Abstract
Background:
This study investigated the efficacy and complications of microwave ablation in combination with chemotherapy in treating peripheral IIIB-IV non-small cell lung cancer (NSCLC).
Materials and Methods:
A total of 100 patients with peripheral IIIB-IV NSCLC were randomly divided into two groups: combination group (n = 52) and chemotherapy group (n = 48). Patients in the combination group were treated with microwave ablation, radiotherapy, and chemotherapy, whereas the patients in the chemotherapy group were treated with pemetrexed disodium or gemcitabine hydrochloride, cisplatin chemotherapy, and conventional radiotherapy.
Results:
The effectiveness and disease control rates were significantly higher in the combination group than in the chemotherapy group (p < 0.05). The second- and third-year survival rates were significantly higher in the combination group than in the chemotherapy group (p < 0.05). However, patients in the combination group had no serious complications, and there were no intraoperative and perioperative deaths.
Conclusions:
Microwave ablation is safe and effective. Combination chemotherapy is superior to chemotherapy in treating peripheral IIIB-IV NSCLC in terms of effectiveness rate, disease control rate, and extended patient survival time.
Introduction
Malignant tumors rank first in terms of incidence rate and death rate. 1 In 2015, 733,000 newly developed lung cancer cases and 610,000 deaths were reported in China, indicating an upward trend year by year. 2 Furthermore, more than 80% of patients with lung cancer have non-small cell lung cancer (NSCLC). However, most patients have advanced disease at the time of diagnosis, and so they lose the opportunity for surgical treatment. 3 Thus, chemotherapy has become the main approach to treating advanced NSCLC. 4 At present, the main treatment for advanced NSCLC involves a platinum-based dual-drug combination regimen. This regimen's effective local rate is 20%–35%, with its 1- and 2-year survival rates reaching 30%–38% and 11%–15%, respectively. 4
However, since most patients start chemotherapy at an advanced stage, the tumor has already widely metastasized. Furthermore, these patients have developed cachexia and other symptoms that are unsuitable for long-term chemotherapy and have minimal efficacy. 5 In addition, although the efficacy of concurrent radiotherapy and chemotherapy has improved, this progress is barely satisfactory. 6 Due to the cumulative effect of adverse reactions of concurrent radiotherapy and chemotherapy, the majority of patients cannot continue their treatment and face rapid disease progression due to intolerance or other reasons, 6 hence the need for a new combination of chemotherapy regimens.
Microwave ablation for lung cancer is a new local treatment approach. Microwave ablation employs two frequencies, 915 and 2450 MHz, with the latter being more common. Under the action of the microwave electromagnetic field, water molecules, protein molecules, and other polar molecules in the tumor tissue produce extremely high-speed vibrations, resulting in mutual collisions and mutual frictions between the molecules. A high temperature of 60°C −150°C is generated in a short period, resulting in cell coagulation and necrosis. 7 –9
Since the local thermal ablation for lung cancer was first reported in 2000, the number of patients treated by microwave ablation has rapidly increased. 10 Microwave ablation has the advantages of rapid warming, high intratumoral temperature, short operation time, direct effect, wide ablation range, and less damage to the surrounding healthy lung tissues. 11 However, the efficacy and safety of microwave ablation in combination with chemotherapy in treating advanced NSCLC still requires further investigation.
This study investigates the clinical efficacy, complications, and adverse reactions of microwave ablation in combination with chemotherapy in treating peripheral IIIB-IV NSCLC. This research is hoped to provide a theoretical basis for the rational application of microwave ablation for treating NSCLC.
Materials and Methods
General data
This study included 100 patients with peripheral IIIB-IV NSCLC, who were treated in the authors' department from August 2016 to August 2018. Among these patients, 56 patients were male, 44 patients were female, and the ages ranged from 52 to 78 years, with an average age of 69.8 years.
All patients were diagnosed with computed tomography (CT)-guided lung biopsy or tracheoscopy, which included 61 patients with adenocarcinoma and 39 patients with squamous cell carcinoma. The lesions were 2.5–11.0 cm in diameter, with an average diameter of 6.4 cm. Patients in both groups had not received any chemotherapy, tumor-targeted drugs, or tumor immunotherapy before being admitted into the group. The expected survival time was more than 6 months, and the Karnofsky Performance Status (KPS) score was >70, and the Eastern Clinical Oncology Group (ECOG) score was <3 for patients with advanced tumors.
