Early Surgical Outcome of Esophagectomy Performed for Carcinoma Esophagus after Neoadjuvant Chemotherapy – a single center experience from Sub Himalayan region

doi:10.21203/rs.3.rs-3610353/v1

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Early Surgical Outcome of Esophagectomy Performed for Carcinoma Esophagus after Neoadjuvant Chemotherapy – a single center experience from Sub Himalayan region

https://doi.org/10.21203/rs.3.rs-3610353/v1

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Esophageal cancer poses a significant global health burden, characterized by high aggressiveness and mortality rates. Despite a decline in overall incidence, certain regions exhibit a rise of adenocarcinoma incidence. At present multimodality approach with neoadjuvant treatment (Chemotherapy, Radiotherapy or both) followed by surgery with or without adjuvant treatment is standard of care, although there is no standard protocol. This retrospective, conducted at a tertiary center in the Himalayan region, explores the outcomes of esophageal and gastroesophageal junctional cancer patients undergoing surgery following neoadjuvant chemotherapy.

Among 106 patients, 87 received preoperative chemotherapy, with demographic data revealing a male predominance and prevalent squamous cell carcinoma histology. Neoadjuvant therapy mainly comprised taxane-platinum regimens, with subsequent surgical procedures predominantly Ivor Lewis or McKeown esophagectomies. 30-day morbidity and mortality were observed in 35.29% of cases, with nonsurgical complications, particularly respiratory issues, being the most common. Our study reported a complete pathological response in 12.5% cases and an R0 resection rate exceeding 93%.

While acknowledging the study’s retrospective and non-randomized nature, these findings suggest that neoadjuvant chemotherapy facilitates safe esophageal cancer surgeries specifically in undernourished patients.

Esophageal cancer stands out as one of the most aggressive malignancies affecting the digestive tract, representing a prominent contributor to global cancer-related mortality [1]. Despite an overall downward trend in incidence, an increasing trend has been observed in some nations with high incidence ratios of Adenocarcinoma /Squamous Cell Carcinoma (SCC). [2, 3] Overall the prognosis is gloomy and five-year overall survival is reported to have less than 25%, with regional and distant failure accounting for the majority of the mortality. [4, 5]

At present multimodality approach with neoadjuvant treatment (Chemotherapy, Radiotherapy or both) followed by surgery with or without adjuvant treatment is considered standard treatment protocol for the management of locally advanced esophageal cancers (LAEC). However, there is no fixed standardized treatment protocol that is followed worldwide and the chemotherapy regimen, dose of radiation, and interval for surgery are followed as per the regional or institutional guidelines, as it still remains unclear whether Neoadjuvant Chemotherapy (NACT) or Neoadjuvant Chemo-radiotherapy (NACRT] is more efficacious in the treatment of locally advanced esophageal cancer. Current data shows that NACRT is associated with an improved pCR (pathological complete response) and R0 resection rate for both the histology; however, the outcome in terms of DFS or OS remains comparable. [6–12] Moreover there is an increased severity of morbidity by the addition of radiation in pre-operative setting. [13, 14]

The current retrospective study shows the experience of esophageal and gastroesophageal junctional cancer patients operated after neoadjuvant chemotherapy at a single institution, in terms of early surgical outcome i.e. 30-day morbidity/mortality, R0 resection rate and pCR rate.

This study was based on a prospectively maintained database of patients who were operated for esophageal and gastroesophageal junctional cancer in the Department of Surgical Oncology, Cancer Research Institute, Swami Rama Himalayan University, Dehradun, Uttarakhand from January 2016 to December 2022. The study was commenced after approval from the Institutional Ethical Committee. All patients operated for esophageal or gastroesophageal junctional cancer were included. Both Adenocarcinoma and Squamous Cell Carcinoma were included. Data regarding neoadjuvant chemotherapy and/or radiotherapy were documented. Patients with inoperable disease and patients who were unable to complete the planned treatment were excluded from the study.

Information regarding the patient’s demographics and baseline characteristics, diagnoses, diagnostic procedure and investigation results, medications, neoadjuvant treatment, surgical details, postoperative morbidity, mortality and hospital stay and final pathology report was documented. Before analysis, all the data were anonymized. Data were compiled in an Excel sheet. SPSS version 20 was used for statistical analysis.

The primary outcome was thirty-day postoperative morbidity and mortality according to the Esophagectomy Complication Consensus Group (ECCG) [15] and CTCAE – V5.0 [16] definition and guidelines. Postoperative complications were compared with previously reported Randomized Control Trials & meta-analyses.

