radiation, chemotherapy and biological therapy in the curative treatment of locally advanced rectal...

Systematic review doi:10.1111/j.1463-1318.2010.02320.x

Radiation, chemotherapy and biological therapy in the curativetreatment of locally advanced rectal cancer

S. Gollins

North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, Denbighshire, UK

Abstract

Objective To review the published evidence relating to

the use of radiotherapy (RT), chemotherapy and biolo-

gical therapy as adjuncts to surgery in the curative

treatment of rectal cancer.

Methods Searches were carried out of the MEDLINE

and CANCERLIT databases together with conference

abstracts from key meetings including the American

Society of Clinical Oncology Annual Meeting and

Gastrointestinal Cancers Symposium and the ECCO ⁄ ES-

MO Multidisciplinary Congress.

Results RT reduces local pelvic recurrence when used

as an adjunct to surgery, even when this is performed

optimally by total mesorectal excision (TME). RT is

usually given as short-course preoperative radiotherapy

(SCPRT) followed by immediate surgery which produces

no or very little downstaging or long-course concurrent

chemoradiation (CRT) followed by a 6-8 week gap prior

to surgery which produces significant downstaging. The

prognostic importance of achieving a clear histological

circumferential resection margin is now well recognised

and pathological assessment of the quality of surgery can

predict long-term outcomes. Internationally there is

considerable heterogeneity in the staging modalities and

criteria used in deciding which approach might be used,

in the reporting of histological results and in RT

parameters (time ⁄ dose ⁄ fractionation ⁄ volume). Attempts

to increase the potency of CRT have included the

addition of concurrent chemotherapeutic and biological

agents to the standard fluoropyrimidine although there is

little randomised data and none with regard to long-term

survival outcomes. Neither SCPRT nor downstaging

CRT have been shown to reduce the rate of subsequent

distant metastatic relapse which remains a significant

clinical problem. The potential additional benefit of

neoadjuvant or adjuvant chemotherapy in addition to

SCPRT or long-course CRT remains ill-defined. Late

morbidity can include bowel and sexual dysfunction,

pelvic fractures and second malignancies with consider-

ably more being known in relation to SCPRT than long-

course CRT.

Conclusions Improvements in imaging, pathology and

surgical technique combined with multimodality treat-

ment using RT and chemotherapy are leading to

continuing improvements in the long term outcome for

patients with rectal cancer although much remains to be

learnt regarding the optimum strategy for use of these in

different clinical contexts and their relationship to long-

term morbidity.

Keywords Rectal cancer, radiotherapy, chemotherapy,

biological therapy

Introduction

Surgery is the mainstay of curative treatment for rectal

cancer with local recurrence (LR) and distant metastases

(DM) being relevant issues to a greater or lesser extent

depending on the stage of the tumour at presentation.

Much recent interest has focused on the circumferential

resection margin (CRM), positivity being generally

defined as tumour £ 1 mm from the surgical resection

margin. Involvement of the CRM has been shown to

be an important, independent prognostic factor, result-

ing in high rates (historically up to 85%) of LR [1–3],

DM [4,5] and worse overall survival (OS) [2,5, 6],

even after total mesorectal excision (TME) surgery [7].

If the CRM is found to be involved following neoad-

juvant therapy, the hazard ratio for LR (although not

survival) after surgery is significantly higher than if the

CRM is involved when no preoperative therapy is

administered (6.3 vs 2.0), possibly because of selection

of populations of tumour cells that are resistant to

therapy [8].

Several ways have been described in which the

histological CRM may be positive including direct or

Correspondence to: Dr Simon Gollins, Consultant Clinical Oncologist, North

Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan,

Denbighshire LL18 5UJ, UK.

E-mail: [email protected]

2 � 2010 The Author. Journal Compilation � 2010 Blackwell Publishing Ltd. Colorectal Disease, 12 (Suppl. 2), 2–24

discontinuous tumour spread, lymph node spread, lym-

phovascular spread and perineural spread [8]. CRM

positivity is also related to the quality of surgery [3,9].

Microscopically spread from the primary tumour to

involve the CRM is often discontinuous involving

isolated mesenteric or lymph node deposits [1,10,11].

Local recurrence may also sometimes occur even in the

absence of an involved CRM, possibly owing to

lymphatic spread from the distal rectum to lymph nodes

on the pelvic side wall [12]. Increasing Dukes stage also

increases the risk of CRM involvement and LR [1]. In

patients undergoing surgery with or without preoperative

radiotherapy (RT), the combination of CRM and lymph

node status has been shown to be a more effective

discriminator of prognosis than TNM staging [13].

The aim of neoadjuvant and adjuvant therapy is to

decrease the risk of local and distant recurrence within the

limits of acceptable morbidity. This review will summa-

rize current evidence relating to combinations of RT,

chemotherapy and biological therapy in the perioperative

treatment of locally advanced rectal cancer.

Radiotherapy alone in resectable rectalcancer

A Colorectal Cancer Collaborative Group [14] meta-

analysis of 22 randomized trials commencing between

1964 and 1987 including 8507 patients established that

both pre- and postoperative RT with a biologically

effective dose of ‡ 30 Gy can reduce rectal cancer LR

rates. Rectal cancer deaths were reduced but an increase

in OS was not seen. A separate meta-analysis [15],

systematic review [16] and Cochrane review [17] support

these findings. Trials included in the CCCG meta-analysis

mostly used relatively crude RT techniques by modern

standards, including treatment of large volumes and the

use of parallel opposed fields, which were related to an

increase in noncancer related deaths [18].

More recent trials have examined short course preop-

erative radiotherapy (SCPRT) delivering a dose of 25 Gy

in five daily fractions, followed by immediate surgery

[19–21]. These have all demonstrated reduced 5-year LR

compared to surgery alone (11% vs 27% in [19] and 5.6%

vs 10.9% in [20]) or selective postoperative chemoradi-

ation (4.7% vs 11.5% in [21]). Only one trial (Swedish

Rectal Cancer Trial [19]) showed improved survival in

patients receiving RT which was perhaps explained by a

marked reduction of a high background rate of LR (9% vs

26%), whereas the rate of DM was not affected (34% in

each arm at 13 years) [22–24]. In the two later trials

(Dutch TME [25] and CR07 [21]), the surgical tech-

nique of TME [26] was used in the majority of patients

which reduced baseline 5- year LR rates.

The Dutch TME trial reported that positive CRM is

the most important independent predictor of local failure

[3]. Local recurrence and disease-free survival (DFS) are

strongly related to the quality of surgery as assessed by

the plane of surgical dissection [9], and low rectal

tumours £ 5 cm from the anal verge have a higher

frequency of CRM involvement (26.5% vs 12.6%) and LR

compared to more proximal tumours [27]. The Dutch

TME trial suggested that SCPRT reduces LR in middle

third rectal tumours and but not tumours £ 5 cm from

the anal verge or for those operated on with abdomino-

perineal resection (APR) [20].

In patients with an involved CRM (£ 1 mm), SCPRT

was ineffective in reducing LR as was postoperative

chemoradiation (CRT) [7]. In addition, SCPRT followed

by immediate surgery did not induce ‘downstaging’ of

rectal cancer [28].

Chemoradiation in resectable rectalcancer

In an effort to increase the efficacy of RT, this has been

combined concurrently with chemotherapy which poten-

tially functions to sensitize cancer cells to radiation

effects. Initially, such regimens used 5-fluorouracil

(5FU) in a variety of bolus or infusional regimes, typically

delivered with approximately a 5- week course of RT to

40–50 Gy. To maximize any downstaging effect, surgery

might typically occur 6–8 weeks following CRT. In the

context of operable rectal cancer, a Cochrane review [17]

has suggested that preoperative CRT provides an incre-

mental benefit for local control compared with RT.

