[Indications and limits of ablative therapies in prostate cancer]. / Indications et limites actuelles des traitements ablatifs dans le cancer de la prostate.

OBJECTIVE: To perform a state of the art about indications and limits of ablative therapies for localized prostate cancer. METHODS: A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 107 articles were analysed. RESULTS: The objective to combine reduction of side effects and oncological control has induced recent development of several ablative therapies. Beyond this heterogeneity, some preferential indications appear: unilateral cancer of low risk (but with significant volume, excluding active surveillance) or intermediate risk (excluding majority of grade 4); treatment targeted the index lesion, by quarter or hemi-ablation, based on biopsy and mpMRI. In addition, indications must considered specific limits of each energy, such as gland volume and tumor localization. CONCLUSION: Based on new imaging and biopsy, ablative therapies will probably increased its role in the future in management of localize prostate cancer. The multiple ongoing trials will certainly be helpful to better define their indications and limits.

[Evaluation and results of ablative therapies in prostate cancer]. / Modalités d'évaluation et résultats des traitements ablatifs dans le cancer de la prostate.

OBJECTIVE: To perform a state of the art about methods of evaluation and present results in ablative therapies for localized prostate cancer. METHODS: A review of the scientific literature was performed in Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of keywords. Publications obtained were selected based on methodology, language and relevance. After selection, 102 articles were analysed. RESULTS: Analyse the results of ablative therapies is presently difficult considering the heterogeneity of indications, techniques and follow-up. However, results from the most recent and homogeneous studies are encouraging. Oncologically, postoperative biopsies (the most important criteria) are negative (without any tumor cells in the treated area) in 75 to 95%. Functionally, urinary and sexual pre-operative status is spared (or recovered early) in more than 90% of the patients treated. More and more studies underline also the correlation between the results and the technique used considering the volume of the gland and, moreover, the "index lesion" localization. CONCLUSION: The post-treatment pathological evaluation by biopsies (targeted with MRI or, perhaps in a near future, with innovative ultrasonography) is the corner stone of oncological evaluation of ablative therapies. Ongoing trials will allow to standardize the follow-up and determine the best indication and the best techniques in order to optimize oncological and functional results for each patient treated.

First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.

BACKGROUND: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma. METHODS: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg. RESULTS: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%). CONCLUSIONS: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

[Does radiation therapy for prostate cancer increase the risk of second cancers?] / La radiothérapie du cancer de la prostate augmente-t-elle le risque de seconds cancers ?

PURPOSE: The increased risk of second cancer after prostate radiotherapy is a debated clinical concern. The objective of the study was to assess the risk of occurrence of second cancers after prostate radiation therapy based on the analysis the literature, and to identify potential factors explaining the discrepancies in results between studies. MATERIALS AND METHODS: A review of the literature was carried out, comparing the occurrence of second cancers in patients all presenting with prostate cancer, treated or not by radiation. RESULTS: This review included 30 studies reporting the occurrence of second cancers in 2,112,000 patients treated or monitored for localized prostate cancer, including 1,111,000 by external radiation therapy and 103,000 by brachytherapy. Regarding external radiation therapy, the average follow-up was 7.3years. The majority of studies (80%) involving external radiation therapy, compared to no external radiation therapy, showed an increased risk of second cancers with a hazard ratio ranging from 1.13 to 4.9, depending on the duration of the follow-up. The median time to the occurrence of these second cancers after external radiotherapy ranged from 4 to 6years. An increased risk of second rectal and bladder cancer was observed in 52% and 85% of the studies, respectively. Considering a censoring period of more than 10 years after irradiation, 57% and 100% of the studies found an increased risk of rectal and bladder cancer, without any impact in overall survival. Studies of brachytherapy did not show an increased risk of second cancer. However, these comparative studies, most often old and retrospective, had many methodological biases. CONCLUSION: Despite numerous methodological biases, prostate external radiation therapy appears associated with a moderate increase in the risk of second pelvic cancer, in particular bladder cancer, without impacting survival. Brachytherapy does not increase the risk of a second cancer.

