Review

Impact of targeted neoadjuvant therapies in the treatment

of solid organ tumours
T. Waddell and D. Cunningham
Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
Correspondence to: Professor D. Cunningham (e-mail: david.cunningham@rmh.nhs.uk)

Background: The advent of affordable technologies to perform detailed molecular profiling of tumours
has transformed understanding of the specific genetic events that promote carcinogenesis and which may
be exploited therapeutically. The application of targeted therapeutics has led to improved outcomes in
advanced disease and this approach is beginning to become established in the management of potentially
curable disease for surgical patients.
Methods: This review article focuses on recent developments in the management of operable cancers
of the gastrointestinal (GI) tract, specifically discussing the currently available data that evaluate the
incorporation of targeted therapies in this setting.
Results: A variety of targeted molecules are now available as treatment options in the management of GI
cancers. Most are aimed at growth inhibition by acting on cell surface targets or intracellular pathways.
Treatment paradigms are gradually shifting towards more prevalent use of systemic treatment prior to
surgical intervention for operable disease with the aim of tumour downsizing and improved rates of
long-term cure.
Conclusion: A large number of ongoing clinical trials are evaluating novel targeted agents as neoadjuvant
therapy in operable GI tumours. Therefore, further progress in the management of early-stage disease
will undoubtedly be made over the next few years as these trials continue to report potentially
practice-changing results.

Paper accepted 25 September 2012

Published online in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.8987

Introduction

Over the past 1520 years there have been unprecedented

advances in the eld of molecular biology and associated
technologies that allow genomic analysis of tissues. These
advances have allowed the oncology community to advance
greatly its understanding of cancer pathogenesis. It is
now understood that individual tumours are frequently
driven by the acquisition of key genetic abnormalities
known as oncogenic drivers that individually or in
combination promote a number of behavioural features
key to the survival of the cancer cells. These drivers may
promote a more aggressive phenotype through increased
cell proliferation and greater potential for invasion and
metastasis, or permit the cancer cell to evade apoptotic
signals or survive the cytotoxic insult from traditional
oncological therapies. Similarly, aberrations leading to loss
of function of host tumour suppressor genes may further
facilitate tumorigenesis.
2012 British Journal of Surgery Society Ltd
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Alongside this knowledge of the molecular abnormalities driving tumour formation and growth, considerable
research has been undertaken to investigate the mechanisms by which these processes may be targeted. Many of
the currently available compounds target specic growth
factor receptors expressed on the cancer cell surface or
attempt to block the growth stimulatory pathways within
the cell. There has been a resultant explosion of novel targeted therapies, mainly in the form of either monoclonal
antibodies that bind to the extracellular domain of a key
receptor, or small-molecule inhibitors that bind to tyrosine
residues on the intracellular domain of the receptor and
block the growth stimulatory signals that occur through
the tyrosine kinase pathway. The aim of these therapies is
primarily to reduce signalling via oncogenic intracellular
pathways and thereby alter the transcriptional events that
occur within the cancer cell nucleus (Fig. 1).
These therapies may have potential benets in all tumour
types and at all stages in the cancer process. Success depends
British Journal of Surgery 2013; 100: 514

T. Waddell and D. Cunningham

Cetuximab
Panitumumab

Trastuzumab

HER-2 Pertuzumab
T-DM1

EGFR/HER-1

Bevacizumab
Aflibercept

PDGFR

VEGF

Lapatinib
Neratinib
Afatinib

KIT

Ramucirumab

Erlotinib
Gefitinib

VEGFR-2

Sunitinib
Sorafenib
Pazopanib
Axitinib

Imatinib
Nilotinib

PI3K

PTEN

RAS
PLC
Vemurafenib

RAF
AKT

MEK
ERK
Proliferation

Invasion/metastasis

NOS
mTOR

Everolimus

Evade apoptosis

Angiogenesis

Common targets and sites of action of inhibitory agents in solid organ tumours. HER, human epidermal growth factor receptor;
EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; VEGF(R), vascular endothelial growth
factor (receptor); PI3K, phosphoinositide 3-kinase; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated
kinase; PLC, phospholipase C; NOS, nitrogen oxide synthase