Two recently reported trials randomized patients

between preoperative long-course RT and CRT (using

similar daily short infusion of 5FU radiosensitizing regimes

in the first and fifth weeks of RT). The EORTC 22921 trial

contained 1011 patients [29,30] and the French FFCD

9203 trial 762 patients [31]. Each used an RT dose of

45 Gy in 25 daily fractions over 5 weeks, both recruited

between 1993 and 2003, both clinically staged approxi-

mately 90% of tumours as T3 and 10% as T4 and both had

OS as a primary end point, yielding strikingly similar

results. A decrease was seen in 5- year LR of 17% (RT) to

9% (CRT) and 16 to 8%, respectively, with the pCR rate

in the CRT arms being 13.7% and 11.4%. However, this

did not translate to an improvement in either 5- year

metastasis rate (32% vs 35% and 36% vs 33%) or OS (66%

vs 65% and 68% vs 67%). Despite pathological down-

staging, it was reported in the EORTC 22921 trial that

there was no difference in the rates of CRM involve-

ment (overall 5.4%) between patients treated with preop-

erative RT or CRT [32]. Acute toxicity was increased by

CRT although well within accepted levels of tolerance.

S. Gollins Rectal cancer treatment

� 2010 The Author. Journal Compilation � 2010 Blackwell Publishing Ltd. Colorectal Disease, 12 (Suppl. 2), 2–24 3

Both trials demonstrated poor compliance with post-

operative adjuvant chemotherapy. In FFCD 9203, 30% of

patients undergoing CRT did not receive their full four

protocol-stipulated cycles of adjuvant chemotherapy

[31]. In EORTC 22921, only 43% of patients received

their full dose of 5FU without delay [30]. However,

EORTC 22921 suggested that patients who received RT

followed sequentially by adjuvant chemotherapy derived

similar benefit in terms of local disease control compared

with those who received concurrent CRT. Further subset

analysis has suggested that in terms of DFS and OS, only

good prognosis pT0-2 patients might benefit from

adjuvant chemotherapy but not pT3-4 [33].

The German Rectal Cancer Trial CAO ⁄ ARO ⁄ AIO-

94 recruited patients between 1994 and 2002 [34],

randomizing 823 patients to receive pre- or postopera-

tive CRT using an infusional 5FU regimen in the first

and fifth weeks of RT. Two-thirds of tumours were

clinically staged as T3, approximately 5% as T2 or T4

with T stage unknown in approximately one quarter.

Patients also subsequently received four, four-weekly

cycles of bolus adjuvant 5FU with the primary end point

OS. Preoperative CRT produced a pCR rate of 8% and

reduced the 5- year LR rate from 13 to 6% compared to

postoperative CRT. However, no difference was seen in

the 5- year DM rate (36% vs 38%), or OS (74% vs 76%).

Compliance was better for preoperative vs postoperative

RT, with 92% receiving the full RT dose preoperatively

compared with 54% postoperatively. The overall rates of

acute grade 3 and grade 4 side effects (27% vs 40%)

including grade 3 and grade 4 diarrhoea (12% vs 18%)

were significantly lower in the preoperative arm in

patients who actually received treatment although the

postoperative RT dose was higher than preoperative

(55.8 Gy vs 50.4 Gy).

Local staging of rectal cancer

MRI scanning of the pelvis is increasingly viewed as the

gold standard for judging threatening or involvement of

the potential mesorectal fascial surgical resection plane.

In 311 patients with operable rectal cancer who were

shortly due to undergo surgery, the MERCURY trial

demonstrated that preoperative MRI has high accuracy,

negative predictive value and specificity in the identifica-

tion of a potentially involved CRM although sensitivity

(15 ⁄ 36: 42%) and positive predictive value (15 ⁄ 21: 71%)

were less impressive [35]. MRI has also been shown to

identify accurately the prognostically important feature of

extra-mural vascular invasion [36].

Although digital rectal examination (DRE) remains an

essential component of patient assessment, this has been

shown to be inferior to MRI in the preoperative staging

of rectal cancer [37]. Despite trans-rectal ultrasound

(TRUS) being accurate at staging early T1 ⁄ T2 lesions,

neither it nor DRE can assess discontinuous mesorectal

deposits that might dictate operability [37].

Significant over staging was reported in the German

Rectal Cancer Study which used clinical examination, CT

scanning and TRUS, with no MRI component [34].

Despite the fact that stage I tumours were to be excluded,

18% of patients in the postoperative CRT arm proved to

have stage I disease. Staging investigations for the

EORTC 22921 [30] and the FFCD 9203 trials [31]

were similar to CAO ⁄ ARO ⁄ AIO-94, and it is thus highly

likely that a significant number of stage I patients were

included in these trials also.

There is retrospective evidence that there is a subset of

patients with early T3N0 disease who may not benefit

from adjuvant treatment [38] and in whom the use of

CRT is excessive [39]. Conversely, concerns have been

expressed about potential understaging of patients in the

T3N0 category [40]. In a retrospective six-centre analysis

of 188 patients who had been staged as cT3N0 (69%

using TRUS and 31% MRI) and who received preoper-

ative CRT, it was found that 22% had pathologically

positive mesorectal lymph nodes [40]. Because of the

downstaging effect of preoperative CRT, it was argued

that an even greater proportion of patients would have

had positive lymph nodes prior to CRT.

A distinction can be made between ‘locally advanced

resectable’ and ‘locally advanced unresectable’ cancers

based on potential CRM involvement. A reasonable

modern definition for cancers in the latter group would

be those in whom MRI suggests that the potential

surgical mesorectal fascial resection margins are involved

or threatened (£ 1 mm).

Although not perfect, at the current time MRI would

appear to be the staging modality most suited to judging

potential involvement of the CRM and thus ultimate

resectability. So far, no phase III randomized trial has

been reported for which MRI staging of rectal cancers

was mandatory. This has led to inaccuracies in staging,

and in addition to varying case mix, it has led to difficulty

in comparing studies.

Short-course preoperative radiotherapy vslong-course concurrent chemoradiation inresectable rectal cancer

Efficacy

One relatively small randomized study [41] has been

carried out in 316 patients with resectable rectal carci-

noma accessible to DRE and without sphincter infiltra-

tion. Patients received either SCPRT using 5 · 5 Gy

Rectal cancer treatment S. Gollins


followed within 7 days by TME or CRT to 50.4 Gy

using bolus 5FU as a radiation sensitizer, followed by

TME after 4–6 weeks. Despite stipulating cT3-T4 cancer

as an entry requirement, 39% of tumours in the SCPRT

arm (which would not be associated with significant

downstaging) were found to be pT1-T2. This trial was

designed to look for a difference in sphincter preservation

rates which were no different between the arms: 61% for

SCPRT vs 58% for CRT. Although a lower pCR rate was

noted for SCPRT compared with CRT (1% vs 16%,

respectively), there was no difference in 4- year LR (9.0%

vs 14.2%), DFS (58.4% vs 55.6%) or OS (67.2% vs

66.2%).

In the ‘locally advanced resectable’ group of patients,

SCPRT remains a valid alternative compared to CRT.

Despite a poor uptake of SCPRT for this group of

patients in the USA, this attitude has recently been

questioned [38].

Early toxicity

Acute toxicity from SCPRT using 3- or 4-field techniques

is acceptable [42]. An increase in postoperative mortality

was seen in the Stockholm I trial using large parallel

opposed radiation fields, especially in the elderly. This was

also seen in three hospitals that violated the protocol in

the Swedish Rectal Cancer Study by using parallel rather

than 3- or 4-field techniques (postoperative mortality

15% vs 3%). Otherwise, there was no increased risk in the

Swedish Rectal Cancer Study (4% after SCPRT vs 3% after

surgery alone) [19] or the Dutch TME trial (30- day

mortality 3.5% for SCPRT vs 2.6% for surgery alone)

[43]. More perineal wound infections were found in the

SCPRT patients in the Swedish Rectal Cancer Trial (20%

vs 10%) but not in anastomotic dehiscence or other

postoperative complications [44].

In the Dutch TME trial, approximately 10% of

patients experienced transient neurological symptoms of

pain in the buttocks or legs during SCPRT. In the

majority this was mild. Significantly more patients treated

with SCPRT experienced postoperative complications

(48% vs 41%), mainly because of differences in perineal

wound healing amongst patients treated with APR [43].

Within the Polish study, treatment-related early grade

3 and grade 4 toxicity was significantly lower for SCPRT

than CRT (3% vs 18%) [41].

