Clinical radiotherapy audits in Belgium, 2011-2014.

Systematic clinical radiotherapy audits have been introduced in Belgium in 2011, as part of the Federal Cancer Plan. This is in compliance with article 11 of the 97/43 Council directive of Euratom states, translated into the Belgian legislation by royal decree in 2002. The principle of clinical audits has thus been part of the federal legal requirements for more than 10 years. However, its application had to wait for the development of a practical approach: what authority will audit, who will be the auditors, along which methodology, at what frequency, etc. Since 2002, the Federal College of Radiotherapy has the mission to monitor quality of radiotherapy at large. It was therefore decided after discussions with the relevant administration at the Ministry of Health and the Federal Agency for Nuclear Control that the College would practically organise the audits. Early in the 2000s, the IAEA developed a manual for comprehensive audits, as a tool for quality improvement. Auditors were professionals of the domain and the audit visit took the form of a peer review. Great care was taken to assemble an audit party able to cover all aspects of clinical radiotherapy with a radiation oncologist, a medical physicist, a radiation therapist and, on demand, a quality officer. The IAEA manual contains a series of questionnaires to be prepared by the audited centre in advance (pre-audit and self-assessment), indicating what specific areas the auditors would assess. It is also a template for the auditors, ensuring that no area is left aside or forgotten during the site visit. The report, at the end of the visit, is drafted according to a specific report template, also developed by IAEA. Several members of the Belgian radiotherapy community have developed their auditor's skills by participating to the IAEA audit program; they are the core of the auditor Belgian team.

A retrospective analysis of the results of p(65) + Be neutrontherapy for the treatment of prostate adenocarcinoma at the cyclotron of Louvain-la-Neuve. Part I: Survival and progression-free survival.

PURPOSE: To retrospectively evaluate survival, progression-free survival (PFS) and biological response in a series of patients irradiated with mixed neutron/photon beams for locally advanced prostate cancer in our institution. PATIENTS AND METHODS: Three hundred and eight patients were treated between January 1990 and December 1996. Fifty-five of these were recruited for pT3 or pN1 tumors after radical prostatectomy. Neoadjuvant androgen deprivation was given in 106 patients. The treatment protocol consisted of a mixed photon/neutron irradiation in a two-to-three proportion, up to a total equivalent dose of 66 Gy (assuming a clinical RBE value of 2.8). Pre- and post-treatment PSA determinations were available in practically all cases. Study endpoints were overall survival (OAS) and progression-free survival (PFS). The Cox proportional hazard regression model was used to investigate the prognostic value of baseline characteristics on survival and progression-free survival were a progression was defined as local, regional, metastatic or biological progression. Mean age was 69 years (49-86); mean pretreatment PSA was 15 (0.5-330) in all patients and 14 (0.5-160) in those receiving neoadjuvant hormonotherapy; seven patients only had an initial PSA < or = 4 ng/mL; 15% were T1, 46% were T2, 28% were T3 or pT3 and 4% were T4 (7% unspecified); WHO grade of differentiation was I in 38%, II in 38% and III in 14% (5% unspecified). RESULTS: The median follow-up was 2.8 years (0-7.8). Five-year overall survival (OAS) was 79% (95% CI: 71-87%) and 5-year progression-free survival (PFS) was 64% (95% CI: 54-74%) for the entire series. PFS in patients with an initial PSA > or = 20 ng/mL was the same. PFS could be predicted by two optimal Cox regression models, one including histological grade (p = 0.003) and initial PSA (p = 0.0009) as cofactors, the other including histological grade (p = 0.003) and T stage (p = 0.02). The main prognostic factors for overall survival were PSA and age. Biological responses with PSA < 1.5 ng/mL, < 1 ng/mL and < 0.5 ng/mL at any time after treatment were documented in 70%, 61% and 47% of the patients, respectively. CONCLUSION: Five-year OAS was 79%, PFS was 64%, and biological response was 70% for prostate cancer patients treated with mixed photon/neutron beams as applied at Louvain-la-Neuve, which are good results as compared with the literature. The usual prognostic factors were confirmed.

Correlation of the response to cisplatin of human ovarian cancer cell lines, originating from one tumor but with different sensitivity, with the recovery of DNA adducts.

Cis-Diamminedichloroplatinum(II) (CDDP) is used in the treatment of various cancers, with or without ionizing radiation. During treatment, resistance may develop, and cross-resistance can also occur. DNA is the main target for CDDP and ionizing radiation, and we therefore evaluated the correlation between the amount of CDDP-DNA adducts and the cytotoxic activity of CDDP in human ovarian cancer cell lines with different platinum sensitivities. DNA-adduct levels were investigated 18 hr after CDDP exposure in three cell lines originating from the same human ovarian cancer. The least sensitive cells appeared to have the largest amounts of CDDP-DNA adducts, while the most sensitive had higher adduct levels than the parental cells. The proportion of the four adducts measured (i.e., Pt-G, Pt-AG, Pt-GG, and G-Pt-G) was comparable in all cell lines, with a preference for Pt-GG adduct formation (> 50% of the adducts). Intracellular CDDP concentrations were higher in sensitive than in resistant cells, in contrast to the degree of CDDP adduct formation. Data obtained following continuous exposure of CDDP-resistant cells to CDDP suggest that DNA repair is partly responsible for resistance to CDDP. We conclude that the amount of CDDP-DNA adduct formation in cancer cells is not a predictor of CDDP cytotoxicity.