Fig. 1

not on the tissue of origin or histological subtype the factors used to make traditional chemotherapy decisions but
rather on the degree of addiction of an individual tumour
to the pathway being targeted. Importantly, some of these
targeted drugs have now demonstrated meaningful benets in the neoadjuvant or perioperative settings where they
may inuence surgical practices, for instance by improving resectability rates as well as increasing the number
of patients cured. This article aims to discuss the use of
targeted therapies in the neoadjuvant setting and their
inuence on the treatment approach for potentially operable tumours of the gastrointestinal (GI) tract. As so many
important lessons have been learned from cancers outside
of the GI tract, notably breast and kidney, these have
been included and provide models that may inuence the
management of GI tumours in the future.
Rationale for neoadjuvant therapy for primary
tumours

Treatment given in the neoadjuvant setting for potentially

operable disease has a number of potential benets
including tumour downsizing, increased likelihood of
complete macroscopic and microscopic clearance of
the primary tumour (R0 resection), earlier treatment
of micrometastatic disease and the ability to assess
responsiveness to therapy directly. Conversely, it can also
2012 British Journal of Surgery Society Ltd
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be a cause for some concern owing to the delay to surgery

with the risk of disease becoming inoperable, the possibility
of clinical deterioration and the potential for increased
perioperative complications. It is therefore important to
demonstrate that the number of patients who benet from
this approach exceeds the number harmed. Neoadjuvant
strategies are perhaps best established in the treatment of
breast and rectal cancers where they form current standards
of care. However, with the advent of more effective targeted
therapies, the use of preoperative treatment is being
explored in a number of different solid organ tumours.
Targeted neoadjuvant therapies proof of
efficacy from breast cancer

The demonstration of hormone (oestrogen, progesterone)

receptors and epidermal growth factor family receptors on
tumour cell surfaces in patients with breast cancer has been
recognized for over 30 years, along with their inuences
on survival. Attempts to target these receptors or pathways
under their control represent some of the earliest efforts at
a targeted approach to cancer treatment.
Human epidermal growth factor receptor 2 (HER-2)
positive breast cancer is currently characterized as
being either strongly positive on immunohistochemistry (IHC 3+) or moderately positive (IHC 2+) but
with conrmation of expression by uorescence in situ
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Targeted neoadjuvant therapies in the treatment of solid organ tumours

hybridization. The randomized phase III NOAH trial

(235 patients) evaluated the addition of trastuzumab
(an anti-HER-2 monoclonal antibody) to neoadjuvant
chemotherapy (doxorubicin, paclitaxel, cyclophosphamide,
methotrexate and uorouracil)1 . Patients who were randomized to the trastuzumab arm completed a total of
1 year of therapy (neoadjuvant plus adjuvant). Addition of
trastuzumab led to signicant improvements in pathological complete response (pCR) rate (43 versus 22 per cent;
P < 0001) and 3-year event-free survival rate (71 versus
56 per cent; hazard ratio 059; P = 0013). Following these
ndings, trastuzumab has become incorporated routinely
into the neoadjuvant and adjuvant treatment of HER-2positive breast cancers.
These promising results with trastuzumab led to the
evaluation of similar agents in the neoadjuvant setting,
including lapatinib (a tyrosine kinase inhibitor (TKI) targeting both EGFR and HER-2) and pertuzumab (a monoclonal antibody that prevents dimerization of the HER2 receptor with three other HER family receptors). In
the randomized phase III Neo-Adjuvant Lapatinib and/or
Trastuzumab Treatment Optimization (NeoALTTO) trial
(455 patients), HER-2-positive patients received neoadjuvant chemotherapy with paclitaxel plus either lapatinib,
trastuzumab or both (dual anti-HER-2 strategy)2 . The
highest pCR rates were achieved with the dual strategy
compared with either lapatinib or trastuzumab alone (513
versus 247 versus 295 per cent respectively; P < 0001).
The Neoadjuvant Study of Pertuzumab and Herceptin in
an Early Regimen Evaluation (neoSPHERE) study evaluated pertuzumab, in combination with docetaxel and/or
trastuzumab3 . Patients treated with all three drugs (107
patients) achieved a pCR rate of 458 per cent; however,
perhaps most strikingly, there was a 168 per cent pCR
rate with the combination of pertuzumab plus trastuzumab
(107 patients), conrming that targeted therapy combinations can demonstrate signicant efcacy in the absence of
cytotoxic chemotherapy.
In HER-2-negative breast cancer, other targeted
therapies might have a role in the neoadjuvant setting,
although the current results are conicting. Bevacizumab
is a humanized monoclonal antibody that inhibits
vascular endothelial growth factor (VEGF) A. Both
the GeparQuinto (1948 patients) and National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-40 (1206
patients) trials conrmed increased pCR rates with the
addition of bevacizumab to chemotherapy4,5 . In the
GeparQuinto study, however, benet was conned largely
to the triple-negative population (oestrogen receptor-,
progesterone receptor- and HER-2-negative) where the
addition of bevacizumab to epirubicin, cyclophosphamide

