Definitive Chemoradiation Therapy

A Radiation Therapy Oncology Group trial (RTOG-8501) randomly assigned patients to receive radiation therapy alone (64 Gy in 32 fractions) or chemoradiation (50 Gy in 25 fractions) with concurrent cisplatin (75 mg/m2) and continuous-infusion 5-FU (1,000 mg/m2 on days 1 to 4 in weeks 1 and 5 followed by two additional cycles of chemotherapy administered 3 weeks apart).[36][Level of evidence A1]

A Radiation Therapy Oncology Group trial (RTOG-8501) randomly assigned patients to receive radiation therapy alone (64 Gy in 32 fractions) or chemoradiation (50 Gy in 25 fractions) with concurrent cisplatin (75 mg/m2) and continuous-infusion 5-FU (1,000 mg/m2 on days 1 to 4 in weeks 1 and 5 followed by two additional cycles of chemotherapy administered 3 weeks apart).[36][Level of evidence A1]

There was an improvement in the 5-year survival rate for the combined modality group (27% vs. 0%).

A Radiation Therapy Oncology Group trial (RTOG-8501) randomly assigned patients to receive radiation therapy alone (64 Gy in 32 fractions) or chemoradiation (50 Gy in 25 fractions) with concurrent cisplatin (75 mg/m2) and continuous-infusion 5-FU (1,000 mg/m2 on days 1 to 4 in weeks 1 and 5 followed by two additional cycles of chemotherapy administered 3 weeks apart).[36][Level of evidence A1]

An 8-year follow-up of this trial demonstrated an OS rate of 22% for patients who received chemoradiation therapy.

Intergroup-0123 (RTOG-9405 [NCT00002631]) was conducted in an attempt to improve upon the results of RTOG-8501. Intergroup-0123 randomly assigned 236 patients with localized esophageal tumors to undergo chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of 5-FU and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.[37][Level of evidence A1]

Intergroup-0123 (RTOG-9405 [NCT00002631]) was conducted in an attempt to improve upon the results of RTOG-8501. Intergroup-0123 randomly assigned 236 patients with localized esophageal tumors to undergo chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of 5-FU and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.[37][Level of evidence A1]

Although originally designed to accrue 298 patients, this trial was closed in 1999 after a planned interim analysis showed that it was statistically unlikely that there would be any advantage to using high-dose radiation.

Intergroup-0123 (RTOG-9405 [NCT00002631]) was conducted in an attempt to improve upon the results of RTOG-8501. Intergroup-0123 randomly assigned 236 patients with localized esophageal tumors to undergo chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of 5-FU and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.[37][Level of evidence A1]

At a 2-year median follow-up, no statistically significant differences in median survival were observed between the high-dose and conventional-dose radiation therapy arms (13 months vs. 18 months), 2-year survival rates (31% vs. 40%), or local and regional failure rates (56% vs. 52%).

Intergroup-0123 (RTOG-9405 [NCT00002631]) was conducted in an attempt to improve upon the results of RTOG-8501. Intergroup-0123 randomly assigned 236 patients with localized esophageal tumors to undergo chemoradiation with high-dose radiation therapy (64.8 Gy) and four monthly cycles of 5-FU and cisplatin versus conventional-dose radiation therapy (50.4 Gy) and the same chemotherapy schedule.[37][Level of evidence A1]

There was a higher treatment mortality rate in the higher-dose arm (9% vs. 2%). However, 7 of 11 deaths in the high-dose arm occurred in patients who had received 50.4 Gy or less.

An Eastern Cooperative Oncology Group trial (EST-1282) evaluated 135 patients.[40][Level of evidence A1]

An Eastern Cooperative Oncology Group trial (EST-1282) evaluated 135 patients.[40][Level of evidence A1]

This trial showed that chemotherapy plus radiation therapy provided a better 2-year survival rate than did radiation therapy alone, similar to results from the intergroup trial.

