1 Unit of Medical Oncology, Department of Internal Medicine and 2 Unit of Hepatobiliary Surgery, Department of General Surgery, Catholic University of Sacred Heart, Rome, Italy
Received 25 September 2003; revised 28 January 2004; accepted 2 February 2004
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ABSTRACT |
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The aim of this study was to observe the effects of neoadjuvant therapy with irinotecan and 5-fluorouracil (5-FU)/folinic acid (FA) on the resection rate and survival of colorectal cancer patients with initially unresectable hepatic metastases.
Patients and methods:
Forty patients received neoadjuvant chemotherapy comprising irinotecan 180 mg/m2 administered intravenously (i.v.) on day 1, FA 200 mg/m2 i.v. on days 1 and 2, 5-FU 400 mg/m2 i.v. bolus on days 1 and 2, and 5-FU 1200 mg/m2 as a continuous 48-h i.v. infusion on day 1. The treatment was repeated every 2 weeks and response was assessed every 12 weeks (six cycles).
Results:
The objective response rate to chemotherapy was 47.5% (n = 19), with two complete responses and disease stabilization in 11 (27.5.%) patients. Responses were unconfirmed for 11 patients undergoing surgery within 2 weeks. Treatment was well tolerated and adverse events were typical of the chemotherapy agents used. Twenty-seven (67.5%) patients reported hematological toxicity (35.0% grade 3/4) and 14 (35.0%) reported gastrointestinal toxicity (12.5% grade 3/4). Thirteen patients (32.5%) underwent potentially curative liver resection following chemotherapy. Chemotherapy was particularly effective in patients with large metastases on entry to the study. The median time to progression is 14.3 months and, at a median follow-up of 19 months, all patients are alive.
Conclusions:
Neoadjuvant therapy with irinotecan combined with 5-FU/FA enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. The effects of treatment on survival have yet to be determined.
Key words: colorectal, 5-fluorouracil, irinotecan, liver, neoadjuvant, unresectable
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Introduction |
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The liver is the most common site of colorectal metastases, and 50% of patients with colorectal cancer have liver metastases [9]. The survival time of patients with untreated liver metastases is <1 year [10, 11]. However, survival is longer in patients with resectable liver metastases and no extra-hepatic disease. Surgical removal of metastases is the only potentially curative therapy for these patients, and resection can provide long-term survival [12, 13], with reports of 4- and 5-year survival rates of ~44% and 30%, respectively [14, 15]. The drawback is that only ~1020% of patients with colorectal metastases are candidates for liver resection [9]. For the remaining patients, although they may have no extra-hepatic disease, surgery is discounted for a number of reasons, including unfavorable location of the metastases (close to the hepatic veins, the inferior vena cava or the liver hilum), large lesions or multiple bilateral lesions. These patients have traditionally received palliative chemotherapy.
Until recently, systemic administration of 5-FU together with folinic acid (FA) was the gold-standard of chemotherapy for metastatic colorectal cancer. However, response rates seldom reached more than 30% [8]. Randomized trials conducted in recent years have shown that combining 5-FU/FA with irinotecan or oxaliplatin has yielded response rates of between 39% and 58% [26, 16]. Importantly, there was evidence that some patients initially treated with palliative intent were able to undergo surgical resection of their metastases after chemotherapy. This highlighted the possibility of using neoadjuvant chemotherapy to effect the downstaging of metastases and so enable curative surgery for initially unresectable disease [9, 17]. The activity of irinotecan- and oxaliplatin-based chemotherapy in metastatic colorectal cancer prompted the investigation of these compounds as neoadjuvant chemotherapy. Most of the currently available data are from retrospective analyses with oxaliplatin-based chemotherapy, and this treatment has effectively downstaged hepatic metastases, allowing surgical resection and improving overall survival [1821]. In an analysis of 701 patients with unresectable liver metastases, neoadjuvant chemotherapy (mainly with oxaliplatin-based chemotherapy) enabled potentially curative resection in 14% of patients, resulting in a 5-year survival rate of 35% from the time of resection, which was comparable to that of patients whose disease was resectable at the outset [21]. Initial investigation with irinotecan suggested that it too may be effective as neoadjuvant therapy [22], making curative resection for hepatic metastases possible [9].
