The early regression index (ERI) predicts treatment response in rectal cancer patients. Aim of current study was to prospectively assess tumor response to neoadjuvant chemo-radiotherapy (nCRT) of locally advanced esophageal cancer using ERI, based on MRI.
From January 2020 to May 2023, 30 patients with esophageal cancer were enrolled in a prospective study (ESCAPE). PET-MRI was performed: i) before nCRT (tpre); ii) at mid-radiotherapy, tmid; iii) after nCRT, 2-6 weeks before surgery (tpost); nCRT delivered 41.4 Gy/23fr with concurrent carboplatin and paclitaxel. For patients that skipped surgery, complete clinical response (cCR) was assessed if patients showed no local relapse after 18 months; patients with pathological complete response (pCR) or with cCR were considered as complete responders (pCR + cCR). GTV volumes were delineated by two observers (Vpre, Vmid, Vpost) on T2w MRI: ERI and other volume regression parameters at tmid and tpost were tested as predictors of pCR + cCR.
Complete data of 25 patients were available at the time of the analysis: 3/25 with complete response at imaging refused surgery and 2/3 were cCR; in total, 10/25 patients showed pCR + cCR (pCR = 8/22). Both ERImid and ERIpost classified pCR + cCR patients, with ERImid showing better performance (AUC:0.78, p = 0.014): A two-variable logistic model combining ERImid and Vpre improved performances (AUC:0.93, p < 0.0001). Inter-observer variability in contouring GTV did not affect the results.
Despite the limited numbers, interim analysis of ESCAPE study suggests ERI as a potential predictor of complete response after nCRT for esophageal cancer. Further validation on larger populations is warranted.

BACKGROUND: Despite obvious advances over the last decades, locally advanced adenocarcinomas of the gastroesophageal junction (GEJ) still carry a dismal prognosis with overall 5-year survival rates of less than 50% even when using modern optimized treatment protocols such as perioperative chemotherapy based on the FLOT regimen or radiochemotherapy. Therefore the question remains whether neoadjuvant chemotherapy or neoadjuvant radiochemotherapy is eliciting the best results in patients with GEJ cancer. Hence, an adequately powered multicentre trial comparing both therapeutic strategies is clearly warranted.
METHODS: The RACE trial is a an investigator initiated multicenter, prospective, randomized, stratified phase III clinical trial and seeks to investigate the role of preoperative induction chemotherapy (2 cycles of FLOT: 5-FU, leucovorin, oxaliplatin, docetaxel) with subsequent preoperative radiochemotherapy (oxaliplatin weekly, 5-FU plus concurrent fractioned radiotherapy to a dose of 45 Gy) compared to preoperative chemotherapy alone (4 cycles of FLOT), both followed by resection and postoperative completion of chemotherapy (4 cycles of FLOT), in the treatment of locally advanced, potentially resectable adenocarcinoma of the gastroesophageal junction. Patients with cT3-4, any N, M0 or cT2 N+, M0 adenocarcinoma of the GEJ are eligible for inclusion. The RACE trial aims to enrol 340 patients to be allocated to both treatment arms in a 1:1 ratio stratified by tumour site. The primary endpoint of the trial is progression-free survival assessed with follow-up of maximum 60 months. Secondary endpoints include overall survival, R0 resection rate, number of harvested lymph nodes, site of tumour relapse, perioperative morbidity and mortality, safety and toxicity and quality of life.
CONCLUSIONS: The RACE trial compares induction chemotherapy with FLOT followed by preoperative oxaliplatin and 5-Fluorouracil-based chemoradiation versus preoperative chemotherapy with FLOT alone, both followed by surgery and postoperative completion of FLOT chemotherapy in the treatment of locally advanced, non-metastatic adenocarcinoma of the GEJ. The trial aims to show superiority of the combined chemotherapy/radiochemotherapy treatment, assessed by progression-free survival, over perioperative chemotherapy alone.
BACKGROUND: ClinicalTrials.gov ; NCT04375605 ; Registered 4th May 2020.

OBJECTIVE: The value of neoadjuvant radiochemotherapy for high rectal cancers is controversial. This study compared surgery plus neoadjuvant radiochemotherapy to surgery alone.
METHODS: Fifty-two patients with stage II/III high rectal cancers treated with surgery plus neoadjuvant radiochemotherapy were matched (1:4) to 208 patients treated with surgery alone. Matching criteria included age (≤65 vs. >65 years), gender and UICC-stage (II vs. III). These criteria were identical in all five patients used for each 1:4 matching. Both groups were compared for overall survival (OS).
RESULTS: On univariate analyses, age ≤65 years (p<0.001) was significantly associated with improved OS. A trend towards improved OS was found for neoadjuvant radiochemotherapy (p=0.078) and UICC-stage II (p=0.060). On multivariate analysis, age (p<0.001) remained significant, and neoadjuvant radiochemotherapy showed a trend towards better OS (p=0.073).
CONCLUSIONS: Given the limitations of this study, the results showed that neoadjuvant radiochemotherapy may improve OS in patients with stage II/III high rectal cancers. However, these results need to be verified in a prospective randomized trial.

