Transcript Document

Neoadjuvant approaches
for localized cancers of
the esophagus and GE
junction
Safa Najafi M.D.
Medical Oncologist & Hematologist
Assistant professor ACECR,JDTUMS
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َAccording to data from the Surveillance,
Epidemiology and End Results (SEER)
Program, the five-year survival for all patients
with esophageal cancer improved modestly over
the last 30 years, from 5 percent in the years
1975 to 1977, to 17 percent during the period
1996 to 2004
َََََ Jemal A; Siegel R; Ward E; Hao Y; Xu J; Thun MJ
Cancer J Clin. 2009 Jul-Aug;59(4):225-49. Epub 2009 May 27.
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only 30 to 40 percent of patients have
potentially resectable disease
Data from contemporary surgical series report
five-year survival rates of 5 to 20 percent for
surgery alone
TI - Chemoradiotherapy followed by surgery compared with surgery alone in
squamous-cell cancer of the esophagus.
AU - Bosset JF; Gignoux M; Triboulet JP; Tiret E; Mantion G; Elias D; Lozach
P; Ollier JC; Pavy JJ; Mercier M; Sahmoud T
SO - N Engl J Med 1997 Jul 17;337(3):161-7.
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It has been proposed that the difference in
tumor location also has implications for the
choice of therapy. Some suggest that induction
chemotherapy alone may suffice for
adenocarcinomas, while results are superior with
chemoradiotherapy for SCCs because of the
greater need for tumor downsizing to achieve a
complete radical resection .
TI - Are squamous and adenocarcinomas of the esophagus the same disease?
AU - Siewert JR; Ott K
SO - Semin Radiat Oncol. 2007 Jan;17(1):38-44.
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Before the era of modern chemotherapy and
combined chemoradiotherapy, RT alone (60 to
66 Gy over a period of 6 to 6.6 weeks) was
associated with five-year survival rates of 5 to 20
percent, depending upon tumor extent
Choi, NC. The role of radiation therapy in the management of malignant
neoplasms of the esophagus. In: Current Therapy in Cardiothoracic Surgery,
Grillo, HC, Austen, WG, Wilkins, EW Jr (Eds), BC Decker Inc., Toronto 1989.
p.197.
Chemo-(radiation) studies
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Chemoradiation studies as non-operative
treatment
Preoperative chemoradiotherapy
NEOADJUVANT CHEMOTHERAPY
Chemoradiation studies as nonoperative treatment
 A landmark RTOG trial compared RT alone (64 Gy in 32 fractions over 6.5
weeks) versus concurrent chemoradiotherapy (two cycles of infusional 5-FU
[1000 mg/m2 per day, days 1 to 4, weeks 1 and 5] plus cisplatin [75 mg/m2
day 1 of weeks 1 and 5] and RT [50 Gy in 25 fractions over five weeks]) in
patients with locoregional thoracic esophageal cancer .
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RTOG 85-01 N Engl J Med 1992 Jun 11;326(24):1593-8.
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In the US Intergroup Study 0123 (INT 0123), 236 patients with nonmetastatic SCC or
adenocarcinoma of the thoracic esophagus received concurrent cisplatin and 5-FU (as
in RTOG 85-01), but they were randomly assigned to one of two different RT doses:
50.4 Gy (28 fractions of 1.8 Gy each, five fractions per week) or 64.8 Gy (36 fractions
of 1.8 Gy each, five fractions per week)
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Intergroup 0123J Clin Oncol 2002 Mar 1;20(5):1167-74
Preoperative chemoradiotherapy
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Irish trial — In an early trial, 113 patients with esophageal or GEJ adenocarcinoma were
randomly assigned to surgery alone or preceded by chemoradiotherapy [41] . Preoperative
treatment consisted of two courses of 5-FU (15 mg/kg by bolus days 1 to 5) and cisplatin (75
mg/m2, on day 7 of each cycle), both administered during weeks 1 and 6 of concurrent RT (40
Gy in 15 fractions over three weeks).