The PRODIGE5/ACCORD17 trial (NCTE) compared the efficacy and safety of oxaliplatin, 5-FU, and leucovorin calcium (FOLFOX) versus 5-FU and cisplatin as the chemotherapy backbone among patients treated with definitive chemoradiation for localized esophageal cancer. In this multicenter, randomized, phase II and III trial, 267 patients were randomly assigned to receive either six cycles of FOLFOX (three cycles concomitant with radiation therapy), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), bolus 5-FU (400 mg/m2), and infusion 5-FU (1,600 mg/m2 over 46 hours) or four cycles of 5-FU (1,000 mg/m2 for 4 days) and cisplatin (75 mg/m2 on day 1). All patients received radiation therapy (50 Gy in 25 fractions).[41][Level of evidence B1]

The PRODIGE5/ACCORD17 trial (NCTE) compared the efficacy and safety of oxaliplatin, 5-FU, and leucovorin calcium (FOLFOX) versus 5-FU and cisplatin as the chemotherapy backbone among patients treated with definitive chemoradiation for localized esophageal cancer. In this multicenter, randomized, phase II and III trial, 267 patients were randomly assigned to receive either six cycles of FOLFOX (three cycles concomitant with radiation therapy), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), bolus 5-FU (400 mg/m2), and infusion 5-FU (1,600 mg/m2 over 46 hours) or four cycles of 5-FU (1,000 mg/m2 for 4 days) and cisplatin (75 mg/m2 on day 1). All patients received radiation therapy (50 Gy in 25 fractions).[41][Level of evidence B1]

With a median follow-up of 25.3 months, there was no significant difference in PFS (9.7 months with FOLFOX vs. 9.4 months with 5-FU and cisplatin; P = .64).

The PRODIGE5/ACCORD17 trial (NCTE) compared the efficacy and safety of oxaliplatin, 5-FU, and leucovorin calcium (FOLFOX) versus 5-FU and cisplatin as the chemotherapy backbone among patients treated with definitive chemoradiation for localized esophageal cancer. In this multicenter, randomized, phase II and III trial, 267 patients were randomly assigned to receive either six cycles of FOLFOX (three cycles concomitant with radiation therapy), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), bolus 5-FU (400 mg/m2), and infusion 5-FU (1,600 mg/m2 over 46 hours) or four cycles of 5-FU (1,000 mg/m2 for 4 days) and cisplatin (75 mg/m2 on day 1). All patients received radiation therapy (50 Gy in 25 fractions).[41][Level of evidence B1]

There was one death caused by toxicity in the FOLFOX group versus six deaths in the 5-FU and cisplatin arm (P = .066).

The PRODIGE5/ACCORD17 trial (NCTE) compared the efficacy and safety of oxaliplatin, 5-FU, and leucovorin calcium (FOLFOX) versus 5-FU and cisplatin as the chemotherapy backbone among patients treated with definitive chemoradiation for localized esophageal cancer. In this multicenter, randomized, phase II and III trial, 267 patients were randomly assigned to receive either six cycles of FOLFOX (three cycles concomitant with radiation therapy), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), bolus 5-FU (400 mg/m2), and infusion 5-FU (1,600 mg/m2 over 46 hours) or four cycles of 5-FU (1,000 mg/m2 for 4 days) and cisplatin (75 mg/m2 on day 1). All patients received radiation therapy (50 Gy in 25 fractions).[41][Level of evidence B1]

There were no significant differences in grade 3 or 4 adverse events between treatment groups. Among toxicities of all grades, paresthesia, sensory neuropathy, and increases in aspartate transaminase and alanine transaminase were more common in the FOLFOX group; increases in serum creatinine, mucositis, and alopecia were more common in the 5-FU and cisplatin group.

A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus. OS was the primary outcome.[38][Level of evidence A1]

A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus. OS was the primary outcome.[38][Level of evidence A1]

The analysis of 172 eligible randomly assigned patients showed that OS rates at 2 years were not statistically significantly different between the two treatment groups (arm A, 39.9%; 95% CI, 29.4%–50.4%; arm B, 35.4%; 95% CI, 25.2%–45.6%; log-rank test for equivalence with 0.15, P < .007).

