LIVER METASTASES: TOWARDS MORE CURATIVE APPROACHES?
Report on the joint ESTRO/ESMO/ESSO Session at ESTRO 29
Wednesday 15 September 2010, Barcelona
By Vincenzo Valentini, President-elect of ESTRO
in collaboration with Henning Köhne, ESMO, and Cornelis van de Velde, ESSO
Speakers:
NEW INSIGHTS IN SYSTEMIC TREATMENT, C. Koehne (Germany)
STEREOTACTIC RADIOTHERAPY, D. Peiffert (France)
INTERVENTION RADIOLOGY, T. DeBaere (France)
SURGICAL TREATMENT OF LIVER METASTASES J. Rothbarth (Netherlands)
About 30% of patients with metastatic colorectal cancer have metastases confined to the liver. Liver resection is still the gold standard in the treatment of colorectal liver metastases (CRLM). Several large studies have reported long-term survival rates and even cure after liver resection with 5-year survival rates up to 50% [1]. Nowadays, the improvement with systemic therapy in controlling occult metastatic disease in patients with colorectal malignancies has raised renewed interest in local therapies for oligometastases and the improvement in imaging, allowing 3D and real time imaging techniques, is helpful to guide the delivery of anticancer therapy for local treatment. Such imaging is used for local drug delivery, namely hepatic intra-arterial chemotherapy (HIAC) and chemoembolisation. More recently, percutaneous image guided therapy for cancer with curative intent has been developed to overcome the limitation of surgery or to target non-surgical candidates. Furthermore, modern radiotherapy techniques (stereotactic extracranial radiotherapy, radiosurgery, intensity-modulated radiotherapy, intra-operative radiotherapy, heavy particles) may benefit from optimal imaging.
A joint ESTRO/ESMO/ESSO session was held at the ESTRO 29 meeting to focus on the contribution of different treatment modalities.
Surgery
Historically, patients were eligible for liver resection if complete resection of a limited number of colorectal metastases confined to the liver was possible with tumour-free margins more than 1 cm and the remaining functional hepatic volume was sufficient to ensure adequate postoperative liver function (around 30% of the total functional liver volume). Following these criteria, resection was curative in about 30 to 40 % of patients. To date, long-term survival data after liver resection have also been encouraging in cases of > 7 metastatic lesions (www.livermetsurvey.org), and multiple metastases do not represent a contraindication for resection. Moreover, it has been stated that the width of the resection margin (< or > 1 cm) does not affect recurrence/survival [2]. In high-volume liver centres, where advanced surgical dissection techniques and improved perioperative management have enabled liver surgery to be a safe procedure with limited morbidity and mortality, and neither age nor co-morbidities preclude liver surgery anymore. Furthermore repeat liver resections can be safely performed in cases of tumour recurrence with survival benefit equal to that of first liver resections [3].
Unfortunately, patients with synchronous, bilobar, large, poorly located or extrahepatic metastases, a future remnant liver < 30% or high age (>70 years) were considered unresectable, and thus incurable.
Chemotherapy
Adjuvant and neoadjuvant treatments are available and may increase the cure rate for these patients. The introduction of novel chemotherapeutic regimens has become an important part of the treatment strategy in patients with CRLM. Oxaliplatin and irinitecan based regimens have shown high response rates (about 70-80% of tumour shrinkage) and even complete (radiological) responses [4-7]. Previously unresectable patients with good tumour response to neoadjuvant chemotherapy can therefore become resectable. A high conversion rate to resectability, and thus potential cure, has been mentioned [8]. Furthermore, downsizing of initially resectable metastases by neoadjuvant chemotherapy allow a more limited and less complicated resection. Again, depending on the clinical criteria, such as the FONG-Score [9], although technically resectable, patients may have a high rate of local recurrence in the liver or may suffer from extrahepatic disease. In addition, the majority of patients presenting with liver metastases only have unresectable disease. The challenge nowadays is the right selection of patients and the selection of the optimal chemotherapy regimen. Monoclonal antibodies against VEGF or the EGF receptor have become available. Starting with the determination of K-RAS mutations, the first molecular markers have found a place in the routine diagnostics i.e. to predict which patients have a higher chance (K-RAS wild type) or very low chance (K-RAS mutation) to respond to EGFR antibody treatment. So that, today, in K-RAS mutant tumours, the FOLFOX-IRI regimen, and in K-RAS Wild type tumours the combination with an EGFR-Receptor antibodies Cetuximab are chemotherapy options [10-13]. Within the CELIM-Study, curative resection (R0) was possible in about one third of patients who had previously unresectable diseases. [14]. Anyway, ongoing randomised trials will clarify better the role of the monoclonal antibodies against VEGF or the EGF receptor in combined approach to CRLM.
