Patterns of Failure After Trimodal Treatment in Esophageal Squamous Cell Carcinoma: Initial Experiences from a High-Risk Endemic Area

Abstract

Recurrence is a significant problem faced in patients with esophageal cancer even after treatment with trimodal approach. We report patterns of failure in our patients of esophageal squamous cell cancer (ESCC) treated with trimodal approach. This is a single-institution retrospective analysis of 46 patients of locally advanced ESCC (treated between 2013 and 2017) managed by trimodal treatment approach. Variables were summarized using descriptive statistics. Survival statistics were estimated using Kaplan-Meier method. With a median follow-up of about 28 months, we noted an overall recurrence rate of 37% (17/46), with most of the failures being distant, with or without locoregional recurrence (4 isolated distant and 6 combined distant and locoregional). Median RFS was 34 months and median OS was yet to be reached at the last follow-up. To conclude, optimization of treatment approaches in ESCC is of utmost importance and need of the hour to further improve outcomes in these patients.

Introduction

Esophageal cancer accounted for 3.2% of all new cancers diagnosed in 2018 worldwide, ranking7th in incidence and being responsible for 1 in every 20 cancer-related deaths [1]. Esophageal cancer has a striking geographical variation in incidence, most probably reflecting the differences in prevalence of its risk factors and differential susceptibility of the underlying population [2]. Kashmir, which is located in the northernmost part of India, lying at an altitude of around 4000 m above sea level, lies near the southern rim of the so-called Asian Esophageal Cancer Belt, extending from northern Sin-Kiang (China) in the east to Caspian littoral area of Iran in the west [2, 3]. In the absence of a population-based cancer registry, the data published from the only hospital-based cancer registry of Kashmir region depicts esophageal cancer to be the leading cancer affecting people from this area [4].

Esophageal cancer comprises two major histological subtypes—squamous cell carcinoma (SCC) and adenocarcinoma (AC), which are considered to be two different entities, etiologically, epidemiologically, clinically, and biologically [5], despite the fact that they have been treated as a homogenous cohort in different studies. Despite significant improvement in treatment outcomes in the past few decades [6, 7], the overall survival in these patients still remains dismal, with only up to 20% of patients living till 5 years [8]. Over the last few decades, a combination of chemotherapy and radiotherapy (CRT) has shown to improve outcomes in locally advanced esophageal cancer (cT3–4 any N and any T N+) when combined with surgery (trimodal approach) in neoadjuvant setting [9–12]. Most of these patients still recur, even after treatment intensification. Studying patterns of failure in these patients provides an insight into the natural history and biology of this disease and can guide our future efforts for intensification of various therapeutic approaches. The purpose of this study was to analyze the patterns of failure in SCC of esophagus after treatment with trimodal approach and is the first study of this kind from our region.

Materials and Methods

We did a retrospective analysis of all patients of locally advanced squamous cell carcinoma of esophagus (cT3–4 any N and any T N+) treated with trimodal approach (from August 2013 to December 2017) in the Department of Surgical Oncology, Regional Cancer Centre (RCC), at Sher-i-Kashmir Institute of Medical Sciences (SKIMS) in Kashmir, India. Data was retrieved from a prospectively maintained database of RCC after proper approval of the Institutional Ethics Committee (IEC). Information related to patients’ demography, clinical status, pretreatment staging, treatment details, and follow-up data was retrieved. Patients with non-squamous histology, and those not treated with trimodal approach or with incomplete records, were excluded from the study. In addition, patients who died within 30 days post-surgery were excluded from the recurrence analysis but were included in the survival analysis.

All patients were assessed by appropriate history and physical examination and, if found fit for treatment, underwent pretreatment diagnostic and staging work-up. Diagnosis was established by upper gastrointestinal endoscopy (UGIE) and biopsy of lesion. Contrast-enhanced computed tomography (CECT) of the chest, abdomen, and pelvis was the primary investigation utilized for staging the disease. Endoscopic ultrasound (EUS) and whole body positron emission tomography (PET)-CT was used optionally. All patients were staged before starting treatment and postoperatively using the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual [13].

