Introduction

Local ablation techniques are widely used in adults for the treatment of both benign and malignant lesions [1–5]. They can be divided, depending on the mechanism they use to cause injury, into thermal therapies such as radiofrequency ablation, percutaneous cryoablation, microwave ablation and interstitial laser thermotherapy; chemical ablative techniques, typified by percutaneous ethanol injection, and irreversible electroporation, which alters the electrical conductivity and permeability of the cell membrane by means of high-voltage pulses, causing both cellular disruption and thermal damage [6]. In some cases, these techniques are included in the algorithms of treatment of oncological diseases at the same level as more aggressive techniques such as surgical resection [7], in others they represent an alternative to surgery in patients who are not candidates for resection due to high anesthetic risk or other circumstances [2, 3, 5]. These techniques may also have an impact on the immune system of patients by activating a tumor-associated antigen-specific T cell response [8–10]. Local ablation can be carried out with curative or palliative intent, either alone or in combination with systemic (immunotherapy or chemotherapy) [11] or locoregional therapies (radiotherapy or chemoembolization) [5, 12]. The effect of systemic chemotherapy may be enhanced by the physiological changes produced by thermal ablation [11]. Furthermore, ablation can sometimes be used as a complement to surgery, individualizing the treatment for each lesion in a single patient [13]. These treatments have been applied to tumors located in almost every organ in the human body including the liver, kidney, lung, musculoskeletal system and pancreas [1–13]. Although thermal ablation is widely regarded as the treatment of choice for osteoid osteoma in extraspinal locations [14] and thermal and chemical ablation techniques have been used for thyroid or benign vascular tumors, among others [15, 16], the use of these techniques still remains exceptional in children with malignancy. In this systematic review we aim to report the techniques and results of ablation for solid malignant or borderline tumors in children.

Materials and methods

We limited the search start to 1995, as the application of these techniques was infrequent even in adults before then. No language restriction was applied. We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement (http://www.prisma-statement.org/statement.htm). We performed a search in MEDLINE including the terms: (radiofrequency) OR (microwave) OR (percutaneous ethanol) OR (interstitial laser) OR (irreversible electroporation) OR cryoablation NOT (osteoid osteoma) AND (malignan* OR tumor). For each paper we extracted: title, authors, year of publication, journal name, type and subtype of journal (medical, surgery, radiology or others and general or pediatrics), type of study, strength of evidence according to the Oxford Centre for Evidence-based Medicine, number of patients (including only those <18 years), mean of time to progression (time from inclusion to radiological progression), mean of time to recurrence (time from inclusion to recurrence), mean time of overall survival (time from inclusion to death) and mean lesion diameter or volume. For each individual patient we recorded: age, sex, body mass, type of tumor (histology), nature of diagnosis (primary or metastatic), size of tumor (diameter or volume), location, other treatment after ablation, ablation technique (radiofrequency ablation, microwave ablation, percutaneous cryoablation, percutaneous ethanol injection, irreversible electroporation, interstitial laser thermotherapy), electrode size, anesthesia type (general [GA], local with or without sedation), number of lesions, number of ablation sessions, guidance technique (US, MRI, CT, fluoroscopy), technical success (proper positioning of the ablation device into the target area with completion of the planned treatment), clinical success (accomplishing clinical goal of ablation), duration of hospitalization following ablation, overall survival, complications and status at the end of the study (died of disease - DOD, alive with evidence of disease – AWED, or no evidence of disease – NED). Abstracts were screened to identify the relevance of the retrieved reports. Further screening of cited references was undertaken to detect any studies that may have been missed from our initial search. Two reviewers independently extracted data from all studies onto a predefined data collection form. Any discrepancies were resolved by consensus among four of the authors (D.J.R, S.S., P.A.P, F.G.M). Due to the small number of studies reporting results of ablation in children, we aimed to include every case describing the use of the techniques stated above for malignant and locally aggressive tumors. We reviewed the resulting cases according to the target organ ablated (liver, lung, bone and/or soft tissues, and kidney or pancreas).

