A pilot study of chemical ablation of peripheral non-small-cell lung cancer: a novel, effective, safe, and inexpensive method

Introduction Chemical ablation with acetic acid or ethanol is effective against hepatocellular carcinoma and therefore its application in peripheral non-small-cell lung cancer (NSCLC) may be beneficial. Aim The aim of the study was to assess the efficacy and safety of percutaneous chemical ablation using acetic acid or ethanol in peripheral NSCLC cases. Patients and methods This was a prospective randomized control study conducted at the Chest and Clinical Oncology Departments, Mansoura, Egypt, from 2011 to 2014. Thirty-three patients were included with a mean age of 60 years, and were randomly divided into three groups: group A (acetic acid plus chemotherapy group) consisted of nine patients; group B (ethanol plus chemotherapy group) consisted of nine patients; and the control group C (chemotherapy alone group) consisted of 15 patients. Patients who were operable, who had tumors infiltrating the main stem bronchi or mediastinum, and those who refused to complete the study were excluded. Clinical and radiological data were evaluated before treatment and 3 and 6 months after treatment. Results There was a significant reduction in both cough score and chest pain in group A after 6 months of treatment, in the hemoptysis score in group A and group B after 6 months of treatment, and in dyspnea score in groups A and B after 3 and 6 months of treatment. There was a statistically significant difference in the tumor response results in both groups after 3 and 6 months of treatment when compared with the control group. There were one or more immediate complications but all were controllable with no mortality. Survival was better in groups A and B than in the control group. The cost of acetic acid and ethanol palliation for each patient was 10 $US. Conclusion Chemical ablation is an effective and inexpensive adjuvant palliative treatment for patients with inoperable peripheral NSCLC.


Introduction
Lung cancer remains one of the leading causes of cancer-related mortality [1]. Approximately 75% of patients with lung cancer presented with locally advanced or metastatic disease at the time of diagnosis [2]. Surgery carries the most favorable response, but in inoperable patients tumor debulking increases survival using multiple modalities in the management of peripheral lung cancer [3].
Introduction Chemical ablation with acetic acid or ethanol is effective against hepatocellular carcinoma and therefore its application in peripheral non-small-cell lung cancer (NSCLC) may be beneficial.
Aim The aim of the study was to assess the efficacy and safety of percutaneous chemical ablation using acetic acid or ethanol in peripheral NSCLC cases.

Patients and methods
This was a prospective randomized control study conducted at the Chest and Clinical Oncology Departments, Mansoura, Egypt, from 2011 to 2014. Thirty-three patients were included with a mean age of 60 years, and were randomly divided into three groups: group A (acetic acid plus chemotherapy group) consisted of nine patients; group B (ethanol plus chemotherapy group) consisted of nine patients; and the control group C (chemotherapy alone group) consisted of 15 patients. Patients who were operable, who had tumors infiltrating the main stem bronchi or mediastinum, and those who refused to complete the study were excluded. Clinical and radiological data were evaluated before treatment and 3 and 6 months after treatment.

Results
There was a significant reduction in both cough score and chest pain in group A after 6 months of treatment, in the hemoptysis score in group A and group B after 6 months of treatment, and in dyspnea score in groups A and B after 3 and 6 months of treatment. There was a statistically significant difference in the tumor response results in both groups after 3 and 6 months of treatment when compared with the control group. There were one or more immediate complications but all were controllable with no mortality. Survival was better in groups A and B than in the control group. The cost of acetic acid and ethanol palliation for each patient was 10 $US.
(start of chemical ablation plus chemotherapy or chemotherapy alone). Follow-up was done by monthly visits during the first 6 months and then by phone for 2 years. The patients were randomly selected using the closed envelop method.

Patients and methods
This study was carried out at the Chest Medicine and Clinical Oncology and Nuclear Medicine Departments, Mansoura University Hospitals, during the period from April 2011 to May 2014. The study included 38 patients (31 men and seven women); only 33 of them completed the study (28 men and five women) with peripheral NSCLC of different pathological subtypes (18 with adenocarcinoma, 11 with squamous cell carcinoma, and four with large cell carcinoma). Their ages ranged from 40 to 76 years, with a mean of 60.10 ± 7.82 years.
Ethical approval had been obtained from the Medical Research Ethics Committee of the Faculty of Medicine, Mansoura University. Patients signed written consent forms after receiving a detailed explanation of the study protocol.

