CLINICAL INVESTIGATION Rectum

CETUXIMAB IN COMBINATION WITH CAPECITABINE, IRINOTECAN, ANDRADIOTHERAPY FOR PATIENTS WITH LOCALLY ADVANCED RECTAL CANCER:

RESULTS OF A PHASE II MARGIT TRIAL

KAROLINE HORISBERGER, M.D.,* ANNE TRESCHL, M.D.,y SABINE MAI, M.D.,z

MANUEL BARRETO-MIRANDA, M.D.,y PETER KIENLE, M.D.,* PHILIPP STROBEL, M.D.,x

PHILIPP ERBEN, M.D.,y CHRISTOPH WOERNLE, M.D.,* DIETMAR DINTER, M.D.,{ GEORG KAHLER, M.D.,k

ANDREAS HOCHHAUS, M.D.,y STEFAN POST, M.D.,* FRANK WILLEKE, M.D.,*** FREDERIK WENZ, M.D.,z

AND RALF-DIETER HOFHEINZ, M.D.,y ON BEHALF OF THE MARGIT (MANNHEIMER ARBEITSGRUPPE FUR

GASTROINTESTINALE TUMOREN)

*Chirurgische Klinik und Poliklinik, yOnkologisches Zentrum, III. Medizinische Klinik, zKlinik fur Strahlentherapie undRadioonkologie, x Institut fur Pathologie, { Institut fur Radiologie und Nuklearmedizin, kSektion fur Chirurgische Endoskopie,

Medizinische Fakultat Mannheim der Universitat Heidelberg, Germany; and **Chirurgische Klinik, Marienhospital Siegen, Germany

Purpose: To evaluate the safety and efficacy of preoperative radiotherapy (RT) in combination with cetuximab,capecitabine, and irinotecan in patients with locally advanced rectal cancer.Methods and Materials: Patients with rectal cancer (clinical stage T3/4 or N+) were scheduled to receive cetuximab(400 mg/m2 Day 1, 250 mg/m2 Days 8, 15, 22, 29) in combination with weekly irinotecan 40 mg/m2 and capecitabine500 mg/m2 twice daily (Days 1–38). RT was given to a dose of 50.4 Gy (45 + 5.4 Gy). Primary endpoint was toxicity,and antitumor activity as assessed by the pathologic complete remission (pCR) rate was a secondary endpoint.Results: Fifty patients were enrolled; 88% showed T3 or T4 and 76% nodal-positive tumors with a median distancefrom the anal verge of 7.5 cm. The actual dose intensity was as follows (median/mean, %): cetuximab 100/92, iri-notecan 100/91, capecitabine 100/89). Main adverse events Grades 2/3/4 were (National Cancer Institute commontoxicity criteria version 3.0, %): leukocytopenia 6/2/2, nausea/vomiting 4/2/0, diarrhea 34/30/0, proctitis 26/2/0,elevation of liver transaminases 8/10/0, and acnelike skin rash 46/6/0. All patients underwent surgery, and no post-operative deaths occurred. Eighty-four percent underwent low-anterior resection, and 68% of the specimenexhibited moderate or good tumor regression, but only 4 patients had a pCR.Conclusion: Preoperative chemoradiation with cetuximab-CapIri-RT has manageable toxicity, with diarrheabeing the most commonly observed adverse event. Nevertheless, the efficacy of this regimen with a pCR rate ofonly 8% was significantly lower than that observed in a previous Phase I trial. � 2009 Elsevier Inc.

Capecitabine, Cetuximab, Chemoradiotherapy, Irinotecan, Rectal cancer.

Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 5, pp. 1487–1493, 2009Copyright � 2009 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/09/$–see front matter

doi:10.1016/j.ijrobp.2008.10.014

INTRODUCTION

Advances in surgery have significantly improved the progno-

sis of rectal cancer. Despite optimized resection techniques

including total mesorectal excision (TME), preoperative

radiotherapy (RT) further reduces local recurrence rates with-

out improving overall survival (1). On the basis of the results

of 3 randomized trials neoadjuvant 5-fluorouracil-(5-FU)-

based chemoradiotherapy is regarded as a standard of care

for locally advanced rectal tumors (2–4). In these trials the

rates of local recurrences in patients undergoing 5-FU-based

preoperative treatment ranged between 6% and 8%, but

Reprint requests to: Ralf-Dieter Hofheinz, M.D., OnkologischesZentrum, III. Medizinische Klinik, Universitatsklinikum Mannheimder Universitat Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135Mannheim, Germany. Tel: (+49) 621-3832854; Fax: (+49) 621-832488; E-mail: ralf.hofheinz@med3.ma.uni-heidelberg.de

14

distant metastases represented the most common site of

treatment failure in approximately 35%–40% of the patients

(2–4).

