VOLUME 23 NUMBER 27 SEPTEMBER 20 2005

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Phase II Trial of Carcinoembryonic Antigen

Radioimmunotherapy With 131I-Labetuzumab After
Salvage Resection of Colorectal Metastases in the Liver:
Five-Year Safety and Efficacy Results
Torsten Liersch, Johannes Meller, Bettina Kulle, Thomas M. Behr, Peter Markus, Claus Langer,
B. Michael Ghadimi, William A. Wegener, Jacqueline Kovacs, Ivan D. Horak, Heinz Becker,
and David M. Goldenberg
From the Departments of General
Surgery, Nuclear Medicine, and Genetic
Epidemiology, University of Gttingen,
Germany; Immunomedics, Inc, Morris
Plains; and Garden State Cancer
Center, Center for Molecular Medicine
and Immunology, Belleville, NJ.
Submitted March 4, 2005; accepted
May 19, 2005.
Presented in part at the 2005 Gastrointestinal Cancers Symposium sponsored
by the American Society of Clinical
Oncology, American Gastroenterological
Association, American Society for Therapeutic Radiology and Oncology, and
Society of Surgical Oncology, in Hollywood, FL, January 27-29, 2005.
Authors disclosures of potential conflicts of interest are found at the end of
this article.
Address reprint requests to Torsten
Liersch, MD, Department of General
Surgery, Medical Center of the GeorgAugust University, Robert Koch Str 40,
37099 Gttingen, Germany; e-mail:
tliersc@gwdg.de.
2005 by American Society of Clinical
Oncology
0732-183X/05/2327-6763/$20.00

Purpose
Although complete resection (R0) of liver metastases (LM) remains the treatment of choice
for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one
third survive for 5 years. The objective of this phase II study was to evaluate the safety and
efficacy of radioimmunotherapy (RAIT) after salvage resection of LM.
Patients and Methods
Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60
mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n 23), disease-free survival (DFS; n 19), and overall survival (OS;
n 19) were determined.
Results
With a median follow-up of 64 months, the median OS time from the first liver resection for
RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time
was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT
benefited patients independently of bilobar involvement, size and number of LM, and
resection margins. The major adverse effect was transient myelosuppression, resulting
mostly in grade 3 neutropenia and/or thrombocytopenia.
Conclusion
Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT
after complete LM resection in CRC, compared with historical and contemporaneous controls
not receiving RAIT, these results justify further evaluation of this modality in a multicenter,
randomized trial.
J Clin Oncol 23:6763-6770. 2005 by American Society of Clinical Oncology

DOI: 10.1200/JCO.2005.18.622

INTRODUCTION

Colorectal cancer (CRC) is responsible for

more than 15% of all malignancies in the
United States and Europe,1 afflicting about
147,000 Americans and killing approximately 57,000 in 2004.2 The liver is the most
common site of distant metastasis, affecting
up to 60% of patients (at least 50,000 in the
United States), and is the only metastatic site
in 30% of CRC patients.3

In unresected patients with metastatic

disease, the 5-year survival rate, irrespective
of systemic therapies, is close to 0%.4,5 At
present, only complete resection offers the
prospect of curing liver metastases (LM)6,7
and has low rates of mortality (3% to 6%) and
morbidity (15% to 25%) at specialized centers.8 After complete resection (R0) of LM, a
5-year survival rate of 25% to 37% is achievable,9 but despite postsurgical adjuvant systemic or intrahepatic chemotherapy, cancer
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Liersch et al