and docetaxel improved the pCR rate from 279 to

393 per cent (P = 0003)4 . There was no benet associated
with bevacizumab in the 1262 patients with hormone
receptor-positive tumours. In contrast, the NSABP B40 study found bevacizumab to improve pCR rates
signicantly among hormone receptor-positive patients
(23 versus 15 per cent), with no signicant effect in the
triple-negative group5 . Given the inconsistency of these
results, the lack of predictive biomarkers and the lack of
long-term outcome data, the use of bevacizumab in this
setting is not currently recommended.

2012 British Journal of Surgery Society Ltd

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Lessons learned from renal cell carcinoma

Renal cell carcinoma (RCC) represents a relatively common cancer in which molecularly targeted therapies have
led to dramatic successes where cytotoxic chemotherapies had previously failed. Several small-molecule protein
kinase inhibitors that block angiogenesis, Akt/mTOR
and/or Ras/Raf pathways (including sunitinib, sorafenib,
pazopanib and everolimus) now have conrmed efcacy
in the setting of advanced disease. In early-stage operable disease there is an increasing tendency towards partial
rather than radical nephrectomy where possible. Partial
nephrectomy represents a safe option in terms of cancer
control and has the benet of preserving long-term renal
function6,7 , which may also improve long-term overall survival by lowering the risk of cardiovascular disease7 . These
ndings have led to interest in the use of neoadjuvant
TKI therapy to downsize larger tumours and allow more
patients to undergo nephron-sparing surgery.
In a prospective clinical trial of preoperative sunitinib,
some degree of tumour shrinkage was seen in 17
of 20 patients, with no apparent increase in surgical
complications8 . Case reports suggest that, for patients
who need to avoid radical nephrectomy, it is possible
to achieve adequate downsizing with sunitinib to allow
partial nephrectomy9,10 . Preoperative sorafenib has also
been investigated in 30 patients before nephrectomy, and
was associated with a decrease in primary tumour size
and loss of intratumoral enhancement in the majority of
patients (83 and 88 per cent respectively) with no surgical
complications related to therapy11 . A series evaluating both
sunitinib and sorafenib found that both were associated
with increased incidence and severity of intraoperative
adhesions that made surgery more difcult, although
this did not translate into an increase in perioperative
complications12 . It is not difcult to see how this principle
might be applied in the GI tract, for instance in the context
of neoadjuvant treatment before liver surgery, where use
British Journal of Surgery 2013; 100: 514