Inclusion criteria
This study included symptomatic patients with peripherally situated NSCLC of any histological type who were not candidates for surgery (inoperable or unfit; they were excluded if they became operable or fit because of downstaging) or radiotherapy. Patients must be fit for chemotherapy with adequate bone marrow reserve, such as white blood cell count greater than 3500/mm 3 , neutrophil count greater than 1800/mm 3 , hemoglobin greater than 10 g/dl, and hematocrit value greater than 30%.

Exclusion criteria
Operable patients, those with tumors infiltrating the main stem bronchi or the mediastinum, patients with small-cell lung cancer, with lung metastasis, patients who refused to be included or to complete the study, patients with pleural effusion on the same side of the peripheral lung cancer, those with uncorrectable bleeding diathesis, patients with creatinine greater than 1.5 mg/dl and FEV 1 less than 35% of the predicted value, and patients unfit for chemotherapy were excluded from the study.
The study started with 38 patients, but only 33 completed the study. In group A, 12 patients started the study but only nine completed, and in group B 11 patients started the study and only nine of them completed. The patients dropped out of the study because of immediate complications such as chest pain, hemoptysis, dry irritative cough, or shortening of breath during the technique.
All patients were diagnosed using computed tomography (CT) and/or ultrasound (US)-guided biopsy with an 18-G tru-cut needle, randomly selected for the treatment method using the enclosed envelop method, and subjected to the following: (1) Clinical evaluation: Thorough medical history with stress on cough, hemoptysis, dyspnea, and chest pain. The four symptoms were scored before the start of treatment and 3 and 6 months after the first session of chemical ablation and chemotherapy. Cough was evaluated according to Belfiore et al. (2004) [8] as no cough (0), intermittent cough (1), and persistent cough (3). Hemoptysis was evaluated according to VanKralingen et al. (1995) [9] as no hemoptysis (0), blood streaked (1), less than 20 ml/day (2), 20-200 ml/day (3), and 600/day or at least 150 ml in a single attack (4). Dyspnea was evaluated according to the mMRC scoring for dyspnea [10] and chest pain scoring according to the McGill Pain Questionnaire [11] as none (0), mild, requiring no medications (1), discomforting, requiring mild analgesics (2), distressing, requiring strong analgesics (3), horrible, requiring narcotic analgesics (4), and excruciating, not responding to narcotic analgesics (5). Performance status was evaluated using the Karnofsky performance scale according to Muers (2001) [12]. CT of the chest was performed in the following sequence: (a) First chest CT for staging and biopsy with CT-guided tru-cut biopsy. (b) Second and third follow-up chest CT scans after 3 and 6 months from the start of chemical ablation.
(1) The size of the tumor was measured according to its largest diameter and the radiological response to treatment was assessed according to the modified response evaluation criteria in solid tumors (RECIST) ( Table 1).
Pelvic-abdominal ultrasonography, CT of the abdomen, CT of the brain and bone scan were performed for evaluation of distant metastasis before starting the study and at 6 months as an endpoint of the study.
(4) Fiberoptic bronchoscopy was performed for all cases once, at the time of diagnosis for evaluation of the bronchial tree and for staging. (5) Staging was done according to the seventh TNM staging system for NSCLC as per Goldstraw et al. [14], before the start of treatment. (6) Chemical ablation was performed according to the technique of Shiina et al. [15]. The volume of absolute ethanol of 99.5% concentration was calculated using the formula V = 4/3π(r + 0.5) 3 and the volume of injected acetic acid of 30% concentration was calculated according to the formula V = 1/3{4/3π(r + 0.5) 3 }, where V is the target volume of ethanol, r is the maximum radius of the lesion (in ml), and 0.5 is the correction for the additional 'surgical margin' [16]. The ablation was scheduled for multiple injection sessions, 10 ml once weekly, and the number of ablation sessions varied according to the size of the tumor mass and radiological response. O 2 saturation with pulse oximetry and ECG was monitored before, during, and 24 h after the procedure. After sterilization of the skin with povidone iodine and alcohol, 2-5 ml of 2% lidocaine was injected to anesthetize the skin and subcutaneous tissue, muscles, and pleura along the assumed track of entry. The ablation procedures were guided with CT or US using a 3.5 MHz probe by free-hand technique and the dose was injected slowly over 20 min using a 18-G spinal needle with a single end bore. By varying the length and rotating the needle, the ablative agents were widely distributed within the tumor. The injection was performed from the deep portions to more superficial portions of the tumor mass. Injection was stopped when: (a) A homogenous perfusion of the lesion was observed, (b) A strong resistance to injection was felt, (c) Or when the ablative agent was seen to spill outside the lesion. Then 1-2 ml lidocaine 2% was injected before needle removal. (7) Chemotherapy protocol: Chemotherapy was continued during the ablation treatment. All patients were treated with cisplatin 75 mg/m 2 on day 1 plus gemcitabine 1250 mg/m 2 on days 1 and 8 every 3 weeks [17]. Cisplatin was administered on day 1 through intravenous infusion over ∼120 min. Gemcitabine was administered on days 1 and 8 through intravenous infusion over ∼30 min. Patients after first-line therapy and with sufficiently good performance score were treated with second-line chemotherapy with docetaxel at 75 mg/m 2 on day 1 every 3 weeks intravenously as a 1-h infusion.