This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the First Hospital of Jiaxing. Written informed consent was obtained from all participants.
As per the main treatment methods, the patients were divided into two groups: (1) combination group, receiving microwave ablation in combination with chemotherapy (n = 52), and (2) chemotherapy group, receiving simple chemotherapy (n = 48). According to the eighth edition of lung cancer tumor–node–metastasis staging division, the combination group included 14 patients in Phase IIIB, 9 patients in Phase IIIC, and 29 patients in Phase IV. The chemotherapy group included 9 patients in Phase IIIB, 5 patients in Phase IIIC, and 34 patients in Phase IV (Tables 1 and 2).
Tumor-Node-Metastasis Classification of the Combination Group
TNM, tumor–node–metastasis.
Tumor–Node–Metastasis Classification of the Chemotherapy Group
TNM, tumor–node–metastasis.
Treatment method
Combination group
Equipment
A spiral CT machine (Siemens, Somatom Huan Yue) was used for all patients for treatment localization and microwave ablation. Siemens Emotion 16 spiral CT and Siemens Definition AS 64 spiral CT machines were used for the preoperative evaluation and postoperative outcome evaluation. The microwave therapy apparatus is manufactured by Nanjing ECO Medical Instrument Co. Ltd. (model: ECO-100A1, registration no.: GXZZ 2017325168). The disposable microwave ablation needle is produced by Nanjing ECO Medical Instrument Co. Ltd. (model: ECO-100AL5; transmitting frequency: 2450 MHZ; output power: 0–150 W; adjustable, antenna length: 15 cm; needle size: 16 G). The tip of the needle was made of peptide alloy, and the surface temperature was reduced using a water cycle cooling system.
Preoperative treatment and anesthesia
The patients fasted for 4 hours before the operation, drank a small amount of water, and emptied their bladders. An intramuscular injection of 10 mg of diazepam (Tianjin KingYork Pharmaceutical Co. Ltd.), an intramuscular injection of 10 mg of metoclopramide (Suicheng Pharmaceutical Co. Ltd.), an injection of 8 mg of ondansetron sodium chloride (Shandong Qidu Pharmaceutical Co. Ltd.) i.v. bolus, and 50 mg of flurbiprofen ester (Beijing Tide Pharmaceutical Co. Ltd.) i.v. bolus were administered half an hour before the operation. Then, 30 mg of codeine (Sinopharm) was orally administered 1 h before the operation. An additional dose of 30 mg was given when the operation exceeded 3 hours. Two lidocaine injections and one bupivacaine injection diluted to 50 mL with normal saline were used as anesthetics for the local anesthesia of the pleura, layer by layer, during the operation.
Operation process
An appropriate posture was chosen according to the location of the lesion. Both upper limbs were lifted and fixed behind the head. The electrocardiogram (ECG) monitor was connected, and continuous oxygen inhalation was maintained at 2–5 L/min. The venous access was checked to assure of the drugs before the operation. The lesion area was fixed with a position paper.
A CT scan was immediately performed to determine the ablation path, direction, and depth, as well as the target skin distance, anesthesia distance, deepest distance, and ablation mode. The target skin distance was the distance from the puncture point to the lesion, which was more than 2 cm in all patients with surgery. Two lidocaine injections and one bupivacaine injection were diluted to 50 mL with normal saline for local anesthesia. The ablation system was checked to ensure that this was working properly.
The needle was initially inserted at the locating point of the preferred layer into the tumor, layer by layer, until this reached the bottom. The ablation needle was punctured from the puncture point to the design depth, and a CT scan was performed. The needle tip was adjusted to 0.5 cm from the tumor's outer edge to determine whether the needle tip was in the correct position. The ablation needle and microwave ablation machine were connected by a cable, and the cold circulating line and circulating pump were connected to adjust the ablation power and time.
Depending on the size of the tumor, the ablation output power was generally within 50–60 W, and the ablation time was within 4–10 min. If the tumor was less than 3.5 cm, a single ablation antenna was used. In contrast, if the tumor was greater than 3.5 cm, multiple ablation antennas were used. The CT was reviewed after the ablation to determine whether there was any complication. The ablation needle was withdrawn after the ablation of the needle tract. The whole procedure was completed under ECG monitoring. Oxygen inhalation, blood pressure, heart rhythm, respiration, consciousness, and pain were carefully monitored. The vital signs of these patients were normal after the operation. No hemoptysis, shortness of breath, or dyspnea was observed. The patients were escorted to the ward.
