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In Reply:

Department of General Surgery, Medical Center of the University of Göttingen, Göttingen, Germany

David M. Goldenberg

Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ

The purpose of our report¹ of a phase II trial of radioimmunotherapy (RAIT) administered after salvage resection of colorectal liver metastases was to show the feasibility and initial efficacy of this approach as a rationale for a future randomized trial comparing this method with standard postoperative care. The efficacy results in this small study were considered in context with various trials conducted in the same general timeframe and with a mix of patients having similar risk factors, as well as a contemporaneous group of patients resected at the same institution by the same group of surgeons and within the same timeframe. We certainly did not claim that our survival results, which were 51% at 5 years for a 64-month median follow-up (in fact, this follow-up was longer than most studies reported in the literature, including those of Abdalla et al^2,3; Table 1), were superior to others in the literature, since many publications, including those of the authors of the letter, failed to provide sufficient details as to the major risk factors for recurrence of their patient populations (Table 1) to allow any comparison to be made. Indeed, none of the studies cited provide the preoperative and postoperative risk scores for cancer relapse in detail. We appreciate that unless the patients are of similar demographics and prognostic risk scores, such comparisons should not be made.

The most important consideration is to compare patients having similar risk factors, for which several systems are available. Using the Nordlinger clinical prognostic scoring system,^7,8 12 of our 19 patients had a poor prognosis (risk level II); with the postoperative histopathologically determined/classified scoring system of Gayowski,⁹ including eight of 12 patients (with mTNM stages of at least 3) had bilobar liver metastases; and 17 of 19 patients having metastases larger than 2 cm in tumor diameter. Further, six of the 19 patients required neoadjuvant chemotherapy to become candidates for salvage resection. Our results showed a 51% 5-year survival versus the 28% found for patients reported with similar risk factors.^7,10 Interestingly, in our study, seven of 10 patients with advanced mTNM stages 2 to 4 were long-term survivors (38 to 78 months). Most importantly, the 5-year survival for the contemporaneous controls with similar demographics and prognostic risk scores was only 7.4%. The results of the studies by Fong et al⁵ and Mann et al¹¹ confirm our results, indicating that patients with Fong clinical risk scores more than 2 had a 5-year survival below 20%.⁵ The four patients not included in our analysis did not fulfill the entry criteria, and were therefore not included in the follow-up results. As with the studies of Abdalla et al and others (Table 1),^2-3,5,11-16 our analysis of controls is hampered because it is retrospective. For this reason, and because of the small number of patients in our studies, our conclusion was that a prospective, randomized study comparing RAIT with standard postoperative therapy should be undertaken, and we are now organizing one.

Because there is now evidence that cancer cells disseminate at the time of surgery,^17-19 it is intuitive to seek a systemic therapy that will mitigate this cause of relapse, and we have therefore proposed, on the basis of supportive preclinical evidence,^20-22 that systemic radiotherapy may be one such option. Of course, RAIT combined with chemotherapy or other therapies may also be worthy of investigation.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other David M. Goldenberg Immunomedics Inc (N/R) Immunomedics Inc (C) Immunomedics Inc (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Liersch T, Meller J, Kulle B, et al: Phase II trial of carcinoembryonic antigen radioimmunotherapy with ¹³¹I-labetuzumab after salvage resection of colorectal metastases in the liver: 5-year safety and efficacy results. J Clin Oncol 23:6763-6770, 2005[Abstract/Free Full Text]

2. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825, 2004[CrossRef][Medline]

3. Aloia TA, Vauthey JN, Loyer EM, et al: Solitary colorectal liver metastasis: Resection determines outcome. Arch Surg 141:460-467, 2006

4. Schnider A, Metzger U: Chirurgie der Lebermetastasen. Schweiz Med Forum 49:1171-1176, 2002

5. 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 230(3):309-321, 1999

6. Kato T, Yasui K, Hirai T, et al: Therapeutic results for hepatic metastasis of colorectal cancer with special reference to effectiveness of hepatectomy: Analysis of prognostic factors for 763 cases recorded at 18 institutions. Dis Colon Rectum 46:S22-S31, 2003

7. Nordlinger B, Guiguet M, Vaillant JC, et al: Surgical resection of colorectal carcinoma metastases to the liver: A prognostic scoring system to improve case selection, based on 1568 patients—Association Francoise de Chirurgie. Cancer 77:1254-1262, 1996[CrossRef][Medline]

8. Jaeck D, Bachellier P, Guiguet M, et al: Long-term survival following resection of colorectal hepatic metastases: Association Française de Chirurgie. Br J Surg 84:977-980, 1997[CrossRef][Medline]

9. Gayowski TJ, Iwatsuki S, Madariaga JR, et al: Experience in hepatic resection for metastatic colorectal cancer: Analysis of clinical and pathologic risk factors. Surgery 116:703-710, 1994[Medline]

10. Bismuth H, Adam R, Lévi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509-522, 1996[CrossRef][Medline]

11. Mann CD, Metcalfe MS, Leopardi LN, et al: The clinical risk score: Emerging as a reliable preoperative prognostic index in hepatectomy for colorectal metastases. Arch Surg 139:1168-1172, 2004[Abstract/Free Full Text]

12. Figueras J, Valls C, Rafecas A, et al: Resection rate and effect of postoperative chemotherapy on survival after surgery for colorectal liver metastases. Br J Surg 88:980-985, 2001[CrossRef][Medline]

13. Bramhall SR, Gur U, Coldham C, et al: Liver resection for colorectal metastases. Ann R Coll Surg Engl 85:334-339, 2003[Medline]

14. Choti MA, Sitzmann JV, Tiburi MF, et al: Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766, 2002[CrossRef][Medline]

15. Fernandez FG, Drebin JA, Linehan DC, et al: Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 240:438-447, 2004[CrossRef][Medline]

16. Pawlik TM, Scoggins CR, Zorzi D, et al: Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 241:715-724, 2005[CrossRef][Medline]

17. Topal B, Aerts JL, Roskams T, et al: Cancer cell dissemination during curative surgery for colorectal liver metastases. Eur J Surg Oncol 31:506-511, 2005[CrossRef][Medline]

18. Koch M, Kienle P, Hinz U, et al: Detection of hematogenous tumor cell dissemination predicts tumor relapse in patients undergoing surgical resection of colorectal liver metastases. Ann Surg 241:199-205, 2005[CrossRef][Medline]

19. Weitz J, Koch M, Kienle P, et al: Detection of hematogenic tumor cell dissemination in patients undergoing resection of liver metastases of colorectal cancer. Ann Surg 232:66-72, 2000[CrossRef][Medline]

20. Sharkey RM, Weadock KS, Natale A, et al: Successful radioimmunotherapy for lung metastasis of human colonic cancer in nude mice. J Natl Cancer Inst 83:627-632, 1991[Abstract/Free Full Text]

21. Behr TM, Blumenthal RD, Memtsoudis S, et al: Cure of metastatic human colonic cancer in mice with radiolabeled monoclonal antibody fragments. Clin Cancer Res 6:4900-4907, 2000[Abstract/Free Full Text]

22. Behr TM, Salib AL, Liersch T, et al: Radioimmunotherapy of small volume disease of colorectal cancer metastatic to the liver preclinical evaluation in comparison to standard chemotherapy and initial results of a phase I clinical study. Clin Cancer Res 5:3232S-3242S, 1999

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