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Prognostic factor for recurrence in esophagus cancer patients who underwent surgery for curative intent: A single-institution analysis

1 Department of Radiation Oncology, DMCH cancer center, Ludhiana, Punjab, India
2 Department of Medical Oncology, DMCH cancer center, Ludhiana, Punjab, India
3 Department of Surgical Oncology, DMCH cancer center, Ludhiana, Punjab, India

Date of Submission16-Dec-2020
Date of Acceptance01-Mar-2021
Date of Web Publication01-Oct-2021

Correspondence Address:
Manjinder S Sidhu,
Department of Radiation Oncology,DMCH cancer center, Ludhiana, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_1702_20

PMID: 34596602

 > Abstract 

Objective: The purpose of this study is to analyze predisposing factors for a higher risk of recurrence in esophageal cancer patient who underwent surgery for curative intent and to do survival analysis of prognostic factors.
Materials and Methods: Between February 2018 and March 2020, we retrospectively identified 28 cases staged T1b to T4a managed electively at our institute as per multidisciplinary management plan. Demographic, clinical, radiological, operative, histopathological parameters, upfront surgery done or not, type of preoperative, and adjuvant treatment used and whether neoadjuvant or adjuvant therapy was planned along with waiting time for surgery, were assessed as potential risk factors. End point of study was to find potential risk factors for recurrence and to do their subgroup survival analysis.
Results: The recurrence rate in our study was 25% with a mean follow-up of 24 months. The median time of recurrence was 8.5 months, all recurrence occurred within 1 year. Overall DFS at 2 years was 72%. On univariate analysis, following prognostic factors were associated with high risk of recurrence, male sex X2 (1) =4.42, p = 0.035; histology subtype of adenocarcinoma X2 (1) = 7.07, p = 0.008; margin positive X2 (1) =3.76, p = 0.05; presence of lymph vascular invasion (LVI) X2 (1) =7.88, p = 0.005; presence of perineural invasion (PNI) X2 (1) =5.97, p = 0.015; postoperative T size >4 cm X2 (1) =3.86, p = 0.049; and nodal positivity X2 (3) =13.47, p = 0.004.
Conclusions: Male sex, adenocarcinoma histological subtype, positive resected margin, presence of LVI and PNI, postoperative T size >4 cm, and high postoperative nodal positivity and whether neoadjuvant versus adjuvant therapy given (on K. M analysis) were the identified predictors of recurrence which compromised DFS.

Keywords: Mid and lower esophagus, prognostic factors, risk of recurrence

How to cite this URL:
Sidhu MS, Paul D, Jain S, Brar GS, Sood S, Jain K. Prognostic factor for recurrence in esophagus cancer patients who underwent surgery for curative intent: A single-institution analysis. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=327438

 > Introduction Top

Esophagus is sixth most common cause of cancer-related disease worldwide.[1] In India, it is the fourth most common cause of cancer-related deaths. In India, squamous cell carcinoma of distal third esophagus is most commonly seen.[2] Despite various combination of radical tri-modality treatment strategy the reported recurrence rate for esophagus cancer is up to 35% to 42%. [3,4] The goal of this study was to analyze potential predisposing factors for higher risk of recurrence in our esophagus cancer patients which were managed as per our institution multidisciplinary approach.

