Local treatment of oligometastatic disease: current role

Abstract

The presence of distant metastases has long been a predictor of poor outcome in solid cancer. However, in an oncologic situation called oligometastatic disease (OMD), multiple studies have revealed a survival benefit with aggressive treatment of these metastases. Besides surgery and radiation therapy, local thermal therapies have developed into a treatment option for OMD. Most studies concerning local therapy of OMD are available for colorectal cancer, which is therefore the focus of this article. Furthermore, this review gives a basic overview of the most popular ablation techniques for treatment of OMD.

Introduction

The presence of metastases has long been a predictor of poor outcome in solid cancer patients.^1,2 However, widespread tumour dissemination in patients with metastatic disease is not obligatory and has been thematized in several publications. Hellman et al³ proposed the concept of “oligometastatic disease” (OMD) for the first time in the Journal of Clinical Oncology in 1995. The authors defined the oncologic status of OMD as a step between a status of locally limited cancer and a systemic disease with widespread metastatic manifestations. Hellman et al theorized that tumours in OMD were tumours early in their metastatic potential and therefore limited in number and location. This concept was contrary to the opinion that oligometastases only represent few detectable manifestations of a widespread occult disease, thus local control of oligometastases would not have a therapeutic benefit.⁴ For colon carcinoma especially, several early studies have shown long-term survival in patients with limited hepatic and pulmonary metastases who underwent hepatic resection or pulmonary resection, supporting the concept of OMD.^5–7 In this tumour entity, there is growing evidence that patients with liver-limited disease belong to a distinct biological cohort who benefit from local resection: 40% of patients with resected liver-limited disease are alive after 5 years, whereas only 1% of patients with disseminated metastases survive 5 years.^4,8 Underlying causes are probably of genetic nature.^9,10

In most publications, oligometastatic state is to date defined as metastatic disease that is limited in total disease burden and in number of detected metastases to a maximum of five metastases; however, there is no general definition of OMD available regarding size and location of metastases.^4,11 For example, according to the European Society for Medical Oncology (ESMO) consensus guidelines for the management of patients with metastatic colorectal cancer (CRC), OMD is specified by five or sometimes more metastases at two or three sites, primarily visceral and lymphonodal.¹² According to this guideline, patients with one or two resectable hepatic metastases and one single bone lesion is considered as OMD, whereas the presence of several osseous lesions exclude the status of OMD, underlining the complexity of definition of this oncologic state. Nevertheless, treatment strategies for patients with OMD should be based on the feasibility of attaining complete removal of the tumour with complete destruction of all tumour masses for cure or long-term disease control by surgery, radiation or local ablation techniques.¹³ The later have become increasingly important predominately in patients with hepatic and pulmonary metastases and are the focus of this article.

Local ablation techniques

Local tumour ablation procedures aim to destroy tumours with a safety margin. Most techniques are based on hyperthermia as temperatures above 60°C almost immediately cause cell death due to irreversible protein denaturation.^14,15 The most common hyperthermic ablation techniques are radiofrequency ablation (RFA), microwave ablation (MWA), high intensity focused ultrasound (HIFU) and laser-induced thermal therapy (LITT), although most studies concerning ablation of liver and lung tumours were conducted with RFA or MWA.^16–18 Cryoablation being one of the oldest ablation techniques is the only one which is based on hypothermia-induced cell death.¹⁹ The newest ablation techniques is irreversible electroporation (IRE), which is not based on thermal energy but more on cell membrane disruption by high-voltage pulses.²⁰

Radiofrequency ablation

The principle of RFA is based on a high-frequency alternating current (with a frequency between 375 and 480 kHz) which is applied between two electrodes.²¹ This current causes rapid movement of ions leading to the development of frictional heat and therewith the formation of an ablation zone.²² In monopolar systems, only one electrode is advanced into the target tumour, and a grounding pad which is attached to the body surfaces closes the electric circuit. In bipolar systems, both electric poles (placed on one or more electrodes) are advanced into the target tissue, therefore an additional grounding pad is not necessary. In both cases, heat is induced around the electrode tip, where the energy density is highest.²³ Advantages of RFA in percutaneous treatment of OMD are the highest number of available studies concerning ablation treatment of different tumour entities in different organs, a confirmed low rate of major complications and a comparatively easy handling of the devices.^21,24,25