Results

Adding the exception of the Hoffer et al. paper [17], which is a phase I study, relevant data was missing for many of the reported cases. The age was reported in all cases. The mean age of the 28 patients identified was 9 years (range: 1 day to 17 years). The sex was reported in 18 patients (64%), 13 females and 5 males. Body mass was reported in only 5 of the 28 patients (18%), with a median of 16 kg (range: 13–41 kg). The histology of all tumors was reported: osteosarcoma in 6 patients (21%), Wilms tumor in 3 (11%), rhabdomyosarcoma in 3 (11%), hepatoblastoma in 3 (11%), desmoid tumor in 3 (11%), adrenocortical carcinoma in 2 (7%) and leiomyosarcoma, Ewing sarcoma, paraganglioma, solid-pseudopapillary neoplasm, sacrococcygeal teratoma, hepatic adenoma, juxtaglomerular cell tumor and plantar fibromatosis in 1 case each (3%). The nature of the lesion (primary, recurrent or metastatic) was reported in 28 of the 29 locations ablated (96%). Among the 29 locations treated, according to chronology, there were primary tumors in 11 cases (38%), local recurrence in 4 cases (14%) and metastases in 12 cases (42%). The diameter or volume of the ablated lesions was described in 26 of the 28 patients (92%). The paper describing the most patients [17] did not list the individual size of the 56 lesions treated, but reported a range from 0.13 ml to 750 ml (median: 7 ml; mean: 46 ml). In the 14 remaining patients the diameter ranged from 8 mm to 170 mm (median: 18 mm; mean: 45 mm). We identified 28 patients treated by means of ablation in 29 regions (one of the patients underwent both lung and bone radiofrequency ablation). Five patients underwent liver ablation (18%), 9 patients lung ablation (32%), 11 patients bone and/or soft-tissue ablation (39%) and 4 patients underwent kidney or pancreas ablation (14%). After the 29 ablations, the need for additional treatment was explained in 28 cases (97%): In 14 cases (50%) the patients did not need further treatment and in 16 cases systemic chemotherapy alone or together with surgery, surgery alone or together with embolization, or radiotherapy (conventional or brachytherapy) were used. The technique was radiofrequency ablation in 26 cases (90%), percutaneous cryoablation in 2 (7%) and percutaneous ethanol injection in 1 (3%). Excluding the patient treated by means of percutaneous ethanol injection, the type of cryoprobe or electrode needle and size was reported in 15 cases (54%). The anesthetic technique was GA in 28 cases (97%) and local anesthetic with sedation in 1 (3%). The total number of ablated lesions was 65 (median: 2) in 92 ablation sessions (median: 3). In Hoffer’s [17] series the median hospital stay was 3 days (range: 2-25 days). Survival was reported for 26 of the 28 patients (93%), with mean overall survival of 22 months (median: 18 months; range: 0.7-96 months).

Bone and soft-tissue ablations (Table 1)

