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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 4  |  Page : 646-651
 

Neoadjuvant chemoradiation for locally advanced resectable carcinoma of the esophagus: A single-center experience from India with a brief review of the literature


1 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Radiation Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India

Date of Web Publication30-Jul-2018

Correspondence Address:
Dr. Arvind Krishnamurthy
Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_452_17

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 » Abstract 


BACKGROUND: The management of locally advanced carcinomas of the esophagus and esophagogastric junction has undergone a major evolution over the past two decades with the widespread use of combined modality therapy. Although many Indian centers practice the combined modality therapy with neoadjuvant chemoradiation (nCRT), published data are sparse. OBJECTIVES: The objective of this study was to study the safety and efficacy of nCRT in patients with locally advanced resectable carcinoma of the esophagus. MATERIALS AND METHODS: Prospective single-arm study of the first fifty patients enrolled over 3 years (2014–2016). RESULTS: The median age was 51 years (M:F = 3:2), 90% of the patients had squamous cell carcinomas, and 69% had lower-third lesions. All accrued patients completed the intended dose of radiation; however, approximately 20% had a treatment delay, which was duly gap corrected. Importantly, there were no treatment-related toxic deaths. Eleven patients could not undergo surgery following nCRT (two patients defaulted, two were deemed medically unfit, and seven (14%) patients had disease progression on imaging). Thirty-nine (78%) patients were planned for definitive surgery; however, a further 7 (14%) were found to be inoperable intraoperatively. Thirty-two patients successfully completed their definitive surgical procedures with R0 resections, of which 19 patients (38%) had a pathological complete response (pCR). There was no postoperative 90-day mortality in our study cohort. Analysis of prognostic factors that predicted a response showed that patients who had adenocarcinoma and with circumferential lesions responded poorly. CONCLUSION: nCRT appears to be a safe and a reasonably well-tolerated option in carefully selected patients with resectable locally advanced esophageal cancers. Although our data are not mature to analyze the survival outcomes with a pCR rate of 38%, it suggests nCRT to be a promising option in the management of locally advanced resectable esophageal cancers.


Keywords: Carcinoma esophagus, chemoradiation, neoadjuvant chemoradiation, neoadjuvant chemotherapy, squamous cell carcinoma esophagus, transhiatal esophagectomy, transthoracic esophagectomy


How to cite this article:
Krishnamurthy A, Mohanraj N, Radhakrishnan V, John A, Selvaluxmy G. Neoadjuvant chemoradiation for locally advanced resectable carcinoma of the esophagus: A single-center experience from India with a brief review of the literature. Indian J Cancer 2017;54:646-51

How to cite this URL:
Krishnamurthy A, Mohanraj N, Radhakrishnan V, John A, Selvaluxmy G. Neoadjuvant chemoradiation for locally advanced resectable carcinoma of the esophagus: A single-center experience from India with a brief review of the literature. Indian J Cancer [serial online] 2017 [cited 2019 Aug 18];54:646-51. Available from: http://www.indianjcancer.com/text.asp?2017/54/4/646/237900





 » Introduction Top


Carcinoma of the esophagus is the eighth most common malignancy and the sixth most common cause of cancer-related mortality worldwide. Although squamous cell carcinoma is the most common histological variant worldwide, there seems to be a distinct geographical histological variation in the reported incidence of carcinoma esophagus. Over the past few decades the numbers of patients diagnosed with esophageal and gastroesophageal junction (GEJ) adenocarcinomas have markedly increased, which is hypothesized to reflect the increasing rates of obesity and gastroesophageal reflux disease. Conventionally, radical esophagectomy was considered to be the sole curative treatment for esophageal cancers.[1],[2],[3],[4],[5] Despite the improvements in surgical techniques and the development of the minimally invasive approaches, the five survival outcomes of patients treated with surgery alone remained dismal, ranging from 15% to 25%. However, over the past two decades, neoadjuvant approaches as a part of multimodality treatment have evolved to become the new standard of care.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] A renewed interest in neoadjuvant chemoradiation (nCRT) in the management of esophageal carcinomas was noted worldwide following the publication of the results of the Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study (CROSS) study.[16],[17] There were concerns with regard to the safety and efficacy of the aggressive nCRT treatment in patients from the Indian subcontinent who are believed to be nutritionally compromised. Although many Indian centers practice the nCRT approach, published data are sparse. We present the results of our first 50 patients who were enrolled in this ongoing nCRT protocol.