OBJECTIVE: To report survival and morbidity of a large homogeneous cohort of patients with a locally advanced esophageal or cardia carcinoma and put in evidence predictive factors of locoregional control and survival.
METHODS: Hundred and two patients were treated at the university hospital of Tours between 1990 and 2010 and received neo-adjuvant chemoradiation therapy with external irradiation (40Gy-44Gy) and two courses of chemotherapy (5-fluoro-uracile and cisplatine). Esophagectomy associated with lymph node dissection was performed about ten weeks after the end of chemoradiation therapy.
RESULTS: The median follow-up was 22.4 months [6-185 months]. The overall survival rates at 2 and 5years were 53% and 27%, respectively. The median overall survival was estimated at 27months. The overall 2-year survival between patients \"responders\" and patients \"non-responders\" was 67% vs 26%, respectively (P<0.0001). In case of histological response, there was a benefit in terms of overall survival (P<0.0001), locoregional control (P<0.0036) and disease-free survival (P<0.001). Overall survival at 2years was 64% for ypN0 group vs 32% for ypN1 group (P<0.0001). The median survival was estimated at 37months against 15months in the absence of lymph node involvement (P<0.0001).
CONCLUSIONS: Our results in terms of survival, tolerance and morbidity and mortality were comparable to those in the literature. Complete histological response of lymph node was associated with an improvement of local control, disease-free survival and overall survival.

OBJECTIVE: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S).
METHODS: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection).
RESULTS: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051).
CONCLUSIONS: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

OBJECTIVE: Esophageal squamous cell carcinoma is increasingly treated with trimodality therapy. The objective of this Phase I/II clinical study is to assess the efficacy and safety of neoadjuvant radiochemotherapy with docetaxel and cisplatin and radiotherapy in patients with esophagectomy for locally advanced squamous cell carcinoma of the esophagus with neoadjuvant chemoradiotherapy.
METHODS: Patients with esophageal squamous cell carcinoma received radiochemotherapy (50 Gy/25 fractions during Weeks 1-5) using a three-dimensional conformal radiation therapy or intensity-modulated radiation therapy technique together with weekly docetaxel (20 mg/m(2) at dose levels 1 and 2, 25 mg/m(2) at dose level 3 on Weeks 1-5) and cisplatin (30 mg/m(2) at dose level 1, 40 mg/m(2) at dose levels 2 and 3 on Weeks 1-5) from January 2009 to December 2011. The dose-limiting toxicities and maximum tolerated dose were the primary endpoints and overall response rate and progression-free survival were the secondary endpoints.
RESULTS: Over this timeframe, a total of 49 patients completed trimodality therapy. Thirteen patients were treated at dose level 1, 21 patients at dose level 2 and 15 patients at dose level 3.The maximum tolerated dose for docetaxel was 20 mg/m(2) and cisplatin 40 mg/m(2). The complete response or partial response was observed in 26.5% (13/49) of patients. Thirty-four patients (69.4%) were treated with neoadjuvant radiochemotherapy followed by surgical resection. The median progression-free survival and median overall survival for all patients (n = 49) were 8 and 17.2 months, respectively. The median overall survival was 27.5 months for patients treated at dose level 2.
CONCLUSIONS: Neoadjuvant radiochemotherapy with docetaxel 20 mg/m(2) and cisplatin 40 mg/m(2) was effective and tolerable induction regimen in patients with esophageal tumors.

OBJECTIVE: The optimum duration between neoadjuvant radiochemotherapy and transmesorectal excision in locally advanced rectal cancer has not been defined yet. This randomized study was designed to compare the efficacy of four-week versus eight-week delay before surgery.
METHODS: One-hundred and fifty-three patients with locally advanced low- or mid-rectum rectal adenocarcinoma were included in this single center prospective randomized trial. Patients were assigned to receive surgical treatment after either four weeks or eight weeks of delay after chemoradiotherapy. Patients were followed for local recurrence and survival, and surgical specimens were examined for pathological staging and circumferential margin positivity.
RESULTS: 4-week and 8-week groups did not differ with regard to lateral surgical margin positivity (9.2% vs. 5.1%, P=0.33, respectively), pathological tumor regression rate (P=0.90), overall survival (5-year, 76.5% vs. 74.2%, P=0.60) and local recurrence rate (11.8% vs. 10.3%, 0.77). Overall survival was better in patients with negative surgical margins (78.8% vs. 53.0%, P=0.04). Local recurrence rate was significantly higher among patients with positive surgical margin (28.5% vs. 9.3%, P=0.02).
CONCLUSIONS: Intentional prolongation of the chemoradiotherapy-surgery interval does not seem to improve clinical outcomes of patients with locally advanced rectal cancer. Surgical margin positivity seems to be more important with this regard.

OBJECTIVE: Concomitant use of chemotherapy and a radiation dose schedule that is more efficient compared to conventional radiotherapy may provide better outcomes in patients with esophageal cancer. This study aimed to assess the efficacy and tolerability of neoadjuvant cisplatin-based chemotherapy and hyperfractionated accelerated radiotherapy regimen in this group of patients.
METHODS: A total of 20 newly diagnosed treatment-naïve esophageal cancer patients were included in the study. Neoadjuvant cisplatin and 5-FU were given with 28-day intervals in a total of three courses. Along with the third course of chemotherapy, hyperfractionated accelerated radiotherapy (HART) was given with the following dose schedule: 5760 cGy/36 fr/16 day.
RESULTS: All patients could receive the planned RT dose of 5760 cGy. Odynophagia was the most frequent grade III acute toxicity (50%). None of the acute toxicity reactions required treatment discontinuation. Grade III or higher subacute/late toxicity occurred in 10 patients (75%) including 5 deaths, mostly esophageal. Radiologically, 8 patients (40%) had complete response, 8 (40%) had partial response, and 3 (15%) had stable disease, with only 1 patient (5%) having progressive disease. Seven patients underwent surgery. Overall, 8 patients (40%) had local control. The 5 years overall survival rate was 38.1%.
CONCLUSIONS: Neoadjuvant hyperfractionated accelerated radiotherapy plus chemotherapy may help to target local disease control and increase survival in patients with esophageal cancer. Further studies to improve neoadjuvant and radical chemoradiotherapy dose schedules are warranted for maximum tumor control rates with minimal toxicity.