of targeted therapies may avoid some of the steatohepatitic

changes seen with conventional chemotherapies.
Oesophagogastric cancer

In operable oesophagogastric adenocarcinoma, the use

of perioperative chemotherapy represents a standard
of care following conrmed overall survival benet in
randomized phase III trials13,14 . At the present time,
targeted therapies do not form part of the treatment
regimen in this setting, although biomarkers of interest
are now beginning to emerge. In HER-2-positive gastric
cancer, following the success of the Trastuzumab for
GAstric cancer (ToGA) trial in advanced disease15 ,
there are now several case reports of patients receiving
chemotherapy plus trastuzumab in the perioperative
setting, with promising results16,17 . Current prospective
trials are therefore evaluating trastuzumab and other
anti-HER-2 therapies within perioperative regimens in
HER-2-positive disease. Additionally, in the UK the ST03
trial is currently evaluating the addition of bevacizumab to
chemotherapy in patients with operable adenocarcinoma
of the stomach and oesophagus, and is undergoing
amendment to include perioperative lapatinib in the
HER-2-positive subset18 .
In oesophageal carcinoma, cetuximab (a chimeric
mousehuman epidermal growth factor receptor (EGFR)
inhibitor) has been evaluated in combination with neoadjuvant chemoradiotherapy within a phase II trial19 . Among 28
patients with adenocarcinoma or squamous cell carcinoma
of the oesophagus, 19 achieved a complete or near complete pathological regression, and treatment toxicities were
considered acceptable with no apparent increase in surgical
complications and no treatment-related deaths. Currently,
therapies targeting the MET and broblast growth factor
receptor pathways are undergoing evaluation in advanced
oesophageal cancer, and successful therapies can be
expected subsequently to enter trials in the operable setting.
Gastrointestinal stromal tumours

The impact of targeted therapies within the past

decade has been more evident in gastrointestinal stromal
tumours (GISTs) than in any other GI cancer. GIST
previously represented a disease entity that was poorly
classied, largely refractory to standard chemotherapies,
and where surgical excision represented the only effective
intervention. Following the discovery that these tumours
were nearly entirely driven by activating mutations in
the c-KIT (over 90 per cent)20,21 and platelet-derived
growth factor receptor (PDGFR-A) proto-oncogenes, a
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T. Waddell and D. Cunningham

targeted therapeutic approach has proven highly successful.

Imatinib is a small-molecule tyrosine kinase inhibitor that
effectively blocks both KIT and PDGFR-A signalling.
In advanced GIST imatinib has been demonstrated
to improve median overall survival dramatically from
approximately 20 months to nearly 5 years22 . However,
not all activating mutations confer the same degree of
sensitivity to imatinib therapy. KIT exon 11 mutations are
associated with increased benet compared with exon 9
mutations or where there is no identiable mutation23 25 .
For this reason mutational analysis is recommended for all
patients, and use of an increased starting dose of imatinib
is advocated in those with exon 9 mutations26 .
Given the impressive response rates with imatinib in
advanced disease, there has been considerable interest in
the potential benets of this therapy prior to resection
in an attempt to improve long-term outcomes. This
is a particularly attractive strategy in patients with
unresectable primary tumours, or where surgery would
result in multivisceral resections with signicant associated
morbidity. It may also be of benet in the treatment of
local recurrences or in the management of potentially
resectable but small-volume metastatic disease. The use
of neoadjuvant imatinib has never been evaluated in a
prospective randomized clinical trial, although a rationale
for its use is supported by case reports, observational studies
and a single-arm phase II study in patients with either
locally advanced primaries (30 patients) or resectable recurrent/oligometastatic disease (22 patients)27 . All patients
received 812 weeks of neoadjuvant imatinib followed
by at least 2 years of adjuvant therapy. In the locally
advanced patient group, 57 per cent remained progressionfree at 5 years, and even in those who were recruited with
recurrent or metastatic disease the 5-year progression-free
survival rate was 30 per cent.
In a reported retrospective series of 46 patients treated
with neoadjuvant imatinib followed by surgery, there
were 11 patients with locally advanced tumours28 . Median
duration of imatinib therapy in this group was 12 months,
and one patient achieved a pCR with a further eight
achieving a radiological partial response. Only one of the
11 patients experienced disease recurrence after nearly
2 years following resection. Despite the lack of randomized
data, neoadjuvant imatinib is often recommended in those
with high-risk features including: size greater than 5 cm,
more than ve mitoses per 50 high-power elds, or
anatomical location that would necessitate a potentially
morbid resection. The European Society for Medical
Oncology guidelines state that neoadjuvant imatinib is
recommended if R0 surgery is not feasible, or it could
be achieved through less mutilating surgery in the case
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Targeted neoadjuvant therapies in the treatment of solid organ tumours

