Department of Radiation Oncology, Zhejiang Cancer Hospital, No.1 Banshan East Road, Hangzhou, Chinak

Background and Aims: Various nations have different current practises for treating locally advanced esophageal squamous cell carcinomas (SCC). In patients with locally advanced resectable SCC, the purpose of this study was to evaluate the outcomes of trimodality therapy with CRT alone.

Patients and Procedures: Eligible patients had locally progressed, resectable SCC of the oesophagus.

Patients who underwent trimodality received preoperative/postoperative chemoradiation in addition to surgery. Patients only received radiation and chemotherapy in the CRT alone group. Assessments were made of local tumour control, 3-year survival, and treatment-related mortality.

Results: 184 patients were examined in a row. 75 patients underwent CRT alone depending on the patients' willingness out of the 109 who received trimodality therapy. In the trimodality group of patients who had resection, 17.4% had locoreginal recurrent disease, compared to 30.7% in the CRT alone group (P=0.036). Patients who got trimodality versus CRT alone had 3-year progression-free survival (PFS) of 53.8% versus 33.5% (P=0.019) and overall survival (OS) of 51.2% versus 39.8% (P=0.011), respectively.

In the trimodality group, treatment-related mortality was 3.7% compared to 1.3% in the definitive CRT group (P= 0.650). Patients receiving a 50.4 Gy radiation dosage did not have a significantly different 3-year OS compared to patients receiving >50.4 Gy radiation dose in the CRT alone group (45.3% vs. 36.4%, P = 0.927).

Esophageal cancer ranks sixth among cancer-related causes of death worldwide and is more prevalent in poorer countries[1]. Histologically, esophageal tumours can be either adenocarcinoma or squamous cell carcinoma (SCC). In Eastern Europe and Asia, SCC is the most common histology, and 95% of esophageal cancers are pathologically identified as SCC in China[2]. Patients with locally advanced resectable SCC of the oesophagus typically receive radiochemotherapy and surgical resection. In an effort to increase effectiveness without compromising safety, lower the likelihood of local recurrence, and lengthen survival, numerous randomised trials have examined the effects of radiotherapy dose modifications, combined-modality therapy, and preoperative/postoperative administration of adjuvant therapy [3–7].

For instance, findings from the largest trial of its kind, the multicenter phase III randomised trial (CROSS study), revealed that preoperative chemoradiotherapy (CRT) with carboplatin and paclitaxel significantly improved overall survival (OS) and disease-free survival (DFS) compared to surgery alone in patients with resectable (T2- 3, N0-1, M0) esophageal or esophagogastric junction (EGJ) cancers[8].

When compared to surgery alone, preoperative CRT and surgery together significantly decreased 3-year mortality and locoregional recurrence, according to two meta-analyses[9,10]. On the other hand, a randomised experiment involving patients with esophageal cancer has not proven that postoperative CRT is more effective than surgery alone. In contrast to surgery alone, postoperative CRT has been linked to improved survival in patients with locally advanced esophageal cancer, including those who are lymph node positive and have deeper primary tumour invasion (pT3, pT4), according to retrospective analyses[11–13].

Last but not least, two randomised studies contrasting trimodality therapy with definitive CRT revealed no OS improvement with the addition of esophagectomy to CRT[14,15], particularly in patients with locally advanced SCC of the oesophagus who exhibit response to initial CRT[15]. As a result, it is still uncertain what multimodality treatment is best for locally progressed SCC of the oesophagus.

The goal of this retrospective analysis was to ascertain the most effective method for providing multimodality therapy to individuals with locally progressed esophageal SCC. The main goal was to ascertain whether combining surgical resection with CRT reduces local recurrence and lengthens survival when compared to CRT alone. In addition, we looked at potential risk variables for survival and recurrence in individuals with locally advanced esophageal SCC.

Between April 2011 and November 2015, patients with locally advanced resectable SCC of the oesophagus (cT3, potentially resectable cT4 or N+) who received preoperative CRT, postoperative CRT, and esophagectomy (trimodality therapy group), or just radiation with chemotherapy (CRT alone group), were included. Patients were considered if they were 18 to 75 years old, had an ECOG/WHO performance score of 2, and had lost less than 10% of their body weight.

