VMAT technique enables concomitant radiotherapy of prostate cancer and pelvic bone metastases

<div><p></p><p><b>Background.</b> Prostate cancer (PCa) patients with metastatic disease often suffer from skeletal pain and urinary retention impairing their quality of life. Prophylactic radiotherapy to bone metastases planned concomitantly with primary PCa radiotherapy could enable more precise control of combined dose in healthy tissues when compared to sequential palliative treatment.</p><p><b>Materials and methods.</b> Volumetric modulated arc therapy (VMAT) was planned for 14 PCa patients with primary bone metastases. The bone planning target volume (PTV_bone) was contoured together with the PTVs of prostate (pr), pelvic lymph nodes (ln) and seminal vesicles (sv). Another virtual plan was calculated excluding PTV_bone for dose volume histogram (DVH) comparison. DVHs were additionally compared to a set of actual VMAT treatment plans of a control cohort of 13 high risk PCa patients treated with PTV_pr, PTV_sv and PTV_ln. The prescribed doses varied between 42 and 76 Gy for PTV_bone.</p><p><b>Results.</b> Recommended healthy tissue tolerances (Quantec) were not exceeded except for one patient's rectum V_50Gy value. Rectum doses did not increase significantly due to the inclusion of PTV_bone. For bladder, there was a slight increase for V_65Gy and V_50Gy (2.7% and 7.4%). The DVHs of metastatic and non-metastatic patients were comparable. There were no differences in the PTV_pr DVH parameters, while mean PTV_ln dose increased by 3.7 Gy–4.4 Gy due to the increased treatment volume related to PTV_bone. All side effects were < grade 3 during the mean follow-up duration of 25 months.</p><p><b>Conclusions.</b> VMAT offers a good optimization tool for adding extra PTVs to the radiotherapy plan. Radiotherapy of bone metastases concomitantly with irradiation of the primary prostate tumor is a safe and well-tolerated approach and deserves to be studied in a randomized setting.</p></div

Oncolytic potency of Ad5/3-hTERT-hNIS.

<p>Prostate cancer cells were infected in triplicates with 0.01 to 100 vp/cell and the cell viability was assessed by MTS-assay. Ad5/3Luc1 is a replication-deficient adenovirus. Ad5 WT is the serotype 5 wild-type adenovirus. Ad5/3-hTERT-Δgp19K is similar to Ad5/3-hTERT-hNIS but does not contain hNIS. ***p<0.001 as compared to replication-deficient adenovirus. Bars represent SD.</p

In vivo iodide uptake and efficacy.

<p>(<b>a</b>) Tumor uptake of ¹²³I⁻ 0.5 h, 2 h and 13 h after i.v. administration of ¹²³I⁻. The tumors were injected twice with hTERT-viruses 24 h and 48 h prior to radioiodide. 1, Mock-injected tumor; 2, Ad5/3-hTERT-Δgp19K-injected tumor; 3 and 4, Ad5/3-hTERT-hNIS-injected tumors. (<b>b</b>) Ad5/3-hTERT-hNIS significantly prolongs the survival of mice bearing intra pulmonary PC-3MM2 tumors. Mice received 5×10¹⁰ vp of Ad5/3-hTERT-hNIS or diluent intravenously. Next day, the mice were injected intraperitoneally with ¹³¹I⁻. The treatments were repeated once a week for a total of three weeks. Pairwise comparisons with the logrank test were used to compare survival curves, **p<0.01, ***p<0.001 as compared to mock-treated mice. (<b>c</b>) Biodistribution of ¹³¹I⁻ in mice 48 h after the first intravenous Ad5/3-hTERT-hNIS-injection and 24 h after first radioiodide-injection. Bars represent SD.</p

hNIS-expression in prostate cancer cells.

<p>(<b>a</b>) Cells were infected with 10 vp of Ad5/3-hTERT-hNIS (lanes 1 and 3) or control virus Ad5/3-hTERT-Δgp19K (lanes 2 and 4). hNIS-RNA -expression was assayed 24 h (lanes 1 and 2) and 48 h (lanes 3 and 4) later by RT-PCR. ß-actin served as an internal control. (<b>b</b>) ¹²⁵I uptake in prostate cancer cells infected in triplicates with 10 vp of Ad5/3-hTERT-hNIS or Ad5/3-hTERT-Δgp19K. The capability of the cells to concentrate iodide was assessed at 24 h and 48 h after infection. Student's t-test was used for statistical analyses, *p<0.05, **p<0.01, ***p<0.001 as compared to uninfected cells. Bars represent SD.</p

SPECT/CT is sensitive for detecting endogenous NIS- and hNIS-expression.

<p>Mice were given Ad5/3-hTERT-hNIS or diluent and ¹²³I⁻ intravenously for SPECT-scanning. After the SPECT/CT-scan, mice received ¹³¹I⁻ or PBS intraperitoneally. The iodide uptakes were calculated weekly and normalized to the injected dose of ¹²³I⁻. (<b>a</b>) Individual tumor uptake of ¹²³I⁻ (the imaging isotope) in Ad5/3-hTERT-hNIS and Ad5/3-hTERT-hNIS+¹³¹I⁻ -treated mice. All mice received ¹²³I⁻ for evaluation of iodide uptake by SPECT. Mice in the latter group also received ¹³¹I⁻ right after the SPECT imaging for therapeutic purposes. Solid grey line, background level in the absence of Ad5/3-hTERT-hNIS; dotted grey lines, ± SD of background. (<b>b</b>) ¹²³I⁻ uptake in the thyroids. Results are expressed as %ID/mm³×1000 ± SD.</p

Increasing amount of ¹²³I⁻ accumulates in the tumor over time showing progressive virus replication and increasing tumor hNIS-expression.

<p>(<b>a</b>) SPECT/CT image (sagittal section) showing ¹²³I⁻ accumulation into tumor in the lungs of a mouse treated intravenously with Ad5/3-hTERT-hNIS and intraperitoneally with ¹³¹I⁻. (<b>b</b>) Control mouse treated with ¹³¹I⁻ only shows no ¹²³I⁻ -accumulation in the lungs on the course of the treatment. (<b>c</b>) Transverse section of the lungs of the mouse shown in (<b>a</b>) shows accumulation of ¹²³I⁻ into the tumor on the third treatment week. (<b>d</b>) Transverse section of lungs of the mouse shown in (<b>b</b>) shows no accumulation of ¹²³I⁻ into the tumor on the third treatment week. The crossing point of red lines indicates tumor localization.</p

Number of mice positive for uptake of the imaging isotope ¹²³I at the tumor.

<p>The total number of mice analyzed at each time point is given in parentheses. Day indicates the day after first intravenous virus injection. -, not analyzed.</p