Prevention of radiation-induced cancers.

The issue of radiation-induced cancers must be taken into consideration during therapeutic irradiations. Risk factors for radiation-induced cancer include: the age of the patients, the volumes irradiated, the presence of risk cofactors and the exposure of critical organs. Those should be part of the therapeutic decision, in terms of indication, as well as choice of the radiotherapy technique (including repositioning systems). We present the update of the recommendations of the French society for radiation oncology on the modalities for preventing radiation-induced cancers.

Prostate cancer brachytherapy: SFRO guidelines 2021.

Prostate brachytherapy techniques are described, concerning both permanent seed implant and high dose rate brachytherapy. The following guidelines are presented: brachytherapy indications, implant procedure for permanent low dose rate implants and high dose rate with source projector, as well as dose and dose-constraints objectives, immediate postoperative management, post-treatment evaluation, and long-term follow-up.

Male pattern baldness and the risk of prostate cancer.

BACKGROUND: Androgens play a role in the development of both androgenic alopecia, commonly known as male pattern baldness, and prostate cancer. We set out to study if early-onset androgenic alopecia was associated with an increased risk of prostate cancer later in life. PATIENTS AND METHODS: A total of 669 subjects (388 with a history of prostate cancer and 281 without) were enrolled in this study. All subjects were asked to score their balding pattern at ages 20, 30 and 40. Statistical comparison was subsequently done between both groups of patients. RESULTS: Our study revealed that patients with prostate cancer were twice as likely to have androgenic alopecia at age 20 [odds ratio (OR) 2.01, P = 0.0285]. The pattern of hair loss was not a predictive factor for the development of cancer. There was no association between early-onset alopecia and an earlier diagnosis of prostate cancer or with the development of more aggressive tumors. CONCLUSIONS: This study shows an association between early-onset androgenic alopecia and the development of prostate cancer. Whether this population can benefit from routine prostate cancer screening or systematic use of 5-alpha reductase inhibitors as primary prevention remains to be determined.

[Low-dose irradiation of non-malignant diseases: Did we throw the baby out with the bathwater?] / Irradiation à faible dose des affections non cancéreuses : avons-nous jeté le bébé avec l'eau du bain ?

The irradiation of non-malignant diseases, essentially for anti-inflammatory purpose, have been largely proposed and performed worldwide until the 1970-80s. At that time, the better assessment of the radio-induced malignancies, essentially in children and young patients, as well as the efficacy of the new anti-inflammatory drugs (steroids and non-steroids), led to the almost disappearance of those techniques, at least in France. In contrast, our German colleagues are still going on treating about 50,000 patients per year for non-malignant (more or less severe) diseases. After a short historical overview, the present article suggests that we were possibly going too far in the rejection of those low-dose irradiations for benign lesions. The recent emergence of new preclinical data, the better understanding of the risk of radio-induced secondary tumours (almost nil in the elderly), and the severity of some situations, such as the cytokine storm of the COVID-19, should probably lead us to reconsider those low - and sometimes very low (less than 1Gy) - irradiations for well-selected indications in the elderly.

[The 30th anniversary of SFRO, the French society of oncological radiotherapy]. / Les 30 ans de la SFRO.

The French society of oncological radiotherapy (Société française de radiothérapie oncologique, SFRO) was created in 1990. On the occasion of its thirtieth annual congress, in October 2019, a session was devoted to it, with the objective of exposing its functioning, its actions and its productions during these three decades during which radiotherapy and oncology have undergone unprecedented transformations. We propose in this article to outline the content of this session.

Molecular therapy in support to radiotherapy.

