Radiofrequency Deep Hyperthermia Combined with Chemotherapy in the Treatment of Advanced Non-Small Cell Lung Cancer
Lung cancer remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. The prognosis for advanced NSCLC patients, particularly those with stage IV disease, is dismal, with a 5-year survival rate of only 3.6%. Chemotherapy remains a cornerstone of treatment for patients without gene mutations, but its efficacy is often limited by toxicity and adverse effects. This study explores the potential of combining radiofrequency deep hyperthermia with chemotherapy to improve outcomes and reduce toxicity in advanced NSCLC patients, particularly those with malignant pleural effusion.
Introduction
Advanced NSCLC patients often present with unresectable disease, making surgical intervention impractical. Chemotherapy, particularly the gemcitabine and cisplatin (GP) regimen, is a standard first-line treatment. However, the GP regimen is associated with significant hematologic, renal, and gastrointestinal toxicity. Hyperthermia, a treatment method that elevates tissue temperature, has shown promise in enhancing the efficacy of chemotherapy and radiotherapy by increasing tumor perfusion, oxygenation, and drug delivery. This study investigates the clinical efficacy and safety of combining hyperthermia with chemotherapy in advanced NSCLC patients.
Methods
This retrospective study evaluated the medical records of 93 advanced NSCLC patients (stage IIIB-IV) treated between March 2011 and January 2014. Patients were divided into two groups: the hyperthermia combined with chemotherapy (HCT) group and the chemotherapy alone (CT) group. The HCT group received the GP regimen combined with regional radiofrequency deep hyperthermia, while the CT group received only the GP regimen. Patients with malignant pleural effusion underwent thoracentesis and intrapleural injection chemotherapy, with or without hyperthermia.
The hyperthermia treatment was administered using the HY7000-I radiofrequency deep hyperthermia system, which heats locoregional lesions deep within the body. The treatment was applied twice a week, with heating durations adjusted based on patient tolerance. The objective was to achieve a skin temperature of 40°C. Chemotherapy consisted of gemcitabine (1000 mg/m² on days 1 and 8) and cisplatin (75 mg/m² divided over 2 to 4 days) every 3 weeks.
Results
The study included 48 patients in the HCT group and 45 in the CT group. Patient characteristics, including age, gender, smoking history, and disease stage, were comparable between the two groups. The overall response rate (ORR) for pleural effusions was significantly higher in the HCT group (81.2%) compared to the CT group (40.0%). Additionally, the HCT group experienced lower incidences of weakness (12.5% vs. 46.7%) and gastrointestinal adverse reactions (25.0% vs. 77.8%) than the CT group.
In terms of tumor response, no complete responses (CR) were observed in either group. The HCT group had a partial response (PR) rate of 37.5%, a stable disease (SD) rate of 33.3%, and a progressive disease (PD) rate of 29.2%. The CT group had a PR rate of 33.3%, an SD rate of 33.3%, and a PD rate of 33.3%. The ORR and disease control rate (DCR) were not significantly different between the two groups.
Survival analysis showed a 1-year survival rate of 54% in the HCT group and 40% in the CT group. The 2-year survival rates were 14.6% and 13.3%, respectively. The median progression-free survival (PFS) was 5.65 months in the HCT group and 5.5 months in the CT group. The median overall survival (OS) was 13.2 months in the HCT group and 10.9 months in the CT group. These differences were not statistically significant.
Discussion
Hyperthermia has been shown to enhance the efficacy of chemotherapy and radiotherapy in various cancers by inducing direct cytotoxicity, sensitizing cancer cells to DNA-damaging agents, and improving drug delivery. This study supports the potential of hyperthermia combined with chemotherapy in managing malignant pleural effusion in advanced NSCLC patients, with a significantly higher ORR in the HCT group.
The reduction in weakness and gastrointestinal adverse reactions in the HCT group suggests that hyperthermia may mitigate some of the toxic effects of chemotherapy. This could be due to the relaxing and metabolism-promoting effects of hyperthermia, which may enhance the efficacy of antiemetics or inhibit the secretion of nausea-inducing neurotransmitters.
The study also highlights the synergistic effects of hyperthermia and intrapleural chemotherapy in managing malignant pleural effusion. The combination of hyperthermia and interleukin-2 intrapleural injections resulted in an ORR of 81.2%, significantly higher than the 40.0% observed in the CT group. This may be due to the induction of heat-shock protein 70 and T-cell activation, which promote tumor cell apoptosis and reduce effusion formation.
Conclusion
Combining radiofrequency deep hyperthermia with chemotherapy offers a promising therapeutic strategy for advanced NSCLC patients, particularly those with malignant pleural effusion. The treatment not only improves the management of pleural effusions but also reduces the incidence of chemotherapy-related weakness and gastrointestinal adverse reactions. While the study did not find significant differences in overall tumor response and survival, the benefits in terms of reduced toxicity and improved quality of life are noteworthy. Further studies with larger sample sizes are warranted to confirm these findings and explore the full potential of hyperthermia in NSCLC treatment.
doi.org/10.1097/CM9.0000000000000156
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