Abstract
Background/Aim: Pulmonary metastases are the second most common site of metastasis in colorectal cancer after the liver, and microwave ablation (MWA) for its treatment has grown in popularity in patients who are not suitable for pulmonary metastatectomy. However, its long-term efficacy remains unknown. Materials and Methods: A systematic review was conducted in July 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using PubMed, EMBASE, Scopus, and Cochrane databases. Studies adopting MWA for colorectal cancer pulmonary metastases were included. Results: A total of 488 lesions were ablated in 230 patients across eight studies. The median duration of ablation was 10 minutes. The mean length of stay in hospital was 2.3 days. Complications included pneumothorax in 128 (52%) patients; pneumonia, which occurred in 4 (1.7%) patients, and pulmonary haemorrhage in 23 (10.0%) patients. Complete remission was achieved in 85 (37.0%) patients, local control was achieved in 103 (44.8%) patients, and residual or progressive disease remained in 85 (37.0%). Survival post ablation at 1 year was 89.2% and at 3 years was 40.3%. Post-ablation disease-free survival was 43.2% at 3 years. Conclusion: MWA is an alternative treatment for pulmonary metastases of colorectal cancer. It has competitive theoretical properties and local recurrence rate compared to radiofrequency ablation.
Colorectal cancer (CRC) is the third most common cancer and second-leading cause of cancer death in the United States of America, Europe, Australia, and in the world overall according to the World Health Organisation (1-8). The lungs are the next most common site of metastasis from CRC, following the liver (8). However, surgical resection with pulmonary metastasectomy can only be offered to a small proportion of patients with pulmonary metastasis of CRC (CRPM) (1, 8-13). Untreated metastatic CRC generally has a poor prognosis, with a median overall survival of only 8 months. Palliative chemotherapy and immunotherapy provide only modest improvement, with extension of overall survival by approximately 4 months (1, 14).
Alternative treatments have been explored in recent years to manage CRPM and to prolong survival in patients that are not operative candidates. These include different types of systemic chemotherapy, radiation therapy, and minimally invasive image-guided techniques, such as percutaneous radiofrequency ablation (RFA) and microwave ablation (MWA) (1, 8, 15-22). RFA has been the choice of percutaneous ablation due to its safety profile and efficacy for locoregional control of CRPM (1-4, 8, 15, 23).
MWA is a relatively new alternative percutaneous thermal technique that creates a much higher frequency electromagnetic radiation field (915 MHz - 2.5 GHz) around a monopolar electrode. The energy propagates directly through air and tissue whereby the lung, which is of high intrinsic impedance, is not a barrier. This then induces homogeneous heating and coagulation necrosis. Charring, which usually leads to high impedance to RFA currents by causing high tissue resistance, is no longer a barrier in MWA. MWA leads to higher temperatures more quickly than RFA and has the potential to simultaneously treat more lesions in the same or shorter time. Theoretically, MWA leads to a larger ablation area compared to monopolar RFA and has been used to treat lesions larger than 5 cm (15). Recurrence due to the ‘heat sink’ effect is also proposed to be reduced in MWA (8, 24).
The advantages of MWA have resulted in its use being favoured over RFA (8, 20, 22, 24). However, from published retrospective series and reviews, it is still unclear whether MWA is comparable to RFA (8, 20). The purpose of this systematic review was to evaluate the current evidence of the efficacy and safety of MWA for treatment of CRPM, with particular emphasis on local tumour control, time to tumour progression, survival rates and procedure-related morbidity.
Materials and Methods
Literature search strategy. A systematic review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (24). The literature search was conducted in July 2022 using PubMed, EMBASE, Scopus and Cochrane databases. The Medical Subject Headings (MeSH) searched included “colorectal”, “cancer”, “pulmonary metastasis”, “thermal ablation” and “microwave ablation” and was limited to original research articles in the English language. A PRISMA flow diagram is detailed in Figure 1. Article abstracts were screened by all Authors after duplicates were removed. Two reviewers (CT and AH) assessed full-text articles based on the inclusion and exclusion criteria given below, with final determination by a third reviewer (DLC) in cases of discrepancies. The reference lists of articles identified were manually searched to locate other articles of relevance.
Preferred reporting items for systematic reviews and meta-analyses flow diagram.
Selection criteria. Inclusion criteria were as follows: i) Pulmonary metastases of colon or rectal primary; ii) adopted microwave ablation therapy; iii) study on humans; iv) with sufficient data on ablation, morbidity and mortality to be included in tabulation. Exclusion criteria were as follows: i) Case reports; ii) letters; iii) reviews; iv) editorials; v) duplicate studies. Where multiple treatments were employed, outcome data needed to be reported separately. Where multiple publications from the same institution were identified, only the most recent update with the largest number of patients was included. Studies were evaluated and categorized according to their level of evidence as described by the US Preventive Services Task Force (25).