Patients with good performance status (World Health Organization performance status 0 or 1) and locally advanced disease located in the thoracic or abdominal esophagus were offered neoadjuvant chemoradiation (NACRT) after ensuring adequate organ function and procuring proper consent. Chemoradiation treatment was at the discretion of the treating radiation oncologist. All patients received weekly paclitaxel (50 mg/m² of body surface area) and carboplatin (AUC 2) at the start of each week till the planned radiotherapy dose was completed. Radiotherapy (40.4–60 Grays) was delivered by a 2D technique on a cobalt-60 machine using conventional fractionation. Gross tumor volume included the primary tumor and any clinically significant regional nodes. Clinical tumor volume included additional 3–4 cm longitudinal and about 1-cm radial margin to account for any microscopic disease at margins. Planning tumor incorporated additional 0.5–1 cm margin to account for any physiological movement during treatment. Patients were re-staged 4–6 weeks posttreatment and operated upon 6–12 weeks after completion of chemoradiation.

Patients were operated by open transthoracic (Ivor Lewis) or McKeown approach depending on the location of tumor and/or regional nodal disease. Those with tumors located in the mid and distal thoracic or abdominal esophagus underwent transthoracic esophagectomy with standard two-field lymph node dissection (upper abdominal nodes, including lymph nodes around branches of celiac artery, and inferior mediastinal nodes extending from the carina downwards), whereas those having tumors localized to the proximal thoracic esophagus or those having enlarged upper mediastinal nodes underwent McKeown esophagectomy with three-field lymph node dissection. The specimens thus retrieved were assessed by the pathologist for response to preoperative therapy, T and N stage, and completeness of resection.

After surgery, patients were kept under close surveillance to detect any late complication or recurrence of disease. Patients were asked to visit outpatient clinics every 3–6 months during the first 2 years, every 6 months during next year and annually thereafter. Besides taking a history and relevant physical examination, complete blood count was ordered on every visit. An UGIE and CECT of the chest and abdomen were ordered annually. Once a recurrence was detected, relevant additional tests (PET-CT, biopsy, cytology, etc.) were done to confirm the diagnosis. Recurrence confined to esophageal lumen/anastomosis was labeled as local failure; disease recurring within the regional nodes (lower cervical, posterior mediastinum, celiac, along superior border of the pancreas—corresponding to the nodes along common hepatic artery and splenic artery) was defined as regional failure, whereas failure in the non-regional nodes and distant sites like the lungs, bones, liver, etc. was considered distant recurrence.

Data was analyzed using statistical software package SPSS version 16. Variables were summarized using descriptive statistics. Survival statistics were estimated using the Kaplan-Meier method. Recurrence-free survival (RFS) was calculated from the time of diagnosis to the time of first recurrence or death, whereas overall survival (OS) was calculated from the time of diagnosis to death due to any cause. Patients not experiencing any event were censored at the time of last follow-up.

Results

During the study period, 69 patients of esophageal squamous cell carcinoma (ESCC) were operated with curative intent. Out of these, 52 patients were operated after NACRT (Fig. 1). All of these patients completed their preoperative treatment without any major issues. The various demographic, surgical, and pathological variables of these patients have been summarized in Table 1. Most of the patients had tumor localized to mid-/distal esophagus or abdominal esophagus (96%). Majority of the patients underwent two-field dissection via transthoracic route (with a median lymph node yield of 11), with 90% of patients achieving R0 clearance (47/52). A complete pathological response was noted in 44.2% of patients, whereas 61.5% of patients had major response to NACRT (tumor response grade ≤ 2). Six patients died within 30 days after surgery and were not included in the recurrence rate calculations, but were included in the survival analysis.

Fig. 1.

Flowchart showing the treatment pathway followed by different patients of ESCC during the study period

Table 1.