Approximately half of all cancer patients are treated with radiation therapy. However, some tumor cells can escape the lethal effects of irradiation by hypoxia, deregulation of the cell cycle or apoptosis or by increasing their ability to repair the DNA damage induced, resulting in recurrence of disease. In order to overcome these resistance mechanisms, various strategies have been developed. Over the last decade, extensive progress in human genomics and genetic tools has been made. Several methods using DNA or RNA molecules have been developed to target angiogenesis or other cellular functions in order to restore sensitivity to irradiation. In this review, we focus on five classes of nucleic acid-based approaches, (i) gene transfer by recombinant plasmid or virus, (ii) immune-stimulating oligonucleotides, (iii) antisense oligonucleotides, (iv) siRNA and shRNA, and (v) siDNA (signal interfering DNA), which target specific proteins or pathways involved in radioresistance. We review the results of the preclinical studies and clinical trials conducted to date by combining nucleic acid-based molecular therapy and radiotherapy.

[Reirradiations: Which decision-making criteria?] / Réirradiations : quels critères décisionnels ?

The decision to reirradiate a volume which had been previously irradiated remains in 2019 one of the most difficult challenge for a radiation oncologist. Such a decision has to be based on a number of clinical and technological criteria, and the radiation oncologist will have to answer three main questions: i) can the patient clinically tolerate a second irradiation in the same previously irradiated area? While waiting for fully reliable individual tests of radiosensitivity, one has to take into account the tolerance of the first irradiation, as well as the comorbidities and/or habits which could impact the patient intrinsic radiosensitivity; ii) do the technical data of the first radiotherapy allow a re-irradiation? Unfortunately, and essentially when the discussion of re-irradiating the patient occurs many years (or even decades) after the first treatment, those precise technical data can be missing; iii) which technique should be used for the re-irradiation? In such a specific situation, the patient should be offered the more precise modern technology: stereotactic radiotherapy, protons, brachytherapy (low-, high-, or pulsed-dose rate). The indisputable improvement of the ballistic precision linked to our new technologies should lead to refine and to develop the indications of re-irradiation in the next future.

[Which alpha/beta ratio for prostate cancer in 2019?] / Quel rapport alpha/bêta pour le cancer prostatique en 2019 ?

In 1999, Brenner and Hall reported for prostate cancer a very low alpha/beta ratio (1.5Gy). In the following years, this value has been confirmed by a large series of papers, so that this very low alpha/beta ratio became a "dogma", on which a large number of hypofractionated schemes were being built. This was logical, since this very low value strongly suggested a beneficial advantage of hypofractionation for prostate cancer. However, more recently, several questions arose; first, a number of authors reported, from the analysis of their own data, values of alpha/beta ratio which were higher than the "dogma". Secondly, the three modern "superiority trials", aiming at demonstrating the advantages of hypofractionated schemes, actually failed to show such a superiority, in spite of high equivalent doses (calculated with an alpha/beta of 1.5Gy), reaching up to 84 - 90Gy. In 2018, three review papers/metanalyses shed a new light on what could be the value of the alpha/beta ratio for prostate cancer. In particular, those studies took into account a "time factor" (for repopulation), a parameter which had been either forgotten or underestimated before. In those three studies, the alpha/beta ratio was ranging from 2.7Gy to 4.9Gy. Those data do confirm the sensitivity to the fraction dose variation of prostate cancer, but this sensitivity could be lower than suggested by an alpha/beta ratio of 1.5Gy.

[Which photon energy for intensity-modulated radiotherapy and volumetric-modulated arctherapy in 2019?] / Quelle énergie de photons pour la modulation d'intensité et l'arcthérapie volumétrique en 2019 ?

For more than a decade, the majority of radiation oncology centres have been delivering intensity-modulated radiotherapy (then volumetric-modulated arctherapy) with 6 MV photons as their standard of care. This « dogma ¼ had been supported by the usual absence of dosimetric advantages with high-energy photons (15 to 18 MV or more), at least for the planning target volume and the dose received by the adjacent organs at risk, and by the neutron component as soon as the photon energy exceeds 10 MV. Recent data could question such a dogma. First, in 2019, one cannot avoid taking into account the integral dose, delivered outside the treated volume. Actually, most available data show that integral dose is higher with low energy photons (as 6 MV) than with higher energies. Moreover, recent studies have shown that the neutron component at high energies may have been overestimated in the past; in fact, the neutron dose appears to be lower, and sometimes much lower, than the dose we accept for imaging. Finally, a few cohort studies did not show any increase in second cancers incidence after high-energy photon radiotherapy. In such a context, the American Association of Physicists in Medicine (AAPM) TG 158 document, released a few months ago, clearly states that there is a trade-off between high- and low-energy treatments. High-energy therapy is associated with neutron production, while low-energy therapy results in higher stray photon dose. According to the AAPM, « the optimal energy is likely an intermediate such as 10 MV ¼.