In the German Rectal Cancer Trial, there was no

difference in the rate of in-hospital mortality between the

pre- and postsurgical CRT arms (0.7% and 1.3%, respec-

tively) or in the overall rate of postoperative complica-

tions (36% vs 34%) [34]. Similarly, in the FFCD 9203

trial, low rates of perioperative death were seen with no

difference between the arms (2% at 60 days) [31]. The

overall surgical complication rate in the FFCD 9203 trial

was 26.9% and 20.9% in the RT and CRT groups,

respectively.

Late toxicity and quality of life

Theoretically, the higher dose per fraction of 5 Gy used

in SCPRT schedules may increase late radiation toxicity

compared to the 1.8 Gy per fraction typically used in

CRT regimes. Currently, considerably more is known

concerning late morbidity related to SCPRT than CRT

with long follow-up periods recorded [23].

Late adverse events associated with RT included bowel

obstruction, bowel dysfunction presenting as faecal

incontinence to gas, loose or solid stool, evacuation

problems or urgency, sexual dysfunction and increased

second malignancies [45]. Fewer late adverse events were

reported in recent studies which generally used smaller

RT volumes and improved multifield techniques. Apart

from the Stockholm trials, rectal irradiation did not

appear to have a major effect on the urinary system [45].

An increase in pelvic insufficiency fractures and of

thromboembolic disorders was noted when the two

Stockholm trials were analysed together (though not

separately) although not in the Swedish Rectal Cancer

Trial or Dutch TME trial [45].

In the two Stockholm trials, 139 patients were

available to complete a questionnaire and clinical exam-

ination at 15 years from surgery [46]. Overall, a greater

proportion of patients who received SCPRT developed

late complications than those who did not (69% vs 43%).

The morbidity related to the relatively crude, large

volume RT techniques in these trials consisted of

cardiovascular side effects (35% vs 19%), faecal inconti-

nence (12 of 21 SCPRT patients vs 11 of 42 patients

receiving anterior resection alone) and urinary inconti-

nence (45% vs 27%).

Questionnaires were completed by 171 (77%) of the

220 patients within the Swedish Rectal Cancer Trial who

were alive with a minimum follow-up of five years [47]

The median bowel frequency per week was statistically

increased in the irradiated group (20) compared to the

surgery-only group (10). Incontinence for loose stools,

urgency and emptying difficulties were all significantly

increased after RT. Bowel dysfunction significantly

impaired the social life of more patients in the irradiated

group (30% vs 10%).

In the Dutch TME trial in 362 stoma-free patients

with a median follow-up of 5.1 years, a greater propor-

tion of irradiated than nonirradiated patients reported

faecal incontinence (62% vs 38%) and pad wearing

owing to faecal incontinence (56% vs 33%) in self

assessment questionnaires. Satisfaction with bowel func-



tion was lower, and the impact of bowel function on daily

activities was greater for irradiated patients. There were

no differences in stoma function or urinary problems

although 57% of patients wore pads because of urinary

incontinence [48]. SCPRT had a negative effect on sexual

function in men and women although no differences

were seen in quality of life (QOL) between irradiated and

nonirradiated patients [49]. The presence of a stoma did

not significantly affect health-related QOL, which echoes

the findings of a previous systematic review [50].

In the Polish study, there were no differences in the

rate of all postoperative complications (23% vs 15%) or

severe complications (deaths or complications requiring

surgical intervention) (12% vs 9%) for the SCPRT and

CRT groups, respectively [41].

In a self-reporting questionnaire in the Polish study,

approximately two-thirds of 58 patients treated with

SCPRT and of 60 patients treated with CRT assessed at a

year from surgery, complained of incontinence of loose

stool and gas, were unable to differentiate stool from gas

and had urgency of defaecation [51] with two-thirds

stating that their symptoms caused a worsening in quality

of life. Approximately three quarters of the men and half

of the women said that the treatment had caused their sex

life to decline although this was not statistically signifi-

cant.

In the German Rectal Cancer Trial, significantly fewer

pre- than postoperative CRT patients who received

treatment experienced grade 3 and grade 4 long-term

side effects (14% vs 24%), including gastrointestinal side

effects (chronic diarrhoea and small bowel obstruction)

and anastomotic strictures [34].

The incidence of late side effects within the EORTC

22921 trial did not differ between the four arms.

Amongst 522 patients who received sphincter-sparing

surgery, 9% reported some form of faecal incontinence,

5.9% developed an anastomotic stricture and 1.4%

required surgery for small bowel complications [30].

The rates of faecal incontinence appeared to be lower in

the EORTC 22921 trial than those in the SCPRT trials.

However, differing methodology was used with anorectal

function being self-reported in the Polish, Dutch and

Swedish trials but scored by attending physicians in

EORTC 22921.

In view of potential long-term morbidity associated

with 5 · 5 Gy SCPRT, the risk ⁄ benefit balance may

favour not giving SCPRT to tumours with a low risk of

LR [23]. Several studies have reported attempts to

hyperfractionate RT to decrease the late normal tissue

complication probability (NTCP) without sacrificing the

predicted tumour control probability (TCP) [52,53].

However, at the current time such modifications have not

been proven in randomized studies.

Radiotherapy in locally advancedunresectable rectal cancer

Approximately 20–30% of patients present with MRI-

defined unresectable rectal cancer, and by definition

some form of downstaging is necessary to increase the

chance of a clear resection margin. Extrapolating data

from the EORTC 22921 and FFCD 9203 trials in

resectable cancer, it would appear that CRT may confer

an advantage compared with RT alone, in terms of

tumour response and downstaging. Previously reported

data comparing RT with CRT for unresectable rectal

cancer, however, are virtually all in the pre-MRI staging

era and suffer from heterogeneity of casemix, staging and

treatment [54,55]. A randomized trial in 70 patients

with fixed, inoperable carcinoma of the rectum recruited

between 1988–2001 [56], demonstrated an advantage

for an unusual CRT regimen of hyperfractionated, split

course RT to a total dose of 40 Gy combined with 5-FU,

methotrexate and folinic acid. Five-year local recurrence-

free survival was 38% vs 66% (P = 0.03) in favour of CRT

with a nonsignificant 5- year survival difference (18% vs

29%).

More recently, a single UK cancer network audit of

150 patients with locally advanced rectal cancer was

reported [5]. Sixty-one per cent of cancers were T4, and

one-third was staged by MRI. Concurrent bolus 5-FU

was administered in weeks 1 and 5 of RT as in the

EORTC 22921 and FFCD 9203 trials. On an intention-

to-treat analysis, an R0 resection was achieved in only

65% of patients, and the pCR rate was 12%. The

prognostic significance of an involved CRM after CRT

was confirmed with 3- year rates of LR of 10% vs 62%, 3-

year DFS of 52% vs 9% and 3- year OS of 64 vs 25% for

R0 vs R1 or R2 resections, respectively. Similarly, a

pooled analysis of 680 patients from seven UK centres

with locally advanced tumours receiving downstaging

CRT using concurrent single agent fluoropyrimidine,

demonstrated an R0 resection rate of only 63% on ITT

analysis and a pCR rate ranging between 2 and 12% [57].

These audits of current clinical practice illustrate the need

for improvement in the treatment of this category of

rectal cancer.

Pathological complete response andcircumferential resection margin status assurrogate markers of the effectiveness ofchemoradiation

Local control, DFS and OS are the end points with

which to compare differing CRT phase III trials.

Intuitively, it might be thought that pCR is also useful

in this respect. A greater chance of achieving a pCR is



associated with the initial T stage, the size of the tumour

and the interval between completion of RT and surgery

[58]. A multivariate analysis of phase II and phase III

rectal neoadjuvant CRT trials comprising 4732 patients

using a fluoropyrimidine with or without a second drug

suggested that significant factors associated with an

increased pCR rate included the use of two drugs rather

than one, the method of fluoropyrimidine administra-

tion (CVI being the most effective) and a dose of RT of

least 45 Gy [59]. At present, however, there are no

long-term survival end points reported for phase III

CRT trials examining the use of a fluoropyrimidine with

or without a second drug. The median number of

patients per CRT arm in the previous analysis was only

37 [59].

