Multimodal sequential approach in colorectal cancer liver metastases: hepatic resection after yttrium-90 selective internal radiation therapy and cetuximab rescue treatment.
ABSTRACT Synchronous or metachronous liver metastases occur in up to one-third of patients with colorectal cancer and are associated with a poor prognosis. Many evidences have shown that surgical resection can be curative, with 5-year survival rates ranging from 37% to 50%, but many patients are ineligible for surgery because of multiple liver lesions, bilobar distribution of liver metastases, or the presence of widespread extrahepatic disease. The management of unresectable liver metastases includes many therapeutic options such as systemic chemotherapy, selective internal radiation therapy (SIRT) with yttrium-90 (Y-90), targeted therapy, and surgery. These treatments can be integrated into a sequential multimodal approach to increase the resection rate. We present a case in which such an approach was put into practice. The favorable result suggests that SIRT, along with systemic chemotherapy and surgery, is a valid treatment option for unresectable colorectal liver metastases.
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ABSTRACT: There is a need for clearly defined and widely applicable clinical criteria for the selection of patients who may benefit from hepatic resection for metastatic colorectal cancer. Such criteria would also be useful for stratification of patients in clinical trials for this disease. Clinical, pathologic, and outcome data for 1001 consecutive patients undergoing liver resection for metastatic colorectal cancer between July 1985 and October 1998 were examined. These resections included 237 trisegmentectomies, 394 lobectomies, and 370 resections encompassing less than a lobe. The surgical mortality rate was 2.8%. The 5-year survival rate was 37%, and the 10-year survival rate was 22%. Seven factors were found to be significant and independent predictors of poor long-term outcome by multivariate analysis: positive margin (p = 0.004), extrahepatic disease (p = 0.003), node-positive primary (p = 0.02), disease-free interval from primary to metastases <12 months (p = 0.03), number of hepatic tumors >1 (p = 0.0004), largest hepatic tumor >5 cm (p = 0.01), and carcinoembryonic antigen level >200 ng/ml (p = 0.01). When the last five of these criteria were used in a preoperative scoring system, assigning one point for each criterion, the total score was highly predictive of outcome (p < 0.0001). No patient with a score of 5 was a long-term survivor. Resection of hepatic colorectal metastases may produce long-term survival and cure. Long-term outcome can be predicted from five criteria that are readily available for all patients considered for resection. Patients with up to two criteria can have a favorable outcome. Patients with three, four, or five criteria should be considered for experimental adjuvant trials. Studies of preoperative staging techniques or of adjuvant therapies should consider using such a score for stratification of patients.Annals of Surgery 10/1999; 230(3):309-18; discussion 318-21. · 6.33 Impact Factor
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ABSTRACT: Colorectal cancer (CRC) caused nearly 204,000 deaths in Europe in 2004. Despite recent advances in the treatment of advanced disease, which include the incorporation of two new cytotoxic agents irinotecan and oxaliplatin into first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the integrated use of targeted monoclonal antibodies, the 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with colorectal liver metastases, liver resection offers the only potential for cure. This review, based on the outcomes of a meeting of European experts (surgeons and medical oncologists), considers the current treatment strategies available to patients with CRC liver metastases, the criteria for the selection of those patients most likely to benefit and suggests where future progress may occur.European Journal of Cancer 10/2006; 42(14):2212-21. · 5.06 Impact Factor
- Journal of Clinical Oncology 01/2006; 23(36):9063-6. · 18.04 Impact Factor
Key words: colorectal cancer liver
metastases, selective internal radia-
tion therapy, yttrium-90.
Correspondence to: Carmine Pinto,
MD, Medical Oncology Unit, S. Orso-
la-Malpighi Hospital, Via Albertoni 15,
40138 Bologna, Italy.
Received March 2, 2009;
accepted May 14, 2009.
