The role of dosimetry and biological effects in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 223Ra: first in human study.

BACKGROUND: 223Ra is currently used for treatment of metastatic castration resistant prostate cancer patients (mCRPC) bone metastases with fixed standard activity. Individualized treatments, based on adsorbed dose (AD) in target and non-target tissue, are absolutely needed to optimize efficacy while reducing toxicity of α-emitter targeted therapy. This is a pilot first in human clinical trial aimed to correlate dosimetry, clinical response and biological side effects to personalize 223Ra treatment. METHODS: Out of 20 mCRPC patients who underwent standard 223Ra treatment and dosimetry, in a subset of 5 patients the AD to target and non-target tissues was correlated with clinical effects and radiation-induced chromosome damages. Before each 223Ra administrations, haematological parameters, PSA and ALP values were evaluated. Additional blood samples were obtained baseline (T0), at 7 days (T7), 30 days (T30) and 180 days (T180) to evaluate chromosome damage. After administration WB planar 223Ra images were obtained at 2-4 and 18-24 h. Treatment response and toxicity were monitored with clinical evaluation, bone scan, 18F-choline-PET/CT, PSA value and ALP while haematological parameters were evaluated weekly after 223Ra injection and 2 months after last cycle. RESULTS: 1. a correlation between AD to target and clinical response was evidenced with threshold of 20 Gy as a cut-off to obtain tumor control; 2. the AD to red marrow was lower than 2 Gy in all the patients with no apparently correlation between dosimetry and clinical toxicity. 3. a high dose dependent increase of the number of dicentrics and micronuclei during the course of 223Ra therapy was observed and a linear correlation has been found between blood AD (BAD) and number of dicentrics. CONCLUSIONS: This study provides some interesting preliminary evidence to be further investigated: dosimetry may be useful to identify a more appropriate 223Ra administered activity predicting AD to target tissue; a dose dependent complex chromosome damage occurs during 223Ra administration and this injury is more evident in heavily pre-treated patients; dosimetry could be used for radioprotection purpose. TRIAL REGISTRATION: The pilot study has been approved from the Ethics Committee of Regina Elena National Cancer Institute (N:RS1083/18-2111).

Absorbed dose measurements from a 90Y radionuclide liquid solution using LiF:Mg,Cu,P thermoluminescent dosimeters.

In the last few years there has been an increasing interest in the measurement of the absorbed dose from radionuclides, with special attention devoted to molecular radiotherapy treatments. In particular, the determination of the absorbed dose from beta emitting radionuclides in liquid solution poses a number of issues when dose measurements are performed using thermoluminescent dosimeters (TLD). Finite volume effect, i.e. the exclusion of radioactivity from the volume occupied by the TLD is one of these. Furthermore, TLDs need to be encapsulated into some kind of waterproof envelope that unavoidably contributes to beta particle attenuation during the measurement. The purpose of this study is twofold: I) to measure the absorbed dose to water, Dw, using LiF:Mg,Cu,P chips inside a PMMA cylindrical phantom filled with a homogenous 90YCl3 aqueous solution II) to assess the uncertainty budget related to Dw measurements. To this purpose, six cylindrical PMMA phantoms were manufactured at ENEA. Each phantom can host a waterproof PMMA stick containing 3 TLD chips encapsulated by a polystyrene envelope. The cylindrical phantoms were manufactured so that the radioactive liquid environment surrounds the whole stick. Finally, Dw measurements were compared with Monte Carlo (MC) calculations. The measurement of absorbed dose to water from 90YCl3 radionuclide solution using LiF:Mg,Cu,P TLDs turned out to be a viable technique, provided that all necessary correction factors are applied. Using this method, a relative combined standard uncertainty in the range 3.1-3.7% was obtained on each Dw measurement. The major source of uncertainty was shown to be TLDs calibration, with associated uncertainties in the range 0.7-2.2%. Comparison of measured and MC-calculated absorbed dose per emitted beta particle provided good results, with the two quantities being in the ratio 1.08.

EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry II. Dosimetry prior to radioiodine therapy of benign thyroid diseases.

