Abstract
Background
The optimal total dose of radiotherapy for non-metastatic resectable esophageal cancer remains unclear. We compared standard (41.4 Gy) versus intensified (50.4 Gy) chemoradiotherapy (CRT) regimen.
Methods
In a prospective, phase II, randomized controlled trial (Iran Cancer Institute, March 2021-March 2023), non-metastatic resectable esophageal cancer patients were randomly assigned 1:1 to 41.4 Gy or 50.4 Gy plus weekly carboplatin-paclitaxel followed by surgery, unless a clinical complete response (cCR) was confirmed or the patient refused. The primary outcome of the study was the composite major response rate, defined as pathological complete response (pCR)/pathological near complete response (pnCR) for surgical patients and cCR for non-surgical patients. Survival outcomes and toxicity were secondary outcomes.
Results
Seventy-eight patients were randomized; 70 cases received the allocated CRT in the standard group (34) and intensified group (36). Subsequently, 23 and 21 patients underwent surgery, respectively. The composite major response rate was 54.8% versus 65.6% in the standard and intensified arms, respectively (p = 0.382). The cCR rates were 35.48% vs 45.16%, respectively (p = 0.437). Among resected patients, pCR rates were 45.45% vs 52.38% (p = 0.650), and R0 resection rates were 95.2% vs 100%, respectively. No significant differences were observed between treatment groups in overall and disease-free survival. Grade 2 or higher pneumonitis was significantly more frequent with 50.4 Gy (25% vs 5.9%, p = 0.028). Additionally, cCR predicted pCR with high specificity (90.5%) but modest sensitivity (60%).
Conclusions
Escalating the total dose of neoadjuvant radiotherapy from 41.4 Gy to 50.4 Gy did not improve response rates or survival but significantly increased pneumonitis. Radiotherapy with a 41.4 Gy dose and concurrent carboplatin-paclitaxel, also known as the CROSS regimen, remains an optimal standard. Our findings also highlight a key clinical dilemma: while a cCR can identify candidates for organ preservation, but does not reliably exclude residual disease.
Trial registration: IRCT20250118064427N1 (Registration date: 2025–07-28).
Keywords: Neoadjuvant chemoradiotherapy, Esophageal cancer, Radiation dose, 41.4 Gy, 50.4 Gy
Introduction
Esophageal cancer is the 7th leading cause of cancer-related death in the world, and its highest incidence remains concentrated in two distinct geographical belts: one stretching from North-Central China through Central Asia to Northern Iran, and the other extending across Eastern to Southern Africa. In Western Europe and North America, adenocarcinoma (ADC) is the predominant subtype, while in the eastern world and Asia, squamous cell carcinoma (SCC) is more prevalent. The overall survival (OS) at 5 years has been around 50% in modern studies [1], [2], [3].
For years, the standard treatment for locally advanced esophageal cancer has been neoadjuvant chemoradiotherapy (CRT) followed by surgery, or definitive CRT in certain cases. The benefit of adding chemotherapy and radiotherapy to surgery is documented by various trials over the past decades. The typical radiotherapy dose range utilized in prominent, well-known clinical trials was between 41.4 to 50.4 Gy. Results of the long-term follow-up of the CROSS trial, using a dose of 41.4 Gy in a neoadjuvant setting with concurrent carboplatin/paclitaxel, reported favorable outcomes with increased OS, and have set this regimen as a new standard of care [4], [5], [6], [7], [8].
Although multiple studies, especially INT-0123 and ARTDECO trials, during the past years investigated the role of dose escalation beyond 50 Gy in esophageal cancer, most of them failed to show any dose–effect relationship [6], [9], [10], [11]. Thus, we know that dose escalation beyond 50–50.4 Gy is not beneficial, but limited data have compared 41.4 Gy vs 50.4 Gy in the neoadjuvant setting. This phase II randomized study is designed to evaluate whether a 50.4 Gy dosage has any advantage over a 41.4 Gy regimen in neoadjuvant CRT of esophageal cancer.
Methods
Study design
This prospective phase II randomized controlled trial enrolled patients with non-metastatic resectable esophageal cancer at the Iran Cancer Institute (March 2021-March 2023). Adhering to CONSORT guidelines, patients were randomized 1:1 to standard (41.4 Gy) or intensified (50.4 Gy) neoadjuvant CRT. The study used a parallel-arm design. The primary analysis was conducted on a modified intention-to-treat (mITT) basis, including all randomized participants who initiated treatment. It was approved by the Institutional Review Board (IRB) and ethics committee of Tehran University of Medical Sciences (Code of Ethics: IR.TUMS.IKHC.REC.1399.527). The trial was registered with the Iranian Registry of Clinical Trials (IRCT20250118064427N1).
Study participants and staging Procedures
Eligible patients were aged 18–80 with histologically confirmed SCC or ADC of the middle/lower esophagus or esophagogastric junction (tumors extending > 2 cm into the stomach were excluded). Staging followed the American Joint Commission on Cancer (AJCC) 8th edition criteria (T1N1 or T2-4a, N0-3, M0). Key exclusion criteria were: unresectable or recurrent disease, prior induction chemotherapy, Karnofsky performance status (KPS) score < 70, inadequate organ function, history of other cancers, prior chemotherapy/radiotherapy, active infection, and pregnancy.