of cytoreduction26 . This advice is echoed by that of the

National Comprehensive Cancer Network in America29 .
Colorectal cancer

Colorectal cancers also have an interesting history

in the evolution of targeted therapies. One of the
intracellular growth signalling pathways activated by
EGFR is the mitogen-activated protein kinase (MAPK)
pathway, involving a KRAS protein. About 40 per cent of
patients with colorectal cancer have tumours with mutant
KRAS. When KRAS is mutated, it does not respond to the
usual EGFR-mediated signals and unrestricted growth can
occur. Attempts to use EGFR inhibitors in patients with
advanced colorectal cancer have therefore demonstrated
that this treatment only improves outcomes in patients
with wildtype (non-mutated) KRAS. This in turn led to
the development of genetic testing for KRAS mutation as
a predictive biomarker of response to treatment. This was
the rst genetic test to be used to guide cancer treatment.
Colon cancer is largely resectable at presentation and
therefore neoadjuvant therapy is not routinely required.
However, for locally advanced tumours, the cancer may be
xed to surrounding structures and therefore neoadjuvant
therapy may improve operability. Targeted therapies have
not been explored in this setting previously; however,
this is one of the goals of the current Fluoropyrimidine
Oxaliplatin and Targeted Receptor Pre-Operative Therapy
(FOxTROT) trial18 . This trial is designed to evaluate
whether neoadjuvant therapy in stage T3/T4 colorectal
cancer will improve disease-free survival, and whether the
addition of panitumumab (a human monoclonal antibody
that specically blocks EGFR) to chemotherapy will
increase tumour shrinkage in patients with KRAS wild-type
tumours.
In rectal cancer, neoadjuvant therapy is commonly recommended to achieve local tumour shrinkage and
facilitate total mesorectal excision for bulky tumours, where
invasion of adjacent organs or the walls of the pelvis can
compromise the ability of the surgeon to achieve an R0
resection. In addition, it is desirable to avoid the permanent
colostomy and high incidence of urinary or sexual
dysfunction associated with abdominoperineal resection
for lower rectal tumours, by achieving sufcient tumour
regression to permit a satisfactory (R0) resection while
restoring intestinal continuity and retaining sphincter
continence. Neoadjuvant chemoradiotherapy therefore
represents the current standard of care for patients with
magnetic resonance imaging-dened high-risk features,
including a potentially positive circumferential resection
margin (CRM), extramural venous invasion and extramural
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spread beyond 5 mm. The goal of therapy is to downsize the

tumour sufciently to allow a sphincter-sparing operation,
and decrease the chances of an involved CRM.
Following data conrming a radiosensitizing role for
cetuximab in head and neck cancers30 , the randomized
phase II EXPERT-C trial evaluated the addition of
cetuximab to a schedule of neoadjuvant chemotherapy,
followed by chemoradiotherapy, surgery and adjuvant
capecitabine/oxaliplatin for rectal cancer31 . This trial
recruited 90 patients with KRAS/BRAF wild-type tumours
and the primary endpoint of the study was pCR rate.
Although the addition of cetuximab did not improve pCR
rates, there were statistically signicant improvements in
both the response to neoadjuvant chemotherapy (71 versus
51 per cent; P = 0038) and overall survival (hazard ratio
027; P = 0034) associated with the use of cetuximab in
this setting.
Hepatocellular carcinoma

Sorafenib is a TKI which acts to inhibit a number

of different protein kinases, notably vascular endothelial
growth factor receptor (VEGFR), PDGFR, and Raf.
In 2008 the SHARP trial conrmed an overall survival
benet associated with the use of sorafenib compared with
placebo in patients with advanced hepatocellular carcinoma
(HCC) (median overall survival 107 versus 79 months;
hazard ratio 069; P < 0001)32 . In early-stage disease
amenable to surgery, partial liver resection represents
the optimal surgical approach but this requires adequate
functional liver reserve. Owing to underlying cirrhosis
and liver dysfunction in the majority of patients with
HCC, an appropriate oncological resection may not be
feasible. Some patients harbouring small tumours may
be candidates for liver transplantation. The potential
use of neoadjuvant sorafenib as a holding measure
before transplantation, and as a means of downsizing
inoperable tumours to allow resection, has attracted
considerable interest. Small case series have conrmed
that in locally advanced disease it is possible to obtain
meaningful improvements with sorafenib therapy that may
subsequently render a tumour operable33,34 . Sorafenib can
cause signicant tumour necrosis and in some reports
no viable tumour cells have been found in the resection
specimen, although this needs to be tempered by concerns
over its safety. Among 33 patients with HCC awaiting
liver transplantation, ten received sorafenib in an attempt
to prevent disease progression35 . Although rates of death
were similar between the two groups, the authors reported
that the preoperative use of sorafenib was associated
with statistically signicant increases in the risk of
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10

biliary complications and acute cellular rejection following

transplantation. Use of neoadjuvant sorafenib therefore
remains experimental and requires further exploration
within a clinical trial setting.