Thus far, the biomodulation of 5-FU (5), the combination

of 5-FU with older cytostatics (e.g., semustine) (6), and the

prolongation of chemotherapy (7) have not improved dis-

ease-free or overall survival. Newer drugs such as irinotecan

or oxaliplatin are expected to improve treatment results. For

instance, the safety of irinotecan in combination with 5-FU or

its pro-drug capecitabine during chemoradiotherapy has been

investigated in several Phase II trials (8–15). Summarizing

Anne Treschl and Karoline Horisberger contributed equally tothis study.

Conflict of interest: none.Received Aug 13, 2008, and in revised form Sept 10, 2008.

Accepted for publication Oct 1, 2008.

87

1488 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 5, 2009

the data from these trials, the rate of pathologic complete re-

missions (pCR) using irinotecan/5-FU-based combinations

appears to be at least twice as high as in 5-FU-based regimens

(approximately 8% in trials with quality-controlled pathol-

ogy) (8–15).

The pCR rate has been identified as a prognostic factor for

patients undergoing neoadjuvant chemoradiation for rectal

cancer (16, 17), and the long-term outcome of patients exhib-

iting pCR is favorable (local relapse rate 1.6%, 5-year cancer-

specific survival 94%) (18). Two-drug regimens were shown

to be associated with higher pCR rates in an analysis of sev-

eral trials including a total of 3,157 patients (19). Therefore

increasing pCR rates is of major interest because it may

also improve long-term results.

Biological factors and molecular targeted agents have

a growing role in the treatment of colorectal cancer. Cetuxi-

mab, an antibody targeting the epidermal growth factor

receptor (EGFR), was initially used as treatment for chemo-

therapy-refractory colorectal cancer (20) and is now also

considered first-line treatment for patients with metastatic

colorectal cancer in combination with chemotherapy (21).

Overexpression of EGFR is a negative prognostic factor

and is associated with resistance to radiotherapy (22, 23).

Therefore, EGFR has emerged as a promising target in radio-

oncology. In head and neck cancer, the addition of cetuximab

to RT resulted in superior outcomes with respect to locore-

gional failure and survival (24). In retrospective analyses, pa-

tients with EGFR expressing rectal cancer undergoing

neoadjuvant RT had a significantly lower disease-free sur-

vival and a lower chance of pCR (25). Thus, there is a clear

rationale to combine cetuximab with radiochemotherapy for

rectal cancer.

We have previously established a dosing regimen for ce-

tuximab in combination with capecitabine and irinotecan-

based chemoradiotherapy (cetuximab-CapIri-RT) (26). The

preliminary efficacy in 20 patients included in this Phase I

trial was promising with 5 patients exhibiting pCR. The ob-

jective of the present Phase II trial was to assess the tolerabil-

ity (primary endpoint) and efficacy (secondary endpoint) of

the cetuximab-CapIri-RT regimen in a larger cohort of

patients.

METHODS AND MATERIALS

The protocol was reviewed and approved by the institutional

review board, and the study was performed according to the

Declaration of Helsinki. All patients provided written informed

consent.

Patients eligibility criteriaPatients with histologically confirmed, locally advanced nonme-

tastatic rectal adenocarcinoma (cT3/4, or cN+ [nodal positivity as

determined by transrectal ultrasonography]; 0–16 cm distance

from anal verge as measured by rigid rectoscopy) were eligible.

We classified every visible lymph node in the transrectal ultrasound

as positive. Cases in which the probe could not pass the tumor com-

pletely were regarded as uTx uNx. In these patients, the cT cN stag-

ing was determined by magnetic resonance imaging (MRI).