If a patient's esophageal cancer was found in the cervical oesophagus, if it was their second cancer, if they were known to have undergone radiation treatment for a place other than the oesophagus, or if they had radiotherapy without concurrent chemotherapy, they were disqualified from the study. Patients who were a part of the ZTOG1201 trial, a randomised controlled study in which eligible patients were randomly allocated to either preoperative CRT plus surgery or surgery plus postoperative CRT (NCT01463501)[16], made up a portion of the patient group.

In the preoperative CRT group and the CRT alone group, concomitant paclitaxel (50 mg/m2 of body surface area) and carboplatin (intravenous; AUC 2 mg/ml per min) chemotherapy was administered on days 1, 8, 15, 22, 29, and 36 during the first and sixth weeks of radiotherapy. The majority of the patients in the postoperative CRT group had postoperative CRT between 4-6 weeks following surgery. Following radiotherapy, the postoperative CRT group received two rounds of sequential paclitaxel (150 mg/m2 of body surface area) and carboplatin (intravenous; AUC 5 mg/mL per min) chemotherapy that were administered three and six weeks later.

Utilizing an intensity-modulated radiation therapy approach, all patients received external beam radiation treatment. The primary tumour and any enlarged local lymph nodes were determined as the gross tumour volume on each pertinent slice of the planning CT. Around the gross tumour volume, the planned target volume (PTV) offered radial margins of 1.3 cm, proximal and distal margins of 4 cm. To provide the best possible sparing of healthy tissue, multileaf collimators used specially tailored beams in each field. The International Commission on Radiation Units and Measurement 50/62 reference point set the daily prescription dose at 1.8 to 2.0 Gy, and the 95% isodose had to cover the whole PTV.

The prescribed dose for the PTV could not be exceeded by more than 7%. The correction for tissue density inhomogeneity was applied. Patients had to be fully informed about both the chemotherapy treatment and the overall radiation planning. As these represent the anticipated ranges for preoperative/postoperative to definitive radiation doses, we restricted our analysis to patients who received radiation doses of 41.4 to 50.4 Gy in the preoperative CRT group, 45 to 50.4 Gy in the postoperative CRT group, and 50 to 64.8 Gy in the definitive CRT group. Paclitaxel and carboplatin were used in the same chemotherapy regimen for all patients. Only patients who were recognised as getting their chemotherapy within a 1-week window before or after were included in the delivery of concurrent CRT.

Surgery was ideally performed on patients in the trimodality therapy group 4-6 weeks following the conclusion of preoperative CRT, or as soon as possible after randomization in the postoperative subgroup.

Depending on the location of the tumour and the patient's characteristics, the surgeon ultimately decided between an open or minimally invasive oesophagectomy (MIE), a neck anastomosis (Mckeown operation), and an intrathoracic gastric tube reconstruction (Ivor Lewis method).

The favoured method was gastric-tube repair with a cervical anastomosis. The N1 lymph nodes were extensively removed locally, including the typical removal of the celiac nodes.

Relapses were divided into local, regional, and distant types. Recurrences at the primary tumour site or locoregional lymph nodes were referred to as locoregional relapses. Additionally regarded as locoregional were lymph node recurrences in the celiac trunk or the supraclavicular region. Non-regional lymph node recurrences, systemic metastases, malignant pleural effusions, or peritoneal metastases were all considered distant recurrences. The majority of patients who were thought to be having recurrence got an endoscopy or a CT scan of the chest and abdomen. Cytology or histology was acquired as needed. A second recurrence was regarded as synchronous if it was discovered within 4 weeks of the first one. Every locoregional and distant recurrence's location and date of identification were noted.

The 2 test, Fisher exact test, and Mann-Whitney test were used, as necessary, to compare demographic information between patients who underwent trimodality treatment or CRT alone.

In order to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and tumour recurrence using the same covariates, age, gender, WHO/ECOG score, tumour location, tumour length, T staging, N staging, radiation dose, and treatment strategy were excluded. Patients receiving different treatments were compared using Kaplan-Meier analyses of OS.decisive radiation at a dose of 50 to 50.4 Gy compared to individuals who got more radiation than this. After stratification by treatment sequence (preoperative CRT or postoperative CRT), survival analyses were also carried out to compare individuals who received final CRT with those who underwent trimodality therapy. P-values under 0.05 were considered significant values.

