Cancer Treatment Reviews 35 (2009) 547552

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevierhealth.com/journals/ctrv

ANTI-TUMOUR TREATMENT

Future directions in neoadjuvant therapy of rectal cancer: Maximizing

pathological complete response rates
Mohammed Mohiuddin a,*, Majid M. Mohiuddin b, John Marks c, Gerald Marks c
a

Geisinger Cancer Institute, 1000 E. Mountain Blvd., Wilkes Barre, PA 18711, United States
Department of Radiation Oncology, University of Maryland, 22 S Green Street, Baltimore, MD 21201, United States
c
Main Line Health System, Lankenau Institute for Medical Research, MOB West, Suite 330, 100 East Lancaster Avenue, Wynnewood, PA 19096, United States
b

a r t i c l e

i n f o

Article history:
Received 24 March 2009
Received in revised form 6 May 2009
Accepted 11 May 2009

Keywords:
Rectal cancer
Neoadjuvant
Chemoradiation

a b s t r a c t
Neoadjuvant therapy is widely accepted as the current standard of care for localized rectal cancer. Downstaging of disease has been signicantly improved and pathological complete response rates (pCR) which
were historically below 10% with preoperative radiation alone, now range from 15% to 30% with preoperative chemo-radiation. While the availability of new chemotherapeutic drugs (Irinotecan, Oxaliplatin,
etc.) and molecular targeted agents (Bevacizamab, Cetuximab, etc.) hold a great deal of promise, results
of recent studies indicate that the pCR rate with neoadjuvant therapy appears to have plateaued at 20
30%. The use of more intensive multidrug combinations has, however, signicantly increased the toxicity
of treatment. New paradigms in neoadjuvant therapy are therefore needed to further improve results of
treatment. This review presents strategies for neoadjuvant therapy, with the potential to improve pCR
rates and also survival of patients.
2009 Elsevier Ltd. All rights reserved.

Neoadjuvant therapy is widely accepted as the current standard

of care for localized rectal cancer and has evolved from the use of
preoperative radiation alone to wider use of preoperative combined modality chemo-radiation. Downstaging of disease has been
signicantly improved and pathological complete response rates
(pCR) which historically were below 10% with preoperative radiation alone, now range from 15% to 30% with preoperative chemoradiation.16 In a number of studies pCR following neoadjuvant
therapy appears to be a strong surrogate for effectiveness of treatment with lower local recurrence of disease and improved sphincter preservation and survival of patients.79 While the availability
of new chemotherapeutic drugs (Irinotecan, Oxaliplatin, etc.) and
molecular targeted agents (Bevacizamab, Cetuximab, etc.) holds a
great deal of promise, we have seen that in many cancers, more
drugs or more dose intensive regimens are not always as successful
as we would have hoped. Early results in Phase II trials of multiagent chemotherapy plus targeted agents with preoperative radiation, appear not to have consistently improved the rate of pCR or
the survival of patients in rectal cancer1013 Table 1. The use of
multi-drug combinations increased the toxicity of treatment hence
resulting in a suboptimal therapeutic ratio. The historical problem
of high local pelvic recurrence following surgery (2030%) no longer is the cause of poor survival in patients. Local recurrence rates
following neoadjuvant chemo-radiation and surgery are less than
* Corresponding author. Tel.: +1 570 332 1108; fax: +1 570 819 5485.
E-mail address: asemuddin@gmail.com (M. Mohiuddin).
0305-7372/$ - see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ctrv.2009.05.002

10% especially with modern surgical techniques of Total Mesorectal Excision (TME)14,15. The problem, therefore, remains the persistent high rate of distant metastasis (3035%) in this disease16,17.
One of the traditional strategies utilized to deal with the problem
of distant metastasis has often been to consider induction chemotherapy prior to starting chemo-radiation. Induction chemotherapy has been utilized for several other tumors1821 and most
recently anal canal22 and rectal cancers23,24 but to date these studies have failed to show any signicant improvement in survival of
patients. In many other sites concurrent chemo-radiation rather
than sequential treatment appears to have most often yielded
the best results25,26. Therefore, as results with neoadjuvant chemo-radiation plateau in rectal cancer, which they appear to have
done, future direction requires a rethinking of our treatment strategy in management of this disease.
There are four key areas that warrant investigation in neoadjuvant therapy of rectal cancer.
1. Optimum drug or drug combination to be used in neoadjuvant
therapy. This is currently being addressed in NSABP RO-4
study27.
2. Impact of genetic ngerprint of tumor in predicting response to
neoadjuvant therapy. This is partially being addressed in RO-4
but needs to be signicantly expanded to create a better predictive model for effectiveness of neoadjuvant therapy.
3. Optimum approach to neoadjuvant radiation with cytotoxic
chemotherapy and/or targeted systemic therapy.