Otherwise, we continued the transrectal ultrasound examination

up to the aortic bifurcation to visualize the iliac and mesorectal

lymph nodes as well. Positive EGFR staining was not required. Fur-

ther inclusion criteria were as follows: Eastern Cooperative Oncol-

ogy Group (ECOG) performance status #2; age $18 years;

adequate bone marrow (leukocyte count >3,000/mL, platelet count

>100,000/mL), renal (serum creatinine #1.4 mg/dL or creatinine

clearance >60 mL/min), and hepatic function (bilirubin #2 mg/

dL). Patients with a history of Gilbert-Meulengracht’s disease

were excluded. Patients of childbearing potential were required to

be using contraception. Patients were excluded if they suffered

from other cancers or had known hypersensitivity to 5-FU, irinote-

can, or cetuximab.

Pretreatment evaluationAll patients underwent a complete history, physical examination,

digital rectal examination, rigid rectoscopy with biopsy, transrectal

ultrasonography, pelvic and abdominal computed tomographic (CT)

scans, MRI, colonoscopy, and chest X-rays. A full blood count with

differential and serum chemistry (including blood electrolytes, cre-

atinine, urea, uric acid, liver transaminases, alkaline phosphatase, to-

tal bilirubin, and lactic dehydrogenase) was obtained before the start

of treatment. Weekly blood counts and serum chemistry every 3

weeks were scheduled during chemoradiotherapy or whenever clin-

ically indicated.

RadiotherapyRT was delivered with a linear accelerator using 18–23 MeV

photons and a three-field box technique consisting of a poste-

rior-anterior and 2 lateral fields. A total dose of 50.4 Gy was given

in daily fractions of 1.8–Gy, 5 days a week. The clinical target

volume (CTV) included the sacrum, the presacral space, and the

posterior wall of the bladder and prostate or vagina. The common

iliac lymph nodes were included in the CTV. The upper border of

the CTV was at the L5–S1 interspace for cN0 and at L4–L5 for

cN+ patients. The lower field border was 5 cm below the macro-

scopic tumor. After a dose of 45 Gy, an additional dose of 5.4 Gy

was given to the boost volume using a shrinking field technique.

To keep the boost volume as large as possible, it was defined as

the initial CTV minus the small bowel as identified on the treat-

ment planning CT or on simulation films after oral contrast admin-

istration in prone position using a belly board. The maximal dose

to small bowel was limited to 46 Gy, accepting potential under-

dosages to small parts of the gross tumor volume in tumors of

the upper third.

Preoperative chemo- and antibody therapy (cetuximab-CapIri regimen)

Starting at Day 1 of RT, patients received weekly cetuximab (400

mg/m2 Day 1 and 250 mg/m2 Days 8, 15, 22, 29; 2 hours before ir-

radiation), weekly irinotecan (40 mg/m2 Days 1, 8, 15, 22, 29;

1 hour before irradiation), and capecitabine orally twice daily (500

mg/m2 twice daily Days 1–38). All patients received standard anti-

emetic prophylaxis using 5-HT3 antagonists and dexamethasone.

If a patient experienced one of the following adverse events

according to National Cancer Institute common toxicity criteria

(version 3.0) at the day of planned irinotecan application, chemo-

therapy was interrupted until adverse events had resolved to Grade

0 or 1: leukocytopenia Grade $2, thrombocytopenia Grade $2,

diarrhea Grade $2, mucositis/stomatitis Grade $2, skin toxicity

Grade $2, other adverse events Grade >2. Treatment was resumed

with a dose reduction of 25% for either drug. Cetuximab dosing

Phase II study with cetuximab and CapIri-RT in rectal cancer d K. HORISBERGER et al. 1489

remained identical. In case of adverse events Grade $2 in the inter-

val between irinotecan applications, we suggested interruption of

chemotherapy and dose reduction of both drugs of 25%. On the sec-

ond occurrence of adverse events Grade $2, the chemotherapy dose

was reduced by 50%.

Every effort was made to continue RT without interruption. The

RT schedule was not modified unless an adverse event Grade $2

was clearly related to radiation. In these cases, RT was withheld

until adverse events resolved to Grades 0 or 1.

Surgery and histopathologySurgical resection with TME was scheduled 4–6 weeks after com-

pletion of chemoradiotherapy. Pathological examination of the

specimen involved opening the specimen, identification of the for-

mer tumor-bearing area, and macroscopic description followed by

fixation in 10% neutral buffered formalin for 24 h. After fixation,

specimens were processed according to standard protocols (27).