The aim of our prospective study was to investigate the activity of neoadjuvant chemotherapy with bimonthly 5-FU, FA and irinotecan in colorectal cancer patients with initially unresectable liver metastases. The principal goal of the study was to observe the effects of treatment on the resection rate of metastases. Secondary objectives were to observe the effects of this approach on disease-free and overall survival.
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Patients and methods |
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Chemotherapy
Chemotherapy consisted of a regimen of irinotecan 180 mg/m2 administered intravenously (i.v.) on day 1, FA 200 mg/m2 i.v. on days 1 and 2, 5-FU 400 mg/m2 i.v. bolus on days 1 and 2, and 5-FU 1200 mg/m2 continuous 48-h i.v. infusion on day 1 (Figure 1). The treatment was repeated every 2 weeks and response was assessed every 12 weeks (six cycles). Treatment was delayed for 1 week in cases of neutropenia (1.5 x 109/l), platelet reduction (
100 x 109/l) or significant non-hematological toxicity. Irinotecan and 5-FU doses were reduced by 25% in cases of grade 3/4 neutropenia or grade 3/4 diarrhea. In cases of grade 3/4 stomatitis, 5-FU doses only were reduced by 25%. The treatment was interrupted in cases of grade 4 hematological toxicity or grade 4 gastrointestinal toxicity lasting for >1 week after a previous dose reduction or a delay in dose administration exceeding 2 weeks. Chemotherapy was continued until an objective response (see below), indicating suitability for surgery, was achieved (or, in the case of a minimal response, if there was a chance of radical resection, indicating surgical investigation), disease progression or unacceptable toxicity (as described previously). Patients undergoing liver resection received a further six cycles of the same chemotherapy regimen post-operatively. Patients with progressive disease were treated at the discretion of the investigators.
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Disease unresectability at the study outset was established for all patients by a team that included the surgeon from the hepatobiliary unit, an oncologist and a radiologist, all from our institution. Criteria for initial unresectability of hepatic metastases, according to our institutions policy, were: unfavorable location of the metastases (contiguity with at least two hepatic veins, the inferior vena cava or the liver hilum); the number of metastases [more than six synchronous metastases in the same lobe and a major hepatectomy (resection of at least four segments) required, or more than three metastases in each of two involved lobes both for synchronous and metachronous metastases]; in the case of synchronous metastases and the requirement for a major hepatectomy, the size of the lesions (largest diameter >5 cm in at least one metastasis if there were six lesions in the same lobe, or three lesions if there was bilobar involvement); insufficient liver reserve (>70% of the liver was involved); and the presence of extra-hepatic disease (Table 1). Resectability of metastases following chemotherapy was assessed by the same team and was based on the response of lesions to chemotherapy and the likelihood of achieving R0 resection.
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Response to chemotherapy was assessed after every six cycles (12 weeks) of treatment, when patients underwent complete re-evaluation by CT scanning. Responses to chemotherapy were determined using World Health Organization (WHO) criteria: an objective response was defined as either a complete response (disappearance of all known disease) or a partial response (50% reduction in the size of the lesion from baseline). Following the assessment of response to chemotherapy, suitability for liver resection was determined.
Toxicity was assessed by a combined oncologist/surgeon team, according to National Cancer Institutes Common Toxicity Criteria, before each dose administration, at the operability assessment, and before the chemotherapy was re-started after the intervention.
