Current Concepts of Neoadjuvant Therapy for Cancer Oesophagus: What Surgeons Must Know

Cancer oesophagus is one of the leading causes of cancer related deaths worldwide. Incidence of 40% over 25 years.^1,2 However, according to ICMR data, in India squamous cell carcinoma (SCC) continues to be the leading cancer subtype accounting for up to 80% of cases. Introduction of neoadjuvant multimodality treatment is one of the important developments that has led to decreased mortality rates and improvement in 5-year overall survival rates from 15.3% in 2000 to the current rates of 30-57%. Over last 2 decades a plethora of clinical trials on treatment have been reported & sometimes for surgeons it is difficult to keep track of these developments. Therefore, we have made an attempt to summarise seminal trials that have led to the standardization of current treatment for oesophageal cancer and important future trials.  

Earlier upfront surgery was considered as the mainstay of treatment for patients with resectable cancer oesophagus with R0 resection rates of approximately 70%.³ Therefore neoadjuvant therapy was introduced in order to achieve higher R0 resection rates and improved survival. Subsequently several randomized controlled trials reported superiority of neoadjuvant chemoradiation (nCRT) plus surgery over surgery alone. The landmark CROSS trial comparing efficacy of multimodality treatment (nCRT + surgery) with surgery alone reported significant improvement in R0 resection rates 92% vs 69% respectively with acceptable adverse events and without increasing mortality rates.⁴ The long-term results of CROSS trial with a follow up duration of 84.1 months demonstrated significantly improved median overall survival following nCRT+ surgery (48.6 months) in comparison to surgery alone group (24.0 months) and thus established neoadjuvant chemoradiotherapy followed by surgery as standard of care for resectable AC & SCC of ooesophagus.⁵ Details of important RCT’s for esophageal cancer are provided in Table 1.

Although the results of CROSS trial were widely accepted, the debate regarding the optimal management strategy for esophageal cancers continued.

With availability of results of FFCD 9102 trial it was argued that for patients (n=259). with resectable locally advanced SCC (T3N0-1M0) who respond to chemoradiation, surgery provided no additional benefit over continuation of chemoradiation. In this trial the median OS of patients with continuation of chemoradiation without surgery was 19.3 months compared to 17.7 months with addition of surgery. Moreover the 3-month mortality rate was significantly low in chemoradiation arm only (0.8% vs 9.3%, p = 0.02).⁶ Subsequent subgroup analysis of clinical non-responder patients who were not randomized in FFCD 9102 trial (111 out of 192 non-randomized patients) revealed that median survival did not differ between responders to induction chemoradiation (17.7 months) and patients having surgery after clinical failure of chemoradiation (17.3 months).Hence oesophagectomy is beneficial for subgroup of SCC patients who do not respond to nCRT⁷ 

Subsequent Cochrane database review supported these findings that for localized SCC (T3 and/or node positive) addition of esophagectomy to chemoradiation provided little or no difference on overall survival (HR 0.99, 95% confidence interval 0.79 to 1.24) albeit treatment related mortality favoured chemoradiation (RR 5.11, 95% CI 1.74 to 15.02, P=0.03).⁸

Japanese surgeons based on the results of Japanese multicentre RCT JCOG 9907did not follow nCRT as the standard treatment for SCC and continued with neoadjuvant/ perioperative chemotherapy (without radiation) followed by esophagectomy. Whereas NCCN guidelines recommend nCRT followed by esophagectomy as the standard treatment for both SCC and AC. Although NCCN guidelines has proposed perioperative chemotherapy (without radiation) and surgery as an alternative strategy but for patients with AC and not for SCC.

To settle these contentious issues several randomized trials are underway and outcomes of these trial may alter the current standard multimodality treatment for cancer oesophagus. Japanese investigators have initiated a 3-arm phase III randomized controlled trial (JCOG 1109) comparing standard preoperative chemotherapy (cisplatin + 5 FU) with enhanced preoperative chemotherapy (docetaxel, cisplatin, 5 FU) and preoperative chemoradiation (cisplatin, 5 FU + radiation).⁹  The ESOPEC trial shall evaluate efficacy of neoadjuvant chemoradiation (CROSS protocol) and perioperative chemotherapy (FLOT protocol) for treatment of localized adenocarcinoma of oesophagus in terms of patient survival, treatment morbidity and quality of life.¹⁰ The NEO-AEGIS trial which is uniquely powered to study the locally advanced adenocarcinoma of the oesophagus and gastro-esophageal junction. This trial will examine whether addition of neoadjuvant radiation therapy impacts overall survival in comparison to standard perioperative chemotherapy.¹¹ In 2018 Noordman et al launched SANO trial that will assess effectiveness of active surveillance in comparison to standard oesophagectomy after neoadjuvant chemoradiation therapy.¹² In 2019 a phase III RCT aimed at investigating the impact of neoadjuvant chemotherapy plus surgery and neoadjuvant chemoradiation plus surgery on overall survival in  patients with locally advanced resectable SCC has also been registered.¹³

In summary, CROSS trial proposed standard treatment protocol including nCRT followed by surgery for both AC & SCC of oesophagus. The focus of current research is aimed at providing optimal treatment strategies based on:

1)     Indications of neoadjuvant radiation

2)     Histologic diagnosis of the cancer i.e SCC or AC

3)     Appropriate chemotherapy protocols

The result of these trials will further increase our understanding of the oesophageal cancer and may modify the current treatment protocols for cancer oesophagus.

