1 Department of Oncology, 2 Cancer Center Statistics, Mayo Clinic, Rochester, MN; 3 Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC; 4 Duluth Clinic, Duluth, MN; 5 Dana-Farber Cancer Institute, Boston, MA; 6 University of Pittsburgh Cancer Institute, Pittsburgh, PA; 7 University of Kansas Medical Center, Kansas City, KS; 8 Iowa Oncology Research Association CCOP, Des Moines, IA, USA; 9 National Cancer Institute of Canada, St Catharines, Canada
* Correspondence to: Dr. D. J. Sargent, Cancer Center Statistics, Mayo Clinic, Kahler 1A, 200 First St Southwest, Rochester, MN 55905, USA. Tel: +1-507-284-5380; Fax: +1-507-266-2477; Email: sargent.daniel{at}mayo.edu
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients and methods: Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n=264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n=267) and (G) oxaliplatin/irinotecan (IROX, n=265) were reviewed. TTP and median OS were calculated.
Results: Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free.
Conclusions: Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.
Key words: chemotherapy, colorectal cancer, resection
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The recent introduction of irinotecan, a topoisomerase I inhibitor, and oxaliplatin, a platinum-based drug, into the management of advanced CRC has provided promising results. Several different combinations of these agents with 5-fluorouracil and leucovorin (5-FU/LV) have achieved objective tumor regression in approximately 40%50% of patients, and extended median survivals to 1520 months [1822
]. A recently completed randomized phase III trial, protocol N9741, studied three different combinations of 5-FU/LV, irinotecan and oxaliplatin (IFL or Saltz regimen, FOLFOX4 or de Gramont regimen, and IROX or Wasserman regimen) in previously untreated metastatic CRC (MCRC). The primary results of this trial demonstrated an improved time to progression (TTP) and OS for the FOLFOX4 regimen compared with either IFL or IROX [23
].
The possibility that such effective therapies may allow metastatic disease resection has therefore generated interest during the past 10 years, and is currently under investigation in several countries [2426
]. The aim of this article is to identify and describe patients treated on Intergroup study N9741 with initially inoperable MCRC who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. We reviewed the records of these patients to determine the impact of potentially curative surgery on median overall and disease-free survival.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The regimens that we consider here are summarized in Table 1. Treatment continued until progression, unmanageable toxic effects, or withdrawal of consent. In the case of attempted or completed surgical resection, treatment was allowed to terminate or continue at the physician's discretion.
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Median TTP in the 24 patients was 18.4 months. Median OS was 42.4 months. When compared with patients achieving CR without resection (n=42), similar results were observed, (median TTP 14.8 months, median OS 39.2 months). Patients experiencing PR without subsequent metastatic resection achieved a median TTP of 10 months and a median OS of 21 months.
Five patients treated by hepatectomy received adjuvant treatment, including hepatic arterial infusion (HAI) of floxuridine (four) and/or systemic infusion of 5-FU/LV (two). After a median 32 months of follow-up, all but one of these patients (80%) remain disease-free.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Surgery remains the only potentially curative treatment for metastatic disease. During the last 10 years, several non-prospective, non-randomized trials have suggested an improvement in 5-year survival in patients operated on for MCRC [816
]. However, <15% of patients with metastatic involvement are candidates for surgery. Newly developed chemotherapeutic agents in CRC treatment, such as irinotecan or oxaliplatin, associated with 5-FU/LV, have demonstrated the ability to reduce tumor burden such that an important fraction of patients initially judged to be inoperable can be resected with curative intent. In particular, administration of 5-FU/LV and oxaliplatin in a neo-adjuvant setting has demonstrated that curative surgery can be performed in patients with initially non-resectable lesions through chemotherapeutic downstaging [20
, 28
30
].
Our trial, although not designed to study post-chemotherapy surgical management of advanced CRC, resulted in a 3.3% metastatic disease resection rate, which represents a small but important subset of patients included in the trial. The low resection rate obtained in our trial, in comparison with the high response rate to chemotherapy, is likely related to the unselected patient population enrolled, as well as the limited expectation and expertise of surgeons in the community setting to perform liver surgery. In addition, patient's disease was limited to the liver or the liver/lung in only 37%39% of patients on the three arms, thus in the majority of patients, possibilities for resection were complicated due to other sites of disease. We feel that these multicenter results are reflective of the current community practice in North America, and illustrate the need for considerable education and publication of the potential role of surgery in patients initially not considered surgical candidates.