In the preoperative CRT arm of the German

CAO ⁄ ARO ⁄ AIO-94 trial, the degree of primary tumour

regression correlated with DFS on univariate but not on

multivariate analysis [60]. A retrospective audit of 566

ypCR patients from 61 centres demonstrated a good

prognosis with 5- year DFS and OS rates of 85% and 90%

and LR and DM rates of 1.6% and 8.9% [61]. At present,

however, pCR has not been prospectively validated as a

reliable surrogate endpoint for DFS and OS [62].

Comparisons between studies are hampered by hetero-

geneity in staging methodology (for example most

reported studies have not required MRI to be obliga-

tory), case mix (differing stage, primary vs recurrent),

drug administration, RT (volume, time, dose, fraction-

ation) and quality assurance, together with the lack of a

recognized standard pathological technique to judge

pCR.

The involvement of the CRM has been demonstrated

prospectively to predict an increased LR rate [9,27],

decreased DFS [9] and decreased OS [27]. Retrospective

analysis has suggested that following CRT, CRM posi-

tivity is also a strong prognostic factor for LR, DFS and

OS [5,63,64]. Mirroring this, it has been shown that

amongst patients with pT3 disease, rates of LR (10% vs

26%) and cancer-specific survival (85% vs 54%) are worse

when the depth of extra-mural extension of tumour

beyond the muscularis into the mesorectum exceeds

5 mm (pT3b) [65].

In the United Kingdom, histopathological examina-

tion of surgically resected specimens (including India

inking of the CRM) is carried out according to guidelines

issued by the Royal College of Pathologists [66].

However, there is no internationally recognized standard

for histopathological assessment and prospective valida-

tion of CRM involvement as a surrogate for DFS and OS

following CRT has not been performed. To make valid

inter-trial comparisons, there is a need to publish CRM

negativity rates including a denominator which includes

all patients who initially commenced CRT, whether they

eventually proved operable or not.

Increasing the potency of chemoradiationregimes: potential radiation sensitizers

For many years, 5-FU was the only radiation sensitizer

commonly combined with RT. More recently, a variety

of chemotherapeutic and biological targeted agents

have been licensed for use in colorectal cancer in the

adjuvant or advanced contexts. These included oral

fluoropyrimidines, irinotecan, oxaliplatin, cetuximab and

bevacizumab. Each of these agents has demonstrated

potential as a radiation sensitizer in vitro and been used

in early phase rectal CRT trials.

Oral single agent fluoropyrimidines

Capecitabine is an orally administered 5-FU prodrug

whose final enzymatic conversion is mediated via thymi-

dine phosphorylase. This enzyme often occurs in a higher

concentration in cancer tissue compared with adjacent

normal tissue, and there is thus a potential advantage in

improving cancer cell kill compared to normal tissue (the

therapeutic ratio) using capecitabine as a radiation

sensitizer compared with intravenous 5-FU. This enzyme

is up-regulated by RT [67]. There are also potential

advantages in terms of patient convenience. At least 12

early phase studies have been reported in locally advanced

rectal cancer using CRT regimes containing single agent

capecitabine used in a variety of doses, timing and RT

schedules (reviewed in [68]). Response rates of 58–97%

and pCR rates of 4–31% have been reported. A dose of

capecitabine at 825 mg ⁄ m2 taken twice daily throughout

a 5 to 6- week course of RT has been recommended

[68].

No randomized phase III comparison of capecitabine

with 5FU has been reported in rectal CRT although a

retrospective analysis in 278 patients suggested that there

appeared to be no difference in pCR rate (11.3% vs

16.1%) for bolus 5FU compared to capecitabine [69].

A randomized trial in 155 patients, of whom more

than 90% had T3 cancer, demonstrated that oral uracil

and tegafur (UFT) plus leucovorin used as a radiation

sensitizer produced an equivalent pCR rate of 13.2% and

resectability rate of approximately 92% when compared to

bolus 5FU [70].

Irinotecan ⁄ fluoropyrimidine doublets

Irinotecan is a topoisomerase-I inhibitor licensed for the

treatment of advanced colorectal cancer. There is evi-

dence that topoisomerase-1 inhibitors have radiosensitiz-



ing properties [71,72], possibly involving cell cycle-

specific inhibition of DNA repair or of repair of poten-

tially lethal radiation damage [73,74].

Several early-phase studies have examined the use of

a fluoropyrimidine and irinotecan concurrently with RT

in the downstaging of locally advanced rectal cancer

[75–86] (Table 1). The main serious toxicity is diar-

rhoea, with lesser degrees of stomatitis, fatigue and

neutropenic sepsis. These studies suggest that irinotecan

may confer an additional benefit to a single agent

fluoropyrimidine as a radiation sensitizer in this context

with R0 resection rates of approximately 80% by an

intention-to-treat analysis and pCR rates of 15–25%

(Table 1).

A randomized phase II trial [79] in 106 T3-4 distal

rectal cancer patients (MRI staging optional) compared

radiosensitization using CVI 5FU 225 mg ⁄ m2 per day

on 7 days per week with CVI 5FU 225 mg ⁄ m2 on 5 days

per week plus irinotecan 50 mg ⁄ m2 once weekly for

4 weeks. Hyperfractionated RT was used for the single

agent 5FU arm and conventional one fraction per day RT

for the dual chemotherapy arm. A high pCR rate of 28%

was recorded in each arm.

Oxaliplatin ⁄ fluoropyrimidine doublets

Oxaliplatin is a third-generation platinum analogue

licensed for the treatment of advanced colorectal cancer

and for the adjuvant treatment of Dukes C colonic

cancer. It causes intrastrand and interstrand DNA cross-

link formation, and there is evidence in vitro [87] and

in vivo [88] that it can act as a radiation sensitizer.

Several phase I ⁄ II trials have examined oxaliplatin plus

a fluoropyrimidine as radiation sensitizers in rectal cancer

CRT [89–101] (Table 2). Response rates in terms of

pCR appear to be increased compared with historical

reports using a single agent fluoropyrimidine. A variety of

regimes have been used including weekly or three-weekly

oxaliplatin. Diarrhoea is the main serious toxicity. Two

phase II studies have stipulated a postoperative adjuvant

phase with six [97] and four [98] three weekly cycles of

oxaliplatin plus capecitabine. However, this proved dif-

ficult to administer, with only 60% of patients in one

study [98] receiving all four cycles and 35% of patients

within the CORE study receiving no chemotherapy at

all [97]. A report in a small number of patients

demonstrated the possible feasibility of administering

adjuvant protocol-stipulated oxaliplatin plus 5FU che-

motherapy post-CRT using these two drugs as radiation

sensitizers [102].

Preliminary toxicity and histology results of two phase

III trials in operable rectal cancer examining neoadjuvant

CRT using oxaliplatin ⁄ fluoropyrimidine doublets were

reported at ASCO 2009. The 747 patient Italian STAR

trial compared CRT using infusional 5FU ± oxaliplatin

[103]. The 598 patient French ACCORD12 ⁄ 0405

PRODIGE-2 trial compared CRT using capecitabine ±

oxaliplatin, increasing the RT dose from 45 Gy to 50 Gy

in the experimental arm [104]. No statistically significant

increase in the pCR rate with oxaliplatin was found in

either trial although the rate of DM found at surgery was

significantly less in the STAR-1 study. Survival endpoints

are awaited.

One report that attempted to use the triplet of

capecitabine, irinotecan and oxaliplatin in a concurrent

CRT regime found this prohibitively toxic [105].

Biological targeted agents

Anti-epidermal growth factor receptor agentsEpidermal growth factor (EGFR) is a commonly

expressed transmembrane glycoprotein of the tyrosine

kinase growth factor receptor family. It is over expressed

in approximately four-fifths of colorectal cancers [106].

Cetuximab is an antibody of the IgG1 subclass with

binding affinity to EGFR greater than the natural ligand

EGF [107]. Cetuximab blocks binding of EGF and TGFato EGFR and inhibits ligand-induced activation. It is

licensed for use in combination with irinotecan in patients

with advanced colorectal cancer after irinotecan failure,

based on the BOND study [106].

