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PROF S.SUBBIAH et al.
CHEMOTHERAPY & CHEMO-
RADIOTHERAPY TRIALS IN
ESOPHAGEAL CANCER
PROF DR. S.SUBBIAH, MS., MCh.,
DR.S.ARAVIND,
RESIDENT,
DEPT OF SURGICAL ONCOLOGY,GRH

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CLASSIFICATION BASED ON THE
UPPER BORDER OF THE TUMOR

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NATURAL HISTORY AND PATTERNS OF
FAILURE
• Lack of serosa & rich submucosal lymphatics network- lead to
high occult nodal metastases- account for high local
recurrence rates.
• CERVICAL DEFINITIVE CHEMORADIATION is the standard care
• UPPER THORACIC SCC MORE COMMON.HENCE LRR
• MIDDLE THORACIC MORE COMMON(RT > Chemo)
• LOWER THORACIC ADC MORE COMMON.HENCE
• OG JUNCTION DISTANT METASTASES MORE
COMMON(Chemo>RT)

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PROF S.SUBBIAH et al.
• Cervical & upper thoracic esophagus(<5 cm from
cricopharyngeus): DEFINITIVE CHEMORADIATION-
50.4 Gy RT with cisplatin& 5-FU(Addition of
paclitaxel- RT DOSE to 45Gy)
• Middle & distal thoracic esophagus:
Preoperative chemoradiation-41.4 Gy RT with
paclitaxel & carboplatin.
• GEJ Adenocarcinoma: Preoperative
chemotherapy with FLOT – 5
FU,Leucovorin,Oxaliplatin,Docetaxel.

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PREOPERATIVE CHEMOTHERAPY-RCTs

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Preoperative chemotherapy with
a combination of etoposide and
cisplatin significantly improved
overall survival in patients with
OSCC
• Chemotherapy followed by surgery versussurgery alone in patients
with resectable oesophageal squamous cell carcinoma: Longterm
results of a randomized controlled trial
• Jurjen J Boonstra, Tjebbe C Kok, Bas PL WijnhovenMark van Heijl
Mark I van Berge Henegouwen Fiebo JW ten Kate, Peter D Siersema
Winand NM DinjensJan JB van Lanschot Hugo W Tilanus and Ate
van der Gaast

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PROF S.SUBBIAH et al.
BOONSTRA ET AL 2011
CS GRP
• Cisplatin 80 mg/m2 D1+
Etoposide 100 mg/m2 D1-2
X 2-4 cycles
• Improved operability
• SX-71% -R0 RESECTION
• 25%-R1 RESECTION
• 4%-R2 RESECTION
• Median survival: 16 months
S GRP
• SX-57% -R0 resection
• 29%-R1 RESECTION
• 14%-R2 RESECTION
• Median survival: 12 months

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PROF S.SUBBIAH et al.
Preoperative chemotherapy with cisplatin
plus 5-fluorouracil can be regarded as
standard treatment
for patients with stage II/III squamous cell
carcinoma(JCOG9907)
• A Randomized Trial Comparing Postoperative Adjuvant Chemotherapy
with Cisplatin and 5-Fluorouracil Versus Preoperative Chemotherapy for
Localized Advanced Squamous Cell Carcinoma of the Thoracic Esophagus
(JCOG9907)
• Nobutoshi Ando, MD, , Hoichi Kato, Hiroyasu Igaki, Masayuki Shinoda, ,
Soji Ozawa, MD,FACS4 Hideaki Shimizu, , Tsutomu Nakamura, MD, Hiroshi
Yabusaki, , Norio Aoyama, Akira Kurita, MDKenichiro Ikeda, , Tatsuo Kanda,
, Toshimasa Tsujinaka, , Kenichi Nakamura, and Haruhiko Fukuda

