RESEARCH ARTICLE

Multicenter phase II clinical trial of preoperative capecitabinewith concurrent radiotherapy in patients with locally advancedrectal cancer

Manuel de las Heras • Fernando Arias • Rosario del Moral-Avila •

Jaime Gomez-Millan • Encarnacion Jimenez • Amadeo Wals •

Jose Luis Tisaire • Ma Pino Alcantara

Received: 5 December 2011 / Accepted: 4 July 2012 / Published online: 2 August 2012

� Federacion de Sociedades Espanolas de Oncologıa (FESEO) 2012

Abstract

Introduction To assess pathologic complete response,

sphincter preservation rates and toxicity profile of preop-

erative chemoradiation with capecitabine in resectable

locally advanced rectal cancer.

Materials and methods Fifty-eight patients from six

Spanish centers were included (March 2004 to June 2005) with

histological/cytological diagnosis of locally advanced rectal

cancer, age between 18 and 80 years, ECOG 0–2, adequate

bone marrow, renal and hepatic functions. Prior chemother-

apy/radiotherapy was not allowed. Preoperative treatment was

capecitabine 825 mg/m2 bid concomitant to radiotherapy

(45 ? 5.4 Gy boost over 5.5 weeks). Surgery was performed

4–8 weeks after completion of chemoradiotherapy.

Results Fifty-eight patients were enrolled in this study:

60.3 % males, median age of 64.5 (30.9–78.7) years, 28.6 %

with ECOG 0 and 71.4 % with ECOG 1. Median distance of

tumor from the anal verge was 7 (1–12) cm. Fifty-two

(89.6. %) patients completed preoperative chemoradiother-

apy. Primary tumor and node downstaging occurred in 61.1

and 69.6 % of patients, respectively. Surgery was performed

in 55 patients (94.8 %): 80 % had negative lymph nodes and

72.7 % underwent sphincter-preserving procedures. A path-

ologic complete response was observed in 10.5 % (95 % CI

2.5–18.5) of the patients. Main grade I–II toxicities were

leucopenia (43.1 %), neutropenia (24.1 %), anemia (36.2 %),

diarrhea (32.8 %) and skin disorders (5.1 %), from which

diarrhea (6.9 %), leucopenia (1.7 %) and skin disorders

(1.7 %) reached grade III. There were no grade IV toxicities.

Conclusions Preoperative capecitabine-based chemora-

diation is a well-tolerated and effective neoadjuvant treat-

ment for locally advanced rectal cancer that achieves

encouraging rates of tumor downstaging.

Keywords Rectal cancer � Capecitabine �Chemoradiotherapy � Radiation � Neoadjuvant treatment

Introduction

Rectal cancer treatment has undergone a substantial evo-

lution throughout the past two decades. The most frequent

M. de las Heras (&)

Head of the Department Radiation Oncology, Hospital Clınico

Universitario San Carlos, c/Profesor Martın Lagos, S/N,

28040 Madrid, Spain

e-mail: mherasg.hcsc@salud.madrid.org

F. Arias

Department Radiation Oncology, Hospital de Navarra,

Pamplona, Spain

R. del Moral-Avila

Head of the Department Radiation Oncology,

Hospital Virgen de las Nieves, Granada, Spain

J. Gomez-Millan

Radiation Oncology Department,

Hospital Virgen de la Victoria, Malaga, Spain

E. Jimenez

Head of Department Clinical Oncology,

Hospital de Jerez, Jerez, Spain

A. Wals

Radiation Oncology Department,

Hospital Carlos Haya, Malaga, Spain

J. L. Tisaire

Radiotherapy Service, Hospital de Alcazar,

Grupo Imo. Alcazar de San Juan, Ciudad Real, Spain

M. P. Alcantara

Radiation Oncology Department, Hospital Clınico San Carlos,

Madrid, Spain

123

Clin Transl Oncol (2013) 15:294–299

DOI 10.1007/s12094-012-0915-y

approach in the past was surgery alone. However, the high

rates of local failure and significant patient morbidity and

mortality led to find out more effective treatments.