Preclinical data suggest that EGFR inhibition influ-

ences radio responsiveness [108–111]. A large random-

ized trial in 424 patients with locoregionally advanced

head and neck cancer compared RT alone vs RT plus

concurrent cetuximab [126]. ‘Proof of principle’ was

established with a marked increase in the mean duration

of locoregional control (24.4 vs 14.9 months) and

median OS (49 vs 29 months) in favour of those

receiving cetuximab [126].

In rectal cancer a number of small Phase I or II studies

investigating the combination of cetuximab and capecit-

abine with RT with or without another chemotherapy

agent have recently been reported [113–118] (Table 3).

These have shown pCR rates in the range of 5–25%. No

randomized studies have as yet been reported.

The intracellular EGFR signalling pathway involves

several molecules including KRAS. In the context of

metastatic colorectal cancer, recent studies have indi-

cated that response to anti-EGFR monoclonal antibody

combined with chemotherapy is increased in tumours

that are of the KRAS wild-type genotype [119,120].

Possibly mirroring this is a study of 40 patients with

rectal cancer receiving 5FU, and cetuximab-containing

CRT has suggested that greater tumour regression

occurred in KRAS wild type than mutant tumours and



Tab

le1

Ph

ase

I⁄I

Ist

udie

sof

neo

adju

vant

rect

alca

nce

rC

RT

usi

ng

afluoro

pyr

imid

ine

plu

sir

inote

can.

Au

thor

Phas

e

No

.of

pat

ients

Clinic

alst

age

Rad

ioth

erap

y

reco

mm

end

ed

do

se(G

y)

Flu

oro

pyr

imid

ine

reco

mm

end

edd

ose

Irin

ote

can

reco

mm

end

ed

dose

Gra

de

3⁄4

dia

rrh

oea

at

reco

mm

end

ed

do

se

pC

R

rate

R0

rese

ctio

nra

te

Mit

chel

let

al.

20

01

[75

]

I49

Pri

mar

yo

rre

curr

ent

T3

⁄T4

45

–54

CV

I5

FU

22

5m

g⁄m

2,

5d

ays

aw

eek

50

mg

⁄m2

wee

kly

·4

(wee

ks1

,2,3

,4)

0⁄7

24

%N

R

Meh

taet

al.

20

03

[76

]

II32

T2

⁄T3

1⁄3

1

50

.4C

VI

5F

U22

5m

g⁄m

2

dai

lyth

rou

gho

ut

RT

50

mg

⁄m2

wee

kly

·4

(wee

ks1

,2,3

,4)

Gr

3in

28

%

No

Gr

4to

xici

ty

37

%3

2⁄3

2(1

00

%)

Kla

utk

eet

al.

20

05

[77

]

II37

T2

⁄T3

⁄T4

2⁄1

9⁄1

6

50

.4C

Vl

5F

U25

0m

g⁄m

2

dai

lyth

rou

gho

ut

RT

40

mg

⁄m2

wee

kly

·6

Gr

3in

27

%

Gr

4in

5%

22

%3

2⁄3

6re

sect

ed

(89

%)

Nav

arro

eta

l.

20

06

[78

]

II74

Res

ecta

ble

T3

⁄T4

64

⁄10

45

CV

I5

FU

22

5m

g⁄m

2,

5d

ays

aw

eek

50

mg

⁄m2

wee

kly

·5

Gr

3in

14

%1

4%

Mo

hiu

dd

in

eta

l.2

00

6

[79

]

II53

T3

⁄T4

40

⁄13

0–9

cmfr

om

anal

verg

e

50

.4(T

3)

54

(T4

)

CV

I5

FU

22

5m

g⁄m

2

dai

lyth

rou

gho

ut

RT

50

mg

⁄m2

wee

kly

·4

(wee

ks1

,2,3

,4)

Gr

3in

35

%

Gr

4in

2%

28

%N

R

Gly

nne-

Jon

es

eta

l.2

00

7

[80

]

I57

DR

Efixi

ty(2

3);

CR

Min

volv

emen

t

on

MR

I(3

3)

45

5F

U3

50

mg

⁄m2

ove

rI

ho

ur

+L

V

20

mg

⁄m2

day

s1

–5

and

29

–33

18

mg

⁄m2

day

s

1–5

and

29–3

3

Gr

3in

12

%2

5%

39

⁄49

rese

cted

(80

%

39

⁄57

ove

rall

(68

%)

Iles

eta

l.

20

08

[81

]

II31

No

nre

sect

able

T3

⁄T4

21

⁄10

45

CV

l5

FU

20

0m

g⁄m

2

dai

lyo

ver

5w

eeks

60

mg

⁄m2

wee

kly

·4

(wee

ks1

,2,3

,4)

Gr

3in

13

%1

9%

22

⁄28

rese

cted

(79

%)

22

⁄31

ove

rall

(71

%)

Ho

fhei

nz

eta

l.2

00

5

[82

]

I19

T3

⁄T4

18

⁄150.4

Cap

ecit

abin

e

50

0m

g⁄m

2b

dd

ays

1–3

8

50m

g⁄m

2

wee

kly

·5

nil

21

%1

00

%

Kla

utk

eet

al.

20

06

[83

]

I⁄I

I28

T2

⁄T3

⁄T4

2⁄1

8⁄8

55.8

Cap

ecit

abin

e

75

0m

g⁄m

2b

dd

ays

1–4

3

40

mg

⁄m2

wee

kly

·6

Gr

3in

38

%1

5%

24

⁄25

rese

cted

(96

%)

Wille

keet

al.

20

07

[84

]

II36

T2

⁄T3

⁄T4

4⁄2

6⁄5

50.4

Cap

ecit

abin

e

50

0m

g⁄m

2b

dd

ays

1–3

8

50m

g⁄m

2

wee

kly

·5

Gr

31

1%

15

%3

4⁄3

4re

sect

ed

(10

0%

)



in tumours with a higher EGFR nuclear gene copy

number [121]. In contrast, a recent study in 38 patients

did not detect a relationship between histological

response and KRAS status [122]. In the latter study, it

was proposed that an antiproliferative effect of cetuximab

was responsible for a reduced capecitabine uptake and

consequent low rate of pCR [122]. Further work on

molecular profiling and biomarkers is required in this

area in larger numbers of patients and including longer-

term survival outcomes.

A phase I ⁄ II trial has been reported using the EGFR

tyrosine kinase inhibitor gefitinib in combination with

CVI 5FU and RT in patients with locally advanced rectal

cancer [123] with 10 of 41 patients (24%) achieving a

pCR.

BevacizumabBevacizumab is an anti-angiogenic humanized mono-

clonal antibody directed against vascular endothelial

growth factor (VEGF). It improves survival in the

context of metastatic colorectal cancer, when used with

5FU-based therapy [124,125]. Laboratory studies have

shown that angiogenesis inhibitors can improve tumour

oxygenation and the response to RT [127]. A variety of

mechanisms might explain this including normaliza-

tion of tumour vasculature and reduction in interstitial

fluid pressure [128,129]. A rapid antivascular effect has

been reported in human rectal cancers treated with

bevacizumab, and the findings of correlative studies of

CRT with bevacizumab in rectal cancer are consistent

with a vascular normalizing effect on the tumour

[129,130].

Two small phase I trials have been reported, mainly in

patients with T3 rectal cancer: In the first, bevacizumab

was used in combination with CVI 5FU as radiation

sensitizers [129,164] with no pCRs noted at the recom-

mended dose (Table 3). In the second, Bevacizumab was

used in combination with capecitabine and oxaliplatin.

Diarrhoea was the main toxicity although a tolerable

regime was described with a pCR rate of 18%. These early

results are encouraging, but more work is required

particularly in view of evidence suggesting increased

morbidity associated with bevacizumab use including a

twofold increase in thromboembolic events associated

with the addition of bevacizumab to chemotherapy

compared with chemotherapy alone [131], an increased

risk of gastrointestinal perforation [124] and an increased

incidence of wound healing complications if surgery is

carried out close to the time of Bevacizumab treatment

[132]. In addition, an increased risk of rectal complica-

tions (mainly perforation) has been reported in patients

with a prior history of pelvic RT who subsequently

receive bevacizumab [133].Tab

le1

(Conti

nued

).