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PROF S.SUBBIAH et al.
ANDO ET AL 2011
PREOP CHEMO
• 2 Cycles of cisplatin 80 mg/m2
+ 5 FU 800 mg/m2, 3 weeks
apart F/B SX
• R0 RESECTION:96%
• 5 yr PFS :44%
• 5 YR OS : 55%
SURGERY
• Upfront Surgery F/B Postop
chemotherapy – 2 cycles of
PF(If pN1)
• RO RESECTION:91%
• 5 YR PFS 39%
• 5 YR OS: 43%

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PROF S.SUBBIAH et al.
Preoperative chemotherapy with a
combination of cisplatin and fluorouracil
did not improve overall survival among
patients with epidermoid cancer or
adenocarcinoma of the esophagus-INT
0113 TRIAL.
• Chemotherapy followed by surgery compared with
surgery alone for localized esophageal cancer.
• D P Kelsen 1, R Ginsberg, T F Pajak, D G Sheahan, L
Gunderson, J Mortimer, N Estes, D G Haller, J Ajani, W
Kocha, B D Minsky, J A Roth

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KELSEN ET AL 1998
• The U.S. Intergroup Trial 113 (INT-0113) randomized
467 -immediate surgery OR to 3 cycles of PF followed
by surgery and then, for those patients whose
resection was curative (R0), 2 cycles of PF as adjuvant .
• No differences in - curative resection rate (59% versus
62%), treatment mortality (6% versus 7%), median OS
(16.1 versus 14.9 months), or 3-year survival (26%
versus 23%)
• The pattern of failure was also similar for the two
treatment groups (local recurrence 31% versus 32%
and distant recurrence of 50% versus 41%).

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Two cycles of preoperative cisplatin and
fluorouracil improve survival without
additional serious adverse events in the
treatment of patients with resectable
oesophageal cancer.(MRC TRIAL)
• Surgical resection with or without
preoperative chemotherapy in
oesophageal cancer: a randomised
controlled trial
• Medical research council esophageal cancer
working group.

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PROF S.SUBBIAH et al.
MRC ESOPHAGEAL CANCER WORKING
GROUP-2002
• 802 patients,31% -SCC & 69% ADENO
• Patients – 2 cycles of cisplatin and
continuous infusion 5-FU followed by surgery
or immediate surgery.
• Rate of curative resection similar.

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MRC
• Cisplatin 160 mg/m2 3weeks
• 5 FU 8000 mg/m2
• No postoperative
chemotherapy
• Shorter time to surgery(2
months)
• Reduced dosages, effective
compliance, shorter time to
surgery lead to translation
to better OS.
INT 0113
• Cisplatin 300 mg/m2 8 weeks
• 5 FU 15,000 mg/m2
• 2 cycles of cisplatin and 5 FU
• Longer time to surgery(3
months)
• High doses of the
chemotherapy lead to high
toxic effects; reduced
compliance & nullified the
benefits of surgery.

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Long-term follow-up confirms that
preoperative chemotherapy improves
survival in operable esophageal cancer
and should be considered as a standard of
care(OEO2 TRIAL)
• Long-term results of a randomized trial of surgery with
or without preoperative chemotherapy in esophageal
cancer
• William H Allum 1, Sally P Stenning, John Bancewicz,
Peter I Clark, Ruth E Langley

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OEO2 TRIAL 2008
SURGERY ALONE(434)
• R0 RESECTION:40%
• R1:17%
• R2:12.9%
5 yr survival:17.1%
PREOP CHEMO(437)
• Cisplatin 80 mg/m2 D1
• 5 FU 1000 mg/m2 D1-D3 X
2 CYCLES 3 weeks apart
• R0-42.4 %
• R1-18%
• R2-8.6%
5 yr survival: 23 %

