Role of Radiation Therapy in the Management of the Patient With Pancreatic Cancer

Role of Radiation Therapy in the Management of the Patient With Pancreatic Cancer

ABSTRACT: Most patients who have pancreatic cancer present with advanced disease that is not amenable to surgery. For patients whose disease is amenable to surgery and who are managed with surgical resection alone, local recurrence rates are high and long-term survival rates are low. The use of radiation therapy to treat pancreatic cancer has been studied in various clinical contexts. Preoperative radiation therapy for resectable or borderline unresectable disease may benefit some patients but is not used routinely. For patients with resected disease, data from the Gastrointestinal Tumor Study Group (GITSG) trials support the use of adjuvant chemoradiation. For patients with locally unresectable disease, the use of radiation therapy plus chemotherapy provides modest benefit, as suggested by the clinical trials of the GITSG and other groups. Additional studies employing modified radiation therapy techniques and improved chemotherapeutic regimens, with enhanced radiosensitization and direct cytotoxicity, are needed to optimize treatment regimens for patients with this disease. [ONCOLOGY 10(Suppl):13-17, 1996]


Treatment strategies for patients with pancreatic cancer differ
based on disease stage. Standard treatment strategies for patients
with T1-T2,NX,M0 disease include surgical resection and adjuvant
or, less commonly, neoadjuvant chemoradiation, whereas therapy
for unresectable presentations includes surgical bypass procedures,
radiation therapy, and/or chemotherapy [1].

Pancreatic cancer is particularly challenging for the radiation
oncologist because of the limited radiation tolerance of adjacent
organs in the upper abdomen, including the kidney, liver, stomach,
small bowel, and spinal cord [2]. The radiotherapy technique usually
used to treat pancreatic cancer is conventional external-beam
radiotherapy (EBRT), although more specialized techniques, such
as intraoperative radiotherapy (IORT) and brachytherapy, have
been described. Intraoperative radiotherapy involves the application
of a single high dose of radiation during a surgical procedure,
while brachytherapy entails the interstitial implantation of radioactive
sources [1,3].

Radiation therapy can be potentiated with the use of radiosensitizing
chemotherapeutic agents. One such agent, fluorouracil (5-FU),
has been shown to be a radiosensitizer in vitro [4]. More recently,
in vitro experiments reported by Shewach and Lawrence showed that
the chemotherapeutic agent gemcita-bine (Gemzar), a deoxycytidine
analog, produced increased radiation sensitivity in human colon
carcinoma (HT-29) cells [5].

Resectable or Borderline Unresectable

Preoperative Radiation Therapy

Pilepich and Miller examined preoperative (neoadjuvant) radiation
therapy as a means of improving the efficacy of surgical resection
in patients with borderline resectable or locally unresectable
disease [6]. In this study, patients received 4,000 to 5,000 cGy
over a 4.5- to 5-week period and were evaluated for surgery 6
weeks after radiotherapy. Of 17 patients, 11 were selected for
laparotomy. At surgery, 4 of the 11 patients had metastatic disease,
1 patient was determined to be locally unresectable, and 6 patients
underwent resection. Only 1 of the 6 patients experienced a clear
conversion from unresectable to resectable disease. The authors
concluded that radical resection was possible after preoperative
radiation in some patients but that a significant number of patients
should be expected to develop metastatic disease during or shortly
after the radiotherapy course [6].

Ishikawa et al conducted a retrospective review of the use of
preoperative irradiation in 18 patients with resectable or borderline
resectable disease [7]. Patients received fractionated radiation
to 5,000 cGy, terminating about 1 month prior to exploratory surgery.
Measurable tumor shrinkage was noted in all 18 patients, and 16
patients underwent pancreatic resection [7]. Although these results
indicate that preoperative radiation is feasible, it is not used
routinely [8].

Resectable Disease

Postoperative Radiation Therapy

Historically, surgery alone has had disappointing results in patients
with pancreatic cancer. For example, Tepper et al showed that
surgery for resectable disease was associated with a 5-year crude
survival rate of 15% and a local recurrence rate of 50% [9]. Similar
results were reported by Griffin et al [10]. Based on these findings,
it was suggested that postoperative radiation therapy might reduce
the incidence of local failure after radical surgery [9,10].