Data extraction and critical appraisal. Data extraction was conducted independently by two Authors (CT and HAR) recorded by tabulation, with final determination by a third reviewer (DLC) in cases of discrepancies. Data extraction included: Study characteristics, patient demographics, disease characteristics and MWA details, with particular interest in procedural morbidity, mortality and survival data. Meta-analysis was not appropriate given the small numbers of studies. Data were instead presented in the form of tabulation with values presented as the median/mean with interquartile range (IQR) and number (percentage).
Ethical approval. This study, being a systematic review, did not require formal ethics approval.
Results
Study selection. Systematic searching of PubMed, EMBASE, Medline, Scopus and Cochrane, using the method detailed above, yielded a total of 452 articles. 273 were duplicates, leaving 179 individual articles. The abstracts of these were then screened for meeting the study inclusion criteria, with 159 being excluded. The remaining 20 articles were assessed; 12 were then excluded due to: Inability to separate data on MWA from that on radiofrequency ablation; inability to separate the source of lung metastasis as being colorectal from other sources (n=4); older data study with subsequent update from the same group (n=4); case report (n=3); letter/review (n=1). A total of eight individual studies met the inclusion and exclusion criteria and were included for review.
Demographics/study characteristics. All eight of the included studies were retrospective cohort studies. Two originated from China (26, 27), two from Australia (24, 28), two from USA (29, 30), one from Germany (8) and one from an undisclosed country of origin (31). The publication dates ranged from 2016 to 2022. Patient recruitment occurred between 2008 and 2019, totalling 230 patients with two to 50 patients (median=27, IQR=19-43) in each study and a total of 488 ablated lesions (Table I).
Study characteristics.
There was a total of 84 females (median=11, IQR=6-11) and a total of 125 (median=21, IQR=12-25) males. Males predominated, making up between 44% and 71% (median=62%) of the population in each study [excluding unstated values from Raspanti et al.] (31). Patient age [excluding unstated values from (31)] ranged from 32 to 86 years. The median age across all studies combined was 61.5 (IQR=57.9-64.3) (Table II).
Patient characteristics.
There was paucity of data on tumour staging and distribution of pulmonary metastases in some studies (8, 26, 27, 30, 31). However, the cohorts from Ferguson et al. (24), Kurilova et al. (24), and Tan et al. (28) consisted of TMN stages I (3%), II (19%), III (29%), and IV (23%) in their combined cohorts. Of the four studies that described lesions by anatomical lobe, 29 (19.3%) of the ablated lesions were in the right upper lobe, 22 (14.7%) were in the right middle lobe, 29 (19.3%) were in the right lower lobe, 47 (31.3%) were in the left upper lobe, and 19 (12.7%) were in the left lower lobe (24, 27, 28, 30). Cheng et al. included 48 lesions in total, with 34 lesions of 20.1-30 mm diameter, eight of 30.1-40 mm, three of 40.1-50 mm, and three greater than 50.1 mm lesions (27). Ferguson et al. included a total of 20 lesions with four under 10 mm in diameter, 12 between 10.1 and 20 mm, and four lesions between 20.1 and 30 mm in diameter (24). Reisenauer et al. included 21 lesions, all measuring less than 10 mm (30). Li et al. did not differentiate lesions by size, with all 22 lesions included being under 35 mm diameter (26). Raspanti et al. (31) did not include tumour diameter, and Vogl et al. included a tumour volume range between 0.5 and 5 mm (0.01-82.8 ml) (8). Tan et al. included 108 lesions of which the median size was 35 mm in diameter (28).
There was notable disparity in MWA protocol between the studies. A total of 488 (median=42, IQR=33-94.5) lesions per study were ablated in 230 patients, across all eight studies. The duration of ablation per lesion ranged from 18 seconds to 36 minutes (8, 24), with a median of 10 minutes. The maximal power output for ablation ranged from 1 to 140 W (median=60 W) (Table III).
Microwave ablation details.
Local progression. Half of the studies included a breakdown of local versus systemic disease progression. Cheng et al. demonstrated eight lesions with local progression (17%), with no systemic progression exhibited by any patient (27). Ferguson et al. had seven patients (50%) with local and seven (50%) with systemic progression, where four (29%) had local control and systemic progression and three (23%) had local and systemic progression (24). There were nine lesions (10%) with local progression and 32 (64%) with systemic progression in the study by Kurilova et al. (29). Reisenauer et al. had one (50%) patient with local progression (30). Tan et al. had five (12%) patients with local progression, 25 (60%) patients with local and systemic progression, and 12 (29%) patients with residual disease (28) (Table IV).