In the analysis, there were 184 patients: 109 (59.2%) received trimodality therapy, including 57 (31.0%) who had preoperative CRT followed by oesophagectomy and 52 (28.2%) who had oesophagectomy followed by postoperative CRT, whereas 75 (40.8%) received CRT alone. 60 years old was the average age (range, 41 to 75 years). Patients receiving trimodality therapy had a higher likelihood of being younger, male, having a larger tumour, and having the tumour in the distal portion of the oesophagus.

In the trimodality therapy group, 33.9% (37/109) of the resected patients had recurrent disease after a median follow-up of 36 months (range, 6 to 53 months) and a median survival time of 31 months (95% CI: 20.2-41.8 months), compared to 50.7% (38/75) in the CRT alone group. Regarding tumour recurrence, there was a significant difference between the two therapy groups (P = 0.023). Compared to 30.7% (23/75) in the definitive CRT group, only 17.4% (19/109) of the resected patients in the trimodality arm had locoregional recurrent disease (P = 0.036). In addition, there were less patients (16.5%, 18/109) in the trimodality arm compared to the CRT alone arm (18.7%, 14/75), albeit this difference was not statistically significant (P = 0.705).

Younger age and CRT alone were prognostic variables that predicted locoregional relapses in univariate analysis. The backward technique in the multivariate analysis revealed that patients who got CRT alone and were younger had a considerably higher likelihood of experiencing a locoregional relapse.

Between the trimodality group and the CRT alone group, there was a significant difference in 3-year progression-free survival (PFS) (53.8%, 95% CI: 42.8-64.8% vs. 33.5%, 95% CI: 20.6-46.4%, respectively; P = 0.019). Figures 1A, 1B, and 1C display the variations.between the trimodality therapy group and the CRT alone group for PFS (53.8%, 95% CI: 42.8-60.8% vs. 33.5%, 95% CI: 20.6-46.4%; P = 0.019), locoregional PFS (65.7%, 95% CI: 54.9-76.5% vs. 47.0%, 95% CI: 32.3-61.7%; P= 0.040), and distant PFS (73.5%, 9 Superior OS outcomes were also linked to trimodality treatment. Compared to the CRT alone group, which had a 3-year OS rate of 39.8% (95% CI: 26.7-52.9%) and a median survival time of 22.0 months (95%: CI 17.1 to 26.9 months; P = 0.011,the trimodality treatment group's 3-year OS rate was 51.2% (95% CI: 36.1-66.3%) and the median survival time was not reached.Additionally, the trimodality group had a treatment-related death rate of 3.7% compared to the definitive CRT group's 1.3% (P = 0.650).

In the CRT alone group, 62.7% (47/75) of patients received a radiation dose above 50.4 Gy, whereas a total of 37.3% (28/75) of patients received a radiation dose between 50 and 50.4 Gy. The median OS for those who received 50 to 50.4 Gy was 26.0 months (95% CI: not achieved), and the 3-year OS was 45.3% (24.7-65.9%). However, the survival rate was not notably higher A 3-year OS of 36.4% (95% CI: 19.4-53.1%) and a median survival of 22.0 months (95% CI: 20.2-23.8 months) were seen in patients who received radiation doses >50.4 Gy, in contrast (P= 0.927) to those patients. The Kaplan-Meier survival curves for individuals who got CRT alone by dosages are shown in Figure 3. Only younger age was related with worse survival in the multivariate analysis (HR= 2.941; 95% CI: 1.441-5.988; P = 0.003), not a greater radiation dose.

As compared to CRT alone, the current study found that adding surgery to CRT for the treatment of clinically resectable, locally advanced SCC of the oesophagus dramatically reduced local recurrence rates, lengthened PFS and OS, and reduced treatment-related mortality. The 3-year OS in the trimodality therapy group was 51.2% (95% CI: 36.1-66.3%), which was higher than the 3-year OS in the CRT alone group (39.8%, 95% CI: 26.7-52.9%), which was similar to the preoperative CRT result in the CROSS trial (51%[8]).Surgery plays a significant role in the management of resectable diseases.

According to information from the National Cancer Database of America, trimodality therapy was linked to better overall survival (P 0.001), with a median survival time of 35.6 months and a three-year survival rate of 49.6%, compared to to CRT patients (median and 3-year OS were respectively 16.8 months and 26.8%)[17]. In two randomised trials[14,15], the impact of combining surgery and CRT in patients with locally advanced SCC of the oesophagus was also examined. Induction chemotherapy followed by CRT or induction chemotherapy followed by surgery were the two groups that Stahl et al. randomly assigned 172 patients to[14]. The 3-year OS was not significantly impacted by the 2-year PFS rate, which was higher in the surgery group (64.3%) than in the CRT group (40.7%). However, lack of accrual led to the early termination of this trial. In contrast, Bedenne et al.

