to radiation therapy, two randomized trials
were designed to examine the role of preoperative chemotherapy
compared with surgery alone in patients with clinically resectable
disease. In the Dutch trial, patients who received two cycles of
preoperative cisplatin and etoposide experienced a significant
increase in median survival over those treated with surgery alone (19
vs 11 months; P = .002).[46]

These results contrasted with those of the INT 0113 trial (RTOG
89-11), which randomized patients who underwent an R0 resection to
receive two cycles of preoperative fluorouracil (5-FU)/cisplatin or
surgery alone. This trial found no differences between the two groups
with respect to median survival (15 vs 16 months), overall survival
at 2 years (35% vs 37%) or 5 years (20% vs 20%), incidence of
postoperative death (7% vs 6%), or local failure (32% vs 31%).[47]

In summary, preoperative chemotherapy as delivered in the above
randomized trials, shows no survival benefit. At present, therefore,
preoperative chemotherapy remains investigational.

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