 » Materials and Methods Top


All consecutive eligible and fit patients of locally advanced esophageal cancers (clinically T3 and/or N plus) of the middle- and lower-third of the esophagus (both squamous and adenocarcinomas) registered at the Institute were offered the study protocol. The main objective of this study was to study the safety and efficacy of this aggressive nCRT approach. The results of our first 50 patients who were enrolled in this ongoing study protocol were analyzed.

Treatment protocol

The nCRT schedule was as follows: on days 1, 8, 15, 22, and 29, carboplatin targeted at an Area Under Curve (AUC) of 2 mg/ml/min and paclitaxel at a dose of 50 mg/m2 of body surface area were administered intravenously. A total radiation dose of 41.4 Gray was given in 23 fractions (conventional fractionation), starting on the first day of the first chemotherapy cycle. The patients were closely monitored for toxic effects of nCRT. The patients were subsequently taken up for a planned definitive surgery, about 6–12 weeks following the completion of nCRT. The surgical technique entailed either a video-assisted thoracic surgery–transthoracic esophagectomy (VATS–TTE) with a two-field lymph node dissection or a transhiatal esophagectomy (THE). A cervical anastomosis using a gastric tube was the preferred technique for restoring the continuity of the digestive tract.

A detailed pathological analysis was done to describe the tumor type and extension, lymph nodes, and resection margins. The pathological responses following surgery were classified in accordance to the tumor regression grade. The planned follow-up assessments were scheduled as follows: first follow-up at 1 month and subsequent follow-up assessments were to be at 3-month intervals for the first 2 years, 6 months for the next 3 years, and annually until death. Late toxic effects, disease recurrence, and death were recorded and analyzed.


 » Results Top


The median age of the study cohort was 51 years, which constituted 30 males and 20 females (M: F = 3:2); 90% of our study population had squamous cell carcinoma as histological type unlike in the CROSS study wherein the vast majority were of the adenocarcinoma histology. 69% (n = 30) of the patients had lower-third lesions, whereas the remaining 40% (n = 20) had their tumors located in the middle-third of the esophagus. All accrued patients completed the intended dose of external beam radiation; however, approximately one-fifth of patients (20%) had a treatment delay, which was duly gap corrected. Barring one patient, all patients completed at least three cycles of the planned chemotherapy, nearly 80% completed four cycles, whereas 50% completed all five cycles. A quarter of the patients had hematological toxicity, and an equal number had gastrointestinal toxicity due to nCRT. Importantly, there were no toxic deaths during nCRT treatment.

Eleven patients could not undergo surgery following nCRT (two patients defaulted, one patient had worsening of her bronchiectasis, and general condition of one patient deteriorated and she was deemed unfit for surgery). Further, seven (14%) patients were found to have progressive disease and were kept on supportive care. Thirty-nine (78%) patients were planned for definitive surgery; however, a further seven (14%) were deemed inoperable intraoperatively. Among the 32 patients who successfully completed their definitive surgical procedure (R0 resections), 25 underwent a VATS–TTE with two-field lymphadenectomy and seven patients underwent a THE [Figure 1]. There was no 90-day postoperative mortality in our study cohort. Nineteen patients (38%) had a pathological complete response (pCR) in our study compared to 29% of patients in the CROSS study. The patients are being actively followed up; there have been six deaths during follow-up at the time of the analysis (survival data are not yet mature).
Figure 1: Management pathway of the patient cohort

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A formal analysis of the factors that predicted a pCR was done; however, no single factor was found to be of statistical significance. However, when an analysis for responders (at least a partial response) versus nonresponders was done, a significant proportion of patients with adenocarcinoma histology (P = 0.02) and patients with circumferential lesions (P = 0.04) was found to be nonresponders [Table 1].
Table 1: Analysis of the factors that predicted a response to neoadjuvant chemoradiation

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 » Discussion Top


Esophageal cancer is emerging as a common cancer in India. In fact, carcinoma esophagus was ranked fifth among males and sixth among females, accounting for 6.4% of all male cancers and 3.5% of all female cancers in the Hospital Cancer Registry (HBCR Chennai) during 2005–2006. SCC was the predominant histology in up to 70% and adenocarcinoma accounted for 10.7% of the cases.

