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24 Radioimmunoguided Surgery
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397
Finally, in 2003, Gu et al. [ 1 , 70 ] from Beijing
Cancer Hospital of Peking University (Beijing,
China) evaluated 29 patients with primary
colorectal cancer who were injected with 1 mCi
(37 MBq) of
125
I-anti-CEA murine MAb (
125
ICL58) into the colonic submucosa at the tumor
surrounding areas (at 2, 4, 6, 8, 10, and 12 o’clock
locations) via colonoscopy at a time of approximately 3–14 days prior to surgery. Tumor localization of
125
I-CL58 with a commercially
available gamma detection probe system was
seen in 27 of 29 (93.1 %) patients, and radioimmunoguided surgery correctly identifi ed negative
surgical resection margins in 42 of 44 (95.5 %)
H&E-negative surgical resection margin specimens. In this study, the authors reported that the
sensitivity (92.0 % vs. 60.0 %; p = 0.0087) and
specifi city (87.8 % vs. 79.2 %; p = 0.0117) of
radioimmunoguided surgery versus traditional
surgical exploration for correctly identifying
lymph node metastases was statistically signifi cantly greater for radioimmunoguided surgery.
24.6.1.6 Radioimmunoguided
Surgery Using Anti-A33
Transmembrane
Glycoprotein Antigen
Humanized Monoclonal
Antibody
In 2008, Strong et al. [ 142 ] at Memorial Sloan-
Kettering Cancer Center (New York, New York,
USA) reported on 2 patients with colorectal cancer undergoing radioimmunoguided surgery
124
using
I-huA33 MAb, a humanized MAb
directed against the A33 transmembrane glycoprotein antigen. Both patients were intravenously
injected with 4 mCi (148 MBq) of
124
I-huA33
MAb at approximately 7 days prior to surgery.
Whole-body positron emission tomography
(PET) imaging was performed within 4 h after
124
I-huA33 MAb injection and again at approxi-
mately 7 days after
124
I-huA33MAb injection
(but within 3 h of the start of surgery).
Radioimmunoguided surgery was undertaken
using a commercially available high-energy
gamma detection probe and a commercially
available beta detection probe, with in situ tumor
counts, in situ background, and ex situ tumor
counts taken. Postoperative specimen PET imaging was performed on surgically resected tissue.
They reported a signifi cantly greater tumor-tobackground count ratio for the beta detection
probe (approximately 6.2-to-1 to 6.3-to-1) as
compared to the high-energy gamma detection
probe (approximately 2.5-to-1 to 3.7-to-1).
24.6.1.7 Radioimmunoguided
Surgery Using a Multiple
Monoclonal Antibody
“Cocktail”
Clinical investigations into the use of a multiple
MAb “cocktail” in radioimmunoguided surgery
are limited to the reported experience of a group
of investigators from University of Milan (Milan,
Italy) [ 108 , 143 ].
In 1995, Di Carlo et al. [ 108 ] from University
of Milan (Milan, Italy) evaluated radioimmunoguided surgery using a doublet MAb “cocktail” of
125
125
I-biotinylated B72.3 murine MAb and
I-biotinylated F023C5 murine MAb in 16
colorectal cancer patients, including 6 with primary colorectal cancer and 10 with recurrent
colorectal cancer. The patients were intravenously injected with a total dose of approximately 2 mCi (74 MBq) of this MAb “cocktail”,
consisting of
125
and
125
I-biotinylated B72.3 murine MAb
I-biotinylated F023C5 murine MAb,
sequentially followed by a subsequent intravenous injection of 1 mg of avidin 48 h after the
initial MAb “cocktail” intravenous injection and
an additional intravenous injection of 3 mg of
avidin 24–48 h prior to surgery for promoting
more rapid clearance of the MAb “cocktail” from
the blood-pool circulation and subsequent surgery performed approximately 6 days after the
initial MAb “cocktail” intravenous injection.
Tumor localization of the doublet MAb “cocktail” with a gamma detection probe was successful in 12 of 16 (75 %) patients, including in 5 of
6 (83 %) primary colorectal cancer patients and
in 7 of 10 (70 %) recurrent colorectal cancer
patients. The intraoperative gamma detection
probe fi ndings were instrumental in modifying
the surgical therapeutic approach in 4 of 10
(40 %) recurrent colorectal cancer patients, thus
leading to removal of occult sites of disease that
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would have otherwise gone unrecognized by traditional intraoperative inspection and palpation
techniques alone.