Pretreatment staging included clinical history, physical exam, upper endoscopy with biopsy, thoracic/abdominopelvic computed tomography (CT) scan, and endoscopic ultrasound (EUS). Positron emission tomography-CT (PET-CT) was encouraged but not mandatory. Surgical consultation confirmed resectability and fitness for surgery. Jejunostomy was placed pre-treatment in severe dysphagia and at risk of significant nutritional compromise.
Randomization, Blinding, and allocation Concealment
Patients were randomly assigned using web-based permuted block randomization (block size of 4) to one of the trial groups. Allocation was concealed using sequentially numbered opaque sealed envelopes. Due to the nature of the intervention, the study was not blinded. Yet, clinicians assessing the outcomes and statisticians were blinded to treatment allocation to minimize bias.
Interventions
Radiotherapy
Patients received 41.4 Gy (control) or 50.4 Gy (intervention) in 1.8 Gy fractions, 5 days/week. Treatment used megavoltage (≥6 MV) 3D conformal radiotherapy (3D-CRT) with conventional fields while patients were positioned supine for 5 and 6 weeks, respectively.
The clinical target volume (CTV) encompassed the gross tumor volume (GTV) and the regional lymph node basins at risk. For the primary tumor, the high-risk CTV was defined as the GTV with a 3 cm craniocaudal margin, including the adjacent periesophageal fatty tissue. For pathologic lymph nodes, a 0.5 cm margin was applied to create the nodal CTV.
Inclusion of specific elective nodal stations (including the subcarinal region and the fatty tissue along the left gastric and celiac arteries) was performed at the discretion of the treating radiation oncologist, based on individual tumor location and risk assessment. Pathologic nodes received a 0.5 cm margin. For gastric-invading tumors receiving 50.4 Gy, a 2 cm cardiac margin was used to reduce anastomotic risk. Volumes were contoured on CT using fused diagnostic images (e.g., PET-CT if applicable). The final planning target volume (PTV) was generated by uniformly applying a 1 cm expansion to the CTV, except for a 1.5 cm inferior expansion for gastroesophageal junction tumors. Dosing adhered to the ICRU 83 standard. Organ-at-risk constraints were: lung V20Gy ≤ 30%, mean lung dose < 20 Gy, mean heart dose < 26 Gy, heart V30Gy < 30%, and spinal cord max < 45 Gy.
Chemotherapy
The concurrent chemotherapy protocol included weekly intravenous carboplatin (AUC 2 mg/ml/minute) and paclitaxel (50 mg/m2). The intensified group (50.4 Gy) received six courses, while the standard group (41.4 Gy) received five. The patients were closely monitored for toxic events through weekly visits and laboratory tests. CRT was delayed by one week for white blood cell counts < 1.0 × 109/L, platelets < 50 × 109/L, or severe mucositis/vomiting. Patients were withdrawn from the study after a treatment interruption lasting more than 10 days. Chemotherapy was completely withheld in cases of febrile neutropenia, significantly reduced renal function, specific heart conditions, or other major organ toxicities at grade 3 or higher (excluding esophagitis); radiotherapy continued without modification in these cases.
Surgery or surveillance
Clinical response was assessed 4–8 weeks post-CRT with CT and endoscopy ± biopsy; select patients underwent PET. Clinical complete response (cCR) was defined as: no progression or metastasis on chest/abdomen CT, no gross tumor/ulceration on endoscopy, negative biopsy, and no abnormal PET activity (if available). Patients with cCR could choose surveillance or surgery. Surgery was indicated for patients with an incomplete response or residual disease. The surgical approach was either a thoracoabdominal esophagectomy or a transabdominal distal esophagectomy plus gastrectomy with lymph node dissection based on tumor anatomy.
Follow-up
Follow-up occurred every 3 months for 2 years, every 6 months in the third year, and annually until 5 years. The non-surgical group underwent CT/PET and endoscopy at each visit. The surgical group had scheduled restaging 3 months post-treatment, with further investigations only if clinically indicated.
Study outcomes
Primary outcome Measure
The primary endpoint was the rate of complete response, analyzed as a composite outcome to account for patients who did not undergo surgery. The composite major response was defined as pathological complete response (pCR) or pathological near-complete response (pnCR) for patients who underwent resection and cCR for patients managed with a non-surgical approach. In patients who underwent surgery, tumor response was determined by histopathological examination of the resected specimen and classified according to a modified tumor regression grade (TRG) system [12]: TRG 0 (pCR), TRG 1 (pnCR), TRG 2 (partial response), and TRG 3 (no response).
Secondary outcome measures
Secondary outcomes measures included the following: 1) OS: time from the randomization until death from any cause; 2) disease-free survival (DFS): time from the randomization until any recurrence or death; 3) locoregional recurrence-free survival (LRRFS): time from the randomization until locoregional recurrence or death; 4) distant metastasis-free survival (DMFS): time from the randomization until distant metastasis or death; 5) mortality rate related to CRT; and 6) the rate of adverse events or treatment-related toxicities as per National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.
