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missing live metastases, which are not visible on high-quality liver imaging and not detectable in the OR (Curr Colorectal Cancer Rep 2014;10:204-210).
Dr. Aloia argued that disappearing liver metastases should absolutely be resected. “It is rare for patients who present with resectable liver metastases treated with a short course of neoadjuvant chemotherapy to develop a disappeared liver metastasis, and in the rare case that they do develop a disappeared liver metastasis, the tumors are rarely missing liver metastases but can typically be detected intraoperatively,” Dr. Aloia said.
According to Dr. Aloia, disappearance on imaging rarely equates to a pathologic complete response (J Gastrointest Surg 2010;14[11]:1691-1700; Cancer 2010;116[6]:1502-1509). “We cannot rely on the imaging to tell us that a lesion that is about to disappear will become a nonrecurrent tumor,” he said.
Dr. Aloia said at-risk lesions, most commonly encountered as small tumors in a multifocal patient, should have fiducial markers placed prior to preoperative systemic chemotherapy. Short-course preoperative systemic therapy should be halted as soon as a response is identified in a resectable patient (Lancet 2008;371[9617]:963-965). “If the intent is to treat with preoperative therapy limited to only two or three months, this strategy combined with judicious fiducial marker placement are both well used preventative measures to avoid the distress of missing metastases in the operating room,” he said.
Dr. Aloia said becoming an expert in intraoperative ultrasound is important (J Am Coll Surg 2005;201[4]:517-528). “Certainly in the setting of a previously treated patient, direct ultrasound examination with the probe on the liver may be our best imaging modality, and we need to maximize its ability to identify small and disappeared lesions to make sure that they do not reach the category of a missing lesion in the operating room,” he said.
Dr. Aloia pointed out that surgeons have many surgical tools to choose from these days. For patients with bilobar colorectal liver metastases, surgical options now include anatomic hepatectomy, one-stage parenchymal sparing hepatectomy, traditional two-stage hepatectomy with or without portal vein embolization, associated liver partition and portal vein ligation for staged hepatectomy, local ablative techniques, and hepatic arterial infusion therapy (Surgery 2017;162[1]:12-17).
“As we look at the spectrum of lesion status from progressing to all the way to missing lesions, it is really the responding and disappearing, but not disappeared or missing lesion, that has the best prognosis with surgery,” Dr. Aloia said. “Therefore, I would argue that the disappearing liver metastases is the ideal clinical situation that should be operated on.” ‘As we look at the spectrum of lesion status from progressing to all the way to missing lesions, it is really the responding and disappearing, but not disappeared or missing lesion, that has the best prognosis with surgery. Therefore, I would argue that the disappearing liver metastases is the ideal clinical situation that should be operated on.’
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—Thomas Aloia, MD
Observing Disappearing Liver Metastases Is a Good Option
Dr. Leah Melstrom, a liver surgeon at City of Hope, offered a somewhat contrary opinion.
“I am here to argue the point today that, indeed, resection of disappearing colorectal liver metastases is not a mandate. Not all disappearing colorectal liver metastases merit resection,” Dr. Melstrom said. “There is a reasonable chance that a disappearing lesion will not return, and I will argue that if it does return, there will remain treatment options. And lastly, and most importantly, if it does return, this small lesion will not likely dictate the survival of your patient.”
Dr. Melstrom pointed out that isolated liver metastases can account for up to 25% of metastatic colorectal cancer presentation. “Since the early 2000s, the response rates have been upwards of 70% with FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], FOLFIRI [irinotecan, 5-fluorouracil, leucovorin] and the biologics, which include bevacizumab, panitumumab [Vectibix, Amgen] and cetuximab [Erbitux, ImClone],” she said. “This improvement in systemic therapy has led to the phenomenon of disappearing liver colorectal metastases to occur in up to 5% to 25% of patients based on the series that you look at.”
Dr. Melstrom said all can agree that resection of isolated colorectal liver metastases is associated with improved survival, and pathologically complete response to chemotherapy in these lesions is also associated with improved survival. However, disappearing colorectal liver metastases on cross-sectional imaging after chemotherapy does not routinely equate to a pathologic or clinical complete response (Dig Surg 2011;28[2]:114-120; Cancer 2010;116[6]:1502-1509; J Gastrointest Surg 2010;14[11]:1691-1700).
In a systematic review of 15 studies involving 479 patients with disappearing colorectal liver metastases, the median age was 59 years, the median number of lesions per patient was one to 8.8, the median size of liver metastases prior to chemotherapy was 1.07 cm, and the median number of cycles of chemotherapy was approximately eight (Surg Oncol 2019;29:7-13). Factors found to be associated with disappearing colorectal liver metastases included lesions that were smaller than 2 cm, increased number of colorectal liver metastases (at least three), presentation of synchronous disease, history of oxaliplatin-based chemotherapy and increased number of treatment cycles.
