Originally published as JCO Early Release 10.1200/JCO.2008.20.2218 on February 2 2009

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In Reply

Assistance Publique—Hôpitaux de Paris, Hôpital Paul Brousse, and Université Paris-Sud, Villejuif, France

Thomas A. Aloia

Hôpital Paul Brousse and Université Paris-Sud, Villejuif, France; and The Methodist Hospital, Weill Cornell Medical College, Houston, TX

We have read with much interest the editorial by Lawrence D. Wagman¹ concerning our recent article in Journal of Clinical Oncology.² In this editorial, the author first argues that in our article we presented only our successes—our "diamonds." He is probably referring to the group of patients with both liver and portal pedicular lymph node metastases who achieved a 25% survival rate at 5 years after combined hepatectomy and lymphadenectomy. However, in writing this, he does not appear to consider the complete reporting of those patients in our series with celiac or para-aortic lymph nodes who experienced a 0% survival rate at 5 years—our "lumps of coal." Certainly, our article represents an honest and complete report of our consecutive series of patients who underwent resection for liver and lymph node metastases, without selection of only successful outcomes. Furthermore, it was not our therapeutic objective to blind to surgical therapy any subset of patients who may have benefited from our combined approach.

Second, Wagman sought to minimize the relevance of our results by emphasizing the size of the study, even though studies of colorectal liver metastases with lymph node involvement represent an under-reported area, and to our knowledge, our series is the largest single-center experience with this disease entity. Indeed, the study population represented 6% of our overall cohort of patients with colorectal liver metastases, a proportion similar to that of previously reported, but smaller, series.^3–5 Mainly, this relates to the low prevalence of patients with metastatic lymph node disease who underwent curative surgical therapy. On the basis of these data, we do not believe that our sample size (which is relatively large, given the rarity of this clinical presentation) should be a reason not to consider this therapeutic strategy for these patients. In other words, we believe that regardless of the number of patients eligible for a treatment, if benefit of that treatment is shown, it should be offered.

Third, by stating that the possibility that patients who experienced disease progression in the nodal area were never sent to the surgical team is a confounding factor that prevents conclusions being drawn from our study, the author seems to miss the main objective of our study. That is, was the response to chemotherapy able to reverse the known poor prognosis of these patients? In studying this clinical problem, we found it logical to operate only on systemic chemotherapy treatment responders. In addition, we have already reported the negative prognostic impact of metastasis progression while patients are receiving chemotherapy before liver resection.⁶ Given our previous findings, it would have been unethical to re-explore this issue by operating on patients with nodal disease progression—a group of patients with the highest risk of dismal postoperative oncologic outcomes.

Fourth, the author postulates that the active modality in the treatment of the liver metastases was not the surgery but rather the chemotherapy. This statement does not seem to consider that the number of liver metastases patients who survive 5 years after chemotherapy alone, even with the current active regimens, approaches 0%.^7,8 Given this comparison, the 5-year survival rate that we reported using an oncosurgical approach gives some hope to these patients. We would be interested to learn of a reference that documents any 5-year survivors with liver and lymph node metastases treated with chemotherapy alone.

Fifth, by contending that removal of metastatic porta hepatis lymph nodes does not change the course of the disease, the author discloses a closed attitude toward patients who undergo this procedure. We would ask, given the tremendous progress that multidisciplinary management has had in this disease and the advances in liver surgery that have made these procedures safer, what treatment strategy should we adopt for a patient with both liver and porta hepatis lymph node metastases who responds to chemotherapy? Is chemotherapy combined with surgery, which provides a 25% chance of 5-year survival not better than chemotherapy alone, which provides almost no chance for long-term survival?