The EANM Dosimetry Committee Series "Standard Operational Procedures for Pre-Therapeutic Dosimetry" (SOP) provides advice to scientists and clinicians on how to perform patient-specific absorbed dose assessments. This particular SOP describes how to tailor the therapeutic activity to be administered for radioiodine therapy of benign thyroid diseases such as Graves' disease or hyperthyroidism. Pretherapeutic dosimetry is based on the assessment of the individual (131)I kinetics in the target tissue after the administration of a tracer activity. The present SOP makes proposals on the equipment to be used and guides the user through the measurements. Time schedules for the measurement of the fractional (131)I uptake in the diseased tissue are recommended and it is shown how to calculate from these datasets the therapeutic activity necessary to administer a predefined target dose in the subsequent therapy. Potential sources of error are pointed out and the inherent uncertainties of the procedures depending on the number of measurements are discussed. The theoretical background and the derivation of the listed equations from compartment models of the iodine kinetics are explained in a supplementary file published online only.

Local tumor control probability to evaluate an applicator-guided volumetric-modulated arc therapy solution as alternative of 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecological cancer.

The purpose of this study was to evaluate the applicator-guided volumetric-modulated arc therapy (AGVMAT) solution as an alternative to high-dose-rate brachytherapy (HDR-BRT) treatment of the vaginal vault in patients with gynecological cancer (GC). AGVMAT plans for 51 women were developed. The volumetric scans used for plans were obtained with an implanted CT-compatible vaginal cylinder which provides spatial registration and immobilization of the gynecologic organs. Dosimetric and radiobiological comparisons for planning target volume (PTV) and organs at risk (OARs) were performed by means of a dose-volume histogram (DVH), equivalent uniform dose (EUD), and local tumor control probability (LTCP). In addition, the integral dose and the overall delivery time, were evaluated. The HDR-BRT averages of EUD and minimum LTCP were significantly higher than those of AGVMAT. Doses for the OARs were comparable for the bladder and sigmoid, while, although HDR-BRT was able to better spare the bowel, AGVMAT provided a significant reduction of d2cc, d1cc, and dmax (p < 0.01) for the rectum. AGVMAT integral doses were higher than HDR-BRT with low values in both cases. Delivery times were about two or three times higher for HDR-BRT with respect to the single arc technique (AGVMAT1) and dual arc technique (AGVMAT2), respectively. The applicator-guided volumetric-modulated arc therapy seems to have the potential of improving rectum avoidance. However, brachytherapy improves performance in terms of PTV coverage, as demonstrated by a greater EUD and better LTCP curves.

Long-term results of a randomized trial on the sequencing of radiotherapy and chemotherapy in breast cancer.

OBJECTIVE: A prospective, phase III randomized study was undertaken to compare the outcomes of 2 different radiotherapy and chemotherapy sequences in conservatively treated patients with breast cancer. METHODS: Between January 1997 and November 2002, 206 patients operated of quadrantectomy and axillary dissection for breast cancer, candidates to receive adjuvant CMF chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) were assigned to concurrent or sequential radiation treatment by using a balanced randomization method. Before randomization patients were stratified by tumor diameter, age, and lymph node status. The primary end point was the freedom from breast recurrence, and secondary end points were overall and disease-free survival. Overall outcomes were analyzed according to the intention-to-treat principle. RESULTS: All 206 patients enrolled and randomized in the trial were analyzed. The median follow-up was 111 months, with no patient lost for follow-up. No difference in 10-years breast recurrence-free, disease-free, metastasis-free, and overall survival rates was observed in the 2 treatment sequence groups. The Hazard Ratios, calculated for each prognostic factor, showed no difference in all outcomes between the 2 treatment sequences. CONCLUSIONS: No influence of the treatment sequence on long-term outcomes was observed in this trial. This finding suggests that to avoid an increased risk of distant recurrence or an excessive toxicity, radiation therapy may be delayed until after the end of the more, recently used, anthracycline-based chemotherapy without increasing the risk of breast recurrences, thus allowing the delivery of full-dose chemotherapy in patients at risk for systemic disease spread.