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Metastatic colorectal cancer: The reality of the present and the optimism of the future

In 2018, over 140 000 people were diagnosed with colorectal cancer in the United States, representing 8.1% of all new cancer cases. Due to the late presentation in most patients (61% are regionally or distantly metastatic), approximately 50 000 Americans die of colorectal cancer annually. Thus mortality from colorectal cancer represents 1 out of every 12 cancer deaths. This special Journal of Surgical Oncology seminar is dedicated to patients with distant metastatic disease, who represent 21% of new diagnoses and have a 5‐year overall survival of only 13.8%. The reality of metastatic colorectal cancer (mCRC) is that it affects a tremendous number of patients with new or recurrent disease, and although their prognosis today is much better than it was one or two decades ago, there is still much work to be done. With a better understanding of the biology of the disease, improved multi‐drug regimens combining cytotoxic and targeted therapies, and safer, yet more aggressive, surgical strategies, we are opening doors to long‐term outcomes that most physicians and patients could not imagine for mCRC. Our first article details the continuous evolution in our understanding and management of mCRC in the past two decades. These developments in mCRC have led to a steady rise in survival rates in mCRC with the goal of turning this stage IV diagnosis into a chronic disease. Colorectal cancer is now treated with multiple episodes of care, proactive surveillance to mitigate the extent of recurrent disease and aggressive treatment of recurrence beyond just palliative intent. The next review analyzes the contemporary systemic options for mCRC patients, highlighting therapeutic efficacy and side effect mitigation. For surgeons, the most common surgical presentation of mCRC is colorectal liver metastases (CLM), and the most important mantra is “the treatment of resectable CLM is resection.” There is much work to be done to increase the number of patients who get appropriately referred upon diagnosis for aggressive resection, and if they get chemotherapy, get resected before chemotherapy‐associated liver injury ensues. Therefore, treatment sequencing and multidisciplinary collaboration is probably the most important lesson to disseminate in the medical oncology and surgical oncology communities. There are, of course, times when the patient has an insufficient future liver remnant (FLR), either due to a small liver, intrinsic liver disease, or being overweight (because the FLR is standardized to a patient's body surface area). This seminar will not resolve the debate between “Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy” (ALPPS) and portal vein embolization with two‐stage hepatectomy; however, we offer articles from two world leaders on their respective expertise for the reader to decide. Cytoreductive surgery (CRS) for mCRC is an evolving concept because as the safety for CRS improves, its indications potentially expand when used in the correct biological context. As with any aggressive surgical technique, patient selection remains the focus. Perhaps the peritoneal carcinomatosis index is too imprecise, just as CLM size and number in the liver do not paint the whole picture. Most recently, our understanding of disease biology has focused on breakthroughs reflective of personalized medicine where mutational signatures including KRAS, BRAF, P53, and SMAD4, plus microsatellite stability facilitate decision‐making for systemic therapy. Together with primary tumor sidedness and the number/location of metastases, these mutations can inform and facilitate surgical decision making, helping us perform aggressive operations on those who have greater potential disease latency and more strongly considering nonoperative approaches when biology cannot be overcome. In this vein, we have an article on the current use of mutation status from next generation sequencing and surgical selection. Where is the fine line between being appropriately aggressive for multiple site disease (CLM +/− lung metastases +/− extra‐regional nodal diseases)? We attempt to tackle this surgical selection question as well. Lung metastases is a common issue that abdominal surgical oncologists deal with when considering clearance of abdominal metastatic disease. One article helps to review the indications of resection and nonoperative treatment of lung metastases. We explore the topic of nonresectional regional local therapies for CLM when resection is not possible for patient or anatomic reasons. Because the mCRC literature is rapidly evolving, we have one article on ongoing and future chemotherapy and immunotherapy trials, so that the JSO readership can understand what is just beyond the near horizon. The immune microenvironment in colorectal cancer has been a key target for therapeutic trial development with the goal of determining factors that can be changed (modulated or enhanced) to optimize immunotherapy in patients that would otherwise currently be characterized as nonresponders. We wrap up the Seminar with two surgical articles. The rapid dissemination of minimally invasive techniques (robotic and laparoscopic) that have driven the adaptation for liver resection of mCRC. To optimize outcomes uniformly at an institution or within a specialty, there has been a global surge of enhanced surgical recovery pathways in many subspecialties. The benefits go beyond traditional hospital metrics of length of stay and financial value and instead now focus on patient‐ centric measures such as return to intended oncologic therapy, reduced opioid use, and faster return to baseline function.