[Permanent implant prostate cancer brachytherapy]. / La curiethérapie du cancer prostatique par implants permanents.

With an experience of more than 20 years for the pionneers (and more than 10 years in France), permanent implant brachytherapy using Iodin 125 seeds is now recognized as a valuable alternative therapy for localized low-risk prostate cancer patients. An extension of the indications of exclusive brachytherapy towards selected patients in the intermediate-risk group is presently under study. Moreover, for patients in the high-risk group, brachytherapy, as an addition to external radiotherapy, could represent one of the best way to escalate the dose for some patients. Various permanent implant brachytherapy techniques have been proposed; preplanning or real-time techniques, loose seeds or stranded seeds, manual or automatic injection of the seeds. The main point here is the ability to perfectly master the procedure and to comply with the dosimetric constraints which have been recently redefined by the Groupe européen de curiethérapie--European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) group. Mid- and long-term results which are now available in the literature indicate relapse-free survival of about 90% at 5-10 years, the best results being obtained with satisfactory dosimetric data. Some comparative data have shown that the incontinence and impotence rates after brachytherapy seemed to be significantly inferior to what is currently observed after surgery. However, a risk of about 3-5% of urinary retention is usually reported after brachytherapy, as well as an irritative urinary syndrome which may be significant and last several months. In spite of those drawbacks, with excellent long-term results and low rates of incontinence and impotence, brachytherapy can be expected to be proposed to an increasing number of patients in France in the next future.

[PSA bounce after permanent implant prostate brachytherapy may mimic a biochemical failure]. / Influence sur les résultats des rebonds du PSA après curiethérapie de prostate: étude de 295 cas avec trois ans de suivi.

PURPOSE: To assess the frequency of the PSA "bouncing" phenomenon after a significant follow-up in a series of patients treated by permanent implant brachytherapy for a prostate cancer. To look for the clinical and dosimetric parameters possibly linked to this transitory secondary PSA increase. To evaluate in which percentage of cases this bouncing could have mimicked a biochemical relapse according to the ASTRO consensus criteria. PATIENTS AND METHODS: From January 1999, to December 2001, 295 patients were treated by a permanent prostate implantation (real-time technique, with free (125)I seeds- Isoseed Bebig-) by the Institut Curie-Hôpital Cochin-Hôpital Necker Paris group. The mean follow-up is 40.3 months (9-66 months). The PSA level was regularly checked, at least every 6 months. We defined as a "bouncing" all increase in PSA, starting at 0.1 ng/ml, subsequently followed by a spontaneous (without any treatment) decrease, with return to the previous level or lower. We particularly focused on the patients fulfilling the criteria for a biochemical relapse according to the ASTRO consensus (Three successive increases in PSA). A multivariate analysis tried to identify independent factors among the usual clinical and dosimetric parameters. RESULTS: In our series, 161 patients (55%) showed a transitory PSA increase (bouncing) of at least 0.1 ng/ml; 145 patients (49%) a bouncing of 0.2 ng/ml, 93 patients (32%) a bouncing of 0.4 ng/ml and 43 patients (15%) a bouncing of at least 1 ng/ml. Mean PSA bounce was 0.8 ng/ml (0.1-4.1), and mean time to bounce was 19 months. Thirty-two patients (11% of the total number) presented three successive PSA increases with a significant (3 months) interval between the dosages, and therefore were to be considered as being in biochemical relapse according to the ASTRO consensus criteria. Actually, among those 32 patients, 18 (56%) subsequently showed a complete normalization of their PSA, without any treatment. Ten patients went on increasing their PSA, and were considered to be really in biochemical relapse. For the last 4 patients, the situation still remains ambiguous. In multivariate analysis, age<70 years (P<0.00001) and D90>200 Gy (P<0.003) were identified as independent factors for a PSA bouncing of at least 0.4 ng/ml. CONCLUSIONS: The observed rate of 32% of patients showing a PSA bouncing of at least 0.4 ng/ml in our series is in good agreement with what has been previously reported in the literature. Age<70 years and D90>200 Gy were found to be independent factors predicting for such a secondary transitory increase in PSA. Interestingly, among 32 patients fulfilling the classical criteria of the ASTRO for a biochemical relapse, 18 (56%) subsequently showed a spontaneous PSA decrease, demonstrating that the ASTRO consensus is not well adapted to the biochemical follow-up of our patients undergoing permanent implant prostate Brachytherapy.