Sample size
In the CROSS trial, the pCR rate was 40% for SCC and 15% for ADC. Since approximately 75% of our patients have SCC, we anticipated a pCR rate of around 33.75% with a dosage of 41.4 Gy. We hypothesized that increasing the dosage to 50.4 Gy could raise this rate to between 45% and 50%. To reach a two-sided significance level of 5% with 80% power, we estimated an approximate sample size of 320 patients for the study.
Statistical analysis
The interim analysis was performed on the modified intention-to-treat (mITT) population after enrolling 25% of the estimated sample size. All statistical analyses were conducted using SPSS software (version 20, IBM Corp., Armonk, NY, USA). Continuous variables were reported as mean ± standard deviation (SD) or median (IQR), and categorical variables were reported as frequencies (%). Between-group comparisons of continuous variables were performed using the independent samples t-test. For categorical variables, Chi-squared or Fisher’s exact tests were applied. Survival outcomes, including OS, DFS, LRRFS, and DMFS, were analyzed with the Kaplan-Meier method. Differences in survival curves were assessed using the log-rank test. A p-value of < 0.05 was considered statistically significant.
Results
Study flow
In accordance with protocol, a preplanned interim analysis for futility and safety was conducted. Due to a declining regional incidence of esophageal cancer, patient accrual was slower than projected. The interim analysis showed increased toxicity without evidence of superior efficacy in the experimental arm. Consequently, the trial was terminated early after approximately 25% of the target enrollment, based on the predefined futility and safety criteria. Overall, 91 patients were screened for eligibility; 13 were excluded (11 not meeting eligibility, 1 declined participation, 1 other reason). According to the CONSORT flow diagram (Fig. 1), 78 patients were randomized: 39 to the standard (41.4 Gy) and 39 to the intensified (50.4 Gy) arm. Following randomization, eight patients deviated from the protocol and did not receive their allocated treatment. This included five patients in the standard group (three due to receiving induction chemotherapy, one due to poor KPS, and one who declined) and three in the intensified group (two due to induction chemotherapy and one who declined). Finally, 34 in the 41.4 Gy arm and 36 in the 50.4 Gy arm received allocated intervention and underwent mITT analysis. After CRT, 23 patients in the standard group and 21 patients in the intensified group underwent surgery. The remaining patients were under watchful surveillance. There was no loss to follow-up in the 41.4 Gy arm. However, one patient in the 50.4 Gy arm was lost to follow-up.
Fig. 1.
CONSORT flow diagram of the study.
Baseline Demographics and clinical characteristics
Baseline characteristics were well-balanced between groups (Table 1). The mean age was similar (59.85 ± 9.66 vs. 59.41 ± 10.98 years; p = 0.861). Most patients were male (58.8% vs. 66.7%; p = 0.497), and squamous cell carcinoma (SCC) was the predominant histology (76.5% vs. 86.1%; p = 0.549). Only 6 of the 70 cases (8.6%) underwent fluorodeoxyglucose-PET (FDG-PET) for staging. Tumor location, T- and N-stage distributions, grade, and length showed no significant differences.
Table 1.
Baseline Demographics, Clinical Characteristics, and Treatment Summary.
| Standard regimen (41.4 Gy) (n = 34) | Intensified Regimen (50.4 Gy) (n = 36) | P-value | |
|---|---|---|---|
| Age [years; mean (SD)] | 59.85 (9.66) | 59.41 (10.98) | 0.861a |
| Sex [n (%)] | 0.497b | ||
|
20 (58.8%) | 24 (66.7%) | |
|
14 (41.2%) | 12 (33.3%) | |
| Location of Lesion [n (%)] | 0.808b | ||
|
14 (41.1%) | 17 (47.2%) | |
|
16 (47.1%) | 17 (47.2%) | |
|
4 (11.8%) | 2 (5.6%) | |
| Histology [n (%)] | 0.549b | ||
|
26 (76.5%) | 31 (86.1%) | |
|
7 (20.6%) | 4 (11.1%) | |
|
1 (2.9%) | 1 (2.8%) | |
| Lesion Grade [n (%)] | 0.087b | ||
|
12 (42.9%) | 4 (15.4%) | |
|
11 (39.3%) | 15 (57.7%) | |
|
5 (17.9%) | 7 (26.9%) | |
| T stage [n (%)] | 0.708b | ||
|
1 (2.9%) | 0 (0%) | |
|
4 (11.8%) | 5 (13.9%) | |
|
24 (70.6%) | 24 (66.7%) | |
|
5 (14.7%) | 7 (19.4%) | |
| N stage [n (%)] | 0.791b | ||
|
3 (8.8%) | 2 (5.6%) | |
|
15 (44.1%) | 13 (36.1%) | |
|
14 (41.2%) | 19 (52.8%) | |
|
2 (5.9%) | 2 (5.6%) | |
| Lesion length [cm; mean (SD)] | 4.45 (1.84) | 4.77 (1.76) | 0.530a |
| Radiotherapy | |||
|
34 (100%) | 36 (100%) | − |
|
32.32 (5.40) | 39.36 (3.73) | <0.001a |
|
6 (17.6%) | 7 (19.4%) | 0.14b |
| Chemotherapy | |||
|
28 (82.3%) | 27 (75%) | 0.254b |
|
3.88 (1.03) | 4.83 (0.84) | <0.001a |
| Surgery | |||
| Number underwent Sx [n (%)] | 23 (67.6%) | 21 (58.3%) | 0.420b |
| Type of Sx | 0.193b | ||
|
12 (52.2%) | 13 (61.9%) | |
|
11 (47.8%) | 8 (38.1%) | |
| Duration from completion of RT to Sx [weeks; mean (SD)] | 9.94 (1.43) | 12.69 (1.23) | 0.652a |
P-value of < 0.05 was considered statistically significant.