“Just as size and number of these lesions matters, the imaging modality also matters,” Dr. Melstrom said.
There are limited data that fluorodeoxyglucose (FDG)-PET is more sensitive and more specific than a CT scan after neoadjuvant chemotherapy (Gastrointest Surg 2007;11[4]:472-478). FDGPET and CT sensitivity are lowered after neoadjuvant chemotherapy (Gastrointest Surg 2007;11[4]:472-478; Ann Surg Oncol 2009;16[5]:1247-1253). “Several factors contribute to this. Chemotherapy has the capability of inducing steatosis and steatohepatitis, and plus there is a decrease contrast differentiation between tumors and the background fatty liver,” she said.
Dr. Melstrom said MRI is superior and may be able to compensate for these factors. “The data on MRI in this
Table 1. Sensitivity and Specificity at Diagnosis of T Colorectal Liver Metastases C
P
Sensitivity Specificity
PET/CT 74% 93.9%
C CT 82.1% 73.5%
M MRI 93.1% 87.3%
S Source: J Magn Reson Imaging. 2018;47(5):1237-1250.
T Table 2. Imaging in Disappearing Colorectal Liver Metastases and Their Accuracy
Number of Patients dCRLM With Complete Response Median Follow-up CT MRI +IOUS (months)
Radiology. 2017;284(2):423-431 87 35% 78% 94% 12
J J Surg Oncol. 2018;117(2):191-197 20 59% 85% 86% 27
setting is growing in recent years,” she said. A 2018 meta-analysis that systematically determined the diagnostic accuracy of multidetector row CT, gadoxetate disodium–enhanced MRI and PET/CT for diagnosing colorectal liver metastases demonstrated that PET/CT was quite specific, but MRI was superior in sensitivity than PET or CT and with better specificity than CT (Table 1) (J Magn Reson Imaging 2018;47[5]:1237-1250).
If surgeons combine preoperative MRI planning with intraoperative use of ultrasound, they can have confidence that disappearing colorectal liver metastases may be a durable finding (Table 2) (World J Surg Oncol 2020;18[1]:264).
Once the lesion has disappeared, what happens next? “This is addressed [in a series of eight studies]. Their findings were that recurrence could be as high as nearly 40% when MRI was added to the imaging modality,” Dr. Melstrom said. “However, it was upwards of 70% if imaging was limited to CT. In the more contemporary series, you can see that really in situ recurrence numbers are as low as 7% to 15% when you use MRI and intraoperative ultrasound.”
Once the lesion has disappeared and left in situ, what impact is there on survival? In three studies, the range for three-year overall survival was 87% to 94%. And in a study by Tanaka et al, the median survival was 63 months (Ann Surg Oncol 2007;14[11]:3188-3194; J Gastrointest Surg 2010;14[11]:16911700; Ann Surg 2011;254[1]:114-118; Ann Surg 2009;250[6]:935-942). These same studies showed disease-free survival ranged from 16% to 64% at three years. “This data is quite compelling,” Dr. Melstrom said.
A recent study aimed to assess management patterns of disappearing colorectal liver metastases from an international body of hepatobiliary surgeons (HPB 2021;23[4]:506-511). The survey involved 226 respondents representing 40 countries with a median age of 45 years. The vast majority of respondents were men, fellowship trained and worked at an academic or university hospital setting. Respondents commented that factors contributing to disappearing colorectal liver metastases not found in the OR included the location, presence of steatosis, small size of the lesions and surgeon experience with intraoperative ultrasound.
“Of these, perhaps the only one we can improve is the intraoperative ultrasound, as we can’t change presentation and we can’t change biology,” Dr. Melstrom said. “In terms of imaging modalities used, 33% still utilized PET, and it was pretty evenly split as it pertains to MRI or CT; 47% to 45% used those modalities.”
When those who were surveyed were asked how to proceed if the disappearing colorectal liver metastases were not identified in the OR, 48% elected for observation and 31% said resect if the presumed area is superficial. Of those electing for observation, 87% still believed that it was possible to treat the lesion if the disappearing liver metastases regrow.
“In summary, I posit that MRI is the optimal modality to identify colorectal liver metastases before and after systemic therapy. Intraoperative maneuvers including ultrasound, localization, palpation and inspection are all useful in helping to visualize these lesions,” Dr. Melstrom said. “However, if you cannot, you can be rest assured that the rate of in situ recurrence can range from 7% to 15% with the above. And if you elect to observe these patients, rather than prophylactic resection or ablation, you are in good company with up to 48% of your colleagues.” ■
‘There is a reasonable chance that ‘Thereis a a disappearing lesion will not a disa return, and I will argue that if it return, a does return, there will remain does r treatment options. And lastly, treatm and most importantly, that if it andmo does return, this small lesion does will not likely dictate the w survival of your patient.’ s
—Laleh Melstrom, MD, MS
Laleh Melstrom, MD, MS Trust the science
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