For obvious residual tumor, at least 4 paraffin blocks were pro-

cessed. If no obvious residual tumor was present, the former tu-

mor-bearing area was sliced and embedded. The completion of

TME, circumferential resection margins, proximal and distal tu-

mor-free margins, tumor mass, fibrotic changes, and irradiation vas-

culopathy were evaluated. Grades of histopathologic regression

were described as defined by the Japanese Society for Cancer of

the Colon and Rectum (JSCCR) (28). Tumors were classified as

good responders when assigned tumor regression Grades 2 or 3

(TRG 2 or TRG 3) and as bad responders in regression Grades

0 or 1 (TRG 0 or TRG 1).

Study design, definitions, and endpointsThe main focus of this Phase II study was to assess the toxicity

(primary endpoint) and efficacy (tumor regression using the JSCCR

grading; secondary endpoint) of the cetuximab-CapIri-RT regimen.

The statistical calculation was made on toxicity issues and was

based on the dose-limiting toxicities (DLT). DLT was defined by

the occurrence of one of the following adverse events: Grade 4 leu-

kocytopenia/neutropenia or thrombocytopenia, symptomatic throm-

bocytopenia, Grade 3/4 febrile neutropenia, diarrhea Grade 3 lasting

for $72 hours despite adequate treatment, or any other Grade $3

nonhematological adverse events except renal adverse events

(Grade $2), nausea/vomiting, and acnelike skin rash. We deter-

mined that the rate of DLTs during this Phase II trial should have

been lower than 17% (i.e., approximately one in six patients).

With a total of 47 patients, a rate of at least 83% of patients experi-

encing no DLTs during radiochemotherapy can be assumed with

a power of 80% and an alpha value of 0.2 if fewer than 8 of 47

patients experienced DLTs.

RESULTS

Fifty patients entered this single-center trial between

March 2006 and February 2008. Patient characteristics are

listed in Table 1. The median age of the patients was 57 years

(range, 33–80 years). All but one patient with a local relapse

had newly diagnosed rectal adenocarcinoma. The median

distance from the lower border of the primary to the anal

verge was 7.5 cm.

Safety and dose intensityAll patients were evaluable for toxicity analysis. No treat-

ment-related deaths occurred, and only 1 patient developed

a Grade 4 toxicity according to National Cancer Institute

common toxicity criteria (leukocytopenia). Adverse events

observed during chemoradiation are listed in Table 2. Diar-

rhea was the most commonly observed toxicity with 15 pa-

tients (30%) developing Grade 3 diarrhea. The median time

to onset of Grade 3 diarrhea was 22 days calculated from

the start of chemoradiation (range, 12–33 days). In 7 patients,

diarrhea Grade 3 lasted <72 hours, but eight patients had di-

arrhea Grade 3 lasting $72 hours despite adequate treatment

using loperamide and oral fluid intake. These patients were

hospitalized for safety reasons and rehydrated. The median

hospital stay of these patients was 7.5 days (range, 5–11

days). No patient developed renal failure as a consequence

of diarrhea. Acnelike skin rash Grades 2 or 3 was seen in

approximately half of the patients.

Hematologic toxicity was mild with only 5 patients

developing Grade 2–4 leukocytopenia. No episode of neutro-

penic fever was reported, and no patient received prophylac-

tic or therapeutic granulocyte colony-stimulating factors

during chemoradiotherapy. The median decrease of the he-

moglobin level was 1.4 g/dL (range, 0–5.6 g/dL), but Grade

4 anemia or major bleeding was not observed. No prophylac-

tic recombinant human erythropoetin was given and no blood

transfusions were required during chemoradiation.

In all, 8 patients (16%) had DLTs. All DLTs (diarrhea $72 h,

n = 8; elevation of liver transaminases, n = 5; elevation of

bilirubin, n = 1; abdominal pain, n = 1; proctitis, n = 1; leuko-

cytopenia, n = 1) were observed in these 8 patients.

Table 1. Patient and tumor characteristics (n = 50)

Age (years)Median 57Range 33–80

SexMale 33 (66)Female 17 (34)

ECOG performance status0 34 (68)1 16 (32)

CEAMedian (mg/L) 2.4Range 0.4–50.3

CA 19-9 (kU/L)Median 10Range 1–298

Clinical stage*cT2 5 (10)cT3 42 (84)cT4 2 (4)Local relapse 1 (2)cN0 13 (26)cN+ 37 (74)

Lower tumor margin to anal verge distance (cm)Median 7.5Range 1–13

Abbreviations: CA = cancer antigen; CEA = carcinoembryonicantigen. ECOG = Eastern Cooperative Oncology Group.

