NEOADJUVANT CHEMORADIOTHERAPY FOLLOWED BY TRANSHITAL ESOPHAGECTOMY IN LOCALLY ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA: IMPACT OF PATHOLOGICAL COMPLETE RESPONSE

ABSTRACT 
Background
 Multimodal therapy with neoadjuvant chemoradiotherapy, followed by esophagectomy has offered better survival results, compared to isolated esophagectomy, in advanced esophageal cancer. In addition, patients who have a complete pathological response to neoadjuvant treatment presented greater overall survival and longer disease-free survival compared to those with incomplete response. 
Aim:
 To compare the results of overall survival and disease-free survival among patients with complete and incomplete response, submitted to neoadjuvant chemoradiotherapy, with two therapeutic regimens, followed by transhiatal esophagectomy. 
Methods:
 Retrospective study, approved by the Research Ethics Committee, analyzing the medical records of 56 patients with squamous cell carcinoma of the esophagus, divided into two groups, submitted to radiotherapy (5040 cGY) and chemotherapy (5-Fluorouracil + Cisplatin versus Paclitaxel + Carboplatin) neoadjuvants and subsequently to surgical treatment, in the period from 2005 to 2012, patients. 
Results
 The groups did not differ significantly in terms of gender, race, age, postoperative complications, disease-free survival and overall survival. The 5-year survival rate of patients with incomplete and complete response was 18.92% and 42.10%, respectively (p> 0.05). However, patients who received Paclitaxel + Carboplatin, had better complete pathological responses to neoadjuvant, compared to 5-Fluorouracil + Cisplatin (47.37% versus 21.62% - p = 0.0473, p <0.05). 
Conclusions
 There was no statistical difference in overall survival and disease-free survival for patients who had a complete pathological response to neoadjuvant. Patients submitted to the therapeutic regimen with Paclitaxel and Carboplastin, showed a significant difference with better complete pathological response and disease progression. New parameters are indicated to clarify the real value in survival, from the complete pathological response to neoadjuvant, in esophageal cancer.

Central message: Chemotherapy with Paclitaxel and Carboplatin associated with neoadjuvant radiotherapy, followed by transhiatal esophagectomy offers a better complete pathological response to esophageal squamous cell carcinoma.
Perspectives: New chemotherapy regimens associated with radiotherapy, in the future, as a neoadjuvant treatment of esophageal squamous cell carcinoma, followed by esophagectomy, may offer better 5 years survival rates.

Racional:
A terapia multimodal com quimioradioterapia neoadjuvantes, seguido de esofagectomia tem oferecido melhores resultados de sobrevida, em comparação à esofagectomia isolada, no câncer do esôfago avançado. Além disso, os doentes que apresentam resposta patológica completa ao tratamento neoadjuvante, têm evoluido com maior sobrevida global e maior sobrevida livre de doença em comparação aos que apresentam resposta incompleta.  16,22 . Another advantage of neoadjuvant is the fact that cytoreduction and the consequent tumor reduction, the patient eats better, gains weight and acquires a more appropriate nutritional status for a possible surgical procedure, in addition to improving the quality of life due to the lower rate of dysphagia 1,3,24,26 .
The several advantages, such as those mentioned above, are notorious, especially when compared to other types of treatments carried out together or isolated. There is a higher rate of R0 resections, in addition to the possibility of a complete response to neoadjuvant therapy, that is, a complete absence of tumor cells in the surgical specimen 4,5,11,12,13,15,20,21,27 .
Therefore, neoadjuvant chemoradiotherapy has been widely used in Postoperative complications are shown in Table 1. There were no significant differences for postoperative complications and perioperative deaths between the two groups.
The etiologies of the deaths were bronchopleuropulmonary complications in 5 cases and abdominal sepsis in one case.
The histopathological findings of the surgical specimens were studied and presented according to the TNM, degree of differentiation and staging by UICC / AJCC / WHO 18 (Tables 2 and 3).  During the outpatient postoperative follow-up period, tumor recurrence was recorded in 20 cases (35.71%), and the remaining 36 cases (64.29%) did not present recurrence. Tumor recurrences were observed in several places, in some cases, in more than one organ. The recurrences diagnosed, during the period of analysis, were: lungs (5 cases), gastric tube (5 cases), cervical lymph nodes (4 cases), liver (2 cases), bones (2 cases) and cerebral (2 cases).
The higher percentage of recurrence was found among patients with incomplete response (43.24%) compared with patients with complete response (21.05%), however, without statistical difference (Table 4). The results of the surgical specimens analysed, according to the different neoadjuvants schemes, are showed in Table 5, with a statistically significant difference for the Paclitaxel + Carboplatin group (p <0.05).  Table 6 and the Kaplan-Meier curve in Figure 1.  The clinical staging of advanced tumors (Table 3), associated with a large number of patients with incomplete response (non-responders) to neoadjuvant treatment, may be the reason that better survival was not recorded for patients with complete response (responders). In addition, these results may be related to high rates of recurrence, directly influencing disease-free survival.
The main recurrence places observed in this study were far from the treated organ, and in lower percentages than other studies 10,14,27 . This fact may mean a possible presence of metastatic and undetected disease at the time of surgery, compromising the real value of the complete pathological response (pCR), since in this finding there was no statistical difference between the groups analyzed.
These discussions corroborate the fact that, perhaps, the available imaging exams to assess the clinical staging are currently limited in accuracy, and do not show the real dimension of the extension of the disease 11,15,21,24 .
Therefore, safely assessing the reduction in staging, just comparing the postneoadjuvant pathological staging with the preneoadjuvant clinical staging, may be controversial. Unfortunately, there are no better tools currently available for preoperative staging. When better methods become available, it will be possible to more accurately identify downstaging 7 . Even the best techniques available at the moment, such as endoscopic ultrasound and PET-CT, which offer better specificity and sensitivity for preoperative staging, they are not used routinely.  The present research, as it is a retrospective and non-randomized study, has limitations. However, since then, with the finding that the neoadjuvant regimen with Paclitaxel + Carboplatin has shown to have a better pathological response rate, this has been the protocol used in the Service, meaning that in the future, the casuistic will be more expressive and may add a better survival rate disease-free and 5-year survival. In addition, transhiatal esophagectomy showed acceptable rates of postoperative complications and in accordance with the literature 17,25 , therefore, still indicated in selected cases.
Finally, considering the results obtained in this research, the authors emphasize the importance of further research to clarify the real value of chemoradiotherapy in the complete pathological response in esophageal cancer, for survival rates.