A National Cancer Institute (NCI) study compared IORT with standard
postoperative radiation therapy in patients with locally confined
pancreatic cancer who were undergoing either total or regional
pancreatectomy [11]. Patients were randomized to receive either
postoperative IORT (2,000 cGy using 9 to 12 MeV to the tumor bed
and regional nodal basins) or postoperative EBRT (5,000 cGy over
a period of 5 to 6 weeks). Although overall survival was similar
between the treatment groups, disease-free survival and local
disease control were better in the IORT-treated patients than
in the EBRT-treated patients. These results suggested that IORT
may provide some benefit in patients with locally confined pancreatic
cancer [11].

More recently, a retrospective study by Zerbi et al examined the
impact of IORT following surgical resection [12]. Patients either
underwent resection alone (47 patients) or resection and IORT
at a dose of 12.5 to 20 Gy (43 patients). Whereas 1-, 2-, and
3-year survival rates and median disease-free survival did not
differ significantly between the treatment groups, local recurrence
was significantly reduced in patients who underwent resection
plus IORT (27% of patients), as compared with those who had a
resection only (56% of patients; P less than .01 by the chi-square
and Mantel-Cox tests).

Although these results provide some support for the concept of
adding of IORT to surgical resection to enhance local control,
it should be noted that no survival benefit was observed. Selection
factors may have contributed to the improved local control observed,
and IORT remains investigational in this context [12].

Postoperative Radiation Therapy Plus Chemotherapy

In 1985, the Gastrointestinal Tumor Study Group (GITSG) reported
the results of a randomized trial that compared surgical resection
alone (N = 22) with surgical resection followed by radiation therapy
plus chemotherapy (N = 21) [13]. Postoperative radiation therapy
(EBRT) consisted of 4,000 cGy given in two courses of 2,000 cGy
each, and chemotherapy consisted of IV 5-FU at 500 mg/m²
daily during the first 3 days of each 2,000-cGy course of radiation.
One month after the completion of radiation therapy, chemotherapy
was continued weekly for up to 2 years or until recurrence.

Accrual into the trial was slow due to the concern that patients
would not tolerate surgery plus radiation and chemotherapy [14].
Nevertheless, this study demonstrated that surgery plus adjuvant
radiation and chemotherapy significantly improved survival compared
with surgery alone (median survival, 20 vs 11 months; P = .03
using a one-sided log-rank test) [13].

The results of the initial GITSG trial led to the design of a
confirmatory trial in which an additional 30 patients received
surgery plus radiation and chemotherapy [15]. Median survival
was 18 months, which was similar to that observed for the adjuvant
therapy group (20 months) in the initial trial. Two-year actuarial
survival was 46% for the confirmatory trial patients who received
adjuvant therapy, 43% for the initial trial patients who received
adjuvant therapy, and only 18% for the initial trial patients
who received surgery alone (Figure 1). The results of both studies
supported the benefit of surgery plus radiation and chemotherapy
in patients with resected pancreatic cancer [16].

The GITSG concluded that "... the combined use of radiation
therapy and fluorouracil as adjuvant therapy after curative resection
is effective and is preferred to no adjuvant therapy [15]."
However, the use of adjuvant radiation therapy and chemotherapy
has been slow to gain acceptance. Reluctance to use this treatment
regimen reflects a variety of concerns, including the possibility
that patients with positive surgical margins may not benefit from
this treatment regimen [17], and doubt surrounding the GITSG study
results due to the low patient numbers (N = 43) and lengthy recruitment
time [2].

However, more-recent data continue to support the GITSG results
[18]. In addition, efforts at improving postoperative adjuvant
radiation therapy by using hepatic radiation and continuous-infusion
5-FU have been initiated, but whether these efforts will result
in improved outcomes with acceptable toxicity is unknown [19].
Decisions about whether or not to use adjuvant therapy for patients
with resectable pancreatic cancer should be made on a case-by-case
basis [1].


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