In 1997, de Nardi et al. [ 143 ] from University
of Milan (Milan, Italy) evaluated radioimmunoguided surgery using a triplet MAb “cocktail”
125
of
I-biotinylated B72.3 murine MAb,
125
I-biotinylated F023C5 murine MAb, and
125
I-biotinylated F023C3 murine MAb in 14
colorectal cancer patients, including 8 with primary colorectal cancer and 6 with recurrent
colorectal cancer. The patients were intravenously injected with a total dose of approximately 2 mCi (74 MBq) of this MAb “cocktail”,
consisting of
125
MAb,
125
and
I-biotinylated F023C3 murine MAb, fol-
125
I-biotinylated B72.3 murine
I-biotinylated F023C5 murine MAb,
lowed by a subsequent intravenous injection of
1 mg of avidin 24–48 h after the initial MAb
“cocktail” intravenous injection for promoting
more rapid clearance of the MAb “cocktail”
from the blood- pool circulation (with a second
and third intravenous injection of avidin, if
needed) and subsequent surgery performed
approximately 4 days after the initial MAb
“cocktail” intravenous injection. Tumor localization of the triplet MAb “cocktail” with a
gamma detection probe was successful in 10 of
14 (71 %) patients, including in 6 of 8 (75 %)
primary colorectal cancer patients and in 4 of 6
(67 %) recurrent colorectal cancer patients. The
intraoperative gamma detection probe fi ndings
were instrumental in modifying the surgical
therapeutic approach in 2 of 6 (33 %) recurrent
colorectal cancer patients, thus leading to
removal of occult sites of disease that would
have otherwise gone unrecognized by traditional
intraoperative inspection and palpation techniques alone. The author postulated that radioimmunoguided surgery using a MAb “cocktail”
could improve the sensitivity of tumor detection
by allowing binding to more antigenic sites.
24.6.2 Gastric Cancer
The feasibility of radioimmunoguided surgery
for gastric cancer has been evaluated in a
somewhat limited fashion by several groups of
investigators [
1 , 98 , 144 – 148 ].
In 1988, Martin et al. [ 1 , 98 ] at The Ohio State
University (Columbus, Ohio, USA) evaluated
125
I-B72.3 murine MAb in 5 patients with gastric
cancer (including 3 primary gastric cancer
patients and 2 recurrent gastric cancer patients)
undergoing radioimmunoguided surgery. The
patients were intravenously injected with approximately 4–5 mCi (148–185 MBq) of
125
I-B72.3
murine MAb at a time of 5–23 days (mean 15
days) prior to surgery. Intraoperative fi nding at
the time of gamma detection probe assessment
revealed tumor localization in 4 of 5 gastric cancer patients (80 %), including correctly identifying lymph node metastases in 4 of 5 patients
(80 %).
In 1994, Xu et al. [ 1 , 144 ] and Liu et al. [ 1 ,
145 ] from Beijing Cancer Hospital of Peking
University (Beijing, China) evaluated
131
I-3H11,
a murine MAb raised against human gastric cancer cells, in 23 patients with primary gastric cancer undergoing radioimmunoguided surgery.
There were 19 patients who received an endoscopic submucosal injection of 0.25–0.8 mCi
(9.25–29.6 MBq) of
131
I-3H11 at 4 points around
the tumor, as well as 4 patients who received an
intravenous injection of a nonspecifi ed dose of
131
I-3H11. Of the 19 patients receiving an endo-
scopic submucosal injection of
131
I-3H11, 18
patients underwent intraoperative gamma detection probe assessment. They reported an ability
to detect “cancer infi ltration of the gastric wall”
with a sensitivity of 94.6 %, specifi city of 96.7 %,
and accuracy of 95.9 %. They reported detection
of metastatic lymph nodes with a sensitivity of
99.2 %, specifi city of 97.7 %, and accuracy of
98.8 %. The authors concluded that radioimmunoguided surgery “may improve the radical
resectability rate and possibly the overall survival
rate in patients with gastric cancer.”
In 1998, Lucisano et al. [
University of Genoa (Genoa, Italy) evaluated
1 , 146 ] from
125
IB72.3 murine MAb in 7 patients with gastric cancer undergoing radioimmunoguided surgery. The
patients were intravenously injected with approximately 2 mCi (74 MBq) of
125
I-B72.3 murine
MAb at a time of 14–30 days (mean 19 days)
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399
prior to surgery. The correct radioimmunoguided
surgery in situ identifi cation of the primary tumor
was seen in 4 of 7 patients (57 %) and of metastatic lymph nodes in 2 of 4 patients (50 %).
Also, in 1998, Mussa et al. [ 147 ] from
University of Turin (Turin, Italy) evaluated
111
InB72.3 murine MAb in 3 patients with gastric cancer undergoing radioimmunoguided surgery. The
patients were intravenously injected with approximately 5 mCi (185 MBq) of
111
In-B72.3 murine
MAb at a time of 7 days prior to surgery.
Intraoperative gamma detection probe assessment
confi rmed in situ tumor-to-background counts of
greater than 2 in all 3 cases and, based upon all
primary tumor site and lymph node basins examined, demonstrated a sensitivity of 100 %, specifi city of 72 %, and no false-negative fi ndings.
Finally, in 2000, Wang et al. [ 148 ] from
Beijing Medical University (Peking, China) eval-
125
uated
I-3H11 murine MAb in 35 patients with
primary gastric cancer undergoing radioimmunoguided surgery. All patients received an endoscopic submucosal injection of a nonspecifi ed
dose of
125
I-3H11 around the tumor at a time of
4–11 days prior to surgery. Of the 35 patients
injected, 33 underwent subsequent successful
radioimmunoguided surgery. They demonstrated
a sensitivity of 83.6 %, specifi city of 95.0 %, and
accuracy of 91.3 % for the detection of lymph
node metastases. The presence of micrometastatic lymph node disease was verifi ed immunohistochemically in 10 of 19 (52.6 %) lymph
nodes that were radioimmunoguided surgery
positive but were H&E negative.