The application of pre- or post-operative radiotherapy in

patients with resectable tumors has provided an improve-

ment in the local control of the disease and in the overall

outcome. Actually, clinical trials carried out since the middle

1980s and 1990s showed that the inclusion of adjuvant

chemoradiotherapy in the treatment schedule resulted in

lower rates of local failure and higher survival rates versus

surgery alone [1]. Preoperative chemoradiotherapy has been

considered the preferred treatment choice for locally

advanced rectal cancer (LARC) in many European countries

in contrast to USA and Germany due to the higher overall

compliance rate, the improvement in the local control rate,

the reduced toxicity, and the tumor downstaging. Although

no survival benefit has been achieved with preoperative

chemoradiotherapy in comparison with postoperative

administration, the previously mentioned beneficial effects

may result in better rates of curative surgery and sphincter

preservation in patients with low-lying tumors [2].

The currently available data support the concurrent use

of preoperative radiation and continuous infusion of

5-fluorouracil (5-FU) in patients with LARC. Preservation

of the anal sphincter without compromising oncological

outcome is an additional benefit of this neoadjuvant ther-

apy for patients with carcinoma in the distal rectum.

Moreover, although a survival advantage was not detected,

5-FU-based chemotherapy has shown to increase the

pathologic complete response rate and reduce local recur-

rence [3]. These effects may be related to 5-FU ability to

render human cells more sensitive to X-rays, which is

established soon after its synthesis and reaches its maxi-

mum efficacy against the squamous-transitional cancers.

However, as a result of the short half-life of 5-FU in plasma

and its intracellular metabolites, it should be administered

as prolonged intravenous infusions [4] during the course of

fractionated radiotherapy to act as a radio-sensitizer.

Capecitabine is an oral prodrug of 5-FU. Capecitabine is

transformed to 5-FU throughout several steps, the last one

being the conversion of 50-deoxy-5-fluorouridine to 5-FU

by thymidine phosphorylase (TP). Capecitabine was

designed to take advantage of the increased levels of TP

observed in tumors, which potentially allows tumor cell-

selective toxicity [5]. The similar capecitabine and 5-FU

pharmacokinetic profile makes feasible the oral adminis-

tration of capecitabine mimic continuous intravenous (i.v.)

infusion of 5-FU. Thus capecitabine has a similar or even

better efficacy and safety profiles than 5-FU, with efficacy

at wider dose ranges and with less intestinal toxicity that

permits chronic dosing [6]. Furthermore, capecitabine

treatment avoids complications derived from long-term

venous access such as risks of infection, bleeding, and

thrombosis, results in a more patient-friendly chemother-

apy because most of the patients prefer oral to i.v.

chemotherapy [7] and home-based rather than hospital/

clinic-based treatment [8].

Therefore, the advantages provided by oral treatment, the

potential downstaging, the sphincter preservation rate, and

the safety profile make the administration of capecitabine

and radiotherapy an attractive approach for rectal cancer

treatment [9]. The present phase II clinical trial was

designed to provide further information about the safety and

efficacy of preoperative capecitabine-based chemoradiation

in LARC patients. This study was designed as a phase II

trial before the results of large phase III clinical trials of

chemoradiotherapy with capecitabine became available.

Materials and methods

Eligibility criteria

Patients with histologically or cytologically confirmed

carcinoma of the rectum, candidates for rectal cancer sur-

gery and with a potential benefit from combined preoper-

ative chemoradiotherapy (i.e. stage cT3, cT4, node positive

tumors) were eligible for this study. Clinical staging during

the screening period was done by computed tomography

(CT) scan of the abdomen and pelvis, rectosigmoidoscopy,

and endosonography of the rectum. The patient age was

also required to be between 18 and 80 years, ECOG PS

between 0 and 2, life expectancy C3 months, and adequate

hematological, hepatic and renal function.

The main exclusion criteria were prior radiotherapy or

chemotherapy for rectal cancer or another malignancy

within the past 5 years; clinically significant cardiac dis-

ease within the past 12 months; gastric or small intestine

diseases or lack of physical integrity of the upper gastro-

intestinal tract or malabsorption syndrome.