SD: standard deviation; SCC: Squamous Cell Carcinoma; ADC: Adenocarcinoma.
Student T-test.
Chi-squared test.
Treatment Delivery
Concurrent chemoradiotherapy
Radiotherapy was completed by all of the patients in both groups. As intended, the intensified arm received a higher total dose and a longer treatment course. RT protocol deviations, primarily attributed to device breakdown, treatment-related adverse events (AEs), and COVID-19 infection, were infrequent and comparable (Table 1).
Fifteen treatment-related adverse events resulted in modifications to the planned concurrent chemotherapies, including holds or delays. Specifically, the chemotherapy course was completed by 82.3% of patients in the standard arm, compared to 75% in the intensified arm (p = 0.254). As designed, the intensified arm received more weekly cycles (intensified arm: 4.83 ± 0.84 vs standard arm: 3.88 ± 1.03; p < 0.001). Dose reduction for ≥ G3 toxicity occurred in 6/34 (17.6%) of the standard arm and 9/36 (25%) of the intensified arm (p = 0.454).
Surgery
A total of 44 patients (62.8%) underwent surgery. The rate of surgery was 67.6% for the standard arm versus 55.6% for the intensified arm. Among the resected patients, the operative approaches were comparable (Table 1). The interval from RT completion to surgery showed variability but did not differ statistically. Of the 43 resections with available margin status, 42 (97.7%) were R0. The R0 resection rate was 21/21 (100%) in the intensified arm and 21/22 (95.5%) in the standard arm, which contained the only R1 resection.
Efficacy outcomes
Clinical and pathological responses
Among evaluable patients, cCR was observed in 11/31 (35.48%) in the standard arm and 14/31 (45.16%) in the intensified arm (p = 0.437) (Figs. 2a and 2b). Among resected patients with available pathology (22 standard, 21 intensified), the overall distribution of responses did not differ (p = 0.489). pCR occurred in 10/22 (45.45%) of the standard arm versus 11/21 (52.38%) of the intensified arm; pnCR in 2/22 (9.09%) of the standard arm versus 2/21 (9.52%) of the intensified arm; partial response in 4/22 (18.18%) of the standard arm versus 6/21 (28.57%) of the intensified arm; and no response in 6/22 (27.27%) of the standard arm versus 2/21 (9.52%) of the intensified arm (Fig. 2c and 2d). Furthermore, a focused comparison of pCR rates alone also showed no significant difference (p = 0.650). When combining cCR and pCR, rates were 48.4% versus 59.4% (p = 0.382), and when combining cCR, pCR, and pnCR, composite major response rates were 54.8% versus 65.6% for standard and intensified arms, respectively (p = 0.382).
Fig. 2.
Pie charts of clinical complete response in a) standard and b) intensified arms and pathological response in c) standard and d) intensified arms.
Exploratory analysis by histology
Given the known differences in radiosensitivity, a subgroup analysis was performed to assess treatment outcomes of two RT doses in the two histologic types (SCC, ADC). The comparison of response rates are summarized in Fig. 3 Distribution of patients and the comparative response outcomes are detailed in Supplementary Table S1. Among the 70 patients, 57 had SCC (41.4 Gy: n = 26; 50.4 Gy: n = 31) and 11 had ADC (41.4 Gy: n = 7; 50.4 Gy: n = 4).
Fig. 3.
Pathologic and clinical response rates by histology and radiation dose.
Within the SCC subgroup, rates of pCR/pnCR were 62.5% (10/16) with 41.4 Gy and 57.9% (11/19) with 50.4 Gy (p = 0.782). Also, cCR rates were 43.5% and 50%, respectively (p = 0.648). The composite major response rates were nearly identical between dose groups (60.9% vs. 60.7%, p = 0.991). In the ADC subgroup, pCR/pnCR rates were 33.3% (2/6) with 41.4 Gy and 100% (2/2) with 50.4 Gy (p = 0.102), though the number of surgical patients in the 50.4 Gy arm was very small. Composite major response rates were 28.6% and 50%, respectively (p = 0.477). No comparisons reached statistical significance in either subgroup.
