Perioperative Chemotherapy

A trial that included patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus randomly assigned 250 patients to receive perioperative chemotherapy and surgery and 253 patients to receive surgery alone. Chemotherapy consisted of three preoperative and three postoperative cycles of IV epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous IV infusion of 5-FU (200 mg/m2 per day) for 21 days. The primary end point was OS.[33]

A trial that included patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus randomly assigned 250 patients to receive perioperative chemotherapy and surgery and 253 patients to receive surgery alone. Chemotherapy consisted of three preoperative and three postoperative cycles of IV epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous IV infusion of 5-FU (200 mg/m2 per day) for 21 days. The primary end point was OS.[33]

After a median follow-up of 4 years, 149 patients in the perioperative chemotherapy group and 170 patients in the surgery-alone group had died.

A trial that included patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus randomly assigned 250 patients to receive perioperative chemotherapy and surgery and 253 patients to receive surgery alone. Chemotherapy consisted of three preoperative and three postoperative cycles of IV epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous IV infusion of 5-FU (200 mg/m2 per day) for 21 days. The primary end point was OS.[33]

Compared with the surgery-alone group, the perioperative chemotherapy group had a higher likelihood of OS (HRdeath, 0.75; 95% CI, 0.60–0.93; P = .009). The 5-year survival rate was 36.3% in the perioperative chemotherapy group (95% CI, 29.5%–43.0%) and 23% (95% CI, 16.6%–29.4%) in the surgery-alone group.[33][Level of evidence A1]

A trial that included patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus randomly assigned 250 patients to receive perioperative chemotherapy and surgery and 253 patients to receive surgery alone. Chemotherapy consisted of three preoperative and three postoperative cycles of IV epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous IV infusion of 5-FU (200 mg/m2 per day) for 21 days. The primary end point was OS.[33]

The PFS rate was also improved in the perioperative chemotherapy group (HRprogression, 0.66; 95% CI, 0.53–0.81; P < .001) compared with the surgery-alone group.

A trial that included patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus randomly assigned 250 patients to receive perioperative chemotherapy and surgery and 253 patients to receive surgery alone. Chemotherapy consisted of three preoperative and three postoperative cycles of IV epirubicin (50 mg/m2) and cisplatin (60 mg/m2) on day 1, and a continuous IV infusion of 5-FU (200 mg/m2 per day) for 21 days. The primary end point was OS.[33]

The rate of postoperative complications was similar in the two groups; 46% in the perioperative chemotherapy group and 45% in the surgery-alone group. The number of deaths within 30 days after surgery was also similar between the two groups.

An open-label, randomized, phase II/III trial compared the efficacy and safety of the docetaxel-based triplet FLOT regimen with the combination of epirubicin and cisplatin plus either 5-FU given as a continuous infusion or capecitabine given orally. The trial included 716 patients with adenocarcinoma in clinical stage cT2 or higher, node-positive stage (cN+), or both, or resectable tumors with no evidence of distant metastases. Patients were randomly assigned to receive either: (1) ECF/ECX (three preoperative and three postoperative 3-week cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] on day 1 plus either 5-FU [200 mg/m2] given as a continuous infusion or capecitabine [1,250 mg/m2] orally on days 1 to 21), or (2) FLOT (four preoperative and four postoperative 2-week cycles of docetaxel [50 mg/m2], oxaliplatin [85 mg/m2], leucovorin [200 mg/m2], and 5-FU [2,600 mg/m2] as a 24-hour infusion on day 1). The primary end point of the trial was OS (superiority) in the intention-to-treat population.[34]

An open-label, randomized, phase II/III trial compared the efficacy and safety of the docetaxel-based triplet FLOT regimen with the combination of epirubicin and cisplatin plus either 5-FU given as a continuous infusion or capecitabine given orally. The trial included 716 patients with adenocarcinoma in clinical stage cT2 or higher, node-positive stage (cN+), or both, or resectable tumors with no evidence of distant metastases. Patients were randomly assigned to receive either: (1) ECF/ECX (three preoperative and three postoperative 3-week cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] on day 1 plus either 5-FU [200 mg/m2] given as a continuous infusion or capecitabine [1,250 mg/m2] orally on days 1 to 21), or (2) FLOT (four preoperative and four postoperative 2-week cycles of docetaxel [50 mg/m2], oxaliplatin [85 mg/m2], leucovorin [200 mg/m2], and 5-FU [2,600 mg/m2] as a 24-hour infusion on day 1). The primary end point of the trial was OS (superiority) in the intention-to-treat population.[34]

OS was longer in the FLOT group than the ECF/ECX group (HR, 0.77; 95% CI, 0.63–0.94). The median OS was 50 months in the FLOT group (38.33–not reached) and 35 months in the ECF/ECX group (27.35–46.26).[34][Level of evidence A1]