Table 1 Reported ablation of malignant or aggressive benign bone and soft-tissue tumors in children
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We identified 11 patients who underwent bone and soft-tissue ablation in six papers [17–22]. The mean and median age of the patients was 10 years. Four were female and two male, and in five patients the sex was not reported. The weight was only reported in one patient, who weighed 41 kg. The histology of the tumors was rhabdomyosarcoma in three patients, desmoid tumor in two and leiomyosarcoma, paraganglioma, osteosarcoma, Ewing sarcoma, plantar fibromatosis and teratoma in one each. The location of the ablation was soft tissue in six patients (presacral, breast, tensor fascia lata, lumbar muscles, oral cavity and plantar fascia) and bone in five (maxilla, radius, femur, ribs and sacrum). In four cases, the tumors were primary; in two local recurrences, in two metastases and for three patients the nature of the lesion was not reported. The mean of the reported diameters of the ablated lesions was 70 mm, and in six cases the size was not reported. A total of 17 lesions were ablated in 32 sessions. Four patients received additional systemic therapy (chemotherapy in three and antiviral therapy in one), one with additional embolization. Two patients were treated with additional regional therapy (embolization and radiotherapy) without systemic therapy. Except for four patients (one percutaneous cryoablation and three radiofrequency ablation), the type of needle used in the procedure was not reported. All of the treatments were performed under GA and except for one patient (with Ewing sarcoma undergoing percutaneous cryoablation) the ablative technique used was radiofrequency ablation. In six cases, the guidance technique was CT; in four, CT and US were combined, and in one case, US was the only modality used. Technical success was achieved in nine cases. Clinical success was obtained in eight patients. The outcome was unreported in one. The duration of post-ablation hospitalization was only specified in two cases (both less than 1 day). Mean overall survival of the patients for whom this data was reported was 15 months (median: 12 months). Eight patients suffered a complication, but only two needed additional active treatment (surgery). Recurrence or progression was observed in five patients and complete tumor ablation in another five: in one case it was not documented. At the time of the reports, five patients were NED, three DOD and three were AWED.

Ablation of lung metastases (Table 2)

Table 2 Reported CT-guided radiofrequency ablation (RFA) of lung metastases in children
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Nine patients reported in two papers underwent radiofrequency ablation for lung metastases [17, 23]. The mean age of the patients was 11 years (median: 12 years). The sex and body mass were only reported in one case, a 4-year-old boy weighing 12.8 kg. The histology of the primary tumors was osteosarcoma in six, Wilms tumor in one, adrenocortical carcinoma in one and hepatoblastoma in one. The diameter of the metastases was not specified in any of the cases, but the mean volume in the eight children reported by Hoffer et al. [17] was 5 ml. However, this volume includes the excluded patients due to be older than 17 years old that could not be excluded to extract the real volume of the included patients. A total of 34 lesions (mean: 4 per patient) were treated in 45 sessions (mean: 5; median: 3). Five patients received additional chemotherapy (two of them accompanied by surgery), one underwent radiotherapy and three did not receive any other treatment. All of the treatments were CT-guided radiofrequency ablation, performed under GA. Clinical success was reported for two patients and achieved in one with adrenocortical carcinoma. Forty-five percent of the lung lesions ablated in the Hoffer’s paper [17] were completely ablated after the first-time treatment with no recurrence, but again, patients older than 17 years of age could not be excluded to extract the real volume of the included patients. The length of stay in the hospital was not reported in any of the treatments. The mean overall survival of the patients was 19 months (median: 13 months). All the patients suffered complications caused by the lung radiofrequency ablation: FEV1 reduction and diaphragmatic hernia in two patients each, and pain, hypoxia, bradycardia, dyspnea and bronchovascular fistula with hemorrhage in one patient each. The treatment of the complications was surgical in two patients. In the patient with bronchovascular fistula, there was an attempt to coagulate a hemorrhage with the radiofrequency ablation needle. Supportive care was sufficient in five cases, and there was no need for treatment in the patient with FEV1 reduction. There was recurrence in one patient and progression in two. At the time of reporting, seven patients were DOD, one was AWED and one was NED. Cryoablation of lung metastases has not yet been reported in children.

Liver ablation (Table 3)

Table 3 Reported ablation of liver tumors in children
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Five patients underwent liver ablation [13, 24–26]. Mean age was 4 years (median: 3 years). Three patients were female and two male. The weight was only reported for one patient (12.6 kg). The histology was hepatoblastoma in two patients, and adrenocortical carcinoma, hepatic adenoma and Wilms tumor in one each. There were two primary tumors, two metastases and one local recurrence. The diameter was reported in four cases (mean: 19 mm). Seven lesions were ablated in seven sessions. US was the image guidance (in two cases it was intraoperative) and technical and clinical success was achieved in all five cases. Mean overall survival was 44 months (median: 36 months). There were no complications and except for one patient with unreported data, no progression or tumor recurrence was described. All five patients were NED at the time of reporting.

