Colorectal cancer metastatic to the liver: Making the unresectable resectable

Alliance for Clinical Trials in OncologyOne of the most common tumor types that surgical oncologists specializing in hepatobiliary and pancreatic neoplasms see in clinical practice is colorectal cancer liver metastases. This fact is unsurprising, given that colorectal cancer is the third most common cancer in the U.S. Approximately one in 20 Americans will develop colorectal cancer in their lifetime.1 Resection of hepatic metastases provides a five-year survival rate of 30 percent to 50 percent and is considered the treatment of choice for patients with resectable disease.2,3 Unfortunately, most patients are not candidates for metastasectomy at time of diagnosis.4-6

Consider, for example, a 51-year-old woman with colorectal liver metastases involving both lobes of the liver with at least 12 lesions specifically described in the magnetic resonance imaging report, which also included the term “innumerable hepatic metastases.” In the 1990s, this disease would have been considered unresectable, and the patient would have received systemic chemotherapy with a median survival of 15 months.7 However, much has changed since then in the treatment of metastatic colorectal cancer, which has led to greatly improved survival, especially for patients with liver-only disease. These new approaches have increased the role of surgeons in the management of these patients.

Advances in chemotherapy

The most important development has been the introduction of more effective chemotherapeutic agents for stage IV colorectal cancer. Drugs such as Oxaliplatin and Irinotecan, when combined with 5-Fluorouracil/Leucovorin, have produced response rates in the 50 percent range and median survivals up to 20 months.8

Hepatic resection

The ability of chemotherapy to decrease the size and number of tumor masses has led to downstaging of liver metastases, which were initially considered unresectable, to resectable. Adam and colleagues demonstrated that systemic chemotherapy downstaged 12.5 percent of patients with inoperable disease, enabling them to undergo hepatic resection. The five-year overall survival of this group was 33 percent.9 A recent paper from China reported that using an even newer systemic therapy regimen containing cetuximab, a biologic agent, plus chemotherapy to downstage unresectable liver metastases, 25 percent of patients were able to undergo surgery with a median survival of 35 months.10 These studies clearly show patients with advanced colorectal liver metastases still have a chance to undergo resection of hepatic metastases if they respond well to systemic therapy.

Clinical trials needed

Questions remain regarding the timing of systemic therapies and the role of surgery that need to be addressed in clinical trials. An editorial in the Journal of Clinical Oncology highlighted some key issues, such as whether patients with resectable disease should undergo neoadjuvant chemotherapy and whether these patients can be stratified into good-risk and poor-risk groups.11 Also raised were questions regarding the best preoperative systemic therapy regimen for patients with unresectable hepatic metastases.11

Although certain patients show some response to neoadjuvant systemic therapy, they still have extensive bilateral disease that may be considered unresectable using traditional surgical approaches. In these cases, patient selection and improvements in surgical technique have allowed surgeons to remove all disease using two-stage hepatic resections combined with portal vein embolization. Vauthey and colleagues at the University of Texas MD Anderson Cancer Center, Houston, reported their outcomes using this approach in 65 patients. In these patients who had responded to systemic therapy, a limited resection of disease in the left liver was performed, followed by right portal vein embolization, and then, at a second operation, an extended right hepatectomy. Approximately 30 percent of patients who had the first surgery dropped out due to tumor progression, but those patients who were able to undergo the second operation had a five-year overall survival rate of 51 percent.12 The patient described earlier was able to undergo this approach and have all hepatic metastases resected. Figures 1A–D demonstrate computed tomography images of her disease at various stages of treatment.

Figures 1A, 1B, 1C, 1D

Because fewer than 10 percent of patients with advanced colorectal cancer would be candidates for this approach, a multicenter trial would be required to answer questions regarding which patients are the best candidates. How much response to systemic therapy is needed, as defined by radiographic imaging or biochemical markers? What is the optimal timing of the liver operations and portal vein embolization? In cases of synchronous metastatic disease, what is the best way to manage the primary?

Colorectal cancer metastatic to the liver is a great model for using advances in multidisciplinary care to get patients to surgery, which offers them the best chance for long-term survival, or even a possible cure. Viable clinical trials to study these interventions and determine which patients are the most appropriate candidates are necessary.


References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA-Cancer J Clin. 2012;62(1):10-29.
  2. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309-318; discussion 318-321.
  3. Abdalla EK, Adam R, Bilchik AJ, et al. Improving resectability of hepatic colorectal metastases: Expert consensus statement. Ann Surg Oncol. 2006;13(10):1271-1280.
  4. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J of Surg. 1995;19(1):59-71.
  5. Scheele J, Altendorf-Hofmann A. Surgical treatment of liver metastases. In: Blumgart LH, Fong Y, editors. Surgery of the Liver and Biliary Tract. 3rd ed. London: WB Saunders; 2000: 1475-1502.
  6. Gertsch P. A historical perspective on colorectal liver metastases and peritoneal carcinomatosis: Similar results, different treatments. Surg Oncol Clin N Am. 2003;12(3):531-541.
  7. de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938-2947.
  8. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol. 2004;22(2):229-237.
  9. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg. 2004;240(4):644-657.
  10. Ye LC, Liu TS, Ren L, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013;31(16):1931-1938.
  11. Kemeny N. Treatment of metastatic colon cancer: “The times they are a-changing.” J Clin Oncol. 2013;31(16):1913-1916.
  12. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after two-stage resection of advanced colorectal liver metastases: Response-based selection and complete resection define outcome. J Clin Oncol. 2011;29(8):1083-1090.

 

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