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Michigan study — In a second trial, 100 patients with locoregional esophageal or GEJ
cancer (25 SCC, 75 adenocarcinoma) were randomly assigned to surgery with or without
induction chemoradiotherapy [37] . Neoadjuvant treatment consisted of infusional cisplatin (20
mg/m2 per day, days 1 to 5, and 17 to 21), infusional 5-FU (300 mg/m2 per day, days 1 to 4 and
17 to 20), and vinblastine (1 mg/m2 per day, on days 1 to 4, and 17 to 20) plus concurrent
accelerated fraction RT (45 Gy in 1.5 Gy twice daily fractions for three weeks, using 3D-CRT
treatment planning). Surgery was performed on day 42, after a three week rest.
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. At a median follow-up of 8.2 years, the median
survival was similar (16.9 versus 17.6 months for
multimodality therapy and surgery respectively)
Necessity for surgery
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Nearly all reports note a higher rate of locally
persistent/recurrent disease when surgery is not a
component of treatment .
J Clin Oncol. 2007 Nov 1;25(31):4895-901.
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In general, there is a lack of data on nonsurgical
management for patients with adenocarcinoma.
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French trial FFCD 9102: At a median follow-up of 47 months,
the surgically treated patients had similar two-year (34 versus 40 percent) and
median survival (17.7 versus 19.3 months) as compared to those assigned to
continue chemoradiotherapy. Surgically treated patients had significantly
lower rates of locoregional recurrence (34 versus 43 percent) and were
significantly less likely to require palliative intervention for dysphagia (24
versus 46 percent).
Induction chemotherapy and
concurrent chemoradiotherapy
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In a phase II trial, 38 patients with resectable esophageal or
GEJ cancer received one or two courses of infusional 5-FU (750 mg/m2 daily
on days 1 to 5) plus cisplatin (15 mg/m2 daily bolus, days 1 to 5) and
paclitaxel (200 mg/m2 over 24 hours on day 1) . This was followed by RT (45
Gy) and concurrent infusional 5-FU (300 mg/m2 daily on days 1 to 5 weekly)
plus cisplatin (20 mg/m2 on days 1 to 5 of RT), and then surgery. Potentially
curative resection was possible in 35, and a pCR was noted in eight (23
percent) . At a median follow-up of 58 months, three- and five-year survival
estimates were 63 and 39 percent, respectively
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TI - A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially
resectable carcinoma of the esophagus or gastroesophageal junction.
AU - Ajani JA; Komaki R; Putnam JB; Walsh G; Nesbitt J; Pisters PW; Lynch PM; Vaporciyan A; Smythe R; Lahoti S; Raijman I;
Swisher S; Martin FD; Roth JA
 SO - Cancer 2001 Jul 15;92(2):279-86.
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In the POET trial, described in detail below, 126 patients with GEJ
adenocarcinoma were randomly assigned to 16 weeks of chemotherapy alone
(cisplatin plus short-term infusional leucovorin-modulated 5-FU) or 12 weeks
of the same chemotherapy regimen followed by low-dose RT (15 Gy over
three weeks) concurrent with cisplatin and etoposide . The pCR rate was
significantly higher after induction chemotherapy followed by
chemoradiotherapy (16 versus 2 percent), and there was a nonsignificant
trend towards better median and three-year survival in this group as well (47
versus 28 percent, p = 0.07).
NEOADJUVANT
CHEMOTHERAPY
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United Kingdom MAGIC trial —study of preoperative
chemotherapy, included patients with resectable gastric (74 percent), GEJ (15
percent), or distal esophageal (11 percent) adenocarcinomas . A total of 503
patients were randomly assigned to surgery with or without perioperative
chemotherapy (consisting of three preoperative plus three postoperative cycles of
ECF [epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2 day 1 and infusional 5-FU
200 mg/m2/day days 1 to 21]).
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French FNLCC/FFCD trial — A similar benefit for
preoperative chemotherapy was noted in a French multicenter trial in
which 224 patients with potentially resectable stage II or greater
adenocarcinoma of the GE junction (n = 144), distal esophagus (n = 25),
or stomach (n = 55) were randomly assigned induction chemotherapy
versus surgery alone [89] . The induction chemotherapy consisted of two
to three cycles of preoperative chemotherapy (infusional 5-FU 800
mg/m2 daily for five days plus cisplatin 100 mg/m2 on day 1 or 2, every
four weeks).
