Abstract
Purpose: The aim of this retrospective study is to determine the optimal timing and number of cycles of systemic chemotherapy in patients with colorectal liver metastases (CLM) treated by ultrasound-guided percutaneous microwave ablation (PMWA).
Materials and methods: In total 199 patients with 318 CLM, median number of tumours one per patient and median maximum size of tumours 3.0 cm, treated by PMWA combined with or without systemic chemotherapy were included in our study. Chemotherapy was administered pre-ablatively in 148 of those patients (74.4%), and post-ablatively in 142 (73.6%). Chemotherapy regimens included FOLFOX/XELOX, FOLFIRI/XELIRI, and sequential monotherapy. Prognostic factors were evaluated by univariate and multivariate analyses, using log-rank test and Cox proportional hazards model, respectively.
Results: The estimated 5-year rates of progression free survival (PFS) and overall survival (OS) were 10.1% and 27.9%, respectively. The number of CLM (P = 0.003), maximum size of CLM (P < 0.001) and topography (P = 0.030) were independent prognostic factors for PFS of patients with CLM while age (P = 0.002), maximum size of CLM (P = 0.006) and post-ablative chemotherapy (P = 0.046) for OS. In further analysis, CLM patients receiving more than six cycles of post-ablative chemotherapy had significantly better OS (P = 0.015) than those without post-ablative chemotherapy.
Conclusion: This study revealed chemotherapy administered after (more than six cycles) PMWA improved the OS of CLM patents. And, PMWA was a safe procedure in view of the absence of procedure-related death and low rate of major complications.
Introduction
Colorectal cancer is the third and second most common cancer in men and women, respectively, with more than 1 million new cases worldwide annually [Citation1]. Moreover, following lung cancer, colorectal cancer is the second leading cause of cancer deaths [Citation2]. Nearly a quarter of colorectal cancer patients are diagnosed with hepatic metastases at the time of diagnosis (synchronous disease), and an additional 20–25% with metachronous liver metastases. When feasible, hepatic resection offers promising results for patients with colorectal liver metastases (CLM), and even for patients with limited metastases at extrahepatic sites, provided that all lesions are resected and the resection is considered potentially curative [Citation3–5]. However, 80% of patients are not suitable for surgical operation due to advanced disease and/or co-morbidities. For unresectable lesions, systemic chemotherapy is the standard treatment. And several randomised controlled trials on systemic chemotherapy have reported a median progression-free survival (PFS) of 5.9–10.7 months and a median overall survival (OS) of 14.5–21.3 months [Citation6–11].
Over the past two decades, ablative therapies, especially radiofrequency ablation (RFA), have already been used in the management of patients with unresectable CLM to achieve local tumour control [Citation12–16]. In a randomised phase II trial involving patients with liver-limited metastases, Ruers et al. [Citation17] reported that systemic chemotherapy combined with RFA achieved significantly longer PFS than systemic chemotherapy alone. Compared with RFA, microwave ablation (MWA) offers many theoretical advantages, including less dependence on electrical conductivity of tissue, less ablation time, higher intratumoural temperature, and a larger and more homogenous and uniform ablation zone [Citation18–20]. Percutaneous microwave ablation (PMWA) has been proven to be a safe and effective method in the treatment of primary and metastatic liver tumours [Citation21–23].
However, to our knowledge, there were few studies on the impact of systemic chemotherapy on survival outcome of CLM patients treated by MWA. This present retrospective study aimed to assess whether timing and number of cycles of systemic chemotherapy would affect survival outcomes of CLM patients treated by PMWA.
Materials and methods
Patients
All patients were selected from the inpatients of our hospital during June 2009 to March 2014. Their medical records and image data were reviewed. Inclusion criteria for this study were as follows: histologically confirmed CLM; maximum size of CLM ≤5 cm and number of CLM ≤3; All PMWA was guided by ultrasonography (US) with curative intention. Patients having CLM with vascular invasion or extrahepatic metastases were excluded. This retrospective study was approved by our institutional review board. Written informed consent for the treatment procedures was obtained from each patient. We reported the clinical result of PMWA for 115 CLM patients in our previous study [Citation24]. In this study we added 84 new patients to the previously reported patients’ cohort. Therefore, in our current study, a portion of the patients were from a previously published study.