Outcomes post microwave ablation.
Mortality and overall survival. Overall survival at 1-, 2-, and 3-years was 79%, 63.1%, and 44.4% respectively in the study by Cheng et al. (27). Kurilova et al. reported corresponding survival rates of 94%, 82%, and 61% (29); Raspanti et al. reported 100%, 78.6% and 66.7% (31), while Vogl et al. reported 82.7%, 67.5% and 16.6% (8). Reisenauer et al. reported 100% survival at 3 years post procedure (30), and Tan et al. reported 95% and 28% survival at 1 and 3 years, respectively (28) (Table V).
Outcomes post microwave ablation.
The median duration of follow-up from MWA was 24.4 months (IQR=19-25.5 months).
Complete remission was achieved in 85 (37.0%) patients, local control was achieved in 103 (44.8%) patients, with residual or progressive disease present in 85 (37.0%) patients. The median rate of overall survival at 1, 2 and 3 years post MWA ablation was 88%, 73%, and 53%, respectively. The median overall post-ablation survival was 31.9 months, with a mean of 32.6 months. The median overall cancer-free survival at 1, 2 and 3 years post ablation was 94.5%, 73.1%, and 44.4%, respectively.
Length of hospital stay. Admission to intensive care units was not included in any study. Cheng et al. (27), Ferguson et al. (24) and Tan et al. (28) reported a mean duration of hospital stay of 3, 1.8 and 2.6 days, respectively. Ferguson et al. reported a mean duration of stay for those patients that had major complications of 6 days, whereas Vogl et al. (8) reported a stay of between 3 and 7 days for major complications requiring therapeutic thoracostomy.
Complications. Complications of MWA were not uncommon (Table VI). A total of 244 (50.0%) complications were reported across the eight studies and across all lesions ablated. The most common complication was pneumothorax, which occurred in 128 (52%) instances. Of the pneumothoraxes that occurred, 58 (45.3%) required the insertion of a chest drain, whereas the others did not require any intervention. Common Terminology Criteria for Adverse Events (CTCAE) grade 1 pulmonary haemorrhage was reported in 23 patients (10%), and grade 1 pleural effusion was reported in 40 (17.4%) patients. Grade 3 pneumonia was reported in four patients (1.7%), and pleuritic pain was reported in 13 cases (5.7%).
Complications post microwave ablation according to Common Terminology Criteria for Adverse Events (CTCAE).
Discussion
The lungs are the next most common site for metastasis from CRC following the liver. There has been an increase in detection since 1985 from one study of CRC statistics in the United States (8). It has been reported that 50% of patients with CRC will die from metastatic disease, that 10-20% of metastasis occurs in the lung and that pulmonary metastasectomy provides 20-40% survival (1-4, 8). The current management priority of CRPM is to improve the patients’ quality of life while trying to prolong their survival, with reduced toxicity and duration of treatment (32).
However, surgery can only be offered to a small group of patients, as contraindications to surgery include the presence of more than three lung metastases, bilateral or deep lung metastasis, significant comorbidities, other distant metastasis, short disease-free interval between primary resection and progression, and the discovery of pulmonary metastases whilst having chemotherapy, and a patient may refuse to undergo surgery (1, 8-13).
Radiofrequency has been the mainstay of ablation for pulmonary metastatic nodules and previous studies have shown that it is a safe and effective method of managing CRPM (1, 20, 23). Since its advent, MWA has been an alternative treatment for ablation of non-surgical lung and liver lesions. MWA has been purported to have theoretical advantages over RFA in that it is able to generate higher ablation temperatures and larger heating radius in the lung, which is a poor conductor of heat, in a much shorter time (8, 20, 24). There have been very few studies comparing RFA and MWA specifically in the treatment of CRPM and the available studies comparing both methods for liver metastasis of CRC have shown that the superiority of MWA to RFA is still debatable (22, 32-34).
To date, there are no systematic reviews on MWA for CRPM (8, 20). The purpose of this study was to evaluate and compare the effectiveness in treatment including short-term outcome, as well as local tumour control, time to tumour progression, and survival rates among patients with CRPM who undergo MWA.
Almost half of the reports originated from Western countries and the other half from Asia, which raises the question for the applicability of their findings in Australia. However, given at least half were from the West and two of them were from Australia, we decided to publish this systematic review to allow an overview of the current data for this topic.
