[Place of Linacs in extracranial stereotactic radiotherapy: Are they now equivalent to Cyberknife®?] / Place des Linacs dans la radiothérapie stéréotaxique extra crânienne : sont-ils désormais non inférieurs au Cyberknife® ?

Extracranial stereotactic radiotherapy has developed recently, since the years 1990-2000. Devices specifically dedicated to this type of treatment were then developed and shared the favors of radiation oncologists: Tomotherapy® and especially Cyberknife®, which offered the advantage of "tracking" with the possibility of real time motion correction, allowing an increase in the precision of targeting volumes. Recently, the latest generations of linear accelerators (Linac) have been developed, integrating much higher dose rates, an improved ballistic precision with a very short treatment duration time and the possibility of real time motion management (with notably the possibility of adaptive radiotherapy in real time with the development of "MLC tracking"). So are Linacs able to perform equivalent (not inferior) extracranial stereotactic radiotherapy treatments to those with Cyberknife®, the historical gold standard in this field? This article presents a comparison of these two treatment devices, by successively considering dose distributions in the irradiated volume, distant received doses from this volume (including the "integral dose"), problems linked to the duration of the sessions and those linked to motion management.

COVID-19-Associated Pneumonia: Radiobiological Insights.

The evolution of SARS-CoV-2 pneumonia to acute respiratory distress syndrome is linked to a virus-induced "cytokine storm", associated with systemic inflammation, coagulopathies, endothelial damage, thrombo-inflammation, immune system deregulation and disruption of angiotensin converting enzyme signaling pathways. To date, the most promising therapeutic approaches in COVID-19 pandemic are linked to the development of vaccines. However, the fight against COVID-19 pandemic in the short and mid-term cannot only rely on vaccines strategies, in particular given the growing proportion of more contagious and more lethal variants among exposed population (the English, South African and Brazilian variants). As long as collective immunity is still not acquired, some patients will have severe forms of the disease. Therapeutic perspectives also rely on the implementation of strategies for the prevention of secondary complications resulting from vascular endothelial damage and from immune system deregulation, which contributes to acute respiratory distress and potentially to long term irreversible tissue damage. While the anti-inflammatory effects of low dose irradiation have been exploited for a long time in the clinics, few recent physiopathological and experimental data suggested the possibility to modulate the inflammatory storm related to COVID-19 pulmonary infection by exposing patients to ionizing radiation at very low doses. Despite level of evidence is only preliminary, these preclinical findings open therapeutic perspectives and are discussed in this article.

Focal Brachytherapy for Localized Prostate Cancer: Midterm Outcomes.

PURPOSE: Focal brachytherapy (F-BT) is a suitable technique for focal therapy in localized prostate cancer. It has the ability to adapt the seed implantation to the volume and location of the tumor. The aim of this study was to assess F-BT oncologic, functional, and toxicity midterm outcomes in men who underwent prostate cancer treatment. METHODS AND MATERIALS: The study included 39 men with low- to intermediate-risk prostate cancer treated with F-BT between 2010 and 2015. The dose prescription was 145 Gy. Failure was defined as the presence of any residual prostate cancer in the treated area. The primary and secondary endpoints were the F-BT oncologic and functional outcomes, respectively. A 2-sided P value < .05 indicated statistical significance. RESULTS: The mean follow-up time was 65 months (range, 43-104 months). After 24 months, 34 patients underwent control biopsies and 5 patients refused. The biopsies were negative in 27 cases (79%) and positive in 7 cases (21%), all outside the volume treated. Biochemical relapse-free survival at 5 years, disease-free survival, and overall survival were 96.8% ± 0.032%, 79.5% ± 0.076%, and 100%, respectively. The mean International Prostate Symptom Score at 2 months was significantly higher than initially (P = .0003), with no significant difference later. No late urinary, sexual, or rectal toxicity was observed. Salvage treatment was possible with good tolerance at 3.4 years of follow-up. Limitations of this study include the retrospective nature and lack of randomization. CONCLUSIONS: F-BT is a safe and effective treatment for selected patients presenting with low- or intermediate-risk localized prostate cancer.

Radiobiology: Foundation and New Insights in Modeling Brachytherapy Effects.