PMWA procedure
All patients were treated with a cooled-shaft system (KY-2000, Kangyou Medical Instruments, Nanjing, China), which was capable of producing a maximum of 100 W of power at 2450 MHz. This system had 21-gauge thermocouple needles, which could be percutaneously placed at a designated location to monitor temperature in real time. After administration of local anaesthetic, US-guided biopsies were performed via the same skin incision that was made for the microwave antenna placement. Microwave antennae (15-gauge, 1.9 mm external diameter, 18 cm long) were then inserted under US guidance. A general anaesthetic was applied after all insertions, and microwave was then emitted. An output setting of 60 W for 300 s was routinely used during ablation sessions. If the heat-generated hyperechoic microbubbles did not completely encompass the entire tumour, prolonged microwave emission was applied until the desired temperature was reached. After the MWA treatment of the tumour, needle track cauterisation was performed to avoid possible seeding of tumour cells [Citation22]. Time intervals between chemotherapy (pre or post) and MWA was dependent on both the patients’ specific condition and therapy aim at the discretion of the doctor in charge.
Chemotherapy administration
Chemotherapy and targeted drugs were administered according to National Comprehensive Cancer Network guidelines. Briefly, FOLFOX (oxaliplatin, leucovorin, 5-fuorouracil) regimen was performed as follows: oxaliplatin 85 mg/m2 intravenously (i.v.) over 2 h, day 1; leucovorin 400 mg/m2 i.v. over 2 h, day 1; 5-fuorouracil 400 mg/m2 i.v. bolus on day 1, then 1200 mg/m2/day ×2 days (total 2400 mg/m2 over 46–48 h) i.v. continuous infusion, repeated every 2 weeks. XELOX (oxaliplatin, capecitabine) regimen was performed as follows: oxaliplatin 130 mg/m2 i.v. over 2 h, day 1; capecitabine 850–1000 mg/m2 per ora (PO) twice daily for 14 days, repeated every 3 weeks. FOLFIRI (irinotecan, leucovorin, 5-fuorouracil) regimen was performed as follows: irinotecan 180 mg/m2 i.v. over 30 90 min, day 1; leucovorin 400 mg/m2 i.v. infusion to match the duration of irinotecan infusion, day 1; 5-fuorouracil 400 mg/m2 i.v. bolus on day 1, then 1200 mg/m2/day ×2 days (total 2400 mg/m2 over 46–48 h) i.v. continuous infusion, repeated every 2 weeks. XELIRI (irinotecan, capecitabine) regimen was performed as follows: irinotecan 180 mg/m2 i.v. over 30–90 min, day 1; capecitabine 850–1000 mg/m2 PO twice daily for 14 days, repeated every 3 weeks. Bevacizumab was administered with 5 mg/kg i.v. on day 1 and repeated every 2 weeks when combined with FOLFOX or FOLFIRI, 7.5 mg/kg i.v. on day 1 and repeated every 3 weeks when combined with XELOX or XELIRI. Cetuximab was administered with 400 mg/m2 i.v. over 2 h first infusion, then 250 mg/m2 i.v. over 60 min weekly, or 500 mg/m2 i.v. over 2 h on day 1, every 2 weeks when combined with FOLFOX or FOLFIRI. Capecitabine as monotherapy was administered with 850–1250 mg/m2 PO twice daily during day 1 to day 14 and repeated every 3 weeks. Leucovorin/5-fuorouracil as monotherapy was administered with 400 mg/m2 i.v. over 2 h on day 1, followed by 5-fuorouracil bolus 400 mg/m2, then 1200 mg/m2/day ×2 days (total 2400 mg/m2 over 46–48 h) continuous infusion and repeated every 2 weeks. Irinotecan as monotherapy was administered with 125 mg/m2 i.v. over 30–90 min, day 1 and day 8, and repeated every 3 weeks.
Follow-up and outcomes measures
All patients were followed up with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Follow-up imaging was performed at 1 and 3 months after MWA and then roughly 3–6-month intervals. We combined contrast-enhanced US in patients in whom CT or MRI findings raised a question of recurrence or a new lesion but were not definite. Follow-up was closed at the time of death or last visit of the patient. For patients who did not visit, we called them or their families to obtain the details of their medical record. The end points of this study were PFS and OS. Local tumour recurrence was defined as presence of tumour at or adjacent to the prior MWA site which had been previously documented as complete ablation. New contrast-enhancing focal lesions at intrahepatic or extrahepatic sites were considered new metastases and defined as intrahepatic progression and extrahepatic progression, respectively. And the objective disease progression included local recurrence, intrahepatic progression and extrahepatic progression. PFS was calculated from the date of MWA of liver metastases to the date of objective disease progression or the last date of follow-up (in patients who did not suffer from objective disease progression). OS was calculated from the date of MWA of liver metastasis to the date of death or last date of follow-up. Major complications were defined as events which caused substantial morbidity and disability that increased the level of care, or led to hospital admission, or substantially prolonged the hospital stay [Citation25].