Finally, Wagman questions the scientific value of our study. Although it is obvious that the study was retrospective and conducted over a long period of time, the eligibility criteria were uniform, and our inclusion criteria for treatment with this approach were clearly defined. In addition, because of the limited number of such patients, it is unlikely that any randomized, controlled trial on this topic would be feasible. The progressive scientific exploration of novel treatment strategies for traditionally poor-prognosis patients has allowed us to conduct these studies and report these data. As we have used these treatment strategies, we have continually examined our results to identify the subsets of patients who most benefit from these strategies. In this way, we can recommend to other centers how to best select patients for surgical resection. We certainly hope that physicians and patients at these centers find the "scientific value" in our work.

Our study explored one treatment strategy and yielded a small number of diamonds, but also many lumps of coal. If we only focus on the most common outcome and base our entire clinical practice on the median outcome, we risk missing the opportunity to help the subset of patients who will benefit from novel therapies. If we had adopted such a policy during the 1980s, when surgical resection was proposed as a radical new treatment for patients with liver metastases, we would probably have lost the opportunity for so many patients to share in the current 40% to 50% 5-year survival rate following liver resection. The same would have occurred when we proposed that surgery could be combined with effective chemotherapy for initially unresectable liver metastases—a "scientifically unproven" concept that currently offers the possibility of long-term survival to a significant number of patients.^9–11

In summary, we strongly disagree with Dr. Wagman's statement that the role of surgery in patients with liver metastases still remains "unsupported by scientific proof." It may be true that there is no scientific proof that every patient can expect that removal of porta hepatis regional nodes with liver resection will change the course of his or her disease. However, comparison of our outcomes to those of patients treated with chemotherapy alone indicates that 25% of patients will respond to this therapy, and we refuse to wait until all patients benefit before offering the treatment to those who do.

Diamonds may be rare but they are worth a fortune to those who possess them!

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: René Adam, Merck Serono; Thomas A. Aloia, Sanofi-aventis Research Funding: René Adam, Sanofi-aventis, Merck Serono Expert Testimony: None Other Remuneration: None

REFERENCES

1. Wagman LD: Expanded criteria for surgery for liver metastases: Thoughtful science or diamond mining? J Clin Oncol 26:3663–3664, 2008.[Free Full Text]

2. Adam R, de Haas RJ, Wicherts DA, et al: Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 26:3672–3680, 2008.[Abstract/Free Full Text]

3. Rodgers MS, McCall JL: Surgery for colorectal liver metastases with hepatic lymph node involvement: A systematic review. Br J Surg 87:1142–1155, 2000.[CrossRef][Medline]

4. Jaeck D, Nakano H, Bachellier P, et al: Significance of hepatic pedicle lymph node involvement in patients with colorectal liver metastases: A prospective study. Ann Surg Oncol 9:430–438, 2002.[CrossRef][Medline]

5. Elias D, Ouellet JF, Bellon N, et al: Extrahepatic disease does not contraindicate hepatectomy for colorectal liver metastases. Br J Surg 90:567–574, 2003.[CrossRef][Medline]

6. Adam R, Pascal G, Castaing D, et al: Tumor progression while on chemotherapy: A contraindication to liver resection for multiple colorectal metastases? Ann Surg 240:1052–1061, 2004.[CrossRef][Medline]

7. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663–669, 1999.[Abstract/Free Full Text]

8. Masi G, Cupini S, Marcucci L, et al: Treatment with 5-fluorouracil/folinic acid, oxaliplatin, and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 13:58–65, 2006.[CrossRef][Medline]

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 240:644–657, 2004.[Medline]

10. Alberts SR, Horvath WL, Sternfeld WC, et al: Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol 23:9243–9249, 2005.[Abstract/Free Full Text]

11. Adam R, Wicherts DA, de Haas RJ, et al: Complete pathologic response after preoperative chemotherapy for colorectal liver metastases: Myth or reality? J Clin Oncol 26:1635–1641, 2008.[Abstract/Free Full Text]

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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 Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Adam, R. Articles by Aloia, T. A. Search for Related Content PubMed Articles by Adam, R. Articles by Aloia, T. A. Social Bookmarking                            What's this?