The majority of resected patients had been assigned to one of the oxaliplatin-based regimen (FOLFOX4 or IROX regimen), confirming the role of oxaliplatin as a key agent in rendering metastatic lesions surgically manageable. Tournigand and colleagues found similar results in their trial, with a significant difference between patients treated with FOLFOX6 and FOLFIRI (22% versus 9%, P=0.02) [31]. Pozzo et al. have recently evaluated the role of irinotecan-based chemotherapy in a prospective trial including patients with unresectable liver disease [32
]. Approximately one-third of the patients experienced liver surgery after completion of their chemotherapy. The rates observed in our trial were lower, likely due to the facts that: (i) the majority of patients in our trial had disease that extended beyond the liver and lungs; (ii) our trial was performed in a population without patient selection for possible resection; and (iii) our trial was performed in a wide variety of practices throughout the United States and Canada.
After a median follow-up of 34 months, median OS of this patient subgroup is 42.4 months, with a median TTP of 14.4 months. These results compare favorably with those observed in patients who experienced a partial response to chemotherapy, but were not subsequently resected for their metastatic disease (TTP 10 months, median OS 21 months), and are similar to those observed in patients enrolled in the N9741 study with a complete response.
Despite the potential of increasing the rate of curative resection secondary to chemotherapy, previous reports suggest that approximately two-thirds of patients will experience recurrence of their metastatic disease, mainly inside the resected organ [24, 28
, 29
]. Our study population shows similar results, with 71% of patients developing disease recurrence after curative surgery, with 94% of these recurrences in the surgically treated organ.
Adjuvant chemotherapy following resection of liver limited metastatic disease has gained acceptance as an efficient method to decrease recurrence rates and improve survival. A prospective randomized study comparing HAI of floxuridine plus infusional 5-FU with no further treatment demonstrated a lower recurrence rate and improved survival in the treated group [33]. Kemeny and colleagues, in a recent prospective study comparing adjuvant HAI plus systemic chemotherapy with systemic chemotherapy alone, demonstrated a significant improvement in 2-year survival after covariate adjustment after HAI and systemic chemotherapy compared with systemic chemotherapy alone [22
]. Interestingly, in the small subset of our patients treated post-operatively with adjuvant chemotherapy, including HAI floxuridine administration and/or systemic infusion of 5FU/LV, four out of five are disease-free to date, supporting the potential role of chemotherapy to consolidate surgical removal of metastatic disease.
Encouraging results have been published in the literature regarding thermo-ablation procedures in the management of CRC liver metastases [34]. However, long-term results, including improvements in survival, have not been clearly demonstrated. We observed, in our patients, a higher recurrence rate with RFA at open laparotomy than with hepatectomy alone (100% versus 56%). Since no prospective, randomized study has, to date, compared hepatic surgery with either RFA or cryosurgery, these procedures should be used with caution in only very selected cases.
In conclusion, in this multi-institutional cooperative group study, selected patients with initially inoperable MCRC obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. These patients have displayed good outcomes, with an impressive median TTP and OS. Ninety-two per cent of the patients able to be resected had received an oxaliplatin-based chemotherapy regimen. Surgical procedure may influence the subsequent outcome, with RFA demonstrating poorer long-term efficacy than surgical procedures. Finally, four out of five patients treated with adjuvant post-resection chemotherapy remain disease-free. These results should encourage aggressive approaches to the treatment of CRC metastases, favoring careful assessment of disease status during chemotherapy to allow the possibility of surgical resection of liver metastases.
