|Year : 2015 | Volume
| Issue : 3 | Page : 413-416
Neoadjuvant chemotherapy and surgery versus surgery alone in resectable esophageal cancer
K Bushan, S Sharma
Department of Surgical Oncology, Asian Institute of Oncology, Mumbai, Maharashtra, India
|Date of Web Publication||18-Feb-2016|
Department of Surgical Oncology, Asian Institute of Oncology, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
The aim of this article is to review randomized and non-randomized trials and meta-analysis comparing neoadjuvant chemotherapy (NAC) plus surgery versus surgery alone in resectable esophageal cancers. The article examines the value of NAC as a standard of care in the era of multimodality treatment with availability of different therapeutic options. The emphasis is on assessment of benefit of NAC in terms of survival (long and short term) rate of RO resection in resectable esophageal cancers of any histopathologic type. The in-hospital post-operative morbidity and mortality in NAC group, chemotherapeutic drug regimens and their response rates and optimal number of cycles to be used will also be addressed
Keywords: Curative (R0) resection, neoadjuvant chemotherapy, overall survival
|How to cite this article:|
Bushan K, Sharma S. Neoadjuvant chemotherapy and surgery versus surgery alone in resectable esophageal cancer. Indian J Cancer 2015;52:413-6
| » Introduction|| |
Esophageal cancer is an aggressive malignancy with an increasing incidence. Globally, it is the 8th most common and 6th most fatal malignancy. The need for upgrading the standard of care for patients with esophageal cancer was clearly and effectively stated by two articles published in British Journal of Surgery in summer of 1980's, which demonstrated dismal results of either surgery or radiotherapy alone after compiling data of 18000 patients. Since then management of esophageal cancer has been evolving. Despite improvements in detection and treatment, overall survival (OS) in esophageal cancers remains lower than most solid tumors, which highlight why further advances are desperately needed.
There is lack of level I evidence to support any treatment protocol in esophageal cancers. There are several standards of care influenced by geographical location, patient status and institutional bias. Pre-operative chemotherapy is more often used in Europe and Asia, pre-operative chemo-radiation in United States. Post-operative chemo-radiation is also a standard of care especially for cancers of gastroesophageal junction if not treated pre-operatively. Definitive chemo-radiation without surgery is also a standard of care, especially in institutions lacking a thoracic surgeon experienced in esophagectomies and for patients unfit or surgery.
Surgery remains the cornerstone for treatment of esophageal cancer, although long-term survival rates are still poor. As a result, there has been increasing interest in combining surgery with neoadjuvant chemotherapy (NAC). The potential benefits include-downstaging of primary tumor, control of systemic disease by eliminating micrometastasis, increases chance of resectability and curative (R0) resection, and improvement of swallowing (dysphagia) resulting in better nutrition. It also allows assessment of completeness of pathological response all of which might influence decision on post-operative management. On the contrary, if the patient doesn't respond to NAC, the prognosis might be worse than that of primary surgical approach and can lead to adverse events, allow tumor progression during chemotherapy, costs time and increases health expenses.
The aim of this article is to review randomized and non-randomized trials and meta-analysis comparing NAC plus surgery versus surgery alone in resectable esophageal cancers. The article examines the value of NAC as a standard of care in the era of multimodality treatment with availability of different therapeutic options. The emphasis is on assessment of benefit of NAC in terms of survival (long and short term) rate of R0 resection in resectable esophageal cancers of any histopathologic type. The in-hospital post-operative morbidity and mortality in NAC group, chemotherapeutic drug regimens and their response rates and optimal number of cycles to be used will also be addressed.
| » Trials and Meta-Analysis|| |
Gebski et al., in 2007 published a meta-analysis of 8 randomised controlled trials (RCTs) done from 1982-1992 with total of 1724 patients [Table 1] 6 RCT's enrolled patients with squamous cell carcinoma (SCC) only and rest two included both SCC and adenocarcinoma (AC). All patients had a resectable disease (T0-3No-1). Median follow-up was 37 months (average 4-72 months).
The combined estimate included 876 patients receiving NAC and 848 patents undergoing surgery alone. With regard to chemotherapy used, dose regimes might have differed between studies, but all studies used cisplatin and 5-fluorouracil (5FU) typically after 1988. The meta-analysis demonstrated that the hazard ratio (HR) for NAC group was 0.90 (0.81-1.00, P = 0.05) which indicates a 2 years absolute survival benefit of 7%. For patients with SCC, NAC didn't demonstrate a survival benefit but for adeno carcinomas, survival benefit was significant.