relapse occurs in the majority of patients.3-9 Because approximately two thirds of resected CRC patients eventually relapse,
with more than one half first experiencing recurrence in the
liver,9-11 it is believed that microscopic tumor cells are trapped
selectively in this organ.
Because of a lack of effective therapies other than surgery for patients with LM of CRC, we studied radioimmunotherapy (RAIT) with a radioiodinated antibody against
carcinoembryonic antigen (CEA) as an adjuvant treatment
after complete resection of LM from CRC. CEA was first
described 40 years ago,12 and it has served as a serum
marker and target for radiolabeled antibody imaging and
other therapeutic strategies because it is expressed in more
than 90% of CRC cells.13 We hypothesized that patients
with no overt disease, but with a high likelihood of recurrence as a result of micrometastases, would be ideal candidates for RAIT because RAIT has been shown to be effective
preclinically in a similar setting.14-16 In the current phase II
trial, the objective was to assess the safety and efficacy of
CEA-RAIT as an adjuvant therapy after salvage resection of
CRC LM to determine whether an expanded, randomized,
multicenter study is warranted.
PATIENTS AND METHODS
Antibody, Radiolabeling, and Administration
Labetuzumab (hMN-14), a CDR-grafted (humanized) antiCEA (CEACAM5) immunoglobulin G1subclass monoclonal antibody, was obtained from Immunomedics, Inc (Morris Plains, NJ).17
Prior clinical trials had not shown significant cross-reactivity with
normal tissues, significant toxicity, or immunogenicity.16,18
Radioiodination of labetuzumab was performed using the
iodogen method and resulted in a specific activity after labeling of
15 mCi/mg antibody.16,18 The amount of unbound radioiodine
was less than 2% in each preparation, and the immunoreactivity
was more than 85%. 131Iodine was chosen as the therapeutic
radionuclide because of its high-energy gamma emission for external camera imaging of in vivo distribution, its lower beta emission energy, and its shorter range of energy deposition compared
with other beta emitters, such as 90Y; thus, it is more appropriate as
an adjuvant therapy for micrometastatic disease,19 as confirmed in
liver phantom studies.20
131
I-labetuzumab was infused over a 30-minute period in a
volume of 50 mL of sterile 0.9% NaCl containing 1.0% to 2.5%
human serum albumin. All patients received a single infusion at a
dose level of 40 to 60 mCi/m2 based on a previous phase I, dosefinding trial.16 Two patients were re-treated at the time of recurrent disease. Whole-body scans were performed with a Picker
Prim 2000 dual-head gamma camera equipped with high-energy
collimators (Picker/Marconi, Cleveland, OH). Anterior and posterior whole-body scans were obtained daily from the day when
each patients whole-body activity decreased to less than 40 mCi
(ie, 2 to 3 days after infusion), as described previously.16
Patient Characteristics
The entry criteria for the protocol approved by the institutional ethics committee included a patient age of at least 18 years
6764