Statistical analysis
Continuous and categorical variables were expressed as median (range) and frequency. PFS and OS were estimated by the Kaplan–Meier method and compared by the log-rank test. Multivariate analysis was performed with the Cox proportional hazards model. For all analyses, p-value was bilateral and <0.05 was considered statistically significant. All statistical analyses were performed by using SPSS, version 19 (IBM, Armonk, NY, USA).
Results
Patients’ characteristics
Of all patients who underwent PMWA for CLM during this study period, a total of 199 patents with 318 CLM were eligible for the inclusion criteria and were included in this study. Among these, six patients were lost to follow up after the PMWA treatment. Patients’ primary characteristics are shown in . The study cohort comprised 132 men and 67 women, and the median age was 60 years (range 30–86 years). At the time of PMWA treatment, the median number of tumours treated was 1 (range 1–3) and the median maximum size of tumours was 3 cm (range 1–5 cm). Development of liver metastases was synchronous with primary tumours in 116 patients and was metachronous in 83 patients. Bilobar disease was noted in 39 cases (19.6%).
Table 1. Baseline data for the study cohort.
Procedure-related deaths and major complications following ablation
There was no PMWA procedure-related death. Major complications related to the PMWA procedure were observed in seven patients (3.5%). One was a liver abscess, which occurred in a diabetic patient. This patient was treated by using catheter drainage combined with antibiotic treatment. In six patients, pleural effusion that caused various degrees of dyspnoea was noted, and these patients required thoracentesis. All the six patients’ symptoms were apparently relieved after drainage. No major complications led to permanent sequelae.
Chemotherapy details
Chemotherapy was administered pre-ablatively in 148 of those patients (74.4%), and post-ablatively in 142 (73.6%). Pre-ablative chemotherapy regimens included FOLFOX or XELOX in 128 (86.5%), FOLFIRI or XELIRI in 48 (32.4%), and others (sequential treatment with monotherapy) in 15 patients (10.1%). Post-ablative regimens included FOLFOX or XELOX 76 (53.5%), FOLFIRI or XELIRI 58 (40.8%), and others 30 patients (21.1%). Bevacizumab and cetuximab were a component of the pre-ablative regimen in 8 (5.4%) and 20 patients (13.5%), respectively, and a component of the post-ablative regimen in 26 (18.3%) and 23 patients (16.2%), respectively.
Survival outcomes
Six patients who were lost to follow-up were not incorporated into our data analysis of survival outcome. For the 193 patients with full information of follow-up, after a median follow-up of 30.2 months (range 6.0–68.4 months), 134 patients presented with progression (10 and 79 patients experienced local tumour and intrahepatic progression, respectively. Extrahepatic and intra-/and extrahepatic progression were found in 37 and 8 patients, respectively), among them, 71 patients deceased. The estimated rate of 5-year PFS was 10.1% and the median PFS was 21.0 months (95%CI 16.5–25.5 months). The estimated rate of 5-year OS was 27.9% and the median OS was 41.0 months (95%CI 34.4–47.6 months).
Univariate and multivariate analyses of prognostic factors
In order to assess prognostic factors for survival outcomes of CLM patients treated by PMWA, we subjected 11 clinical parameters (age, gender, primary tumour, node status, histology grade, character, number of CLM, maximum size of CLM, topography, pre-ablative chemotherapy, and post-ablative chemotherapy) into univariate and multivariate analyses.
The results of univariate analysis show that the number of CLM (p < 0.001), maximum size of CLM (p < 0.001) and topography (p < 0.001) were the prognostic factors for PFS. While age (p < 0.001), number of CLM (p = 0.026), maximum CLM size (p < 0.001) and use of post-ablative chemotherapy (p = 0.002) were the prognostic factors for OS ().
Table 2. Univariate analysis of prognostic factors for progression free survival and overall survival.
Multivariate analysis revealed that the number of CLM (p = 0.003, hazard ratio (HR) = 1.925), maximum size of CLM (p < 0.001, HR =2.240) and distribution of CLM (p = 0.030, HR =1.678) were the independent prognostic factors for PFS. Meanwhile, age (p = 0.002, HR =2.310), maximum size of CLM (p = 0.006, HR =2.035) and post-ablative chemotherapy (p = 0.046, HR =0.573) were the independent prognostic factors for OS ().
