Multimodal therapy has become the most optimal treatment strategy in the management of resectable oesophageal cancers. The current guidelines entail the administration of some form of neoadjuvant treatment, either chemoradiation or chemotherapy alone, prior to surgical resection.(15) The recent Neo-AEGIS trial suggests that both chemotherapy and chemoradiotherapy have similar benefits in the adenocarcinoma of the oesophagus.(16) However, limited data is available comparing preoperative chemotherapy vis a vis chemoradiotherapy in oesophagal SCC. The present study compared the outcomes of NACT and NACRT administration followed by surgery in patients with resectable esopahgeal SCC.
In the present study, the radiological and pathological complete response (pCR) rate was significantly higher in the NACRT group than in the NACT group. More than 50% of the patients had complete or near-complete tumor regression in the NACRT group as compared to only 13.3% in the NACT group. Thus, there was a significantly higher tumor response to the NACRT as compared to the NACT group. Similarly, a retrospective analysis of 902 patients (827 – NACRT, 75 – NACT) also showed a similar high pCR rate in esophagal SCC (33.7% vs 1.2%, p − 0.002).(17) However, after a median follow-up of 32.5 months, the median recurrence-free survival (RFS) was higher in the NACT group (57 months) as compared to the NACRT groups (36 months) but not statistically significant (p-value – 0.831). This is despite non-significant higher recurrence rate in the NACT group as compared to NACRT groups (33.3% vs 30.3%). The median OS was yet to reach in both the groups in Kaplan Meier survival analysis, but there was no significant difference between the two groups (p-value – 0.576). In a retrospective analysis by Miller et al comparing NACRT with NACT in esophagal SCC, the median OS was also higher in the NACT (40.8 months) group as compared to NACRT (36 months).(18) They also reported a 5-y survival of 39% for the NACRT group and 43% for the NACT group (p − 0.721).(17)
This finding from the present study implies that despite a higher tumor response in the NACRT group, it did not translate into increased overall and recurrence-free survival. This is in concurrence with the RCT by Tang et al. where NACRT was compared with NACT in locally advanced esophageal SCC (cT3-4aN0-1M0).(18) They also reported that NACRT followed by MIE had a comparable 3-year survival rate (64.1% in NACRT vs 54.9% in NACT, p – 0.28) and recurrence-free survival (49.2 vs 50.2 months, p – 0.75) with NACT despite having significantly higher pCR (27.7% vs 2.9%, p - <0.001) and primary tumor regression grade (p - <0.001) in the NACRT group.(19)
Further, these findings are also consistent with RCTs comparing preoperative CRT with CT in adenocarcinoma of the oesophagus.(20–22) In NeoAegis trial(ref), the NACRT group had significantly higher pCR (odds ratio 0·33 [95% CI 0·14–0·81], p − 0·012), pathological response rates (0·21 [0·12–0·38], p < 0·0001), and R0 rates (0·21 [0·08–0·53], p = 0·0003) but the NACT group had non-inferior 3-year OS (55% in NACT vs 57% in NACRT, p = 0·82) and median disease-free survival (32·4 months vs 24·0 months, p = 0·41). The pattern of recurrence, locoregional or systemic, was also not significantly different (odds ratio 1·35 [95% CI 0·63–2·91], p = 0·44).(16) The JCOG1109 (NExT) study for cStage II or III esophageal SCC compared preoperative doublet chemotherapy (CF group - cisplatin + 5-FU), triplet chemotherapy (DCF group - docetaxel + cisplatin + 5-FU) and chemoradiotherapy (CF-RT group - cisplatin + 5-FU + radiation at 41.4 Gy). The OS was significantly higher in the DCF group than in the CF group; the study did not show any superiority of CF-RT over CF Field.(23, 24) Thus, the results of our study and the above-mentioned RCTs are consistent with the finding that NACT is comparable to NACRT.