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In patients with operable gastric or
lower esophageal adenocarcinomas, a
perioperative regimen of ECF
decreased tumor size and stage and
significantly improved progression-
free and overall survival(MAGIC
TRIAL)
• Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer
• David Cunningham, M.D., William H. Allum, M.D., Sally P. Stenning, M.Sc., Jeremy N. Thompson,
M.Chir.,
• Cornelis J.H. Van de Velde, M.D., Ph.D., Marianne Nicolson, M.D., J. Howard Scarffe, M.D., Fiona J.
Lofts, Ph.D.,
• Stephen J. Falk, M.D., Timothy J. Iveson, M.D., David B. Smith, M.D., Ruth E. Langley, M.D., Ph.D.,
• Monica Verma, M.Sc., Simon Weeden, M.Sc., and Yu Jo Chua, M.B., B.S., for the MAGIC Trial
Participants

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CUNNINGHAM ET AL 2006
• 503 patients - 3 cycles of preoperative and 3
cycles of postoperative epirubicin/cisplatin/5-
FU(ECF) or surgery alone.
• 26% -GEJ and lower esophagus.
• Preoperative chemotherapy - with a 6-month
improvement in PFS, a 4-month improvement
in median survival, and a 13% improvement in
5-year OS (23% to 36%)

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PROF S.SUBBIAH et al.
In patients with resectable
adenocarcinoma of the lower
esophagus, GEJ, or stomach,
perioperative chemotherapy using
fluorouracil plus cisplatin significantly
increased the curative resection
rate, disease-free survival, and OS
• Perioperative Chemotherapy Compared With Surgery Alone for Resectable
Gastroesophageal Adenocarcinoma: An FNCLCC and FFCD Multicenter
Phase III Trial
• Marc Ychou, Vale´rie Boige, Jean-Pierre Pignon, Thierry Conroy, Olivier
Bouche´, Gilles Lebreton,
• Muriel Ducourtieux, Laurent Bedenne, Jean-Michel Fabre, Bernard Saint-
Aubert, Jean Gene`ve, Philippe Lasser, and Philippe Rougier.

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PROF S.SUBBIAH et al.
FNCLCC / FFCD Multicenter Phase III
Trial 2011
• Perioperative Chemotherapy Compared With Surgery Alone
for Resectable Gastroesophageal Adenocarcinoma.
• 224 patients -- perioperative chemotherapy and surgery or
surgery alone .
• Chemotherapy consisted of 2-3 preoperative cycles of IV
cisplatin (100 mg/m2 ) on day 1, and a continuous IV infusion
of fluorouracil (800 mg/m2 /d) for 5 consecutive days (days 1
to 5) every 28 days and 3-4 postoperative cycles of the same
regimen.

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• RESULTS: Compared with the S group, the CS group had a
better OS (5-year rate 38% v 24%) and a better disease-
free survival (5-year rate: 34% v 19%. )
• Perioperative chemotherapy significantly improved the
curative resection rate (84% v 73%).
• Grade 3 to 4 toxicity occurred in 38% of CS patients
(mainly neutropenia).
• Postoperative morbidity was similar in the two groups.

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Multimodal treatment is superior to
surgery alone for patients with
resectable adenocarcinoma of the
esophagus.
• A COMPARISON OF MULTIMODAL THERAPY AND
SURGERY FOR ESOPHAGEAL ADENOCARCINOMA
• THOMAS N. WALSH, M.D., NOIRIN NOONAN, M.B.,
DONAL HOLLYWOOD, PH.D., ALAN KELLY, PH.D.,
C.STAT., NAPOLEON KEELING, M.D., AND THOMAS P.J.
HENNESSY, M.D

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WALSH ET AL 1996
• SURGERY ALONE ARM
• Median survival : 11
months
• PREOP CRT ARM
• 5 FU 15mg/kg D1-D5 +
• Cisplatin 75 mg/m2 D7
X 2 cycles
• F/B 40 GY RT
• Median survival: 32
months

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Combined therapy increases the
survival of patients who have
squamous or adenocarcinoma of the
Esophagus T1-3 N0-1 M0 compared
with RT alone(RTOG 85-01 TRIAL)
• Chemoradiotherapy of locally advanced esophageal
cancer
• Long term followup of a randomised trial RTOG 85-01

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PROF S.SUBBIAH et al.
RTOG 85-01 1999
• Randomisation: Combined modality group – 50 Gy RT with
cisplatin 75 mg/sq.m and 5 FU 1gm/sq.m VS RT alone 64 Gy
in 32#.
• RESULTS: Combined therapy survival > RT alone.
• OS at 5 yr -26 % in CT vs 0 % RT alone.
• This trial did not address the potential role of surgery .