![]() |
Acknowledgements |
---|
Received for publication April 23, 2004. Revision received November 5, 2004. Accepted for publication November 8, 2004.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Steele GD Jr. The National Cancer Data Base report on colorectal cancer. Cancer 1994; 74: 19791989.[ISI][Medline]
3. Steele G Jr, Ravikumar TS. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 1989; 210: 127138.[ISI][Medline]
4. Bozzetti F, Doci R, Bignami P et al. Patterns of failure following surgical resection of colorectal cancer liver metastases. Rationale for a multimodal approach. Ann Surg 1987; 205: 264270.[ISI][Medline]
5. Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg 1995; 19: 5971.[ISI][Medline]
6. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352358.[Abstract]
7. Poon MA, O'Connell MJ, Moertel CG et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7: 14071418.[Abstract]
8. Fong Y. Surgical therapy of hepatic colorectal metastasis. CA Cancer J Clin 1999; 49: 231255.
9. Fortner JG, Silva JS, Golbey RB et al. Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer I. Treatment by hepatic resection. Ann Surg 1984; 199: 306316.[ISI][Medline]
10. Adson MA, van Heerden JA, Adson MH et al. Resection of hepatic metastases from colorectal cancer. Arch Surg 1984; 119: 647651.[Abstract]
11. Fong Y, Cohen AM, Fortner JG et al. Liver resection for colorectal metastases. J Clin Oncol 1997; 15: 938946.[Abstract]
12. McCormack PM, Burt ME, Bains MS et al. Lung resection for colorectal metastases. 10-year results. Arch Surg 1992; 127: 14031406.[Abstract]
13. Regnard JF, Grunenwald D, Spaggiari L et al. Surgical treatment of hepatic and pulmonary metastases from colorectal cancers. Ann Thorac Surg 1998; 66: 214218, discussion 218219.
14. Vigneswaran WT. Management of pulmonary metastases from colorectal cancer. Semin Surg Oncol 1996; 12: 264266.[CrossRef][ISI][Medline]
15. McAfee MK, Allen MS, Trastek VF et al. Colorectal lung metastases: results of surgical excision. Ann Thorac Surg 1992; 53: 780785. (Discussion, pp. 785786).[Abstract]
16. Girard P, Ducreux M, Baldeyrou P et al. Surgery for lung metastases from colorectal cancer: analysis of prognostic factors. J Clin Oncol 1996; 14: 20472053.[Abstract]
17. Steele GD Jr, Bleday R, Mayer RJ et al. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol 1991; 9: 11051112.[Abstract]
18. 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: 29382947.
19. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 10411047.[CrossRef][ISI][Medline]
20. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracilleucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18: 136147.
21. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905914.
22. Kemeny N, Huang Y, Cohen AM et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341: 20392048.
23. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 18.
24. Tanaka K, Adam R, Shimada H et al. Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver. Br J Surg 2003; 90: 963969.[CrossRef][ISI][Medline]
25. Wein A, Riedel C, Bruckl W et al. Neoadjuvant treatment with weekly high-dose 5-fluorouracil as 24-hour infusion, folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer. Oncology 2003; 64: 131138.[CrossRef][ISI][Medline]
26. Adam R, Huguet E, Azoulay D et al. Hepatic resection after down-staging of unresectable hepatic colorectal metastases. Surg Oncol Clin N Am 2003; 12: 211220.[Medline]
27. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457481.[ISI]
28. Adam R, Avisar E, Ariche A et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001; 8: 347353.
29. Bismuth H, Adam R, Levi F et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996; 224: 509520, discussion 520522.[CrossRef][ISI][Medline]
30. Rivoire M, De Cian F, Meeus P et al. Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma. Cancer 2002; 95: 22832292.[CrossRef][ISI][Medline]
31. Tournigand C, Andre T, Achille E et al. FOLFIRI follwed by FOLFOX6 or the reverse squence in advanced colorectal: a randomized GERCOR study. J Clin Oncol 2004; 15: 229237.
32. 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 2004; 15: 933939.
33. Kemeny MM, Adak S, Gray B et al. Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: surgical resection of hepatic metastases in combination with continuous infusion of chemotherapyan intergroup study. J Clin Oncol 2002; 20: 14991505.
34. Erce C, Parks RW. Interstitial ablative techniques for hepatic tumours. Br J Surg 2003; 90: 272289.[CrossRef][ISI][Medline]