1 University Hospital Dresden, Germany; 2 Mayo Clinic, Rochester, MN, USA; 3 Hospital Oldenburg, Germany
* Correspondence to: Prof. C.-H. Köhne, Hospital Oldenburg, Department of Oncology and Hematology, Dr.-Eden-Str. 10, 26133 Oldenburg, Germany. Tel: +49-441-403-2611; Fax: +49-441-403-2654; Email: onkologie{at}klinikum-oldenburg.de
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Abstract |
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Methods:: We analysed all published or presented trials and retrospective studies that report the rate of objective response and the rate of resection of initially unresectable metastases to correlate objective response and the rate of resection of metastases.
Results:: In studies that enrolled patients with metastases confined to the liver, 2454% of patients were resected following chemotherapy, compared to 126% of patients in trials that included non-selected patients with metastatic colorectal cancer. A strong correlation was found between response rates and the resection rate in studies with patients with isolated liver metastases (r = 0.96, P=0.002). Likewise, in studies with non-selected patients, the resection rate of metastases also was associated with the objective response rate (r = 0.74, P <0.001).
Conclusions:: Patient selection and efficacy of pre-operative chemotherapy are both strong predictors for resectability of liver metastases. Resectability is a novel endpoint focusing on the curative potential of treatment compared with classical endpoints of response or progression-free survival that are important if palliation is the aim. Therefore, patients with potentially resectable liver metastases should be investigated in special trials and interdisciplinary teams.
Key words: colorectal cancer, liver metastases, neoadjuvant chemotherapy, resection
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Introduction |
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Chemotherapy of colorectal cancer has improved substantially over the last 10 years. While infusional 5-fluorouracil (5-FU) [7] or the combination of 5-FU/folinic acid (FA) [8
, 9
] result in response rates of <25% and a median overall survival of about 12 months, combination chemotherapy including modulated infusional 5-FU plus irinotecan and oxaliplatin, can achieve a response rate of
50% and a median overall survival in excess of 20 months with the use of active second-line therapies [10
16
].
Attempts to further improve the efficacy of systemic chemotherapy in patients with metastatic colorectal cancer include the use of four drug regimens with irinotecan, oxaliplatin and 5-FU/FA. In a phase I trial, a response rate of 50%, a relatively long median progression free (11.2 months) and median overall survival (26 months) was achieved, but at the cost of 9% treatment-related deaths [17]. Very high response rates of 79% and 73% were reported by Roth et al. [18
], and in a French study using infusional 5-FU, leucovorin, oxaliplatin and irinotecan (FOLFOX/CPT-11) in selected patients with liver metastases only [19
]. A phase III randomised comparison between the four drug regimen of oxaliplatin/irinotecan/5-FU/FA and irinotecan/LV5FU2 in patients with metastatic colorectal cancer demonstrated a trend to an increased objective response and overall survival, but did not reach statistical significance [20
].
The most recent development in the therapy of colorectal cancer is the introduction of monoclonal antibodies. Cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), induces responses in 10% and 23% of patients with irinotecan-refractory colorectal cancer as monotherapy [21
23
] or in combination with irinotecan [22
, 24
], respectively. Response rates of 4381% were observed with cetuximab in combination with irinotecan or oxaliplatin and 5-FU/FA in phase I/II studies in first-line therapy [25
28
]. Bevacizumab, a humanised antibody against the vascular endothelial growth factor (VEGF) significantly prolonged median progression-free survival (10.6 versus 6.2 months, P <0.001) and overall survival (20.3 versus 15.6 months, P <0.001) in combination with irinotecan/bolus-5-FU/FA (IFL) compared to IFL alone [29
]. In comparison, its effect on response rate was not as apparent, though still statistically significant (45 versus 35%, P=0.004) [29
].