Major disadvantages are based on the dependence of an electric current. Thus RFA is limited by charring around the applicator at higher temperatures, thus ablation temperature is limited to approximately 100°C in clinical use leading to longer ablation times.^26,27 Another limitation in RFA, is the so called “heat sink effect” in which adjacent hepatic blood vessels have a cooling effect on the targeted tissue which can result in incomplete ablation and increased local recurrence rates.^28,29

Thermoablation of hepatic malignancies can be impaired by the target tumour location. Tumours in the vicinity of major bile ducts should be avoided, as these patients have an increased risk of bile duct injuries causing complications such as strictures, cholangitis, bilioma or development of liver abscess by secondary infection. The latter can have severe consequences, particularly if additional chemotherapy is planned for a patient.^30,31 Alternative non-thermal ablation techniques as IRE or brachytherapy may be a treatment option in this situation.^32,33 For patients with tumours close to vulnerable structures such as the colon, an acceptable safety distance has to be preserved.³¹ To protect vulnerable structures around the liver, such as the colon or stomach, injection of a glucose solution (hydrodissection) can be performed to expand the space around the targeted lesion.^34,35

Microwave ablation

MWA was first introduced in the 1990s and is a rapidly evolving ablation technology provided by several manufacturers.^36,37 In MWA, an ablation zone is developed by electromagnetic waves emitted from an antenna which has been introduced into a target tumour.^38,39

MWA systems are based on a microwave generator working at a frequency of 930 MHz or 2.45 GHz, a microwave antenna and a coaxial cable transporting the energy from the generator to the antenna.⁴⁰ In the early days of MWA, the systems suffered from technical problems as heating of the coaxial cable and the antenna shaft caused elongated ablation zones and the risk of soft tissue burns.³⁹ Meanwhile, most ablation devices have overcome these initial technical problems and are equipped with a perfusion cooling of the antenna shaft enabling the application of a power up to 180 W and formation of larger and more spherical ablation zones.^41,42

In comparison to RFA, MWA is independent from a closed electric circuit and therefore from impedance changes around the ablation zone. Consequently, higher ablation temperatures can be applied resulting in larger ablation zones and shorter ablation durations compared to RFA.^43,44 Another theoretical advantage is the direct energy transmission to a larger target volume in comparison to RFA.³⁹ Many authors assume a lower rate of local recurrence due to a lower “heat sink” effect under the use of MWA; however, other studies could not confirm this hypothesis.^45–47

Nevertheless, a meta-analysis by Huo et al regarding the outcome after RFA and MWA found a significantly lower local recurrence rate in the subgroup analysis of ablation therapy of oligometastases in the liver after MWA in comparison to RFA.⁴⁸

Irreversible electroporation

Irreversible electroporation is a non-thermal ablation procedure that generates high voltage pulses between electrodes that are ideally positioned around the tumour. These pulses irreversibly disrupt cell membranes causing apoptosis of the target tissue. However with this method, the skeleton of connective tissue, vessels, and bile ducts should theoretically be preserved.⁴⁹ Compared to thermal ablation techniques, IRE is not limited by the “heat sink effect” or potential collateral damage to adjacent structures such as nerves or bile ducts.^20,50 Other possible advantages are extremely sharply defined ablation margins.²⁰ However, patient management during IRE is very complex and requires general anaesthesia with muscular relaxation.⁴⁹ IRE may have potential in many different tumour types, especially those located close to vulnerable structures; however the amount of data after treatment of OMD is limited.