and a diagnosis of resected primary CRC with synchronous or

metachronous hepatic spread amenable to potentially curative
resection. Admission to the study took place after complete resection (R0) of the LM. CEA-expressing cancer cells of resected LM
had to be proven immunohistochemically.
Conventional radiologic tests (computed tomography [CT]
and/or magnetic resonance imaging) had to show the absence of
detectable, tumor-suspicious, extrahepatic lesions within 2 weeks before RAIT. An interval of at least 4 weeks after major surgery before
LM resection, external radiation, and/or any other therapy was required; complete bone marrow recovery after primary therapy at the
time of RAIT was also required. Adjuvant chemotherapy after surgical resection of the primary tumor was permitted, but no RAIT
patient was administered chemotherapy after resection of the LM
until there was a recurrence. Also, no prior therapy with murine or
other antibodies was allowed. Women of childbearing age had to
practice contraception during therapy and for 3 months after therapy.
Admission criteria were a minimal life expectancy of more
than 3 months; a Karnofsky performance score of more than 70;
and normal serum chemistries, peripheral CBC counts, and serum
CEA ( 5 ng/mL). To exclude thyroid hyperfunction or other
conditions in anticipation of administering high-dose radioiodine, the thyroid-stimulating hormone level of all patients was
determined, and a scintigram of the thyroid was taken.
Twenty-three patients who underwent explorative surgery
for LM of CRC were studied (Table 1). Of these 23 patients administered 131I-labetuzumab, two patients were excluded from the efficacy
analysis because of extrahepatic metastases despite preoperative CT
staging, and another two were excluded because postoperative chemotherapy was started (Table 2). Thus, safety was evaluated in all 23
patients, whereas disease-free survival (DFS) and overall survival
(OS) were determined by the Kaplan-Meier survival estimates in 19
patients who fulfilled all inclusion criteria. In these 19 patients, LM
were completely removed by either segmental resection (n 9) or
combined segmental and lobe resection of the left (n 3) and right
liver lobes (n 7) under ultrasound control intraoperatively. The
mortality rate from the operative procedure was 0%, and the postoperative morbidity rate was 15%. All patients who underwent an R0
were considered as putatively cured if imaging (intraoperative ultrasound), surgical bimanual palpation, or histopathologic examination
failed to reveal macroscopic or microscopic intrahepatic or extrahepatic disease.
Table 2 lists all primary tumor stages, adjuvant and/or neoadjuvant fluorouracil (FU) -based procedures, radionuclide and
antibody doses, and the corresponding hematologic toxicities. Ten
patients received adjuvant FU-based chemotherapy or chemoradiotherapy after resection of the primary CRC, whereas six patients
(patients 5, 9, 10, 13, 17, and 21) were treated by dose-intensified
FU-based neoadjuvant chemotherapy before resection of the LM.
All patients who entered the study underwent baseline procedures within 5 days before RAIT, including CT scans of the chest,
abdomen, and pelvis; abdominal ultrasound; serum CEA levels; and
safety laboratories (hematology and serum chemistry). After informed consent was obtained, the patients were premedicated with
potassium iodide 200 mg daily, which was initiated 24 hours before
the antibody administration to decrease thyroid and gastric uptake
and continued until radiation restrictions were removed.
At the time of recurrence, more than one LM occurred in 12
patients, and both lobes of the liver were affected in eight patients.
Follow-up was conducted according to the guidelines of the German Cancer Society.
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CEA Radioimmunotherapy After Resection in CRC

Table 1. RAIT Patient Characteristics

RAIT Study
Characteristic
Patients treated
Sex
Male
Female
Age, years
Median
Range
Primary disease site
Colon
Rectum
Colon and rectum
Primary disease stage
UICC I
UICC II
UICC III
UICC IV
Nodal status at primary surgery
pN0
pN1
pN2
Therapy after primary surgery
None
Neoadjuvant RT/CT adjuvant CT
CT
RT/CT CT
DFS from surgery of the primary to intrahepatic cancer relapse, months
Median
Range
No. of liver tumors
0
1
1
Liver lobes affected by metastases
1
2
Liver tumor size
5 cm
5 cm
mTNM stages after liver resection
x, no liver metastases
1, mT1N0M0
2, mT2N0M0
3, mT3N0M0
4a, mT4N0M0
Clinical risk score for cancer relapse
I, high
II, intermediate
III, low
ECOG performance status at study entry
0
1
CEA level at study entry/after liver resection, ng/mL
Median
Range

All Patients
(No.)

Eligible Patients According

to Study Protocol (No.)

23

19

13
10

12
7

61
44-76

63
44-76
9
12
2

7
10
2

2
6
7
8

2
4
6
7

11
4
8

9
4
6

9
1
9
4

7
1
8
3

13
0-153

1.9
0.5-5.6

7
0-41
2
8
13

7
12

13
8

11
8

17
4

15
4

2
0
8
5
8

0
0
7
4
8

3
14
6

3
12
4

22
1

19

1.9
0.5-5.6

Abbreviations: RAIT, radioimmunotherapy; UICC, International Union Against Cancer; RT/CT, chemoradiation; CT, chemotherapy; DFS, disease-free survival;
m, metastatic; ECOG, Eastern Cooperative Oncology Group; CEA, carcinoembryonic antigen.

Postoperative mTNM classification of liver metastases (LM) according to Gayowski et al21; definitions of mTNM stages are as follows: 1 (mT1) solitary
LM 2 cm; 2 (mT2) solitary LM 2 cm, unilobar; multiple LM 2 cm, unilobar; 3 (mT3) multiple LM 2 cm, unilobar; 4a (mT4) solitary or multiple
LM, bilobar; invasion of major vessels (portal vein and hepatic artery) or bile duct.