Demographic, operative, and pathological characteristics of patients

Characteristics	Trimodal cohort (n = 52)
Age (years)
< 60	36
> 60	16
Gender
Male	24
Female	28
Location of tumor
Upper thoracic	2
Middle thoracic	33
Lower thoracic/abdominal	17
Operative approach
TTE+2FD	47
ME+2FD	4
ME+3FD	1
Grade
Well/moderately differentiated	37
Poorly differentiated	5
Unknown	10
ypTNM staging
0	23
I	11
II	8
III	10
ypN status
N0	33
N+	13
Margin status
R0	47
R1/2	5
Lymph node yield
Median	11
IQR	8
Tumor regression grade
Grade ≤ 2	32
Grade > 2	14
Missing data	6
LVI/PNI
Absent	35
Present	7
Missing data	10
Postoperative mortality	6

TTE + 2FD transthoracic esophagectomy + 2-field dissection, ME + 2FD McKeown esophagectomy + 2-field dissection, ME + 3FD McKeown esophagectomy + 3-field dissection, IQR interquartile range, LVI/PNI lymphovascular invasion/perineural invasion

Median follow-up of our patient cohort was 27.9 months (interquartile range 21 months). Overall, recurrence was experienced by 17 patients (37%); local in 2 (anastomotic), regional in 5 (one in the mediastinum, one in the cervical node, and 3 in the neck and mediastinum synchronously), isolated distant in 4 (one in the non-regional nodes, two in the lungs and one in the brain), and combined regional and distant recurrence in 6 patients (two in the lungs and mediastinum; one in the neck, lungs, and bones; one in the mediastinum and retroperitoneal nodes; one in the neck, liver, and lungs; and one in the neck and liver) (Fig. 2). Among the patients surviving surgery (n = 46), at the time of last follow-up, 61% of patients were alive without disease, 13% were alive with recurrence, 22% had expired due to recurrence, and 4% had expired due to other causes. Median RFS was 34 months and median OS was yet to be reached at last follow-up (Fig. 3).

Fig. 2.

Pie chart depicting patterns of recurrence (n = 17)

Fig. 3.

Kaplan-Meier plots showing relapse-free survival (RFS) and overall survival (OS)

Discussion

Esophageal cancer continues to be an enigma for clinicians and researchers, besides being a major healthcare burden worldwide and in Kashmir [1, 3, 4]. Most of the patients present with locally advanced disease, with its attendant poor outcomes [1, 8, 14–16]. A number of phase III trials and meta-analysis have established the role of NACRT in the treatment landscape of esophageal cancer, which has shown significant beneficial effect on survival end points [9–12]. The biological differences between the two major histological subtypes of esophageal cancer (SCC and AC) are well established [5, 17], despite the fact that most of the studies have treated both of these with therapeutically monolithic approaches [18–20]. In general, SCC of the esophagus is considered to be more sensitive to chemoradiotherapy, yielding higher complete pathological response (pCR) rates than AC, however, with a controversial differential impact on RFS and OS [21]. We incorporated NACRT in our treatment paradigm for ESCC since 2013. In this first report from Kashmir (which is a high-risk endemic zone for ESCC), we investigated patterns of failure in locally advanced ESCC after trimodal treatment.

In addition to decreasing the overall risk of recurrence, trimodal therapy also influences the patterns of failure in patients with locally advanced ESCC. In general patients treated with trimodal approach have a significantly better locoregional control, with more distant failures (isolated or in combination with locoregional recurrence) [22]. The recurrence pattern in our patient cohort largely mirrors the findings reported in other studies (Table 2). All of these studies have included both SCC and AC in their analysis, with the latter histotype being proportionately more in most of the studies. As is evident from our findings, most of the patients recur at distant sites (10/17), with or without locoregional failure, which is corroborated by other studies also [19, 30].

Table 2.