Cryotherapy

Cryoablation is the only ablation technique that uses low temperatures for tumour cell destruction. This freezing process is caused by an intra- and extracellular ice crystal formation and additionally leads to damage of the supplying vessels resulting in ischaemic hypoxia of tumour tissue.^19,49 Depending on the target tissue, temperatures of −35 to −20°C are required to enable sufficient necrosis.¹⁹ One advantage of cryoablation is the possibility of continuous and precise controlling of the ablation zone during the procedure by CT, MRI and sonography due to good visualization of the expanding ice ball.^19,49 Application of this ablation technology is depending on the tumour site. While cryoablation is frequently used in the treatment of kidney tumours, a complication called “cryoshock” has been reported predominately in the treatment of liver tumours. In these cases, ice crystals melt within the ablation zone during the defrosting process which results in reperfusion and release of the cell debris into the systemic circulation causing an inflammatory response.^51,52

OMD in colorectal cancer

Local treatment of hepatic metastases

With approximately 1.2 million diagnoses per year, colorectal carcinoma is the fourth most common cancer diagnosis in the world and the second most fatal cancer disease.⁸ The most common location of colorectal metastases is the liver followed by the lung and about 25% of patients with newly diagnosed CRC have liver metastases.^53,54 Nevertheless, only 10–15% of patients with colorectal liver metastases (CRLM) are amenable to partial hepatic resection.^5,55 In this context, thermoablation has become a treatment option for this patient group with promising clinical outcomes in the latest publications (Table 1) ; however surgical resection is regarded as the gold-standard for patients with resectable metastases. This circumstance makes a comparison of the outcome after thermoablation and surgical resection difficult, especially regarding to the lack of prospective randomized trials. Gillams et al published a position paper in 2015 which included 15 publications evaluating a total of 1613 patients who had received thermal ablation of colorectal liver metastases.³¹ In this study, the mean number of metastases was 2.2 and the mean tumour size was 2.6 cm (range 1.7–4.0 cm). After the first ablation procedure an average 3 year survival of 50% (37–77%) and a 5 year survival of 31% (17–51%) was determined. However, in almost all investigated studies, only patients who were not suitable for hepatic resection were treated with thermal ablation. In patients where hepatic resection would have been feasible but were treated with radiofrequency ablation a 5 year survival of 50% was assessed.

Table 1.

Latest clinical studies regarding local tumour control and outcome in patients with CRLM treated with thermoablation

Author	No. of patients	Mean age (years)	Mean tumour size (cm)	Metastases	Ablation system	Local tumour control	OS	Comment
Shady et al.56	162		1.8	233	RFA	median LTPFS: 26 months LTP: 48% (median follow-up: 55 months)	1-y: 90% 3-y: 48% 5-y: 31%
Solbiati et al.15	99	65.1	2.2	202	RFA	LTP: 11.9%	1-y: 98% 3-y: 69.3% 5-y: 47.8% 10-y:18%	Patients were additionally treated with systemic chemotherapy
Hamada et al.57	84	64.6	2.3	141	RFA	LTP: 27.7%	1-y: 90.6% 3-y: 44.9% 5-y: 20.8%
Ou et al.58	109	53.84	3.4	109	RFA		1-y: 92.3% 3-y: 50.7% 5-y: 41.6%	only Patients with single liver metastasis
Qin et al. 59	137	54.9	1.5	411	MWA	LTP: 5.35%	1-y: 98.1% 2-y: 90.6% 3-y: 85.9%

CRLM, colorectal liver metastases; LTP, local tumour progression; LTPFS, local tumour progression free survival; OS, overall survival.

In comparison, a meta-analysis of 60 studies examined the survival of patients after hepatic resection in colorectal carcinoma.⁶⁰ 5- and 10 year survival after resection in metastatic colorectal cancer ranged between 16–74% (median 38%) and 9–69% (median 26%). Similar or even slightly better survival rates after radiofrequency ablation in selected non-surgical patients were indicated in another study in 100 patients with a 5 year survival of 31%.⁶¹ Solbiati et al analyzed 99 patients with small liver colorectal metastases in an up to 10 year follow-up, with 5 year survival in 47.8% and 10 year survival in 18% of patients.¹⁵

Metastases under 3 cm are delineated by Gillams et al as being particularly suitable for thermal ablation. This is based on studies which show a correlation between local recurrence rate and tumour diameter: a local recurrence rate of 3% has been reported for CRLM with a diameter below 3 cm, whereas a local recurrence rate of up to 27–54% has been reported for CRLM with a diameter above 5 cm.^62,63