Despite these early promising results, no further clinical investigations into the clinical utility
of radioimmunoguided surgery for gastric cancer
have been subsequently pursued.
24.6.3 Pancreatic Cancer
The feasibility of radioimmunoguided surgery
for pancreatic cancer has been previously
evaluated in an extremely limited fashion [ 1 ,
139 , 149 ].
In 1997, LaValle et al. [ 1 , 149 ] from The
Ohio State University (Columbus, Ohio, USA)
evaluated radioimmunoguided surgery for assessing of the extent of disease in 10 cases of pancreatic adenocarcinoma that were deemed resectable
by preoperative CT scan, including 9 patients
with primary lesions and 1 patient with a presumed solitary hepatic metastasis at a time of 1
year following prior pancreaticoduodenectomy.
The patients were intravenously injected with
125
2 mCi (74 MBq) of
I-CC49 murine MAb and
then underwent surgery after adequate clearance
of the blood-pool background was determined by
precordial gamma detection probe counts at a
mean time of 26.1 days (range 7–35 days) after
injection. At the time of surgery, patients underwent surgical exploration at the time of laparotomy using traditional inspection and palpation,
followed by a systematic re-exploration of the
surgical fi eld using a commercially available
gamma detection probe system. There were 3
patients who ultimately underwent pancreatic
resection for locoregional disease, whereas the
other 7 patients had visceral metastases, carcinomatosis, or both that were detected at the time of
laparotomy. All sites suspicious for tumor by traditional inspection and palpation assessment of
the abdomen were verifi ed to be radioimmunoguided surgery positive. However, additional occult
pancreatic adenocarcinoma was identifi ed by
radioimmunoguided surgery assessment alone,
demonstrating dissemination of disease to both
the abdominal viscera and lymph nodes.
Radioimmunoguided surgery assessment
detected signifi cantly more total sites (viscera
and lymph node sites) of metastatic disease than
traditional inspection and palpation assessment
(73 sites vs. 31 sites for radioimmunoguided surgery assessment vs. traditional inspection and
palpation assessment, respectively, p < 0.05),
with the greatest difference being observed for
lymph node metastases (44 sites vs. 6 sites for
radioimmunoguided surgery assessment vs. traditional inspection and palpation assessment,
respectively, p < 0.001).
In 2000, Mayer et al. [
139 ] from University
College London (London, United Kingdom)
evaluated
125
I-MFE-23-his, an anti-CEA murine
single-chain monoclonal antibody fragment, in a
single patient with hepatic metastases from
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pancreatic cancer undergoing radioimmunoguided surgery, as well as in addition to 34 other
patients with colorectal cancer. However, the
details regarding the radioimmunoguided surgery
procedure fi ndings for the single patient with
hepatic metastases from pancreatic cancer were
not described in this report.
Despite these early promising results, no further clinical investigations into the clinical utility
of radioimmunoguided surgery for pancreatic
cancer have been subsequently pursued.
24.6.4 Breast Cancer
The feasibility of radioimmunoguided surgery
for breast cancer has been evaluated in a somewhat limited fashion by several groups of investigators [ 1 , 98 , 110 , 150 – 153 ].
In 1989, Nieroda et al. [ 1 , 98 , 150 ] from The
Ohio State University (Columbus, Ohio, USA)
evaluated radioimmunoguided surgery for the
intraoperative assessment of 14 patients with
breast cancer undergoing either modifi ed radical
mastectomy or breast-conserving surgery and
axillary lymph node dissection. All patients were
intravenously injected with 5 mCi (185 MBq) of
125
I-B72.3 murine MAb at a time of 6–24 days
prior to surgery. A commercially available
gamma detection probe system was used intraoperatively for determining in situ and ex situ probe
counting within the breast tissue and the axillary
tissue. Gamma probe counting correctly identifi ed histologically confi rmed tumor in 7 of 8
patients (88 %) with an intact breast tumor and
correctly confi rmed the absence of tumor in 4 of
6 patients (67 %) with no residual intact breast
tumor (secondary to a prior diagnostic surgical
excisional breast biopsy). Gamma probe counting within the breast tissue was suspicious in 2 of
14 patients in which histopathology could not
confi rm residual tumor within the breast tissue.
Unexpected occult breast tumor was identifi ed in
3 of 14 patients (21 %). In the axillary tissues,
probe counting identifi ed 1 of 2 cases (50 %) of
histologically confi rmed lymph node involvement and confi rmed the absence of lymph node
involvement in 8 of 12 patients (67 %). Gamma
probe counting within the axillary tissues was
suspicious for lymph node involvement in 4 of 14
patients (29 %) in which histopathology could
not confi rm lymph node involvement. The
authors concluded that radioimmunoguided surgery appeared to be useful for identifi cation of
residual, subclinical, and multicentric carcinoma
of the breast and accurately delineates the pattern
of antigenic drainage of tumor into the regional
lymph nodes.