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PROF S.SUBBIAH et al.
Based on existing trials, there was no clear evidence
that preoperative radiotherapy improves the survival
of patients with potentially resectable esophageal
cancer. These results indicate that if such preoperative
radiotherapy regimens do improve survival, then the
effect is likely to be modest with an absolute
improvement in survival of around 3 to 4%. Trials or a
meta-analysis of around 2000 patients would be
needed to reliably detect such an improvement (15--
>20%).
• Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using
individual patient data (Oesophageal Cancer Collaborative Group)
• S J Arnott 1, W Duncan, M Gignoux, D J Girling, H S Hansen, B Launois, K Nygaard,
M K Parmar, A Roussel, G Spiliopoulos, L A Stewart, J F Tierney, W Mei, Z Rugang

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META ANALYSIS 1998

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PROF S.SUBBIAH et al.
Randomized trial of preoperative
chemoradiation versus surgery alone
for patients with potentially resectable
esophageal carcinoma did not
demonstrate a statistically significant
survival difference
• Randomized trial of preoperative chemoradiation
versus surgery alone in patients with locoregional
esophageal carcinoma.
• S G Urba 1, M B Orringer, A Turrisi, M Iannettoni,
A Forastiere, M Strawderman

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URBA ET AL 2001
SURGERY ALONE
• Upfront Trans- hiatal
esophagectomy.
Median survival: 17.6 months
3 yr survival: 16 months
PREOP CRT
• Cisplatin 20 mg/m2( D1-D5
& D17-D21)
• 5 FU 300 mg/m2/d (D1-
D21)
• Vinblastine 1mg/m2/d(D1-
D4 & D17-D21)
• RT-45 Gy (1.5 Gy #)
Median survival :16.9 months
3 yr survival : 30 months

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PROF S.SUBBIAH et al.
The promising 5-year survival results and low rate of
late cancer-related deaths suggest that these
regimens of intensive neoadjuvant therapy may
improve the overall cure rate. The pathologic stage
after neoadjuvant therapy is an important predictor
of survival and may be useful in selecting patients for
novel adjuvant therapies. Isolated local failure is
uncommon, indicating that efforts to improve the
therapeutic outcome should focus on optimizing
systemic therapy rather than intensifying the RT.
Additional randomized data are needed to assess the
benefits of this therapeutic approach fully.
• Mature survival results with preoperative cisplatin, protracted infusion 5-fluorouracil, and 44-Gy radiotherapy for
esophageal cancer
• Lawrence Kleinberg 1, Jonathan P S Knisely, Richard Heitmiller, Marriana Zahurak, Ronald Salem, Barbara Burtness,
Elizabeth I Heath, Arlene A Forastiere

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PROF S.SUBBIAH et al.
KLEINBERG ET AL 2003
TRIAL A(50)
• 44 Gy RT+ Cisplatin 26
mg/m2 D1-5 & D26-30 +
5-FU 300 mg/m2/d D1-30
Surgery done
No adjuvant treatment
TRIAL B(42)
44 Gy RT+ Cisplatin 20
mg/m2 D1-5 & D26-30
+5 FU 225 mg/m2/dD1-30
Surgery done
Adjuvant chemotherapy-
paclitaxel 135 mg/m2 D1 &
cisplatin 75 mg/m2 D2 X 3
cycles.
The observed 2- and 5-year survival rate and median survival
was 57%, 40%, and 35 months, respectively.

