Neoadjuvant Treatment for Surgically Resectable Metastatic Colorectal Cancer: Is There an Optimal Succession?

January 15, 2016

It remains difficult to decipher which patients are appropriate candidates for conversion therapy vs upfront surgery. Therefore, in predicting potential outcomes, several factors should be considered. Here, we will attempt to address such factors and provide insights.

While colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States, both its incidence and mortality rate continue to decline.[1] These improvements are likely due to better cancer prevention/screening, earlier diagnoses, and improved treatments. Nevertheless, 20% of patients with newly diagnosed colon cancers present with metastatic disease, and 80% to 90% of these patients present with unresectable metastatic liver disease.[1,2] Cure is possible in a percentage of this patient population.[3] Drs. Al-Hajeili, Marshall, and Smaglo present a comprehensive review of the available data on preoperative or induction/conversion therapy in patients with resectable disease, as well as disease initially deemed unresectable, at diagnosis [4]; however, it remains difficult to decipher which patients are appropriate candidates for conversion therapy vs upfront surgery. Therefore, in predicting potential outcomes, several factors should be considered. Here, we will attempt to address such factors and provide insights.

Should the pattern of metastatic occurrence influence resection and/or perioperative therapy? In two-thirds of patients with metastatic colorectal cancer, metastases develop in a metachronous manner; however, up to 20% to 35% of patients present with synchronous liver metastases, which may have a worse prognosis than metastatic colorectal liver disease that develops metachronously.[2,5,6] In a retrospective series of 155 patients who had undergone liver resection for metastatic disease, those with synchronous lesions had more sites of liver involvement and more bilobar metastases than those with metachronous metastases.[6] Thus, these patients may require more careful monitoring and aggressive perioperative chemotherapy, since this type of presentation may be an indicator of disseminated disease.

Is there any use for positron emission tomography/computed tomography (PET/CT) in the evaluation of distant metastatic disease? According to the National Comprehensive Cancer Network Clinical Practice Guidelines, the radiographic workup for metastatic colon cancer includes CT scanning with intravenous contrast of the chest, abdomen, and pelvis. Magnetic resonance imaging of the abdomen and pelvis can be considered when other imaging is inadequate, to help identify hepatic metastases more clearly. Although PET/CT is not routinely recommended for staging or follow-up in colon cancer, it may be beneficial to evaluate for unrecognized metastatic disease that would impede surgery in those with potentially resectable colorectal cancer and isolated liver metastases.[7] In a randomized clinical trial by Moulton et al, the role of preoperative PET/CT was evaluated in patients with resectable metachronous liver metastases to help identify those with occult metastases and thus to avoid noncurative surgery. While PET/CT had no impact on overall survival, surgical management was altered in 8% of patients, with 2.7% of patients identified as having additional metastatic disease (bone, peritoneum/omentum, abdominal lymph nodes).[8] In addition, fluorodeoxyglucose (FDG)-PET has been shown to be superior to CT alone. In a systematic review of retrospective data, the pooled sensitivity and specificity of FDG-PET were 80% and 92%, respectively, for hepatic disease, and 91% and 98%, respectively, for extrahepatic disease. With CT alone, the pooled sensitivity and specificity for hepatic disease were 83% and 84%, respectively, and 61% and 91%, respectively, for extrahepatic metastases.[9] Therefore, the addition of PET to CT may increase the accuracy of resection.

Diagnostic laparoscopy may help identify occult intraperitoneal metastases in those with potentially resectable metastatic liver lesions; however, this modality is commonly reserved for patients thought to be at highest risk. Such patients include those with suspicion for peritoneal carcinomatosis on radiographic imaging or those with metachronous presentation of multiple liver metastases not responsive to chemotherapy. In patients with potentially resectable metastatic colon cancer, multidisciplinary evaluation is recommended, including surgical consultation with an experienced hepatic surgeon to assess resectability and potential for cure with preservation of adequate liver reserve.[7] Thus, resection should be considered only if a complete or R0 resection is possible, since incomplete resection has not been shown to be beneficial.[3,10,11] Previously, contraindications to liver resection included the presence of more than four lesions, bilobar distribution, inability to achieve a 1-cm resection margin, portal lymphadenopathy, or other extrahepatic metastases. However, with better chemotherapy and surgical strategies (ie, staged procedures), the optimal selection of resection candidates is evolving, with a focus on residual liver function and volume.[12]

As Al-Hajeili et al mention in their review, chemotherapy-related liver toxicity is a concern, both in patients with a history of liver disease and in those without, particularly with the use of preoperative irinotecan- or oxaliplatin-containing regimens. Hepatic sinusoidal abnormalities, as well as nodular regenerative hyperplasia, have been described predominantly in those patients receiving oxaliplatin before resection. Irinotecan-containing regimens are more often associated with steatosis or steatohepatitis.[13,14] With the increasing epidemic of obesity in this country, steatohepatitis has been seen more often in patients with higher body mass index.[15,16] While the data are conflicting with regard to perioperative morbidity/mortality in relation to liver damage,[13,17-19] it is important to recognize affected patients and to consider upfront resection if possible; however, there have been no randomized studies or large meta-analyses to date.

What lies in the future? Perhaps, with a greater understanding of cancer genomics, certain biomarkers may prove valuable in identifying patients who might benefit from induction/conversion therapy followed by metastasectomy, even though at this time the prognostic value of such markers is not known. A promising example may be found in recently published data by Le et al, who evaluated the clinical activity of pembrolizumab, an anti–programmed death 1 (PD-1) immune checkpoint inhibitor, in patients with progressive metastatic colorectal cancer and found that pembrolizumab had activity in the subset of patients with mismatch repair deficiency.[20] Conceivably, the combination of genomic markers and “traditional parameters” could influence or enhance clinical evaluation, guide therapy, and assist in determining the optimal sequence of therapies in the future.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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