Fundamentals in radiobiology commonly known as the '4R's' concept (ie, reoxygenation, repair, redistribution, and repopulation) have mostly been investigated for external beam radiotherapy. However, these fundamentals can be applied to brachytherapy (BT) by accounting for differences in dose rate, fractionation, and response to immunologic agents for this treatment modality. Many improvements have been achieved in the era of dosimetric optimization but still limited data are available regarding radiobiological opportunities for BT. As BT is characterized by a large degree of dose heterogeneity, a wide range of dose rates and fractionations exist within the implanted volume. Calculations based on the linear quadratic model can be used to estimate the dose-response equivalence between various BT modalities. Such models are helpful in daily practice and open possibilities in terms of radiobiological optimization. However, some limitations should be highlighted in terms of the applicability of the linear quadratic model. Furthermore, in vitro models do not account for the complex interplay between the tumor and its microenvironment, including vascularization and/or immune response. Recently, an improved understanding of the tumor's microenvironment has led to investigations of immunomodulatory agents in combination with radiotherapy. BT is a promising candidate to enhance the immunogenic response with concomitant immunotherapy. This review summarizes some of the main mechanisms involved in tissue response to BT. Preclinical data, clinical evidence, as well as novel approaches to radiobiology are highlighted.

Is there any benefit to particles over photon radiotherapy?

Particle, essentially, proton radiotherapy (RT) could provide some benefits over photon RT, especially in reducing the side effects of RT. We performed a systematic review to identify the performed randomised clinical trials (RCTs) and ongoing RCTs comparing particle RT with photon therapy. So far, there are no results available from phase 3 RCTs comparing particle RT with photon therapy. Furthermore, the results on side effects comparing proton and carbon ion beam RT with photon RT do vary. The introduction of new techniques in photon RT, such as image-guided RT (IGRT), intensity-modulated RT (IMRT), volumetric arc therapy (VMAT) and stereotactic body RT (SBRT) was already effective in reducing side effects. At present, the lack of evidence limits the indications for proton and carbon ion beam RTs and makes the particle RT still experimental.

Inferring postimplant dose distribution of salvage permanent prostate implant (PPI) after primary PPI on CT images.

PURPOSE: To evaluate the dose distribution of additional radioactive seeds implanted during salvage permanent prostate implant (sPPI) after a primary permanent prostate implant (pPPI). METHODS AND MATERIALS: Patients with localized prostate cancer were primarily implanted with iodine-125 seeds and had a dosimetric assessment based on day 30 postimplant CT (CT1). After an average of 6 years, these patients underwent sPPI followed by the same CT-based evaluation of dosimetry (CT2). Radioactive seeds on each CT were detected. The detected primary seeds on CT1 and CT2 were registered and then removed from CT2 referred as a modified CT2 (mCT2). Dosimetry evaluations (D90 and V100) of sPPI were performed with dedicated planning software on CT2 and mCT2. Indeed, prostate volume, D90, and V100 differences between CT2 and either CT1 or mCT2 were calculated, and values were expressed as mean (standard deviation). RESULTS: The mean prostate volume difference between sPPI and pPPI over the 6 patients was 9.85 (7.32) cm3. The average D90 and V100 assessed on CT2 were 486.5 Gy (58.9) and 100.0% (0.0), respectively, whereas it was 161.3 Gy (47.5) and 77.3% (25.2) on mCT2 (p = 0.031 each time). The average D90 the day of sPPI [145.4 Gy (11.2)] was not significantly different from that observed on mCT2 (p = 0.56). CONCLUSION: Postimplant D90 and V100 of sPPI after pPPI can be estimated on CT images after removing the primary seeds.

Focal brachytherapy for localized prostate cancer: Urinary toxicity depends on tumor location.

PURPOSE: To evaluate whether patients with prostate cancer have worse functional urinary recovery with focal brachytherapy (FBT) at the base versus the apex of the prostate. METHODS AND MATERIALS: The functional outcomes of patients treated with FBT at the base of the prostate were compared with those of patients treated with FBT at the apex. Urinary symptoms, continence, and erectile dysfunction were measured using the International Prostate Symptom Score (IPSS), International Continence Score (ICS), and International Index of Erectile Function (IIEF-5) questionnaires, respectively, at baseline and at 6, 12, and 24 months after treatment. RESULTS: Twenty-eight and 13 patients were treated with FBT at the apex and the base, respectively, of the prostate. A significant difference between groups was found in the IPSS score at 6 months (mean IPSS: apex 6.4 ± 4.7, base 10.6 ± 5.7; p = 0.02), but not at baseline or at 12 and 24 months after treatment. On multivariate analysis, only FBT at the base of the prostate remained an independent predictor of worsening urinary symptoms (odds ratio, 5.8; p = 0.04). CONCLUSIONS: At 6 months after FBT, significantly less urinary toxicity was found in patients who underwent FBT at the apex versus the base of the prostate. Continence and sexual side effects were minimal in all patients.