Table 3. Multivariate analysis of prognostic factors for progression free survival and overall survival.
The optimal duration of chemotherapy for CLM remains controversial. Two potential strategies for adjuvant therapy in CLM patients are recommended in 2014 ESMO guidelines: post-operative adjuvant chemotherapy or perioperative for 6 months. So the survival outcomes of CLM patients receiving one to six cycles and more than six cycles of pre-ablative (or post-ablative) chemotherapy were compared with that of CLM patients without pre-ablative (or post-ablative) chemotherapy, respectively, to further investigate the impact of a different number of cycles of systemic chemotherapy on survival outcomes of CLM patients treated by PMWA. After the adjustment of baseline data (age, gender, primary tumour, node status, histology grade, character, number of CLM, maximum size of CLM, topography), there was no difference for PFS and OS between patients receiving one to six cycles of pre-ablative chemotherapy and those without pre-ablative chemotherapy (p = 0.279 and 0.114, respectively). And there was no difference for PFS and OS between patients receiving more than six cycles of pre-ablative chemotherapy and those without pre-ablative chemotherapy either (p = 0.070 and 0.112, respectively). However, more than six cycles of post-ablative chemotherapy significantly improved OS (p = 0.015, HR =0.416) for patients compared to those without post-ablative chemotherapy, but there was a comparable result for PFS between the two groups (P = 0.118). Moreover, one to six cycles of post-ablative chemotherapy did not obtain better PFS (p = 0.617) and OS (p = 0.240) for patients compared to those without post-ablative chemotherapy ().
Table 4. Multivariate analysis of the impact of different systemic chemotherapy cycles on progression free survival and overall survival.
Discussion
Almost 50% of CLM patients develop hepatic metastases in the course of their disease [Citation26]. Surgical resection with curative intention has gradually become the standard of treatment for resectable CLM, with 10-year survival rates as high as 25–26% and median survival 44–46 months [Citation5,Citation27]. However, the great majority of CLM patients are not eligible for surgical resection, and thus it is only a feasible choice in approximately 20% of patients [Citation28].
Compared to surgical resection, ablative therapies have many advantages including the potential application in a wider patient population, especially those who are not surgical candidates, or refuse surgery based on various reasons, and thus these kinds of procedures are applied more and more in clinical practice. So far, RFA is the most studied ablative therapy in the published literature. Long-term results of using RFA to treat CLM have been reported, the 5-year rates for OS were from 25–48.5% [Citation14,Citation16,Citation29–32]. Moreover, for small CLM (less than 3 cm), RFA achieved comparable survival outcome compared to hepatic resection [Citation32]. Currently, MWA ablation has been used more and more often in the management of CLM [Citation21,Citation22,Citation33,Citation34]. It was reported that intraoperative MWA achieved a lower local recurrence rate than intraoperative RFA (P < 0.01) [Citation35]. Another study also reported 100% technical success in treating unresectable hepatic metastases and the authors concluded that PMWA of liver metastases >3 cm or located near vessels (>3 mm) could be considered an effective and safe option [Citation36].
In a study involving 1136 patients, Liang et al. reported that the MWA-related death and major complication rates were 0.2% and 2.6%, respectively, and the authors concluded that MWA was a well-tolerated technique in view of the low rate of major complications in the treatment of malignant liver tumours [Citation22]. In our study, there was no PMWA procedure-related death, and incidence of major complication was 3.5%, which was comparable to previous reports [Citation21,Citation22].
In our study, the estimated 5-year rate of OS was 27.9% for all patients with full information of follow-up, and this was comparable to the previous result of a RFA-treated study which only included patients with solitary colorectal liver metastasis [Citation30].
The number and size of CLM have been proven to be prognostic factors for survival of CLM patients treated by RFA in previous studies [Citation32,Citation37–41]. However, the existing literature on prognostic factors following MWA of CLM, either intraoperative or percutaneous, is sparse [Citation42]. In our study, the number of CLM, maximum size, and topography were independent prognostic factors for PFS, while age, maximum size of CLM, and post-ablative chemotherapy were independent prognostic factors for OS.
