Role of neoadjuvant chemoradiation in locally advanced carcinoma

1. Role Of Neoadjuvant Chemoradiation In Locally Advanced
Carcinoma Esophagus
DR NEELAM AHIRWAR

2. • The aim of combining neoadjuvant chemotherapy and radiotherapy is
to use the radiosensitising effects of chemotherapy to reduce the
tumour size and maximise local control

3. Neoadjuvant CRT
• Downstage the disease
• Increase the rate of complete resection with negative margins
• Eradicate occult micrometastasis
• Reduce risk of local recurrence

5. Irish trial
• 58 patients were randomized to neoadjuvant chemoradiation with two cycles of 5-FU
and cisplatin with 40 Gy radiation in 15 fractions followed by surgery versus surgery
• statistically significant survival advantage in the neoadjuvant group (median survival of16
months) compared to the upfront surgery group (median survivalof 11 months
• criticized -small sample size, short median follow up (average 10 months
Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, HennessyTP. A comparison of multimodal
therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335(7):462–7.

6. EORTC trial
• Evaluated patients with squamous cell carcinoma and compared neoadjuvant CRT followed by
surgery with surgery alone.
• Radiation was delivered in two one-weekly courses, 2 weeks apart, with five daily fractions of 3.7 gy
each; cisplatin was given before each course of radiation
• Complete pathological response was seen in 26% of patients with combined treatment
• DRAWBACKS - higher mortality rate was attributed to the higher dose of radiation per fraction, the
use of cisplatin monotherapy
Bosset J-F, Gignoux M, Triboulet J-P, Tiret E, Mantion G, Elias D, et al. Chemoradiotherapy followed
by surgery compared with surgeryalone in squamous-cell cancer of the esophagus. N Engl J
Med.1997;337(3):161–7.

7. The Trans-Tasman Radiation Oncology Group (TROG) and the
Australasian Gastro-Intestinal Trials Group (AGITG)
• randomized 256 patients equally to surgery alone (128) or to neoadjuvant chemoradiation
followed by surgery (128)
• One cycle of cisplatin and 5-FU was given along with 35 Gy radiation (in 15 days) in the neoadjuvant
treatment group
• no benefit with NACRT in either PFS or OS, although a subset analysis showed superior survival in patients
with squamous cell carcinoma
• This trial was criticized for the suboptimaldose of radiation (35 Gy) and single cycle of chemotherapy
Burmeister BH, Smithers BM, Gebski V, Fitzgerald L, Simes RJ,Devitt P, et al. Surgery alone versus
chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomisedcontrolled
phase III trial. Lancet Oncol. 2005;6(9):659–68.

9. CALGB 9781
• An intent-to-treat analysis showed a median survival of 4.48 v 1.79
years in favor of trimodality therapy (exact stratified log-rank, P .002)
• Five-year survival was 39% (95% CI, 21% to 57%) v 16% (95% CI, 5%
to 33%) in favor of trimodality therapy

10. CROSS trial
• The role of NACRT has now been widely accepted globally
• Patients in the neoadjuvant chemoradiation group received weekly carboplatin and paclitaxel
for 5 weeks with a radiation dose of 41.4 Gy in 23 fractions.
• Statistically significant R0 resections were seen in the neoadjuvant CRT group.
• Median overall survival was 49.4 months in the CRT followed by surgery group and 24 months
in the surgery group (P = .003)
• no significant difference in postoperative morbidity or mortality
van Hagen P, Hulshof M, van Lanschot J, Steyerberg EW,Henegouwen MIVB, Wijnhoven B, et al.
Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J
Med.2012;366(22):2074–84

11. CROSS TRIAL
• Long-term results confirmed the overall survival advantage with
neoadjuvant CRT in all subgroups and also improved DFS, and local
and distant recurrence rates
Shapiro J, Van Lanschot JJ, Hulshof MC, van Hagen P, van Berge Henegouwen MI,
Wijnhoven BPL, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery
alone for oesophageal or junctionalcancer (CROSS): long-term results of a randomised
controlledtrial. Lancet Oncol. 2015;16(9):1090–8.