In a further study, Otto et al⁶⁴ compared patients with early colorectal liver metastases who would have been suitable for surgical resection but were treated with radiofrequency ablation. They indicated an average hospital stay of 2 days for patients treated with RFA compared to 13 days when surgical resection was performed. Furthermore, a total of 7 patients of their study group that were treated with RFA had complications, compared to 30 undergoing surgical resection. Local recurrence occurred in 32% at the ablation site, compared to 4% at the site of resection. Despite the negative impact of RFA on recurrence in this study, the higher rate of patients suitable for a second hepatic intervention finally resulted in identical rates of absence of disease and identical 3 year overall survival in both treatment groups (67% for RFA vs 60% for surgical resection) underlining the advantage of repeatability of thermoablation.

With respect to absence of prospective randomized trials comparing resection and thermoablation of CRLM, Tanis et al published an interesting review comparing two study arms of two different independent prospective randomized EORTC trials⁶⁵ : The EPOC trial randomized 364 patients with resectable CRLM between the combination of resection and systemic therapy compared with surgery alone.⁶⁶ The CLOCC trial randomized 119 patients with unresectable CRLM between RFA + systemic therapy FOLFOX alone.⁶⁷ Tanis et al compared the resection +systemic therapy arm of the EPOC trial (81 patients) with the ablation + systemic therapy arm of the CLOCC trial (55 patients) regarding local tumour control. Both therapies showed similar results regarding local tumour control with a local recurrence rate on a lesion basis of 6% after RFA and 5.5% after resection. If only metastases with a diameter below 3 cm were considered, local recurrence rate decreased to 2.9% in the ablation group.⁶⁵

Local treatment combined with resection

After surgical resection of CRLM there is a potential risk of recurrence and repeated hepatic resections can be technically difficult and demanding due to adhesions and deranged hepatic anatomy.^68,69 Thus, minimally invasive thermal ablation can be a potential alternative to hepatic resection due to its lower morbidity and mortality and preservation of liver parenchyma for recurrent CRLM.^31,68

Van der Pool et al analyzed 51 patients with recurrent CRLM who were treated with local therapy (RFA or stereotactic body radiation therapy) or surgery after initial hepatic resection.⁷⁰ In this study, no difference in recurrence or survival was reported between the three different treatment modalities with a 5 year survival of 35% and median survival of 37 months.

Sofocleus et al evaluated the outcome of 56 patients who underwent 82 CT-guided RFA procedures for a total of 71 recurrent CRLM after partial hepatectomy.⁷¹ The time interval between surgery and RFA ranged from 3 to 83 months and tumour size ranged from 0.5 to 5.7 cm (10 metastases with a diameter above 3 cm). Complete ablation was reached in 94% of cases. Median local progression-free survival was 10 months, and 1-, 2-, and 3 year local progression-free survival rates were 50%, 37%, and 30%, respectively. However, a tumour diameter above 3 cm again showed an increased risk for local tumour progression (with a 12 months local progression free survival rate of 54% for tumours below 3 cm and 17% for tumours above 3 cm, respectively).

Retreatment of recurrent metastases is not only limited to the first recurrence. Vigano et al reported 323 consecutive patients with CRLM who initially underwent resection.⁷² 206 patients developed hepatic and extrahepatic recurrence afterwards and 105 of these patients were retreated with radical treatment (surgery, RFA or stereotactic body radiation therapy). 78% of these patients had a second recurrence and 54% of these patients could be retreated with radical local treatment. This approach was repeated until the fourth recurrence. The proportion of radically treated patients did not decrease in the patient population even after several recurrences thanks to the switch from surgical to non-surgical option for liver metastases. Cases of long term survival were observed and the radical recurrence treatment reached a 3 year survival rate of 62.9% (patients who only received chemotherapy after the first recurrence had a 3 year survival rate of 13.4%).⁷²

These studies suggest a multidisciplinary approach including local ablative therapies for treatment of recurrent CRLM. Furthermore, another option is prospectively combining local treatment and surgery in patients in whom complete surgical resection is not possible.^73,74 For example, in patients with bilobar hepatic metastases, the dominant lesions can be resected whilst contralateral lesions that cannot be resected may be treated using local ablative therapies (Figure 1).⁷⁵ Conclusively liver resection and local ablation should be considered as a combined therapy and not as a replacement for each other. Both methods can potentially be combined and increase the rate of curative intended treatments.