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Results |
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Adverse events were typical of the chemotherapy agents used (Table 3). Hematological toxicity was reported by 26 (67.5%) patients. Fourteen patients (35.0%) experienced grade 3/4 neutropenia, but there were no reports of febrile neutropenia. Gastrointestinal toxicity was acceptable: five patients (12.5%) experienced grade 3/4 diarrhea, but no patient required hospitalization. Grade 3/4 nausea and vomiting were rare (2.5%). In three patients, a dose reduction was required because of grade 4 neutropenia (two patients) and grade 3 diarrhea (one patient). Toxicity was evaluated as a cumulative overall safety profile, including pre- and post-surgery. No differences were reported for the post-surgery period.
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In terms of the main causes of initial unresectability, the resection rate following chemotherapy was highest in those with large metastases (60%) (Table 5). Among 10 patients, all with synchronous metastases with a largest lesion >5 cm, three had bilobar involvement and three had metastases in the right lobe only at diagnosis. After chemotherapy, all lesions were reduced in size by at least 50% and there were no lesions >3 cm in diameter. In accordance with the study criteria, radical resections were performed in all 10 patients. Fourteen patients, 10 with synchronous and four with metachronous metastases, had unfavorable location of metastases at diagnosis, and five (35.7%), all with synchronous metastases, underwent surgery. Three of these patients had achieved a partial response, and post-chemotherapy assessment showed that metastases were easily resectable and sufficiently distant from the hilum (n = 2) or large vessels (n = 1). Radical resection was also attempted in the remaining two of the five patients who had only stable disease/a minor response following chemotherapy, with less than a 50% reduction in lesion size. Two (14.2%) out of 14 patients with a high number of metastases achieved an objective response and underwent resection: for one of them a right lobe resection and for the other, who had at diagnosis a bilobar involvement but only three lesions, a multisegmental resection become possible, according to initial criteria. No patients with insufficient liver reserve were suitable for resection. Among the 16 patients who underwent surgery, there were 13 R0 liver resections, and one R1 (biopsy of a peritoneal nodule positive for metastasis) and two R2 in patients who were not resected (one because of macroscopic peritoneal involvement and one because of the presence of abdominal metastatic nodes).
There was no postoperative mortality in the 2 months following surgery. However, one patient who presented at diagnosis with a large (>8 cm) unresectable metastatic lesion and who achieved a partial response after neoadjuvant chemotherapy experienced prolonged post-operative anemia due to intra-abdominal bleeding. For this reason, post-surgery chemotherapy was not completed. This patient is being closely observed and at 15 months of follow-up remains disease-free.
Time to recurrence
The median disease-free survival in operated patients is 14.3 months (range 221 months). At a median follow-up of 19 months (range 630 months), all resected patients are alive. The median time to progression for patients not undergoing surgery is 5.2 months. The median overall survival has not yet been reached.
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Discussion |
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Systemic administration of 5-FU-based chemotherapy prolongs the survival of patients with advanced colorectal cancer, compared with supportive care [24], but the response rate is relatively low [8]. The use of hepatic arterial infusion (HAI) may improve chemotherapy efficacy by delivering drugs directly to the liver, thereby achieving a higher local drug concentration and lower systemic toxicity than systemically administered agents [25, 26]. The rationale for this approach is based on the fact that liver metastases derive most of their blood supply from the hepatic artery, while healthy hepatocytes are served predominantly by the portal vein. HAI with floxuridine (a 5-FU derivative that has a high first-pass extraction in the liver) met with some success in patients with unresectable metastases, and an improved response rate [27] and survival [28] compared with systemically administered chemotherapy has been reported. In a randomized study in 100 patients, survival benefits were achieved without comprising quality of life [28]. However, HAI is associated with a number of complications related both to the catheter (hepatic artery occlusion, thrombosis and displacement) and chemotherapy (gastrointestinal symptoms, hepatitis, bone marrow toxicity and biliary toxicity) [29]. There is also a risk of extra-hepatic disease progression, possibly because of the low plasma level of the drug as a consequence of the first-pass hepatic extraction.