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Rotterdam trial — In a multicenter trial from the Medical Research Council in the
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Meta-analyses — A survival benefit for neoadjuvant chemotherapy
United Kingdom, 802 patients with operable esophageal or GEJ cancer (two-thirds
adenocarcinoma) were randomly assigned to resection alone or resection preceded by
two courses of cisplatin (80 mg/m2 on day 1) and 5-FU (1000 mg/m2 by continuous
infusion days 1 to 4) given three weeks apart . Preoperative radiation, administered at
the discretion of the treating clinician, was received by 9 percent of the patients in each
group. The percentage of patients undergoing surgery was similar for the two groups,
92 versus 97 percent, as was the curative resection rate (ie, R0 resection), 60 versus 54
percent.
relative to surgery alone was also suggested in a review of eight randomized
trials of surgery alone or chemotherapy followed by surgery for esophageal
cancer (n = 1724 patients, any histology, excluding cervical esophageal
cancers) [44] . The hazard ratio for all-cause survival at two years favored
chemotherapy followed by surgery (hazard ratio [HR] for all-cause
mortality 0.90, 95% CI 0.81 to 1.0), a difference which translated into a
two-year absolute survival benefit of 7 percent. There was no significant
benefit for chemotherapy among patients with SCC, while there was a
significant benefit for those with adenocarcinoma, which was based
only on data from the United Kingdom MRC trial [81] (HR 0.78, 95%
CI 0.64-0.95).
INDUCTION
CHEMORADIOTHERAPY
VERSUS CHEMOTHERAPY
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German POET (PreOperative chemotherapy or
radiochemotherapy in Esophagogastric adenocarcinoma
Trial) trial: which focused exclusively on GE junction adenocarcinomas .
Patients were randomly assigned to 16 weeks of chemotherapy alone (cisplatin plus
short-term infusional leucovorin-modulated 5-FU) or 12 weeks of the same
chemotherapy regimen followed by RT (15 Gy over three weeks) concurrent with
cisplatin (50 mg/m2 on days 2 and 8) and etoposide (80 mg/m2 on days 3 to 5). The
trial was closed because of poor accrual after only 126 of the planned 394 patients
were enrolled. Microscopically complete (R0) resection was possible in a similar
proportion of each group (70 and 72 percent after chemotherapy and
chemoradiotherapy, respectively), although the pCR rate was significantly higher after
chemoradiotherapy (16 versus 2 percent). At a median follow-up of 46 months,
patients undergoing chemoradiotherapy had better median (33 versus 21 months) and
three-year survival (47 versus 28 percent, p = 0.07), but these potentially clinically
meaningful differences were not statistically significant. One reason may have been the
relatively low RT dose and the substitution of etoposide for 5-FU during the RT.
Although low in both groups, postoperative mortality was nonsignificantly higher after
chemoradiotherapy (10.2 versus 3.8 percent, respectively)
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J Clin Oncol 2009 .Feb 20;27(6):851-6. Epub 2009 Jan 12 .
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Patients with locally advanced (uT3-4NXM0) adenocarcinoma of the lower
esophagus or gastric cardia were randomly allocated to one of two treatment
groups: induction chemotherapy (15 weeks) followed by surgery (arm A); or
chemotherapy (12 weeks) followed by chemoradiotherapy (3 weeks) followed
by surgery (arm B). Primary outcome was overall survival time.
A total of 354 patients were needed to detect a 10% increase in 3-year survival
from 25% to 35% by addition of radiation therapy. The study was
prematurely closed due to low accrual.
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Although the study was closed early and statistical
significance was not achieved, results point to a survival
advantage for preoperative chemoradiotherapy
compared with preoperative chemotherapy in
adenocarcinomas of the esophagogastric junction.
Unanswered questions in
chemotherapy
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To date there is no standard chemotherapy
regimen for use in neoadjuvant ,combined
modality setting.
Several ongoing studies are evaluating the
feasibility of incorporating targeted therapies in
chemotherapy regimens.
These chemotherapy regimens are not as
effective as neoadjuvant therapy when they use
as adjuvant.