Multimodal sequential approach in colorectal
cancer liver metastases: hepatic resection after
yttrium-90 selective internal radiation therapy
and cetuximab rescue treatment
Sara Pini1, Carmine Pinto1, Bruna Angelelli1, Emanuela Giampalma2,
Annabella Blotta3, Francesca Di Fabio1, Donatella Santini4, Rita Golfieri2,
and Andrea Angelo Martoni1
1Medical Oncology Unit,2Radiology Unit,3Radiotherapy Unit,4Pathology Unit, S. Orsola-Malpighi
Hospital, Bologna, Italy
Synchronous or metachronous liver metastases occur in up to one-third of patients
with colorectal cancer and are associated with a poor prognosis. Many evidences
have shown that surgical resection can be curative, with 5-year survival rates ranging
from 37% to 50%, but many patients are ineligible for surgery because of multiple liv-
er lesions, bilobar distribution of liver metastases, or the presence of widespread ex-
trahepatic disease. The management of unresectable liver metastases includes many
therapeutic options such as systemic chemotherapy, selective internal radiation ther-
apy (SIRT) with yttrium-90 (Y-90), targeted therapy, and surgery. These treatments
can be integrated into a sequential multimodal approach to increase the resection
rate. We present a case in which such an approach was put into practice. The favor-
able result suggests that SIRT, along with systemic chemotherapy and surgery, is a
valid treatment option for unresectable colorectal liver metastases. Free full text
available at www.tumorionline.it
Synchronous or metachronous liver metastases occur in up toone-third of patients
with colorectal cancer and are associated with a poor prognosis. Many evidences
have shown that surgical resection can be curative, with 5-year survival rates ranging
from 37% to 50%1, but only 10%-20% of patients are candidates for a surgical ap-
proach2. The reasons for ineligibility for surgical resection include the presence of
multiple liver lesions, bilobar distribution of liver metastases, and the presence of
widespread extrahepatic disease. At present, the standard treatment for unresectable
liver metastases is systemic chemotherapy to downsize the liver disease and obtain
resectability3. Several studies have shown that the use of 5FU/folinic acid plus oxali-
platin- or irinotecan-based first-line chemotherapy can convert a variable rate of pa-
tients (14-60%) from an unresectable to a resectable liver metastasis status4-6.The ad-
dition of new biological agents such as cetuximab to oxaliplatin-based chemothera-
py as first-line treatment resulted in a liver metastasis resection rate of approx. 20%7,8.
The combination of cetuximab and irinotecan as first-line treatment has been re-
ported to result in a liver metastasis resection rate of 9.8%9to 24%10.
Recently, Adam et al.11have reported on the use of cetuximab in patients with col-
orectal liver metastases refractory to first-line conventional chemotherapy. They
found that the addition of cetuximab to irinotecan or oxaliplatin in these pre-treated
patients as second- or higher-line therapy may lead to a 7% resectability rate without
increasing the operative mortality.
A new therapeutic option for unresectable colorectal liver metastases is selective
internal radiation therapy (SIRT) with microspheres of yttrium-90 (Y-90), a beta-par-
ticle-emitting radioisotope administered into the he-
patic artery through the femoral artery12. This locore-
gional therapy is based on the principle that Y-90 mi-
crospheres deposit in the metastatic vasculature, deliv-
ering high local radiation to the metastases but sparing
the normal liver parenchyma13. Y-90 SIRT is a safe and
effective regional therapy for unresectable colorectal
liver metastases, and phase I dose-escalation trials have
shown the safety of the combination of oxaliplatin or
irinotecan withY-90 SIRT14,15.
The management of unresectable colorectal liver
metastases includes many therapeutic options such as
systemic chemotherapy, SIRT with Y-90, targeted thera-
py, and surgery. These treatments can be integrated into
a sequential multimodal approach to increase the resec-
fully with such an unconventional approach.
In January 2005, a 67-year-old man underwent a left
colon resection for a moderately differentiated intestin-
al carcinoma (pT2N0M0). In March 2005, a computed
tomography (CT) scan revealed 6 metastatic nodules in
the sixth, eighth, second, third, and fourth liver seg-
ments and one between the fifth and eighth segments.