Pancreatic cancer

Owing to the anatomical location and aggressive nature of

pancreatic cancers, these tumours are frequently inoperable at presentation, with less than one-fth of patients
presenting with operable disease. However, a further
1520 per cent have locally conned disease which is
inoperable by virtue of close proximity to, or direct
invasion into, surrounding structures. There is therefore a potential role for treatment to downsize locally
advanced tumours and render them operable. To date,
targeted therapies have not established themselves in
this setting, and current neoadjuvant treatment consists largely of either gemcitabine-based chemotherapy, chemoradiotherapy or both. Data on the use of
triplet chemotherapy with oxaliplatin, irinotecan, uorouracil and leucovorin (FOLFIRINOX) in this indication is currently awaited following conrmation of
a 316 per cent response rate and more than 4-month
improvement in overall survival in patients with metastatic
disease36 .
There is, however, increasing information regarding potential therapeutic targets for biological therapy
in pancreatic cancer. KRAS mutations are found in
7080 per cent of these tumours37,38 and EGFR amplication is reported to occur in almost 50 per cent37 . Further
molecular classication has delineated three distinct subgroups of pancreatic cancer that may have differential
responses to treatment39 and future studies may stratify according to these molecular signatures. Regarding
targeted therapies, there have already been trials evaluating the use of cetuximab40 , erlotinib41,42 (another
EGFR inhibitor), bevacizumab43 45 and axitinib46 (a TKI
that inhibits multiple targets including VEGFR receptors,
PDGFR and c-KIT) in combinations with chemotherapy
in advanced disease. Of these, only the addition of erlotinib
to gemcitabine has resulted in any improvement in overall survival41 , the benet being marginal. A retrospective
series has suggested that the benets of erlotinib may be
predominantly limited to KRAS wild-type tumours47 . The
hedgehog signalling pathway is also currently being targeted in pancreatic cancer trials and the next decade is
likely to see the development of more effective targeted
therapies in this disease designed to improve resectability
and long-term survival.
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T. Waddell and D. Cunningham

Neoadjuvant therapy for metastatic disease

In addition to the use of targeted therapies in the

neoadjuvant setting, the advent of more effective systemic
treatments has led to greater interest in surgical
interventions for metastatic disease. As the overall survival
of patients with advanced disease gradually improves,
the potential role of palliative surgery alongside targeted
therapies has been increasingly evaluated.
In colorectal cancer the addition of targeted therapies
to improve treatment response and resectability of
liver metastases has been explored widely within phase
II trials, including the BOXER (bevacizumab)48 and
CELIM (cetuximab)49 trials. This has also been evaluated
and reported as a secondary endpoint within large
phase III studies evaluating bevacizumab, cetuximab
and panitumumab in advanced colorectal cancer50 53 .
In diseases such as GIST, RCC and melanoma, it is
becoming increasingly common to resect known sites of
metastatic disease following demonstration of response
or stabilization with targeted therapy54 58 . Additionally,
case reports have described patients developing progressive
disease at a single site who undergo resection of this one
metastasis while continuing targeted therapy for control
at other sites59 . Since this phenomenon is likely due to
development of resistant clones at an individual site of
disease, surgery may have an increasing role in maintaining
longterm disease control.
Conclusions

The number of targeted therapies being developed and

evaluated in all stages of oncological clinical trials has
increased dramatically in the past few years. These
therapies are now impacting on the management of all
stages of disease, including in the operable setting. Table 1
lists some of the ongoing clinical trials evaluating a targeted
therapy in the neoadjuvant setting in the GI tract. Patients
who would previously have undergone surgery alone are
increasingly receiving neoadjuvant therapies to improve
the chances of a successful surgical outcome and long-term
cure.
This process remains in its infancy and only a few
molecularly targeted therapies to date have established
themselves as components of routine clinical practice in
early-stage disease. This will undoubtedly change over
the next decade as understanding of carcinogenesis and
resistance mechanisms continues to expand and new targets
can be exploited. A wealth of biomarker data further
aims to identify the specic subgroups that maximally
benet from each therapy, and effective biological
therapies will increasingly be combined without the need
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Targeted neoadjuvant therapies in the treatment of solid organ tumours