During the study period total 106 patients were operated, among them 87 patients received preoperative chemotherapy. Out of 106 patients, 21 were excluded due to incomplete data (16 patients) and histology other than SCC and adenocarcinoma (5 patients). Analysis was done on data of rest of the 85 patients. Demographic and baseline characters are shown in Table 1. In our study 50 (58.8%) patients were male and 35 (41.2%) were female (M:F ratio 1.43: 1). Age of the patients was 55.09 ± 9.90 year (mean ± SD) (range 30–75) and BMI was 20.97 ± 4.42 kg/m² (mean ± SD) (range 11.69–30.43) (Table 1). Regarding risk factor 19 (22.4%) and 43 (50.6%) patients had a history of alcohol intake and smoking respectively. 36 (42.4%) patients had history of comorbidity of which 10 (11.8%) had h/o diabetes mellitus, 20 (23.5%) had cardiac and 6 (7.1%) had pulmonary disease. Regarding tumor location most of the patients had lower third and GE junction tumor (n = 43, i.e. 50.6%) followed by middle third (n = 39, i.e. 45.9%) and upper third (n = 3, i.e. 3.5%) tumor, whereas histology wise there was mostly squamous cell carcinoma (ESCC) (n = 62; 72.9%) and adenocarcinoma EAC in 23 (27.1%).

Table 1

Baseline characteristics
	n = 85	%
Gender
Male	50	58.8
Female	35	41.2
Age	30–75	55.09 ± 9.90
BMI	11.69–30.43	20.97 ± 4.42
Preoperative Albumin		3.68 ± 0.61
Addiction
Alcoholic	19	22.4
Smoker	43	50.6
Both	5	5.88
Co-morbidities	36	42.4
T2DM	10	11.8
Cardiac	20	23.5
Pulmonary	6	7.1
Others	10	11.8
Location of primary
Upper 1/3	3	3.5
Middle 1/3	39	45.9
Lower 1/3 & GEJ	43	50.6
Histopathology
Squamous cell carcinoma	23	27.1
Adenocarcinoma	62	72.9
Neoadjuvant Treatment
NACT	63	74.1
NACRT	7	8.2
NART	2	2.4
No	13	15.3

Among all patients 72 (84.7%) patients received neoadjuvant therapy and 13 (15.3%) patients underwent upfront surgery. As per our institutional protocol, most patients received a regimen containing a taxane (Paclitaxel 175 mg/m²) and a platinum (Carboplatin AUC 5) as neoadjuvant chemotherapy. Patients with lower esophagus with GEJ (predominantly adenocarcinoma) received mostly FLOT (5Fu, Leucovorin, Oxaliplatin and Docetaxel) & DCF/DCX regimen. For radiotherapy, patients received median doses of 45 Gy in 25 fractions on 6MV Linear accelerator (LINAC) machine by conformal technique.

In the neoadjuvant group 63 patients received NACT and 7 patients received NACRT. Most of our patients underwent the Ivor Lewis procedure (2-stage esophagectomy) (50.6%) followed by the McKeown procedure (3-stage esophagectomy) (44.7%). Elective mechanical ventilator support was given to 50.6% of patients until the first postoperative day. The average duration of surgery was 447.29 ± 110.87 min (mean ± SD) (180–810 min) and mean blood loss was 437.53 ± 252.15 ml (mean ± SD) (100–1250 ml), 29 patients (34.1%) received blood transfusions of which 7 (8.2%) patients required ≥ 2 units. (Table 2)

Table 2

Intraoperative details
	n	%
Surgery
Ivor Lewis Esophagectomy	43	50.6
McKeown Esophagectomy	38	44.7
Transhiatal Esophagectomy	1	1.2
Others	3	3.5
Duration of surgery (min)		447.29 ± 110.87
Blood loss (ml)		437.53 ± 252.15

Table 3

Perioperative events and complications
	Present	%	Absent	%
Elective ventilation	42	50.6	43	49.4
Hemorrhage	2	2.4	83	97.6
pulmonary complications	16	18.8	69	81.2
Cardiac complications	13	15.3	72	84.7
Enteral feed started
D2-3	40	47.1
D4-6	39	45.9
>D6	3	3.53
Wound complications	7	8.2	78	91.8
Anastomotic leak	7	8.2	78	91.8
Reexploration	6	7.1	79	92.6
Mortality	2	2.4	83	97.6
30 Day outcome
Discharged	77	90.6
Still in hospital	6	7.1
Death	2	2.4
Clavin Dindo group
0	55	64.71
I	9	10.59
ID	2	2.35
II	11	12.94
IIIA	1	1.18
IIIB	4	4.17
IV	1	1.18
V	2	2.35