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PROF S.SUBBIAH et al.
Preoperative chemoradiotherapy
improved survival among patients
with potentially curable esophageal
or esophagogastric-junction cancer.
The regimen was associated with
acceptable adverse-event
rates(CROSS PROTOCOL)
• Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer
P. van Hagen, M.C.C.M. Hulshof, J.J.B. van Lanschot, E.W. Steyerberg, M.I. van Berge
Henegouwen, B.P.L. Wijnhoven, D.J. Richel, G.A.P. Nieuwenhuijzen, G.A.P. Hospers, J.J.
Bonenkamp, M.A. Cuesta, R.J.B. Blaisse, et al., for the CROSS Group*

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CROSS PROTOCOL 2015
• Randomisation - weekly administration of 5
cycles of NACRT (IV carboplatin [AUC 2] & IV
paclitaxel [50 mg/m²] for 23 days) with
concurrent RT (41·4 Gy, given in 23 fractions of
1·8 Gy on 5 days per week) followed by
surgery, OR Surgery alone.
• 368 patients; 188 in surgery alone & 180 in
CRT f/b Surgery. 84 –SCC; 184-
Adenocarcinoma.

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PROF S.SUBBIAH et al.
• RESULTS: median follow-up of 84·1 months ,
median OS- 48·6 months in the NACRT + surgery
group ; 24 months in the surgery alone group .
• Median overall survival for patients with SCC was
81·6 months in the NACRT + surgery group and
21·1 months in the surgery alone group ;
• For patients with adenocarcinomas, it was 43·2
months in the NACRT + surgery group and 27·1
months in the surgery alone group.

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PROF S.SUBBIAH et al.
• Long-term follow-up confirms the overall survival benefits for
NACRT when added to surgery.
• This improvement is clinically relevant for both squamous cell
carcinoma and adenocarcinoma subtypes.

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Data suggest that, in patients with
locally advanced thoracic esophageal
cancers, especially epidermoid, who
respond to chemoradiation, there is
no benefit for the addition of surgery
after chemoradiation compared with
the continuation of additional
chemoradiation-FFCD 9102 TRIAL
• Chemoradiation followed by surgery compared with chemoradiation alone in squamous
cancer of the esophagus: FFCD 9102
• Laurent Bedenne 1, Pierre Michel, Olivier Bouché, Chantal Milan, Christophe Mariette,
Thierry Conroy, Denis Pezet, Bernard Roullet, Jean-François Seitz, Jean-Philippe Herr,
Bernard Paillot, Patrick Arveux, Franck Bonnetain, Christine Binquet

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PROF S.SUBBIAH et al.
FFCD 9102 2007
• 2 cycles of PF +45 Gy RT
• ARM A ARM B
(complete response)
• SURGERY 3 cycles of PF+20 Gy RT
2 yr survival:34% 2 yr survival:40%
Median survival:17.7 m median survival:19.3 m

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PROF S.SUBBIAH et al.
Adding surgery to
chemoradiotherapy improves local
tumor control but does not increase
survival of patients with locally
advanced esophageal SCC. Tumor
response to induction chemotherapy
identifies a favorable prognostic
group within these high-risk patients,
regardless of the treatment group
• Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of
the esophagus
• Michael Stahl , Martin Stuschke, Nils Lehmann, Hans-Joachim Meyer, Martin K Walz, Siegfried Seeber,
Bodo Klump, Wilfried Budach, Reinhard Teichmann, Marcus Schmitt, Gerd Schmitt, Claus Franke,
Hansjochen Wilke

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PROF S.SUBBIAH et al.
STAHL ET AL 2005
3 cycles of FLEP
• ARM A ARM B
• PE + 40 Gy RT PE +65 Gy RT
• SURGERY NO SURGERY
• 2 yr PFS: 64.3% 2 yr PFS:40.7%
• Mortality: 12.8% Mortality: 3.5%

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