Risk of second cancers in the era of modern radiation therapy: does the risk/benefit analysis overcome theoretical models?

In the era of modern radiation therapy, the compromise between the reductions in deterministic radiation-induced toxicities through highly conformal devices may be impacting the stochastic risk of second malignancies. We reviewed the clinical literature and evolving theoretical models evaluating the impact of intensity-modulated radiation therapy (IMRT) on the risk of second cancers, as a consequence of the increase in volumes of normal tissues receiving low doses. The risk increase (if any) is not as high as theoretical models have predicted in adults. Moreover, the increase in out-of-field radiation doses with IMRT could be counterbalanced by the decrease in volumes receiving high doses. Clinical studies with short follow-up have not corroborated the hypothesis that IMRT would drastically increase the incidence of second cancers. In children, the risk of radiation-induced carcinogenesis increases from low doses and consequently the relative risk of second cancers after IMRT could be higher than in adults, justifying current developments of proton therapy with priority given to this population. Although only longer follow-up will allow a true assessment of the real impact of these modern techniques on radiation-induced carcinogenesis, a comprehensive risk-adapted strategy will help minimize the probability of second cancers.

Focal radiotherapy as focal therapy of prostate cancer.

PURPOSE OF REVIEW: Focal radiotherapy treatment procedures play an increasingly important role in function-preservation and organ-preservation treatment techniques. As an alternative to traditional whole-gland radiotherapy regimes, focal prostate radiotherapy may be of benefit for both primary tumor as well as locally recurrent disease. This is a review of the current literature on the topic, including patient selection, preliminary toxicity, and outcome data as well as a technical overview on treatment delivery techniques. RECENT FINDINGS: Partial organ treatment in early prostate cancer (PCa) is now technically feasible with both newer external-beam and brachytherapy technology. To date, only small and generally monoinstitutional series have been published in the literature. Early feasibility and toxicity data are encouraging, and demonstrate potential advantages for the role of focal brachytherapy in early PCa. Although some advanced external-beam techniques can also be used to deliver focal therapy within the prostate, there is no relevant publication in the literature. SUMMARY: Radiotherapy, especially interventional radiotherapy (brachytherapy), is a technically feasible treatment technique to deliver focal radiotherapy for PCa. To date, only preliminary results are available for all forms of interventional radiotherapy (high dose rate, low dose rate, and pulsed dose rate) for focal PCa treatment and no large cohort comparative results are published. As interventional radiotherapy (brachytherapy) as yet lacks any such long-term studies, comparative outcome data are not available to suggest differences in efficacy for one form of brachytherapy or another.

[The issue of low doses in radiation therapy and impact on radiation-induced secondary malignancies]. / Le problème des faibles doses en radiothérapie : quel risque de carcinogenèse radio-induite ?

Several studies have well documented that the risk of secondary neoplasms is increasing among patients having received radiation therapy as part of their primary anticancer treatment. Most frequently, radiation-induced neoplasms occur in volume exposed to high doses. However, the impact of "low" doses (<5 Gy) in radiation-induced carcinogenesis should be clinically considered because modern techniques of intensity-modulated radiation therapy (IMRT) or stereotactic irradiation significantly increase tissue volumes receiving low doses. The risk inherent to these technologies remains uncertain and estimates closely depend on the chosen risk model. According to the (debated) linear no-threshold model, the risk of secondary neoplasms could be twice higher with IMRT, as compared to conformal radiation therapy. It seems that only proton therapy could decrease both high and low doses delivered to non-target volumes. Except for pediatric tumors, for which the unequivocal risk of second malignancies (much higher than in adults) should be taken into account, epidemiological data suggest that the risk of secondary cancer related to low doses could be very low, even negligible in some cases. However, clinical follow-up remains insufficient and a marginal increase in secondary tumors could counterbalance the benefit of a highly sophisticated irradiation technique. It therefore remains necessary to integrate the potential risk of new irradiation modalities in a risk-adapted strategy taking into account therapeutic objectives but also associated risk factors, such as age (essentially), chemotherapy, or life style.

Focal brachytherapy for selected low-risk prostate cancers: a pilot study.