 > Materials And Methods Top

Between February 2018 and March 2020, we retrospectively identified 28 patients who underwent esophagectomy with curative intent along with preoperative treatment or postoperative treatment as per multidisciplinary management plan. The eligibility criteria were: (1) histologically proven squamous cell cancer or adenocarcinoma of middle and lower esophagus; (2) R0 resection; (3) standard McKeown esophagectomy or Ivor-Lewis esophagectomy; (4) clinical T1b to T4a or any N stage; (5) age of ≥18 years and Karnofsky performance status of ≥80; (6) adequate bone marrow, renal, and hepatic functions; and (7) underwent upfront surgery or some form of preoperative or post-operative therapy as per institution protocol. The exclusion criteria were cervical/upper esophageal tumors, a Siewert type 3 locations on initial endoscopy, advanced disease (T4b or M1) at presentation. The last date of follow-up for all the patients was November 2020. The variables explored for a relationship with recurrence in addition to basic patient-related demographic variables were histological type, pathologic grade, initial radiological TNM stage, tumor location, whether upfront surgery done or not, type of preoperative modality used, type of postoperative modality, neoadjuvant versus adjuvant therapy planned, pathological response to neoadjuvant treatment, margin status, status of lymph vascular invasion (LVI), status of perineural invasion (PNI), impact of postoperative tumor size, pathological T and N stage, and mean number of lymph node dissection done. Variables having significant relationship with recurrence are shown in [Table 1].
Table 1: Variable having significant relationship with recurrence

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A circumferential margin of <1 mm and a longitudinal margin of <1 cm on the final histopathology report was defined as positive or close. Waiting time of more than 6 weeks after neoadjuvant therapy was considered as delayed.[5]

The primary endpoint was to evaluate significant prognostic factors leading to high risk of recurrence. The secondary endpoint is to study the relation of the prognostic factors on disease-free survival based on Kaplan–Meier analysis. Disease-free survival was defined as time from date of end of treatment to date of event defined as first documented progression of death due to progression.

Patient was managed as per multidisciplinary board decision based on their initial diagnostic assessment as per upper gastrointestinal endoscopy. Positron emission tomography-computed tomography (PET-CT was done in all patients for staging. Mean dose of preoperative radiotherapy was 45 Gy and mean dose of postoperative radiotherapy was 50 Gy. Carboplatin-paclitaxel-based regime was used for neoadjuvant chemoradiotherapy and postoperative concurrent chemoradiotherapy modality. Some cases of adenocarcinoma of true cardia (Siewert type 2) also received perioperative chemotherapy on modified MAGIC protocol[6] as per multidisciplinary board decision.

After treatment completion, patients were followed up regularly every 3 monthly interval for initial 2 years. Follow-up CT of the chest and abdomen with contrast was repeated at a 1-year interval unless prompted for by symptoms or signs of recurrence. Endoscopy was only performed for the evaluation of any significant dysphagia-associated symptoms. If recurrence was suspected by the above investigations, additional tests included PET-CT, and biopsy was done for confirmation.

Statistical analysis

The study design was retrospective. All data were analyzed using SPSS Statistics for Windows, Version 20.0 (IBM Corp., Aemonk, NY, USA). Generalized linear modeling was done for univariate analysis to establish the association of prognostic factors for the assessment of risk of recurrence. Continuous variables were dichotomized according to their mean values or split into subgroups depending on their clinical significance. Pearson's Chi-square test was done for categorical variables. Multivariate analysis by logistic regression was not done in view of insufficient sample size. Survival and recurrence curves were estimated using the Kaplan–Meier method and compared using the log-rank test. For all practical purpose, a P ≤ 0.05 was considered statistically significant.