Interventional Radiology
For patients who are not suitable for surgery, other local treatment methods, especially radiofrequency ablation (RFA) are emerging as alternative curative options, although the proximity of the lesion to the gall bladder or main vessels, the sub-diaphragmatic location, or the presence of a non-echogenic lesion (for ultrasound-guided RFA), constitute major problems in using this treatment [15]. Other thermal ablative techniques (microwaves, laser, .. ) and non-thermal ablative techniques (irreversible electroporation, ..) are under investigation. All these techniques require accurate probe placement to deliver the therapeutic stimulus and are linked with quality of imaging, anesthesia and miniaturisation of the tools used for thermal ablation. Fusion imaging is also a useful adjunct when tumours are barely visible on one imaging modality. Computerisation and automatic guidance systems to target more accurately small tumours are being actively developed by the industry and electromagnetic needle guidance is today a reality. Tools used for thermal ablation have greatly improved since the late nineties when the initial versions of probes and RF generators appeared. RFA is now able to produce more repeatable ablation and larger volume of destruction, thus improving the results of RFA. Nevertheless, some limitations of RFA remains such as the impossibility of activating several probes at the same time and heat sink effect - which is convection tissue cooling close to large vessels. In order to try to overcome these limitations, new thermal ablation techniques such as microwaves (less heat sink effect, several probes activated at the same time to provide a larger volume of ablation) are under development. Non-thermal ablation, such as electroporation are reaching the clinical field and carry great hopes of no heat sink effect. Such techniques are highly effective in small size tumours and today, tumour size remains a predictive factor for success in the vast majority of reports. As ablation systems today are able to destroy up to 5 cm, the best results are obtained in tumours below 3 cm that give room for a 1 cm safety margin. Indeed, oversizing ablation size compared to tumour size allows better local tumour control. Liver metastases treated with RFA demonstrated a high success rate of ablation over 90% in small tumour size away from large vessels. However, survival of patients treated with RFA is usually lower than that reported on surgical series. Several explanations for this lower survival exist, including more advanced disease in the RFA population, which is most often offered to non-surgical candidates. It is, however, difficult to propose RFA to surgical candidates due to the lack of complete abdominal exploration. Nevertheless, RFA has been demonstrated to be superior to chemotherapy and RFA must be offered when possible in non-surgical candidates. Ruers et al. [16] demonstrated that there is an improvement in disease free overall survival in the RFA group of a randomised controlled study comparing chemotherapy alone versus RFA+chemotherapy. Hepatic Intra-Arterial Chemotherapy (HIAC) represents a very promising therapeutic tool, especially today with the use of percutaneous port implantation. As recently reported in the literature, HIAC can induce a dramatic response rate shifting about 25% of inoperable patients to a curative intent surgery [8, 14, 17].
Radiotherapy
Radiation therapy (RT) has traditionally had a limited (palliative) role in the treatment of unresectable hepatic metastases, primarily because of the low whole-liver tolerance of RT, with a 5% risk of radiation-induced liver disease (RILD) after whole-liver doses of 30-35 Gy in 2 Gy per fraction [18-19]. The development of 3-dimensional conformal RT and protocols in which toxicity was prospectively recorded, has allowed the quantitative collection of dose-volume data on which the partial liver tolerance to RT can be determined [20]. With better knowledge of the partial liver tolerance and safer dose escalation, uncomplicated local control may be possible for more patients with liver metastases. If the effective liver volume irradiated is very low (less than 25%), very high-dose radiation can be used to treat liver tumours safely, as long as the liver function is good. Stereotactic body radiation therapy (SBRT) has no strict restrictions regarding lesion location, and offers the possibility of a high precision non-invasive treatment, using small margins [21]. A high local control rate (up to 92% at 2 years) in the absence of severe late toxicity has been reported in SBRT liver metastases treatment [22, 23]. McCammon and co-workers in a large single-institution series suggest a dose-control relationship within the range of SBRT doses applied. Excellent local control rates were achieved with a nominal dose of 54 Gy or greater (equivalent uniform dose > 65.3 Gy). These results support the use of aggressive SBRT regimens when durable tumour control is the primary objective [24]. Today, notwithstanding the absence of phase III data, focal treatment by stereotactic radiotherapy alone or in combination with transarterial chemoembolisation has become a potential new treatment option for primary and metastatic liver tumours around the world [25-28] and can be offered as an alternative to patients unsuitable for surgery or RFA. Moreover, new innovative treatment devices such as robotic radiosurgery with the CyberKnife have emerged [29].
Conclusions
In summary, in recent years the ’resectability’ of CRLM has been further extended, due to advanced surgical and perioperative management, the improved efficacy of chemotherapy and the introduction of new local treatment modalities such as radiofrequency ablation, HIAC and stereotactic radiotherapy. It is mandatory to centralise liver surgery in high-volume liver centres, where advanced surgical dissection techniques and improved perioperative management have enabled liver surgery to be a safe procedure with limited morbidity and mortality [30]. From a medical oncologist’s point of view, the challenge nowadays is the right selection of patients, the selection of the optimal chemotherapy regimen and the administration modality. Again, RFA, HIAC and stereotactic body radiation therapy have to be considered feasible alternatives in liver metastases, with an acceptable toxicity and encouraging local control, although more studies including larger numbers of patients are necessary to verify these results and to find optimal schemes. Nowadays, almost all patients, even those with (limited) extrahepatic disease, are considered potentially curable but, it is essential that patients with CRLM are discussed in and treated by multidisciplinary teams with dedicated surgeons, medical oncologists, hepatologists, radiologists and radiotherapists [31,32].
The Authors thank Dr Gabriella Macchia for the editorial support for this article
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