S. Supiot

Cancer radioimmunotherapy with alpha-emitting nuclides

In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with β-emitters for the treatment of refractory cases. The development of novel RIT with α-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of α-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with α-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of α-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an α-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with α-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of α-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial

BACKGROUNDnHow best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy.nnnMETHODSnThis open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475.nnnFINDINGSnBetween Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be free of biochemical progression or clinical progression at 5 years (80% [95% CI 75-84] vs 62% [57-67]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). No additional late adverse events occurred in patients receiving short-term androgen suppression compared with those who received radiotherapy alone. The most frequently occuring acute adverse events related to goserelin were hot flushes, sweating, or both (30 [8%] of 366 patients had a grade 2 or worse event; 30 patients [8%] had hot flushes and five patients [1%] had sweating in the radiotherapy plus goserelin group vs none of 372 patients in the radiotherapy alone group). Three (8%) of 366 patients had grade 3 or worse hot flushes and one patient had grade 3 or worse sweating in the radiotherapy plus goserelin group versus none of 372 patients in the radiotherapy alone group. The most common late adverse events of grade 3 or worse were genitourinary events (29 [8%] in the radiotherapy alone group vs 26 [7%] in the radiotherapy plus goserelin group) and sexual disorders (20 [5%] vs 30 [8%]). No treatment-related deaths occurred.nnnINTERPRETATIONnAdding short-term androgen suppression to salvage radiotherapy benefits men who have had radical prostatectomy and whose PSA rises after a postsurgical period when it is undetectable. Radiotherapy combined with short-term androgen suppression could be considered as a reasonable option in this population.nnnFUNDINGnFrench Ministry of Health, AstraZeneca, and La Ligue Contre le Cancer.

Stereotactic body radiation therapy for abdominal oligometastases: a biological and clinical review

Advances in imaging and biological targeting have led to the development of stereotactic body radiation therapy (SBRT) as an alternative treatment of extracranial oligometastases. New radiobiological concepts, such as ceramide-induced endothelial apoptosis after hypofractionated high-dose SBRT, and the identification of patients with oligometastatic disease by microRNA expression may yet lead to further developments. Key factors in SBRT are delivery of a high dose per fraction, proper patient positioning, target localisation, and management of breathing–related motion. Our review addresses the radiation doses and schedules used to treat liver, abdominal lymph node (LN) and adrenal gland oligometastases and treatment outcomes. Reported local control (LC) rates for liver and abdominal LN oligometastases are high (median 2-year actuarial LC: 61 -100% for liver oligometastases; 4-year actuarial LC: 68% in a study of abdominal LN oligometastases). Early toxicity is low-to-moderate; late adverse effects are rare. SBRT of adrenal gland oligometastases shows promising results in the case of isolated lesions. In conclusion, properly conducted SBRT procedures are a safe and effective treatment option for abdominal oligometastases.

Current state of knowledge regarding the use of antiangiogenic agents with radiation therapy

Angiogenesis has been a central theme of oncologic research for several years. Recently, improved understanding of its mechanisms has led to the development of several antiangiogenic agents. Some have demonstrated their effectiveness in large randomized studies; however, no antiangiogenic agent has yet been approved for treatment in combination with radiotherapy. Numerous preclinical studies and a few small clinical trials have recently reported encouraging results. The objective of this article is to review the concept of targeted antiangiogenic agents and the early clinical results of their use in combination with radiation therapy.

« Dose-painting »: mythe ou réalité ?

Dose-painting radiotherapy allows for a heterogeneous delivery of radiation within the tumour volume by targeting radioresistant areas defined by functional imaging. Within gross tumour volume, it is possible to define one or more target volumes based on biology (biological target volume [BTV]) and to apply a strategy of intensity modulated radiation therapy (IMRT) that will deliver a higher dose to these regions. In this review of the literature, we will highlight the biological elements responsible for radioresistance, and how to image them, then we will detail the radiotherapy techniques necessary for this approach, before presenting clinical results in various situations (head and neck tumours, prostate, brain tumours, etc.). Despite many difficulties that make dose-painting IMRT unusable in routine nowadays, biology-guided radiation therapy represents one of the major pathways of development of radiotherapy in the coming years.