MRCOE02 Trial  between March 1992 and June 1998, The Medical Research Council Oesophageal Cancer Working Group (MRCOCWG) recruited 802 patients from 42 European centers with resectable esophageal cancer previously untreated of any histopathologic type (67% AC, 33% SCC). They were randomly allocated either two 4 days cycles, 3 weeks apart, of cisplatin (80 mglm 2) by infusionover 4 h plus 5FU (1000 mglm 2) continuous infusion for 4 days followed by surgical resection[chemosurgery (CS) group, n = 400] or resection alone (S group, n = 402). Clinicians were allowed to choose radiotherapy pre-operatively and 9% patients in each group received the same. Primary outcome measured was survival time and analysis was by intention to treat. No patient dropped out of study. Resection was microscopically complete in 233 (60%) of 390 amenable CS group patients and 215 (54%) of 397 S-group patients. OS was better in CS group (hazard ratio 0.79,95%, confidence interval 0.67-0.93) P = 0.004). Median survival rate was 43% in CS group and 34% in S-group. The trial report was published in 2002 and favored two cycles of pre-operative cisplatin based chemotherapy in terms of improvement in survival without addition of serious events post-operatively.
Orlando et al., updated data from Medical Research Council Of Cancer Working Group's (MRCOCWG's) trial, Medical Research Council Of Esophagus-02 (MRCOE-02) trial. At a median follow up of 6 years, the 5 survival rate was 23% in NAC group compared to 17% in S-group. The difference in survival in favour of NAC remained consistent in both histologic types-SCC and AC. An evaluation of all patients by resection status showed a substantial benefit for patients in whom RO resection was achieved as compared to R1, R2 resection. Three years survival rates were 42%, in RO, 18%, in R1 and 9% in R2 resections with median survival of 2.1 year in RO, 1.1 year in R1 and 0.8 years in R2 resection.
Japanese study-Japanese Cancer Oncology Group (JCOG) 9907., JCOG randomized 330 patients with stage II-III SCC of the thoracic esophagus to two cycles of pre-operative chemotherapy with cisplatin (80mg/M 2 on day1) plus 5-FU (800 mg/m 2/d on day 1-5) followed by surgery versus surgery alone. At a planned interim analysis in March 2007, median progression free survival was 3 years in NAC group versus 2 years in surgery alone group. The results improved even in comparison to post-operative chemotherapy as was proved by their earlier tiral JCOG 9204 studying effect of surgery plus adjuvant chemotherapy versus surgery alone in resectable esophageal cancers. With pre-operative chemotherapy, no significant adverse events were seen. Furthermore, downstaging and RO resection rates were effectively achieved, though the survival benefit was seen more in stage II disease.
US Intergroup (IG) Trial–0113 Kelsen et al., conducted a multicentric phase III RCT involving 440 patients (44% SCC, 51% AC, 5% not categorized to either type). Two hundred and thirteenpatients were subjected to three cycles of cisplatinand 5FU based chemotherapy followed by surgery followed by adjuvant three cycles of chemotherapy with same drug regimen and radiotherapy (if margin positive) 227 patient = s were subjected to surgery alone. Median follow- up was 3.9 years. In pre-operative chemotherapy. The 2 year survival rate was 35% compared to 37% in surgery alone group. The 3 year survival rates were 23% in the pre-operative chemotherapy group versus 26% in surgery alone group. Median survival was 14.9 months in NAC group versus 16.1 months in surgery alone group. This trial didn't show any survival benefit with neo adjuvant chemotherapy, but strongly suggested that survival improves with curative (RO) resection. The 3 year survival rates noted in RO, R1 and R2 resections were 39%, 12%, and 4% respectively.
Malthaner et al., in 2004, in an earlier systematic review and meta-analysis coding 1-year mortality from 6 RCT's detected no statistically significant difference in mortality for patients given NAC when compared with surgery alone patients.
Malthaner et al., in 2006 conducted a meta-analysis of 11 phase III TCT's enrolling 2051 patients with resectable esophageal cancers of any histology, to determine whether pre-operative chemotherapy improved survival. Cancers of cervical esophagus were excluded. Clinical relevance was based on median survival and 1-5 year survival rates. The meta-analysis of this Cochrane systematic review database (2003) showed no difference in survival at 1 and 2 years in both groups. Pooled response rate to chemotherapy was 36% with pathological complete response (PCR) rate in 3% cases of NAC group. Survival advantage started in NAC group at 3 years and reaches statistical significance at 5 years (RR = 1.44, 95% confidence interval - 1.05-1.97, P = 0.02). This meta-analysis showed 12% reduction in risk of mortality in the pre-operative chemotherapy group when compared to surgery alone group.
Kaklamanos et al., in their meta-analysis of seven trials enrolling a total of 1683 patients, showed modest improved 2 year survival rate in NAC group compared to surgery alone. The absolute difference was 4.4% (95%, confidence interval, 0.3-8.5%). They also noted that treatment related mortality increased by 1.7% with NAC (95% confidence interval,−0.9-4.3%. Urschel et al., in their meta-analysis of 11 RCT's including 1976 patients detected no significant difference between NAC and surgery alone in terms of survival at 1,2 or 3 years.
Bhansali et al., published a meta-analysis of 12RCT's only four of trials compared NAC with surgery alone. Rest studies compared chemotherapy in a variety of combinations with radiotherapy with or without surgery. No benefit of cisplatin based NAC was detected.
