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Carcinoma of the Esophagus Part 1: Primary Therapy

Carcinoma of the Esophagus Part 1: Primary Therapy

ABSTRACT: The two general treatment approaches for esophagel cancer include 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 appropach but need further confirmation. For patients treated with combined-modality therapy, the ideal regimen remains to be determined. The first part of this two-part article focuses on the rationale for and results of primary therapy for esophageal carcinoma. Part 2, which will appear in next month’s issue, covers adjunctive therapy. [ONCOLOGY 13(9):1225-1236,1999]


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
will examine the rationale for and results of primary therapy for
esophageal cancer. Part 2, which will appear in next month’s
issue, deals with adjuvant therapy.

The epidemiology of esophageal cancer has changed during the past
decade. The most notable change has been an increase in the incidence
of adenocarcinoma, most commonly occurring at the gastroesophageal
junction.[1] Therefore, histology should be considered when comparing
the results of various treatment approaches. Adenocarcinoma is seen
more frequently in middle-aged males with a history of
gastroesophageal reflux, whereas squamous cell cancers occur more
commonly in the proximal and middle esophagus of older patients who
have a history of smoking and alcohol abuse.

At present, the available data are conflicting with respect to
histology. Some series report different results according to
histology, whereas other series report no such difference.
Fortunately, the National Cancer Institute–sponsored,
intergroup, randomized trials are now stratified by histology. Until
these stratified results are available, the impact of histology
cannot be adequately assessed, and it is reasonable to treat both
histologies in a similar fashion.

Selection Bias in Trials of Primary Therapy

Surgical and nonsurgical approaches have had similar results when
used as primary therapy for esophagel cancer. However, it must be
emphasized that the patient population selected for treatment with
each modality is usually different, resulting in a selection bias
against nonsurgical therapy.

First, patients with poor prognostic features, including those who
have medical contraindications to surgery and those with primary
unresectable or metastatic disease, are more commonly selected for
nonsurgical therapy. Second, surgical series report results based on
pathologically staged patients, whereas nonsurgical series report
results based on clinically staged patients. Pathologic staging has
the advantage of excluding some patients with metastatic disease.
Third, since some patients who receive nonsurgical therapy are
treated palliatively rather than for cure, the intensity of
chemotherapy and the doses and techniques of radiation therapy can be suboptimal.

Nonsurgical Primary Therapy

Radiation Therapy Alone

Many series have reported the results of external-beam radiation
therapy alone. Most of these series include patients with unfavorable
features, such as clinical T4 disease and positive lymph nodes. For
example, in the series by De-Ren, 184 of the 678 patients had stage
IV disease.[2] Overall, the 5-year survival rate for patients treated
with radiation therapy alone is 0% to 10%.[2-4]

The use of radiation therapy as a potentially curative modality
requires doses of at least 5,000 cGy administered at 180 to 200 cGy
per fraction. Furthermore, given the large size of many unresectable
esophageal cancers, doses of ³ 6,000
cGy are probably required. However, even in the radiation
therapy-alone arm of the Radiation Therapy Oncology Group (RTOG)
trial 85-01, in which patients received 6,400 cGy of radiation
delivered with modern techniques, all patients were dead from
esophageal cancer by 3 years.[5,6]

There is one report of radiation therapy alone for patients with
clinically early-stage disease. The trial by Sykes et al was limited
to 101 patients (90% of whom had squamous cell carcinoma) with tumors
< 5 cm who received 4,500 to 5,250 cGy in 15 to 16 fractions. The
5-year survival rate was 20%.[7]

In summary, radiation therapy alone should be reserved for palliation
or for patients who are medically unable to receive chemotherapy. As
will be discussed below, combined-modality therapy has had more
favorable results and represents the standard of care.

Combined-Modality Therapy

Conventional Approaches—Numerous single-arm,
nonrandomized trials have evaluated combined-modality therapy alone
in patients with esophageal cancer.[8-12] Selected series are
summarized in Table 1.

The series reported by Coia and associates is the only one in which
patients with early-stage disease (clinical stages I and II) were
analyzed separately from those with more advanced disease.[9] These
patients were treated with flourouracil (5-FU) and mitomycin
(Mutamycin) administered concurrently with 6,000 cGy of radiation.
Combining clinical stages I and II, the local failure rate was 25%,
the 5-year actuarial local relapse-free survival rate was 70%, and
the 5-year actuarial survival rate was 30%.