In 1996 and again identically re-reported in
1998, Percivale et al. [ 1 , 151 ], Badellino et al. [ 1 ,
152 ], and Bertoglio et al. [ 110 ] from University
of Genoa (Genoa, Italy) evaluated radioimmunoguided surgery for the intraoperative assessment of 21 patients with locally advanced breast
cancer who underwent 3 cycles of neoadjuvant
fl uorouracil, epidoxorubicin, and cyclophosphamide prior to surgery with modifi ed radical mastectomy. Patients were intravenously injected
with either 1.5 mCi (56 MBq) of
125
I-B72.3
murine MAb ( n = 11) or 1.5 mCi (56 MBq) of
125
I- F023C5 (an anti-CEA murine MAb fragment) ( n = 10) at a mean time of 21.7 or 10.3 days,
respectively, prior to the surgical procedure. A
commercially available gamma detection probe
system was used intraoperatively for determining
in situ and ex situ gamma probe counting within
the breast tissue, axillary region, and internal
mammary region. In the
125
I-B72.3 murine MAb
group, radioimmunoguided surgery correctly
identifi ed the primary breast tumor in 7 of 11
patients (64 %) and identifi ed occult multicentric
disease in 2 of 4 patients (50 %). Likewise, in the
125
I-B72.3 murine MAb group, there were 8 of 11
patients (73 %) who had histologically confi rmed
lymph node involvement, with 3 of 8 such
patients (38 %) correctly identifi ed by radioimmunoguided surgery. In the
125
I- F023C5 group,
radioimmunoguided surgery correctly identifi ed
the primary breast tumor in 4 of 10 patients
(40 %) and identifi ed occult multicentric disease
in 1 of 2 patients (50 %). Likewise, in the
125
IF023C5 group, there were 9 of 10 patients (90 %)
who had histologically confi rmed lymph node
involvement, with 3 of 9 such patients (33 %)
correctly identifi ed by radioimmunoguided surgery. There were no false-positive results
24 Radioimmunoguided Surgery
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401
observed in either group. The authors concluded
that radioimmunoguided surgery appeared to be
safe and reliable technique for intraoperative
assessment of breast cancer; however, since
radioimmunoguided surgery did not identify all
neoplastic tissue, further investigations using
other more breast-specifi c MAbs would be
warranted.
In 2001, Burak et al. [ 1 , 153 ] from The Ohio
State University (Columbus, Ohio, USA) evaluated radioimmunoguided surgery for the intraoperative assessment of 10 patients with breast
cancer undergoing primary tumor excision.
Patients were intravenously injected with 2 mCi
(74 MBq) of
125
I-labeled NR-LU-10, an anti17- 1A murine MAb fragment, at 2, 4, or 7 days
prior to surgery. Preoperative pharmacokinetics
were evaluated. A commercially available gamma
detection probe system was used for determining
in situ and ex situ gamma probe counting of the
primary breast tumor, as well as in situ gamma
probe counting of the resection cavity and ex situ
gamma probe counting of excised cavity resection margin specimens. Gamma probe counting
of the breast tumor in situ was able to distinguish
tumor from surrounding nonmalignant background tissues in only 7 of 10 patients (70 %),
secondary to elevated levels of the gamma probe
counts noted within the surrounding nonmalignant background tissues in those 3 cases. Normal
surrounding nonmalignant breast tissues had the
highest relative amount of radioactivity within
the central/periareolar breast region. However, ex
situ gamma probe counting of the breast tumor
after tumor excision in those 3 cases subsequently
showed elevated tumor-to-surrounding nonmalignant background tissue gamma probe count
ratios. There were 12 of 38 H&E-negative excised
cavity resection margin specimens which showed
elevated levels of the gamma probe counts, representing only a 32 % specifi city. The authors concluded that
125
I-labeled NR-LU-10 had favorable
pharmacokinetics and tumor-binding ability as a
targeting agent for breast cancer; yet its binding
to in situ surrounding nonmalignant breast tissue
and elevated gamma probe counts in H&Enegative excised cavity resection margin specimens limited its potential role for intraoperative
in situ tumor identifi cation and evaluation of
tumor surgical resection margins.
At the current time, despite the development of
MAbs targeted against human epidermal growth
factor receptor 2 (Her2/neu) and for which Her2/
neu is overexpressed in approximately 15–30 % of
breast cancers, there have been no subsequent clinical investigations into the potential feasibility and
role of radioimmunoguided surgery using MAbs
targeted against Her2/neu in Her2/neu-positive
breast cancer patients.
24.6.5 Ovarian Cancer
The feasibility of radioimmunoguided surgery
for ovarian cancer has been previously evaluated
in a limited fashion by various groups of investigators [ 1 , 98 , 114 , 154 – 160 ]. The fi rst descrip-
tion of radioimmunoguided surgery for ovarian
cancer was reported in 1988 by Martin et al. [ 1 ,
98 ] at The Ohio State University (Columbus,
Ohio, USA). Patients planned for a second-look
laparotomy after postoperative systemic chemotherapy were intravenously injected with approximately 4–5 mCi (148–185 MBq) of
murine MAb at a time of 7–20 days (mean 13
days) prior to surgery. Intraoperative fi ndings at
the time of gamma detection probe assessment
using a commercially available gamma detection
probe system were mixed, revealing defi nite
tumor localization in only 4 of 8 ovarian cancer
patients (50 %), with 1 patient having borderline
tumor localization and with 3 patients having no
tumor localization by radioimmunoguided surgery. Of the 3 patients having no tumor localization by radioimmunoguided surgery, 1 patient
had micrometastatic disease detected at secondlook laparotomy, and 2 patients had obvious
tumor at the time of traditional inspection and
palpation assessment during second-look
laparotomy.