An open-label, randomized, phase II/III trial compared the efficacy and safety of the docetaxel-based triplet FLOT regimen with the combination of epirubicin and cisplatin plus either 5-FU given as a continuous infusion or capecitabine given orally. The trial included 716 patients with adenocarcinoma in clinical stage cT2 or higher, node-positive stage (cN+), or both, or resectable tumors with no evidence of distant metastases. Patients were randomly assigned to receive either: (1) ECF/ECX (three preoperative and three postoperative 3-week cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] on day 1 plus either 5-FU [200 mg/m2] given as a continuous infusion or capecitabine [1,250 mg/m2] orally on days 1 to 21), or (2) FLOT (four preoperative and four postoperative 2-week cycles of docetaxel [50 mg/m2], oxaliplatin [85 mg/m2], leucovorin [200 mg/m2], and 5-FU [2,600 mg/m2] as a 24-hour infusion on day 1). The primary end point of the trial was OS (superiority) in the intention-to-treat population.[34]

The number of patients with related serious adverse events (including those occurring during a hospital stay for surgery) was similar between the two groups: 96 patients (27%) in the ECF/ECX group and 97 patients (27%) in the FLOT group.

An open-label, randomized, phase II/III trial compared the efficacy and safety of the docetaxel-based triplet FLOT regimen with the combination of epirubicin and cisplatin plus either 5-FU given as a continuous infusion or capecitabine given orally. The trial included 716 patients with adenocarcinoma in clinical stage cT2 or higher, node-positive stage (cN+), or both, or resectable tumors with no evidence of distant metastases. Patients were randomly assigned to receive either: (1) ECF/ECX (three preoperative and three postoperative 3-week cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] on day 1 plus either 5-FU [200 mg/m2] given as a continuous infusion or capecitabine [1,250 mg/m2] orally on days 1 to 21), or (2) FLOT (four preoperative and four postoperative 2-week cycles of docetaxel [50 mg/m2], oxaliplatin [85 mg/m2], leucovorin [200 mg/m2], and 5-FU [2,600 mg/m2] as a 24-hour infusion on day 1). The primary end point of the trial was OS (superiority) in the intention-to-treat population.[34]

The number of deaths due to toxicity (two [<1%]) was similar in both groups. Hospitalization for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group.

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

With a median follow-up of 55 months, the 3-year OS rate was 57.4% (95% CI, 50.1%–64.0%) in the FLOT group and 50.7% (95% CI, 43.5%–57.5%) in the CROSS group (HRdeath, 0.70; 95% CI, 0.53–0.92; P = .01). The median OS was 66 months (95% CI, 36–not estimable) in the FLOT group and 37 months (95% CI, 28–43) in the CROSS group.[35][Level of evidence A1]

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

The 3-year PFS rate was 51.6% (95% CI, 44.3%–58.4%) in the FLOT group and 35.0% (95% CI, 28.4%–41.7%) in the CROSS group (HRdisease progression or death, 0.66; 95% CI, 0.51–0.85).

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

Neoadjuvant treatment was given to 403 patients: 207 patients in the FLOT group and 196 patients in the CROSS group. In the FLOT group 193 patients (89%) received four full cycles of chemotherapy before surgery, and 118 patients (53%) received four full cycles of chemotherapy after surgery. In the CROSS group, 147 patients (68%) received five full cycles of chemotherapy.

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

Surgery was performed in 374 patients: 192 patients in the FLOT group and 179 patients in the CROSS group. R0 resection occurred in 182 of 193 patients (94.3%) in the FLOT group and in 172 of 181 patients (95.0%) in the CROSS group.

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

Pathological complete response after surgery, defined as a pathological stage of ypT0 ypN0 (no residual invasive cancer in the resected primary tumor and lymph nodes), was seen in 32 of 192 patients (16.7%) in the FLOT group and 18 of 179 patients (10.1%) in the CROSS group.

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

At 90 days after surgery, 3.1% of patients in the FLOT group and 5.6% of patients in the CROSS group had died.

The ESOPEC trial (NCT02509286) compared (1) perioperative FLOT (four 2-week cycles of chemotherapy before surgery and four 2-week cycles of chemotherapy after surgery) and surgery with (2) neoadjuvant chemoradiation therapy with the CROSS regimen (41.4 Gy of radiation therapy plus carboplatin and docetaxel) followed by surgery. The trial enrolled 438 patients with clinical (c)T1, cN+, cM0 or cT2–4a, any cN, cM0 resectable esophageal adenocarcinoma. Patients were assigned to the FLOT group (n = 221) or the CROSS group (n = 217). The primary end point was OS.[35]In the ESOPEC trial, patients randomly assigned to the CROSS arm did not receive 1 year of adjuvant nivolumab. In the CheckMate 577 trial, 1 year of adjuvant nivolumab improved DFS when compared with placebo in patients who had resected specimens that did not show pathological complete responses. However, OS data from CheckMate 577 have not been published.

The study noted grade 3 or higher adverse events that occurred in 5% or more of patients. In the FLOT group, those adverse effects included neutropenia (19.8%), diarrhea (6.8%), leukopenia (6.3%), and pneumonia (5.8%). In the CROSS group, those adverse effects included leukopenia (9.7%) and pneumonia (9.2%).