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Adjuvant/Neoadjuvant Chemoradiation for Gastric and Pancreatic Cancer

Adjuvant/Neoadjuvant Chemoradiation for Gastric and Pancreatic Cancer

ABSTRACT: Both gastric and pancreatic cancer remain leading causes of cancer death in the United States and worldwide. While surgical resection continues to be required for long-term cure of both these neoplasms, 5-year survival rates remain poor following surgery alone. For both gastric and pancreatic cancers, studies examining patterns of recurrence following apparently curative resection repeatedly demonstrate high rates of locoregional relapse. In this setting, the addition of chemoradiation delivered either before or following surgery represents a logical strategy to improve local tumor control and possibly improve survival. Data suggest that 5-fluorouracil–based chemoradiation, when given at sufficient doses, can effectively palliate patients with unresectable gastric cancer. Whether this approach improves response and survival in patients with resectable gastric cancer remains investigational. Results of ongoing and recently completed trials will provide further information on the utility of 5-fluorouracil–based regimens, as well as the use of other radiation sensitizers, in the adjuvant setting. In patients with resectable pancreatic cancer, the primary goal should be to perform a margin-negative pancreaticoduodenectomy. The use of neoadjuvant chemoradiation may increase the likelihood of achieving this goal, and this approach is being investigated. [ONCOLOGY 13(Suppl 5):121-130, 1999]


Introduction

Adenocarcinomas of the stomach and pancreas
continue to represent a leading cause of cancer death. In addition to
early systemic spread, inadequate local tumor control following
surgery contributes to poor patient survival. The addition of
chemoradiation either before or after surgery therefore represents a
logical strategy to improve outcome in patients with gastric or
pancreatic cancer. In this review, we discuss the contribution of
chemoradiation to local tumor control for these patients, with an
emphasis on novel neoadjuvant approaches.

Gastric Cancer

Carcinoma of the stomach will be diagnosed in an estimated 21,900
patients in the United States in 1999.[1] The signs and symptoms are
generally nonspecific, and thus diagnosis is often made at an
advanced stage of disease. Cure rates after surgery alone remain
uniformly poor unless the disease is confined to the superficial
layers of the gastric wall. In Western series, fewer than half of
patients present with localized disease; when carcinoma extends
beyond the gastric wall, the 5-year survival rate is only 10% to
20%.[2] Even after a potentially curative resection, disease recurs
in 70% of patients.

While the high incidence of peritoneal and liver metastases is well
recognized, pattern-of-failure studies have repeatedly demonstrated
locoregional recurrence to be a frequent site of relapse. In a
reoperative series, Gunderson et al identified locoregional
recurrence as the only site of failure in 54% of patients and as a
component of failure in 88%.[3] Landry et al examined sites of
relapse in 130 patients who had undergone gastrectomy with curative
intent.[4] Using clinical criteria, they noted locoregional failure
as a component of all recurrences in 38% of patients. Local
recurrence was the sole site of relapse in 24% of those patients who
developed recurrent or progressive disease. Similar figures were
reported previously by McNeer et al[5] in an autopsy series (Table
1
).[3-5]

From these collected series, it is evident that locoregional failure
is common following apparently curative surgery for gastric cancer
and that sites of locoregional failure include both the gastric
remnant, the bed of resection, and regional nodal basins. Ongoing
prospective randomized trials of D1 vs D2 lymphadenectomy from
Britain and the Netherlands have yet to report data on patterns of
relapse. However, in the Mayo Clinic series, more radical surgery,
such as D2 lymphadenectomy and omentectomy, failed to affect patterns
of recurrence or survival. Thus, it is likely that locoregional
therapy may be required in addition to surgery to effectively control
these tumors.

Studies of Locally Advanced Unresectable Disease

While adding radiation to extirpative surgery has successfully
decreased locoregional recurrence when used to treat carcinoma of the
esophagus, rectum, and breast, its role in treating gastric
adenocarcinoma is not nearly as well defined. Single-institution
noncontrolled trials, often comprising heterogeneous patient groups,
have generated most of the available data regarding the utility of
radiation in treating gastric cancer. Most of the small number of
controlled trials that investigated this issue have been flawed by
poor randomization schemes or small patient numbers.

Not until the 1960s did investigators first examine the use of
radiation to treat gastric cancer. Takahashi compared patients who
received radiation, either alone or after palliative gastrectomy,
with historical controls who did not receive radiation.[6] Survival
for the irradiated group was 74% at 1 year and averaged 9 to 10
months longer than the control group.

To enhance local disease control and to combat the high incidence of
distant metastases in patients with locally advanced gastric cancer,
investigators soon sought to combine the use of radiation and
chemotherapy. The Mayo Clinic reported a randomized trial of 48
patients with locally advanced “unresectable” disease that
compared 35 to 40 Gy external-beam radiation given over 3 to 4 weeks
with or without 5-fluorouracil (5-FU) (15 mg/kg bolus, days 1 through
3, week 1).[7] Median survival for the combined-modality arm was 13
months compared with 5 months for the radiation arm (P < .01).

A Gastrointestinal Tumor Study Group (GITSG) trial examined
split-course radiation (50 Gy) given with or without 5-FU (500
mg/m²/day, days 1 through 3, weeks 1 and 6) followed by
maintenance 5-FU, methotrexate, and lomustine.[8] The combined-modality
arm again had a survival advantage. Four-year survival was 18%
compared with 6% for the radiation arm. A second GITSG trial failed
to demonstrate a survival advantage for the combined-modality arm.[9]
This study has been criticized, however, since 46% of the
combined-modality group failed to complete the prescribed course of radiation.