 > Results Top

General data

Overall, our sample consisted of 19 males and 9 females (median age, 56 years; range, 33–76 years). The majority of patients presented with clinical T3 disease (60.7%, n = 17) and 53.6% (n = 15) had clinical node positive disease hence 67.9% (n = 19) had locally advanced disease (stage III and above). The majority of tumors (78.6%, n = 22) were squamous cell carcinoma with moderate differentiation as the most common grade (67.9%). Overall, 42.9% (n = 12) were located in lower esophagus/GOJ Siewert type 1 and 32.1% (n = 9) were in mid esophagus location and 25% (n = 7) were located in GOJ Siewert type 2 location. 39.3% (n = 11) of patient received preoperative chemotherapy alone with carboplatin-paclitaxel-based regime and 7.1% (n = 2) received preoperative chemoradiotherapy. Median time between surgery and preoperative therapy was 4 weeks and average stay in hospital postsurgery was <11 days. The mean number of lymph node dissected was 20 and mean number of metastatic nodes was 2 (range, 0–7). There was nonsignificant (X2 [3] =2.5, p = 0.475) downstaging of T and N disease (X2 [3] =2.6, p = 0.456) after neoadjuvant therapy with overall pathological complete response of 30%. In postoperative histopathology report, 78.6% (n = 22) had negative margins, while LVI and PNI was not seen in 53.6% (n = 15) and 75% (n = 21) cases, respectively. Based on postoperative histopathological disease assessment as per multidisciplinary tumor board decision, 35.6% (n = 10) received adjuvant chemotherapy alone, 21.4% (n = 6) received adjuvant chemoradiotherapy, 14.3% (n = 4) received adjuvant chemotherapy followed by adjuvant chemoradiotherapy, 3 patients deferred treatment and 4 were kept on follow as per institution protocol. Out of total 28 patients 46.4% (n = 13) received neoadjuvant therapy and 53.6% (n = 15) received adjuvant therapy. Among patients who received neoadjuvant therapy 53.8% (n = 7) were of squamous cell histology and 46.4% (n = 6) were of adenocarcinoma histology.

Recurrences and univariate analysis

A total of 28 patients with a mean follow-up of 24 months (median not reached) were evaluated. The length of follow-up was longer for the group without recurrence (median: 19 months) as compared with the patients who develop a recurrence (median: 8.5 months).

Only 1 recurrence which was at anastomotic site was confirmed by biopsy and the remaining recurrences were scored using imaging studies. The recurrence rate in our study is (n = 7) 25%. Out of these 85.7% (6 cases) were distant metastatic recurrences including peritoneal disease and nonregional lymph nodes. These distant metastases occurred mainly in adenocarcinoma histology subtype constituting 66.7% (n = 4). While 14.3% (1 case) were found to have anastomotic site recurrence which was seen in squamous cell carcinoma histology subtype. All recurrence occurred in 1 year of follow-up [Figure 1].
Figure 1: KaplanMeier curve: Time to recurrence

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On univariate analysis by GLIM, following prognostic factors were associated with high risk of recurrence, male sex X2 (1) = 4.42, p = 0.035; histology subtype of adenocarcinoma X2 (1) = 7.07, p = 0.008; margin positive X2 (1) = 3.76, p = 0.05; presence of LVI X2 (1) = 7.88, p = 0.005; presence of PNI X2 (1) = 5.97, p = 0.015; postoperative T size >4 cm X2 (1) = 3.86, p = 0.049; and nodal positivity X2 (3) = 13.47, P = 0.004.

Overall DFS at 2 years was 72%, median not reached [Figure 2]. Kaplan–Meier curves for prognostic factors were done [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8].
Figure 2: KaplanMeier curve: Overall disease free survival

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Figure 3: KaplanMeier curve: Subgroup analysis histology subtype

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Figure 4: KaplanMeier curve: Subgroup analysis margin status

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Figure 5: KaplanMeier curve: Subgroup analysis lymphovascular-invasion status

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Figure 6: KaplanMeier curve: Subgroup analysis peri-neural invasion status

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Figure 7: KaplanMeier curve: Subgroup analysis postoperative mean tumor size

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Figure 8: KaplanMeier curve: Between neoadjuvant therapy versus adjuvant therapy

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Pairwise comparison with Log Rank Statistics showed significant difference in recurrence rate between N0 versus N2 (p = 0.013) and N3 (p = 0.00) and between N1 and N3 (p = 0.003) [Figure 9].
Figure 9: Pairwise comparison of postoperative nodal status

