Should we resect distant metastases?—reconsidering radical resection of pancreatic cancer with liver metastases

The mechanism of cancer metastasis is far more complex than the mere mechanical shedding of tumor cells into the circulation, followed by cell proliferation within an organ where they accidentally get lodged. Metastatic spread is also not random; different primary tumors exhibit predilections for specific organs they metastasize to. This notion dates back to 1889 when Stephen Paget described the “seed and soil” hypothesis, suggesting that the spread of tumor cells is governed by close interactions between specific cancer cells (seed) and the host organ (soil). Other crucial processes of metastatic spread, such as cell intravasation, extravasation, tumor latency, metastatic niche formation, and the development of micrometastasis and macrometastasis, have been delineated over the last few decades. Also, recent studies have shown that target organs are prepared for metastatic deposits through the development of premetastatic niches that promote tumor cell homing, colonization, and subsequent growth at the target organ. These premetastatic niches consist of deregulated immune cells and extracellular matrix proteins within the target organ, and are developed by primary tumor-derived soluble factors, which mobilize bone marrow-derived hematopoietic cells to the target organ before tumor cell arrival. Metastases themselves do not possess the “ability” to mount these processes, which are necessary for further metastatic spread. In simple terms, distant metastases do not metastasize (1). With the major advancements in surgical and systemic therapies for cancer patients in recent years, this understanding may have a significant impact on clinical decision-making.

A prominent example can be found in the case of pancreatic ductal adenocarcinoma (PDAC). In PDAC, the existence of even a single distant metastasis is traditionally perceived as the “tip of the iceberg”. This is considered a biomarker of tumor aggressiveness, and contraindicates a resection, as the imminent terminal event, is usually related to full-blown dissemination of the disease. Hence, metastatic PDAC, even with low burden of disease, is considered non-resectable, and these patients are directed to palliative therapies. However, with the significant development in systemic treatment for PDAC, mainly the introduction of FOLFIRINOX, the prognosis of these patients is improved, and some patients experience marked response in the metastatic lesions. With this data, attempts have been made to resect oligometastases in combination with the primary tumor. Reports have demonstrated that resection of liver oligometastases together with or after resection of the primary tumor, leads to improved long-term outcomes compared to non-surgical palliative treatments, and consensus statements supported radical resection of both the primary lesion and oligometastases in selected patients (2-4). Some reports have even described major liver resections to remove small PDAC liver metastases together or following resection of the primary tumor (2). Studies have also discussed “favorable” disease biology that would allow radical resection of the tumor and metastases (5).

However, as distant metastases do not metastasize (1), we believe there are only three possible scenarios and corresponding logical ways to address oligometastatic PDAC:

• Scenario 1: the oligometastatic disease is indeed just the “tip of the iceberg”, with imminent full-blown spread.
  In this case, surgery is futile for both the primary lesion and the metastases. We believe that this is the most common scenario of oligometastatic PDAC.
• Scenario 2: the oligometastatic PDAC has “favorable” biology, but the metastases themselves pose a threat by causing local complications.
  In this case, resection of both the primary tumor and metastases may be indicated (pancreatectomy and hepatectomy). However, the likelihood that limited liver disease would cause local complications is very low. Hence, in our opinion, this is the least common scenario. Moreover, it should be taken under account that local complications caused by small oligometastases may, by itself, be indicative of tumor aggressiveness that would render futile attempts for radical resection.
• Scenario 3: the oligometastatic PDAC has “favorable” biology and the metastases would not cause local complications in the near future.
  In this case, in light of the notion that metastases do not metastasize, we stress that only the primary lesion should be resected, and the oligometastases should be ignored. Of course, if the lesions are superficial and their removal requires minimal surgical undertake, there is no reason not to resect. On the other hand, if the lesion requires substantial hepatic resection, such as segmentectomy or even hemihepatectomy, as previously described (2), we suggest “leaving it alone”. Studies demonstrating benefit in radical resection of the primary lesion and the metastases compared the results to those in which the surgery was aborted altogether. These studies are not designed to demonstrate a benefit from metastasectomy, but rather indicate that despite the metastatic disease, some patients benefit from resection of the primary tumor.

A prospective study designed to evaluate whether there is a benefit in the resection of oligometastases, should include three groups of patients:

• Oligometastatic patients that undergo resection of the primary lesion and metastases.
• Oligometastatic patients that undergo resection of the primary lesion only without resection of metastases.
• Oligometastatic patients who are directed to systemic therapy without surgery.

Only in such a study, can the potential benefit of resecting liver metastases be truly evaluated. According to current knowledge, in such a study, no difference between groups 1 and 2 would be found, and both may or may not do better compared to group 3, depending on whether the disease has favorable or unfavorable characteristics.

This concept can be applied to other types of metastatic cancers, such as gastric cancer with liver oligometastases, in which recent studies showed improved long-term survival in selected patients with liver oligometastases who underwent radical resection of both the primary lesion and metastases (6). Can we really determine what is the contribution of liver resection of oligometastatic disease? We believe that resection of distant metastases should be considered only if they cause or threaten to cause local complications.

Under this concept, the chase for “no evidence of disease” (NED) should be replaced with “no evidence of effective disease” (NEED), when dealing with metastatic cancer.

Acknowledgments

Funding: None.

Footnote

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