12. NACRT VS NACT

13. Strength- pretherapy staging (EUS,Laparoscopy)
Randomised 119 patients with siewart I-III
CRT –
• significant higher pathologic complete response (15.6% v 2.0%)
• higher tumor-free lymph nodes (64.4% v 37.7%) at resection
• 3-year survival rate from 27.7% to 47.4%
Postoperative mortality was non significantly increased in the chemoradiotherapy group
Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer H-J, Riera-Knorrenschild J, et al. Phase III comparison of
preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced
adenocarcinoma of the esophagogastric junction. J ClinOncol. 2009;27(6):851–6.

14. POET TRIAL
• Local progression-free survival after tumour resection was significantly
improved by CRT (hazard ratio [HR] 0.37; p = value 0.01) and 20 versus
12 patients were free of local tumour progression at 5 years
Stahl M, Walz MK, Riera-Knorrenschild J, Stuschke M, SandermannA, Bitzer M, et al. Preoperative
chemotherapy versus chemoradiotherapyin locally advanced adenocarcinomas of the oesophagogastricjunction
(POET): long-term results of a controlled randomisedtrial. Eur J Cancer. 2017;81:183–90

15. • the study closed early,
• median OS and PFS showed a statistically insignificant trend favoring the NACRT arm,
but the postoperative in hospital mortality was 10.2% in the NACRT arm compared to
3.8% in the NACTarm.

16. • Patients assigned to arm A received 12 applications of chemotherapy with
weekly 5- fluorouracil (2000 mg/m2 , 24 h infusion)/folinic acid (500
mg/m2 , 2 h infusion) and biweekly cisplatin (50 mg/ m2 , 1 h infusion),
within 14 weeks, followed by another 3-weekly applications.
• Patients assigned to arm B received the same 14-weeks chemotherapy for
induction, followed by a 3-week course of combined CRT with cisplatin (50
mg/m2 , 1 h infusion, days 2 and 8) and etoposide (80 mg/m2 , 1 h
infusion, days 3-5)
• A total dose of 30 Gy was applied, using 15 fractions of 2 Gy within 3 weeks

18. • Patients were randomised to receive preoperative CT with cisplatin
(80 mg/m2 ) and infusional 5 fluorouracil (1000 mg/m2 /d) on days 1
and 21, or preoperative CRT with the same drugs accompanied by
concurrent radiation therapy commencing on day 21 of
chemotherapy and the 5 fluorouracil reduced to 800 mg/m2 /d. The
radiation dose was 35 Gy in 15 fractions over 3 weeks.

19. • In the CT arm the median PFS and OS were 14 and 29 months and for CRT the median
PFS and OS were 26 and 32 months. The overall 5 year survival was 36% in the CT group
and 45% for those having CRT
• The overall loco-regional recurrence rate was 28% in the CT group compared with 18% in
the CRT group
• Following CRT, five patients (13%) had a pathological complete response but none were
seen after CT
• addition of concurrent radiation therapy at a dose of 35 Gy to preoperative CT did not
add to CT toxicity or surgical morbidity
• Small and underpowered

20. NeoRes trial
• complete responses (the primary endpoint) and R-0 resection rates were higher with NACRT,
overall survival was identical in the two groups
• An updated report with longer follow up confirmed the lack of benefit in overall survival and there
were no differences in recurrence patterns

21. Awaited trails
• JCOG 1109 NExT trial
• ESOPEC trial
• Neo-AEGIS trial

22. META ANALYSIS

24. • Toxicity was similar for CT and CRT.
• The histopathological response rate (CRT 31% versus CT 8%, p = 0.01)
• R1 resection rate (CRT 0% versus CT 11%, p = 0.04) favoured those receiving CRT.
• no difference in survival,
improvement from preoperative CRT with respect to margin involvement makes
NACRT a reasonable option for bulky, locally advanced resectable adenocarcinoma
of the oesophagus

25. • Showed weak evidence in favour of neoadjuvant chemoradiotherapy,
but this comparison might also have been prone to selection bias
• A clear advantage has not been established

26. 2019

29. • Neoadjuvant chemoradiation increases the rate of complete resection
• Improved locoregional control
• Increased lymph nodes retrieval
• No difference in survival
• Optimum neoadjuvant treatment yet controversial
• Further studies required

30. Thankyou