Abstract
Background
With increasing efficacy of preoperative chemotherapy for colorectal cancer, more patients will present with one or more disappearing liver metastases (DLM) on preoperative cross-sectional imaging.
Patients and Methods
A retrospective review was conducted evaluating the radiological response to preoperative chemotherapy for 168 patients undergoing surgical therapy for colorectal liver metastases at Johns Hopkins Hospital between 2000 and 2008.
Results
Forty patients (23.8%) had one or more DLM, accounting for a total of 127 lesions. In 22 patients (55%), all DLM sites were treated during surgery. Of the 17 patients with unidentified, untreated DLM, ten patients (59%) developed a local recurrence at the initial site, half of which also developed recurrences in other sites. While the intrahepatic recurrence rate was higher for patients with DLM left in situ (p = 0.04), the 1-, 3-, and 5-year overall survival rate was not significantly different for patients with DLM left in situ (93.8%, 63.5%, and 63.5%, respectively) when compared to patients with a radiological chemotherapy response in whom all original disease sites were surgically treated (92.3%, 70.8%, and 46.2%, respectively; p = 0.66).
Conclusions
DLM were frequently observed in patients undergoing preoperative chemotherapy for liver metastases. Survival was comparable in patients with untreated DLM, in spite of high intrahepatic recurrence rates seen in these patients. Therefore, aggressive surgical therapy should be considered in patients with marked response to chemotherapy, even when all DLM sites cannot be identified.
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Discussant
Dr. Eddie K. Abdalla (Houston, TX, USA): This question of what to do with disappearing metastases is an important one. I have a comment and a couple of questions. It seems to me your title with regard to disappearing metastases must be "we should be concerned." Your paper develops a proposal for a new (perhaps dangerous) goal of surgery to debulk or palliate liver metastases and leave some lesions behind to be followed. So I want to be careful about the data before we go down the road of debulking as you propose, because your data strongly suggest this proposed path is the wrong way right now.
My first question is with regard to the median follow-up, which is only 19 months. Is that long enough to declare the missing lesions gone? Because your reported 16% 3-year recurrence-free survival in the "debulked group" is by no means cured, and it's far lower than the recurrence-free survival in the group where you resected all the disappearing lesions. Worse, you only salvaged a few of them. So, in fact, you've shown that leaving lesions in place led to poor outcomes. Thus, the proposal to leave "disappearing lesions" in place and to follow and wait for recurrence (or hope for no recurrence) does not seem to be a rational conclusion from your data or a reasonable oncologic approach, does it?
Leaving disappearing lesions in place is basically hoping for a complete pathologic response. So I will try to sum up some issues regarding pathologic response. When we look at pathologic response to chemotherapy, we know that this is an extremely powerful predictor of survival. There are two explant studies that show the pathologic complete response rate overall is about 10%, even with the use of biologic agents. Bottom line, it’s a matter of time before nearly all the patients will recur if you don’t resect all the sites of disease ever present.
In these two studies in the Journal of Clinical Oncology, one from our group authored by Blazer et al. (J Clin Oncol. 2008 Nov 20; 26 (33):5344–51), and the other from the Paul Brousse authored by Adam et al. (J Clin Oncol. 2008. Apr 1; 26 (10):1653–41), the 5-year overall survival following resection with a finding of pathologic complete response is about 75%, and the disease-free survival is about 70%. So how do you reconcile only a 58% three-year overall survival in this cohort with a so-called complete response (lesions disappeared) when the 5-year survival should be nearly 75%? You cannot draw that conclusion. Rather, I think it proves that we have to go after every site of disease that was ever present, and that the radiologic complete response cannot be treated as a pathologic complete response. I am more than a little concerned about going down the path of debulking surgery that you are proposing in this paper based on existing data and the data you present.
Closing Discussant
Dr. Mark G. Van Vledder: To address your concern and your first question, indeed, we should be concerned about these disappearing liver metastases, and I think the goal should be to completely resect or ablate all initial sites that were diagnosed prior to chemotherapy, when possible.
To address your question about the follow-up for these patients, we found that most of the disappearing lesions that were left in place recurred within 1 year, so we think it is safe to conclude most lesions that would have recurred did so within these 19 months time of follow-up.
Discussant
Dr. David Mahvi (Chicago, IL, USA): I have two questions. Do you think there’s ever a liver metastasis cured with chemotherapy? Is there a size below which chemotherapy would just fix it?
