Annals of Oncology Advance Access originally published online on January 27, 2005
Annals of Oncology 2005 16(3):425-429; doi:10.1093/annonc/mdi092
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© 2005 European Society for Medical Oncology
Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741
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
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Abstract |
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Background: Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease.
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
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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In 2002,
150 000 Americans were newly diagnosed with colorectal cancer (CRC), the second leading cause of cancer death worldwide [1
]. Fifteen to 25% of these patients will present with metastatic disease [2]. Approximately half of them will develop liver metastases at some point during the course of the disease [3–6]. Patients with untreated metastatic disease have a median survival of <10 months and a 5-year survival <5% [7]. When metastases can be surgically resected, longer median overall survivals (OS) of 3 years have been reported [8–17].
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 15–20 months [18–22]. 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 [24–26]. 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.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Detailed descriptions of the patient populations, eligibility criteria, patient evaluation, randomization schema and statistical design have been published elsewhere [23
]. Patients were required to have known locally advanced, locally recurrent or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent. The protocol did not include specific criteria for resection of metastatic disease. Attempted curative resection was allowed at any time, based on physician discretion. 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.
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We first isolated from the N9741 database patients who were potentially able to benefit from surgical resection of their metastatic disease, i.e. patients who achieved a disease status of stable disease (SD), partial response (PR) or regression (REGR) (n=450). We subsequently reviewed the research records of these patients to identify individuals who obtained sufficient benefit from chemotherapy to permit removal of their metastatic disease. Data on patient demographics (age, gender at diagnosis of CRC, vital status at last follow-up), chemotherapy features (type, number of courses and treatment duration), metastatic disease characteristics (metastases location and number, relapse date and location) and surgical aspects (surgery date and type) were collected for each patient. For the present analysis of patients eligible for resection, we present descriptive statistics, including point estimates and 95% confidence intervals. Median TTP and survival were estimated by the Kaplan–Meier method [27
]. All randomized patients are included for efficacy analyses according to the intention-to-treat principle. |
Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Seven hundred and ninety-five patients were enrolled in the study between May 1999 and April 2001. Patient characteristics are listed in Table 2. Thirty-seven per cent to 39% of patients had disease limited to the liver, or to the liver and lungs only. The response rate for oxaliplatin/5-FU/LV was significantly better than for irinotecan/5-FU/LV (P=0.02) or for oxaliplatin plus irinotecan (P=0.01). The response rates for irinotecan/5-FU/LV and oxaliplatin plus irinotecan did not differ (P=0.91) (Table 3).
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A total of 450 records were reviewed, including 267 patients experiencing PR, 147 having a SD and 36 with a regression. Twenty-six patients (3.3%) underwent attempted post-chemotherapeutic resection of their metastatic disease (Table 4). These include 15 males and 11 females, median age 55 years (range 27–77). Two patients were found to have peritoneal involvement at surgery, thus a total of 24 patients are considered as operated on with a curative intent. Surgical procedures included partial hepatectomy in 16 patients, radiofrequency ablation (RFA) at open laparotomy in six, and lobectomy for lung involvement in two. Three patients had their primary tumor simultaneously removed with metastases. The majority of patients suffered from liver metastases (22 out of 24). The median number of metastases in the entire cohort was two (range one to four). Twenty-two out of 24 patients who underwent curative resection of their metastatic disease had been treated with oxaliplatin-based regimens. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin-containing regimens (P=0.02). Specifically, the number and rates of resection by arm were: IFL, two patients (0.7%); FOLFOX4, 11 patients (4.1%); and IROX, 11 patients (4.2%).
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With a median follow-up of 34 months, 14 (58%) of the resected patients are alive, and seven (29%) remain disease-free, all of whom were treated with hepatectomy. Both patients who underwent lobectomy for lung involvement have recurred. Recurrences mainly occurred in the resected organ. Only one patient experienced metastases outside the resected organ.
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.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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CRC is the second leading cause of cancer death worldwide, primarily attributed to metastatic disease rather than to the primary tumor. Approximately 50% of patients with CRC will present with metastases at some point in their illness, with the liver often being the only or principal site of metastatic involvement.
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 [8–16]. 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.
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Acknowledgements |
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This trial was supported by grant CA25224 from the National Cancer Institute.
Received for publication April 23, 2004. Revision received November 5, 2004. Accepted for publication November 8, 2004.
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References |
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