Concordance between cCR and pCR
Among the 41 patients who had both post-CRT clinical reassessment and resection pathology, we treated cCR as the index test and pCR as the reference standard (Table 2). Accordingly, the sensitivity of cCR for detecting pCR was 60% (12/20), and the specificity for excluding pCR was 90.5% (19/21). The positive predictive value (PPV) of cCR for true pCR was 85.7% (12/14), whereas the negative predictive value (NPV) of non-cCR for absence of pCR was 70.4% (19/27). Overall diagnostic accuracy was 75.6% (31/41). In practical terms, a cCR strongly predicts pCR (high specificity and PPV), but the absence of cCR does not reliably exclude pCR (modest sensitivity and NPV).
Table 2.
Concordance between clinical and pathological complete responses.
| Measure | Results n (%) |
|---|---|
| pCR + and cCR+ | 12 |
| pCR + and cCR- | 8 |
| pCR- and cCR+ | 2 |
| pCR- and cCR- | 19 |
| Diagnostic Accuracy Metrics | |
| Sensitivity | 12/20 (60%) |
| Specificity | 19/21 (90.5%) |
| Positive Predictive Value (PPV) | 12/14 (85.7%) |
| Negative Predictive Value (NPV) | 19/27 (70.4%) |
| Overall Accuracy | 31/41 (75.6%) |
Mortality
Overall mortality did not differ between the standard arm (18/34 [52.9%]) and the intensified arm (20/36 [55.6%]) (p = 0.826). The mortality rate from the start of treatment through one month post-CRT was 3/34 (8.8%) in the standard arm versus 4/36 (11.1%) in the intensified arm (p = 0.999). Post-operative mortality among resected patients was 5/23 (21.7%) versus 3/21 (14.3%) for the standard and intensified arms, respectively (p = 0.701) (Table 3).
Table 3.
Mortality rates across trial groups.
| Variable | Standard regimen (41.4 Gy) | Intensified Regimen (50.4 Gy) | P-value |
|---|---|---|---|
| Overall Mortality | 18 (52.9%) | 20 (55.6%) | 0.826a |
| Mortality from the start of chemoradiotherapy until one month after its completion | 3 (8.8%) | 4 (11.1%) | 0.999b |
| Post-operation Mortality | 5 (21.7%) | 3 (14.3%) | 0.701b |
P-value of < 0.05 was considered statistically significant;
Chi-squared test.
Fisher's Exact test.
Survival
The median follow-up time in the standard and intensified groups were 26.21 months (25.03–32.97) and 24.9 months (20.87–27.12), respectively. In the total cohort, no significant differences were observed between arms for OS, DFS, LRRFS, or DMFS (Fig. 4a-d).
Fig. 4.
Survival curves for a) overall, b) disease-free, c) locoregional recurrence-free, and d) distant metastasis-free survivals across standard and intensified arms.
OS
In non-surgical patients, median OS was 13 months (95%CI: 0.87–25.13) for the standard arm vs 18 months (95%CI: 9.16–26.84) for the intensified arm (p = 0.709). In surgical patients, median OS was 24 months vs 23 months (95%CI: 17.94–28.06) for the standard and intensified arms, respectively (p = 0.999). Overall cohort median OS was 22 months (95%CI: 12.58–31.42). Adjusted log-rank (accounting for surgery) demonstrated no significant between-arm differences (p = 0.823).
DFS
Among non-surgical patients, median DFS was 7 months (95%CI: 2.15–11.86) for the standard arm vs 11 months (95%CI: 5.95–16.05) for the intensified arm (p = 0.250). In surgical patients, median DFS was 20 months for the standard arm vs 19 months (95%CI: 14.75–23.25) for the intensified arm (p = 0.9). Overall median DFS was 14 months (95%CI: 6.73–21.27). Adjusted log-rank (accounting for surgery) demonstrated no significant between-arm differences (p = 0.545).
LRRFS
In non-surgical patients, median LRRFS was 10 months (95%CI: 2.45–17.55) for the standard arm vs 14 (95% CI: 4.32–23.68) for the intensified arm (p = 0.256). In surgical patients, median LRRFS was 30 (95%CI: 3.46–56.54) for the standard arm vs 19 (95%CI: 12.20–25.80) for the intensified arm (p = 0.739). Overall median LRRFS was 17 months (95%CI: 9.24–24.76). Adjusted log-rank (accounting for surgery) demonstrated no significant between-arm differences (p = 0.663).
DMFS
In non-surgical patients, median DMFS was 10 months for the standard arm vs 13 (95%CI: 9.21–16.79) for the intensified arm (p = 0.746). In surgical patients, median DMFS was not reached for the standard arm vs 23 (95%CI: 11.65–34.36) for the intensified arm (p = 0.931). Overall median DMFS was 20 months. Adjusted log-rank (accounting for surgery) demonstrated no significant between-arm differences (p = 0.896).
Safety and Tolerability
During neoadjuvant CRT
Acute toxicities were broadly similar between groups (Table 4, Fig. 5). During neoadjuvant CRT, the most common toxicity in the standard arm was grade ≥ 2 neutropenia, occurring in 17.6% of patients. Similarly, in the intensified arm, adverse events were dominated by hematologic toxicity: grade ≥ 2 neutropenia was the most prevalent adverse event, affecting 36.1% of patients, followed by grade ≥ 2 anemia and grade ≥ 3 nausea/vomiting at 13.9%.
Table 4.