Study design and treatment

The primary objective of this prospective, open-label, non-

controlled, multicenter phase II study was to determine

the pathologic complete response (pCR) to preoperative

capecitabine-based chemoradiation in patients with

resectable LARC. Secondary objectives were to evaluate

the overall clinical response, anal sphincter preservation

and safety profile.

Capecitabine dosage levels were selected on the basis of

the phase I trial carried out by Dunst et al. [10]. Capecit-

abine was daily administered at a dose of 825 mg/m2 po

bid (within 30 min after meals, every 12 h) for 38 days

from the first to the last day of radiotherapy (Fig. 1). The

first dose intake was 2 ± 0.5 h before radiotherapy.

Clin Transl Oncol (2013) 15:294–299 295

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Radiotherapy

Preoperative radiotherapy was delivered using preferably a

high-energy linear accelerator (16–20 MV). All patients

were treated in prone position with 45 Gy in 28 fractions

over 5 weeks and a boost of 5.4 Gy in 3 fractions.

Surgery and assessments

Surgery was scheduled from 4 to 8 weeks after the che-

moradiotherapy. Prior to the start of the treatment,

sphincter-preserving surgery was evaluated taking into

account the distance from the lower pole of the primary

tumor to the anal verge measured at baseline and after

chemoradiotherapy. Non-centralized pathologic evaluation

of the specimen was performed after surgery.

Safety evaluation

Patients were clinically evaluated on days 19 and 38 to

assess toxicity and compliance with the chemoradiation

schedule. Dose reductions for grade II to IV adverse events

(according to NCI-CTC version 2.0) were carried out for

capecitabine as previously described [6].

Efficacy evaluation

Clinical and pathologic responses were assessed according to

World Health Organization criteria and defined according to

the pTNM and TNM staging system. A pCR was considered

when no malignant cells were observed in the surgical spec-

imen. Evaluation of the response was performed by CT of the

abdomen and pelvis, rectosigmoidoscopy and endosonogra-

phy of the rectum. The effect of preoperative chemoradio-

therapy on tumor downstaging was assessed by comparing

both the pretreatment and postoperative TNM stages.

Statistical methods and analysis

The primary endpoint was pCR rate. Simon’s method was

used to calculate the sample size. Considering the optimal

two-stage design for a phase II study, with the difference

p1 – p0 = 15 % between ‘standard’ chemoradiation with

continuous infusion of 5-FU or 5-FU/leucovorin (p0 =

10 %) and ‘new therapy’ (p1 = 25 %), and fixing error

probabilities (a = 0.05 and b = 0.20), the number of

patients for the first step was 18. If two or less pCRs were

seen in these 18 patients, the study had to be terminated;

otherwise, the accrual had to be continued to a total of 43

patients. As there were more than two pCRs at the interim

analysis for the first step, the study proceeded to the second

step and an additional group of 25 patients were accrued.

After a total of 43 patients, the accrual continued assuming

that about 20 % or more patients were not evaluable. Data

analyses were performed on the intention-to-treat popula-

tion. Pathologically assessed complete remission rates with

95 % confidence intervals (CI) were reported. Statistical

analysis was performed using the Statistical Package for

Social Sciences, version 12.0 (SPSS Inc., Chicago, IL, USA).

Ethics

This study was conducted according to the Good Clinical

Practice Guidelines for Clinical Trials and the Declaration

of Helsinki. The study protocol was approved by the Ethics

Committee of each institution. Written informed consent

was obtained from all patients.

Results

Patients’ characteristics

Between March 2004 and June 2005, a total of 58 patients

with locally advanced rectal cancer were accrued onto the

study from six Spanish hospitals. The patient characteristics

at baseline are shown in Table 1. Median age was 64.5 years

(range 30.9–78.7) with ECOG 0 (28.6 %) or 1 (71.4 %). The

most frequent tumor was a moderately differentiated ade-

nocarcinoma (G2) (48.3 %), T3N0 (56.9 %) and located at a

median distance from anal verge of 7.0 (1.0–12.0) cm.