Although few patients were reported before the era of new drugs [30], the advances that have been made in systemic chemotherapy have prompted reports of resections of initially unresectable liver metastases following chemotherapy. The first large series was presented by Bismuth and colleagues in 1996 [44
] and updated in the following years. The 5-year overall survival of 50% [95% confidence interval (CI) 3368%] observed in patients with resection following neoadjuvant chemotherapy was comparable to patients with primarily resectable patients as reported by Scheele et al. [3
] (39%, 469 patients), Nordlinger et al. [5
] (28%, 1568 patients), Fong et al. [4
] (37%, 1001 patients) and Figueras et al. [31
] (36%, 235 patients).
We reviewed recently reported trials and retrospective studies to explore whether a more effective chemotherapy in terms of response rates (as measured by response rate) and the selection of patients influences the probability of potentially curative liver resections.
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Methods |
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Retrospective analyses and prospective trials (phases IIII) in patients with colorectal cancer treated with systemic chemotherapy that were fully published in manuscript form (MEDLINE analysis using the key words colorectal cancer or colorectal carcinoma and liver metastases or liver metastasis and resection and chemotherapy) or presented at large international meetings (ASCO, ESMO, ECCO) were reviewed. Patient selection or entry criteria, response rates and resection rates were abstracted. Abstracts that presented only early results of ongoing trials were excluded.
We divided the studies and reports of liver resection into studies that included only patients that have no extrahepatic metastases (selected patients) and in those that included all patients with metastatic colorectal cancer (non-selected patients).
If studies included both patients with resectable and non-resectable (liver) metastases, initially resectable patients were excluded from our analysis. In patients with resectable liver metastases, patients with macroscopically incomplete resection were not considered for the calculation of the resection rate. Since it is well established that the response rate decreases in second- or third-line setting and a decreased resection rate might by expected in pretreated (and thus more advanced) patients, we only included studies if either the results of patients with first-line therapy were separately reported, or if the proportion of patients with second-line treatment was low (<30%).
The Pearson's correlation coefficient was separately calculated for studies including only patients without extra-hepatic metastases and for trials that enrolled patients with metastatic colorectal cancer regardless of the number of tumour manifestations.
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Results |
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Eventually, five prospective phase II trials and one retrospective study were included in the analysis. These studies investigated the combinations of oxaliplatin/5-FU/FA (two studies [33, 42
]), irinotecan/5-FU/FA [32
], oxaliplatin/5-FU/FA (two trials [19
, 34
]) and irinotecan/5-FU/FA in combination with intra-arterial chemotherapy [43
].
Response and resectability rate
The French group of Bismuth [44] and Giacchetti [33
] published the first large retrospective analysis of patients who became resectable for liver metastases following neoadjuvant chemotherapy. Seventy-seven of 151 patients with liver metastases who were initially regarded as non-resectable and treated with chemotherapy (oxaliplatin/5-FU/FA) underwent secondary surgery of metastases; in 58 patients (38%), a macroscopic complete resection was achieved with 48 patients (31%) having microscopically tumour-free margins. Following resection, a 5-year overall survival of 50% (95% CI 3861%) was observed in the 77 operated patients [33
]. Median disease-free survival in patients who underwent liver resection was 17 months. Later updates of the same study [6
, 45
] did not report response rates and could therefore not be used for our analysis.
In two prospective phase II trials the FOLFOX4 [42] or the FOLFIRI (CPT-11/LV5FU2) [46
] regimens were used. A response rate of
50% was reported in both trials resulting in the resection of liver metastases in 33% and 40% of patients, respectively.
Higher response rates of 64% [34] and 73% [19
] were found with a four-drug combination (oxaliplatin/irinotecan/5-FU/FA), which translated into secondary liver resections in 43% or 54%, respectively. Since 18 patients in the study by de la Camara et al. [34
] were resectable at study entry, they were excluded from our analysis of resection rate of formerly unresectable patients. Zelek and co-workers [43
] investigated a combination of systemic (irinotecan/5-FU/FA) and local (pirarubicine) chemotherapy. With a response rate of 48%, a total of 35% of patients had resectable metastases. All results are summarised in Table 1.