Au

tho

rP

has

e

No

.o

f

pat

ients

Clinic

alst

age

Rad

ioth

erap

y

reco

mm

end

ed

do

se(G

y)

Flu

oro

pyr

imid

ine

reco

mm

end

edd

ose

Irin

ote

can

reco

mm

ended

do

se

Gra

de

3⁄4

dia

rrh

oea

at

reco

mm

end

ed

do

se

pC

R

rate

R0

rese

ctio

nra

te

Kla

utk

eet

al.

20

07

[85

]

II2

0T

2⁄T

3⁄T

4

1⁄1

6⁄3

55.8

Cap

ecit

abin

e

75

0m

g⁄m

2b

dd

ays1

–

14

,2

2–3

5

60

mg

⁄m2

wee

kly

·4

(wee

ks

1,2

,4,5

)

15

%3

5%

19

⁄20

(95

%)

Go

llin

set

al.

20

09

[86

]

I4

6M

RI:

Mes

ore

ctal

fasc

iath

reat

ened

(£2

mm

)o

r

invo

lved

;

T3

⁄4<

5cm

fro

m

anal

verg

e

45

Cap

ecit

abin

e500,

650

or

82

5m

g⁄m

2b

d

day

s1

–35

50

,6

0o

r

70

mg

⁄m2

wee

kly

·4

(wee

ks1

,2,3

,4)

21

%gr

3

dia

rrh

oea

27%

36

⁄41

rese

cted

(88

%)

Day

1=

firs

td

ayo

fR

T.

Dpw

,day

sper

wee

k;N

R,

not

report

ed;

DR

E,

dig

ital

rect

alex

amin

atio

n;

CR

M,

circ

um

fere

nti

alre

sect

ion

mar

gin

;C

RT

,ch

emora

dia

tion;

RT

,ra

dio

ther

apy.



Tab

le2

Ph

ase

I⁄I

Ist

udie

sof

neo

adju

vant

rect

alca

nce

rC

RT

usi

ng

afluoro

pyr

imid

ine

plu

soxa

lipla

tin.

Auth

or

Ph

ase

No

.o

f

pat

ients

Clinic

alst

age

Rad

ioth

erap

y

reco

mm

end

ed

do

se(G

y)

Flu

oro

pyr

imid

ine

reco

mm

end

edd

ose

Oxa

lipla

tin

reco

mm

end

ed

do

se

Gra

de

3⁄4

dia

rrh

oea

at

reco

mm

end

ed

dose

PC

R

rate

(ypT

0)

R0

rese

ctio

nra

te

Alo

nso

eta

l.

20

04

[89

]

II5

3T

3⁄T

4

43

⁄10

50

.4C

VI

5F

U2

00

mg

⁄m2,

5d

ays

aw

eek

60

mg

⁄m2

wee

kly

·6

Gr

3in

7.5

%2

3%

NR

Asc

hel

eet

al.

20

05

[90

]

I⁄I

I4

6T

2⁄T

3⁄T

4

2⁄2

8⁄1

6

50

.4C

Vl

5F

U2

25

mg

⁄m2

dai

lyth

roughou

tR

T

60

mg

⁄m2

wee

kly

·6

Gr

3in

16

%2

8%

89

%(4

1⁄4

6)

Rya

net

al.

20

06

CA

LG

B8

99

01

[91

]

I⁄I

I4

4T

3⁄T

4⁄u

nkn

ow

n

31

⁄11

⁄25

0.4

CV

l5

FU

200

mg

⁄m2

dai

lyth

roughou

tR

T

60

mg

⁄m2

wee

kly

·6

Gr

3in

34

%

Gr

4in

3%

25

%30

⁄32

(94

%)

Ro

del

eta

l.20

03

[92

]

I⁄I

I3

2T

2⁄T

3⁄T

4

4⁄1

5⁄1

3

50.4

Cap

ecit

abin

e825

mg

⁄m2

bd

day

s1

–14

and

22

–35

50

mg

⁄m2

day

s

1,8

,22

,29

Gr

3in

8%

19

%29

⁄31

(94

%)

Tucc

iet

al.

20

04

[93

]

II1

6T

3⁄T

4

13

⁄354

Cap

ecit

abin

e825

mg

⁄m2

bd

day

s1–4

0

60

mg

⁄m2

two

-

wee

kly

·3

Gr

3in

19

%

No

Gr

4to

xici

ty

29

%14

⁄14

(10

0%

)

Alo

nso

eta

l.

20

07

[94

]

II6

7T

2⁄T

3⁄T

4

3⁄5

8⁄6

50.4

Cap

ecit

abin

e825

mg

⁄m2

bd

5d

ays

aw

eek

50

mg

⁄m2

wee

kly

·6

Gr

3⁄4

in2

5%

19

%N

R

Mac

hie

lset

al.

20

05

[95

]

II4

0T

2⁄T

3⁄T

4

1⁄3

5⁄3

45

Cap

ecit

abin

e825

mg

⁄m2

bd

5d

ays

aw

eek

50

mg

⁄m2

wee

kly

·5

Gr

3⁄4

:3

0%

14

%30

⁄36

(83

%)

Gly

nne-

Jon

es

eta

l.2

00

5[9

6]

(SO

CR

AT

ES)

I⁄I

I94

Unre

sect

able

rect

al

cance

r

45

Cap

ecit

abin

e650

mg

⁄m2

bd

day

s1–3

5

13

0m

g⁄m

2d

ays

1an

d2

9

Gr

3⁄4

in1

0%

18

%70

⁄80

rese

cted

(87

%)

*R

utt

enet

al.

20

06

[97

]

(CO

RE

)

II8

7M

RI:

Mes

ore

ctal

fasc

iath

reat

ened

(£2

mm

)o

r

invo

lved

;

T3

⁄4<

5cm

fro

m

anal

verg

e

45

Cap

ecit

abin

e825

mg

⁄m2

bd

5d

ays

aw

eek

50

mg

⁄m2

wee

kly

·5

Gr

3in

12

%

Gr

4in

4%

13

%57

⁄85

(67

%)

�Rod

elet

al.

20

07

[98

]

II1

04

T2

⁄T3

⁄T4

3⁄8

6⁄1

5

50.4

Cap

ecit

abin

e825

mg

⁄m2

bd

day

s1

–14

and

22

–35

50

mg

⁄m2

day

s

1,8

,22

,29

Gr

3in

11

%

Gr

4in

1%

16

%98

⁄10

3(9

5%

)

Ari

stu

eta

l.20

08

[99

]

I⁄I

I2

0T

3⁄T

44

7.5

Gy

in

19

frac

tio

ns

IMR

T

Cap

ecit

abin

e825

mg

⁄m2

bd

5d

ays

aw

eek

60

mg

⁄m2

day

s

1,

8,

15

Gr

3in

10

%2

0%

17

⁄20

(85

%)



Neoadjuvant and adjuvant chemotherapy

Strategies involving SCPRT and CRT have reduced LR

but have not made an impact on the DM rate. In

addition, no OS advantage for such strategies has been

described except in the Swedish Rectal cancer Trial [22].

If the distant micrometastasis rate could be reduced, then

this might have an impact on survival, and there is thus a

rationale for treatment of patients with locally advanced

rectal cancer with neoadjuvant chemotherapy (NACT) or

adjuvant chemotherapy.

There is some evidence that adjuvant chemotherapy

may confer an advantage when added to perioperative

RT. Twenty years ago, the NSABP R01 trial established

that an adjuvant chemotherapy regime containing 5FU,

semustine and vincristine (‘MOF’) was associated with

improved survival when compared with surgery alone or

surgery plus postoperative radiation [134]. An Italian trial

randomized 583 patients with locally advanced rectal

cancer to preoperative CRT with or without 5FU-based

adjuvant chemotherapy [135]. Survival results are

awaited. Within the EORTC 22921 trial, postoperative

chemotherapy following preoperative RT appeared able

to reduce LR compared with preoperative RT alone.