Preoperative chemoradiotherapy

Fifty-two patients (89.65 %) completed preoperative

capecitabine concomitant and radiotherapy treatment. Only

Fig. 1 Administration

schedule

296 Clin Transl Oncol (2013) 15:294–299

123

six patients had permanent interruption of chemoradio-

therapy (3 due to non-hematologic toxicities, 1 due to

hematologic and non-hematologic, 2 due to AE).

Surgery

After chemoradiotherapy, 94.8 % (N = 55) of the patients

underwent definitive surgery. Three patients did not

undergo surgery due to progression or withdrawal. Time

from the end of preoperative treatment to surgery lasted a

median of 6 weeks. Tumor histology was adenocarcinoma

in all patients. Lymph nodes were not involved in most of

the patients (40 cases; 80 %). Upper anterior resection was

performed in 37 patients, abdominoperineal resection in 12

and lower anterior resection in 1. Fifty-one patients were

circumferential margin involvement (CRM) free and only

one patient was CRM positive. Information regarding

CRM was not available in three patients. Anal sphincter

preservation was achieved in 40 patients (72.7 %), six of

them with a distance to the anal verge B5 cm (Table 2).

Efficacy

One patient was not evaluated for response due to with-

drawal by patient’s decision. Overall response rate was

68.4 % (95 % CI 56.4–80.5 %) including six patients

with pathologic compete response (10.5 %). Pathologic

complete response was achieved in patients with T3N0

(4 cases) or T3N1 (2 cases) at diagnosis. As stable disease

was observed in 14 patients (24.6 %), disease control rate

was 91.3 % (Table 3).

Safety

Safety issues were evaluated in the overall population

(n = 58). The most frequently observed adverse events are

shown in Table 4. Neither grade IV toxicities nor treat-

ment-related mortality was observed. Main toxicities were

leucopenia, diarrhea, anemia and neutropenia. Hand–foot

syndrome was only observed in one patient (1.7 %).

Discussion

The present study shows that a strategy based on the

replacement of 5-FU by oral capecitabine in the concurrent

treatment with radiotherapy of LARC patients is feasible.

Preliminary results of this study were presented in ASTRO

Congress 2006 [11]. However, a higher efficacy, as mea-

sured by pCR rate, has not been demonstrated. This

expected superiority in efficacy was based on preclinical

data which showed an increased antitumor activity in

human cancer xenograft models for capecitabine, when

compared with uracil/tegafur, and also on data supporting a

higher additive effect than that observed with 5-FU when

administered concurrently with radiotherapy [12]. Preop-

erative 5-FU-based chemoradiation results in a better local

control rate and a decreased rate of acute and late adverse

Table 1 Baseline patient characteristics (n = 58)

n (%)

Median age, years (range) 64.5 (30.9–78.7)

Sex

Male 35 (60.3)

Female 23 (39.7)

ECOG

ECOG 0 16 (28.6)

ECOG 1 40 (71.4)

Histologic type

Adenocarcinoma 58 (100)

Differentiation degree

G1: well differentiated 7 (12.1)

G2: moderately differentiated 28 (48.3)

G3: poorly differentiated 5 (8.6)

GX: non evaluable 18 (31.0)

cTN

T3N0 33 (56.9)

T3N1 18 (31)

Others (T3N2, T4N0, T4N1) 7 (12.1)

Stage

II 25 (43.1)

III 33 (56.9)

Site of primary tumor

Upper rectum 3 (5.3)

Middle rectum 18 (31.6)

Lower rectum 28 (49.1)

Unknown 10 (17.5)

Tumor distance B5 cm from anal verge 13 (22.4)

Tumor distance (cm) from anal verge,

median (range)

7 (1.0–12.0)

Lesion sites: n = 1 54 (94.7)

Table 2 Surgery (n = 55)

n (%)

CRM free 51 (92.7)

Anal sphincter preservation rate: 40 (72.7)

cT4 3 (8)

cN0 22 (55)

Tumor distance B5 cm from anal verge 6 (15)