Less than one-fifth of the cases presenting to the authors' center received cancer-directed treatments, and the 5-year overall survival (OS) by actuarial method for patients treated during 2001 and followed through 2006 was 13.9%. Even in developed countries, more than 85% of the patients die within 2 years of diagnosis, making it the sixth most common cause of cancer-related deaths in the world. Clinical trials involving multimodality treatment options have been conducted over the years to improve patient survival with esophageal cancer amid a remarkable change in histology and epidemiology.

Numerous randomized trials and meta-analysis have compared neoadjuvant chemotherapy (NACT) with surgery versus surgery alone, some with conflicting results. The two major randomized studies are the Intergroup 113[18] and the Medical Research Council[19] studies, the former showed no difference and the latter showed a benefit with NACT. However, a recent meta-analysis by Sjoquist et al.,[20] including 10 randomized controlled trials (RCTs), conclusively showed an absolute survival benefit difference of 5.1% at 2 years favoring the NACT group.

A combination of chemotherapy and radiation is believed to interact and improve outcomes in several cancers. The cytotoxic agents used in combined modality therapy of esophageal cancers are those that have both antitumor activity against esophageal cancer as well as clinically important radiosensitizing effect, i.e., fluoropyrimidines and cisplatin. Other active agents in esophageal CRT regimens include taxanes and camptothecins. The combination of chemotherapy and radiation followed by surgery has been investigated for more than two decades, with the goal of improving survival by addressing the substantial local and distant failure rates.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15] As the combination of 5 Fluoro uracil (5FU) and cisplatin has been demonstrated to be beneficial when added to definitive radiation in the Radiation Therapy Oncology Group 8501,[6] these drugs have formed the backbone of many studies and remain a commonly used doublet concomitant with radiotherapy.

Several randomized trials have been performed with nCRT in esophageal cancers, and similar to NACT, most earlier studies showed divergent results.[10],[11],[12] It must be noted that most early trials were underpowered and that there was significant heterogeneity in the doses of chemotherapy/radiation as well as in surgical techniques. However, data from earlier meta-analyses[21],[22] and the meta-analysis by Sjoquist et al.[20] reported an absolute survival benefit years favoring the nCRT approach, albeit frequently at the cost of increased postoperative morbidity and mortality.

A recently published large RCT of 368 patients, the CROSS Group study,[16],[17] randomly assigned patients with esophageal/esophagogastric junction cancers to receive surgery alone or the nCRT protocol. The median OS was 49.4 months in the nCRT group, whereas it was 24 months in the surgery-alone group. The OS was significantly better in the nCRT group (hazard ratio, 0.657; P = 0.003). The investigators concluded that nCRT improved survival among patients with potentially curable esophageal/esophagogastric-junction cancers and that the regimen was associated with acceptable adverse event rates.

The nCRT protocol similar to that used in the CROSS study was administered in our study cohort as well. A few striking differences in the demographic characteristics of our patient cohort were as follows. The median age of the study cohort was 51 years, which is a decade younger than what is seen in the CROSS study. Squamous cell carcinoma was our predominant histology (90%) compared to the CROSS study, wherein 75% of the patients were of the adenocarcinoma histology. The tumors in our patient cohort were longer with a mean length of 5.5 cm compared to 4 cm in the CROSS study. Although 42% of our patients had baseline malnutrition, patients who had nutrition status were corrected by enteral therapy and then included in the protocol. This could partly explain the treatment delays/modifications while delivering the nCRT regimen. Interestingly, patients who have lost >10% of their original body weight were excluded from the CROSS study.

During the follow-up of the 368 patients in the CROSS study, 16 patients died from treatment-related causes of whom nine were in the nCRT plus surgery group and seven in the surgery-alone group. No treatment-related toxic deaths were noted in the first 50 patients of our study.

Analysis of the CROSS study revealed that the benefit of the nCRT protocol was more pronounced in patients with the squamous cell histology, with a median survival of 81 months compared to 43 months for patients with adenocarcinoma histology. Our study also showed that patients with squamous cell carcinoma were more likely to respond to the nCRT protocol compared to adenocarcinomas. Further analysis of the adenocarcinoma histology subgroup in the CROSS study showed that the 5-year OS for nCRT was 47% compared to 33% in the surgery-alone group. Incidentally, this difference is similar to the 13% absolute survival benefit for NACT as seen in the MAGIC trial.[23]

