Chemoradiation therapy

LAP07 (NCT00634725): The LAP07 study was an international, randomized, phase III study based on the results of the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[20][Level of evidence A1]The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.

LAP07 (NCT00634725): The LAP07 study was an international, randomized, phase III study based on the results of the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[20][Level of evidence A1]The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.

The primary end point was OS. After interim analysis, the study was stopped early because of futility.

LAP07 (NCT00634725): The LAP07 study was an international, randomized, phase III study based on the results of the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[20][Level of evidence A1]The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.

With a median follow-up of 36.7 months, the median OS from the date of the first randomization was not significantly different between chemotherapy at 16.5 months (95% CI, 14.5–18.5) and chemoradiation therapy at 15.2 months (95% CI, 13.9–17.3; P = .83).

LAP07 (NCT00634725): The LAP07 study was an international, randomized, phase III study based on the results of the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) study. In total, 449 patients were enrolled between 2008 and 2011, with random assignment via a two-step randomization process. In the first step, patients were randomly assigned to induction gemcitabine (n = 223) or gemcitabine plus erlotinib (n = 219) for four cycles. For the second step, patients with controlled tumors were randomly assigned (n = 269) a second time to receive either chemotherapy (n = 136) or chemoradiation therapy (n = 133). A total dose of 54 Gy in 30 daily fractions was prescribed with concurrent capecitabine at a dose of 800 mg/m2 twice daily on days of radiation therapy.[20][Level of evidence A1]The LAP07 study represents the most robust, prospective, randomized phase III data regarding the role of chemoradiation therapy in the setting of gemcitabine-based induction chemotherapy that demonstrates no OS benefit. However, this study was initiated before the advent of FOLFIRINOX chemotherapy, which has been widely adopted into the locally advanced setting. The role of chemoradiation in the setting of more active chemotherapy regimens, including gemcitabine/paclitaxel and FOLFIRINOX, has yet to be evaluated.

Median OS after the first randomization was 13.6 months (95% CI, 12.3–15.3) for the patients who received gemcitabine and was 11.9 months (95% CI, 10.4–13.5; P = .09) for the patients who received gemcitabine plus erlotinib.

Gastrointestinal Tumor Study Group (GITSG) GITSG-9273 trial: Before 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.[16][Level of evidence A1]

Gastrointestinal Tumor Study Group (GITSG) GITSG-9273 trial: Before 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.[16][Level of evidence A1]

The study was stopped early when the chemoradiation therapy groups were found to have better efficacy. The 1-year survival rate 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.

Gastrointestinal Tumor Study Group (GITSG) GITSG-9273 trial: Before 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.[16][Level of evidence A1]

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 OS was not statistically significant when compared with the 40 Gy arm.[21]

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/d on days 2–5 and 28–31) plus mitomycin (10 mg/m2 on day 2).[17]

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/d on days 2–5 and 28–31) plus mitomycin (10 mg/m2 on day 2).[17]

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/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d 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.[22][Level of evidence A1]

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/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d 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.[22][Level of evidence A1]

Median survival was superior in the gemcitabine group (13 vs. 8.6 months; P = .03).

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/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d 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.[22][Level of evidence A1]

Nonhematological grade 3 to 4 toxicities (primarily gastrointestinal) were significantly more common in the chemoradiation therapy group (44% vs. 18%; P = .004), and fewer patients completed at least 75% of induction therapy (42% vs. 73%).

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/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d 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.[22][Level of evidence A1]

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 group because of a greater incidence of grades 3 to 4 hematological toxicities (71% vs. 27%; P = .0001).

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/d of continuous-infusion 5-FU on days 1–5 for 6 weeks and 20 mg/m2/d 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.[22][Level of evidence A1]

As a result of this study, giving induction chemoradiation therapy has lost support.

ECOG: The results of the FFCD-SFRO study counter 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.[19] Of note, the study was closed early as the result of poor accrual.

ECOG: The results of the FFCD-SFRO study counter 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.[19] Of note, the study was closed early as the result of poor accrual.

The primary end point was survival, which was 9.2 months (95% CI, 7.9–11.4) for chemotherapy and 11.1 months (95% CI, 7.6–15.5) for combined modality therapy (one-sided P = .017 by stratified log-rank test).

ECOG: The results of the FFCD-SFRO study counter 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.[19] Of note, the study was closed early as the result of poor accrual.

Grades 4 and 5 toxicity were greater in the chemoradiation therapy arm than in the chemotherapy arm (41% vs. 9%).

GERCOR: Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with locally advanced 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.[23][Level of evidence C1]

GERCOR: Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with locally advanced 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.[23][Level of evidence C1]

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.

GERCOR: Given the increased toxicity of chemoradiation therapy and the early development of metastatic disease in a large percentage of patients with locally advanced 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.[23][Level of evidence C1]

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).