He was treated with standard first-line FOLFOX-4
chemotherapy. In June 2005, CT reassessment showed
progression of liver disease and an increase in CEA; in
view of his refractoriness to FOLFOX the patient contin-
ued systemic chemotherapy with the FOLFIRI regimen
for 9 cycles until November 2005, when, given his stable
disease, he was treated with hepatic arterial chemother-
apy consisting of mitomycin C + fluorouracil for 3 cy-
cles. In February 2006, instrumental reassessment again
ed on oral capecitabine, which was interrupted after 1
cycle because of poor clinical tolerance.
In May 2006, he was referred to our hospital where, in
view of his previous treatments and his stable liver dis-
ease, he was treated with hepatic intra-arterial adminis-
tration ofY-90 microspheres using an approach from the
femoral artery. Pretreatment assessment included liver
function tests and CT showed multiple bilobar liver
metastases from 1.6 cm to 5.0 cm in diameter with par-
tial intralesional calcification as the outcome of prior lo-
coregional treatment (Figure 1A). FDG-PET and celiac
angiography showed a common hepatosplenomesen-
teric trunk with a solitary origin of the left and right he-
patic artery. It was therefore necessary to perform left
hepatic artery embolization in order to create a single
hepatic vascular pedicle (Figure 2A-B). The patient un-
derwent technetium-99m macroaggregated albumin
scintigraphy with the catheter in the right hepatic artery,
decided to reduce the dose in order to avoid radiation
158 S PINI, C PINTO, B ANGELELLI ET AL
pneumonitis. After pre-therapy planning,Y-90 SIRT was
performed with a single personalized dose of 1010 MBq
(27.16 mCi).The clinical tolerance was good and the pa-
Three months after Y-90 treatment, CT reassessment
showed a decrease in the size of the liver lesions and an
increase in intralesional calcification (Figure 1B).
In November 2006, in view of the radiographic pro-
gression of liver disease and an increase in tumor mark-
ers, we started systemic chemotherapy with the FOLFIRI
regimen every 2 weeks plus cetuximab weekly for 10 cy-
cles, until July 2007. In September 2007, a partial re-
sponse of the liver disease allowed surgical resection of
segments IVb,V,VI, andVII, and wedge resection of seg-
ments II, III, and VII. Histopathological examination of
the liver metastases showed moderate to high intrale-
sional necrosis and fibrosis. Moreover, pathological ex-
amination at the site of theY-90 treatment showed many
get structures (Figure 3A-B). Post-surgery reassessment
in November 2007 showed no radiographic evidence of
Figure 1 - A) Pre-Y-90 computed tomography scan showing many
bilobar liver metastases with partial intralesion calcification as the
outcome of previous locoregional treatment. B) Computed tomog-
raphy scan 3 months after Y-90 treatment showing a size decrease in
liver metastases with an increase in intralesional calcification.
Figure 2 - Right hepatic angiography. A) After left hepatic arterial
embolization, a right hepatic angiography confirms that bilobar he-
patic perfusion has been obtained, which is necessary for whole-liv-
er radioembolization. B) During the parenchymal phase expansive
lesions with peripheral enhancement are visualized.
COLORECTAL CANCER LIVER METASTASES ANDYTTRIUM-90 SIRT 159
disease, so we attempted to stabilize the surgery result
with weekly infusion of irinotecan + cetuximab.
The unconventional treatment approach in this pa-
able for unresectable colorectal liver metastasis, which
can be used in a variable sequential modality.The aim is
to improve the resection rate and increase the overall
survival. SIRT can be part of such sequential multimodal
approaches in colorectal liver metastases. This novel lo-
coregional radiotherapy technique can be included in
the therapeutic algorithm of unresectable colorectal liv-
er metastases along with systemic chemotherapy and
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Figure 3 - Liver metastases. A) Fibrosis and giant-cell conglomerate
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ture (hematoxylin-eosin). B) Magnification of the giant-cell con-
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eosinophil target structure (hematoxylin-eosin).