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M. Mohiuddin et al. / Cancer Treatment Reviews 35 (2009) 547552

Table 1
Recent results of neoadjuvant therapy in rectal cancer.
Trial

Chemotherapy
Regimen

RT dose

pCR rate (%)

Carlomagno 1
ECOG E1297 2
Shivnani 3
Rodel 4
Aschele 5
SOCRATES 6
CAO/ARO/AIO-94
Czito 10
Horisberger 11
Jakobsen 12
Valentini 13

CAPOX
FU + OXAL
FU + OXAL
XELOX
FOLFOX
CAPOX
FU
CAPOX + BEV
FU + Cetuximab
UFT + Celocoxib
FU + Iressa

50.4 Gy
50.4 Gy

21
26
25
16
28
18
8
23
8
21
30

16

60 Gy

Toxicity (%)
(PGrade 3)

12
16
22
27
60
49
41

a. Impact of total dose of radiation on pCR rates.

b. Effect of radiation dose/time fractionation on pCR rates especially in tumors with select gene mutations.
4. Reduction of distant metastasis rates by minimizing the development of adaptive resistance during interval to surgery.

The problem of high rates of distant metastasis

A reection of the early results of preoperative radiation for rectal cancer may provide clues to the persisting high rates of distant
metastasis in spite of the recent addition of chemotherapy. It has
long been established in several early studies that signicant
downstaging of tumor was seen with preoperative radiation and
reduction of local recurrence following surgery was consistently
observed but overall survival remained unchanged.28,29 While at
rst this appears counterintuitive, data from several studies (Table
2)30,31 show that patients receiving preoperative radiation exhibit
a higher rate of distant metastasis as initial site of failure compared
to patients undergoing surgery alone. Any benet from the down
staging and local control of cancer is offset by this higher rate of
distant failure. Reasons for this higher rate of distant failure may
be complex but has not received enough attention or investigation.
A simplistic explanation is often that these patients had higher
numbers of occult disease prior to starting therapy. On the other
hand the biological response of tumors to radiation may provide
other plausible explanations and may also be relevant to neoadjuvant chemo-radiation. It has been well established from experimental studies that tumors that are not completely eradicated as
a result of the treatment, undergo accelerated repopulation.32 Willet et al. 33 have shown that tumor proliferative activity persists
following preoperative radiation and can be quite extensive and
can have a signicant impact on survival of patients. Radiation is
also known to produce a signicant increase in the activation of
macrophages stimulating the production of brogenic and angiogenic cytokines resulting in growth stimulation that may not be
limited to local disease but manifests systemically.34 In addition
GoldieColdman35 hypothesized that tumors that are under treated also develop resistance to treatment from a change in their
phenotype which leads to multidrug resistance. Therefore, the benet of preoperative radiation or chemo-radiation may provide a

Table 2
Randomized RTOG phase II studies.
Complete response rate
RTOG
0247
0012

RT dose

RT + Cap/ox

RT + Cap/CPT-11

RT + 5FU

21%

10%
28%

28%

50.4 Gy
5560 Gy

substantial improvement in survival of patients that achieve complete eradication of disease but may also create more aggressive
phenotypes in patients not achieving a pCR, potentially making
their prognosis worse. As a result of these counter effects, the overall survival of the whole group may remain unchanged. This is similar to the pattern of outcome seen with neoadjuvant
chemotherapy in other tumors such as breast cancer36 where patients achieving a pCR have a dramatically better survival but the
overall survival remains unchanged. The only randomized studies
to show a survival advantage with preoperative radiation in rectal
cancer have been short course radiation followed by immediate surgery.37 This is the group where partial response with adaptive
reacceleration of tumor growth has not had time to occur and
hence higher than expected distant metastasis is unlikely. The Polish rectal cancer trial provides an interesting biological model.38
This study compared short course (25 Gy in 1 week followed by
immediate surgery) with conventional preoperative chemo-radiation (50.4 Gy + 5FU for 6 weeks followed by 46 week interval to
surgery). There was greater downstaging of disease, higher pCR
rate, fewer patients with positive surgical margins with chemoradiation, but survival of patients was not improved. There was
in fact a higher rate of local recurrence (14% vs. 9%) and a higher,
though not signicant, rate of distant metastasis in the chemoradiation arm (35% vs. 31%).39 While these differences may appear
small, they follow a consistent pattern in the literature seen in earlier studies. It is possible that patients not receiving chemotherapy
had earlier locoregional relapse before having a chance to fail distantly or that patients receiving chemoradiation may manifest a
delay in eventual distant relapse, but long-term follow up in studies suggests that partial responders continue to exhibit a poorer
overall response.
Therefore, to prevent partially treated tumors developing
aggressive phenotypes and compromise overall survival, neoadjuvant therapy in rectal cancer, must be designed to signicantly
maximize up front pathological complete responses, at least greater than 50%.
Reducing the high rate of distant metastasis
There are two strategies that could potentially reduce the high
rates of distant metastasis in this disease:
a. Prevent the development of adaptive resistance.
b. Increase the rate of pCR to greater than 50% to impact overall
survival.