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Liersch et al

Table 2. Characteristics of CRC Patients, Chemotherapy Procedures, LM, RAIT Doses, RAIT-Induced Adverse Effects (n 23), and Outcome of RAIT in All
Eligible Patients (n 19)

Primary CRC

Patient Tumor UICC

No.
Site Stage

Postoperative
Therapy

CRC LM: Preoperative Therapy, Characteristics of

LM, mTNM, and Clinical Staging
No. of
Size of
Affected
Largest
Preoperative Liver
No. of Lesion mTNM
Therapy
Lobes Lesions (cm)
Stage CS

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

Colon
Rectum
Rectum
Both
Rectum
Both
Colon
Rectum
Colon
Rectum
Colon
Rectum
Rectum
Rectum
Colon
Colon

IV
III
III
II
IV
II
IV
III
IV
I
II
IV
IV
II
III
II

adja) RT/CT
neo1) RT/CT adj CT
adja) RT/CT
3
adjc) CT
adjb) CT
adja) RT/CT

adjc) CT

neo2) CT

neo4) CT
neo3) CT

neo2) CT

2
ND
2
2
2
1
ND
1
2
1
1
1
1
ND
2
1

2
ND
3
2
3
1
ND
1
2
3
1
1
3
ND
6
1

2.5
ND
3.0
4.0
2.5
2.2
ND
7.0
10.0
1.3
2.6
2.0
2.2
ND
3.0
8.5

17
18
19
20
21
22
23
9A
12A

Rectum
Rectum
Rectum
Rectum
Colon
Colon
Colon
Colon
Rectum

IV
I
IV
III
III
III
II
IV
IV

adja) RT/CT
adjb) CT
adjb) CT

neo2) CT
2
4

1
2

1
1

2
2
neo3) CT
1
4

1
2

ND
ND
RAIT re-treatment
RAIT re-treatment

3.5
3.5
9.5
2.7
6.0
3.5
ND

II

4
4
4
2

II
III
I
III

2
4
3
2
2
3

III
I
II
III
II
II

4
2

I
II

4
3
2
4
3
2

II
II
II
II
II
II

RAIT: Patient Age, RAIT Dose,

RAIT-Induced Hematologic
Adverse Effects (NCI-CTC
Version 2.0 Grading)

Follow-Up

Patient
Age at
WBC Platelets
Last
RAIT 131I-Level CTC
CTC
DFS
First CRC
OS
Performance
(years) (mCi/m2) Grade Grade (months) Relapse (months)
Status
47
53
65
70
69
64
50
53
54
76
68
63
60
49
60
64

40
45
45
45
50
50
50
50
55
55
55
55
60
60
60
60

0
0
3
0
3
2
0
2
3
2
1
0
2
1
3
4

0
0
3
0
2
2
1
2
3
0
0
0
3
0
3
3

18
ND
12
25
22
3
ND
71
23
18
68
31
11
ND
2
38

HEP
ND
HEP, PUL
PER
Local
Local
ND

HEP
Local

HEP
HEP
ND
PUL

55
ND
24
64
55
46
ND
71
70
23
68
69
42
ND
43
38

Dead
ND
Dead
Alive,
Alive,
Dead
ND
Alive,
Alive,
Dead
Alive,
Dead
Alive,
ND
Alive,
Alive,