In our study cohort, pre-ablative chemotherapy did not improve the PFS and OS of patients compared with patients without pre-ablative chemotherapy. Hamada et al. reported pre-ablative systemic chemotherapy was not associated with survival of CLM patients treated by RFA [Citation43]. Our result was also similar to those that were found in surgery-treated studies [Citation44–46]. Similar to the impact of preoperative chemotherapy on surgical resection of CLM, the importance of pre-ablative chemotherapy lies in its ability to assess the tumour response to chemotherapeutics, reduce the volume of the tumour, and treat systemic occult disease. However, pre-ablative chemotherapy might increase the potential risk of tumour progression during therapy and lead to chemotherapy-associated hepatotoxicity and complications. Some previous studies reported that preoperative chemotherapy was not associated with perioperative outcome, but was associated with hepatic injury that was regimen-specific [Citation47,Citation48]. Therefore, up to now the value of preoperative systemic chemotherapy on survival has been controversial. Although in our study pre-ablative chemotherapy was not associated with survival, definitive conclusion regarding its value cannot be reached by this study considering its retrospective nature. Large and prospective trials are needed to investigate the value of pre-ablative systemic chemotherapy on the survival of CLM patients treated by MWA.
In contrast, post-ablative chemotherapy significantly improved OS for CLM patients treated by PMWA (P = 0.046) in our study. Post-ablative adjuvant systemic chemotherapy could eliminate occult residual diseases which are common after ablation of the visible lesions in liver considering the high rate of local tumour recurrence [Citation43,Citation49,Citation50]. The fact that post-ablative systemic chemotherapy was a significant prognostic factor for survival outcome was observed in studies of CLM treated by RFA with or without surgical resection [Citation51,Citation52]. Similarly, previous studies in which CLM were treated by surgical resection have demonstrated that patients could benefit from post-operative adjuvant systemic chemotherapy [Citation45,Citation46,Citation53]. The result about the benefit of post-ablative chemotherapy in our study was similar to those of RFA-treated or surgery-treated studies [Citation45,Citation46,Citation51–53], further confirming the value of post-operative adjuvant systemic chemotherapy.
In further analysis of the efficacy of different numbers of cycles of systemic chemotherapy on survival outcome for patients with CLM, multivariate analysis showed that more than six cycles of post-ablative chemotherapy significantly improved OS (P = 0.015) compared with absence of post-ablative chemotherapy, but there was a comparable result on PFS between the two groups (P = 0.118). So, in our study, PMWA plus more than six cycles post-ablative chemotherapy was the optimal combining treatment strategy. In a study involving 89 patients with 132 liver metastases, Liu et al. [Citation54] reported that more than six cycles of post-ablative chemotherapy was the independent prognostic factor for overall recurrence. But their study cohort only included 38 colorectal cancer patients. Also, patients were treated by RFA or MWA. Therefore, it is difficult to evaluate whether number of cycles of systemic chemotherapy affected survival outcome of CLM patients in their study. To our knowledge, in our present study it was the first time that the impact of the number of cycles of systemic chemotherapy on survival of patients treated by MWA was assessed. As MWA is applied more and more to treatment of CLM, it is important to comprehend the added value of systemic chemotherapy on MWA in order to formulate an optimal combined treatment plan of MWA and systemic chemotherapy.
An important limitation of our study is its retrospective design. It lacks a comparison with other therapy methods. Second, analysis of more long-term outcome is prevented due to limited duration of patient follow-up. The third limitation is that the analysis did not include the addition of targeted drugs. The reasons included a small number of patients accepted the addition of targeted drugs and survival benefit from additional targeted drugs is controversial because though most studies showed that the addition of targeted drugs could improve survival in metastatic colorectal cancer patients compared to standard chemotherapy alone, recent important randomised controlled trials indicated that it failed to extend survival of metastatic colorectal cancer patients [Citation55,Citation56]. A large, multi-institutional randomised-controlled study is required to make the result of this study more convincing and to make it the standard of care for patients treated by MWA.
In conclusion, despite these limitations, we demonstrated in this study that CLM patients receiving more than six cycles of post-ablative chemotherapy achieved better OS than those without post-ablative chemotherapy. Therefore, we concluded that PMWA plus more than six cycles of post-ablative chemotherapy was the optimal combining treatment strategy in this study. And, PMWA was a safe procedure with no mortality and a low rate of major complications. These results are promising and serve as a foundation for future large, multi-institutional randomised-control trial to further explore the impact of systemic chemotherapy on survival in order to determine an optimal combination treatment plan of MWA and systemic chemotherapy in the management of CLM.
Disclosure statement
This study was supported by the Ministry of Science and Technology Support Program (grant no. 2013BAI01B01) and the National Natural Science Foundation of China (grant no. 81430039 and 81127006).
No conflict of interest exits in the submission of this manuscript. The authors alone are responsible for the content and writing of the paper.
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