[Clinical and dosimetric analysis of 469 prostate cancer patients treated in France in 2005 by permanent implant brachytherapy using the Iodin 125 seeds IsoSeed Bebig: report to the French Economic committee of health products (CEPS)]. / Analyse clinique et dosimétrique de 469 patients traités en France en 2005 par implantation prostatique de grains d'iode 125 IsoSeed Bebig: rapport pour le Comité économique des produits de santé (CEPS).

A French decree of February 3rd 2005, allowed the Iodin 125 seeds from several companies to be reimbursed after a permanent implantation brachytherapy for a prostate cancer. Within this frame, the French "Comité économique des produits de santé" (CEPS; Economic committee for health products) made mandatory the annual writing and publication of a follow-up study with three main aims; make sure that the seeds were used for prostate cancer patients with criterias corresponding to the national recommendations, analyze the quality of the dosimetric data, and report all side effects, complications and possible accidents. We therefore report here a clinical and dosimetric analysis of 469 patient cases treated in France in nine centers in 2005 with the Iodin 125 IsoSeed Bebig. This analysis shows that: 1) The national recommendations for selecting patients for exclusive prostate brachytherapy have been taken into account in 97% of the cases; 2) The dosimetric quality criterias totally fulfilled the recommendations in a large majority of cases; the intra-operative D90 was found to be superior to 145 Gy in 98% of the patients, and the intra-operative V100 was superior to 95% in 96% of the cases; 3) The early toxicity (mainly urinary) was found to be at the lower range of what is reported in the literature, with in particular a retention rate of 2.4%.

[Hypofractionated irradiation of prostate cancer: What is the radiobiological understanding in 2017?] / Irradiation hypofractionnée du cancer de prostate : quelles connaissances radiobiologiques en 2017 ?

For prostate cancer, hypofractionation has been based since 1999 on radiobiological data, which calculated a very low alpha/beta ratio (1.2 to 1.5Gy). This suggested that a better local control could be obtained, without any toxicity increase. Consequently, two types of hypofractionated schemes were proposed: "moderate" hypofractionation, with fractions of 2.5 to 4Gy, and "extreme" hypofractionation, utilizing stereotactic techniques, with fractions of 7 to 10Gy. For moderate hypofractionation, the linear-quadratic (LQ) model has been used to calculate the equivalent doses of the new protocols. The available trials have often shown a "non-inferiority", but no advantage, while the equivalent doses calculated for the hypofractionated arms were sometimes very superior to the doses of the conventional arms. This finding could suggest either an alpha/beta ratio lower than previously calculated, or a negative impact of other radiobiological parameters, which had not been taken into account. For "extreme" hypofractionation, the use of the LQ model is discussed for high dose fractions. Moreover, a number of radiobiological questions are still pending. The reduced overall irradiation time could be either a positive point (better local control) or a negative one (reduced reoxygenation). The prolonged duration of the fractions could lead to a decrease of efficacy (because allowing for reparation of sublethal lesions). Finally, the impact of the large fractions on the microenvironment and/or immunity remains discussed. The reported series appear to show encouraging short to mid-term results, but the results of randomized trials are still awaited. Today, it seems reasonable to only propose those extreme hypofractionated schemes to well-selected patients, treating small volumes with high-level stereotactic techniques.