The Southwest Oncology Group (SWOG) 9060 trial reported by Poplin et
al included 32 patients who received 5-FU/cisplatin (Platinol)
concurrently with 5,000 cGy of radiation, followed by two cycles of
5-FU/cisplatin.[13] Since the choice of further management
(observation, radiation, chemotherapy, and/or surgery) was based on
tumor response, this trial cannot be considered a pure
combined-modality therapy series. Although the median survival was 20
months, the authors concluded that the complexity and toxicity of
this combined-modality program precluded its further use.

Six randomized trials have compared radiation therapy alone with
combined-modality therapy (Table 2).[5,14-19]
Of the six trials, five used suboptimal doses of radiation and three
employed inadequate doses of systemic chemotherapy.

For example, in the series by Araujo and colleagues,[14] patients
received only one cycle of 5-FU, mitomycin, and bleomycin
(Blenoxane). The European Organization for Research and Treatment of
Cancer (EORTC) trial used subcutaneous methotrexate.[15] In the
Scandinavian trial reported by Nygaard and associates, patients
received low doses of chemotherapy (cisplatin [20 mg/m²] and
bleomycin [10 mg/m²] for a maximum of two cycles).[16]

In the Eastern Cooperative Oncology Group (ECOG) EST-1282 trial,
patients who received combined-modality therapy had significantly
increased median survival, compared with those treated with radiation
alone (15 vs 9 months; P = .04), but showed no improvement in 5-year
survival (9% vs 7%). However, this was not a pure nonsurgical trial
since approximately 50% of patients in each arm underwent surgery
after receiving 4,000 cGy of radiation. Furthermore, this decision
depended on the individual investigator’s preference. Operative
mortality was 17%.

Lastly, the Pretoria trial reported by Slabber and colleagues, which
was limited to a total of 70 patients with T3 squamous cell cancers,
used a low-dose (4,000-cGy) split-course radiation schedule.[18]

The only trial designed to deliver adequate doses of systemic
chemotherapy with concurrent radiation therapy was the RTOG 85-01
trial reported by Herskovic et al (Figure
1
).[5,17] This intergroup trial primarily included patients with
squamous cell carcinoma. They received four cycles of 5-FU (1,000
mg/m²/24 h × 4 days) and cisplatin (75 mg/m² on day
1). Radiation therapy (5,000 cGy at 200-cGy/d) was given concurrently
with day 1 of chemotherapy. Curiously, cycles 3 and 4 of chemotherapy
were delivered every 3 weeks (weeks 8 and 11) rather than every 4
weeks (weeks 9 and 13). This intensification may explain, in part,
why only 50% of the patients finished all four cycles of
chemotherapy. The control group received radiation therapy alone,
albeit at a higher dose (6,400 cGy) than patients in the
combined-modality therapy arm.

Patients who received combined-modality therapy demonstrated a
significant improvement in median survival (14 vs 9 months) and
5-year survival (27% vs 0%; P < .0001), compared with radiation
alone.[17] The actuarial incidence of local failure as the first site
of failure was also significantly decreased in the combined-modality
group (45% vs 68%; P = .0123).

The protocol was closed early due to these positive results.
Following this early closure, an additional 69 patients were treated
with the same combined-modality therapy regimen, and similar results
were seen (3-year survival rate of 30%).

Toxicity—Although combined-modality therapy achieves
better results than radiation alone, it is associated with a higher
incidence of toxicity. In the RTOG 85-01 trial, patients who received
combined-modality therapy had more acute grade 3 toxicity (44% vs
25%) and acute grade 4 toxicity (20% vs 3%) than patients given
radiation therapy alone. Including the one treatment-related death
(2%), the total incidence of acute grade 3+ toxicity in this trial
was 66%. Although the acute grade 3+ radiation-related toxicity was
higher with combined-modality therapy than with radiation therapy
alone (35% vs 12%), there was little difference in late toxicity (29%
vs 23%).

Based on the positive results of the RTOG 85-01 trial, the
conventional nonsurgical treatment for esophageal carcinoma is
combined-modality therapy. These results notwithstanding, the local
failure rate in the RTOG 85-01 combined-modality therapy arm was 45%.
Thus, there is room for improvement, and new approaches, such as
intensification of combined-modality therapy and escalation of the
radiation dose, have been developed in an attempt to improve upon
these results.

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