Table 1. Cancer Oesophagus - Landmark trials 

S.No	Trial	Patients			Treatment modality	R0 resection	Survival	Mortality	Conclusion
		N	SCC (%)	AC (%)
1	OEO 2 (2002)14	802	31	66	(Periop Chemo +/- RT + Sx) Vs Sx alone	60% Vs 54% (p<0.0001)	16.8 Vs 13.3 months (Median) (p=0.001)	10%Vs 10%	Preop chemo improves survival without additional adverse effects
2	MAGIC (2006) 15	503	-	100	(Peri-op Chemo + Sx) Vs (Sx alone)	79.3 vs 70.3 (p=0.03)	36% Vs 23% (5-yr OS)	5.6% Vs 5.9%	Peri-op ECF ↓tumor stage & improved PFS & OS
3	Stahl M (2005) 16	186	100	-	nCTRT + Sx Vs CTRT	82%	16.4 Vs 14.9 months (median survival)	12.8 % Vs 3.5%	Sx improves local tumor control but does not improve OS
4	FFCD 9102 (2007) 6	259 (T3N0-1M0)	88.8	11.2	(nCRT+Sx) Vs CTRT	75%	17.7 Vs 19.3 months (Median)	9.3 Vs 0.8%	SCC responding to CTRT – no additional benefit of Sx
5	CROSS (2012) 4	366	23%	75%	(nCRT + Sx) Vs (Sx alone)	92% Vs 69%	49.4 Vs 24 months (Median)	4% Vs 4%	nCRT improved survival with acceptable adverse events
6	JCOG 9907 (2012) 17	330 (Stage II & III)	100%	-	Neoadjuvant Chemo Vs Adjuvant Chemo	89.6 Vs 88.5	55% Vs 43% (5-yr OS)	0.6 Vs 0.6%	Neoadjuvant chemo (Cisplatin +5FU) standard treatment for SCC Stage II & III
7	SAKK 75/08 2018	300 (Resectable esophageal carcinoma)	37%	63%	nCRT + Sx   Cetuximab + Vs Cetuximab -	95% Vs 97%	5.1 vs 3 years (Median OS)	6% Vs 6%	Adding cetuximab significantly improved loco-regional control & clinically relevant (but not significant) improvement in PFS & OS

 

 

References        

1.      Bray F, Jemal A, Grey N et al. Global cancer transitions according to the Human Development Index (2008-2030): A population-based study. Lancet Oncol 2012;13:790-801.

2.      Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the oesophagus among white Americans by sex, stage, and age. J Natl Cancer Inst 2008;100:1184-7

3.      Hulscher JB, van Sandick JW, de Boer AG et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the oesophagus. N Engl J Med. 2002;347:1662–1669

4.      Hagen PV, Hulshof MCCM, van Lanschot JJB et al for CROSS group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012

5.      Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS):  long term results of a randomized controlled trial. Lancet Oncol 2015;16(9):1090-1098

6.      Bedenne L, Michel P, Bouche O et al. Chemoradiation followed by surgery compared with chemoradiation alone for squamous cell carcinoma of oesophagus: FFCD 9102. J Clin Oncol 2007;25(10):1160-1168

7.      Vincent J, Mariette C, Pezet D et al. Early surgery for failure after chemoradiotherapy in operable thoracic esophageal cancer – Analysis of nonrandomized patients FFCD 9102. Eur J cancer 2015;51(13):1683-1693

8.      Vellayappan VA. CTRT versus CTRT with surgery for esophageal cancer. Cochrane database systematic review 2017.

9.      Nakamura K, Kato K, Igaki H et al. Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study). Jpn J Clin Oncol. 2013 Jul;43(7):752-5.

10.   Hoeppner J, Lordick F, Brunner T et al. ESOPEC: Prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the oesophagus. BMC Cancer. 2016;16:503

11.   Reynolds JV, Preston SR, O’Neil B et al. ICORG 10-14: NEOadjuvant Trial in Adenocarcinoma of the ooesophagus and oesophago-gastric Junction International Study (Neo-AEGIS). BMC Cancer. 2017;17(1):401.

12.   Noordman BJ, Wijnhoven BPL, Lagarde SM et al. Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial. BMC Cancer. 2018;18:142.

13.   Sun HB, Xing WQ, Liu XB et al. Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma: a single-Centre, open-label, randomized, controlled, clinical trial (HCHTOG1903). BMC Cancer. 2020 Apr 15;20(1):303.

14.   Girling DJ et al. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002;359:1727-1733

15.   Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11-20

16.   Stahl M, Stuschke M, Lehmann N et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the oesophagus. J Clin Oncol. 2005; 23(10):2310-2317

 

Authors:

Dr Nitin Vashistha, MS, FIAGES, FACS

Dr Dinesh Singhal, MS, FACS, DNB (Surg Gastro)

Department of Surgical Gastroenterology,
Max Super Speciality Hospital, Saket, New Delhi, India
E mail: gi.cancer.india@gmail.com

www.gicancerindia.com