The introduction of the combination chemotherapy regimens of 5-FU with irinotecan and oxaliplatin led to impressive efficacy in terms of progression-free and overall survival, and response rates [26, 16]. Response rates were significantly higher with 5-FU in combination with irinotecan (3949%) [24] or oxaliplatin (5153%) [5, 6] compared with the 5-FU-based regimen alone (2132% and 1622%, respectively). The significant activity of these combinations led to their evaluation in a potential neoadjuvant role. Two analyses indicated that 5-FU in combination with oxaliplatin was effective, with potentially curative resection rates of 14% [21] and 51% [20] following neoadjuvant chemotherapy. The 5-year survival from both analyses was very promising (3550%).
In our prospective study, we have evaluated the efficacy of a combination regimen of 5-FU and irinotecan in the neoadjuvant treatment of patients with unresectable liver metastases. The potential efficacy of irinotecan in this setting has already been observed [9, 22]. The present study confirmed the well known efficacy of the 5-FU/FA/irinotecan regimen, with a 47.5% objective response rate (not confirmed for operated patients) and disease stabilization in 27.5% of patients. The R0 resection rate of 32.5% was relatively high, and similar to that reported in a study with 5-FU and oxaliplatin [20]. The median disease-free survival of R0 radically resected patients was 14 months, longer than the 12 months reported by Giacchetti et al. with oxaliplatin-based chemotherapy [20]. The high R0 resection rate achieved in this study reinforces the benefit of using the irinotecan/5-FU/FA combination in the first-line treatment of colorectal cancer.
In line with what we expected, most radical resections were performed in patients with a small number of metastases (52.3% of patients with less than three lesions), especially when there was no bilobar involvement. However, in terms of the main cause of unresectability, our data indicate that neoadjuvant chemotherapy is effective mainly for patients whose metastases are considered unresectable because of their size: 60% of patients whose largest lesion measured >5 cm in diameter were considered suitable for surgery after neoadjuvant chemotherapy.
The crucial end point of neoadjuvant treatment is the achievement of high R0 resection rates. Strategies that result in higher response rates can lead to a high R0 rate. The present study did not evaluate the possibility of combining neoadjuvant chemotherapy with other treatment modalities, such as cryotherapy or radiofrequency ablation, in patients with unresectable disease. Results from a retrospective analysis of 131 patients suggested that a combination of neoadjuvant chemotherapy and cryotherapy together with surgical resection could be a promising treatment strategy for patients with very advanced liver involvement or poor liver reserve [30]. The possibility of combining HAI with systemically administered chemotherapy to improve the resection rate and the systemic control of the disease should be investigated further. In addition, combination neoadjuvant regimens containing three or more chemotherapeutic agents may enhance activity. Preliminary results with a triple combination of 5-FU, irinotecan and oxaliplatin showed a high objective response rate of 71% in patients with advanced colorectal cancer [18]. In this study, 11 patients with liver metastases only underwent R0 liver resections. As such, this combination is a potential candidate for investigation as neoadjuvant treatment for unresectable liver metastases. Another way to increase the R0 resection rate is to enhance the efficacy of the irinotecan/5-FU combination by increasing the dose of irinotecan. In a study in 55 patients, irinotecan at a dose of 260 mg/m2 combined with 5-FU/FA in first-line treatment was associated with an overall response rate of 53%, and 11 of 17 patients (20%) who were operated on for liver metastases with curative intent had a R0 resection [31].
In conclusion, neoadjuvant chemotherapy with a combination of 5-FU/FA and irinotecan appears to be a promising approach to the management of patients with initially unresectable colorectal liver metastases. Treatment led to a downsizing of lesions, which facilitated surgical resection in a high proportion of patients. The role of neoadjuvant chemotherapy in improving disease-free and overall survival in patients with unresectable liver metastases should now be investigated in a prospective, randomized controlled trial.
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FOOTNOTES |
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