Preventing the development of adaptive resistance

The traditional approach to neoadjuvant radiation or chemoradiation is to wait 48 weeks after the completion of radiation before surgery is undertaken. This was primarily designed to allow
acute radiation effects to dissipate prior to surgical resection. There
is no biological rationale why, during this critical period, chemotherapy is also discontinued. Continuing the chemotherapy during
the interval to surgical intervention (23 weeks) could suppress
the development of resistant clones and potentially prevent adaptive resistance. In a recent exploration of this concept Habr-Gama
et al.40 have published results of two sequential studies. In the rst
study, they treated patients with rectal cancer with a traditional
approach using two cycles of 5-FU/LV  3 days at the beginning
and end of the radiation treatment (50.4 Gy at 1.8 Gy per fraction).
In 416 patients they reported a clinical complete response (cCR)
rate of 25%. These patients were followed without surgical resection for a median of 46 months. In the second study41, 29 patients
were treated as in the rst study but were given three additional

M. Mohiuddin et al. / Cancer Treatment Reviews 35 (2009) 547552

cycles of 5-FU/LV after the completion of radiation during the rest

period. They observed a dramatically higher (62%) rate of cCR.
While this is an early report of the study, it highlights the possibility of substantial benet from continuing the chemotherapy during
the supposed rest interval before surgery.
Increasing pathological complete response rates
Current strategies to improve pCR have focused on intensifying
the systemic therapy to enhance a local effect. For the last several
years the role of radiation in treatment of rectal cancer has not had
signicant scrutiny. The low rates of local recurrence, with the current standard dose of radiation (50.4 Gy), has been used as an argument against dose escalation in this setting. Radiation remains the
single most effective targeted therapy against cancer cells and its
effectiveness is underscored by the results of the German rectal
cancer trial42 where in spite of chemotherapy, radiation in adequate time and adequate dose was an independent prognostic factor for outcome and survival of patients.
Radiation dose
Studies have shown that there is a steep radiation dose response rate for control of rectal tumors in the adjuvant setting44
Fig. 1. The fear of surgical complications has often limited the
use of higher dose preoperative radiation for the treatment of this
disease. Now with modern surgical techniques, surgical resections
are safely being carried out following high45 and ultra high dose
reirradiation (>85 Gy) of the pelvis.46 Data from recent studies of
neoadjuvant chemo-radiation highlights the role of radiation dose
in pathological complete response to treatment. The German rectal
cancer trial7 used a dose of 50.4 Gy with infusion 5-FU given at
1000 mg/m2 in the rst and last weeks of radiation. They achieved
a pCR rate of 25% for T2 tumors, 10% in T3 cancers and 0% in T4
cancers, indicating that for T34 cancers this radiation dose may
be inadequate. These differences are quite large for the different
stages of disease and the imprecise inclusion of different tumor
stages (T2 vs. T3 vs. T4) in many Phase II studies can result in signicant variability in pCR rates.54
The RTOG-0012 study47 treated T34 tumors with a higher radiation dose of 50.460 Gy and reported a pCR rate of 35% for T3 (72%
of the total patients) and 18% for T4 tumors without reporting increased post surgical complications. PCR rates were reported based
on institutional pathological assessment and not on central reviews. A Princess Margaret Hospital study48 found that an incre-