PURPOSE: To evaluate the feasibility and the early toxicity of focal brachytherapy in highly selected localized prostate cancer patients. METHODS AND MATERIALS: Twenty-one patients underwent a focal brachytherapy between February 2010 and March 2012, representing 3.7% of the cases treated by our group during this period. Patient selection was based on (at least) two series of prostate biopsies and a high-resolution MRI. Only patients with very limited and localized tumors, according to strict criteria, were selected for the procedure. The technique used a real-time procedure with the implantation of free (125)I seeds and dynamic dose calculation. The prescribed dose for the focal volume was 145Gy. RESULTS: The treated volume corresponded to a mean value of 34% of the total prostatic volume (range, 20-48%). For the focal volume, the mean D90 and V100 was 183.2Gy (range, 176-188Gy) and 99.3% (range, 98.8-100%), respectively. The technique was performed in an hour and a half. When compared with a previous cohort treated by whole-prostate brachytherapy, urinary toxicity (International Prostate Symptom Score) was borderline reduced (p = 0.04) at 6 months only, whereas the recovery of the International Index of Erectile Function 5 was better (p = 0.014). The International Continence Score was nil in almost all cases as well as rectal toxicity. CONCLUSION: Focal treatment by brachytherapy is easily feasible with little acute toxicity. Further investigation is needed to assess the results in terms of tumor control and long-term toxicity.

Morbidity of focal therapy in the treatment of localized prostate cancer.

BACKGROUND: Focal therapy (FT) for prostate cancer (PCa) seems to be part of a natural evolution in the quest to improve the management of early organ-confined disease. OBJECTIVE: To assess the morbidity of the initial experience of FT in a tertiary referral center for PCa management. DESIGN, SETTING, AND PARTICIPANTS: From 2009 to 2011, a total of 1213 patients with clinically localized PCa were treated at our institution. Of these patients, 547 were considered to have indolent disease according to the D'Amico criteria for low-risk disease plus unilateral disease with a maximum of three positive biopsies. A total of 106 patients underwent FT using high-intensity focused ultrasonography (HIFU), brachytherapy, cryotherapy, or vascular-targeted photodynamic therapy (VTP). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complications were prospectively recorded and graded according to the Clavien-Dindo scale. Data were prospectively collected and retrospectively analyzed. RESULTS AND LIMITATIONS: This study included 106 patients, median age 66.5 yr (interquartile range [IQR]): 61-73), who had a prostate hemiablation; 50 patients (47%) had cryotherapy, 23 patients (22%) had VTP, 21 patients (20%) received HIFU, and 12 patients (11%) had brachytherapy. The median prostate-specific antigen (PSA) level was 6.1 ng/ml (IQR: 5-8.1), all the patients had a biopsy Gleason score of 6, and the median prostate weight was 43 g (IQR: 33-55). The median International Prostate Symptom Score was 6 (IQR: 3-10), and the median International Index of Erectile Function score was 20 (IQR: 15-23). After treatment, the median PSA at 3, 6, and 12 mo was 3.1 2.9, and 2.7 ng/ml (IQR: 2-5.1, 1.1-4.7, and 1-4.4), respectively. Thirteen percent of the patients experienced treatment-related complications. There were 11 minor medical complications (10 grade 1 complications and 1 grade 2 complication), 2 grade 3 complications, and no grade 4 or higher complications. CONCLUSIONS: FT for a highly selected population with PCa is feasible and had an acceptable morbidity with <2% major complications.

[Evolution of prostate cancer brachytherapy]. / L'évolution de la curiethérapie du cancer de prostate.

Curietherapy, more commonly named brachytherapy, is one of the oldest irradiation techniques used for prostate cancer. Prostate brachytherapy evolved according to the scientific and technological progress. After a historical reminder of the evolution of prostate brachytherapy, different technical aspects are discussed: low-dose rate brachytherapy using permanent or temporary implants, high-dose rate brachytherapy as well as new imaging modalities. Prostate brachytherapy indications are listed regarding to the evidence-based medicine data for low, intermediate and high risks prostate cancers. Potential indications and new research programs (focal therapy, high-dose rate, single-dose brachytherapy) are also presented.

One-step customized transurethral resection of the prostate and permanent implant brachytherapy for selected prostate cancer patients: technically feasible but too toxic.