The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial  Researchers affiliated with national cancer research institute upper gastrointestinal study group, presented at the 2005 annual meeting of American Society of Clinical Oncology, result of MAGIC trial. Patients with operative gastric or lower esophageal ACs were randomly subjected to pre and post-operative chemotherapy and surgery alone (Total patients 503, 250 patients in chemotherapy arm, 253 in surgery arm). In chemotherapy arm, three cycles of cisplatin (60 mg/M 2), bolus epirubicin (50 mg/M 2) and continuous infusion 5FU (200 mg/M 2) were given at 3 weekly interval and same regimen repeated post-operatively. At 2 years and 5 years, survival was 50% and 36% in chemotherapy arm versus 41% and 23% respectively in surgery arm. The researchers concluded that pre- and post-operative chemotherapy improved progression free and OS in patients with gastroesophageal ACs compared to surgery alone.
FFCD (Federation Francophone delacancerologie digestive) trial  recruited 224 patients with adeno carcinoma esophagus and randomized patients to NAC (n = 113) and surgery alone (n = 111). Two cycles of cisplatin and 5FU were used. Median follow-up was 5.7 years. Threeyearsurvivalrate was 48% in NAC group versus 35%, in surgery alone group (P = 0.02).
Halli day et al., in a non-randomized study, compared post-operative complication rate and survival rates of patients undergoing surgery with or without pre-operative chemotherapy. 167 patients were included (89-NAC group, 78 surgeries alone). The inhospital post-operative mortality rates of NAC group (n = 2 deaths, 2.2%) were significantly lower than in non-NAC (n = 6 deaths, 7.7%) Most deaths were due to cardiorespiratory complications. However, no difference in rates of chest infections, wound infections or leaks in both groups. Two year survival and long-term survival rates in NAC group were higher (2 year SR 60.7% in NAC group vs. 48.7%, in surgery alone group and median survival 793 days in NAC group vs. 554 days in surgery alone group). However, these differences were not significant statistically.
[Table 2] shows RCT's of NAC versus surgery alone-clinical complete response based on endoscopic visualization and imaging ranged from 19% to 58% and PCR 2.5-13% with NAC. This is an unsurprising trend considering the relative ineffectiveness of chemotherapy alone in treatment of esophageal cancers.
[Table 3] and [Table 4] shows RCT'S of perioperative chemotherapy versus surgery alone of 213 patients in perioperative arm (Kelsen et al., only 66 later received adjuvant chemotherapy (CT), 26% had AC of GEJn and lower esophagus, 11% had esophageal AC. Of 113 patients in perioperative arm (Bioge et al., 2004), only 54 later received adjuvant CT. Those studies that focused solely on esophageal cancers didn't reveal any survival benefit, while 2 RCT'S that included AC of lower esophagus and GE junction did show some benefits with NAC.
| » Discussion|| |
RCT'S and meta-analysis investigating effect of NAC on esophageal cancer have been inconsistent. The results of North American IG0113 trial are totally in contrast with results of MRCOE2 trial. Comparisons of these two large RCT's might help to explain discrepant results [Table 4]. Marked clinical heterogeneity due to different chemotherapy protocols, use of post-operative chemotherapy in IG trial, longer delay before surgery as well as fewer patients in chemotherapy group undergoing surgery in IG trial and use of pre-operative radiotherapy in MRC trial might explain the different outcomes. Though, MRC trial is appealing in terms of OS, DFS and good adherence with acceptable morbidity in NAC group compared to surgery alone group, there are several questions that remain unanswered. The optimal chemotherapeutic regime, dosage, schedule and timing in relation with surgery is yet to be proved since results have shown only modest responses clinically and very less pathologic response. Furthermore, questions were raised by researchers that whether it is a good practice to compare survival between treatment arms by resection status as downstaging with NAC maker it inappropriate. An ongoing UK Trial (OE05) is addressing the question of the most appropriate chemotherapeutic combinations for these patients.
NCCN was concerned that survival benefit observed in MRCOE2 might not hold up, but a 6 year follow-up of the trial showed that benefit was indeed maintained.
The impact of The RCT'S and meta-analysis is still unclear due to disproportionate number of patients in both the arms, who did not receive or completed their assigned treatment. Questions have been raised whether benefit in pre-operative chemotherapy arm is due to better delivery of drugs as practically one can get more chemotherapy into patients before they become too debilitated. Furthermore, NAC is associated with a protective pre-conditioning phenomenon, which subsequently improves post-operative recovery signifying lesser morbidity post-operatively and good outcome.
| » Conclusion|| |
Currently NCCN guidelines do not recommend NAC as a standard of care for resectable esophageal cancers. Their primary recommendation is for treatment that involves chemo-radiation. Whatever data available, NAC seems to be an option for ACs of lower esophagus and GE Junction tumors. Multi-institutional prospective randomized trials are still required to study value of NAC in esophageal cancers before making it a standard.
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[Table 1], [Table 2], [Table 3], [Table 4]
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