NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy.

BACKGROUND: To determine by treatment plan comparison differences in toxicity risk reduction for patients with head and neck squamous cell carcinoma (HNSCC) from proton therapy either used for complete treatment or sequential boost treatment only. MATERIALS AND METHODS: For 45 HNSCC patients, intensity-modulated photon (IMXT) and proton (IMPT) treatment plans were created including a dose escalation via simultaneous integrated boost with a one-step adaptation strategy after 25 fractions for sequential boost treatment. Dose accumulation was performed for pure IMXT treatment, pure IMPT treatment and for a mixed modality treatment with IMXT for the elective target followed by a sequential boost with IMPT. Treatment plan evaluation was based on modern normal tissue complication probability (NTCP) models for mucositis, xerostomia, aspiration, dysphagia, larynx edema and trismus. Individual NTCP differences between IMXT and IMPT (∆NTCPIMXT-IMPT) as well as between IMXT and the mixed modality treatment (∆NTCPIMXT-Mix) were calculated. RESULTS: Target coverage was similar in all three scenarios. NTCP values could be reduced in all patients using IMPT treatment. However, ∆NTCPIMXT-Mix values were a factor 2-10 smaller than ∆NTCPIMXT-IMPT. Assuming a threshold of ≥ 10% NTCP reduction in xerostomia or dysphagia risk as criterion for patient assignment to IMPT, less than 15% of the patients would be selected for a proton boost, while about 50% would be assigned to pure IMPT treatment. For mucositis and trismus, ∆NTCP ≥ 10% occurred in six and four patients, respectively, with pure IMPT treatment, while no such difference was identified with the proton boost. CONCLUSIONS: The use of IMPT generally reduces the expected toxicity risk while maintaining good tumor coverage in the examined HNSCC patients. A mixed modality treatment using IMPT solely for a sequential boost reduces the risk by 10% only in rare cases. In contrast, pure IMPT treatment may be reasonable for about half of the examined patient cohort considering the toxicities xerostomia and dysphagia, if a feasible strategy for patient anatomy changes is implemented.

Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis.

PURPOSE: The purpose of this study was to determine, by treatment plan comparison along with normal tissue complication probability (NTCP) modeling, whether a subpopulation of patients with head and neck squamous cell carcinoma (HNSCC) could be identified that would gain substantial benefit from proton therapy in terms of NTCP. METHODS AND MATERIALS: For 45 HNSCC patients, intensity modulated radiation therapy (IMRT) was compared to intensity modulated proton therapy (IMPT). Physical dose distributions were evaluated as well as the resulting NTCP values, using modern models for acute mucositis, xerostomia, aspiration, dysphagia, laryngeal edema, and trismus. Patient subgroups were defined based on primary tumor location. RESULTS: Generally, IMPT reduced the NTCP values while keeping similar target coverage for all patients. Subgroup analyses revealed a higher individual reduction of swallowing-related side effects by IMPT for patients with tumors in the upper head and neck area, whereas the risk reduction of acute mucositis was more pronounced in patients with tumors in the larynx region. More patients with tumors in the upper head and neck area had a reduction in NTCP of more than 10%. CONCLUSIONS: Subgrouping can help to identify patients who may benefit more than others from the use of IMPT and, thus, can be a useful tool for a preselection of patients in the clinic where there are limited PT resources. Because the individual benefit differs within a subgroup, the relative merits should additionally be evaluated by individual treatment plan comparisons.

Hsp90 Inhibitors NVP-AUY922 and NVP-BEP800 May Exert a Significant Radiosensitization on Tumor Cells along with a Cell Type-Specific Cytotoxicity.

Targeting heat shock protein 90 (Hsp90) provides a promising therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation (IR). To explore the impact of scheduling drug-IR administration, in the present study, we analyzed the response of lung carcinoma A549 and glioblastoma SNB19 cells to simultaneous drug-IR treatment followed by a long-term drug administration. Cellular response was evaluated at different time intervals after IR-alone, drug-alone, or combined drug-IR treatments by colony counts and expression profiles of Hsp90 and its clients, along with several apoptotic markers and cell cycle-related proteins, as well as by IR-drug-induced cell cycle arrest, DNA damage, and repair. A short 30-minute exposure to either Hsp90 inhibitor did not affect the radiosensitivity of both tumor cell lines. Increasing the duration of post-IR-drug treatment progressively enhanced the sensitivity of SNB19 cells to IR. In contrast, the response of A549 cells to drug-IR combination was largely determined by the cytotoxic effects of both drugs without radiosensitization. Combined drug-IR treatment induced more severe DNA damage in both tumor cell lines than each treatment alone and also protracted the kinetics of DNA damage repair in SNB19 cells. In addition to large cell cycle disturbances, drug-IR treatment also caused depletion of the antiapoptotic proteins Akt and Raf-1 in both cell lines, along with a decrease of survivin in A549 cells in case of NVP-AUY922. The data show that simultaneous Hsp90 inhibition and irradiation may induce cell type-specific radiosensitization as well as cytotoxicity against tumor cells.