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Pancreatic Cancer
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Adjuvant Therapy: Chemotherapy & Chemoradiation
Chemotherapy and chemoradiation in management of pancreatic cancer.
An objective of adjuvant therapy following surgical resection is reduction of relapse and improvement of the likelihood of long-term survival.
As documented earlier, high failure rates for patients undergoing resection have led to adoption of adjuvant treatment strategies, some of which include radiotherapy.26
Failure pattern following pancreatectomy involves local recurrence (50%-80% likelihood) with distant metastases also likely (75%).
The rationale for management of this scenario initially (historically) considered radiation used to mitigate local relapse while using chemotherapeutic agents to prevent/manage the disease at sites with distant from the surgical site.
Although radiation efficacy continues to be a source of uncertainty, one of two approaches to adjuvant treatment involves chemoradiation as an element of therapy; whereas, the other approach is based on systemic chemotherapy by itself.9
Although no longer considered an "first-line" agent by itself or in combination62, 5-fluorouracil (5-FU) a number of studies have evaluated adjuvant 5-FU-based chemoradiation approaches for patients following pancreaticoduodenectomy with curative intent.
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Three trials of particular interest include those conducted by (1) Gastrointestinal Study Group (GITSG), (2) the European Organization for Research and Treatment of Cancer (EORTC) and (3) the European Study Group for Pancreatic Cancer (ESPAC).9
Gastrointestinal Study Group (GITSG) Findings:66
In 1985 results from the GITSG study were reported.
Enrollment in the clinical trial required that the patient both underwent surgical resection and that the results of the resection included negative (microscopically) surgical margins, i.e. R0 margins and an absence of peritoneal metastases. 66
Patients included in the study had histologically determined ductal, acinar, or undifferentiated pancreatic adenocarcinoma; however, those patients with periampullary carcinoma, cystadenocarcinoma or islet cell carcinoma were excluded. Patient entered the study from 4 to 10 weeks postoperatively.66
Exclusion criteria included malignant disease history within the previous 36 months, any previous systemic cancer chemotherapy within the previous 12 months, prior radiation treatment that would overlap with the field to be used in the present study, inadequate oral nutrition prior to randomization, inability to maintain stable weight prior to randomization of patients into control/treatment branches, abnormal laboratory findings such as white blood cell (WBC) count <4000/mm3, platelet count <150000/mm3, hematocrit <30%, serum urea nitrogen >25 mg/dL, bilirubin level >3 mg/dL, serum glutamic-oxaloacetic transaminase level >100 IU, alkaline phosphatase level >25% above institutional normal and any active and significant coexistent disease which might result in prohibitive patient risk with respect to the chemotherapy + radiation treatment protocol.66
A total of 22 patients were in the control group with 21 in the treated group. 66
Patients in the treated group received both radiation and 5-fluorouracil (5-FU) chemotherapy.
The radiation therapy was given in two courses of 2000 rad (20 Gy) with a two-week separation between courses: (4000 rad (40 Gy) total). Treatment was provided five days a week with treatment fields not exceeding 400cm2.
For the first three days of each radiation course, 5-fluorouracil was administered concurrently.
The radiation field was intended to cover the entire pancreas-right duodenal border to the pancreatic tail as well as the pancreatic bed (including the region of resective disease). The celiac axis, pancreaticosplenic, peripancreatic, and retroperitoneal nodes were included in the radiation field.
With respect to chemotherapy, 5-FU was administered both at the beginning of each radiation therapy course and was continued on a once-weekly interval either for two years or until disease recurrence.
5-fluorouracil
treatment was interrupted based on hematological toxicities at these
thresholds: WBC count <4000/mm3; platelet count <100000 mm3; hemoglobin <10 g/dL.
The 5-FU daily dose was 500mg/m2 by IV bolus injection, given, as noted above, for three consecutive days at the beginning of each 20 Gy treatment course.66
Results:
In this study, radiotherapy + chemotherapy offered an apparent survival advantage throughout the follow-up timeframe (p = .03). 66
The authors report that the median survival for the treatment group was about twice as great compared to the control group (20 months compared to 11 months). 66
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The median disease-free survival for the treated group was about 11 months compared to nine months for controls.
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The authors identify the study is the first one suggesting that adjuvant treatment following attempted curative pancreaticoduodenectomy might prolong survival.
The adjuvant treatment consisted of fluorouracil bolus infusions coupled with radiotherapy (40 Gy).66
Considering all the patients (43), the median survival was about 15 months with a two-year survival of 28% with an estimated five-year survival of about 14%. 66
The treated group exhibited a median survival of about twice the control group; moreover, the two-year estimated survival appeared three times greater in the treated compared to controls. 66
The authors note that the small number of patients in the study is a limiting factor in assessment of the basic conclusions.66
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