CRM Circumferential margin involvement

Clin Transl Oncol (2013) 15:294–299 297

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events, as compared with postoperative chemoradiation

[2]. Addition of chemotherapy to preoperative radiation to

develop a combined chemoradiation strategy results in a

further improvement in the local control rate, as it was

recently reported in a pooled-analysis [13] of two clinical

trials (FFCD 9203 and EORTC 22911). Thus, although an

improvement in overall survival is lacking, all these data

led the way for preoperative 5-FU-based chemoradiother-

apy to reach its current position as standard of care for

operable rectal cancer. The primary end point of this,

among many others, phase II trials of neoadjuvant con-

current chemoradiotherapy, is pCR rate. It is well known

that the degree of tumor regression achieved is associated

with outcome. Previous results of phase II studies showed

that 5-FU plus radiation achieve a 10 % pCR, consistently

across trials, whereas capecitabine-radiation achieves

between a 4 and 24 % pCR rate. Chemoradiation with

either capecitabine or 5-FU continuous infusion results in

the same outcomes, regarding both efficacy and toxicity.

However, the toxicity profile is slightly different, with a

higher incidence of hand–foot syndrome in the patients

treated with capecitabine. Other frequent adverse events

observed with capecitabine when used in the neoadjuvant

setting of rectal cancer patients are diarrhea, proctitis and

epithelitis. In the present study, the combination regimen

consisting of capecitabine and concomitant radiation

(45 Gy in 28 fractions and a boost of 5.4 Gy in 3 fractions)

was well tolerated, diarrhea being the most important

observed toxicity. Of note, no grade IV adverse events

were observed. Results of large head-to-head comparisons

between 5-FU and capecitabine have recently been pre-

sented in abstract form. These randomized trials have

shown pCR rates of 22 % [14] and 13 % [15] rates for

preoperative capecitabine-radiation without significant

differences when compared with pCR rates shown by

preoperative 5-FU-radiation. The study of the German

MARGIT group [15], although a mixture of neoadjuvant

and adjuvant patients, showed that capecitabine is an

option that could replace 5-FU in the treatment of rectal

cancer after having demonstrated non inferiority for the

comparison. In turn, the results of the NSABP R04 showed

equivalency between both strategies in terms of efficacy

and toxicity. Taken together, all these data allow oncolo-

gists to consider a capecitabine-based chemoradiation

regimen to be an option when preoperative treatment of an

operable rectal patient is being planned. In the present

study we have observed a 10 % pCR rate, an efficacy

outcome which is in line with previous retrospective and

prospective results of the combination of fluoropyrimidine

and radiation.

Surgery outcomes and related procedures are among the

most important issues in trials on neoadjuvant treatment of

operable rectal cancer. In fact, the development of this

strategy was historically prompted to investigate the pos-

sibility of allowing a sphincter-saving procedure in low-

lying tumors. It is currently accepted that a percentage of

sphincters are saved thanks to this strategy. Achievement

of a complete mesorectal excision with all margins

(including circumferential) disease-free is the cornerstone

of the treatment of rectal cancer and this objective is often

given by preoperative chemoradiation. Although not

directly designed to answer this question, the 73 % rate of

sphincter-sparing surgery should be considered satisfactory

in our study performed in a non-selected population. It

should be highlighted that six of the patients who were

operated with a sphincter-sparing procedure initially had

tumors located at B5 cm from the anal verge.

The most important limitation of the present study is its

non-randomized design. Thus, it is not possible to draw

firm conclusions from it. However, randomized studies on

the same topic have recently been reported as seen earlier.