Data presented as number of patients, with percentage in paren-theses, unless otherwise noted.

* As determined by transrectal ultrasonography and magnetic res-onance imaging.

1490 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 5, 2009

Table 2. Incidence and severity of adverse events observed during radiochemotherapy (n = 50)

NCI-CTC grades (version 3.0) 0 1 2 3 4

HematologicAnemia 40 52 6 2 —Thrombocytopenia 92 8 — — —Leukocytopenia 56 34 6 2 2

NonhematologicStomatitis 88 12 — — —Nausea/vomiting 54 40 4 2 —Diarrhea 16 20 34 30 —Abdominal pain 66 22 8 4 —Proctitis 46 26 26 2 —ASAT/ALAT elevation 50 32 8 10 —Bilirubin elevation* 98 — — 2 —Creatinine elevation 100 — — — —Alopecia 98 — 2 — —Hand-foot skin reaction 86 10 4 — —

Acnelike skin rash 12 36 46 6 —Anorexiay 96 4 — — —

Abbreviations: ASAT/ALAT = aspartate aminotransferase/alanine aminotransferase; NCI-CTC = National Cancer Institute Common Tox-icity Criteria.

Data presented as percentage of patients.* Grade 3 hyperbilirubinemia was recorded in a patient with previously unknown Gilbert-Meulengracht’s disease).y Median weight loss during radiochemotherapy was 4 kg (range 0–17 kg).

The dose intensity (i.e., applied doses divided by the

scheduled doses � 100 [%]) of cetuximab, irinotecan, and

capecitabine was as follows (median/mean [%]): cetuximab

Table 3. Surgical parameters and tumor regression gradingof the primary tumor after neoadjuvant cetuximab-CapIri-RT

(n = 50)

Surgery typeLow anterior resection 42 (84)Abdominoperineal resection 7 (14)Hartmann’s procedure 1 (2)

Resection statusR0 50 (100)

Time of surgery (min)Median 270Range 135–565

Hospital stay (days)Median 14Range 7–48+

Blood loss (mL)Median 500Range 100–2100

ComplicationsWound healing 12 (24)Anastomotic leak 8 (16)Bowel atonia 11 (22)Abscess 5 (10)Pneumonia 1 (2)

Tumor regression grading (JSCCR)1a 11 (22)1b 5 (10)2 30 (60)3 4 (8)

Abbreviation: JSCCR = Japanese Society for Cancer of the Colonand Rectum.

Data presented as number of patients, with percentage in paren-theses, unless otherwise noted.

100/92 (range, 29–100), irinotecan 100/91 (range, 33–100)

and capecitabine 100/89 (range, 29–100).

In 3 patients, radiotherapy was stopped prematurely be-

cause of toxicity (34.2 Gy, n = 1; 45 Gy, n = 2). The remain-

ing patients (n = 47) received the scheduled dose of 50.4 Gy.

Surgery and pathologyTME surgery was performed in all patients after a median

of 35 days (range, 21–68 days) following the completion of

chemoradiation. R0 resection was accomplished in all pa-

tients. Forty-two patients were treated with a low anterior re-

section, 1 patient with a Hartmann’s procedure and 7 with an

abdominoperineal resection. All patients undergoing sphinc-

ter-sparing surgery had a transient ileostomy. Surgical pa-

rameters and complications are listed in Table 3. No

postoperative deaths occurred, and the median hospital stay

was 14 days.

A median of 13 lymph nodes were examined (range,

2–22). Thirty-six patients were nodal-negative. Twelve pa-

tients had 1–3 lymph nodes involved (N1), and 2 patients

had more than 4 positive lymph nodes (N2). Nodal status

downstaging (cN+ to ypN0) was detected in 24 of 37 patients

(65%), T-category was downstaged in 22 patients (45%;

Table 4). Using the JSCCR regression grading, 68% had

moderate or good tumor regression (Grade 2 and 3), but

pCR was observed in only 4 patients (8%).