Postsurgical treatment
These patients were given bed rest, first-grade nursing, ECG monitoring, and oxygen inhalation. Blood pressure and respiration were measured, and the 24-h intake and output were recorded. The patient drank water after 2 h and received a semifluid diet after 6 h. The chest CT plain scan was reviewed every 24 h.
Afterward, 50 mg of flurbiprofen ester (Beijing Tide Pharmaceutical Co. Ltd.) and a glucose injection containing 1500 mL of intravenous drip was given for 3 d. (A reduction for patients with heart failure and an addition of neutral insulin based on the proportion of glucose for diabetes patients were considered). Subsequently, 5 mg of dexamethasone injection (Suicheng Pharmaceutical Co. Ltd.), 20 mg of furosemide injection (Shanghai Harvest Pharmaceutical Co. Ltd.), and 2 ku of i.v. bolus of snake venom hemagglutinin injection (Zhaoke Pharmaceutical Co. Ltd.) were given for 3 d. Finally, 60 mg of pantoprazole injection (Zhejiang Yatai Pharmaceutical Co. Ltd.) of intravenous drip was given for 3 d.
Chemotherapy
Patients received chemotherapy within 2–4 weeks after the microwave ablation. Patients with adenocarcinoma were treated with cisplatin (Jiangsu Hansoh Pharmaceutical Co. Ltd.) in combination with pemetrexed disodium injection (Jiangsu Hansoh Pharmaceutical Co. Ltd.). In contrast, patients with squamous cell carcinoma were treated with cisplatin (Jiangsu Hansoh Pharmaceutical Co. Ltd.) in combination with gemcitabine hydrochloride injection (Jiangsu Hansoh Pharmaceutical Co. Ltd.). Afterward, 40 mg of cisplatin at day 1–3, 500 mg/m2 of pemetrexed disodium injection at day 1, and 1000 mg/m2 of gemcitabine hydrochloride injection at day 1, day 8, and day 21–28 were given for one cycle, constituting a total four cycles of chemotherapy.
Treatment group
Chemotherapy was performed with a regimen of cisplatin in combination with pemetrexed disodium injection (adenocarcinoma) or cisplatin in combination with gemcitabine hydrochloride injection (squamous cell carcinoma). The time, dose, and cycle of chemotherapy were the same as those in the combination group.
Other treatments
Patients with bone metastasis were treated with diphosphate drugs and radiotherapy for local bone metastases. Patients with intracranial metastasis were treated with total intracranial radiotherapy and an appropriate dose of radiotherapy for local intracranial metastases. For patients with pleural or pericardial effusion, routine catheter drainage and 40 mg of intracavitary injection of cisplatin (Jiangsu Hansoh Pharmaceutical Co. Ltd.) were given. For patients with liver metastases, interventional embolization was considered based on each patient's condition. However, no local treatment was carried out for adrenal gland metastasis. After two cycles of chemotherapy, the patients received conventional radiotherapy from 5500 to 6000 cGy for enlarged lymph nodes in the hilum or mediastinum. After radiotherapy, two cycles of chemotherapy were performed.
Efficacy evaluation
The clinical efficacy of these two treatment regimens was assessed with reference to the Response Evaluation Criteria In Solid Tumors (RECIST). 12 The common adverse events were evaluated using NCI-CTCAEV 4.0. Two groups of patients were followed up for an extended period. The CT was followed up every 6 months after 1, 3, 6, 9, and 12 months. The first-, second-, and third-year survival rates were, respectively, calculated. The specific causes of death were registered for patients who died.
Statistical method
The IBM Statistical Package for Social Sciences (SPSS) 22.0 software package was used for the statistical analysis of the data. The response rate of treatment was compared using the X 2 test. The survival time was calculated using the Kaplan–Meier method, and the survival rate was compared using the log-rank test. p < 0.05 was considered statistically significant.