44
60
67
61
61
64
62

60
60
60
60
60
60
60
40
60

1
0
4
2
2
4
3
2
1

0
3
4
3
3
3
1
2
3

5
16
5
23
5
4
ND

HEP
Local
HEP, PUL
PER, HEP
HEP
HEP
ND

25
43
17
40
9
29
ND

Dead
Alive, NED
Dead
Alive, SD
Dead
Dead
ND

PD
PD

NED
PD
NED
PD
PD
NED

Abbreviations: CRC, colorectal cancer; RAIT, radioimmunotherapy; LM, liver metastases; UICC, International Union Against Cancer; NCI-CTC, National
Cancer Institute Common Toxicity Criteria; FU, fluorouracil; adja) RT/CT, adjuvant, FU-based chemoradiation (RT/CT) according to the guidelines of the German
Cancer Society; adjb) CT, 3 cycles of folinic acid (500 mg/m2) followed by high-dose FU (2,600 mg/m2) chemotherapy (CT); adjc) CT, adjuvant, FU-based CT
according to the guidelines of the German Cancer Society; adjd) CT, adjuvant CT with biweekly irinotecan (80 mg/m2) and folinic acid (500 mg/m2) followed
by high-dose FU (2,600 mg/m2); adje) CT, adjuvant CT with weekly oxaliplatin (85 mg/m2) and folinic acid (500 mg/m2) followed by high-dose FU (2,600
mg/m2); neo1) RT/CT, neoadjuvant FU-based RT/CT in rectal cancer, followed by adjuvant FU-based CT, postoperatively; neo2) CT, neoadjuvant CT (3 cycles)
with folinic acid (500 mg/m2) followed by high-dose FU (2,600 mg/m2); neo3) CT, neoadjuvant CT (3 cycles) with biweekly oxaliplatin (85 mg/m2) and folinic
acid (500 mg/m2) followed by high-dose FU (2,600 mg/m2); neo4) CT, intrahepatic arterial infusion with FU and folinic acid in neoadjuvant intention for
resection of liver metastases, additionally 1 cycle of mitomycin was administered; RAIT, radioimmunotherapy re-treatment; after cancer recurrence, patients
9A and 12A were re-treated with RAIT; ND, data not shown, patients did not fulfill entry criteria for follow-up analysis; 3, chemotherapy followed in
neoadjuvant intention to achieve resectability of LM; CS, clinical prognostic score; DFS, disease-free survival; OS, overall survival; NED, no evidence of CRC
at restaging as of September 20, 2004; SD, stable disease under treatment with FU and irinotecan; PD, progressive disease; HEP, intrahepatic; PUL,
intrapulmonary; PER, peritoneal CRC relapse.

Cancer of bladder, second malignancy in patient 8 without recurrence of CRC during the whole follow-up.

Imaging, Toxicity, and Follow-Up

According to the study protocol, routine blood chemistry and
CBC counts with differential counts were obtained 2 weeks, and 1, 2,
and 3 months after antibody administration in cooperation with the
referring physicians and on an outpatient basis. Serum CEA levels
were controlled monthly, whereas CT scans (chest, abdomen, and
pelvis) were obtained at 1, 3, 6, and 12 months after RAIT. Thereafter,
abdominal ultrasound and/or CT studies were performed every 3 to 6
months. All adverse effects of RAIT were documented according to
the National Cancer Institute Common Toxicity Criteria (version 2.0;
http://ctep.cancer.gov/reporting/ctc.html).
Histopathology, Staging, and Risk Assessments
LM was diagnosed histologically in 21 patients, when tumor
staining for CEA was also confirmed (Table 1). Staging before
RAIT was performed according to the current TNM classification
of the International Union Against Cancer (UICC).22 Further6766

more, the size, quantity, and location of the LM were classified

according to the metastatic (m) TNM method and the determination of tumor-free margins (R classification).21,23
The risk of hepatic recurrence of CRC was assessed by a clinical
scoring system described previously,23,24 which provided an evaluation of such factors as lymph node metastases of primary CRC, serosal
infiltration of the primary tumor, a time interval of less than 2 years
from primary surgery to LM, less than 1-cm tumor-free margin of the
resected LM, more than four LM resected, more than 5-cm diameter
size of the LM, and more than 60 years of age.24,25 The high-risk score
(level I) included five to six of these factors; the intermediate-risk
score (level II) included three to four factors; and the low-risk score
(level III) included zero to two factors (Table 1).
Statistics
The Kaplan-Meier survival estimates method was used to
calculate OS and DFS with 95% CIs. With regard to DFS, all
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CEA Radioimmunotherapy After Resection in CRC

patients who remained without CRC relapse were censored at the

time of analysis; one patient survived cancer of the bladder without any signs of CRC relapse during the entire period of observation. Survival rates for 1, 2, and 5 years were calculated. The
analysis was performed using the statistical software R version
1.9.1 (http://www.r-project.org).
RESULTS