[In vitro effects of piracetam on the radiosensitivity of hypoxic cells (adaptation of MTT assay to hypoxic conditions)]. / Effets in vitro du piracetam sur la radiosensibilité des cellules hypoxiques (adaptation du test au MTT aux conditions d'hypoxie).

This paper describes the adaptation of the MTT assay to hypoxic conditions in order to test the in vitro effect of piracetam on hypoxic cells and particularly on the radiosensitivity of hypoxic cells since this drug has shown clinical effect on acute and chronic hypoxia. The V79 cell line was selected by reference to preliminary hypoxic experiments using clonogenic assay and euoxic experiments using clonogenic and MTT assays. Cell growth and survival in our hypoxic conditions were assessed using MTT assay with an enclosure and special 48-well plates both made of glass. Growth curves on glass versus reference polystyrene plates were comparable and confirm the validity of using special glass plates. Growth curves on glass plates after 1-hour exposure to nitrogen versus air were comparable, so there is no bias effect due to gas composition. Survival curves using MTT versus reference clonogenic assay were comparable after radiation exposure in eu- and hypoxic conditions, and confirm the validity of our original technique for creating hypoxia. The Oxygen Enhancement Ratio was of about 3 for 1-hour hypoxic exposure. Piracetam gave no cytotoxic effect up to 10 mM of piracetam. Growth curves after continuous drug exposure and 1-hour euoxic versus hypoxic exposure gave no cytotoxic effect up to 10 mM of piracetam. Survival curves after continuous drug exposure to 10 mM of piracetam gave no significant effect on the radiosensitivity of hypoxic V79 cells using MTT or clonogenic assay. However, this does not preclude a potential in vivo effect of piracetam on the radiosensitivity owing to its action on microcirculation and its rheologic properties. The adaptation of the MTT assay to hypoxic irradiation conditions yields the easy screening of radiosensitizing drugs: shorter incubation, semi-automatic method and simultaneous analysis with different serial concentrations thanks to the special 48-well glass plates.

Resistance patterns between cis-diamminedichloroplatinum(II) and ionizing radiation.

Cross-resistance between cis-diamminedichloroplatinum(II) (CDDP) and radiation resistance has been suggested from clinical and experimental data (C. T. Coughlin and R. C. Richmond, Semin. Oncol., 16: 31-43, 1989). To determine whether cross-resistance patterns between both cytotoxic approaches exist, resistance against CDDP and ionizing radiation was induced separately in human ovarian cancer cells in a cross-over design. Subsequently sensitivity changes were determined for both treatment modalities. CDDP resistance was induced previously (P. J. Kuppen et al., Cancer Res., 48: 3355-3359, 1988), and resistant cells were grown at three different levels of CDDP:0 ng/ml; 250 ng/ml; and 500 ng/ml. Resistance with resistance factor (RF) 3.4 to 5.1 proved to be stable, since withdrawal of CDDP pressure for at least 6 mo did not alter resistance patterns. CDDP-resistant cells also demonstrated stable resistance against ionizing radiation, with RF ranging from 1.7 to 2.0. The resistance patterns could not be explained by differences in growth kinetics and DNA content. Resistance to ionizing radiation was induced in the same human ovarian cancer cells as used for CDDP resistance studies. Exposure with 1.5 Gy of intermittent irradiation during 6 mo, at time intervals of 48 h, resulted in cells which were able to grow under chronic ionizing radiation pressure. RF was 2.0; the resistance was lost after 6 mo of culturing without ionizing radiation pressure. With intermittent radiation doses of 0.5 and 1.0 Gy, no significant resistance could be induced. Cells intermittently exposed to 0.5, 1.0, and 1.5 Gy during 6 mo demonstrated increased sensitivity to CDDP, with 0.22 less than RF less than 0.43. Increased sensitivity was associated with proportionally increased formation of the platinum-DNA adducts. Differences in sensitivity for both ionizing radiation and CDDP were lost after 6 mo of culturing without radiation pressure; therefore, resistance toward ionizing radiation and, likewise, the increased sensitivity to CDDP, were judged to be unstable. In conclusion, data of the present study demonstrated that development of stable resistance to CDDP is associated with development of stable resistance to ionizing radiation in human ovarian cancer. Contrastingly, increased sensitivity to CDDP was found when resistance against irradiation was induced in the same cells.