Preoperative Chemoradiation Therapy

The CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma.[23,26][Level of evidence A1]

The CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma.[23,26][Level of evidence A1]

With a median follow-up of 84 months, preoperative chemoradiation was found to improve median OS from 24 months in the surgery-alone group to 48.6 months (HR, 0.68; 95% CI, 0.53–0.88; P = .003). Median OS for patients with squamous cell carcinomas was 81.6 months in the preoperative chemoradiation group, compared with 21.1 months in the surgery-alone group (HR, 0.48; 95% CI, 0.28–0.83; log-rank P = .008); for patients with adenocarcinomas, median OS was 43.2 months in the preoperative chemoradiation group, compared with 27.1 months in the surgery-alone group (HR, 0.73; 95% CI, 0.55–0.98; log-rank P = .038).[26]

The CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma.[23,26][Level of evidence A1]

Additionally, preoperative chemoradiation improved the rate of R0 resections (92% vs. 69%; P < .001). R0 is defined as complete resection with no tumor within 1 mm of resection margins.

The CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma.[23,26][Level of evidence A1]

A complete pathological response was achieved in 29% of patients who underwent resection after chemoradiation therapy. A pathological complete response was observed in 23% of patients with adenocarcinoma, compared with 49% of patients with squamous cell carcinoma (P = .008).

The CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma.[23,26][Level of evidence A1]

Postoperative complications and in-hospital mortality were equivalent in both groups. The most common hematologic side effects in the chemoradiation group were leukopenia (6%) and neutropenia (2%). The most common nonhematologic side effects were anorexia (5%) and fatigue (3%).

The CROSS study randomly assigned 366 patients with resectable esophageal or junctional cancers to receive either surgery alone or weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area]) and concurrent radiation therapy (41.4 Gy in 23 fractions) administered over 5 weeks. Most patients enrolled in the CROSS trial (75%) had adenocarcinoma.[23,26][Level of evidence A1]

With a median follow-up of 84 months, the 5-year progression-free survival (PFS) rate was 44% in the preoperative chemoradiation group, compared with 27% in the surgery-alone group (HR, 0.61; 95% CI, 0.47–0.78). Preoperative chemoradiation therapy reduced locoregional recurrence from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). There was a small but significant effect on hematogenous dissemination in favor of the chemoradiation therapy group (35% vs. 29%; P = .025).[24,26][Level of evidence B1]

A multicenter, prospective, randomized trial compared preoperative combined chemotherapy (i.e., cisplatin) and radiation therapy (37 Gy in 3.7-Gy fractions) versus surgery alone in patients with squamous cell carcinoma.[19][Level of evidence A1]

A multicenter, prospective, randomized trial compared preoperative combined chemotherapy (i.e., cisplatin) and radiation therapy (37 Gy in 3.7-Gy fractions) versus surgery alone in patients with squamous cell carcinoma.[19][Level of evidence A1]

The study showed no improvement in OS and a significantly higher postoperative mortality rate (12% vs. 4%) in the combined-modality arm.

In patients with adenocarcinoma of the esophagus, a single-institution phase III trial was conducted in patients treated with induction chemoradiation therapy consisting of 5-FU, cisplatin, and 40 Gy (in 2.67-Gy fractions) plus surgery compared with resection alone.[20][Level of evidence A1]

In patients with adenocarcinoma of the esophagus, a single-institution phase III trial was conducted in patients treated with induction chemoradiation therapy consisting of 5-FU, cisplatin, and 40 Gy (in 2.67-Gy fractions) plus surgery compared with resection alone.[20][Level of evidence A1]

The results demonstrated a modest survival benefit of 16 months for combined modality therapy versus 11 months for surgery alone.

A subsequent single-institution trial randomly assigned patients (75% with adenocarcinoma) to 5-FU, cisplatin, vinblastine, and radiation therapy (1.5 Gy twice daily to a total of 45 Gy) plus resection versus esophagectomy alone.[21][Level of evidence A1]

A subsequent single-institution trial randomly assigned patients (75% with adenocarcinoma) to 5-FU, cisplatin, vinblastine, and radiation therapy (1.5 Gy twice daily to a total of 45 Gy) plus resection versus esophagectomy alone.[21][Level of evidence A1]

At a median follow-up of more than 8 years, there was no significant difference between the surgery alone and combined modality therapy with respect to median survival (17.6 months vs. 16.9 months), OS rate (16% vs. 30% at 3 years), or DFS rate (16% vs. 28% at 3 years).

An intergroup trial (CALGB-9781 [NCT00003118]) planned to randomly assign 475 patients with resectable squamous cell or adenocarcinoma of the thoracic esophagus to treatment with preoperative chemoradiation therapy (5-FU, cisplatin, and 50.4 Gy) followed by esophagectomy and nodal dissection or surgery alone. The trial was closed as a result of poor patient accrual; however, results from the 56 enrolled patients, with a median follow-up of 6 years, were reported.[22][Level of evidence A1]

An intergroup trial (CALGB-9781 [NCT00003118]) planned to randomly assign 475 patients with resectable squamous cell or adenocarcinoma of the thoracic esophagus to treatment with preoperative chemoradiation therapy (5-FU, cisplatin, and 50.4 Gy) followed by esophagectomy and nodal dissection or surgery alone. The trial was closed as a result of poor patient accrual; however, results from the 56 enrolled patients, with a median follow-up of 6 years, were reported.[22][Level of evidence A1]

The median survival was 4.48 years (95% CI; range, 2.4–not estimable) for trimodality therapy versus 1.79 years (95% CI, 1.41–2.59) for surgery alone (P = .002), with a 5-year OS rate of 39% for trimodality therapy (95% CI, 21%–57%) versus 16% for surgery alone (95% CI, 5%–33%).

