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.[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:
- Palliative surgery: palliative surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.[2,3]
- Chemoradiation followed by chemotherapy.
- Chemotherapy followed by chemoradiation, for patients without metastatic disease.
- Chemotherapy: gemcitabine; gemcitabine and erlotinib; gemcitabine and nab-paclitaxel; or 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX).
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.
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.
|Trial||Regimen||Chemoradiation||Radiation Alone||Chemotherapy Alone||P 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.|
|GITSG ||Radiation alone vs. 5-FU/60 Gy XRT||40 weeks||20 weeks||<.01|
|ECOG ||Radiation vs. 5-FU, mitomycin C/59 Gy XRT||8.4 months||7.1 months||.16|
|FFCD ||GEM vs. GEM, cisplatin, 60 Gy XRT||8.6 months||13 months||.03|
|ECOG ||GEM vs. GEM/50.4 Gy XRT||11.1 months||9.2 months||.017|
Evidence (chemoradiation therapy):
Three trials attempted to look at combined modality therapy versus radiation therapy alone.[5-7] 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.
- 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.[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.
- 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). 
- The trial reported no difference in OS between the two groups.
- 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. [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.
- 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. 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%).
- 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.[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).
Taken together, the FFCD and GERCOR studies provide support for gemcitabine-based chemotherapy for at least 3 months, followed by chemoradiation in the absence of metastatic disease. This approach has yet to be validated in a prospective phase III trial.
Chemotherapy is the primary treatment modality for patients with locally advanced pancreatic cancers. Although gemcitabine has long been considered the standard regimen, newer chemotherapy regimens have recently emerged.
- Gemcitabine versus 5-FU: Gemcitabine has demonstrated activity in patients with pancreatic cancer and is a useful palliative agent.[12-14] A phase III trial of gemcitabine versus 5-FU as first-line therapy in patients with advanced or metastatic adenocarcinoma of the pancreas reported a significant improvement in survival among patients treated with gemcitabine (1-year survival was 18% with gemcitabine compared with 2% with 5-FU; P = .003).[Level of evidence: 1iiA]
- Gemcitabine alone versus gemcitabine and erlotinib: The National Cancer Institute of Canada performed a phase III trial (CAN-NCIC-PA3 [NCT00026338]) that compared gemcitabine alone versus the combination of gemcitabine and erlotinib (100 mg/day) in patients with advanced or metastatic pancreatic carcinomas.[Level of evidence: 1iiA]
- The addition of erlotinib modestly prolonged survival when combined with gemcitabine versus gemcitabine alone (hazard ratio [HR] = 0.81; 95% CI, 0.69 to 0.99; P = .038).
- The corresponding median and 1-year survival rates for patients who received erlotinib versus placebo were 6.2 months and 5.9 months, and 23% versus 17%, respectively.
- Platinum analog or fluoropyrimidine versus single-agent gemcitabine: Many phase III studies have evaluated a combination regimen with either a platinum analog (cisplatin or oxaliplatin) or fluoropyrimidine versus single-agent gemcitabine.[16,17]
- Not one of these phase III trials has demonstrated a statistically significant advantage favoring the use of combination chemotherapy in the first-line treatment of metastatic pancreatic cancer.
- Gemcitabine and nab-paclitaxel versus gemcitabine: A multicenter, international phase III trial (NCT00844649) included 861 patients with metastatic pancreatic adenocarcinoma (Karnofsky Performance Status of ≥70) who had not previously received chemotherapy for metastatic disease.[Level of evidence: 1iiA] Patients who received adjuvant gemcitabine or any other chemotherapy were excluded. The patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2 of body-surface area) weekly for 3 of 4 weeks or gemcitabine monotherapy (1000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
- The median OS was 8.5 months in the nab-paclitaxel/gemcitabine group compared with 6.7 months in the gemcitabine group (HRdeath, 0.72; 95% CI, 0.62–0.83; P < .001).
- Median progression-free survival was 5.5 months in the nab-paclitaxel/gemcitabine group and 3.7 months in the gemcitabine group (HRdisease progression, 0.69; 95% CI, 0.58–0.82; P < .001).
- Nab-paclitaxel/gemcitabine was more toxic than gemcitabine. The most common grade 3 toxicities were neutropenia (38% in the nab-paclitaxel/gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group), and neuropathy (17% in the nab-paclitaxel/gemcitabine group vs. 1% in the gemcitabine group). Febrile neutropenia occurred in 3% of the nab-paclitaxel/gemcitabine group versus 1% in the gemcitabine group. In the nab-paclitaxel/gemcitabine group, the median time from grade 3 neuropathy to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% were able to resume treatment at a reduced dose within a median of 23 days after onset of a grade 3 event.
- On the basis of this trial, nab-paclitaxel plus gemcitabine is a standard treatment option for patients with advanced pancreatic cancer.
- Quality of life data have not yet been published regarding this regimen, and this study does not address the efficacy of nab-paclitaxel/gemcitabine versus FOLFIRINOX.