In 1989, Gitsch et al. [
University of Vienna (Vienna, Austria) evaluated
radioimmunoguided surgery in 12 patients with
ovarian cancer, including 4 patients with primary
ovarian cancer and 8 patients strongly suspected
to have recurrent ovarian cancer who were
125
I-B72.3
154 – 156 ] from
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undergoing second-look laparotomy. Patients
were intravenously injected with 3 mCi
(111 MBq) of
131
I-OC-125 (an anti-CA-125
murine MAb which is specifi cally targeted
against the MUC16 antigen) at a time of up to 8
days prior to surgery. A prototype gamma detection probe system was utilized for intraoperative
tumor localization. The presence of tumor localization with
131
I-OC-125 was correctly confi rmed
in 6 of 8 patients (75 %) with histologically confi rmed disease, and the absence of tumor localization with
131
I-OC-125 was correctly confi rmed
in all 4 patients (100 %) without any histologically confi rmed disease.
In 1990, Bell et al. [ 157 ] from The Ohio State
University (Columbus, Ohio, USA) and Riverside
Methodist Hospital (Columbus, Ohio, USA)
evaluated radioimmunoguided surgery in 9
patients suspected of recurrent ovarian cancer
who were undergoing second-look laparotomy
and who were intravenously injected with
approximately 4–5 mCi (148–185 MBq) of
125
IB72.3 murine MAb at a time of 12–28 days
(mean 14 days) prior to surgery. Intraoperative
fi ndings using a commercially available gamma
detection probe system were again mixed.
Gamma detection probe assessment correctly
detected true positive counts in 3 of 6 evaluable
patients (50 %) with histologically confi rmed
disease. There was 1 patient with histologically
confi rmed disease who was unevaluable secondary to high background counts. Conversely,
gamma detection probe assessment correctly
detected true negative counts in 1 of 2 evaluable
patients (50 %) without histologically confi rmed
disease.
In 1990, Jäger et al. [
158 ] from University of
Erlangen-Nürnberg (Erlangen, Germany) evaluated radioimmunoguided surgery in 22 patients
with suspected recurrent ovarian cancer undergoing a planned second-look laparotomy after prior
administration of postoperative systemic chemotherapy using a
antibody fragment (
131
I-OC-125 murine monoclonal
131
I-IMACIS II). Patients
were intravenously injected with approximately
1.9–3.0 mCi (70–110 MBq) of
131
I-IMACIS II
MAb at a time of 4–13 days (mean 8 days) prior
to surgery. Histologic confi rmation of recurrent
disease at second-look laparotomy was found in
10 of 22 patients (45 %). At the time of secondlook laparotomy, traditional inspection and palpation assessment identifi ed the histologically
confi rmed disease in only 4 of those 10 patients
(40 %), while radioimmunoguided surgery identifi ed the histologically confi rmed disease in 9 of
those 10 patients (90 %), with histologically confi rmed disease being identifi ed solely by radioimmunoguided surgery in 6 of those 10 patients
(60 %). Although there were 7 of 12 patients
(58 %) without histologically confi rmed disease
who had elevated gamma probe counts at the time
of radioimmunoguided surgery, it is very noteworthy to emphasize that 6 of those 7 patients
(85 %) without histologically confi rmed disease
but who had elevated gamma probe counts at
radioimmunoguided surgery developed clinically
detectable signs of disease progression within a
4-month time frame after their second-look laparotomy procedure. The authors concluded that
radioimmunoguided surgery was potentially helpful for detecting cancerous tissues at the time of
second-look laparotomy and for defi ning patients
at increased risk for early recurrence of disease.
In 1992, Krag et al. [
114 ] from University of
California at Davis (Sacramento, California, USA)
and University of Vermont (Burlington, Vermont,
USA) evaluated radioimmunoguided surgery in 5
patients with suspected recurrent ovarian cancer
undergoing a planned second- look laparotomy
after prior postoperative systemic chemotherapy
111
using
In-CYT-103. Patients were intravenously
injected with approximately 5 mCi (185 MBq) of
111
In-CYT-103 at a time of 4–15 days prior to surgery. At the time of surgery, patients underwent
surgical exploration at the time of laparotomy
using traditional inspection and palpation, followed by a systematic re-exploration of the surgical fi eld using a commercially available gamma
detection probe system. However, the authors did
not perform a subgroup analysis of their data for
the 5 patients with suspected recurrent ovarian
cancer as compared to the other 8 included patients
with colorectal cancer, thus making it impossible
to gleam any information regarding their radioimmunoguided surgery experience specifi cally with
ovarian cancer.
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403
In 1994, Ind et al. [ 159 ] from Saint
Bartholomew’s Hospital (London, United
Kingdom) evaluated radioimmunoscintigraphy
and radioimmunoguided surgery in 16 patients
with proven or suspected ovarian cancer, specifi cally using
99m
Tc-SM3 murine MAb (which binds
with an epitope on polymorphic epithelial mucin,
MUC1) in 15 patients and
99m
Tc-H17E2 murine
MAb (which binds with an epitope on placentalderived and germ cell-derived alkaline phosphatase) in 1 patient. Patients were intravenously
injected with 16.2 mCi (600 MBq) of
99m
or
Tc-H17E2 at a time of approximately
99m
Tc-SM3
24–30 h prior to radioimmunoguided surgery.