(FFCD 9102 study) revealed that patients with locally advanced SCC of the oesophagus who responded to initial CRT did not benefit from subsequent surgery compared to therapy with additional CRT[15].

The results of non-randomized patients in the FFCD 9102 phase III trial, however, showed that OS did not differ between patients who responded to induction CRT and those who underwent salvage surgery following CRT's clinical failure[18],(FFCD 9102 study) revealed that patients with locally advanced SCC of the oesophagus who responded to initial CRT did not benefit from subsequent surgery compared to therapy with additional CRT[15]. The results of non-randomized patients in the FFCD 9102 phase III trial, however, showed that OS did not differ between patients who responded to induction CRT and those who underwent salvage surgery following CRT's clinical failure[18].

The current recommended ranges for preoperative, postoperative, and final radiation are 41.4 to 50.4 Gy, 45 to 50.4 Gy, and 50 to 50.4 Gy, respectively, according to the National Comprehensive Cancer Network (NCCN) [21].

Due to the historical scenario in China, we discovered that radiation doses above 50.4 Gy were administered in 58.7% of patients in the CRT alone group in our retrospective investigation, despite the fact that there was little evidence to warrant radiation dose escalation.

However, as compared to individuals who received radiation doses between 50 and 50.4 Gy, we found no survival benefit to a dosage escalation of >50.4 Gy. The 5-year OS was 26% in patients receiving chemotherapy and radiotherapy (to a total dose of 50 Gy) in a prior study on the use of definitive CRT (the RTOG 8501 trial), and 0% when radiotherapy (to a total dose of 64 Gy) was used alone[3]. The Intergroup 0123 trial subsequently randomised patients to receive the same chemotherapy with either 50.4 Gy or 64.8 Gy of radiation due to the low OS and high local failure rate with definitive CRT[4].

However, the trial was terminated early after an interim analysis revealed that there was no significant difference between the high-dose and standard-dose arms in terms of 2-year median survival (13 vs. 18.1 months) or locoregional failure rates (56% vs. 52%). In a similar vein, neither the trimodality nor CRT alone groups showed any differences in OS or recurrence based on the radiation dose administered. Our work shown that, even with higher radiation dose for locally advanced SCC of the oesophagus, CRT alone could not replace surgery. Subsequent studies have not found a substantial benefit to dose escalation above 50.4 Gy in the CRT alone group.

correct analysis of intent to treat. Furthermore, despite the fact that the incidence of esophageal adenocarcinoma is sharply rising in Western nations, the findings of our study should not be extrapolated to patients in North America and Europe until a randomised study involving those with the disease verifies our findings.Furthermore, based on our research, it is uncertain if extra locoregional therapy combined with surgery would be beneficial for patients who had a clinically full response to CRT. Additionally, we were unaware of the necessity and timing of oesophagectomy in (all) patients. We may be able to identify the types of patients who benefit from surgical therapy and exhibit improved OS in the future thanks to the development of molecular biology techniques[22–25].

Additionally, we did not examine whether patients in the CRT alone group underwent salvage therapy like salvage esophagectomy, which may have had an impact on survival results. It is necessary to conduct more research on the novel interdisciplinary approach to treating patients with locally advanced esophageal cancer (preoperative CRT followed by salvage esophagectomy). In fact, the clinical response evaluation following neoadjuvant chemotherapy and radiation therapy in esophageal cancer (NTR4834) study investigators in the Netherlands are now investigating this strategy[26].

In conclusion, for the treatment of patients with SCC of the oesophagus, adding surgery to CRT seems to have superior local control, PFS and OS, with equivalent treatment-related mortality. Even with a higher radiation dose, CRT alone could not take the place of surgery.

The Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents (to YapingXu) provided funding for this work. The 15th World Congress of the International Society for Diseases of the Esophagus, which will take place on September 19–21, 2016 in Singapore, has approved this article for oral presentation (Abstract ID: 1942).

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Chenxue Jiang1,Xiang Zhu. The role of surgery in the treatment of locally advanced esophageal squamous cell carcinoma when compared to chemotherapy alone. Insights of Clinical and Medical Images 2022.