Figure 1.

a-d: MRI: 63-year old male patient with two hepatic metastases of a colorectal carcinoma in the liver segment IVa and VIII. The patient initially underwent left-sided hemihepatectomy for the metastasis in segment IVa with a remaining metastasis in segment VIII (arrow in Figure 1a and b). Thereafter, this remaining metastasis was treated with microwave ablation (Figure 1c). Contrast enhanced control imaging shows the ablation zone surrounding the target tumour (Figure 1d).

“Test of time” in CRLM

Only a small percentage of patients with CRLM are candidates for resection and furthermore many of those patients who underwent metastasectomy will develop recurrent metastases. The challenge is that at the time of diagnosis of an apparently resectable CRLM, further synchronous metastases can be present but are not yet visible, and these patients will not profit from surgery.

With the “test-of-time” approach in patients with CRLM, a hepatic resection is delayed to identify possible further metastases that are not yet detectable. This concept is based on a study by Lambert et al who showed that delayed hepatic resection does not affect survival but enables better selection of patients who will benefit from hepatic resection.⁷⁶

Livraghi et al⁷⁷ assessed the potential role of RFA during the interval between diagnosis and hepatic resection. In this study, 88 patients who would have been potential candidates for surgical resection underwent RFA prior to re-evaluation. Of these 88 patients, 23 patients (26%) remained disease-free after RFA alone. 44 patients (50%) developed new liver metastases and became unsuitable for hepatic resection. As a result, a less invasive procedure with lower morbidity was performed in 23 patients and unnecessary surgery was avoided in 44 patients as it is unlikely that they would have benefited from hepatic resection. An alternative to RFA would have been to not perform treatment during the waiting interval before re-evaluation for surgery. However, none of the patients who received ablation became inoperable due to a recurrence of the treated lesion. Therefore, offering the patient RFA in a “test-of-time” approach with a potential cure and avoidance of unnecessary surgery can be justified.

Local treatment of pulmonary metastases

In patients with CRC, the lung is the second most common localization of metastases after the liver. About 10% of patients with CRC develop pulmonary metastases during the course of the disease and without treatment the 1 year survival rate is only 30%.^78,79

Surgical resection is the first-line method for pulmonary metastases. However, surgery is associated with complications and in some patients, surgery is not feasible due to comorbidities such as chronic obstructive pulmonary disease. In the event of recurrence, repeated thoracotomy is difficult and lung function can be further impaired.^78,80 Patients with pulmonary metastasis from CRC who have undergone resection have a reported 5 year survival rate of 36–67% and median survival duration of 35–50 months.^81,82 In comparison, the median survival duration of patients with pulmonary metastasis from CRC treated with local thermoablation ranges between 33 and 67 months and the 5 year survival rates are 35–56%.^78,83–85 Therefore, both methods attain similar results.

Lyons et al analyzed 8 studies including 903 patients who underwent RFA for CRC pulmonary metastases. Major complication rates were noted in 0.5 to –8% of patients with minor complications ranging between 7 and 33%. 23% of patients required a chest tube after the ablation procedure. Local progression rate was stated between 9 and 21% in this metaanalysis.⁸⁶

Local treatment of OMD in melanoma

The incidence of melanoma is increasing and while early stages of the disease are curable, patients with an advanced metastatic stage (Stage IV) have a life expectancy of only 10– to 13 months.^87,88 Cutaneous melanomas and ocular melanomas differ in their pattern of metastatic spread. Cutaneous melanomas metastasize most frequently to soft tissue and lymph nodes while only about 10–15% develop liver metastases with survival rates of 2–8 months.^89–91 In metastatic ocular melanoma, up to 80–90% of patients have liver metastases with a median survival of 5–7 months.^88,92,93 Some studies reported a prolonged survival if hepatic metastases are resected or treated with thermoablation.^94,95 Doussot et al evaluated the outcome of 48 patients who underwent resection or thermoablation for hepatic metastases. The overall survival was 25.9 months without significant differences regarding the two therapy forms.⁸⁸

Bale et al⁸⁹ evaluated the outcome of 20 patients with 75 hepatic metastases from cutaneous and ocular melanoma treated with stereotactic radiofrequency ablation. Median overall survival was 19.3 months and median disease-free survival was 9.5 months without significant difference for patients with cutaneous and ocular melanoma.