Overall, our results are in agreement with those of these

Table 4 Most common (grade III–IV or more than one patient)

treatment-related adverse events per patient (n = 58)

Adverse event All grades, n (%) Grade 3, n (%)

Leucopenia 26 (44.8) 1 (1.7)

Diarrhea 23 (39.7) 4 (6.9)

Anemia 21 (36.2) 0 (0)

Neutropenia 14 (24.1) 0 (0)

Thrombocytopenia 3 (5.2) 0 (0)

Hyperbilirubinemia 7 (12.1) 0 (0)

Creatinine 2 (3.4) 0 (0)

Transaminases 4 (6.9) 0 (0)

Skin NOS 4 (6.9) 1 (1.7)

Hand-foot Syndrome 1 (1.7) 1 (1.7)

Asthenia 4 (6.9) 0 (0)

Nausea 3 (5.2) 0 (0)

Abdominal pain 4 (6.8) 1 (1.7)

Cardiac NOS 1 (1.7) 1 (1.7)

Grade IV AE was not observed

NOS Not otherwise specified

Table 3 Response rates (n = 58)

pCR,

n (%)

PR,

n (%)

SD,

n (%)

PD,

n (%)

T3N0 4 (6.9) 16 (27.6) 10 (17.2) 2 (3.4)

T3N1 2 (3.4) 11 (19.0) 4 (6.9) 1 (1.7)

Others (T3N2, T4N0,

T4N1)

– 6 (10.3) – 1 (1.7)

Total 6 (10.3) 33 (56.9) 14 (24.1) 4 (6.9)

One patient was not evaluable due to premature withdrawal by

patient’s decision

298 Clin Transl Oncol (2013) 15:294–299

123

large randomized clinical trials. Another limitation of the

study is the short planned follow-up that prevented us from

assessing overall survival and disease free survival and to

analyze the correlation of such endpoints with pCR rates.

The incorporation of oxaliplatin as a partner for the

fluoropyrimidine was the logical following step after the

demonstration of the efficacy of oxaliplatin in increasing

overall survival in colon cancer patients in the adjuvant

setting. However, the results of three large randomized

clinical trials STAR-01 [16], ACCORD 12 [17] and

NSABP R04 [14] have clearly shown that addition of

oxaliplatin did not result in better efficacy outcomes

(especially pCR rate). Moreover, it was associated with

higher toxicity as compared with that observed in the

fluoropyrimidine-alone arm. These results were highly

disappointing for the oncologic community [18]. As a

matter of fact, they mean a sudden stop in the plethora of

advances achieved in the past 20 years in the field

of curative treatment of rectal cancer. In turn, addition of

irinotecan to fluoropyrimidine-based chemoradiation is

being investigated in an ongoing phase III clinical trial (the

ARISTOTLE trial). And finally, addition of biologics to

neoadjuvant treatment of rectal has been studied in phase I

and II trials. Initial disappointing results showed a decrease

of the pCR rate with the addition of cetuximab to regimens

including fluoropyrimidines or fluoropyrimidines plus ox-

aliplatin. However, these data should be further refined

taking into account the KRAS gene mutational status,

before considering that cetuximab does not have a place in

the treatment of rectal cancer [19]. On the other hand,

bevacizumab has shown, in clinical trials, both promising

activity and synergy with chemotherapy at the cost of a

higher rate of postsurgical complications [20]. Thus, bev-

acizumab deserves further investigation to place it in its

correct location in the neoadjuvant setting of rectal cancer

treatment. All these pharmacological issues, together with

the refinement of radiation techniques and procedures, will

be the focus of the clinical research in the field of the

curative strategies for rectal cancer patients in the next few

years.

In conclusion, our safety and efficacy results on a

capecitabine-based chemoradiation strategy are in agree-

ment with those previous phase II and III clinical trials,

which clearly supports the concept that capecitabine may

replace 5-FU in the standard preoperative chemoradiation

regimen in operable rectal cancer patients.

Acknowledgments This study was supported in part by a grant

from ROCHE Espana. The sponsors had no role in the design and

conduct of the study, in the collection, analysis, and interpretation of

data or in the preparation, review, or approval of the manuscript. The

authors’ work was independent of the funders. Writing and editing

assistance was provided by Marta Mas (TFS Spain).

Conflict of interest The authors declare no conflict of interest.