Correlation between response and resection rate
Rates of objective response and resection rates in the retrospective and prospective studies of patients with metastases confined to the liver are shown in Figure 1 (filled squares). A strong and highly significant correlation between the rates of liver resection and the tumour response to chemotherapy was found (r = 0.96, P=0.002). The rate of R0 resection did not significantly correlate with the response rate (r = 0.43).
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Discussion |
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In all neoadjuvant approaches, patient selection is conceivably a crucial factor. In those prospective trials of selected patients (with metastases confined to the liver), the criteria for non-resectability not only differed between the studies but were most often poorly defined. While in one trial [19] patient inclusion criteria predefined technical non-resectability, in most other studies the definition of non-resectability was left to the discretion of the local surgeon/radiologist, which inevitably limits the comparability of these studies (Table 1). Nevertheless, individual patients were most likely re-evaluated by the same surgeon (or the same group of surgeons) who initially diagnosed non-resectability. Thus, the criteria to evaluate one individual patient have conceivably been relatively consistent. Also, in most trials of selected patients, the criteria for non-resectability included factors that indicate poor prognosis such as size/number of metastases or presence of synchronous metastases [32
, 33
]. Though despite some technically resectable metastases, an upfront operation was not felt to be oncologically reasonable in some patients. This was supported by a recent multivariate analyses that consistently found the prognostic negative influence of the number and size of metastases, the time interval between surgery of the primary tumour and the development of metastases, tumour stage of the primary and resection-free margins after primary liver resection and also following neoadjuvant treatment in patients with resectable [31
, 53
] and with initially non-resectable [45
] liver metastases. Adam and coworkers [45
] analysed 138 patients and observed nearly no long-term survivors (<1%) if patients with three or more risk factors were resected following neoadjuvant treatment. These risk factors were: more than two liver metastases, large tumour size (>10 cm), elevated tumour markers (CA 199), R1 resection, primary rectal cancer, and no repeated hepatic resection [45
]. This group also showed that even patients with primarily resectable metastases who do not respond to systemic chemotherapy do not benefit from resection [54
].
While there is no general consensus about the exact definition of non-resectability and resectability, the value of a surgical resection in some resectable patients is also under discussion and must be evaluated especially in the case of a high number of liver metastases and high risk of recurrence after surgical therapy [45]. In the series of Adam and coworkers [45
], the percentage of long-term survivors is low (4%) when an intention-to-treat analysis (that includes all patients with liver metastases of colorectal cancer regardless of additional tumour sites) is performed. This rate corresponds to the rate of resections in phase III studies (Table 2). Patients that are candidates for liver surgery have no extrahepatic disease (liver metastases only) and thus belong to a group with a relatively good prognosis. If only 5-FU therapy was administered those patients would have a median survival of 14.7 months instead of the 10.5 and 6.5 months in patients in more unfavourable prognosis groups [55
].
Since long-term follow-up of patients treated with the newer chemotherapy regimens is lacking, it cannot be excluded that a similar 5-year survival can be achieved with new combination chemotherapy alone [56]. The addition of monoclonal antibodies to conventional chemotherapy may affect not only the rate of liver surgery but also (or even more) the survival of patients with systemic therapy alone. While long-term remission of non-resected liver metastases has been reported [57
], it will be a major aim for further trials to define which patients benefit from the more aggressive approach of resection with prolonged survival or even cure.
There is a need for a prospective definition of resectability, which may include technical and oncological aspects. Nevertheless, a recently published long-term follow-up revealed that 23% of patients with initially unresectable liver metastases survive at 10 years and are thus considered cured by resection (compared to 30% in patients with initially resectable liver metastases) [45]. Therefore, surgery remains the treatment of choice at least for those patients with good risk factors.