Statistical analysis
Data were analyzed using SPSS (Statistical Package for Social Sciences), version 15 (International Business Machines Corporation, New York, USA). Qualitative data were presented as number and percentage. Comparison between groups was done by means of the χ 2 -test. Quantitative data were presented as mean ± SD. The Student t-test was used to compare between two groups. P value less than 0.05 was considered statistically significant.  The laboratory tests for complete blood count, liver function, and kidney function were within normal values (Fig. 1).

Group
There was no statistically significant difference between the three groups as regards the median of symptom scores for cough, chest pain, hemoptysis, and dyspnea before the treatment, and all patients were symptomatic. There was a statistically significant reduction in cough score, chest pain, hemoptysis, and dyspnea in both group A and group B (3 and 6 months after treatment vs. before treatment). When compared with the control group, there was a significant reduction in both cough score and chest pain in group A after 6 months of treatment. There was a statistically significant reduction in hemoptysis score in group B after 6 months of treatment and there was a significant reduction in dyspnea score in groups A and B after 3 and 6 months of treatment.
As regards the Karnofsky scale, there was a significant improvement from 63 to 72 in group A (P = 0.009) and an improvement from 65 to 74 in group B 6 months after treatment when compared with that before treatment (P = 0.035), and there was a statistically significant difference in group A versus the control group after 6 months of treatment (P 2 = 0.006) and in group B versus the control group after 6 months (P ≤ 0.001).
The radiological size of the tumor was 27.21 ± 15.74 in group A, 27.21 ± 15.74 in group B, and 31.67 ± 12.06 in group C. In group A, imaging was performed with US in four patients, with CT in four patients, and with both US and CT in one patient. In group B imaging was performed with US in two patients, CT in six patients, and with both US and CT in one patient.
Comparison between clinical symptoms in the three groups before and after treatment. Data are presented as median.  There were many immediate complications such as chest pain, hemoptysis, dyspnea, wheezes, cough, and pneumothorax, all of which were controlled without ICU admission and no mortality.
Distant metastasis developed in one patient (11.1%) of group A, in two patients (22.2%) of group B, and in five patients (33.3%) of group C. There was no statistically significant difference in tumor metastasis between the three groups.
The 2-year survival rate was 13 patients (72%) in both group A and group B and five patients (33%) in the control group, which was statistically significant (P = 0.025).