Adjuvant Radiation Trials

Most reports of adjuvant radiation as a single modality have used
intraoperative radiation alone or in combination with external-beam
radiation. Calvo et al used 15 Gy radiation intraoperatively in
combination with external-beam radiation 40 to 46 Gy to treat 48
patients postgastrectomy.[10] Most patients had locally advanced
disease. The investigators reported an overall survival of 33% at a
follow-up of 76 months. Five of 18 patients (28%) had local recurrence.

The Radiation Therapy Oncology Group reported a phase II study of
intraoperative radiation (12.5 to 16.5 Gy) plus 45 Gy external-beam
radiation postoperatively.[11] Twenty-seven patients received the
intraoperative radiation, 23 of whom also received external-beam
radiation. Eighty-three percent of patients had serosal involvement,
and 70% had lymph node metastases. Actuarial 2-year survival was 47%.
Disease recurred locally in 15% of patients.

Three phase III trials using intraoperative radiation and/or
external-beam radiation postoperatively have been reported. Abe and
Takahashi examined the use of a single intraoperative dose (28 to 35
Gy) after resection and found a survival advantage for patients with
disease stages II, III, and IV (gross residual disease without
metastases).[12] Unfortunately, patients were randomized without
regard to stratification criteria. Results from the other two
randomized trials that examined adjuvant radiation alone suggest it
may affect local failure rates but does not improve survival.

A three-arm randomized trial from Britain examined gastrectomy alone
vs gastrectomy followed by 5-FU, doxorubicin (Adriamycin), and
methotrexate vs gastrectomy and postoperative radiation (45 Gy in 25
fractions).[13] This trial failed to reveal a survival benefit for
any of the treatment arms. Nonetheless, a decreased rate of local
recurrence was noted in the radiation arm.

A small randomized trial from the National Cancer Institute examined
the value of external-beam radiation (45 Gy) vs intraoperative
radiation plus external-beam radiation (45 Gy) following
gastrectomy.[14] No survival advantage was noted for either group,
but the group that received radiation intraoperatively had a lower
local recurrence rate.

Adjuvant Chemoradiation for Resectable Disease

Based on the apparent superiority of 5-FU plus external-beam
radiation vs radiation alone in a randomized controlled trial
involving patients with unresectable gastric cancer, most
investigators have chosen to investigate combined-modality strategies
in patients with resectable disease as well. Despite this, much
existing data regarding the utility of adjuvant chemoradiation for
gastric cancer are derived from single-institution phase II trials (Table
2
).[15-18] The Massachusetts General Hospital (Boston, Mass)
reported a 4-year survival of 43% among 14 patients treated with
resection and adjuvant chemoradiation.[15] All patients had poorly
differentiated tumors and 80% had lymph node metastases. Similar
results were reported by Gez et al, who treated 25 patients who had
locally advanced disease with resection followed by 5-FU–based
chemoradiation and maintenance 5-FU.[16] Seven patients had residual
disease postresection, and 22 had lymph node metastases. Actuarial
median and overall survivals were 33 months and 40%, respectively.

A few phase III trials have compared surgery with surgery plus
adjuvant chemoradiation (Table 3).[19-21]
Unfortunately, each of these studies is fraught with methodologic
flaws. The European Organization for Research and Treatment of Cancer
performed a trial with four treatment arms: surgery plus
postoperative radiation (55.5 Gy), surgery plus radiation with short-term
5-FU (given during days 1 through 4 of radiation only), surgery plus
radiation with long-term 5-FU (given every 2 weeks for 18 months or
until disease progression), and surgery plus radiation with both
short-term and long-term 5-FU.[19] Analysis revealed a survival
advantage for the arm incorporating both short-term and long-term
5-FU. Prognostic factors were not properly stratified, however, and
correcting for the errors eliminated the statistical significance.

Dent et al performed a trial comparing gastrectomy alone with
gastrectomy plus 20 Gy external-beam radiation and 5-FU.[20] The
study revealed no significant difference between the treatment arms.
The study was underpowered, however, enrolling only 66 patients overall.

The Mayo Clinic reported a prospective randomized trial comparing
gastrectomy alone with gastrectomy and postoperative external-beam
radiation (37.5 Gy in 24 fractions) plus 5-FU (15 mg/kg bolus, days 1
through 3).[21] Unfortunately, the study was flawed by a
randomization scheme that assigned patients to a treatment arm before
their consent was obtained. As a result, 10 patients randomized to
chemoradiation ultimately refused the adjuvant therapy. Analyzed by
intent-to-treat, the results demonstrated a statistically significant
advantage in favor of the adjuvant therapy arm, with a 5-year
survival of 23% vs 4% for the patients treated with surgery alone.
When the analysis was conducted by actual treatment received,
however, the difference between the groups was no longer significant.
The authors argued that if patients were compared with regard to poor
prognostic factors, the 5-year survival figures favored the
combined-modality arm, 20% vs 4%. It is clear that the 10 patients
who refused adjuvant therapy had more favorable prognostic factors,
including fewer proximal lesions and lower histologic grade. In an
attempt to clarify the Mayo Clinic data, Intergroup 0116 has just
completed accrual of patients randomized to receive either
gastrectomy alone or gastrectomy followed by 5-FU–based
chemoradiation. Chemotherapy consists of bolus 5-FU with leucovorin
for four courses. External-beam radiation to 45 Gy was initiated
concomitantly with the second course of 5-FU. The results of this
study await further follow-up.

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