We observed morbidity in total 30 patients (35.29%) of which Calvin Dindo grade III/IV complications were in 6 patients (7.08%). Most common complications were nonsurgical, which are respiratory 16 (18.8%) followed by hemodynamic instability/ cardiac morbidity 13 (15.3%) and wound infection 7 (8.2%). Surgical complications such as Anastomotic leak, Reexploration and hemorrhage were observed in 7 (8.2%), 6(7.1%) and 2(2.4%) respectively. 4 patients with anastomotic leak required reexploration and others were managed conservatively; whereas the other 3 patients that were explored in the postoperative period were due to hemorrhage. 2 patients had Calvin Dindo grade I-D morbidity having recurrent laryngeal nerve injury & hoarseness of voice. The overall 30-day outcome was – 77 patients (90.6%) were discharged, 6 patients (7.1%) were still hospitalized and 2 patients (2.4%) expired. Details of operative morbidity and mortality are tabulated in Table 3.

Table 4

Final histopathology
	n	%
Tumor pathology
ypT0	7	11.11
ypT1	1	1.59
ypT2	24	38.10
ypT3	31	49.21
Tumor pathology
ypN0	36	57.14
ypN1	22	34.92
ypN2	4	6.35
ypN3	1	1.59
Pathological complete response	7	11.11
Circumferential margin R0	59	93.65
Number of nodes analyzed (Mean & range)	18.6 (3–70)
Number of nodes involved (Mean & range)	1.1 (0–13)

Table 4 shows the details of the final pathology report. On analyzing the postoperative histopathology reports we found a complete pathological response in 9 patients (12.5%) and a partial response was seen in 49 (68.6%) patients. The positive margin was seen in 11 patients (12.94), of which CRM was involved in 9 patients and proximal margin positive was in 2 patients. R0 resection was seen in 87.06% patients. In post-NACT group (Table 4) CRM was positive in 4 patients and R0 resection was in 93.65% patients, pCR was seen in 7 (11.11%) patients.

Esophageal cancer is one of the most common digestive tract cancers, overall seventh most common cancer and sixth leading cause of cancer-related death worldwide [1]. It is a disease of the elderly population with a peak incidence in the 7th & 8th decades, although our patients are a decade younger. Equal gender predilection is seen in squamous cell carcinoma (ESCC) but Adenocarcinoma (EAC) is 3–4 times more common in men. In our observation we found an M:F ratio of 1.4:1. Histologically, between the 2 most common types of esophageal cancers, squamous cell carcinoma (ESCC) is more common in Asian countries as in our study also. [2, 3]

The optimum management of esophageal cancers is a challenging clinical problem still date. Surgery is the main treatment method for resectable disease, but the effectiveness of surgery alone is not satisfactory (local recurrence is as high as 40%-60%, and the 5-year OS rate is less than 30% [17, 18].

Hence At present multimodality approach is the standard of care for the management of locally advanced esophageal cancers (LAEC) and surgery is supplemented by Chemotherapy, Radiotherapy or both. The addition of neoadjuvant chemotherapy compared to surgery alone has been shown to increase the R0 resection rate and improve overall survival for both adenocarcinoma and ESCC, though the evidence for the latter is limited. Two important landmark trials The UKMRC OE02 and JCOG9907 trial proved the benefit of NACT and based on the latter preoperative chemotherapy is now the current standard treatment in Japan for LAEC. [19–26]

Evidence from the studies that evaluated NACRT also showed an increased rate of R0 resection and better survival benefits compared to surgery alone. Surgery followed by NACRT became the standard of care for LAECs on the basis of results from CROSS and NEOCRTEC5010 trials especially in the western countries. [27–34]

Nowadays, a range of neoadjuvant therapy protocols are used globally, including well recognized CROSS, MAGIC, and FLOT regimens. [14, 35–37] As per our institutional protocol most patients received a regimen containing a taxane (paclitaxel) and a platinum (cisplatin/carboplatin) as neoadjuvant chemotherapy (CROSS trial chemotherapy regimen without radiation). Patients with lower esophagus with GEJ (predominantly adenocarcinoma) received mostly FLOT (5Fu, Leucovorin, Oxaliplatin and Docetaxel) & DCF/DCX regimen. We observed a R0 rate > 80% and pCR of 12.5%.

The CROSS trial (EAC = 75%) showed a complete pathological response in 23% patients without any increased postoperative mortality and morbidity in the NACRT group than the surgery group.[30] The FLOT regimen also demonstrated a significantly improved pCR rate up to 16% [26].