Radioimmunoscintigraphy was performed 10
min, 4–6 h, and 20–24 h after injection of the
99m
Tc-labeled murine MAb. Radioimmunoscintig-
raphy demonstrated tumor localization of
99m
TcSM3 in 8 of 8 patients with ovarian cancer, in 3 of
6 patients with benign ovarian tumors, and in 1
patient with an ovarian metastasis from
colonic adenocarcinoma. Radioimmunoscintigraphy demonstrated tumor localization of
99m
TcH17E2 in the 1 patient with an ovarian cancer.
The authors’ presentation of their gamma detection probe data was somewhat restricted, thus
limiting an in-depth analysis of their result.
However, the authors did report that the use of the
gamma detection probe during radioimmunoguided surgery had an 82 % sensitivity and a 72 %
specifi city for detecting malignancy when the
tumor-to-background uptake ratio exceeded 1.5to-1.0 and had a 68 % sensitivity and an 81 %
specifi city for detecting malignancy when the
tumor-to-background uptake ratio exceeded 2.3to-1.0. The authors concluded that radioimmunoscintigraphy and radioimmunoguided surgery
had potential clinical benefi t for perioperative
localization of ovarian cancer at laparotomy.
In 1997, McIntosh et al. [
160 ] from the
University of Nebraska (Omaha, Nebraska, USA)
evaluated 10 patients with ovarian cancer undergoing a planned second-look laparotomy after
completing prior primary treatment using
125
ICC49 murine MAb. Patients were intravenously
injected with approximately 2 mCi (74 MBq) of
125
I-CC49 murine MAb at a time of 23–27 days
(mean 24.5 days) prior to surgery. At the time of
surgery, patients underwent surgical exploration
at the time of laparotomy using traditional inspection and palpation, followed by a systematic reexploration of the surgical fi eld using a
commercially available gamma detection probe
system. At the time of second-look laparotomy, 6
of 10 patients were ultimately found to have histologically confi rmed disease, and 4 of 10 patients
were ultimately not found to have histologically
confi rmed disease. At the time of second-look
laparotomy, traditional inspection and palpation
assessment deemed 4 of 10 patients as cancer
positive, with all 4 of those patients having histologically confi rmed disease but with only 2 of
those 4 patients being assessed as gamma detection probe positive. At the time of second-look
laparotomy, traditional inspection and palpation
assessment deemed 6 of 10 patients as cancer
negative, with 4 of 6 of those patients having no
histologically confi rmed disease. Whereas, radioimmunoguided surgery with the gamma detection
probe judged 5 of those 6 traditional inspectionand palpation-assessed cancer- negative patients
as gamma detection probe positive, with 2 of
those 5 gamma detection probe-positive but traditional inspection- and palpation-assessed cancernegative patients having histologically confi rmed
disease. Of those 4 patients who were ultimately
not found to have histologically confi rmed disease at the time of second-look laparotomy (and
who incidentally all initially judged as cancer
negative by traditional inspection and palpation
assessment), 3 patients were initially judged as
gamma detection probe positive. Interestingly, 2
of those 3 gamma detection probe-positive
patients without histologically confi rmed disease
at the time of second- look laparotomy went on to
develop clinical/radiographic detectable recurrent
disease at 24 and 42 months after radioimmunoguided surgery. The authors concluded that
radioimmunoguided surgery permitted occult disease detection that could potentially lead to benefi cial changes in patient management.
Despite these multiple early reports showing
promising results, no further clinical investigations into the clinical utility of radioimmunoguided surgery for ovarian cancer have been
subsequently pursued.
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24.6.6 Prostate Cancer
The feasibility of radioimmunoguided surgery
for prostate cancer has been previously evaluated
in an extremely limited fashion, consisting of a
small clinical report using
MAb [ 1 , 161 ] and a single patient case report
111
using
In-capromab pendetide [ 1 , 162 ].
In 1993, Badalament et al. [ 1 , 161 ] from The
Ohio State University (Columbus, Ohio, USA)
reported on the feasibility of radioimmunoguided surgery in a clinical series of 10 patients
with prostate cancer who were planned for radical retropubic prostatectomy and bilateral pelvic
lymphadenectomy. Patients were intravenously
injected with approximately 2 mCi (74 MBq) of
125
I-CC49 murine MAb at a time of 17–38 days
(mean 26.3 days) prior to surgery. Intraoperative
gamma detection probe assessment during radioimmunoguided surgery successfully localized
tumor within the prostate of all 10 patients.
Likewise, intraoperative gamma detection probe
assessment was able to identify otherwise clinically occult bilateral intraprostatic tumor in 3
patients. Furthermore, intraoperative gamma
detection probe assessment was able to correctly
identifi ed regional lymph node metastases in 2
patients. The authors concluded that radioimmunoguided surgery was technically feasible during radical prostatectomy and pelvic
lymphadenectomy and could be a future useful
adjunctive tool during laparoscopic pelvic
lymphadenectomy.