However, overall, no additional benefit was conferred by

postoperative chemotherapy when added to preoperative

CRT [30]. Although the prognosis is poor for locally

advanced rectal cancer which remains histologically node

positive after CRT [136], there is currently no definitive

evidence that adjuvant chemotherapy confers any advan-

tage in addition to preoperative CRT.

Increasingly effective chemotherapy regimes with or

without biological therapy have now been developed in

the context of advanced colorectal cancer, and there is

increased interest in examining their use in rectal cancer.

In view of the difficulty administering adjuvant chemo-

therapy after CRT and surgery, investigators are now

beginning to use such chemotherapy regimes in a

neoadjuvant fashion before CRT. The EXPERT trial

investigated patients with MRI-defined poor risk rectal

cancer, Patients received 12 weeks of NACT using

oxaliplatin plus capecitabine, then CRT to 54 Gy over

6 weeks with concurrent capecitabine, followed by adju-

vant single agent capecitabine for a further 12 weeks

[137].

Of the initial 77 patients, 67 underwent TME with an

R0 resection achieved in all but one and a pCR in 16

patients (21% on an intent-to-treat basis). However, of

concern was the fact that nine patients did not complete

their course of NACT, of whom four (5%) died and three

patients who received NACT did not receive CRT. The

causes of death were cardiac ⁄ thromboembolic in three

patients and neutropenic colitis in the other prompting a

Tab

le2

(Co

nti

nu

ed).

Au

tho

rP

has

e

No

.o

f

pat

ients

Clinic

alst

age

Rad

ioth

erap

y

reco

mm

ended

do

se(G

y)

Flu

oro

pyr

imid

ine

reco

mm

end

edd

ose

Oxa

lipla

tin

reco

mm

end

ed

do

se

Gra

de

3⁄4

dia

rrh

oea

at

reco

mm

ended

do

se

PC

R

rate

(ypT

0)

R0

rese

ctio

nra

te

�Ko

eber

le

eta

l.2

008

[10

0]

II6

0T

2⁄T

3⁄T

4

1⁄5

3⁄6

45

Cap

ecit

abin

e825

mg

⁄m2

bd

day

s1–1

4an

d2

2–3

5

50

mg

⁄m2

day

s

1,8

,22

,29

Gr

3in

20

%1

2%

7⁄5

8

57

⁄58

(98

%)

Fak

ihet

al.

2008[1

01]

II2

5T

2⁄T

3⁄T

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protocol amendment to exclude patients with a signifi-

cant cardiac history. Similarly, in another study in which a

single cycle of NACT using oxaliplatin ⁄ capecitabine was

delivered prior to CRT, one of 60 patients died from

neutropenic sepsis during the NACT phase [100].

These results are intriguing but on an intention-to-

treat basis do not appear to be superior to reports of CRT

regimes using lower doses of RT (45 Gy) concurrently

with a doublet of a fluoropyrimidine plus oxaliplatin or

irinotecan. They do raise concerns about toxicity con-

nected with an aggressive NACT approach, in potentially

jeopardizing the CRT element of treatment, either

through toxicity or the phenomenon of accelerated

repopulation [138].

A regime with lower apparent toxicity was reported by

Elsaid et al. [139]. Fifty-two patients with locally

advanced rectal cancer (12 T3 and 40 T4) were treated

with four, two-weekly cycles of NACT using oxaliplatin

and 5FU (FOLFOX4), then CRT to 54 Gy with

concurrent bolus 5FU, followed by two further cycles

of FOLFOX4. No grade 3 or grade 4 toxicity was

observed. The majority of patients experienced symp-

tomatic improvement during NACT, and all patients

underwent an R0 resection with a pCR in 12 patients

(23%).

In several tumour types being treated by radical

surgery other than rectal cancer, the addition of NACT

has been shown to confer a survival advantage and

has become a standard of care, for example gastric

cancer [140] and oesophageal cancer [141]. In

tumours being radically treated with CRT, however,

in most instances the evidence does not support the

use of NACT as either an adjunct or alternative to this

treatment [138,142,143]. However, a recent random-

ized trial has demonstrated that NACT using docetaxel,

cisplatinum and 5FU prior to CRT in patients with

advanced head and neck cancer conferred an OS

advantage compared with NACT using cisplatinum

and 5FU alone [144].

There remain many unanswered questions with

regard to the use of NACT prior to CRT in rectal

cancer including assessment of the relative contributions

to tumour cell kill and potential morbidity, the balance

between efficacy and toxicity and the relative merits of

NACT vs adjuvant chemotherapy. Will concurrent CRT

regimes of increased potency themselves eventually have

an impact on the rate of DM? This question will only

be answered through randomized controlled trials

which include stipulation of the NACT or adjuvant

chemotherapy that patients are to receive. Although the

use of adjuvant CT post-CRT and surgery might as yet

be unproven, it would now be very difficult to recruit

to a randomized trial where one arm stipulated specif-Tab

le3

(Conti

nued

).

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ically that patients were not to receive NACT or

adjuvant CT. Such difficulties were one reason behind

the premature closure of the CHRONICLE trial [145]

in the United Kingdom in 2008 because of poor

recruitment.

Can preoperative downstaging withchemoradiation allow more conservativesurgical treatment?

As the potency of CRT regimes increases, it is hoped that

in some patients more conservative surgery might be

possible including an increased chance of a sphincter-

sparing procedure. A systematic review of 10 randomized

trials [146] concluded that there is no beneficial effect for

preoperative RT or CRT on the rate of anterior resections

performed. In the Polish study, even in patients who had

an excellent clinical response, surgeons appeared to base

their operative decision on the pretreatment tumour

volume [41]. It was also observed, however, that distal

intramural spread may occur some distance from the

microscopic distal aspect of the primary tumour [147]. In

the German Rectal Cancer Trial, there did not appear to

be a difference in sphincter-sparing resection between the

pre and postoperative CRT arms (69% vs 71%, respec-

tively). However, subgroup analysis of 194 patients who

had been declared to need an APR prior to randomiza-

tion revealed that a greater proportion of pre- than

postoperative patients underwent a sphincter-sparing

resection (39% vs 19%) [34] although there was also a

higher incidence of low tumours in the postoperative

CRT group.

In future, prospective information gathered on

sphincter preservation rates and recurrence must be

presented together with corresponding data on sphincter

function and quality of life of patients undergoing such

ultra-low anastomoses.

Habr-Gama et al. [148] studied 265 patients with

resectable distal rectal cancer (not MRI staged). Patients

received 5FU-based CRT to 50.4 Gy and if they were

deemed to have had a complete clinical response at 8-

week post-CRT, they were then simply observed. All

other patients proceeded to surgery. Of the 71 patients in

the observation group, 70% were initially staged T3 and

10% T4 (overall 20% node positive) and 20% at T2N0. At

a median follow-up of 57 months, OS and DFS were

100% and 92%, respectively. The corresponding figures

for the resection group were 88% and 83%. Three of the

71 observational patients developed metastatic disease

and two endoluminal relapses, both of which were

successfully salvaged. The same group have recently

reported that a delay in surgery of more than 12 weeks

following CRT to evaluate tumour response does not

negatively influence survival, even in a subset of complete

clinical responses where the delay was almost a year

[149].

At present, however, this approach remains experi-

mental. Further such studies need to be carried out using

optimum staging modalities including MRI and en-

hanced CRT regimes with or without protocol-defined

NACT or adjuvant chemotherapy. The Royal Marsden

Hospital and Pelican Centre Foundation in the United

Kingdom have launched an ambitious pilot study in

patients with locally advanced rectal cancer. Patients will

be treated with an EXPERT-type regimen, and if they

have a complete clinical and radiological response, will

avoid surgery and enter an intensive follow-up pro-

gramme [150].

It would be a major asset to be able to predict

accurately those patients who have attained a pCR

following CRT although at the present time this ‘Holy

Grail’ has not been attained.

DRE has a low positive predictive value and sensitivity

in being able to identify patients with a pCR post-CRT.

Of patients identified as having an incomplete response

by DRE in the study by Habr-Gama et al. [148], 7%

proved to have had a pCR. In a study of 94 patients with

locally advanced rectal cancer, DRE was able to identify

only 3 of 14 patients who had achieved a pCR post-CRT

[151].