Second, is there any disadvantage to not resecting a metastasis the first time? If the lesion is not visible by imaging, can you come back when it does appear and have a similar outcome?
Closing Discussant
Dr. Mark G. Van Vledder: Thank you Dr. Mahvi for your questions. Regarding whether a durable complete response can be achieved with chemotherapy in small lesions, perhaps this can best be estimated by the frequency of complete pathologic response. We did not specifically look at this. However, one study from Memorial Sloan–Kettering Cancer Center did not find a significant correlation between lesion size the rate of pathologic complete response.
Your second question relates to the salvage rate when an undetected and untreated lesion recurs. We found that of those patients in which they only recurred at the original site, a true local only recurrence, a second procedure to resect or ablate was possible in all cases. Of course, it is likely that patients were only operated upon in our series where all original sites were in potentially treatable locations. So, we feel that while only patients who are potentially resectable or ablatable based on the number and location of all original sites, if for some reason all sites cannot be identified at the time of surgery and a blind resection is not feasible or safe, one can consider leaving them in place with an option for potential subsequent salvage therapy if they recur.
Discussant
Dr. Mukund Didolkar (Baltimore, MD, USA): I know your study related mainly CT scans, but did you study PET CT, which would be a functional scan? And did that complete disappearance or negative PET CT correlate with the histology?
Closing Discussant
Dr. Mark G. Van Vledder: Many patients in this study did indeed undergo PET imaging prior to and after chemotherapy. And in many of these patients, complete response of one or more lesions on PET imaging was observed. In fact, tumors often responded to a greater extent on PET than on CT. However, in this study, we did not use PET imaging to define complete radiological response but relied only on complete disappearance on CT. We have not looked into the relationship between PET response and pathologic response.
Discussant
Dr. Thomas Biehl (Seattle, WA, USA): I have noticed over the years that almost all of these “disappearing mets” come back. And with that observation, I usually recommend what I call a chemotherapy holiday between the time when they finish chemotherapy and the recommendation for an operation. I’m wondering how much time did you have between the completion of chemotherapy and operation? And do you ever use this to help plan your operation?
Closing Discussant
Dr. Mark G. Van Vledder: This is an interesting question. Similarly, might the wait time between a radiologic response following chemotherapy and surgery, without evidence of recurrence at that site, determine the probability of a complete pathologic response. In our study, the median time in between the last cycle of chemotherapy and surgery was 2 months, ranging from 1 month to 24 months. In only on a very limited number of patients did we actually waited for longer period of time to allow metastases to declare themselves during follow-up. Such a concept is a useful one which warrants further investigation.
Discussant
Dr. Merril T. Dayton (Buffalo, NY, USA): Your study focuses on disappearing hepatic metastases. And your message is pretty clear that even when they disappear, they should be resected.
You didn’t say much, though, about how chemotherapy may change an unresectable liver met into a resectable liver met. Do you have any data on that? In other words, - - maybe the ultimate utility of the chemotherapy is in converting lesions which are unresectable into resectable ones.
Closing Discussant
Dr. Mark G. Van Vledder: For this study, we primarily focused on patients that underwent curative intent surgery, some of whom were considered initially resectable and some that were felt to have been converted to a resectable state. It is difficult for me to specifically answer your question. Our general management philosophy has been to operate on only those patients in whom we feel all original sites were potentially resectable, even if converted.
Discussant
Dr. Heriberto Medina-Franco (Mexico City, Mexico): What would be your approach in a patient that received conversion chemotherapy for bilobar disease, and disappear the lesions in only one side of the liver?
Closing Discussant
Dr. Mark G. Van Vledder: Indeed, cases such as that which you describe can be quite difficult to manage. As mentioned, at least for now, our philosophy is to operate only upon those patients in which treating all original sites of disease is feasible, and every attempt should be made to identify and treat all of these sites. In cases in which contralateral disease cannot be found and hemihepatectomy is required to resect detectable disease, one can feel comfortable leaving these sites behind, provided that contralateral recurrence occurs at these sites, a salvage operation or procedure can be performed at a later date.
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van Vledder, M.G., de Jong, M.C., Pawlik, T.M. et al. Disappearing Colorectal Liver Metastases after Chemotherapy: Should we be Concerned?. J Gastrointest Surg 14, 1691–1700 (2010). https://doi.org/10.1007/s11605-010-1348-y
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DOI: https://doi.org/10.1007/s11605-010-1348-y