Standard Chemotherapy regimens
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5FU Based:
5FU+Cis ,ECF ,TCF ,Etoposid CF,
FOLFOX
Capcitabin based
TCX ,ECX ,…..
Other Platiniums: Carboplatin,Oxaloplatin.
Irinotecan,…
Tegafur & S1
Targeted agents
Bevacizomab & Erlotinib
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This phase II study evaluated the combination of carboplatin, paclitaxel, 5-FU,
bevacizumab, and erlotinib with RT as preoperative treatment of localized esophageal
cancers .
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Eligibility included previously untreated stage I, II, or III surgical
candidates with histologically confirmed cancer of the esophagus
or gastroesophageal junction. The treatment regimen was:
carboplatin AUC 5.0 d 1, 22, paclitaxel 200mg/m2 d 1, 22, 5-FU
225 mg/m2/d IVCI d 1-35, bevacizumab 15 mg/Kg d 1, 22, and
erlotinib 100 mg PO d-42. RT was 1.8 Gy M-F to a total dose of
45 Gy. Patients were restaged between weeks 9-11 and had
surgical resection between weeks 12-14.
Abst 48 ASCO 2010
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Gefitinib
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Eligibility required T3, N1, or M1a esophageal or gastroesophageal junction
squamous cell or adenocarcinoma staged by esophageal ultrasound and
positron emission tomography/computed tomography .
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Four-day continuous intravenous infusions of cisplatin (20
mg/m/d) and fluorouracil (1000 mg/m/d) began on day 1 of
preoperative radiation (30 Gy and 1.5 Gy bid). Surgery followed
in 4 to 6 weeks, and an identical course of CCRT 6 to 10 weeks
postoperatively. G 250 mg/d was given with preoperative CCRT
for 4 weeks and restarted with postoperative therapy for 2 years.
Results were retrospectively compared with our historical series
of 93 patients given CCRT without G.
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Abst 49 ASCO 2010
J Thorac Oncol. 2010 Feb;5(2):229-35.
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Herceptin
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About 22% of patients with advanced gastroesophageal cancer
were found to have tumors that overexpress human epidermal
growth-factor receptor 2 (HER2), and these patients had
significantly improved overall survival when trastuzumab
(Herceptin )was added to chemotherapy, compared with
chemotherapy alone .
American Society of Clinical Oncology (ASCO) 45th Annual
Meeting: Abstract LBA4509. Presented June 2, 2009.
Cetoximab
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Whether these results are better than can be achieved with
chemotherapy alone is unclear. The benefit of adding cetuximab
to cisplatin plus 5-FU was addressed in a randomized phase II
German trial of 66 previously untreated patients with metastatic
squamous cell cancer (SCC) .
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TI - Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil
alone in first-line metastatic squamous cell carcinoma of the esophagus: a
randomized phase II study of the Arbeitsgemeinschaft Internistische
Onkologie.
AU - Lorenzen S; Schuster T; Porschen R; Al-Batran SE; Hofheinz R; ThussPatience P; Moehler M; Grabowski P; Arnold D; Greten T; Muller L;
Rothling N; Peschel C; Langer R; Lordick F
SO - Ann Oncol. 2009 Oct;20(10):1667-73. Epub 2009 Jun 23.
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Conclusion 1
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combined modality therapy using preoperative
chemoradiotherapy followed by surgery rather than either
surgery alone or definitive chemoradiotherapy for patients with
stages IIA, IIB, and III esophageal SCC or adenocarcinoma of
the distal esophagus or GEJ (Grade 2B).
We also suggest induction chemoradiotherapy instead of
chemotherapy alone followed by surgery (Grade 2B).
The benefit of preoperative chemoradiotherapy for
patients with stage I esophageal or GEJ
adenocarcinoma or SCC is less clear. We recommend
surgery alone in these patients . (Grade 1B).
Conclusion 2
 However, combined modality therapy is a reasonable approach
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for patients who are not surgical candidates.
Although the optimal type, dose, combination, and schedule of
drugs is unclear, we suggest multiagent chemotherapy rather than
single agent cisplatin
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(Grade 2B).
We suggest not administering concurrent chemoradiotherapy
with a taxane or irinotecan-containing regimen outside of the
context of a clinical trial
(Grade 2C).