DISCUSSION

Combined-modality treatment with 5-FU and pelvic RT is

a mainstay of preoperative treatment of locally advanced rec-

tal cancer (2–4). Nevertheless, despite using perioperative

chemoradiation approximately 35%–40% of the patients

eventually develop distant metastases and die of their disease.

Phase II study with cetuximab and CapIri-RT in rectal cancer d K. HORISBERGER et al. 1491

This highlights the need for more effective perioperative sys-

temic treatment. Two main strategies are currently pursued:

(1) treatment intensification with newer chemotherapeutic

agents such as irinotecan or oxaliplatin and (2) the use of mo-

lecular targeted therapies, for example, cetuximab, a mono-

clonal EGFR antibody. The rate of pCR is regarded as

a potential early marker to estimate the efficacy of radioche-

motherapy regimens involving newer agents in view of its

prognostic value and the outstanding prognosis of patients

achieving pCR.

In this study, we conjointly investigated both strategies

adding cetuximab and irinotecan to capecitabine-based

chemoradiotherapy (cetuximab-CapIri-RT). This regimen

showed promising results in a previous Phase I study in

20 patients. In this Phase II trial, we sought to expand

the safety data before investigating this regimen in a ran-

Table 4. Pathologic staging (ypT) compared with clinicalstaging (cT) at baseline (n = 49)

Pathologic stage

Clinical stage ypT0 ypT1 ypT2 ypT3 ypT4 ypN+

cT2 (n = 5) 0 1 1 3 0cT3 (n = 42) 4 0 16 21 1cT4 (n = 2) 0 0 1 0 1cN+ (n = 37) 13cN- (n = 12) 1Total (n = 49) 4 1 18 24 2 14

One patient with a local relapse is not included in this analysis.Downstaging occurred in 22 of 49 patients (45%) in T stage andin 24 of 37 patients (65%) in N stage.

domized trial. Consequently, the determination of

dose-limiting toxicities was chosen as primary endpoint.

In all, eight patients developed DLTs (16% of all patients).

Thus, our hypothesis that not more than 17% of all patients

should develop DLTs was met. The cetuximab-CapIri-RT

regimen generally proved to be well tolerated, but gastro-

intestinal toxicity was pronounced in several patients.

The rate of diarrhea Grade 3 was 30%, and 8 patients

had to be hospitalized. This underlines the need for rigor-

ous management of diarrhea when using cetuximab-CapIri-

RT.

The assessment of pCR was the secondary endpoint in this

trial. Despite applying this intensified regimen with a very

low likelihood of treating patients at suboptimal doses, we

observed a comparably low rate of pCR (8%).

This might be a consequence of an unfavorable patient se-

lection and the small number of patients in the trial. Nonethe-

less, our findings are in line with 2 recent trials investigating

cetuximab in conjunction with capecitabine (29) or capecita-

bine/oxaliplatin (30) (Table 5). One hundred fifty-five pa-

tients can be analyzed with respect to pCR rates taking the

results of the 2 trials (29, 30), our previous Phase I study

(26) and this Phase II trial together. Only 15 of these 155 pa-

tients (9.7%) exhibited a pCR after cetuximab-based chemo-

radiation. In general, crosstrial comparisons are problematic,

but this pCR rate is lower than the pCR rates observed with

the same chemoradiotherapy regimens without cetuximab.

For instance, we observed a pCR rate of 15% with the Cap-

Iri-regimen in 34 patients (15), and Rodel et al. (31) reported

a pCR rate of 16% in 103 patients receiving the capecitabin/

oxaliplatin regimen. On the basis of this crosstrial

Table 5. Comparison of safety and efficacy data of published clinical trials using cetuximab in conjunction with neoadjuvantradiochemotherapy in rectal cancer

Reference Evaluable patients (n) Cetuximab-combination regimen*Main Grade 3–4 adverse

events (NCI-CTC criteria) pCR rate

Hofheinz et al. 2006 (26) 20 Capecitabine 400–500 mg/m2 b.i.d. Leukocytopenia 0% 5/20 (25%)Irinotecan 40–50 mg/m2 weekly � 5 Nausea/vomiting 5%Radiotherapy 28 � 1.8 Gy (50.4 Gy) Diarrhea 20%

Skin rash 0%Machiels et al. 2007 (29) 40 Capecitabine 650-825 mg/m2 b.i.d. Neutropenia 3% 2/40 (5%)