In 2000, Anderson et al. [
Anderson Regional Medical Center (Meridian,
Mississippi, USA) reported on a single patient
with suspected metastatic prostate cancer. The
patient was intravenously injected with 5 mCi
(185 MBq) of
111
In-capromab pendetide, a
murine MAb that recognizes prostate-specifi c
membrane antigen. Planar gamma camera
imaging and SPECT was undertaken on day 0
and day 4, showing uptake within the prostate,
mesenteric lymph nodes, right pulmonary
hilum, and the left supraclavicular region. In
order to confi rm a diagnosis of metastatic prostate cancer, the patient subsequently received a
repeat intravenous injection of 5 mCi
125
I-B72.3 murine
1 , 162 ] from
111
(185 MBq) of
In-capromab pendetide and
then underwent radioimmunoguided surgery at
a time of 4 days after the repeat
111
In-capromab
pendetide injection. At the time of radioimmunoguided surgery, successful gamma detection
probe-directed surgical excision of a gamma
detection probe-positive (but clinically occult)
left supraclavicular lymph node was accomplished. The gamma detection probe-positive
left supraclavicular lymph node contained metastatic prostate cancer, thus providing histologic confi rmation of the diagnosis of metastatic
prostate cancer.
Despite these two early promising reports, no
further clinical investigations into the clinical
utility of radioimmunoguided surgery for prostate cancer have been subsequently pursued.
24.6.7 Clear Cell Renal Cell Cancer
The feasibility of radioimmunoguided surgery
for clear cell renal cell cancer has been previously evaluated in a limited fashion, consisting of
two small case series reports [ 1 , 84 , 142 ].
In 2008, Strong et al. [ 1 , 142 ] at Memorial
Sloan-Kettering Cancer Center (New York,
New York, USA) reported on 2 patients with clear
cell renal cell cancer undergoing radioimmunoguided surgery using
were intravenously injected with 5 mCi (185 MBq)
124
of
I-cG250 approximately 7 days prior to surgery. Whole-body PET imaging was performed
within 4 h after
again at approximately 7 days after
MAb injection (but within 3 h of the start of surgery). Radioimmunoguided surgery was undertaken using a commercially available high-energy
gamma detection probe and a commercially available beta detection probe, with in situ tumor
counts, in situ background, and ex situ tumor
counts taken. Postoperative specimen PET imaging was performed on surgically resected tissue.
There was no signifi cant difference in the tumorto- background count ratio detected by the highenergy gamma detection probe (approximately
2.8-to-1 to 3.5-to-1) as compared to the beta detection probe (approximately 2.2-to-1 to 2.4-to-1).
124
I-cG250 MAb. Both patients
124
I-cG250 MAb injection and
124
I-cG250
24 Radioimmunoguided Surgery
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405
In 2013, Povoski et al. [ 84 ] from The Ohio
State University (Columbus, Ohio, USA)
reported on a multimodal imaging and detection
approach in 2 patients with clear cell renal cell
cancer using
124
I-cG250 MAb. Patient 1 was
intravenously injected with 5.4 mCi (200 MBq)
124
of
I-cG250 at 4 days prior to surgery. Patient 1
underwent preoperative PET imaging, followed
by a laparoscopic right radical nephrectomy with
retroperitoneal lymph node dissection, with
intraoperatively utilization of a commercially
available laparoscopic gamma detection probe
for in situ and ex situ counting. The laparoscopic
gamma detection probe correctly identifi ed
increased
124
I-cG250 MAb activity within the primary tumor of the right kidney, as well as within
adjacent retroperitoneal lymph node tissues.
Postoperative specimen PET imaging was performed on intact excised right radical nephrectomy specimen and the intact excised
retroperitoneal lymph node dissection specimen,
clearly identifying the sites of disease within
both excised specimens. Patient 2 was intravenously injected with 5.2 mCi (192 MBq) of
124
IcG250 at 5 days prior to surgery. Patient 2
underwent preoperative PET imaging, followed
by an open right partial nephrectomy of the inferior pole of the right kidney. At the discretion of
the operating surgeon, an intraoperative gamma
detection probe was not utilized during the surgical procedure. However, postoperative specimen
PET imaging was performed on both the intact
excised right partial nephrectomy specimen and
on the excised right partial nephrectomy specimen after post-excisional specimen bisection,
clearly identifying the tumor size and tumor location within the intact and bisected specimens and
the relationship of the tumor to the adjacent normal parenchymal surgical resection margin surface within the bisected specimen. In their report,
Povoski et al. [
124
I-cG250 MAb multimodal imaging and detec-
84 ] discussed that this innovative
tion approach appeared to be useful for accurate
preoperative and intraoperative localization and
confi rmation of complete removal of all sites of
disease during both laparoscopic and open surgical resection of clear cell renal cell cancer and for
cases with or without known/suspected regional
lymph node involvement. Furthermore, they went
on to concluded that (1) as specifi cally pertaining
to laparoscopic surgical resection of clear cell
renal cell cancer, this approach could allow for
identifi cation and complete surgical resection of
the known primary tumor and of any sites of
occult disease (i.e., regional lymph node metastases) by a minimally invasive laparoscopic surgical approach, which otherwise would not be
124
technically feasible without the aid of the
IcG250 MAb targeting agent; (2) as specifi cally
pertaining to attempted partial nephrectomy by
either laparoscopic or open surgical resection for
patients with early-stage clear cell renal cell cancer, this approach could improve the success rate
of complete surgical resection by providing supplemental confi rmatory information to the urologic surgeon and the pathologist about the
kidney parenchyma surgical resection margin
status; and (3) as specifi cally pertaining to radical
nephrectomy by either laparoscopic or open surgical resection of more advanced-stage but still
potentially surgically resectable disease (i.e.,
such as larger primary tumors and/or bulky
regional lymph node involvement), this approach
could be advantageous for providing intraoperative guidance to the urologic surgeon for assessing the exact extent of disease and for confi rming
completeness of surgical resection.