A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus. OS was the primary outcome.[38][Level of evidence A1]

The local 2-year PFS rate was higher in the surgery group (64.3%; 95% CI, 52.1%–76.5%) than in the chemoradiation therapy group (40.7%; 95% CI, 28.9%–52.5%; HR for arm B vs. arm A, 2.1; 95% CI, 1.3–3.5; P < .003).

A phase III German trial also compared induction chemotherapy (three courses of bolus 5-FU, leucovorin, etoposide, and cisplatin) followed by chemoradiation therapy (cisplatin, etoposide, and 40 Gy) followed by surgery (arm A), or the same induction chemotherapy followed by chemoradiation therapy (at least 65 Gy) without surgery (arm B) for patients with T3 or T4 squamous cell carcinoma of the esophagus. OS was the primary outcome.[38][Level of evidence A1]

The treatment-related mortality rate was higher in the surgery group (12.8%) than in the chemoradiation therapy group (3.5%) (P < .03).

FFCD 9102 (NCTE) randomly assigned 259 patients with T3N0–1M0 thoracic esophageal cancer to receive either two cycles of 5-FU and cisplatin (days 1–5 and 22–26) and either conventional radiation therapy (46 Gy in 4.5 weeks) or split course (15 Gy, days 1–5 and 22–26). Patients with response were then randomly assigned to receive either surgical resection (arm A) or continuation of chemoradiation (arm B: three cycles of 5-FU plus cisplatin and either conventional 20 Gy or split-course 15 Gy radiation therapy).[39][Level of evidence A1]

FFCD 9102 (NCTE) randomly assigned 259 patients with T3N0–1M0 thoracic esophageal cancer to receive either two cycles of 5-FU and cisplatin (days 1–5 and 22–26) and either conventional radiation therapy (46 Gy in 4.5 weeks) or split course (15 Gy, days 1–5 and 22–26). Patients with response were then randomly assigned to receive either surgical resection (arm A) or continuation of chemoradiation (arm B: three cycles of 5-FU plus cisplatin and either conventional 20 Gy or split-course 15 Gy radiation therapy).[39][Level of evidence A1]

Of the 259 randomly assigned patients, 230 (89%) had squamous cell carcinoma, and 29 patients (11%) had adenocarcinomas.

FFCD 9102 (NCTE) randomly assigned 259 patients with T3N0–1M0 thoracic esophageal cancer to receive either two cycles of 5-FU and cisplatin (days 1–5 and 22–26) and either conventional radiation therapy (46 Gy in 4.5 weeks) or split course (15 Gy, days 1–5 and 22–26). Patients with response were then randomly assigned to receive either surgical resection (arm A) or continuation of chemoradiation (arm B: three cycles of 5-FU plus cisplatin and either conventional 20 Gy or split-course 15 Gy radiation therapy).[39][Level of evidence A1]

The 2-year OS rate was 34% in patients randomly assigned to receive surgery versus 40% in patients randomly assigned to receive definitive chemoradiation (HR, 0.90; P = .44). Median survival was 17.7 months for surgery and 19.3 months for definitive chemoradiation.

FFCD 9102 (NCTE) randomly assigned 259 patients with T3N0–1M0 thoracic esophageal cancer to receive either two cycles of 5-FU and cisplatin (days 1–5 and 22–26) and either conventional radiation therapy (46 Gy in 4.5 weeks) or split course (15 Gy, days 1–5 and 22–26). Patients with response were then randomly assigned to receive either surgical resection (arm A) or continuation of chemoradiation (arm B: three cycles of 5-FU plus cisplatin and either conventional 20 Gy or split-course 15 Gy radiation therapy).[39][Level of evidence A1]

The 3-month mortality rate was 9.3% in the surgery arm, compared with 0.8% in the chemoradiation arm (P = .002).