Radiotherapy 25 x 1.8 Gy (45.0 Gy) Nausea/vomiting 3%Diarrhea 15%Skin rash 0%

Rodel et al. 2008 (30) 45 Capecitabine 500-825 mg/m2 b.i.d. Leukocytopenia 6% 4/45 (9%)Oxaliplatin 50 mg/m2 days 1,8,22,29 Nausea/vomiting 4%Radiotherapy 28 x 1.8 Gy (50.4 Gy) Diarrhea 19%

Skin rash 4%Current data 50 Capecitabine 500 mg/m2 b.i.d. Leukocytopenia 4% 4/50 (8%)

Irinotecan 40 mg/m2 weekly x 5 Nausea/vomiting 2%Radiotherapy 28 x 1.8 Gy (50.4 Gy) Diarrhea 30%

Skin rash 6%Total 155 15/155 (9.7%)

Abbreviations: NCI-CTC = National Cancer Institute Common Toxicity Criteria; pCR = pathologic complete remission.pCR data presented as number of patients achieving a pCR in relation to treated patients with percentage in parentheses.* Cetuximab was administered with the following doses: 400mg/m2 loading dose and 250mg/m2 weekly thereafter. Cetuximab treatment

was initiated one week before the start of chemoradiation in the trials by Machiels et al. and Rodel et al. In the current trial and in the trialby Hofheinz et al., cetuximab was initiated at the first day of chemoradiotherapy.

1492 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 5, 2009

comparison, an additional benefit for the addition of cetuxi-

mab appears unlikely. Nevertheless, the rate of gastrointesti-

nal toxicity (i.e., diarrhea) is clearly augmented by the

addition of cetuximab, an effect that has also been observed

in randomized clinical trials in patients with metastatic colo-

rectal cancer (21).

There are several possible reasons for the low pCR rate,

as well as various conclusions to be drawn from these ob-

servations. First, a possible explanation, as suggested by

Rodel et al. (30), for the low efficacy is the G1 cell-cycle

arrest caused by the addition of cetuximab which impairs

the efficacy of 5-FU-derivatives, oxaliplatin, or irinotecan,

all of which exert their main cytotoxic or radiosensitizing

mode of action mainly in the S/G2/M phases. Second, for

patients with metastastic colorectal cancer, the negative im-

pact of KRAS mutations on the efficacy of EGFR anti-

bodies was recently demonstrated (32). Moreover, the

addition of cetuximab to standard chemotherapy (capecita-

bin/oxaliplatin/bevacizumab) in patients with KRAS muta-

tions not only had no additional effect but was harmful

for these patients, resulting in a significantly shorter time

to tumor progression (33). However, the KRAS mutational

status has not been investigated thus far in either of the rec-

tal cancer trials using cetuximab. Third, although the results

of cetuximab-based chemoradiation obtained in several

Phase I/II trials indicate no benefit for the addition of the

EGFR antibody, from a methodological point of view, it

should be noted that the small sample size is susceptible

to biased statistical results. Only randomized, adequately

powered trials are required to answer the question satisfac-

torily. Fourth and finally, pCR is an early surrogate end-

point that is far from being universally accepted (34).

Clearly, patients exhibiting pCR after conventional chemo-

radiation have an excellent long-term prognosis (18).

Whether this also holds true for regimens including mono-

clonal antibodies remains to be shown.

The data on chemoradiation including EGFR tyrosine-ki-

nase inhibitors are contradictory. A trial investigating capeci-

tabine/gefitinib-based chemoradiotherapy was closed early

because of toxicity issues (35), and a recent trial using

5-FU instead of capecitabine reported acceptable gastrointes-

tinal toxicity and a pCR rate of 30% in 41 patients (36).

In conclusion, this study shows that the cetuximab-CapIri

regimen has pronounced albeit manageable toxicity. Never-

theless, the pCR rate was only 8%. This adds to a growing

body of evidence suggesting that the combination of anti-

EGFR antibodies with conventional chemoradiotherapy pro-

vides no additional antitumor activity. We do not recommend

using this regimen outside of clinical trials. Nevertheless, the

combination of anti-EGFR molecular drugs with radiother-

apy should be investigated further, ideally within randomized

trials. These trials should also focus on correlative tumor tis-

sue and biomarker analysis to gain more information on

potential benefits of such combinations.

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