Adverse events across trial groups (per CTCAE v.4).
| Adverse Event | Standard regimen (41.4 Gy) n (%) | Intensified regimen (50.4 Gy) n (%) | p-values | |
|---|---|---|---|---|
| During Neo-adjuvant chemoradiotherapy | Raised Cr G2+ | 0 (0.0%) | 3 (8.3%) | 0.24b |
| HBT G1+ | 1 (2.9%) | 3 (8.3%) | 0.615b | |
| N/V G3+ | 4 (11.8%) | 5 (13.9%) | 0.999b | |
| Diarrhea | 1 (2.9%) | 4 (11.1%) | 0.358b | |
| Dermatitis G2+ | 1 (2.9%) | 1 (2.8%) | 0.999b | |
| Anemia G2+ | 2 (5.9%) | 5 (13.9%) | 0.430b | |
| Neutropenia G2+ | 6 (17.6%) | 13 (36.1%) | 0.083a | |
| Thrombocytopenia G2+ | 0 (0.0%) | 2 (5.6%) | 0.493b | |
| Esophagitis G3+ | 0 (0.0%) | 2 (5.6%) | 0.493b | |
| After chemoradiotherapy /surgery | Neuropathy G2+ | 1 (2.9%) | 4 (11.1%) | 0.358b |
| Stenosis G3+ | 1 (2.9%) | 6 (16.7%) | 0.107b | |
| Pneumonitis | 2 (5.9%) | 9 (25.0%) | 0.028a | |
| Fistula | 1 (2.9%) | 1 (2.8%) | 0.999b | |
| Abscess | 2 (5.9%) | 1 (2.8%) | 0.609b | |
| Infection | 6 (17.6%) | 5 (13.9%) | 0.666a |
Cr: creatinine; HBT: Hepatobiliary toxicity: N/V: nausea/vomiting.
Chi-Squared test.
Fisher's Exact test.
Fig. 5.
Treatment-related adverse events.
Radiation Dosimetry and pulmonary toxicity
To investigate the association between radiation dose and the observed increase in pneumonitis, a dosimetric analysis was performed for patients with available planning data (Supplementary material Table S2). Compared to the standard regimen, the intensified regimen delivered a significantly higher dose to the lungs. The mean lung dose increased from 13.9 Gy to 17 Gy (p = 0.006), and the median V20 increased from 24.7% to 37.5% (p = 0.003).
After CRT or surgery
In the standard arm, the most common event was infection (17.6%), exceeding other late complications such as pneumonitis (5.9%), stenosis (2.9%), and neuropathy (2.9%). In the intensified arm, pneumonitis was the most prevalent post-treatment event, occurring in 25% of patients, higher than infection (13.9%), stenosis (16.7%), and neuropathy (11.1%). Notably, post-treatment events were mostly comparable between arms, with one statistically significant difference (Table 4); pneumonitis occurred more often after 50.4 Gy (25% in the intensified arm vs 5.9% in the standard arm; p = 0.028).
Discussion
This randomized phase II study found that escalating neoadjuvant radiotherapy from 41.4 Gy to 50.4 Gy, concurrent with weekly carboplatin and paclitaxel, failed to improve oncological or survival outcomes, while simultaneously increasing the risk of pneumonitis. Additionally, an exploratory analysis comparing the two radiation doses in SCC and ADC cases, separately, although limited by small subgroup sizes, particularly for ADC, did not provide evidence of a differential benefit from dose escalation by histology in this trial population. These results demonstrate a therapeutic plateau for radiation dose escalation within this chemoradiation backbone. Consequently, 41.4 Gy appears to be an effective dose, and further improvements in outcomes will likely require innovations in systemic therapy, such as new concomitant chemotherapy regimens or novel agents, rather than increased radiation dose.
The 41.4 Gy regimen popularized by CROSS significantly improved R0 resection, pCR, and OS versus surgery alone, with an acceptable toxicity profile, establishing a standard treatment modality for both histologic tumor types [7]. In the exclusive SCC subset, the NEOCRTEC5010 trial similarly demonstrated survival gains with neoadjuvant CRT (40 Gy) compared with surgery alone. Their findings substantiated that a low preoperative dose, coupled with active systemic agents, is sufficient to improve long-term outcomes [13]. Despite the cohort's predominant SCC histology, a histology known to yield higher pCR after a neoadjuvant CROSS-based regimen and numerically higher pathologic responses with 50.4 Gy, we observed no significant benefit in survival, surgical outcomes, or composite response rates. This aligns with a SCC-focused retrospective study showing no pCR or survival benefit for a dose range of > 45 Gy versus ≤ 45 Gy [14]. This finding was also validated in the subgroup analysis of the ARTDECO trial [10]. These data indicate that histology-dependent radiosensitivity enhances tumor response at standard dose; however, higher dose escalation is not reliably associated with a pathologic response or survival benefit. Additionally, Multiple propensity-adjusted National Cancer Database analyses report no advantage in pCR or survival for preoperative doses above 41–45 Gy, and in some instances signal lower perioperative mortality and better OS with 41.4 Gy versus 50.4 Gy [6], [11], [15], [16]. A notable counterpoint is the multicenter series by Mantziari et al., which associated 50.4 Gy with higher pCR than 41.4 Gy, particularly in ADC cases, without gains in DFS or OS, highlighting the limited reliability of pCR as a surrogate marker for long-term outcomes, aligning with our observation of a trend-level difference in pCR without a corresponding survival benefit [17]. Dose-painting intensity-modulated strategies (IMRT) to 56 Gy can further raise pCR and locoregional control relative to 50.4 Gy, yet still lack a clear survival advantage and may increase postoperative atrial fibrillation, highlighting the trade-offs as dose climbs [18]. This result is somewhat in line with the high-quality ARTDECO trial, which aimed to improve upon previous research by employing the modern IMRT-SIB (simultaneous integrating boost) technique; however, it found no advantage to dose escalation beyond 50.4 Gy [10]. Similarly, a systematic review favored lower biologically effective doses (40–41.4 Gy) for an optimal therapeutic ratio, especially when modern conformal techniques are used [19]. Taken together, the body of evidence suggests diminishing returns from dose escalation in the neoadjuvant or definitive setting, along with prioritizing normal-tissue sparing and systemic control over incremental tumor-bed dose.
