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Pancreatic Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage III Pancreatic Cancer Treatment

Treatment Options for Stage III Pancreatic Cancer

While stage III and stage IV pancreatic cancer are both incurable, the natural history of stage III (locally advanced) disease may be different than it is for stage IV disease. An autopsy series demonstrated that 30% of patients presenting with stage III disease died without evidence of distant metastases.[1][Level of evidence: 1iiA] Therefore, investigators have struggled with the question of whether chemoradiation for patients presenting with stage III disease is warranted.

Treatment options for stage III pancreatic cancer include the following:

  1. Palliative surgery: palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.[2,3]
  2. Chemoradiation therapy:
    • Chemoradiation followed by chemotherapy.
    • Chemotherapy followed by chemoradiation, for patients without metastatic disease.
  3. Chemotherapy: gemcitabine; gemcitabine and erlotinib; or 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX).

Palliative surgery

A significant proportion (approximately one-third) of patients with pancreatic cancer will present with stage III or locally advanced disease. Patients with stage III pancreatic cancer have tumors that are technically unresectable because of local vessel impingement or invasion by tumor. These patients may benefit from palliation of biliary obstruction by endoscopic, surgical, or radiological means.[4]

Chemoradiation therapy

The role of chemoradiation in locally advanced pancreatic cancer remains controversial. Table 8 summarizes phase III randomized studies of chemoradiation for stage III pancreatic cancer.

Table 8. Randomized Studies in Stage III Pancreatic Cancer: Median Survival

TrialRegimenChemoradiationRadiation AloneChemotherapy AloneP Value
5-FU = 5-fluorouracil; ECOG = Eastern Cooperative Oncology Group; FFCD = Fédération Francophone de Cancérologie Digestive; GEM = gemcitabine; GITSG = Gastrointestinal Tumor Study Group; Gy = gray (unit of absorbed radiation of ionizing radiation);P value = probability value; XRT = x-ray or radiation therapy.
Pre-2000 
GITSG[5]Radiation alone vs. 5-FU/60 Gy XRT40 weeks20 weeks <.01
ECOG[6]Radiation vs. 5-FU, mitomycin C/59 Gy XRT8.4 months7.1 months .16
Post-2000 
FFCD[7]GEM vs. GEM, cisplatin, 60 Gy XRT8.6 months 13 months.03
ECOG[8]GEM vs. GEM/50.4 Gy XRT11.1 months 9.2 months.017

Evidence (chemoradiation therapy):

Three trials attempted to look at combined modality therapy versus radiation therapy alone.[5,6,7] The trials had substantial deficiencies in design or analysis. Initially, the standard of practice was to give chemoradiation therapy based on data from the first two studies; however, with the publication of the third study, standard practice has changed to chemotherapy followed by chemoradiation in the absence of metastases.

  1. Gastrointestinal Tumor Study Group (GITSG)-9273 trial: Prior to 2000, several phase III trials evaluated combined modality therapy versus radiation therapy alone. Before the use of gemcitabine for patients with locally advanced or metastatic pancreatic cancer, investigators from the GITSG randomly assigned 106 patients with locally advanced pancreatic adenocarcinoma to receive external-beam radiation therapy (EBRT) (60 Gy) alone or concurrent EBRT (either 40 Gy or 60 Gy) plus bolus 5-FU.[5][Level of evidence: 1iiA]
    • The study was stopped early when the chemoradiation therapy arms were found to have better efficacy. The 1-year survival was 11% for patients who received EBRT alone compared with 38% for patients who received chemoradiation therapy with 40 Gy and 36% for patients who received chemoradiation therapy with 60 Gy.
    • After an additional 88 patients were enrolled in the combined modality arms, there was a trend toward improved survival with 60 Gy EBRT plus 5-FU, but the difference in time-to-progression and overall survival (OS) was not statistically significant when compared with the 40-Gy arm.[9]
  2. Eastern Cooperative Oncology Group (ECOG) E-8282 trial: Investigators from the ECOG randomly assigned 114 patients to receive radiation therapy (59.4 Gy) alone or with concurrent infusional 5-FU (1,000 mg/m2 daily on days 2–5 and 28–31) plus mitomycin (10 mg/m2 on day 2). [6]
    • The trial reported no difference in OS between the two groups.
  3. Fédération Francophone de Cancérologie Digestive-Société Française de Radiothérapie Oncologie (FFCD-SFRO) trial: As it became clear that radiation therapy alone was an inadequate treatment, investigators evaluated combined modality approaches versus chemotherapy alone. Investigators from the FFCD-SFRO randomly assigned 119 patients to induction chemoradiation therapy (60 Gy in 2 Gy fractions with 300 mg/m2 /day of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2 /day of cisplatin on days 1–5 during weeks 1 and 5) or induction gemcitabine (1,000 mg/m2 weekly for 7 weeks). Maintenance gemcitabine was administered to both groups until stopped by disease progression or treatment discontinuation as a result of toxicity. [10][Level of evidence: 1iiA]
    • Median survival was superior in the gemcitabine arm (13 vs. 8.6 months; P = .03).
    • Nonhematological grade 3 to 4 toxicities (primarily gastrointestinal) were significantly more common in the chemoradiation therapy arm (44% vs. 18%; P = .004), and fewer patients completed at least 75% of induction therapy (42% vs. 73%).
    • Nonetheless, the survival benefit persisted in a per-protocol analysis of patients receiving at least 75% of planned therapy. Notably, the dose intensity of maintenance gemcitabine was significantly less in the chemoradiation therapy arm because of a greater incidence of grades 3 to 4 hematological toxicities (71% vs. 27%; P = .0001).
    • As a result of this study, induction chemoradiation therapy has fallen out of favor.
  4. ECOG: The results of the FFCD-SFRO study stand in contrast to the results of a study from ECOG in which investigators randomly assigned 74 patients to either gemcitabine alone or gemcitabine with radiation followed by gemcitabine.[8] Of note, the study was closed early as the result of poor accrual.
    • The primary endpoint was survival, which was 9.2 months (95% confidence interval [CI], 7.9–11.4 months) and 11.1 months (95% CI, 7.6–15.5 months) for chemotherapy and combined modality therapy, respectively (one-sided P = .017 by stratified log-rank test).
    • Grades 4 and 5 toxicity were greater in the chemoradiation therapy arm than in the chemotherapy arm (41% vs. 9%).
  5. Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR): Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with stage III pancreatic cancer, investigators are pursuing a strategy of selecting patients with localized disease for chemoradiation therapy. With this strategy, the selected patients have an absence of progressive disease locally or systemically after several months of chemotherapy.[11][Level of evidence: 3iiiA]
    • A retrospective analysis of 181 patients enrolled in prospective phase II and III GERCOR studies revealed that 29% had metastatic disease after 3 months of gemcitabine-based chemotherapy.
    • For the remaining 71%, median OS was significantly longer among patients treated with chemoradiation therapy than among patients treated with additional chemotherapy (15.0 months vs. 11.7 months; P = .0009).[11]
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