Thus, it is clear that, based on survival data from several RCTs and meta-analyses, neoadjuvant treatment is the new standard of care for locally advanced resectable esophageal cancers; however, a major unanswered question remains as to whether nCRT is clearly superior to NACT. Although the pCR rates are higher in the nCRT arm when compared to the NACT arm (25% vs. 10%), there are no head-to-head comparisons of the survival outcomes between nCRT and NACT. Two smaller trials attempted to address this question; however, neither trial showed a clear advantage for one over the other. However, a pooled analysis of all the studies in the meta-analyses found a statistically nonsignificant trend toward improved survival with nCRT compared to NACT.[20]

A recent comprehensive review and network meta-analysis comparing the various multimodality treatments in the management of squamous cell carcinoma of the esophagus (including 25 trials comprising of 3866 patients) revealed that nCRT was associated with the most robust survival advantage among the different multimodality treatment options (HR 0.73)[24] Another network analysis studying the survival after neoadjuvant and adjuvant treatments in resectable esophageal cancers including 33 RCTs with 6072 patients also found nCRT followed by surgery to be the most effective strategy in improving the survival of resectable esophageal cancers.[25] The data from the above pooled/network analysis derived across trials should not be strictly used to directly compare the oncological outcomes of nCRT with NACT, and thus, the question of which of the neoadjuvant approaches is superior remains unanswered.

The convincing benefit seen in the results of the CROSS trial with neoadjuvant carboplatin/paclitaxel/RT combination has made this regimen one of the favored regimens in clinical practice although optimal regimen for nCRT is not clearly established. The ongoing Japanese randomized NExT trial (JCOG1109)[26] and the Irish randomized Neo-AEGIS trial (ICORG 10–14)[27] will hopefully provide more definitive evidence on the best possible perioperative treatment for patients of squamous cell carcinoma and adenocarcinoma of the esophagus, respectively. The Japanese JCOG1109 NExT study is comparing NACT cisplatin/5-fluorouracil to NACT DCF and to nCRT (concurrent cisplatin/5-fluorouracil, 41.4 Gy in 23 fractions over 5 weeks) in squamous cell carcinoma of the thoracic esophagus. The Neo-AEGIS trial is currently randomizing patients with operable esophageal/GEJ adenocarcinomas between the CROSS regimen and perioperative ECX. This study will possibly provide a more definitive answer, but until then, clinicians managing esophageal adenocarcinomas can choose either of the neoadjuvant approaches.

Attempts to further improve response rates in the neoadjuvant approaches include the use of induction chemotherapy prior to nCRT, the use of targeted/immunotherapies therapies in the nCRT platform, and adding anti-HER2 therapies to the neoadjuvant treatment of HER2 neu-positive esophageal/GEJ tumors. The use of induction chemotherapy prior to nCRT seems to only increase the toxicity without any discernible benefit.[28],[29]

A positron emission tomography (PET)-based response to direct further treatment in adenocarcinomas of the esophagus has also been explored A reduction in the metabolic activity of a tumor (defined as a 35% decrease in fluorodeoxyglucose uptake compared to baseline) after 2 weeks of NACT has been prospectively validated as a prognostic biomarker.[30],[31] A follow-up trial, MUNICON-II,[32] attempted to clarify the role of salvage nCRT for patients failing to demonstrate a PET response following 14 days of cisplatin/5-fluorouracil-based induction chemotherapy.

The modification of CRT with biological agents appears to be an attractive option considering its relative success in the management of head and neck cancers; however, the use of this option in locally advanced esophageal carcinomas still remains investigational. However, with close to 400 ongoing clinical trials exploring various therapies including novel targeted therapies, activated immune cell therapies, esophageal cancer vaccines, and immune checkpoint inhibitors, the field continues to show promise in exploring newer therapeutic options in the management of this formidable disease.[33],[34]

Finally, it is prudent to mention that the results of the neoadjuvant trials should be viewed with caution as not every patient of resectable carcinoma esophagus is medically fit to undergo an aggressive combined modality treatment. Case selection will continue to play a very crucial role, especially in developing nations, wherein a great majority of patients are nutritionally compromised at the time of diagnosis, as was seen in our cohort as well.


 » Conclusion Top


CRT appears to be a safe and a reasonably well-tolerated option in carefully selected patients with locally advanced but resectable esophageal cancers with no treatment-related deaths in our study cohort. Although our data are not mature to analyze the survival outcomes with a pCR rate of 38%, our study demonstrates nCRT to be a promising option in the management of locally advanced resectable esophageal cancers.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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