In the 23 patients entered, the primary disease site was colon

in nine patients, rectum in 12 patients, and both sites in two
patients (Table 1). The classification of rectal or colon cancer was based on the TNM/UICC classification used in Germany, which considers rectal cancer to extend to 16 cm
beyond the anal verge. If the US classification of up to 12 cm
beyond the anal verge were used, then the primary disease site
would be colon in 14 patients, rectal in seven patients, and both
sites in two patients. At primary surgery, 12 of 23 patients with
CRC had lymph node involvement. Fourteen patients received
adjuvant chemotherapy or chemoradiotherapy (Table 1).
Eight patients had synchronous hepatic metastases; the primary tumor stages were UICC stage I in two patients, UICC
stage II in six patients, UICC stage III in seven patients, and
UICC stage IV in eight patients (Table 1). In four patients with
synchronous LM at primary surgery (patients 5, 9, 13, and 17),
dose-intensified FU-based chemotherapy ( folinic acid
oxaliplatin) was administered to achieve resection of LM with
tumor-free margins (Table 2).
Both liver lobes were involved with metastases in eight
of 23 patients; and in 17 of 23 patients, the liver tumor size
was 5 cm in diameter. Postoperatively, the histopathologic findings of the resected liver tumors demonstrated
tumor-free margins in all patients; 13 of 23 patients had a
poor prognosis (mTNM stage 3) and a high risk for
hepatic recurrence. The clinical risk for developing a relapse
was high (level I) in three patients and intermediate (level
II) in 14 patients (Table 1). Despite this poor prognosis in
75% of the patients, they all had an acceptable performance
status and normal CEA serum levels at study entry (median,
1.9 ng/mL).
All 23 patients received a single infusion of 131Ilabetuzumab at a dose of 40 to 60 mCi/m2 (Table 2), and two
patients (patients 9A and 12A) received second infusions 5 and
31 months later as a result of disease recurrence. At first, lower
doses were administered in anticipation of optionally repeating the RAIT therapy later under the approved protocol, but
instead, for logistical reasons, all but two patients received only
one dose, and the majority of patients (15 of 23 patients) were
administered 55 to 60 mCi/m2. During the time of observation, no infusion-related events occurred. All severe toxicities
(grades 3 and 4) were hematologic. In 13 RAIT procedures
administered to 12 patients (patient 12A was re-treated), grade
3 or 4 hematologic toxicities (WBC, platelets, and hemoglobin) were observed without spontaneous bleeding during the

first 10 weeks after RAIT. Complete bone marrow recovery

resulted in all patients, with four patients requiring granulocyte colony-stimulating factor and one undergoing platelet
transfusions. These myelosuppressive side effects seemed to be
independent of prior chemotherapy. No cumulative toxicity
was documented in the two patients who were re-treated.
Although 23 patients were treated with 131I-labetuzumab,
19 were eligible according to the protocol for determining DFS
and OS (Table 1) because four patients (patients 2, 7, 14, and
23) had to be excluded, as described earlier. The median DFS
time (as of September 20, 2004) for 19 patients receiving RAIT
was 18.0 months (95% CI, 11.0 to 31.0 months). Current DFS
rates are 57.9% at more than 1 year and 26.3% at more than 2
years for these patients (Fig 1).
The median OS time from complete LM resection for
patients receiving RAIT was 68.0 months (95% CI, 46.0
months to infinity), and the survival rates are 94.7% at more
than 1 year, 78.9% at more than 2 years, and 51.3% at more
than 5 years (Fig 1). With a post-RAIT follow-up time of a
median of 64 months, 10 patients (52.6%) remain alive, and
four patients have no evidence of disease at the last date of
observation. One patient had stable disease, and five patients experienced progression (Table 2).
Cancer relapse after RAIT was primarily locoregional
in four patients, hepatic in seven patients, pulmonary or
peritoneal in two patients; and in three patients, there was
a combination of hepatic, peritoneal, and/or pulmonary
spread at the time of recurrence. Post-treatment follow-up
for up to a median of 64 months demonstrated DFS in four
patients (21.1%).
According to the mTNM stages and clinical risk levels
of the 19 patients, 12 patients had a poor prognosis (mTNM

Fig 1. Disease-free survival and overall survival (OS) after R0 resection of

liver metastases in patients (n 19) with postoperative radioimmunotherapy (RAIT).