To further evaluate the impact of neoadjuvant chemoradiation therapy for early-stage disease, the FFCD 9901 study randomly assigned 195 patients with stage I or stage II esophageal cancer to receive surgery alone or neoadjuvant chemoradiation therapy (45 Gy in 25 fractions administered with two courses of 5-FU [800 mg/m2] and cisplatin [75 mg/m2]) followed by surgery.[25][Level of evidence A1]

To further evaluate the impact of neoadjuvant chemoradiation therapy for early-stage disease, the FFCD 9901 study randomly assigned 195 patients with stage I or stage II esophageal cancer to receive surgery alone or neoadjuvant chemoradiation therapy (45 Gy in 25 fractions administered with two courses of 5-FU [800 mg/m2] and cisplatin [75 mg/m2]) followed by surgery.[25][Level of evidence A1]

At interim analysis, accrual to the study was stopped early because of futility.

To further evaluate the impact of neoadjuvant chemoradiation therapy for early-stage disease, the FFCD 9901 study randomly assigned 195 patients with stage I or stage II esophageal cancer to receive surgery alone or neoadjuvant chemoradiation therapy (45 Gy in 25 fractions administered with two courses of 5-FU [800 mg/m2] and cisplatin [75 mg/m2]) followed by surgery.[25][Level of evidence A1]

With a median follow-up of 94 months, there was no significant improvement in 3-year OS rates with chemoradiation (48% vs. 53%; P = .94); there was a significantly higher postoperative mortality rate of 11.1% versus 3.4% (P = .049).

The NRG Oncology/RTOG-1010 trial (NCT01196390) evaluated the addition of trastuzumab to trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) in patients with untreated HER2-overexpressing esophageal adenocarcinoma. This phase III trial entered 606 patients for HER2 assessment. A total of 203 patients with HER2-positive disease were randomly assigned to receive chemoradiation therapy plus trastuzumab (n = 102) or chemoradiation therapy alone (n = 101). The primary end point was DFS. The median duration of follow-up was 2.8 years.[27] In conclusion, this trial confirmed that trastuzumab does not have a role in the preoperative treatment of HER2-positive esophageal or gastroesophageal cancer, either with chemotherapy alone or with chemoradiation therapy.

The NRG Oncology/RTOG-1010 trial (NCT01196390) evaluated the addition of trastuzumab to trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) in patients with untreated HER2-overexpressing esophageal adenocarcinoma. This phase III trial entered 606 patients for HER2 assessment. A total of 203 patients with HER2-positive disease were randomly assigned to receive chemoradiation therapy plus trastuzumab (n = 102) or chemoradiation therapy alone (n = 101). The primary end point was DFS. The median duration of follow-up was 2.8 years.[27] In conclusion, this trial confirmed that trastuzumab does not have a role in the preoperative treatment of HER2-positive esophageal or gastroesophageal cancer, either with chemotherapy alone or with chemoradiation therapy.

The median DFS was 19.6 months (95% CI, 13.5–26.2) for patients who received chemoradiation therapy plus trastuzumab and 14.2 months (10.5–23.0) for patients who received chemoradiation therapy alone (HR, 0.99; 95% CI, 0.71–1.39; log-rank P = .97).[27][Level of evidence B1]

The NRG Oncology/RTOG-1010 trial (NCT01196390) evaluated the addition of trastuzumab to trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) in patients with untreated HER2-overexpressing esophageal adenocarcinoma. This phase III trial entered 606 patients for HER2 assessment. A total of 203 patients with HER2-positive disease were randomly assigned to receive chemoradiation therapy plus trastuzumab (n = 102) or chemoradiation therapy alone (n = 101). The primary end point was DFS. The median duration of follow-up was 2.8 years.[27] In conclusion, this trial confirmed that trastuzumab does not have a role in the preoperative treatment of HER2-positive esophageal or gastroesophageal cancer, either with chemotherapy alone or with chemoradiation therapy.

Grade 3 treatment-related adverse events occurred in 41 of 95 patients (43%) who received trastuzumab and 52 of 96 patients (54%) of patients who received chemoradiation therapy alone. Grade 4 treatment-related adverse events occurred in 20 patients (21%) who received trastuzumab and 21 patients (22%) who received chemoradiation therapy alone.

The NRG Oncology/RTOG-1010 trial (NCT01196390) evaluated the addition of trastuzumab to trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) in patients with untreated HER2-overexpressing esophageal adenocarcinoma. This phase III trial entered 606 patients for HER2 assessment. A total of 203 patients with HER2-positive disease were randomly assigned to receive chemoradiation therapy plus trastuzumab (n = 102) or chemoradiation therapy alone (n = 101). The primary end point was DFS. The median duration of follow-up was 2.8 years.[27] In conclusion, this trial confirmed that trastuzumab does not have a role in the preoperative treatment of HER2-positive esophageal or gastroesophageal cancer, either with chemotherapy alone or with chemoradiation therapy.

There were five treatment-related deaths in the trastuzumab group (bronchopleural fistula, esophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three deaths in the chemoradiation therapy group (two multiorgan failure and one sepsis).