549

ment of 10% in preoperative radiation dose, from 46 to 50 Gy,

resulted in a signicant improvement in disease-free survival
(p = 0.024), local recurrence-free survival (p = 0.025) and over all
survival (p = 0.066). Other studies that have examined the impact
of radiation dose in the neoadjuvant setting have consistently
found substantial improvements in pCR rates at higher doses of
radiation [4951].
A more recent RTOG-0247 randomized study52 compared Oxaliplatin/Capecitabine plus radiation (50.4 Gy) (Arm 1) with Irinotecan/Capecitabine plus radiation (50.4 Gy) (Arm 2). Eighty nine
percent of patients had T3 cancers and the pCR rates were 18% in
Arm 1 and 10% in Arm 2. Arm 2 in this study was similar to Arm
2 in the RTOG-0012 study47 using Irinotecan/5FU plus radiation
(50.455 Gy) but the pCR rate in the RTOG-0012 study was 28%
in this arm. In fact the arm 1 of the RTOG-0012 utilizing just 5FU infusion plus radiation (5560 Gy) also had a 28% pCR rate
which appears much higher than the pCR rate with Oxaliplatin or
Irinotecan arms in RTOG-0247 even though the latter included
fewer T4 cancers. The major difference in the two studies was
the higher dose of radiation in RTOG-0012 (Table 2).
Radiation dose response has been shown to be a factor in postoperative adjuvant therapy of rectal cancer especially with minimal residual disease[53,54]. Radiation dose may therefore be of
signicant importance in neoadjuvant treatment but dose escalation (>50.4 Gy) has not been tested with the addition of newer
cytotoxic agents in addition to 5-FU. With the evolution of IMRT
dose painting techniques, higher doses of focal radiation can be given to the primary tumor while excluding the anal canal where
possible. High doses of radiation should no longer be a limiting factor especially as the high dose region of the rectum is likely to be
sacriced in the surgical specimen. The benet to the patient, however, could be substantial in pCR rates, disease control and survival.
Personalized approach to radiation
Recent data has shown that molecular targeted therapy is
greatly affected by the genetic ngerprint of tumors 55. K-ras mutations in colon and rectal tumors can negatively impact on the outcome when patients are treated with EGFR inhibitors (Cetuximab,
Panitumamab, etc.).5660 K-ras testing has become required for
treatment decision making in these tumors. At the same time Kras function is known to have a signicant effect on the radiation
sensitivity of cancers.61 Radioresistance to K-ras mutated cells is
mediated through EGFR dependent pathways.62 EGFR status of tumors has also been shown to be a signicant predictor of response
to preoperative chemoradiation.63 In a study looking at the predictive value of EGFR gene copy number (GCN) and K-ras mutations
for pathological response to preoperative Cetuximab, 5-FU, and
radiation therapy in locally advanced rectal cancer, Bengala
et al.64, reported that 52.4% of patients with high GCN had a
TRG3/4 (Tumor Regression Grade) as compared to 5.6% with low
GCN (p = 0.0016). Patients with K-ras mutations also had a lower
rate of TRG3/4 (20% vs. 38%). To overcome the negative effect of
low EGFR copy number and K-ras mutation status, radiation strategy may also need to be modied and a more personalized approach to radiation may be necessary.
Radiation dose/fractionation

Fig. 1. Radiation sensitivity for adjuvant therapy of rectal cancer [43].

There have been very few studies that have examined the role
of radiation dosetime fractionation in treatment of rectal cancers.
One of the largest reports of radiation for the treatment of primary
rectal cancer was undertaken at the Princess Margaret Hospital utilizing a dose of 2.5 Gy per fraction for a total of at least 40 Gy delivered in four weeks.65 Two hundred and seventy-one patients were

550

M. Mohiuddin et al. / Cancer Treatment Reviews 35 (2009) 547552

treated and the results showed a remarkable biological effectiveness of this dose in control of rectal tumors. Complete response
to treatment was observed in 49% of mobile cancers, 22% in partially xed cancers and 9% in xed cancers. The overall ve-year
survival was 48%, 26% and 6%, respectively. In contrast the EORTC
study31 of preoperative radiation at 1.8 Gy to a dose of 45 Gy for
operable rectal cancers had a complete response rate of only 6%
suggesting a signicantly lower effectiveness for doses of 1.8
2 Gy per fraction. Derdel et al.66 undertook a study to compare
the effect on tumor downstaging with conventional 1.8 Gy per
fraction to doses of 4550 Gy and compared it with 2.5 Gy fractions given four times a week, for a total of 40 Gy in preoperative
treatment of rectal cancer without chemotherapy. They reported
(>50%) regression in 62% of patients in the group receiving
2.5 Gy/fraction with 20% pCR as compared with 35% downstaging
and 0% pCR in patients treated at 1.8 Gy per fraction.
In experimental in vitro tumor models of combined-modality
therapy it is also apparent that the biological effect of combined
therapy increases with increasing dose of radiation.67 Our experimental data on 5-FU/radiation interaction suggests that in wild
type tumors radiation at 1.82 Gy induces thymidylate synthase
induction and produces modest sensitization or additive effect,
but at higher dose per fraction, greater sensitization is seen in wild
type cells and an exponentially greater effect is seen in mutant cell
lines.68 Therefore in rectal cancers where p53, K-ras and other
mutations are common or tumors with low EGFR GCN, treatment
with even modestly higher dose per fraction (2.252.5 Gy), or
hyperfractionated radiation in the presence of infusional 5-FU,
may yield substantially higher pCR rates than conventional treatment and needs further investigation. Dose painting techniques
using intensity modulated radiation allow the delivery of a differential dose to tumor and deescalate doses to critical normal structures. Higher dose fractions to the tumor (2.5 Gy) while delivery of
1.8 Gy to pelvic structures should not compromise safety of overall
treatment while achieving the objective of higher pCR rates.