Despite all the limitations discussed above, our analysis demonstrates a close correlation between response rates and rates of liver resection. The 5-year overall survival of 40% in resected patients [33
] shows that chemotherapy followed by liver surgery carries curative potential. If highly active schedules are used in selected patients, it may be speculated, that a response rate of
70% [19
, 25
, 48
] with a resection rate of
50% (Figure 1) can be expected.
Our finding that response rate correlates with rate of secondary resection does not come as a surprise since tumour shrinkage is a condition for a later resection of metastases that are initially unresectable. However, the direct relationship between tumour response and resectability supports the strategy of using the most active regimens, particularly in potential curable patients. In our analysis, the correlation in selected patients was not only steeper but also on a higher level than in unselected patients, meaning that a higher number of patients could be rendered potentially resectable. The correlation of tumour response and resection in selected patients is based on a relatively low number of studies and patients, and is probably influenced by the variations in the definition of non-resectability between the different studies as discussed above. In addition, the resection rate was chosen as a primary endpoint in two prospective studies only [19, 42
]. In non-selected patients, the rate of liver resection is lower than in studies with selected patients. One obvious reason is the inclusion of patients with lymph node involvement or multiple metastatic sites in these trials, which were mainly designed to identify the efficacy and tolerability of new regimens and secondary resection was reported as an incidental observation. Nevertheless, the correlation between tumour response and resection of metastases includes a larger number of studies that enrolled more than 2900 patients. Therefore, the correlation is highly significant (P <0.001), albeit less strong (r = 0.74).
The correlation between response rate and liver resection could be influenced by the access to liver surgery also, as studies with selected patients were initiated by interdisciplinary teams, mostly with high volume liver surgery. In contrast, large phase III studies (with non-selected patients) were performed in a wider spectrum of hospitals, which probably interfered with access to specialised departments with experience in liver surgery and will interact with the chance to be offered a secondary liver resection.
Therefore, prospective trials that specifically investigate neoadjuvant approaches in patients with potentially resectable liver metastases are needed as the treatment strategy in these patients can differ from patients with multi-visceral metastases.
To correlate response with the rate of resection in general or with the number of macroscopically complete resections may be criticised since overall the rate of R0 resection is most relevant. Unfortunately, information on the quality of resection was made available only in a few studies, but it should be reported in all future trials. Interestingly, the initially mentioned report by the French group referred to macroscopically complete resection (in 48 patients with R0 and 10 patients with R1 resection) and found a plateau of 50% in the survival curve at 5 years [33].
The recent developments in the chemotherapy of colorectal cancer have not only improved response rates and prolonged the median overall survival but have also added treatment-associated toxicity and increased the financial burden of therapy. With the substitution of the Mayo Clinic regimen by three drug regimens (IFL, FOLFIRI or FOLFOX), the medication costs have already increased by a factor of 150. The combination with VEGF- or EGFR-antibodies further increases the monthly costs (for medication only) to $10,00015,000 and could double the yearly expenses for drugs used in palliative treatment of colorectal cancer in the USA to $1.2 billion [58
].
Both added toxicity and the costs of the newest four-drug regimens raise the question of whether or not it is justifiable to offer any schedules and medical resources to all patients with metastatic disease, or whether they should rather be reserved for those patients more likely to benefit.
Achieving a high response rate is not necessarily the primary goal of palliative chemotherapy in patients with metastatic disease. Patients with multi-visceral metastases that are not expected to become resectable following chemotherapy are probably best treated with palliative therapies that prolong progression-free and overall survival, and relieve tumour-related symptoms at a minimum of toxicity. In contrast, patients with metastases that might become resectable following chemotherapy are preferably treated with a regimen that induces high response rates, since tumour shrinkage alone provides the chance of a secondary resection. However, response may be considered as a poor surrogate for resectability. In some patients tumour shrinkage of only 30% (minor response) may be sufficient to achieve resectability, while in another patient an 80% reduction in the size of the tumour (good partial response) may have been necessary for a secondary resection. More pronounced, a complete clinical response may be undesirable as it may make the work of the surgeon difficult, if not impossible. Thus, in the strategy of neoadjuvant chemotherapy resectability following chemotherapy is a distinct endpoint from the more classical endpoints of response, progression-free survival or to prolong the median survival without achieving a plateau at the end of the survival curve. It is for this reason that we plea for special trials in patients with potentially resectable metastases.
