Proton therapy (PT) combined with concurrent chemotherapy for locally advanced non-small cell lung cancer with negative driver genes

Abstract

Purpose: To discuss the optimal treatment modality for inoperable locally advanced Non-Small Cell Lung Cancer patients with poor physical status, impaired cardio-pulmonary function, and negative driver genes, and provide clinical evidence.

Materials and methods: Retrospective analysis of 62 cases of locally advanced non-small cell lung cancer patients with negative driver genes treated at Tsukuba University Hospital(Japan) and Qingdao University Affiliated Hospital(China).The former received proton therapy with concurrent chemotherapy, referred to as the proton group, with 25 cases included; while the latter underwent X-ray therapy with concurrent chemoradiotherapy followed by 1 year of sequential immunomodulatory maintenance therapy, referred to as the X-ray group, with 37 cases included.The treatment response and adverse reactions were assessed using RECIST v1.1 criteria and CTCAE v3.0, and radiotherapy planning and evaluation of organs at risk were performed using the CB-CHOP method.All data were subjected to statistical analysis using GraphPad Prism v9.0, with a T-test using P < 0.05 considered statistically significant.

Results: (1)Target dose distribution: compared to the X-ray group, the proton group exhibited smaller CTV and field sizes, with a more pronounced bragg peak.(2)Organs at risk dose: When comparing the proton group to the X-ray group, lung doses (V5, V20, MLD) and heart doses (V40, Dmax) were lower, with statistical significance (P < 0.05), while spinal cord and esophagus doses showed no significant differences between the two groups (P > 0.05).(3)Treatment-related toxicities: The incidence of grade 3 or higher adverse events in the proton group and X-ray group was 28.6% and 4.2%, respectively, with a statistically significant difference (P < 0.05). In terms of the types of adverse events, the proton group primarily experienced esophagitis and pneumonia, while the X-ray group primarily experienced pneumonia, esophagitis, and myocarditis. Both groups did not experience radiation myelitis or esophagotracheal fistula.(4)Efficacy evaluation: The RR in the proton group and X-ray group was 68.1% and 70.2%, respectively (P > 0.05), and the DCR was 92.2% and 86.4%, respectively (P > 0.05), indicating no significant difference in short-term efficacy between the two treatment modalities.(5)Survival status: The PFS in the proton group and X-ray group was 31.6 ± 3.5 months (95% CI: 24.7 ~ 38.5) and 24.9 ± 1.55 months (95% CI: 21.9 ~ 27.9), respectively (P > 0.05), while the OS was 51.6 ± 4.62 months (95% CI: 42.5 ~ 60.7) and 33.1 ± 1.99 months (95% CI: 29.2 ~ 37.1), respectively (P < 0.05).According to the annual-specific analysis, the PFS rates for the first to third years in both groups were as follows: 100%, 56.1% and 32.5% for the proton group vs. 100%, 54.3% and 26.3% for the X-ray group. No statistical differences were observed at each time point (P > 0.05).The OS rates for the first to third years in both groups were as follows: 100%, 88.2%, 76.4% for the proton group vs. 100%, 91.4%, 46.3% for the X-ray group. There was no significant difference in the first to second years (P > 0.05), but the third year showed a significant difference (P < 0.05). Survival curve graphs also depicted a similar trend.

Conclusion: There were no significant statistical differences observed between the two groups in terms of PFS and OS within the first two years. However, the proton group demonstrated a clear advantage over the X-ray group in terms of adverse reactions and OS in the third year. This suggests a more suitable treatment modality and clinical evidence for populations with frail health, compromised cardio-pulmonary function, post-COVID-19 sequelae, and underlying comorbidities.

Keywords: Cardio-pulmonary function; DVH; Negative driver genes; Non-small cell Lung cancer(NSCLC); Proton therapy.

Fig. 1

Radiotherapy Target Area and Field. Note: A and B represent the target area and field distribution for intensity-modulated radiation therapy (IMRT) with X-rays, respectively; C and D represent the target area and field distribution for fixed-angle proton therapy, respectively

Fig. 2

Dose Distribution and DVH. Note: A and B represent the dose distribution and DVH (Dose-Volume Histogram) for intensity-modulated radiation therapy (IMRT) with X-rays, respectively; C and D represent the dose distribution and DVH for fixed-angle proton therapy, respectively

Fig. 3

Adverse Event Severity and Types. Note: A represents the severity and proportions of adverse events induced by X-rays (black) and proton therapy (red); B and C depict the types and proportions of adverse events induced by X-rays (Pneumonia: blue, Esophagitis: orange, Myocarditis: gray) and proton therapy

Fig. 4

PSF and OS for Two Groups. Note: The vertical axis represents time (months), the horizontal axis represents groups, and A and B represent PFS and OS, respectively. The black bars represent the X-ray group, and the red bars represent the Proton group

Fig. 5

PSF Rate and OS Rate for Two Groups. Note: The vertical axis represents rates (%), the horizontal axis represents time (months), and A and B represent PFS and OS, respectively. The black lines represent the X-ray group, and the red lines represent the Proton group

Fig. 6

Schematic Dose-Depth Profiles for X-rays and Proton Beams. Note: Citing reference from [20]