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 > Discussion Top

Esophageal cancer is aggressive disease. Despite best efforts, the 5-year survival rate following curative therapy rarely exceeds 30%. High risk of recurrence is seen even in early stage disease. Vast majority of patients do not survive due to disease recurrence either at the surgical site or at extra thoracic sites. A number of studies have analyzed prognostic factors influencing recurrence in patient with esophageal cancer postsurgical treatment with or without neoadjuvant/adjuvant chemotherapy/chemoradiotherapy. According to the Union International Centre le Cancer/American Joint Cancer Committee seventh-edition staging system, margin status, age, and histologic subtype were independent prognostic factors of survival, whereas tumor grade and site were not.[7] In a study of 582 patients undergoing surgical resection as primary treatment, tumor length significantly affected survival, with 5-year survival rates of 77%, 48%, 38%, and 23% for tumor lengths of 1, 2, 3, or > 3 cm, respectively (p < 0.001).[8] Another study of 1,553 patients with squamous cell carcinoma of the esophagus showed that tumor size, grade, lymphadenopathy, stage, and family history were prognostic following surgery. In this study, approximately 50% received adjuvant chemotherapy or adjuvant radiotherapy.[9] In another study from the Mayo Clinic, clinicopathologic factors that affected prognosis included T and N status, tumor grade, age >76 years, extracapsular lymph node extension, and the absence of chemotherapy or radiotherapy but anatomic location did not influence survival.[10] Obtaining negative pathologic margins at resection is of significant importance with regard to long-term outcome.[11] Meta-analysis of 13 series showed that PNI is an adverse prognostic factor in esophageal cancer, often associated with advanced stage and poor differentiation.[12] Our study also showed similar prognostic factors responsible for high risk of recurrence. In addition, we found the presence of LVI was also responsible for high risk of recurrence specifically associated with N2 and N3 disease.

Recurrence rate in our study was 25%, which is comparable to reported recurrence rates of other studies (29%–45%).[13-16]

In our series, the mean DFS was 24 months (median was not reached) with 2-year DFS was 72%. Lee et al. showed independent predictors of DFS to be same as predictors of risk of recurrence in their series except for histopathological tumor grade like in our study.[4]

Review of literature shows that approximately 25%–30% patients receive pathological complete response after preoperative therapy. [17,18] In our study, the overall pathological complete response was 30%. Among this, squamous cell has more pathological complete response (40%) compared to adenocarcinoma which had 20%.

In our study, the median time between surgery and preoperative therapy was 4 week and it showed no significant impact on recurrence rate. The optimal timing of surgery should be individualized but remains a contentious issue. Conflicting data exists in the literature for esophageal cancer. As per Tessier et al., who retrospectively analyzed 257 esophagectomy patients and used 7 weeks as cut off. They showed that R0 resection rate, median survival and pattern of recurrence were not significantly different.[19] On the other hand, Ruol et al. concluded in their study of 129 patients that delayed surgery beyond 46 days did not compromise outcome and might reduce tumor recurrences rate and may improve prognosis after R0 resection.[20] As per Tong survival was not compromised by early resection.[21]

We found significant better disease-free survival among patients who received neoadjuvant therapy compared to patient who received adjuvant therapy which is supported by NCCN guidelines[22] which gives category 1 recommendation for neoadjuvant therapy for squamous cell/adenocarcinoma histology clinically staged T1b-T4a, N0-N+.

Similar risk factors which were significant in our univariate analysis has been proven significant determinates of recurrence-free survival for other solid organ malignancies.[23-25] The major limitation of our study was that we were not able to do Multivariate Logistic regression analysis on our Univariate analysis in view of less sample size. This necessitates further evaluation with more rigorous study protocols to assign this high-risk group either to a better treatment protocol or to offer them additional treatment to decrease the likelihood of recurrence. Until then, these results can motivate clinicians while designing therapeutic strategies.

 > Conclusions Top

Our study concluded that prognostic factors which were predictors of risk of recurrence in esophageal cancer patients treated with curative intend are: male sex, adenocarcinoma histological subtype, positive resected margin, presence of LVI, presence of PNI, postoperative T size >4 cm, and higher nodal positivity. Kaplan–Meier analysis showed adenocarcinoma histology, postoperative positive margin status, presence of LVI, presence of PNI, high postoperative nodal positivity and when adjuvant therapy (compared to neoadjuvant therapy) was planned compromised disease-free survival.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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