Safety findings in our trial merit emphasis. Regarding radiation-related toxicity, the intensified regimen significantly increased radiation exposure to lung tissue, providing a dosimetric explanation for its higher incidence of grade ≥ 2 pneumonitis compared to the standard regimen. This risk underscores the importance of technique, as modern radiotherapy modalities such as IMRT and volumetric modulated arc therapy (VMAT) provide superior sparing of organs at risk, including the lungs and heart, compared with 3D-CRT used in this study. This dosimetric advantage is consistently demonstrated in planning comparisons and is crucial for minimizing toxicity [20], [21], [22]. Current evidence links radiation-related pneumonitis to lung dose-volume metrics. In fact, it has been substantiated that keeping V20 below 23% and minimizing the dose is associated with fewer events and improved outcomes [23], [24]. However, the translation of dosimetric advantages into reduced clinical pneumonitis has been inconsistent. A meta-analysis found that although IMRT significantly reduced irradiated lung and heart volumes at high doses and was associated with improved OS, it did not show a statistically significant reduction in the incidence of radiation pneumonitis compared with 3D-CRT in the pooled analysis [25]. Additionally, the improved high-dose conformality with these modern techniques may come at the expense of a larger volume of normal tissue receiving low-dose radiation [26], a trade-off that raises theoretical concerns about long-term risks of secondary malignancies. However, for tumors in close proximity to critical structures like the lungs, the immediate benefit of reducing the risk of severe, dose-limiting toxicities such as pneumonitis is paramount. Furthermore, the prolonged administration of concurrent carboplatin-paclitaxel in the intensified arm may have independently contributed to pulmonary risk, based on theoretical and reported associations between this regimen and pneumonitis in definitive CRT settings [27], [28], [29]. Additionally, regarding the chemotherapy-related toxicities, in our study, a non-significant increase in neuropathy was observed with the intensified regimen (11.1% vs. 2.9%), consistent with its longer treatment duration and greater number of concurrent chemotherapy cycles. Our findings caution that intensification confers a dual risk: heightened radiation exposure to the lungs and increased cumulative chemotherapeutic burden. Therefore, pursuing such a strategy necessitates the use of the most conformal, organ-sparing radiotherapy techniques alongside careful consideration of the trade-offs associated with prolonged cytotoxic therapy.
In our study, cCR was a highly specific predictor of pCR; however, its modest sensitivity indicates that a single-modality clinical assessment fails to identify a substantial portion of patients who actually achieve a pCR. This limitation, where true pathologic responders may not be recognized clinically, underscores the critical need for multimodal response assessment strategies. As demonstrated in the preSANO trial, a rigorous algorithm that incorporates endoscopic biopsies, EUS with nodal fine-needle aspiration, and PET-CT is superior for accurate restaging of patients after neoadjuvant therapy [30]. Furthermore, emerging research on quantitative imaging biomarkers, such as early changes in apparent diffusion coefficient on diffusion weighted magnetic resonance imaging (DW-MRI) or total lesion glycolysis on FDG-PET/CT, has shown high potential to discriminate pathologic responders very early during treatment, potentially improving patient selection for adaptive strategies [31].As noted, a non-surgical approach was considered acceptable for patients achieving cCR. This strategy was motivated by evidence, particularly in SCC, suggesting esophagectomy after CRT may not improve OS despite better local control, while adding significant treatment-related morbidity and mortality [32], [33], [34]. Compounding this evidence, our institution's prior experience with a high post-operative mortality rate (similar to the results of approximately 20% in our trial) led us to consider organ preservation in eligible patients. This strategy has been validated by the recent SANO trial, which supports non-surgical management, particularly for ADC cases. The phase 3 SANO trial reported that active surveillance was non-inferior to standard immediate esophagectomy for 2-year OS after confirmed cCR, which supports the case for response-adapted management in selected patients [35]. In this regard, our results demonstrated little justification for preoperative dose escalation merely to induce higher clinical or pathological response.