treatments were associated with signicant small bowel complications and have since been abandoned. The upper border is set at
the L5S1 level during treatment of the whole pelvis. The inferior
border of the eld is sometimes adjusted to the location of the primary tumor in the rectum.
Several studies in Europe, particularly in France, have used a
more limited volume to treat rectal cancer (10 by 10 cm elds).70,71
They and others have reported excellent local control of disease,
with very few failures occurring in the region of the common iliac
lymph nodes. Current approaches using intensity modulated radiation certainly is a way of reducing the toxicity of treatment, but
titrating the probability of pelvic nodal involvement to stage of disease is likely to further minimize consequences of unnecessary
radiation. The primary nodal drainage from the rectum is along
the hemorrhoidal arterio-venous system for distal rectal cancers
and the superior and inferior rectal branches of the inferior mesenteric artery and vein. Most of the spread to the iliac lymph nodes
appears secondary to involvement of the primary nodal chains
along the draining vessels. Data from extended pelvic nodal dissections72 indicates that the internal iliac lymph nodes are involved in
less than 10% of patients with T3/4 cancers in the proximal rectum
(>8 cm from anal verge). For tumors of the distal rectum the probability of involvement of lateral pelvic nodes is 0.9% for T1, 5.4% for
T2, 13.5% for T3 and 29% for T4 tumors.72 Common iliac lymph
nodes are rarely involved even in the presence of T4 tumors of
the distal rectum. Several studies7375 have now looked at the pattern of local recurrence in rectal cancer. Site of tumor recurrence is
rarely above the S12 interface and in 75% of cases is in the low
pelvis or the presacral region. It may therefore be more appropriate, where higher doses of radiation are planned, to limit the proximal extent of the radiation eld to the sacral promontory and not
treat to the L5S1 junction except in cases of large T4 cancers.
Since acute and late radiation affects are a function of both volume
irradiated and dose delivered, many potential side effects of high
dose radiation can be minimized by reducing the volume included
in neoadjuvant therapy of rectal cancers.

Radiation treatment volumes

Future strategies
Treatment volume for neoadjuvant radiotherapy of rectal cancer has also undergone signicant evolution over the last couple
of decades. Initial studies of preoperative radiation utilized large
elds to encompass the nodal drainage from the anal verge all
the way to L1 (the root of the inferior mesenteric vessels).69 These

A strategy to increase the pCR rate by combing higher radiation

dose titrated to the stage of disease with a personalized approach
to radiation dose/time fractionation based on the genetic ngerprint of the tumor and the use of extended chemotherapy to

K-ras (wt)/ High EGFR

R
E
C
T
A
L
C
A
N
C
E
R

RT (55 Gy at 1.8 Gy/Fx)*

Chemo
Chemo

2/3 wks

Surgery
EGFR inhibitors

* 45 Gy to pelvis and 10.8 Gy boost at 1.8 Gy/Fx

K-ras (mutant)/Low EGFR
RT (52.5 Gy at 2.5 Gy/Fx)**
Chemo
Chemo

2/3 wks

Surgery
Cox 2 ?

** 45 Gy to pelvis at 1.8 Gy/Fx / 52.5 Gy to Tumor at 2.5 Gy/Fx

++ EGFR Gene Copy Number
Fig. 2. The new paradigm.

M. Mohiuddin et al. / Cancer Treatment Reviews 35 (2009) 547552

prevent the development of adaptive resistance in partial responders is a potential model to substantially enhance the results of neoadjuvant chemo-radiation in rectal cancer. Each of these strategies
needs to be validated rst in robust randomized Phase II studies
with genetic correlates before large scale national trials are initiated. A future treatment design could very well be as shown in
Fig. 2. Optimized approach to local treatment and not just the
tweaking of systemic therapy is critical for future success in management of this disease.

22.

23.

24.

25.

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