- FOLFIRINOX versus gemcitabine: A multicenter phase II/III trial included 342 patients with metastatic pancreatic adenocarcinoma with an ECOG performance status score of 0 or 1.[Level of evidence: 1iiA] The patients were randomly assigned to receive FOLFIRINOX (oxaliplatin [85 mg/m2], irinotecan [180 mg/m2], leucovorin [400 mg/m2], and 5-FU [400 mg/m2] given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine (1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks).
- The median OS was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (HRdeath = 0.57; 95% CI, 0.45–0.73; P < .001).
- Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (HR for disease progression = 0.47; 95% CI, 0.37–0.59; P < .001).
- FOLFIRINOX was more toxic than gemcitabine; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of quality of life, versus 66% in the gemcitabine group (HR = 0.47; 95% CI, 0.30–0.70; P < .001).
- On the basis of this trial, FOLFIRINOX is considered a standard treatment option for patients with advanced pancreatic cancer.
- 5-FU, leucovorin, and oxaliplatin (OFF regimen) versus best supportive care (BSC): Second-line chemotherapy after progression on a gemcitabine-based regimen may be beneficial. The CONKO-003 investigators randomly assigned patients in the second line of chemotherapy to either the OFF regimen or BSC.; [Level of evidence: 3iA] The OFF regimen consisted of leucovorin (200 mg/m2) followed by 5-FU (2,000 mg/m2 [24-hour continuous infusion] on days 1, 8, 15, and 22) and oxaliplatin (85 mg/m2 on days 8 and 22). After a rest of 3 weeks, the next cycle was started on day 43. The trial was terminated early because of poor accrual, and only 46 patients were randomly assigned to either the OFF regimen or BSC.
- Median survival on second-line chemotherapy was 4.82 months (95% CI, 4.29–5.35) with the OFF treatment regimen and 2.30 months (95% CI, 1.76–2.83) with BSC alone (HR = 0.45; 95% CI, 0.24–0.83).
- Median OS was 9.09 months for the sequence of gemcitabine (GEM)-OFF and 7.90 months for GEM-BSC.
- The early closure of the study and the very small number of patients made the P values misleading. Therefore, second-line chemotherapy with the OFF regimen may be falsely associated with improved survival.
Treatment Options Under Clinical Evaluation for Stage III Pancreatic Cancer
Treatment options under clinical evaluation include the following:
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III pancreatic cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Iacobuzio-Donahue CA, Fu B, Yachida S, et al.: DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27 (11): 1806-13, 2009. [PUBMED Abstract]
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- Baron TH: Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344 (22): 1681-7, 2001. [PUBMED Abstract]
- Sohn TA, Lillemoe KD, Cameron JL, et al.: Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg 188 (6): 658-66; discussion 666-9, 1999. [PUBMED Abstract]
- A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. The Gastrointestinal Tumor Study Group. Ann Surg 189 (2): 205-8, 1979. [PUBMED Abstract]
- Cohen SJ, Dobelbower R Jr, Lipsitz S, et al.: A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys 62 (5): 1345-50, 2005. [PUBMED Abstract]
- Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced non metastatic pancreatic cancer: a FFCD-SFRO study. [Abstract] J Clin Oncol 24 (Suppl 18): A-4008, 180s, 2006.
- Loehrer PJ Sr, Feng Y, Cardenes H, et al.: Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 29 (31): 4105-12, 2011. [PUBMED Abstract]
- Moertel CG, Frytak S, Hahn RG, et al.: Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. Cancer 48 (8): 1705-10, 1981. [PUBMED Abstract]
- Chauffert B, Mornex F, Bonnetain F, et al.: Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol 19 (9): 1592-9, 2008. [PUBMED Abstract]
- Huguet F, André T, Hammel P, et al.: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25 (3): 326-31, 2007. [PUBMED Abstract]
- Rothenberg ML, Moore MJ, Cripps MC, et al.: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 7 (4): 347-53, 1996. [PUBMED Abstract]
- Burris HA 3rd, Moore MJ, Andersen J, et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15 (6): 2403-13, 1997. [PUBMED Abstract]
- Storniolo AM, Enas NH, Brown CA, et al.: An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 85 (6): 1261-8, 1999. [PUBMED Abstract]
- Moore MJ, Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25 (15): 1960-6, 2007. [PUBMED Abstract]
- Poplin E, Feng Y, Berlin J, et al.: Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 27 (23): 3778-85, 2009. [PUBMED Abstract]
- Colucci G, Labianca R, Di Costanzo F, et al.: Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28 (10): 1645-51, 2010. [PUBMED Abstract]
- Von Hoff DD, Ervin T, Arena FP, et al.: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369 (18): 1691-703, 2013. [PUBMED Abstract]
- Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364 (19): 1817-25, 2011. [PUBMED Abstract]
- Pelzer U, Kubica K, Stieler J, et al.: A randomized trial in patients with gemcitabine refractory pancreatic cancer. Final results of the CONKO 003 study. [Abstract] J Clin Oncol 26 (Suppl 15): A-4508, 2008.
- Pelzer U, Schwaner I, Stieler J, et al.: Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group. Eur J Cancer 47 (11): 1676-81, 2011. [PUBMED Abstract]
- Tepper JE, Noyes D, Krall JM, et al.: Intraoperative radiation therapy of pancreatic carcinoma: a report of RTOG-8505. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 21 (5): 1145-9, 1991. [PUBMED Abstract]
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