[Salvage prostate brachytherapy: A solution for local failures after a primary radiation therapy?] / Curiethérapie prostatique de rattrapage : solution pour les rechutes localisées après irradiation ?

Salvage brachytherapy after a first prostate radiation therapy is an emerging technique, which has to be considered in the therapeutic armamentarium in the clinically challenging context of patients with isolated local failure from prostate cancer who may still be considered for cure. These occult failures are more and more frequently diagnosed at an early stage, thanks to targeted biopsies and advances in imaging modalities, such as multiparametric MRI and PET-CT. Salvage brachytherapy benefits from the implantation accuracy of brachytherapy procedures using 3D dosimetry and has resulted in more than 50% tumour control rates with long-term. Incontinence rates are always below those of other salvage treatments such as radical prostatectomy, HIFU or cryotherapy. Today, a consensus has been reached to better define good candidates for salvage brachytherapy with respect to disease characteristics at baseline and at failure. No consensus has been clearly defined yet regarding the choice of the technique (low or high dose rate), the total dose to be delivered, or the volume to be implanted (whole gland or focal). While we await robust data from recently completed phase II studies and given the heterogeneous results in the literature, this technique (although already included in the last 2016 NCCN guidelines) remains to be precisely evaluated, optimally within the frame of controlled trials.

[Repair and time-dose factor: The example of spinal cord irradiation]. / Réparation et facteur temps : l'exemple de l'irradiation médullaire.

The question whether a reirradiation is possible, with either curative of palliative intent, is a frequent issue and a true therapeutic challenge, in particular for a critical organ sensitive to cumulative dose, such as the spinal cord. Preclinical experimental data, based on debatable models that are hardly transferable to patients, suggest that there is a possibility of reirradiation, beyond the classical threshold for dose constraints, taking into account the "time-dose factor". Although the underlying biological mechanisms are however uncertain, scarce clinical data seem to confirm that the tolerance of spinal cord to reirradiation does exist, provided that a particular attention to total dose is given. In the context where modern stereotactic irradiation facilities expand therapeutic perspectives, we review the literature on possibilities of reirradiation, through the example of spinal cord reirradiation.

Second malignancies after permanent implant prostate cancer brachytherapy: A single-institution study of 675 patients treated between 1999 and 2003.

PURPOSE: To analyse the rate of secondary malignancies observed in a series of 675 prostate cancer patients who underwent a permanent implant brachytherapy between 1999 and 2003, and to compare the incidence with the expected rate in a matched general French population. MATERIAL AND METHODS: The cohort included low-risk patients and a selection of "favourable-intermediate" risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125-iodine seeds and a prescription dose of 145Gy. The mean follow-up was 132 months. RESULTS: The 10-year overall survival for the entire cohort was 92% (95% confidence interval [CI]: 90-94). The 10-year relapse-free survival rate was 82% (95% CI: 79-85). Overall, 61 second cancers were registered. When comparing with a matched general French population, the standard incidence ratio (SIR) for bladder cancer was 1.02 (95% CI: 0.46-1.93). For colorectal cancer, the SIR was 0.45 (95% CI: 0.19-0.89). For lung cancer, the SIR was 0.38 (95% CI: 0.17-0.76). The SIR for all cancers was 0.61 (95% CI: 0.47-0.79). When excluding secondary colorectal and lung cancers (both with low SIRs in this series), the SIR for all cancers was 1.06 (95% CI: 0.77-1.29). CONCLUSION: With a mean follow-up of more than 11 years, this series does not detect any excess risk of second cancers associated with permanent implant prostate brachytherapy. However, due to power limitation, a small increase in the risk of secondary malignancies cannot be totally ruled out.