Results
Efficacy
Four cycles of chemotherapy and conventional radiotherapy were performed after microwave ablation for 48 patients in the combination group. Among these patients, 9 were treated with zoledronate (Chiatai Tianqing Pharmaceutical Group Co. Ltd.) to prevent bone destruction. Furthermore, total skull radiotherapy was performed for 1 patient, closed thoracic drainage was performed for 10 patients, and the cisplatin intracavitary injection was performed for 3 patients. In the chemotherapy group, 42 patients completed more than four cycles of chemotherapy and conventional radiotherapy. Among these patients, 12 patients were treated with zoledronate to prevent bone destruction, one patient was treated with whole skull radiotherapy, 8 patients were treated with closed thoracic drainage, and 4 patients were given an intracavitary injection of cisplatin.
The recent efficiency and disease control rates of these two groups are presented in Table 3. No complete remission was observed in either group. However, in the combination and chemotherapy groups, 16 patients (33.3%) and 4 patients (9.5%) had partial remission, 26 patients (54.2%) and 22 patients (52.4%) had stable diseases, and 6 patients (12.5%) and 16 patients (38.1%) had progressive diseases, respectively. Complete remission and partial remission were considered to be effective. Hence, the effective rates were 33.3% and 9.5% in the combination and chemotherapy groups, respectively, with the rate in the combination group being significantly higher than in the chemotherapy group (p < 0.05).
Comparative Efficiency and Disease Control Rates Between the Two Groups
Recent efficiency rate = CR + PR; disease control rate = CR + PR + SD.
CR, complete remission; PD: progressive disease; PR, partial remission; SD, stable disease.
Nondisease progression is defined as disease control. Therefore, the disease control rate was 87.5% in the combination group and 61.9% in the chemotherapy group, with the rate in the combination group being significantly higher than in the chemotherapy group (p < 0.05).
Survival rate
The follow-up results for the survival rate in the combination and chemotherapy groups are presented in Table 4. The follow-up time was 3 years, and lost to follow-up was calculated as per the number of deaths. Three of 48 patients in the chemotherapy group were lost to follow-up. (One patient was lost to follow-up in 1 year, and 2 patients were lost to follow-up in 2 years.) However, none of the 52 patients in the combination group was lost to follow-up.
Comparative Survival Rates Between the Two Groups (n, %)
The first-year follow-up survival rates were 61.5% (n = 32) and 54.2% (n = 26) in the combination and chemotherapy groups, respectively. However, the difference was not statistically significant (p > 0.05) between these two groups. The second-year follow-up survival rates were 55.8% (n = 29) and 25.0% (n = 12) in the combination and chemotherapy groups, respectively, with the rate in the combination group being significantly higher than in the chemotherapy group (p < 0.05). The third-year follow-up survival rates were 30.8% (n = 16) and 12.5% (n = 6) in the combination and chemotherapy groups, respectively, with the rate in the combination group being significantly higher than in the chemotherapy group (p < 0.05).
Adverse reactions and complications
Myelosuppression
Patients in both groups had bone marrow suppression, including various degrees of leukopenia, as well as hemoglobin and platelet decline. Four patients (8.3%) in the chemotherapy group, but none (0%) in the combination group, terminated their treatment due to bone marrow suppression. Furthermore, 12 patients (23%) in the combination group and 20 patients (42%) in the chemotherapy group had bone marrow suppression, with the difference being statistically significant (p < 0.05) between these two groups.
Other adverse reactions and complications
Gastrointestinal reactions occurred in 25 patients in the combination group and 23 patients in the chemotherapy group. One patient in each group had interstitial pneumonia. Four patients in the combination group and 3 patients in the chemotherapy group had hepatic dysfunction. One patient in each group had renal impairment. Only one patient in the chemotherapy group, but none in the combination group, had peripheral vasculitis. Three patients in each group had rashes. One patient in each group had cardiac toxicity. No significant difference was noticed in the adverse reactions between the two groups (p > 0.05).