References

1. Krook JE, Moertel CG, Gunderson LL (1991) Effective surgical adjuvanttherapy for high-risk rectal carcinoma. N Engl J Med 324:709–715

2. Sauer R, Becker H, Hohenberger W, Rodel C et al, German Rectal CancerStudy Group (2004) Preoperative versus postoperative chemoradiotherapy forrectal cancer. N Engl J Med 351:1731–1740

3. Glynne-Jones R, Harrison M (2007) Locally advanced rectal cancer: what is theevidence for induction chemoradiation? Oncologist 12:1309–1318

4. Piedbois P, Rougier P, Buyse M et al (1998) Efficacy of intravenous continuousinfusion of fluorouracil compared with bolus administration in advanced colo-rectal cancer. Meta-analysis group in cancer. J Clin Oncol 16:301–308

5. Van Cutsem E, Cunningham D, Hoff PM et al (2001) Thymidine phosphorylase(TP) activation: convenience through innovation. Oncologist 6(suppl 4):1–2

6. Van Cutsem E, Twelves C, Cassidy J et al (2001) Oral capecitabine comparedwith intravenous fluorouracil plus leucovorin in patients with metastatic colo-rectal cancer: results of a large phase III study. J Clin Oncol 19:4097–4106

7. Liu G, Franssen E, Fitch MI, Warner E (1997) Patient preferences for oralversus intravenous palliative chemotherapy. J Clin Oncol 15:5–110

8. Borner M, Scheithauer W, Twelves C et al (2001) Answering patients’ needs:oral alternatives to intravenous therapy. Oncologist 6(Suppl 4):6–12

9. Velenik V, Anderluh F, Oblak I et al (2006) Capecitabine as a radiosensitizingagent in neoadjuvant treatment of locally advanced resectable rectal cancer:prospective phase II trial. Croat Med J 47:693–700

10. Dunst J, Reese T, Sutter T et al (2002) Phase I trial evaluating the concurrentcombination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol20:3983–3991

11. de las Heras M, Arias F, del Moral R, Gomez-Millan J, Wals A, Alcantara P(2006) Phase II trial of preoperative capecitabine with concurrent radiotherapyin patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys66(3 Supplement):S305

12. Sawada N, Ishikawa T, Sekiguchi F et al (1999) X-ray irradiation inducesthymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) inhuman cancer xenografts. Clin Cancer Res 5:2948–2953

13. Bonnetain F, Bosset J, Gerard J (2011) An analysis of preoperative chemora-diotherapy with 5FU/leucovorin for T3-4 rectal cancer on survival in a pooledanalysis of EORTC 22921 and FFCD 9203 trials. J Clin Oncol 29 (suppl;abstr3506)

14. Roh MS, Yothers MJ, O’Connell et al (2011) The impact of capecitabine andoxaliplatin in the preoperative multimodality treatment in patients with carci-noma of the rectum: NSABP R-04. J Clin Oncol 29 (suppl;abstr 3503)

15. Hofheinz R, Wenz FK, Post A et al (2011) Capecitabine versus 5-fluorouracil-based (neo) adjuvant chemoradiotherapy (CRT) for locally advanced rectalcancer: long-term results of a randomized, phase III trial. J Clin Oncol 29(suppl;abstract 3504)

16. Aschele C, Cionini L, Lonardi S et al (2011) Primary tumor response to pre-operative chemoradiation with or without oxaliplatin in locally advanced rectalcancer: pathologic results of the STAR-01 randomized phase III trial. J ClinOncol. doi:10.1200/JCO.2010.34.4911 (published online before print in May23)

17. Gerard JP, Azria D, Gourgou-Bourgade S et al (2010) Comparison of twoneoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer:results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol28:1638–1644

18. Weiser MR (2011) Rectal cancer trials: no movement. J Clin Oncol. doi:10.1200/JCO.2011.35.7053 (published online before print in May 23)

19. Bengala C, Bettelli S, Bertolini F et al (2009) Epidermal growth factor receptorgene copy number, K-ras mutation and pathological response to preoperativecetuximab, 5-FU and radiation therapy in locally advanced rectal cancer. AnnOncol 20:469–474

20. Crane CH, Eng C, Feig BW, Das P et al (2010) Phase II trial of neoadjuvantbevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer.Int J Radiat Oncol Biol Phys 76:824–830

Clin Transl Oncol (2013) 15:294–299 299

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