Clinical trialPhase 3Oesophageal cancer

Preoperative chemoradiotherapy for esophageal or junctional cancer

N Engl J Med · 2012368 patients (366 patients in the analysis)

van Hagen P, Hulshof MC, van Lanschot JJ, et al. N Engl J Med. 2012. 366:2074-2084

Study type: Clinical trial
Study name: CROSS
Phase: Phase 3
Design: Multicentre randomised trial (Netherlands), chemoradiotherapy followed by surgery versus surgery alone
Sample size: 368 patients (366 patients in the analysis)
Source: N Engl J Med · 2012

In plain words

In this Dutch study, patients who had about 5 weeks of mild weekly chemotherapy together with radiotherapy before surgery for oesophageal cancer typically lived twice as long as those who had surgery alone (about 4 years versus 2 years). In nearly a third of them, no living cancer cells were left in the surgical specimen. This approach, known as the "CROSS regimen", has for years been one of the standard treatments before surgery.

Key results

49.4 vs 24.0 months

Median overall survival

HR 0.657 (95% CI 0.495–0.871); P=0.003

92% vs 69%

Complete resection with clear margins (R0)

P<0.001

29% (47 of 161 patients)

Pathological complete response

In patients who underwent surgery after chemoradiotherapy

4% in both groups

In-hospital postoperative mortality

38% vs 25%

10-year overall survival (long-term follow-up)

HR 0.70; Eyck et al., J Clin Oncol 2021

Drugs in this study:Carboplatin (Paraplatin)Paclitaxel (Taxol)

Dose and schedule cards

Preoperative chemoradiotherapy (CROSS regimen)

Resectable cancer of the oesophagus or gastroesophageal junction (squamous cell carcinoma or adenocarcinoma); in adenocarcinoma, for patients who are not suitable for FLOTCycle length: WeeklyOn the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent

Resectable cancer of the oesophagus or gastroesophageal junction (squamous cell carcinoma or adenocarcinoma); in adenocarcinoma, for patients who are not suitable for FLOT

Drug	Dose	Route	Schedule
Carboplatin	AUC 2 mg/mL/min	IV	Weekly (Days 1, 8, 15, 22 and 29)
Paclitaxel	50 mg/m²	IV	Weekly (Days 1, 8, 15, 22 and 29)
Concurrent radiotherapy	41.4 Gy in 23 fractions	External beam radiotherapy	5 days per week

Cycle length: Weekly
Duration: 5 weeks, followed by oesophagectomy

Regimen from the CROSS trial. The carboplatin dose is calculated in mg (not based on body surface area) using the Calvert formula: total dose = target AUC × (GFR + 25). In CROSS, the most common severe adverse events were leukopenia (6%) and anorexia (5%).

On the page “Oesophageal cancer” · Locally advanced disease: treatment with curative intent

CROSS

Resectable oesophageal cancer, before oesophagectomyCycle length: WeeklyOn the page “CROSS regimen: chemoradiotherapy before oesophageal surgery”

Resectable oesophageal cancer, before oesophagectomy

Drug	Dose	Route	Schedule
Carboplatin	AUC 2	IV	Days 1, 8, 15, 22 and 29
Paclitaxel	50 mg/m²	IV	Days 1, 8, 15, 22 and 29
Radiotherapy	41.4 Gy in 23 fractions		5 days a week, concurrent

Cycle length: Weekly
Duration: 5 weeks; surgery about 4 to 6 weeks after completion

Doses as in the CROSS study. Adjuvant nivolumab: 240 mg every 2 weeks for 16 weeks, then 480 mg every 4 weeks up to one year.

On the page “CROSS regimen: chemoradiotherapy before oesophageal surgery”

CROSS: weekly carboplatin + paclitaxel with radiotherapy

Oesophageal or junctional cancer, preoperative chemoradiotherapy (off-label use)Cycle length: WeeklyOn the page “Carboplatin (Paraplatin)” · Standard dosing and combination regimens

Oesophageal or junctional cancer, preoperative chemoradiotherapy (off-label use)

Drug	Dose	Route	Schedule
Carboplatin	AUC 2	IV	Weekly
Paclitaxel	50 mg/m²	IV	Weekly
Radiotherapy	41.4 Gy in 23 fractions		5 days a week

Cycle length: Weekly
Duration: 5 weeks, then surgery

Doses from the CROSS trial.

On the page “Carboplatin (Paraplatin)” · Standard dosing and combination regimens

CROSS (chemoradiotherapy before surgery)

Resectable oesophageal or gastro-oesophageal junction cancerCycle length: WeeklyOn the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

Resectable oesophageal or gastro-oesophageal junction cancer

Drug	Dose	Route	Schedule
Paclitaxel	50 mg/m²	IV	Weekly
Carboplatin	AUC 2	IV	Weekly
Radiotherapy	41.4 Gy in 23 fractions	—	5 days a week

Cycle length: Weekly
Duration: 5 weeks, then surgery

The CROSS trial regimen; not in the FDA label.

On the page “Paclitaxel (Taxol)” · Other regimens: key trials and nab-paclitaxel

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Chemoradiotherapy followed by surgery (178 patients)

Weekly carboplatin dosed to reach an area under the curve (AUC) of 2 mg/mL per minute, with weekly paclitaxel 50 mg/m² of body-surface area, for 5 weeks; concurrently with radiotherapy 41.4 Gy in 23 fractions (5 days a week); followed by oesophagectomy.

2Surgery alone (188 patients)

Oesophagectomy without preoperative treatment.

Source of the regimen details: Doses taken from the abstract of the published paper (N Engl J Med 2012).

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with resectable cancer of the oesophagus or gastro-oesophageal junction; of the 366 patients analysed, 75% had adenocarcinoma, 23% squamous cell carcinoma and 2% large-cell undifferentiated carcinoma. Enrolment from March 2004 to December 2008 (Netherlands Trial Register NTR487).

Endpoints

Primary endpoint: overall survival. Other endpoints: rate of complete resection with clear margins (R0), pathological complete response, and postoperative complications and mortality.

Safety and side effects

The most common severe haematological adverse events in the chemoradiotherapy group were leucopenia (6%) and neutropenia (2%), and the most common severe non-haematological adverse events were anorexia (5%) and fatigue (3%). Postoperative complications were similar in the two groups.

Clinical significance and place in guidelines

CROSS made preoperative chemoradiotherapy one of the standards of treatment for locally advanced, resectable oesophageal cancer. Ten-year follow-up (Eyck et al., J Clin Oncol 2021) showed that the survival benefit persists for at least 10 years. This regimen remains a main option for oesophageal squamous cell carcinoma; but in adenocarcinoma, after the ESOPEC trial, the 2025 update of the ESMO guideline prefers perioperative FLOT chemotherapy and proposes CROSS for patients who are not suitable for FLOT. CROSS was also the basis for the CheckMate 577 trial (adjuvant nivolumab after chemoradiotherapy and surgery).

Limitations

Most patients (75%) had adenocarcinoma, and the number of patients with squamous cell carcinoma (the predominant type in many high-incidence regions) was relatively small; the control group was surgery alone and there was no comparison with perioperative chemotherapy; the study was conducted before the immunotherapy era.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.