In the context of neoadjuvant therapy, the key questions remains as to which of the currently available treatment regimens can be considered optimal to downsize metastatic disease. Clearly, modulated infusional 5-FU regimens combined with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) produce high response rates of >50% and successful secondary resections have been reported. In a randomised trial comparing FOLFIRI to FOLFOX6 [14], an almost identical response rate in the range of 55% was found for both regimens. In this trial, 24 patients treated with FOLFOX6, and only 10 patients in the FOLFIRI arm were eligible for secondary resection of metastases (P=0.03), but the number of R0 resections did not significantly differ with 14 patients in the FOLFOX arm and eight patients in the FOLFIRI arm (58% and 80% of the resected patients, respectively). These differences may be due to the bias of broader indication for liver resection after FOLFOX, because in earlier reports resection of metastases was preferentially performed after treatment with oxaliplatin-containing schedules [33
, 44
]. However, the number of patients was rather low, conceivably also because secondary resection was not a predefined study endpoint. Although there is no other head-to-head comparison of FOLFOX and FOLFIRI especially in the neoadjuvant setting, we believe that it is not the specific drug but a more active regimen that is important.
Based on the results of phase II trials, cetuximab appears to add substantial efficacy to oxaliplatin- [25] and irinotecan-based combination regimens, which translates into high response rates in first-line therapy. When cetuximab was combined with an infusional 5-FU/LV plus irinotecan regimen, five out of 19 patients became candidates for secondary resection that was successfully performed in four patients (because the fifth patient denied surgery) [48
]. Interestingly, this fifth patient is in complete remission 3 years later. The limited number of patients with a secondary resection indicates no major post-operative complications.
The anti-VEGF antibody bevacizumab is also able to enhance the activity of cytotoxic chemotherapy leading to an 10% increase in higher response rates. In addition to bevacizumab's inhibitory effect on angiogenesis, an enhanced delivery of chemotherapeutic agents into the tumour by lowering intratumoural tissue pressure is discussed. However, when in a larger phase III trial bevacizumab plus IFL was followed by surgery, 5/59 patients had postoperative bleeding or impaired wound healing compared to 0/29 patients with IFL alone [59
]. Although this difference was not significant (P=0.12), further investigation should be performed with caution. If bevacizumab/IFL was given more than 28 days after surgery, 3/215 patients had complications versus 0/180 patients with IFL alone (P=0.11) [59
]. Due to this observation and the rather long half-life time of bevacizumab it is currently advised to perform an operation, if possible, 28 days after the administration of this compound.
Generally, liver resection following neoadjuvant treatment is a safe procedure. With the use of the FOLFOX- or a capecitabine/oxaliplatin-regimen, Gruenberger and coworkers reported a peri-operative mortality of 0% in 50 patients [53]. In further studies in 138 patients treated with oxaliplatin [45
] or in 57 patients receiving FOLFIRI [35
], a perioperative mortality of 0.71.7% was noted. This compares favourably to the 2.84% [3
, 4
, 31
] peri-operative mortality reported in larger series of patients with initially resectable liver metastases. In the absence of randomised trials, these reports suggest that the type of chemotherapy (oxaliplatin- or irinotecan-based) does not influence the perioperative mortality.
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Conclusions |
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Received for publication November 16, 2004. Revision received March 10, 2005. Accepted for publication March 14, 2005.
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References |
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