Post-neoadjuvant therapy complications are always a matter of concern. In the CROSS trial, NACRT was associated with grade 3 or higher side effects in 7% of the patients.(1) Further, the NeoRes trial showed higher Clavien Dindo grade IIIA or more complications with preoperative CRT than CT.(10) In our study, both haematological and non-hematological chemotherapy-related adverse events were comparable in both groups. Further, in the previous studies, the NACRT with surgery also had a significantly higher incidence of odynophagia after preoperative treatment, impaired cardiac function after surgery, and symptoms like chronic cough affecting the quality of life (QOL).(23, 25)
In these two approaches of NACT and NACRT in the management of esophagal SCC, the common important factor which is often ignored is the quality of surgery. The rate of R0 resection and extent of lymphadenectomy also add to the overall patient outcome in both approaches. In our study, the R0 resection rate was 93.9% and 100%, and the median lymph node yield was 19 and 21.5 in the NACT and NACRT groups, respectively. One advantage of our study is that all the surgical procedures were either thoracoscopic or robot-assisted MIE with two field lymphadenectomy performed by surgeons of similar experience. The magnified view of the thoracoscope improves the dissection of both primary and lymph nodes and is helpful in doing a radical resection with decreased post-operative morbidity. However, the surgical technique had been heterogeneous in past studies. In both the CROSS trial and the NeoRes trial, some patients underwent transhiatal esophagectomy.(1, 10) As only abdominal lymphadenectomy is performed in transhiatal esophagectomy, there is a chance of early recurrence in the thoracic lymph nodes, which was not addressed during surgery, especially in patients not receiving radiotherapy or are surgery alone. The rationale behind the consideration of NACT over NACRT is to avoid overtreatment of local disease with radiation and surgery. In our study, the systemic treatment received in both groups was the same, but the NACRT group received two local treatments (surgery and radiation). So, if a good quality surgery with adequate lymphadenectomy is feasible, then one might consider avoiding radiation among these patients.
The operative duration of the thoracic phase was slightly higher in the NACRT group, but the median blood loss was similar, indicating some sort of surgical difficulty in the NACRT group due to associated fibrosis in the RT group. Though we could not monitor it prospectively, it needs to be analysed in future studies. The post-operative complications and hospital stays were comparable in both groups. It might be because of the surgical experience of the team in minimally invasive esophageatomy and standardised post-operative management with enhanced recovery after surgery protocol. Further, the NeoRes trial showed that the incidence of surgical or nonsurgical complications and 90-day mortality rates was not significantly different between the preoperative chemotherapy and chemoradiation groups (p-value = 0.69 and 0.13, respectively).(10)
The treatment of oesophagal SCC has further evolved after the introduction of immunotherapy agents. The CheckMate 577 trial concluded significantly longer disease-free survival among those who received nivolumab adjuvant therapy in patients with esophageal or gastroesophageal junction cancer who underwent surgery after neoadjuvant chemoradiotherapy.(26) Based on the results of this trial, the FRONTiER study aims to evaluate the role of nivolumab along with chemotherapy in the neoadjuvant setting.(27) The appropriate approach to treat locally advanced oesophagal SCC will further evolve with the use of neoadjuvant and adjuvant immunotherapy combined with chemotherapy.
Our study has several limitations. First, the allocation to the two study arms was not randomised, which could have further strengthened the results of the study. Second, the operative difficulty grading could have been done to assess the intra-operative challenges encountered. Although ample literature is available with regard to the management of esophageal SCC, further RCTs are needed to identify an optimal neoadjuvant strategy for esophageal SCC.
In conclusion, NACT shows non-inferior outcomes when compared with the CROSS NACRT regimen despite inferior pathological responses. Thus, radiation can be avoided if local control can be achieved with a good surgical resection with adequate lymphadenectomy. NACT can be considered a feasible strategy vis a vis NACRT in case RT is contraindicated or unavailable in certain situations.