Adverse effects and complications of microwave ablation in the combination group
In the combination group, the microwave ablation-related specific adverse reactions and other complications were as follows: (1) postablation syndrome: the main manifestation was fever, which occurred in 22 patients accounting for 42%. The body temperature recovered to normal at 1 week after the microwave ablation; (2) Postablation pain: the pain was mainly in the treatment site in 45 patients accounting for 86%. Most of these patients improved at 1 week after ablation; (3) Nausea and dizziness: one patient had nausea and dizziness, accounting for 2%. This patient improved on the same day after being sent to the ward; (4) Ten patients had postgenetic neuralgia caused by intercostal nerve injury accounting for 19%; (5) Pneumothorax: 29 patients had a pneumothorax, accounting for 56%, without tension pneumothorax. Among these patients, one patient had a closed thoracic drainage indwelling catheter, while 5 patients received chest puncture aspiration. The other types of pneumothorax were self-absorbed, and no serious consequences were reported; (6) Five patients contracted infection accounting for 10%. All of these patients recovered after treatment with antibiotics; (7) Bleeding: 18 patients had bleeding, accounting for 35%. All of these patients had slight bleeding on the puncture path. Among these patients, 4 patients had hemoptysis after the operation, accounting for 8%, which improved after taking hemostatic drugs; (8) Six patients had reactive pleural effusion accounting for 12%; and (9) One patient had hiccups, accounting for 2%.
Discussion
As a local thermal ablation, percutaneous microwave ablation has been a rapidly developing method for the local treatment of lung cancer in recent years. The remarkable advantages of this technique are minimal invasiveness, accuracy, efficiency, low toxicity, and limited side effects, which compensate for radiotherapy and chemotherapy's poor specificity and considerable toxicity and side effects. 13
According to the RECIST efficacy standard evaluation results, the effectiveness and disease control rates in the combination group were significantly higher than in the chemotherapy group, with the difference being significant between the two groups. The mechanism of radiotherapy and chemotherapy is to induce apoptosis. In contrast, the mechanism of microwave ablation is to produce heat, which induces the coagulation necrosis of tumor tissues, thereby shrinking the tumor volume. 14 Chest CT enhancement suggests that coagulation necrosis illustrates a low-density shadow without enhancement, which is hardly considered a tumor activity. With the absorption of necrotic materials, the tumor lesions gradually diminish during CT imaging.
In this study, the effectiveness and disease control rates were higher than those in the chemotherapy group. Previous studies have revealed that for lesions <3.0 cm, microwave ablation can completely inactivate this at one time. Nearly 91.1% of patients remain under control or remission after 24 months of follow-up, hence the low local recurrence rate of microwave ablation. 15 In addition, microwave ablation is suitable for the local treatment of lung cancer due to its short ablation time, broad ablation range, and limited influence on blood perfusion. 15 Therefore, for advanced lung cancer patients, microwave ablation can enhance the effectiveness of first-line chemotherapy and reduce chemotherapy dose, while ensuring the efficacy of chemotherapy, thereby reducing complications and improving patients' quality of life.
Cancer patients' survival rates can be construed as the gold standard for evaluating antitumor drugs. 16 This study revealed no significant difference in the first-year survival rate between the combination and chemotherapy groups. In contrast, there was a significant difference in the second- and third-year survival rates, with the rate in the combination group being significantly higher than in the chemotherapy group. This indicates that microwave ablation, in combination with radiotherapy and chemotherapy, can significantly prolong patients' survival with peripheral IIIB-IV NSCLC when compared with chemotherapy.
In effect, this study has only collected 3 years of follow-up information due to time constraints, hence the need for 5-year survival data in future studies. The second- and third-year survival rates were significantly higher in the combination group than in the chemotherapy group, suggesting that microwave ablation can improve chemotherapy's efficacy.
In this study, 52 patients received microwave ablation without severe complications, including no intraoperative and perioperative deaths, no adverse reactions (e.g., massive hemoptysis and massive hemorrhage), and no uncontrollable complications (e.g., pneumothorax, infection, and pleural effusion). Therefore, microwave ablation can be construed as safe and well tolerated by patients. After the coagulation and necrosis of some lung cancer tumors under microwave ablation, the effective tumor volume immediately shrank, and the tumor load substantially decreased, thereby significantly improving the sensitivity of chemotherapy drugs. Therefore, these two have a synergistic effect. In addition, the body's antitumor immune function can be enhanced after microwave ablation for lung cancer. 17
Conclusion
Microwave ablation is a safe, effective, and well-tolerated local treatment method. In combination with chemotherapy, microwave ablation can improve the disease control rate and prolong patient survival with advanced NSCLC. This provides an effective new method for the treatment of advanced NSCLC.
Footnotes
Disclosure Statement
No competing financial interests exist.
Funding Information
This study was supported by the funds from Clinical Research Project of Microwave Ablation Combined with Chemotherapy in the Treatment of Stage IIIB-IV Peripheral Non-Small Cell Lung Cancer (2018AD32087).