Kidney or pancreas ablation (Table 4)

Table 4 Reported ablation of renal and pancreatic lesions in children
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Four patients were treated with ablation for retroperitoneal tumors [27–30]. The mean age was 11 years, and all patients were female. The weight was only reported in one case (16 kg). The histology was Wilms tumor in two, juxtaglomerular cell tumor in one, and solid and papillary epithelial neoplasm of the pancreas in one patient. The ablation was performed in the kidney (2), surgical bed following nephrectomy (1) and pancreas (1). In each case the tumor was primary, except for one patient with local recurrence of Wilms tumor [28]. The median diameter of the ablated lesions was 18 mm. The diameter was unreported in one patient [28]. All of the lesions were treated with radiofrequency ablation, and in all the cases the electrode size and type were reported. A total of five lesions were ablated in six sessions. One patient subsequently received brachytherapy [28] and another surgery due to failure of the radiofrequency ablation [29]. In all the treatments GA was used; image guidance was CT in three and intraoperative US in one. Technical success was accomplished in all four cases. Clinical success was obtained in three patients. The duration of hospitalization was only specified for one procedure (1 day) [27]. Mean overall survival was 12 months. Only one patient suffered a complication (abdominal pain), but this did not require treatment. Recurrence or progression was observed in one patient. At the time of the reporting, two patients were NED, one was AWED and one had died of another cause (leukemia).

Discussion

As expected, there is very limited experience with ablation in children. Even though the manuscript summarizes the overall experience, it may not provide significant help in decision-making for surgeons/interventional radiologists to decide appropriate use of ablation use in children. The number of cases and pathology treated with these techniques is also small to draw conclusions about efficacy of ablative techniques in pediatric pathology.

This systematic review confirms that ablative therapies are feasible in children with primary, recurrent or metastatic tumors in various organs. Most reports implicitly describe treatment with palliative intent in patients that in many cases have failed to respond to almost every other available therapy. This selection for poor candidates may contribute to a failure to achieve similar results to those observed in adults.

Because pediatric cancer is relatively rare, and indications for ablative therapies are few, the only way to evaluate individual modalities in specific clinical situations will be to develop multicenter international studies.

It is notable that many published cases are poorly described, in terms of both the technical aspects of the procedures and the clinical outcomes. These deficiencies should be addressed in future research studies. To this end, we propose a minimum data set for future reports (Table 5). These include recommended data to improve the quality of the reported cases and to facilitate their interpretation in future systematic reviews and meta-analysis about pediatric tumor ablation. These data concern:

Table 5 Required data for reporting local ablation for cancer
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  • The patient (age, sex, weight, target organ function tests, pain evaluation pre- and post-procedure, quality of life assessment).

  • The tumor (tumor histology, tumor location including possible factor reducing efficacy, tumor chronology, tumor volume, tumor markers).

  • The technique (clinical indication and clinical success definition, technical success definition, ablated volume, neoadjuvant or adjuvant therapies, type and size of electrode or antenna or probe, energy generated, ablation protocol, image guidance technique, number of lesions treated, number of treatments for every lesion in a single session, number of sessions in a single lesion, complications and its level by OMS/SIR classification, hospitalization length, image follow-up technique, response criteria [response evaluation criteria in solid tumors, modified response evaluation criteria in solid tumors, criteria of the European Association for the Study of the Liver] response classification).

  • The cancer-related relevant endpoints (time follow-up, overall survival, disease-free survival, time to recurrence, time to progression, time to local recurrence, event-free survival, progression-free survival).

Conclusion

Although ablative techniques are feasible and promising treatments for certain pediatric tumors, large multicenter prospective trials will be needed to establish efficacy. As ablation procedures for malignant tumors in children are infrequent, reporting data in a structured way becomes an essential instrument to perform analysis in future systematic reviews.