Discussion
Percutaneous chemical ablation with acetic acid injection in 15-50% concentration has stronger necrotizing power compared with pure ethanol [18] and may be equally effective or even superior to ethanol injection in treating small hepatocellular carcinoma [19]. Acetic acid is superior to ethanol in treating tumors with resistance to perfusion with ethanol [7].
To our knowledge, this is the first study to evaluate the safety and efficacy of percutaneous image-guided chemical ablation (acetic and ethanol injection) of peripheral NSCLC.  As regards the clinical response, our results were in agreement with those of Huang et al. [6], who studied nine patients with malignancies and pleural or chest wall invasion who were treated with percutaneous ethanol injection; they reported a significant reduction in cough score, chest pain (relieved obviously and pain degree reduced to 0-3), hemoptysis, and dyspnea after 6 months. These results were in agreement with other studies who used another ablative therapy in the treatment of NSCLC: El-Badrawy et al. [21] studied 25 patients, 10 of them were treated with combined radiofrequency ablation (RFA) and chemotherapy and they reported a significant reduction in cough score from 1.9 to 0.2 6 months after treatment. Those results were in agreement with the findings of Belfiore et al. [8], who studied 32 patients with unresectable primary lung cancer treated with RFA alone and reported reduction of cough score from 1.5 to 1 after 6 months of treatment. In our study, a significant decrease in symptom scores (cough, chest pain, hemoptysis, and dyspnea) was seen, which may be due to greater reduction of tumor size in both groups compared with the control group.
As regards the Karnofsky scale our results were in agreement with Huang et al. [6], who reported improvement in Karnofsky performance score, which was over 90, and with the results of El-Badrawy et al. [21], who reported a significant increase in the Karnofsky scale versus the control group 6 months after treatment after radiofrequency abation (P ≤ 0.001). Improvement in Karnofsky performance scale, which is a measurement of performance status, may be due to reduction in tumor burden. Further, performance status is the single best factor for identifying individuals who can tolerate and benefit from chemotherapy.
There was a statistically significant difference in CT morphological changes in group A and group B after 3 months of treatment when compared with the control group (P = 0.001 and 0.003, respectively) ( Table 2). These results were in agreement with those of Lee et al. [22], who studied 24 patients with NSCLC who were subjected to RFA and reported CT changes 3 months after treatment: central necrosis without cavitation was reported in eight patients (80%), of which two progressed to solid mass at 6 months' follow-up; necrosis with cavitation was reported in two patients (20%), which persisted at 6 months' followup. Our results were also in agreement with Bojarski et al. [23], who studied 26 patients with NSCLC treated with RFA and reported that cavitation occurred in 31% of the tumors imaged 3 months after treatment. These cavitated lesions did not become a site for infection and there was no need for long-term antibiotics on follow-up.
There was a statistically significant difference in tumor response in groups A and B after 3 months of treatment when compared with the control group (P = 0.004 and 0.036, respectively). There was a statistically significant difference in tumor response in groups A and B after 6 months of treatment when compared with the control group (P = 0.016 and 0.062, respectively) ( Table 3). These results were in agreement with those of Huang et al. [6], who reported a significant reduction in tumor size and better local control, and also in agreement with the finding of Yang-Kui et al. [24], who reported a reduction in the size of 31 lesions out of 37 lung metastatic lesions in 17 patients who received intratumoral ethanol injection on lung metastasis from liver cancer. Our results were also in agreement with the findings of Masaki et al. [25] who reported a reduction in tumor size in three out of five patients with lung cancer who were injected intraoperatively with ethanol directly into the tumor by grasping the lung including the tumor.
As regards the immediate complications of chemical ablation (Table 4), chest pain was controlled by assurance and with paracetamol as a mild analgesic agent. Hemoptysis varied between being blood streaked to being less than 20 ml, and was stopped within 6 h with hemostatic drugs. Seven patients of group A developed wheezy chest; six of them had mild dyspnea. In group B, six patients developed wheezy chest; two of them had mild dyspnea and were relieved with inhaled salbutamol. Pneumothorax was recorded in two patients (22%) in group A and in one patient (11%) in group B. One of them resolved spontaneously with oxygen therapy and two patients were managed with intercostal tube drainage accompanied by surgical emphysema. These results were in agreement with those of Yang-Kui et al. [24] who studied 17 patients who received CTguided intratumoral dehydrated ethanol injection on lung metastasis from liver cancer; pneumothorax was reported in two patients with lung compressed by less than 30%, which self-restored 3 days after pneumothorax drainage. These results were different from those of Zhu et al. [26], who performed 129 RFA sessions in 100 patients with inoperable lung tumors and reported pneumothorax in 32% of treatment sessions, as well as pleuritic chest pain (18%), hemoptysis (7%), pleural effusions (12%), and chest drain insertion (20%). The difference between the current study and the above listed studies as regards the rate and type of complications following chemical ablation may be due to the difference in the number of included patients in each study, difference in the skill of the operator, difference in site or size of the tumor, or difference in the ablative techniques used.
In the current study, distant metastasis was reported in one patient (11%) in group A, in two patients (22%) in group B, and in five patients (33%) in the control group 6 months after treatment. This was less than that reported by Ambrogi et al. [27] who studied 30 NSCLC cases treated with RFA and reported distant metastasis in 39% of patients at a mean follow-up period of 23.7 months. The difference between the current study and the other study may be the difference in the length of the follow-up period or the number of studied cases.

Conclusion
Chemical ablation is an effective and cheap adjuvant palliative treatment for systemic chemotherapy in patients with inoperable peripherally located NSCLC with tolerable nonserious complications, and it prolongs the longevity of patients.

Financial support and sponsorship
Nil.