Despite these two promising reports, no further clinical investigations into the clinical utility
of radioimmunoguided surgery for clear cell
renal cell cancer have been subsequently
described.
24.6.8 Lung Cancer
The feasibility of radioimmunoguided surgery
for lung cancer has been previously investigated
in an extremely limited fashion by two groups of
investigators [ 1 , 163 , 164 ].
In 1998, Grazia et al. [ 1 , 163 ] from University
of Bologna (Bologna, Italy) reported on the feasibility of radioimmunoguided surgery in a small
clinical series of 8 patients with primary adenocarcinoma of the lung using
MAb. Patients were intravenously injected with
125
I-B72.3 murine
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S.P. Povoski et al.
0.9–1.5 mCi (33–56 MBq) of
125
I-B72.3 murine
MAb at a time of 11–44 days (mean 20.4 days)
prior to surgery. Tumor localization of
125
I-B72.3
murine MAb was demonstrated during radioimmunoguided surgery in all 8 patients (100 %)
with histologically confi rmed primary adenocarcinoma of the lung. However, they did encounter
persistently elevated precordial counts over the
region of the heart in 2 of 8 patients with primary
adenocarcinoma of the lung. The authors concluded that this high radioactive background
count activity found over the region of the heart
within these two particular cases could represent
a potential limiting factor for successful gamma
detection probe assessment within the thorax.
In 1998, Mansi et al. [ 1 , 164 ] from Second
University of Naples (Naples, Italy) reported on
radioimmunoguided surgery performed on a single patient with primary non-small cell lung cancer using
125
I-B72.3 murine MAb and on a single
patient with squamous cell lung cancer using
99m
Tc-F023C5 murine MAb fragment. The
patient with primary non-small cell lung cancer
was intravenously injected with 2 mCi (74 MBq)
125
of
I-B72.3 murine MAb and underwent radioimmunoguided surgery 29 days following injection, and for which there was no in situ selective
localization of
125
I-B72.3 murine MAb detected
within the area of the primary lung tumor with
the gamma detection probe at the time of surgery.
The patient with squamous cell lung cancer was
intravenously injected with 15 mCi (555 MBq) of
99m
Tc-F023C5 murine MAb fragment and underwent radioimmunoguided surgery 36 h following
injection. In this particular patient, there was no
in situ selective localization of
99m
Tc-F023C5
murine MAb fragment to the primary lung tumor,
but for which there was in situ selective localiza-
99m
tion of
Tc-F023C5 murine MAb fragment to a
small lymph node metastasis detected by the
gamma detection probe at the time of surgery
(and for which this small lymph node metastasis
was not previously identifi able on preoperative
diagnostic computed tomography or radioimmunoscintigraphy). Furthermore, the authors
reported that the resected primary lung tumor and
the resected small lymph node metastasis from
this patient both demonstrated a 2:1 tumor-to-
background count ratio on ex situ counting with
the gamma detection probe.
24.6.9 Squamous Cell Cancer
of the Skin of the Face
and Scalp
The feasibility of radioimmunoguided surgery
for squamous cell carcinoma of the skin has been
limited to a single published report in the literature by Argenzio et al. [ 1 , 165 ] from Second
University of Naples (Caserta, Italy) in 1999. In
this report, they described 2 patients with squamous cell carcinoma of the skin of the face and
scalp region who were intravenously injected
with 15 mCi (555 MBq) of
99m
Tc-anti-CEA murine MAb fragment.
99m
Tc-F023C5, a
Diagnostic gamma camera imaging was performed at 4 and 12 h after injection of
99m
Tc-
F023C5. Subsequently, 36 h after injection of
99m
Tc-F023C5, intraoperative gamma detection
probe assessment was performed using a commercially available gamma detection probe system to defi ne the boundaries of the primary
tumor, guide the extent of the surgical resection,
and assess the adequacy of the surgical resection
margins. The authors reported that a tumor-tobackground tissue ratio of greater than 2 was a
clearly discriminate value for defi ning diseased
tissue and concluded that radioimmunoguided
surgery had a potential role in the surgical management of squamous cell carcinoma of the skin.
However, no other such reports have been published since that time.
24.6.10 Recurrent Medullary
Thyroid Cancer
The feasibility of radioimmunoguided surgery
for recurrent medullary thyroid cancer has been
evaluated in a limited fashion by several groups
of investigators [ 1 , 166 – 168 ].
From 1993 to 1998, Peltier, Barbet, and colleagues [ 1 , 166 , 167 ] from multiple medical
institutions across France reported on radioimmunoguided surgery using a combination of four
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