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Liersch et al

stage 3 and risk level II), with eight patients having

bilobar LM and 17 having metastases more than 2 cm
(Tables 1 and 2). Interestingly, among the long-term survivors, there were four patients with mTNM stage 4 and two
patients with mTNM stage 3. Independently of the involvement of both liver lobes, the size of LM, and the width of
tumor-free margins at liver resection, these patients seemed
to benefit from RAIT.
DISCUSSION

Because two thirds of patients with salvage R0 resection of LM

have disease recurrence26 and only 10% to 20% are amenable
to curative resection,27 it is clear that some form of additional
therapy is essential. However, no randomized trial has been
reported that confirms the survival advantage of any postoperative therapy in this population. Justification for using adjuvant chemotherapy after resection of LM has been based on
data supporting the use of chemotherapy after resection of
primary tumors in patients with lymph node and/or distant
spread. The Eastern Cooperative Oncology Group reported
that intrahepatic artery infusions with floxuridine, combined
with continuous infusion of FU, may reduce the risk of recurrence compared with surgery alone, but there was no benefit in
overall survival.28 The use of intrahepatic artery infusions with
FU and folinic acid without systemic therapy demonstrated no
benefit over surgery alone.29 At this time, no chemotherapeutic intervention for the treatment of CRC after resection of LM
has been established, although recent promising results of improved survival as a result of drug combinations with or without antibody therapy provide such options.30,31 Hence,
therapeutic measures with good feasibility, safety, and an enhanced efficacy are needed to improve the outcome of patients
receiving salvage surgery for LM.
In this context, the anti-CEA RAIT investigated here
may provide such an option. Crossfire radiation from CEApositive cancer cells targeted by the radiolabeled antibody
may deliver tumoricidal doses to surrounding intrahepatic
tumor cells,19 especially to occult micrometastases smaller
than 1 mm, because the average path length of 131I is 0.8
mm.19 Indeed, the potential therapeutic effects of radiolabeled antibodies on occult micrometastases or minimal
disease have been described previously in preclinical models and clinical studies.14-16,19,32
In terms of safety, myelosuppression was the only significant toxicity, and a maximum single dose of 50 to 55
mCi/m2 seems to be safe for future trials. In addition, two
patients (patients 9A and 12A, both treated initially with 55
mCi/m2) were re-treated with 40 and 60 mCi/m2, respectively, without signs of cumulative toxicity, suggesting that
re-treatment after several months could be tolerated.
The median OS time from the first liver resection for
patients receiving RAIT was 68.0 months (95% CI, 46.0
6768