Comparative findings of patterns of failure after trimodal therapy

	Number operated	Locoregional recurrence (%)	Isolated distant recurrence (%)	Combined
Kim et al. [23]	53	8 (15)	10 (19)	2 (4)
Meluch et al. [24]	96	3 (3)	39 (41)	NR
Kesler et al. [25]	85	7 (8)	19 (22)	1 (1)
Burmeister et al. [26]	103*	11 (10.7)	46 (44.7)	4 (3.9)
Berger et al. [27]	131	16 (12.2)	28 (21.4)	NR
Lin et al. [28]	61	14 (23)	12 (20)	6 (10)
Luu et al. [29]	64	4 (6)	14 (22)	NR
Shaikh et al. [22]	132	19 (14.5)	32 (23.5)	NR
Xi et al. [21]	895	58 (6.5)	230 (25.7)	80 (8.9)
CROSS trials [19]	213	7 (3.3)	44 (20.7)	23 (10.8)
Our data	46	7 (15.2)	4 (8.7)	6 (13%)

NR not reported, *only patients who had R0 resection

A number of factors have been identified to predict the risk of recurrence after trimodal therapy in locally advanced esophageal cancer. Response to NACRT has been shown to be an independent predictor of relapse in a number of studies, with pCR intuitively being associated with significantly lesser risk of locoregional failure [19, 21, 22, 27, 31]. We noticed a pCR of around 44% in our patient cohort which is almost identical to the rates reported in other large studies [19, 21, 23, 24], although some have reported rates lesser than 20% [26, 29]. A number of studies have proven histology-dependent differential response to NACRT, with SCC being associated with higher pCR rates, which probably can explain our findings [10, 20, 32].

No trial till date has shown significant survival benefit of different operative approaches of esophagectomy (transthoracic, transhiatal, McKeown, or minimally invasive techniques) over each other [2, 33]. Irrespective of the approach adopted, the goal is to achieve complete extirpation of the tumor (R0 resection), as status of the resection margins has been shown to be of prognostic importance [34, 35]. Our standard approach for esophagectomy was transthoracic with McKeown’s in few. We achieved R0 resection in 90% of our patients, which is concordant with most of the other studies [19, 22, 25, 26, 29], although some studies have reported rates as low as 56% [36].

A residual leftover node harboring residual disease can be an important source of locoregional failure. The radicality of lymphadenectomy has been a topic of debate for a long time, with studies reporting its contradicting benefits on survival [37–40]. The AJCC recommends resection of at least 12 nodes during surgery for proper staging of the disease [13]. There is limited data in the form of observational studies to suggest the survival benefit of increased lymph node yield or lower lymph node ratio even after application of neoadjuvant therapy in esophageal cancer [41–43]. It is pertinent to mention here that in addition to radicality of surgery, lymph node yield also depends on the quality of pathological assessment and use of preoperative therapy. Our median lymph node retrieval was 11, which is slightly lower on the other side and can be attributed to unstandardized techniques of pathological assessment of surgical specimen and relative inexperience of the surgical team. Nonetheless it is interesting to note that the impact of lymph node harvest on locoregional recurrence has yielded contradictory results [22, 44].

The study of patterns of failure of a disease informs us about its natural history and thus guides us in focusing our therapeutic efforts in proper areas and further provides us with a rationale for optimum surveillance in these patients [45]. Our study suffers from limitations of a retrospective design (with its inherent biases), limited patient numbers, and a relatively short follow-up period. Because of small sample size and limited number of events, we have not attempted to do analysis of factors predicting failure. Nonetheless, its main strength lies in its focus on a single histology (SCC) and relatively robust follow-up with very few dropouts.

Conclusion

To conclude, a significant number of patients with locally advanced ESCC fail even after receiving NACRT, most of them at distant sites (with or without locoregional failure). This emphasizes the need for novel systemic and/or locoregional protocols to further improve the recurrence rates and outcomes in these patients.

Funding Statement

No funding involved.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.