The landscape of esophageal cancer treatment is evolving due to recent publications, including the SANO and ESOPEC studies. The ESOPEC trial demonstrated the superiority of the FLOT chemotherapy regimen over CRT with the CROSS protocol for esophageal ADC [36]. Although these results were unavailable during the entire duration of our trial, the ESOPEC study has since been met with serious critique. Primary concerns involve a notably lower rate of completed chemotherapy cycles in the CRT arm (67%) relative to prior studies, almost inconsistent results compared to previous studies, a statistical issue termed “Skimming the Median” [37], and the omission of adjuvant nivolumab for patients without pCR. As adjuvant nivolumab is now a standard evidence-based therapy that improves DFS [38], this specific shortcoming must be addressed in a future clinical trial. In short, despite meaningful progress in the management of esophageal cancer during the last year, many critical questions still need to be answered. The recent success of novel agents like immune checkpoint inhibitors (ICIs) in the first-line treatment of gastric cancer has opened a promising new avenue for addressing this need in esophageal cancer [39]. Immunotherapy has also shown potential in both esophageal SCC, our cohort's predominant histology, and gastroesophageal ADC, in which combining ICIs with neoadjuvant CRT has demonstrated manageable toxicity and encouraging pathologic responses. While early-phase trials in esophageal SCC report pCR rates of 40–60% with such combinations, the optimal radiation dose and sequencing remain undefined, underscoring the need for future randomized trials to define the safest and most effective protocols within these novel combinations [40], [41].
Limitations and Strengths
The interpretations of this study are tempered by its limitations, including a small sample size, disruptions from the COVID-19 pandemic, significant patient heterogeneity, and a lack of long-term follow-up. Furthermore, administration of adjuvant nivolumab was not feasible in this trial because the drug was not available in our country during the study period. Nonetheless, randomization, balanced baseline characteristics, and paired clinical and pathological response assessment increase confidence in the main conclusion.
Conclusion and practical Implications
For resectable non-metastatic esophageal cancer, 41.4 Gy remains a reliable option that delivers high R0 and substantial pCR with fewer pulmonary complications. Given the lack of survival benefit and higher pneumonitis with the 50.4 Gy regimen in this trial, consistent with broader evidence, routine preoperative dose escalation should be avoided outside of trials or highly selected anatomic scenarios. These interpretations are offered with the recognition that our study’s early termination and subsequent small sample size limit the statistical power to detect differences in survival endpoints. Future efforts should focus on meticulous normal-tissue sparing, robust multimodality response evaluation to enable organ-preserving strategies where appropriate, and optimization of systemic therapy and perioperative care, which are more likely to influence long-term outcomes than an additional radiation dose.
Declarations
Ethical approval and consent to participate: All participants provided written informed consent for participation before study enrollment (Code of Ethics: IR.TUMS.IKHC.REC.1399.527).
Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Ebrahim Esmati: Supervision, Conceptualization, Validation, Resources, Methodology, Writing – review & editing. Reza Nazari: Methodology, Investigation, Data curation, Writing – original draft. Ali Aqamolaei: Investigation, Data curation, Writing – original draft, Writing – review & editing. Afsane Maddah Safaei: Resources, Methodology, Writing – review & editing. Rouhollah Miri: Resources, Methodology, Writing – review & editing. Mohammad Shirkhoda: . Amirmohsen Jalaeefar: Resources, Methodology, Writing – review & editing. Samaneh Salarvand: Resources, Methodology, Writing – review & editing. Mahdi Aghili: Resources, Methodology, Writing – review & editing. Farshid Farhan: . Nima Mousavi Darzikolaee: Resources, Methodology, Writing – review & editing. Kasra Kolahdouzan: Data curation, Formal analysis, Visualization, Writing – review & editing. Romina Abyaneh: Investigation, Visualization, Writing – review & editing. Reza Ghalehtaki: Conceptualization, Supervision, Validation, Resources, Methodology, Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
None
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ctro.2026.101155.
Contributor Information
Ebrahim Esmati, Email: eb_esmati@yahoo.com.
Reza Nazari, Email: rz.nzr.89@gmail.com.
Ali Aqamolaei, Email: a-aqamolaei@razi.tums.ac.ir.
Afsane Maddah Safaei, Email: afsan1980@ymail.com.
Rouhollah Miri, Email: srmiri@sina.tums.ac.ir.
Mohammad Shirkhoda, Email: mshirkhoda@sina.tums.ac.ir.
Amirmohsen Jalaeefar, Email: Jalaeefar@gmail.com.
Samaneh Salarvand, Email: sm.salarvand@gmail.com.
Mahdi Aghili, Email: aghili@tums.ac.ir.
Farshid Farhan, Email: Farhan@tums.ac.ir.
Nima Mousavi Darzikolaee, Email: mousavi.nima@yahoo.com.
Kasra Kolahdouzan, Email: Kakol_72@yahoo.com.
Romina Abyaneh, Email: r-abyaneh@farabi.tums.ac.ir.
Reza Ghalehtaki, Email: rghalehtaki@tums.ac.ir.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Data availability
The data can be available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data can be available from the corresponding author upon reasonable request.