We evaluated a total of eight studies that evaluated MWA of 488 lesions in 230 patients. The details of the ablation strategy are as described in Table III. Complete remission was achieved in 85 (37.0%) patients, local control was achieved in 103 (44.8%) of patients, with residual or progressive disease present in 85 (37.0%) patients.
The median duration of overall survival post MWA was less when compared to RFA for CRPM, where the overall survival rate was 95% at 1 year, 85.5% at 2 years and 54.7% at 5 years according to Fonck et al. (35). However, the same study showed MWA was more competitive when compared to RFA, the median cancer-free survival duration being 7.6 months and the cancer-free survival rate being 63.9%, 33.1%, 18.4% and 11.2% at 6 months and 1, 2 and 5 years, respectively (35). RFA proved to lead to better overall survival but was not superior in terms of cancer-free survival compared to MWA. The median local progression rate was better with MWA (16%) than RFA (71%) (35), keeping in mind the follow-up period for RFA would be longer than for MWA. This was similar to the results from a systematic review comparing MWA to RFA for liver metastasis, where the overall survival after RFA was 3 years longer than after MWA, despite MWA having lower local recurrence and disease-free survival rates (32). The mean length of stay in hospital was 2.3 days, which was slightly shorter than that of patients treated with RFA (mean of 3 days) (35).
Due to a paucity of data, accuracy of stratifying results with respect to tumour size, distribution and staging was not possible, as only two studies considered tumour size (24, 27), three others considered distribution (24, 27, 30), and three studies considered tumour staging (24, 28, 29). Therefore, the theoretical advantage of MWA being able to achieve higher temperatures, shorter ablation times, and a larger tumour ablation size compared to RFA will have to be considered from the studies of Vogl et al. (8) and Ferguson et al. (24). That is, MWA is superior to RFA in treating larger tumours, and this was also seen from our own study (28) (largest size=60 mm; median lesion size=25.3 mm IQR=12.9-37.7 mm), although not to any significance.
Systemic treatment prior or post MWA has proven to be of some benefit (35). We attempted to review the results, however, only two studies included systemic chemotherapy in their analysis, where all patients in both groups had chemotherapy (24, 29).
The rate of complications post MWA was higher than RFA, particularly those of pneumonia and pulmonary haemorrhage, as previously discussed (1, 20, 36). This may be due to the reduced ‘heat-sink’ effect and larger probe size of RFA, resulting in a larger necrotic area, compared to the higher risk of vessel damage with MWA, although it may be prudent to factor in improved statistical comparison with time and increased numbers (8, 32).
Study limitations. There are several limitations to our study. Firstly, we studied retrospective studies with no standard randomisation, which may create a bias for selection. However, as mentioned in Table I, no significant difference according to baseline characteristics between the two treatment groups was detectable in any of the studies included.
Secondly, the number of studies included was small due to the strict inclusion criteria, even after including conference reports with incomplete data. However, the restrictive inclusion criteria strategy used in our review suggests that the quality of the articles reviewed was mostly high, thus increasing the strength of our findings.
Thirdly, the MWA equipment used across all eight studies was different and might have had a degree of impact on the direct comparison of the studies. Due to small cohort numbers in each study, a subgroup analysis based on equipment was not possible.
Finally, due to the small number of studies, a meta-analysis, multi-variate analysis, risk analysis and risk stratification of outcomes according to lesion size was not possible. However, we were able to analyse outcomes (local recurrence rate, overall survival) and, more importantly, complication rates in more detail.
Despite these limitations, our study is the only available, most comprehensive and up-to-date review evaluating MWA for CRPM.
Conclusion
In conclusion, this study shows that percutaneous MWA provides an alternative method of treatment for CRPM. It is as competitive if not superior in terms of its technical properties and lower local recurrence and disease-free survival rates, particularly in patients with larger tumours, compared to RFA, although RFA has a favourable overall survival rate and safety profile. More longer-term randomised controlled trials and animal studies are required to understand the benefits of MWA compared to RFA (32). We suggest the use of MWA for larger tumours, in conjunction with systemic treatment (35).
Footnotes
Authors’ Contributions
Charis Tan: Methodology; investigation; resources; data curation; writing – original draft, review and editing; visualization; project administration. Andy Ho: Data curation. Hayden Robinson: Data curation. Linna Huang: Writing – review and editing. Praveen Ravindran: Data curation. Daniel L. Chan: Writing - review and editing; visualization. Nayef Alzahrani: Supervision. David Morris: Conceptualization and supervision.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received January 1, 2023.
- Revision received May 9, 2023.
- Accepted May 29, 2023.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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