months to infinity), and on an intent-to-treat basis, including also four ineligible patients in the RAIT group, OS was
maintained, although this kind of analysis is usually made
in larger, phase III, randomized trials. The survival results in
the treated patients seem to be much longer than the median
survival of 28 to 40 months reported in the literature.9 This
survival advantage for patients receiving RAIT is confirmed
when they are compared with a group of 19 contemporaneous
patients at our institution who did not receive RAIT (13 of 19
of these patients received adjuvant chemotherapy after completion of resection of LM; data not shown). These patients,
who had similar demographics and prognostic risk scores to
the RAIT patient population, had a median overall survival
time of 31 months (95% CI, 24.0 to 59.0 months). The corresponding survival rates were 94.7% at more than 1 year, 78.9%
at more than 2 years, and 51.3% at more than 5 years for the
RAIT group, and 94.7% at more than 1 year, 64.9% at more
than 2 years, and 7.4% at more than 5 years for this control
population analyzed retrospectively (data not shown). At recurrence, all RAIT patients were treated by early surgical reintervention in cases of resectable disease or by different
chemotherapy regimens. Patients 8, 11, 16, and 18 in the RAIT
group remained disease free, and patients 9A and 12A were
re-treated with RAIT at first diagnosis of CRC relapse. Of
course, we appreciate that comparisons to historical or contemporaneous controls are not as rigorous as a randomized,
prospective trial, but the suggested improvement encourages
further study.
The median DFS time for patients receiving RAIT was
18 months (95% CI, 11 to 31 months). From the last date of
observation (September 20, 2004), 21% of patients remained without any signs of CRC. The DFS rates were
57.9% at more than 1 year and 26.3% at more than 2 years
for patients treated with RAIT (Fig 1).
When considering the prognostic risk scoring classifications, it was found that the patients had a better outcome
than would be predicted. In an analysis of 1,596 patients,
the 2-year survival rates after resection of LM were 43%,
60%, and 79% in patients with risk levels of I, II, and III,
respectively.24,25 However, 15 (79%) of 19 RAIT patients
with level I (n 3) and level II (n 12) risk scores had a
more than 2-year survival rate of 78.9% (compared with the
expected 43% to 60%) and a survival rate of 51% at 5 years
(v the expected 28%). Similarly, when comparing the outcome of RAIT patients by mTNM stage at resection in this
study, seven of 10 patients with advanced mTNM stages of 2
to 4 were long-term survivors (38 to 78 months), and four
of these patients with mTNM stage 2 (n 3) and stage 3
(n 1) remain free of disease over a median follow-up of 64
months (Table 2). Thus, these results suggest that RAIT has
a clinical benefit independent of the major risk factors, such
as bilobar involvement, size and number of LM, and resection margins.
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CEA Radioimmunotherapy After Resection in CRC

Our findings support the prospect of improving survival in patients with multiple LM from CRC by engaging a
multimodal approach, combining resection with systemic
RAIT. We appreciate that this was a single-institution study
with a relatively small number of patients, but over a long
median follow-up time of 64 months, our study clearly shows
that this adjuvant therapy is feasible and has survival results
that are double those reported in the literature and those of the
comparable, contemporaneous, control patients analyzed retrospectively at this same institution (data not shown). The
findings also provoke speculation that this modality may be
useful in neoadjuvant or adjuvant settings for primary CRC
therapy, either alone or in combination with other modalities,
particularly chemotherapy that potentiates radiation because
RAIT is targeted radiotherapy. Furthermore, recent experimental evidence demonstrated that nonradioactive labetuzumab is effective in inhibiting metastasis and enhancing the

effects of chemotherapy in a metastatic CRC xenograft model,33 suggesting that even higher doses of this antibody with
RAIT may increase efficacy.
In conclusion, this feasibility study of adjuvant RAIT in
CRC patients after salvage resection of LM provides the first
evidence of promising OS and 5-year survival rates. Therefore, these results require confirmation in a larger, multicenter, randomized trial, which is being developed.

Acknowledgment
This article is dedicated to the memory of Prof Wolfgang Becker, MD, who was an inspiration and participant in
these studies and who fostered cooperation between surgical and nuclear radiology specialties. He served with distinction as President of the European Association of
Nuclear Medicine, when he died so early and at the peak of
his career.

Authors Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members
indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the
investigation. For a detailed description of the disclosure categories, or for more information about ASCOs conflict of interest
policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Authors

Employment

William A. Wegener

Immunomedics, Inc

Leadership

Immunomedics, Inc
(C)

Jacqueline Kovacs

Immunomedics, Inc

Immunomedics, Inc
(A)

Ivan D. Horak

Immunomedics, Inc Immunomedics, Inc

(C)

Immunomedics, Inc
(C)

David M.
Goldenberg

Immunomedics, Inc Immunomedics, Inc

(C)

Immunomedics, Inc
(C)

Dollar Amount Codes

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