For ESCC, though there was reported a higher efficacy in the NACRT arm in the CROSS trial (pCR rate: 49%), approximately only one-fourth patients having ESCC, makes it less convincing benefit of ESCC [30, 31, 32]. Previous study reports of CF-based NACT resulted in only 5% pCR rate [23] whereas recent studies (phase II trial) with docetaxel, cisplatin, and 5-FU (DCF) reported much better results (90.5% R0 resection and pCR rate of 17%) [24, 25]. The JCOG1109 NExT trial also demonstrated that the DCF regimen was more efficacious in terms of survival and pCR rate with acceptable toxicity profile. [36, 37] Other studies i.e. NEOCRTEC5010, Preoperative therapy in Esophagogastric Adenocarcinoma (POET] and Neoadjuvant Chemotherapy Versus Radio chemotherapy for Cancer of the Esophagus or Cardia (NeoRes) trial also demonstrated a significantly higher R0 rate and pCR rate was 43.2%, 14.3% and 19%. [8–10, 33].

Results from both clinical trials as well as meta-analyses, it has become evident that the addition of neoadjuvant therapy (CT, RT or both) is more beneficial for locoregional control and survival for esophageal or gastroesophageal junction cancer patients compared to surgery alone or adjuvant therapy [6, 38, 39]. Moreover, irrespective of histological types locally advanced esophageal cancer patients are more likely to achieve R0 resection and pCR after NACRT compared to NACT; however, this finding fails to translate into the improvement of overall survival. [6, 13, 14] The adverse effects of treatments and complications during the perioperative period may contribute to this issue.

As per prior reported studies, although there was no significant difference in the frequency of complications after esophagectomy, these are much more severe in the NACRT group than in the NACT group. We collected & documented the morbidity data according to the Esophagectomy complication consensus group (ECCG) [15] and CTCAE – V5.0 [16] definition and guidelines. We categorized the morbidities into two main groups - surgical and nonsurgical [21]. We observed morbidity in a total of 30 patients (35.29%) of which Calvin Dindo grade III/IV complications were in 6 patients (7.08%). [40] Most common complications were nonsurgical, which are respiratory 16 (18.8%) followed by HD instability/ cardiac morbidity 13 (15.3%) and wound infection 7 (8.2%). Surgical complications such as Anastomotic leak, reexploration and hemorrhage were observed in 7 (8.2%), 6 (7.1%) and 2 (2.4%) respectively. 3 patients with anastomotic leak were managed conservatively whereas 4 patients required exploration. Another 3 patients who were explored in postoperative period were due to hemorrhage. We observed no conduit necrosis or chylothorax in our patients. 2 patients had Calvin Dindo grade I-D morbidity having recurrent laryngeal nerve injury & hoarseness of voice.

The overall 30-day outcome was – 77 patients (90.6%) were discharged, 6 patients (7.1%) were still hospitalized and 2 patients (2.4%) expired. Perioperative death, defined as death within 30 days after surgery, occurred in 2 out of 85 patients (2.4%). F. Klevebro et al observed that perioperative mortality was more in the NACRT group (10.2% vs 3.8%) [22].

Theoretically, the inclusion of radiation therapy to preoperative chemotherapy in the management of esophageal cancer could augment the frequency of postoperative complications. This increase may be attributed to the radiation-induced tissue damage to the nearby organs like the lungs, the heart, and the future gastric conduit. Furthermore, chemotherapy regimens containing taxane are associated with an increased risk of postoperative pulmonary complications. [6, 35, 38, 39]

Although the addition of NACRT did not increase the frequency of postoperative morbidities in the CROSS trial, they were more severe (higher grade) than previously reported studies. In cross study, they reported postoperative pulmonary complications of 46% and anastomotic leak of 22%, which is much higher than our findings [30, 31, 32]. In our study, Post-operative complications were less frequent than in POET and NeoRes trials and other reported evidence also. [7–10, 39]

The strength of our study is that it included a large number of patients from difficult-to-reach sub-Himalayan centers, to best of our knowledge it is the first study to give insight to manage carcinoma esophagus that has much more morbidity and mortality at such centers. Limitations of our study were 1) It was a retrospective nature, 2) Non-randomized type, 3) single center.

In conclusion, curative esophageal carcinoma surgeries following neoadjuvant chemotherapy are a safe and feasible option as it has acceptable morbidity and mortality. Our study showed excellent pCR (> 11%) and > 93% R0 resection rate with neoadjuvant chemotherapy. However long-term follow-up results are awaited. In our context, where we treat patients from the challenging terrain of the Himalayan region and poor nutritional status, neoadjuvant chemotherapy provides a viable option for better outcomes. However, a properly planned randomized controlled trial would be desirable to draw a meaningful conclusion and our study can provide a basis for the same.

Competing interests: The authors declare that they have no competing interests

Funding: No funding was obtained from the private or public sector for this research

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Early Surgical Outcome of Esophagectomy Performed for Carcinoma Esophagus after Neoadjuvant Chemotherapy – a single center experience from Sub Himalayan region

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