INTRODUCTION: Patients with prominent median lobe hyperplasia and/or high International Prostate Symptom Score (IPSS) are often contraindicated for prostate brachytherapy, mainly because of the risk of post-implant urinary retention. We evaluated an approach combining in the same operative step a limited transurethral resection (TURP) of the median lobe, immediately followed by permanent implant-free seed brachytherapy. METHODS AND MATERIALS: From January 2007 to November 2008, 22 patients underwent a customized limited TURP of their median lobe immediately before brachytherapy. All patients fulfilled our criteria for permanent implant brachytherapy, but presented with a more or less prominent median lobe and/or a high IPSS. RESULTS: The procedure appeared to be technically feasible, with only 0.3% of migrating seeds, a mean post-implant D90 of 173.4 Gy and a mean post-implant V100 of 96.6%. However, 5 patients (23%) experienced a urinary retention, with two patients having to undergo a complementary post-implant TURP. Moreover, urinary toxicity was more pronounced than in our current experience, with high IPSS at 2 months (mean 19.2) and 6 months (mean 15.8). CONCLUSION: Although technically feasible, with relatively few migrating seeds and satisfactory post-implant dosimetric parameters, one-step TURP and brachytherapy was found to be poorly tolerated, with higher than usual urinary retention and urinary toxicity rates. Considering those results, our group is presently evaluating a two-step procedure, with a customized TURP followed after 4-6 months by brachytherapy.

70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial.

PURPOSE: To perform a randomized trial comparing 70 and 80 Gy radiotherapy for prostate cancer. PATIENTS AND METHODS: A total of 306 patients with localized prostate cancer were randomized. No androgen deprivation was allowed. The primary endpoint was biochemical relapse according to the modified 1997-American Society for Therapeutic Radiology and Oncology and Phoenix definitions. Toxicity was graded using the Radiation Therapy Oncology Group 1991 criteria and the late effects on normal tissues-subjective, objective, management, analytic scales (LENT-SOMA) scales. The patients' quality of life was scored using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item cancer-specific and 25-item prostate-specific modules. RESULTS: The median follow-up was 61 months. According to the 1997-American Society for Therapeutic Radiology and Oncology definition, the 5-year biochemical relapse rate was 39% and 28% in the 70- and 80-Gy arms, respectively (p = .036). Using the Phoenix definition, the 5-year biochemical relapse rate was 32% and 23.5%, respectively (p = .09). The subgroup analysis showed a better biochemical outcome for the higher dose group with an initial prostate-specific antigen level >15 ng/mL. At the last follow-up date, 26 patients had died, 10 of their disease and none of toxicity, with no differences between the two arms. According to the Radiation Therapy Oncology Group scale, the Grade 2 or greater rectal toxicity rate was 14% and 19.5% for the 70- and 80-Gy arms (p = .22), respectively. The Grade 2 or greater urinary toxicity was 10% at 70 Gy and 17.5% at 80 Gy (p = .046). Similar results were observed using the LENT-SOMA scale. Bladder toxicity was more frequent at 80 Gy than at 70 Gy (p = .039). The quality-of-life questionnaire results before and 5 years after treatment were available for 103 patients with no differences found between the 70- and 80-Gy arms. CONCLUSION: High-dose radiotherapy provided a better 5-year biochemical outcome with slightly greater toxicity.

Localized low-dose radiotherapy for follicular lymphoma: history, clinical results, mechanisms of action, and future outlooks.

The extreme radiosensitivity of indolent lymphomas was reported in the early years of radiotherapy (RT). The efficacy of low-dose total body irradiation (1.5-2 Gy) was particularly demonstrative. Higher doses were considered appropriate for localized disease. The optimal (or conventional) dose of curative RT derived from the early studies was determined to be 30-35 Gy. Nevertheless, in older series addressing the tumoricidal radiation dose in non-Hodgkin's lymphomas, investigators noted that a significant number of "nodular" lymphomas were controlled with a dose of <22 Gy for >3 years. The idea of reintroducing localized low-dose radiotherapy (LDRT) for indolent non-Hodgkin's lymphomas came from a clinical observation. The first study showing the high efficacy of LDRT (4 Gy in two fractions of 2 Gy within 3 days) in selected patients with chemoresistant, indolent, non-Hodgkin's lymphomas was published in 1994. Since this first report, at least eight series of patients treated with localized LDRT have been published, showing a 55% complete response rate in irradiated sites, with a median duration of 15-42 months. How LDRT induces lymphoma cell death remains partly unknown. However, some important advances have recently been reported. Localized LDRT induces an apoptosis of follicular lymphoma cells. This apoptotic cell death elicits an immune response mediated by macrophages and dendritic cells. Follicular lymphoma is probably an ideal model to explore these mechanisms. This review also discusses the future of LDRT for follicular lymphoma.