Because of difficulty in distinguishing residual scar

tissue from active tumour and an inability to identify

accurately small mesorectal deposits of viable tumour,

MRI scanning post-CRT is an unreliable method of

assessing response and resectability after CRT [64]. It is

possible that in the future, additional modalities such as

the use of diffusion MRI [152] and novel contrast

agents such as iron oxide [153] and USPIO [154]

may be of additional benefit. The magnitude of decrease

in SUV on PET scanning has been shown to correlate

with the degree of pathological response and downstag-

ing following CRT [155,156], but at present the use of

PET to predict response to CRT is experimental.

Predictive molecular markers have been investi-

gated including direct sequencing of p53, which has

revealed gene mutations which are significantly associated

with radioresistance and worse prognosis [157]. p21

protein expression is immunohistochemically associated

with responsiveness to RT and survival [158], and a high

spontaneous apoptosis index can predict increased radia-

tion-induced apoptosis [159]. Gene expression profiling

of tumours using microarray technology prior to treat-

ment has identified a 33-gene set [160] and a 54-gene set

[161] whose expression allows prediction of tumour

response to preoperative RT with a high degree of

accuracy. Low immunohistochemical levels of EGFR



expression were reported as predictive for increased rectal

cancer downstaging with CRT [162].

In the future, it is hoped that optimum combinations

of clinical, radiological and molecular techniques might

be able to identify patients with a high likelihood of

having achieved a pCR to preoperative CRT so that a

more conservative approach to their surgical management

might be adopted. At the present time, however, such

predictive models are not sufficiently reliable to be useful

in routine clinical practice.

Ongoing and future trials in locallyadvanced rectal cancer

Considerations with regard to the design of trials in

locally advanced rectal cancer

It is reasonable to make a distinction between ‘locally

advanced resectable’ cancer, which does not threaten the

mesorectal resection margin and ‘locally advanced unre-

sectable’ cancer which does and thus needs downstaging

prior to attempted surgery. The former category is

predominantly included in the German Rectal Cancer

Study [34], FFCD 9203 [31] and EORTC 22921 trials

[30]. At present, MRI scanning appears to be the

imaging modality best placed to make this distinction.

In patients with locally advanced unresectable cancer,

the risk of pelvic LR is of great importance in addition to

distant metastatic disease. It may be the case that

increasing the potency of CRT with the use of dual or

even triplet CRT regimes might impact on the endpoints

of DFS and OS although long-term morbidity must also

be recorded.

The integration of NACT or adjuvant chemotherapy

has the potential to reduce the rate of DM. It would

appear easier to give this in a neoadjuvant rather than

adjuvant setting, but this has to be balanced against

worries over potential compromise of the CRT compo-

nent of treatment through toxicity and for radiobiolog-

ical reasons. Translational elements are essential in future

studies if predictive models are to be developed which

may allow more conservative surgery.

Current trials

Locally advanced resectable rectal cancerThe Trans Tasman Oncology Group completed the

TROG 01-04 study in 2006 comparing SCPRT

(5 · 5 Gy) to CRT (50.5 Gy with CVI 5FU) in 326

patients with resectable T3 tumours. The results are

awaited. It has been suggested that increasing the gap

between RT and surgery from 2 to 6–8 weeks can increase

tumour downstaging [163]. The ongoing Stokholm III

trial [23] is comparing SCPRT followed by immediate

surgery, with SCPRT followed by delayed surgery and

conventionally fractionated RT of 50 Gy then delayed

surgery, examining a potential downstaging effect of

SCPRT if followed by a gap before surgery. The ongoing

NSABP R04 trial includes operable patients with T3-4 ⁄ N0

or T1-4 ⁄ N1-2 rectal cancer undergoing preoperative

CRT. In a 2 · 2 factorial fashion, patients receive CVI

5FU vs oral capecitabine concurrent with RT, with or

without oxaliplatin. Postoperatively, patients are strongly

encouraged to receive adjuvant chemotherapy.

The randomized EORTC PETTAC 6 trial in 1090

patients with T3-4 ⁄ N0 or T1-4 ⁄ N1-2 resectable rectal

cancer compares preoperative CRT using concurrent

capecitabine followed by capecitabine adjuvant CT, with

or without oxaliplatin.

Locally advanced unresectable rectal cancerThe completed 160-patient UK randomized phase II

EXPERT-C trial [165] has similar MRI-defined entry

criteria to the EXPERT study [137]. EXPERT-C strad-

dles the categories of locally advanced resectable and

unresectable cancer as defined previously. Patients were

randomized between treatment as in EXPERT, with or

without the addition of cetuximab. Within EXPERT-C,

the dose of RT in both arms was reduced to 50.4 Gy and

the dose of capecitabine reduced to 850 mg ⁄ m2 in view

of the toxic deaths encountered during the NACT

element of EXPERT [137].

The current UK phase II XERXES trial examines

MRI-defined rectal cancer that threatens the mesorectal

fascia. This randomized phase II trial compares CRT

using concurrent capecitabine with or without 4 weekly

cycles of cetuximab pre-CRT and 5 weekly cycles of

cetuximab post-CRT.

The ongoing phase II EXCITE trial opened in April

2009 and includes patients with MRI-defined rectal

cancer that threatens or involves the mesorectal fascia or

is < 5cm from the anal verge. Patients receive an initial

loading dose of 400 mg ⁄ m2 cetuximab followed a week

later by CRT using RT to 45 Gy in 5 weeks concur-

rently with a triplet of capecitabine, irinotecan and

cetuximab. Efficacy and late toxicity will be assessed plus

KRAS ⁄ BRAF status of tumours, although the latter

results will not be revealed until all patients have

completed surgery.

The 920-patient UK phase III randomized ARIS-

TOTLE trial aims to recruit patients based on similar

MRI-defined criteria as the EXCITE trial. Patients receive

preoperative downstaging RT with concurrent capecita-

bine with or without irinotecan. Adjuvant chemotherapy

can be given according to declared clinician preference.

ARISTOTLE will open in 2010.



One of the questions being examined in ARISTOTLE

is whether short-term outcomes including R0 resection

rate and tumour regression grade can be used as surrogate

endpoints for DFS, and there will be a translational

component examining predictors of response and toxic-

ity.

Conclusions

1 A distinction needs to be made between tumours which

can be excised with clear histological margins (> 1 mm)

and those which cannot (£ 1 mm) and therefore need an

attempt at preoperative downstaging. MRI scanning is

the staging investigation best suited to defining CRM

involvement and to deciding treatment approach and

should be used in routine clinical practice and as a

mandatory clinical trial entry criterion.

2 In future clinical trials there is a need for continuing

the current process of streamlining histological metho-

dology and reporting, including the definition of

pathological complete response (ypCR) and ‘near’

ypCR.

3 In future clinical trials there is a need for increased

quality assurance of RT including planning and delivery.

4 The short-term endpoint of ypCR is commonly

reported when adding concurrent chemotherapeutic or

biological agents to form doublet or triplet CRT regimes,

as a surrogate for long-term survival outcomes. However,

there is no consistent prospective randomised data to

validate this assumption which should be a prominent

aim of future phase III trials.

5 The benefit or not of neoadjuvant or adjuvant

chemotherapy as an adjunct to SCPRT or long-course

CRT needs to be investigated in future randomised trials,

especially with regard to reducing the rate of distant

metastatic relapse.

6 There is a need for increased understanding and

prospective quantification of late radiation morbidity

following both SCPRT and long-course CRT which

should be included as an end point in all future

randomised trials. This is relevant to risk-benefit assess-

ment in the treatment of early rectal cancer and also when

considering a recent tendency for more aggressive

cylindrical excisions in lower rectal cancer.

7 It is possible that following CRT, especially with

increased potency, some cancers can be managed

conservatively without excision of the rectum. How-

ever, the data thus far is based largely on a single

institution experience and there is a need for further

studies which are ongoing. The development of

predictive markers of response to CRT complements

this approach.

Conflicts of interest

Dr Gollins has received research grants from Aventis

Pharma Limited and Roche Products Limited.

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