This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petrelli, N. J. Articles by Minsky, B. Search for Related Content PubMed PubMed Citation Articles by Petrelli, N. J. Articles by Minsky, B. Social Bookmarking                            What's this?

Hepatic Resection: The Last Surgical Frontier for Colorectal Cancer

Helen F. Graham Cancer Center, Newark, DE
The University of Texas M.D. Anderson Cancer Center, Houston, TX
Memorial Sloan-Kettering Cancer Center, New York, NY

This issue of the Journal of Clinical Oncology is devoted to gastrointestinal tumors. Pancreatic, gastric, colorectal, esophageal, and biliary tract tumors are discussed. Therapy, diagnostic modalities, and molecular markers are presented by experts in the oncology field. Readers will find the contents informative and, more importantly, very current. The latter was a top priority given to the authors so that the contents of the manuscripts would not be outdated.

With regard to gastric cancer, two articles dealing with resectable disease are included. The first, by Soetikno et al, examines the role of endoscopic mucosal resection (EMR) for early disease. Although T1 tumors still comprise a relatively small percentage of the patients with gastric cancers seen in the United States, that percentage appears to be slowly increasing. The techniques of EMR are highly specialized, and few centers in the United States have significant experience with them. Nevertheless, given the excellent prognosis of appropriately selected patients, and the far superior quality of life with an intact stomach, EMR will likely see increasing application. Centers in which large numbers of patients are treated with this approach (primarily in Japan) are expanding the limits of what can be removed safely by this technique.

The second article, by Jansen et al, examines more aggressive local therapy for gastric cancer. The role of extended lymphadenectomy in Western patients continues to simmer despite the failure of two prospective randomized trials to show a benefit. While these studies suffered from such high operative mortality from the extended resections that any potential benefit would be obscured, single centers routinely perform extended node dissections with mortality rates dramatically lower than that of the control arm of the randomized trials. A large prospective randomized trial of extended node dissections in Japan has completed accrual with a mortality rate of less than 1%. For some, the question of extended resections remains an issue given the highly positive results of the INT-0116 trial (utilizing chemoradiotherapy), in which many contend that substandard surgery was performed, implying that adjuvant therapy was simply making up for inadequate surgery. Perhaps the most important lesson out of this is that future studies of multimodality therapy for gastric cancer must pay at least as much attention to the surgical procedures performed as to the chemotherapy regimens and radiotherapy portals.

Nevertheless, as one looks over the table of contents of this JCO Special Series gastrointestinal issue, there is no discussion on hepatic resection for colorectal carcinoma metastases. This would seem to be a major deficit in this issue in view of recent drug developments that have increased the potential for hepatic resection. However, to satisfy the readers of JCO, in upcoming issues of the Journal there will be several articles and a commentary on developments for improving resectability with curative intent in colorectal metastases to the liver.

So why would one consider hepatic resection the last surgical frontier for colorectal cancer? If one were to ask what other important surgical questions there are to answer in colorectal cancer, although the list may be considerable, the important issue is whether the questions would be clinically relevant. For example, the question of whether laparoscopically assisted surgery for colon cancer would compromise survival by failing to achieve a proper oncologic resection or adequate staging was answered by the Clinical Outcomes of Surgical Therapy Study Group in the New England Journal of Medicine in 2004.¹ This multi-institutional prospective study concluded that the rates of recurrent cancer were similar after laparoscopically assisted colectomy and open colectomy, suggesting that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer when performed by experienced and credentialed surgeons. So that leaves the question of laparoscopically assisted versus open resection for rectal cancer. Is this a trial that is worth the time and resources to complete? The answer is no. How about a trial comparing segmental colon resection to hemicolectomy? Again, the answer is no, because the morbidity and mortality with either one of these approaches is extremely low in experienced hands. What about the issue of sentinel lymph node staging of resectable colon cancer? The results of Cancer and Leukemia Group B (CALGB) Protocol 80001, in my opinion, put the question of sentinel lymph node mapping for colon cancer to rest.² This prospective study, conducted by 25 surgery and pathology teams at 12 institutions, was designed to determine whether sentinel lymph node sampling could identify a subset of lymph nodes that predict the status of the nodal basin for resectable colon cancer. The authors concluded that sentinel lymph node failed to predict nodal status in 52% of cases. It would not seem prudent to spend resources on a confirmatory trial. There is the surgical approach involving local excision of early stage rectal cancer. However, recent reports have demonstrated recurrence rates ranging from 11% to 24% following local excision.^3,4 Many individuals would state that local excision should be reserved for low-risk cancers, but the real problem is identifying those low-risk cancers. Perhaps with better chemotherapeutic and targeted agents that are now available, these outcomes might improve. Lastly, there is the issue of cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP) for colorectal carcinomatosis. Some may argue that the real question is what is the role of IPHP in this environment in view of the newer systemic agents. The American College of Surgeons Oncology Group is formulating a trial.