Table 1

11

Currently registered, recruiting trials in gastrointestinal cancer that are evaluating targeted therapies within the neoadjuvant

setting

Oesophagogastric cancer
Bevacizumab

Trastuzumab
Trastuzumab
Cetuximab
GIST
Imatinib
Imatinib
Imatinib
Colorectal cancer
Panitumumab
Panitumumab
Panitumumab
Bevacizumab
Sorafenib
Hepatocellular carcinoma
Sorafenib

Sorafenib
Pancreatic cancer
LDE-225 (hedgehog inhibitor)
GDC-0449 (hedgehog inhibitor)
Erlotinib
CP-870,893 (CD40 agonist)

Disease setting

Phase

Stomach + type III GOJ: stage

IbIV, M0; type I/II GOJ, lower
oesophagus: stage IIIVa
HER-2-positive, stomach; locally
advanced resectable
HER-2-positive GOJ, stomach;
stage IIII
Stomach, GOJ and oesophagus

III

Safety, overall survival

UK

NCT00450203
(ST03 trial)

II

Disease-free survival

Spain

NCT01130337

II

pCR

Germany

NCT01472029

Safety

USA

NCT01183559

Resectable or locally advanced

Locally advanced
Locally advanced, initially
unresectable

II
II
II

Response rate
Recurrence rate
Response rate

Brazil
China
Canada

NCT01483014
NCT01267695
NCT00290485

Colonic, wild-type KRAS; T4 or T3

with poor prognosis
Rectal, wild-type KRAS; T3ac
Rectal cancer; T3/4 or N12
Rectal cancer; locally advanced
Rectal cancer; T3/4 or N12

III

Recurrence rate, pathological

response
Resection rate
Pathological response
pCR
Toxicity, pathological
response

UK

NCT00647530
(FOxTROT trial)
NCT01263171
NCT00967655
NCT00828672
NCT00869570

II
II
II
I/II

Index tumour measuring 48 cm;

ChildPugh A

II

Eligible for curative resection

II

Borderline resectable
Resectable
Resectable
Resectable

I/II
I
II
I

Primary endpoint

Country

UK
USA
Belgium
Switzerland,
Hungary

Trial no.

Radiological complete
response, time to
recurrence
Pathological response,
antiangiogenic effects

Italy

NCT01507064

France

NCT01182272

Safety, resection rate

Pharmacodynamics, safety
Overall survival
Safety

USA
UK
USA, Canada
USA

NCT01431794
NCT01096732
NCT00733746
NCT01456585

From ClinicalTrials.gov18 . GOJ, gastro-oesophageal junction; HER, human epidermal growth factor receptor; pCR, pathological complete response.

for accompanying cytotoxic therapy. The increased use

of techniques such as gene expression proling, and
reduced costs of deep sequencing technologies, are now
permitting the complete genetic analysis of individual
tumours. This approach is continuing to identify novel
molecular aberrations associated with carcinogenesis, some
of which may represent the therapeutic targets of the
future.
This molecular approach to cancer treatment is therefore
advancing towards a foreseeable situation where each
patient would have their tumour proled at presentation
in order to determine the optimal combination of targeted
therapies that would exploit the dependencies of their
cancer. Throughout treatment, further analyses would then
aim to identify emerging resistance mechanisms and allow
a change in treatment strategy accordingly. As knowledge
and treatment strategies continue to advance towards this
goal, an increasing number of locally advanced tumours
2012 British Journal of Surgery Society Ltd
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will be rendered resectable. Furthermore, as incurable

cancers become increasingly chronic in their disease course,
the resection of metastatic disease sites may become
increasingly important as a means of prolonging overall
survival.
Disclosure

The authors declare no conict of interest.

References
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Lluch A, Tjulandin S et al. Neoadjuvant chemotherapy with
trastuzumab followed by adjuvant trastuzumab versus
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