Underestimation of dose delivery in preclinical irradiation due to scattering conditions

UNLABELLEDnThe aim of this study was to evaluate, by comparing simulation results with measurement results, the impact of the lack of scattering volume in experimental conditions of preclinical irradiation. First, a Monte Carlo model of a small animal irradiator, the Faxitron CP-160, was developed with GATE (Geant4 Application for Tomography Emission). To validate the model, simulated data were compared to depth dose and off-axis ratio profiles measured with a plane-parallel ionization chamber and Gafchromic(®) EBT films, respectively, in a solid water phantom. The AAPM TG-61 protocol was applied to measure the dose rate at the surface of a semi-infinite reference phantom. Then, the model was used to determine the dose distributions in three different phantom settings: a semi-infinite water phantom, a 2.8-cm-thick water phantom and a 2.8-cm-diameter cylindrical water phantom. The dose distributions measured and simulated with Monte Carlo methods in a semi-infinite water phantom were similar (<2%), thus validating our Monte Carlo model. The highest dose underestimation was observed between the reference and the cylindrical phantom (more than 15% difference for the entrance dose) and was due to the lack of lateral scatter and backscatter. The use of standard backscatter factors and AAPM TG-61 protocol may result in a significant underestimation of the dose absorbed by small irradiated phantoms, such as mice or cells, in preclinical studies.nnnBACKGROUNDnFor preclinical radiotherapy studies, radiobiologists were used to determine the irradiation time depending only on the source surface distance. This work aimed to demonstrate that scatter conditions have a large impact on dose rate. Measurements and Monte Carlo simulations were used.

Toxicité rectale de la radiothérapie : signes cliniques, physiopathologie et prise en charge

Radiotherapy is a major treatment of pelvic tumours. It exposes to the risk of acute and long-term side effects, such as radiation proctitis. Radiation proctitis is a complex disease requiring support ranging from initial contact with the patient until several years after completion of radiotherapy. This care includes preventive measures (clinical and dosimetric factors), detection and medical and surgical treatments. This article aims to make a review of radiation proctitis induced during the treatment of pelvic cancers.

Doses délivrées par l’imagerie de contrôle en radiothérapie externe guidée par l’image

Image-guided radiotherapy is defined by the use of images acquired in the treatment room to improve the accuracy of patient positioning. Most of imaging devices use X-rays and deliver an additional dose to the patients. These non-negligible doses have to be evaluated and reported. Several studies have investigated organ-absorbed dose due to in-room imaging. Some organ doses are reported to give an idea of the magnitude, in particular for prostate cancer. Then, principles based on the as low as reasonably achievable (ALARA) concept are described and adapted to image-guided radiotherapy. Justification (what is the patient outcome?) and optimisation (image modality, acquisition frequency, treatment site...) are two main issues. They have a really big impact on patient treatment and staff organization.

Radiothérapie des cancers de l’enfant

The purpose of this article is to describe the specificities of paediatric radiation oncology: cancer types, radiotherapy indications, techniques, organisation and reglementary framework.

Daily versus weekly prostate cancer image-guided radiotherapy: Phase 3 multicenter randomized trial

PURPOSEnThe optimal frequency of prostate cancer image guided radiation therapy (IGRT) has not yet been clearly identified. This study sought to compare the safety and efficacy of daily versus weekly IGRT.nnnMATERIALS AND METHODSnThis phase 3 randomized trial recruited patients with N0 localized prostate cancer. The total IGRT doses in the prostate ranged from 70xa0Gy to 80xa0Gy, sparing the lymph nodes. Patients were randomly assigned (1:1) to 2 prostate IGRT frequency groups: daily and weekly (ie, on days 1, 2, and 3 and then weekly). The primary outcome was 5-year recurrence-free survival. Secondary outcomes included overall survival and toxicity. Post hoc analyses included biochemical progression-free interval, clinical progression-free interval, and other cancer-free interval.nnnRESULTSnBetween June 2007 and November 2012, 470 men from 21 centers were randomized into the 2 groups. Median follow-up was 4.1xa0years. There was no statistically significant difference in recurrence-free survival between the groups (hazard ratio [HR]xa0=xa00.81; Pxa0=xa0.330). Overall survival was worse in the daily group than in the weekly group (HRxa0=xa02.12 [95% confidence interval (CI), 1.03-4.37]; Pxa0=xa0.042). Acute rectal bleeding (grade ≥1) was significantly lower in the daily group (6%) (n = 14) than in the weekly group (11%) (n = 26) (Pxa0=xa0.014). Late rectal toxicity (grade ≥1) was significantly lower in the daily group (HRxa0=xa00.71 [95% CI, 0.53-0.96]; Pxa0=xa0.027). Biochemical progression-free interval (HRxa0=xa00.45 [95% CI, 0.25 - 0.80]; Pxa0=xa0.007) and clinical progression-free interval (HRxa0=xa00.50 [95% CI, 0.24-1.02]; Pxa0=xa0.057) were better in the daily group, whereas other cancer-free interval was worse in the daily group (HRxa0=xa02.21 [95% CI, 1.10-4.44]; Pxa0=xa0.026).nnnCONCLUSIONSnCompared with weekly control, daily IGRT control in prostate cancer significantly improves biochemical progression-free and clinical progression-free interval, and rectal toxicity.