This leaves the liver as the last surgical frontier in colorectal cancer. Hepatic resection for colorectal metastases without extrahepatic disease has become a standard of care, and at present remains the only potentially curative treatment for liver and lung metastases. Despite the fact that recent literature has concluded that extrahepatic disease should no longer be considered as a contraindication to hepatectomy, this concept needs to be tested in the future in a multi-institutional prospective trial setting.⁵ In the last 5 to 10 years, there has been considerable effort directed towards increasing the number of patients who could benefit from hepatic resection. Areas of improvement in surgical techniques have included intraoperative ultrasound, preoperative portal vein embolization for hypertrophy of the future liver remnant, staged hepatic resection, and unique devices for parenchymal transection. In the past, curative resection was possible in less than 25% of those patients with disease limited to the liver, which translated into 5% to 10% of the original group developing colorectal cancer. However, the development of newer chemotherapeutic agents, such as oxaliplatin and irinotecan, have demonstrated capabilities of inducing significant tumor shrinkage and have potentially allowed an additional 10% to 20% of patients thought to initially be unresectable for cure to subsequently undergo hepatic resection.^6-8 These studies demonstrate that long-term survival rates for these patients previously treated in the palliative environment are now comparable to those of primarily resected patients.

However, it is also important to emphasize that single-institution trial results need to be reproduced in the multi-institutional prospective trial environment. Hence, because of these newer chemotherapeutic agents and surgical techniques, there is great enthusiasm for increasing the resectability rates for hepatic metastases from colorectal cancer. One trial, N014A, is under the direction of the North Central Cancer Treatment Group. The primary end point of this trial is to evaluate the surgical resectability rate of patients with advanced colorectal carcinoma confined to the liver initially considered suboptimal for resection before treatment with cetuximab, oxaliplatin, fluorouracil, and leucovorin. This study complements a National Surgical Adjuvant Breast and Bowel Project Protocol, C-09, a phase III trial comparing systemic chemotherapy with oxaliplatin plus capecitabine and hepatic arterial infusion floxuridine to oxaliplatin plus capecitabine alone postoperatively following resected and/or ablated liver metastases for colorectal cancer. In addition, the American College of Surgeons Oncology Group is developing a trial for resectable hepatic metastases with the addition of neoadjuvant chemotherapy. Also, a European Organisation for Research and Treatment of Cancer (EORTC) trial has already completed accrual of pre- and postoperative FOLFOX (fluorouracil, leucovorin, oxaliplatin) versus no chemotherapy for resectable liver metastases. Aside from the cooperative group mechanism, more than likely, the pharmaceutical industry will be interested in pursuing similar trials, both in the neoadjuvant setting for resectable disease and in the context of rescue surgery for initially unresectable hepatic metastases downstaged by chemotherapy with the newer chemotherapeutic and targeted agents. The addition of targeted agents to chemotherapy, such as bevacizumab and cetuximab, may certainly increase the rate of hepatic resection. However, as recently described by Ellis et al,⁹ this brings in question the effect of targeted therapies with or without cytotoxic chemotherapy on wound healing and hepatic regeneration in patients who undergo liver resection after neoadjuvant therapy.

Newer agents allow the multidisciplinary team of oncologists to potentially increase the number of patients with initial unresectable colorectal liver metastases for rescue surgery and potentially curative hepatic resection. The problem is that some of the hepatic trials mentioned in this Editorial and those in development will overlap, using the same patient populations, which leaves the problem of a relatively small cohort of eligible patients spread out among several prospective randomized trials. Under these circumstances, history demonstrates that either accrual to trials will be slow or the targeted accrual will not be achieved. Hence, with greater cooperation among all the North American cooperative groups, studies will be more likely to get done. In this way, eligible patients will be accrued rapidly to the trials and definitive answers can be obtained.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050-2059, 2004[Abstract/Free Full Text]

2. Bertagnolli M, Redston M, Miedema B, et al: Sentinel node staging of resectable colon cancer: Results of CALGB 80001. Proc Am Soc Clin Oncol 22:2465, 2004 (abstr 3506; suppl)

3. Garcia-Aguilar J, Mellgren A, Sirivongs P, et al: Local excision of rectal cancer without adjuvant therapy: A word of caution. Ann Surg 231:345-351, 2000[CrossRef][Medline]

4. Paty P, Bentrem D, Okabe S, et al: T1 adenocarcinoma of the rectum: Transanal excision or radical surgery? Proc Am Surg Assoc, ABSE:42, 2005

5. Elias D, Sideris L, Pocard M, et al: Results of R0 resection for colorectal liver metastases associated with extrahepatic disease. Ann Surg Oncol 11:274-280, 2004[Abstract/Free Full Text]

6. Adam R, Avisar E, Ariche A, et al: Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal cancer. Ann Surg Oncol 8:347-353, 2001[Abstract/Free Full Text]

7. Adam R: Chemotherapy and surgery: New perspectives on the treatment of unresectable liver metastases. Ann Oncol 14:ii13-ii16, 2003[Abstract]

8. Pozzo C, Basso M, Cassano A, et al: Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol 15:933-939, 2004[Abstract/Free Full Text]

9. Ellis L, Curley S, Grothey A: Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol, in press

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. Benoist, A. Brouquet, C. Penna, C. Julie, M. El Hajjam, S. Chagnon, E. Mitry, P. Rougier, and B. Nordlinger Complete Response of Colorectal Liver Metastases After Chemotherapy: Does It Mean Cure? J. Clin. Oncol., August 20, 2006; 24(24): 3939 - 3945. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Petrelli, N. J. Articles by Minsky, B. Search for Related Content PubMed PubMed Citation Articles by Petrelli, N. J. Articles by Minsky, B. Social Bookmarking                            What's this?