Thermoablation of metastatic melanoma is not only limited to the liver. White et al analyzed the outcome of 33 patients with Stage IV ocular and nonocular melanoma who underwent thermoablation of 66 metastases in the lung, bones, liver and soft tissue.⁹⁶ Patients were only included in this retrospective study if all metastases were amenable for ablation therapy. In this patient collective, a remarkable median survival time of 3.8 years was reported. Local recurrence occurred in 5 of 33 patients.

Local treatment of OMD in other entities

Depending on tumour biology, long term survivors have been reported in patients with metastatic breast carcinoma, especially in the situation of OMD.⁹⁷ Published data suggest that about 5% of patients with less than five metastases at the time of diagnosis may remain disease free over more than a decade, if treated with curative intent.^98,99 Several retrospective studies are available concerning the local thermoablation (in most cases RFA) in this patient group, predominately in patients with hepatic OMD.^100–103 In a recent study, Barral et al published the outcome in 79 females with oligometastases in the lungs, liver and bone who were treated with curative intent using percutaneous thermal ablation associated with systemic chemotherapy or hormone therapy.⁹⁹ In this patient group, 1- and 2 year disease free survival rates were 54.2 and 30.4%. Again, a larger tumour diameter (the authors stated a critical value of 4 cm) was associated with a higher local recurrence rate.

Further small number retrospective studies are available regarding focal therapies in OMD in other tumour entities. Erie et al recently published their experience with local thermal ablation (RFA and cryoablation) of nodal and osseous prostate cancer metastases in the oligometastatic state.¹⁰⁴ The authors stated a 1- and 2 year progression free survival rate of 56 and 43% and discussed the local treatment as an alternative, especially for patients who want to delay initiation of androgen-deprivation therapy.

Future trends in oligometastatic disease

Aside from cell necrosis, induction of anti-tumoral immune response has been observed in patients with different tumour entities during thermal ablation.¹⁰⁵ This issue initially came up after observation of regression in distant untreated tumours in patients treated with thermal ablation.^106,107 Within a few hours to days following ablation, necrotic cells release their content in the extracellular space and trigger an immune response. Heat shock proteins are elevated after tumour ablation and seem to be of importance for the activation of anti-tumour T-cell immunity.¹⁰⁸ Enhancement of this effect with additional immunomodulation can be a future treatment option for patients with OMD. In a Phase II/III study, Li et al analyzed the safety and efficacy of the combination of RFA and cytokine-induced killer cells (CIK) transfusion for patients with CRLM. 30 patients with RFA alone (Group A) and 30 patients with RFA plus cytokine-induced killer cells transfusion (Group B) were juxtaposed. The results were promising with a significantly longer progression-free survival rate in Group B (18.5 months vs 23 months; p = 0.034) and a post-treatment increase of carcinoembryonic antigen (CEA)-specific T-cell response in this group.¹⁰⁹

Conclusion

Thermal ablation is an integrative minimally invasive therapy for a more individualized treatment, and currently several ablation techniques are currently available with different advantages and disadvantages. Therefore, a basic understanding of the underlying technical aspects is essential for the treatment of OMD at different sites and oncologic situations. In general, ablation is considered in non-surgical candidates, but is a treatment option at this juncture in patients with OMD disease. The best clinical outcomes are achieved for tumours smaller than 3 cm, especially in the liver. Bearing in mind that thermal ablation can be performed multiple times, local therapies can be advantageous in comparison to surgery in this respect. Furthermore, surgery and local ablation can be considered as a combined therapy and not as a replacement for one another. Both methods can potentially be combined and increase the rate of curative intended treatments in patients with OMD.