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
