Stereotactic ablative body radiotherapy combined with immunotherapy: Present status and future perspectives

Radiotherapy is along with surgery and chemotherapy one of the prime treatment modalities in cancer. It is applied in the primary, neoadjuvant as well as the adjuvant setting. Radiation techniques have rapidly evolved during the past decade enabling the delivery of high radiation doses, reducing side-effects in tumour-adjacent normal tissues. While increasing local tumour control, current and future efforts ought to deal with microscopic disease at a distance of the primary tumour, ultimately responsible for disease-progression. This review explores the possibility of bimodal treatment combining radiotherapy with immunotherapy.     

Toxicité et qualité de vie comparées après curiethérapie par iode 125 et radiothérapie stéréotaxique des cancers prostatiques

Quality of life is a major issue for good prognostic prostate cancer, for which brachytherapy is one of the reference treatments. Stereotactic Body Radiotherapy (SBRT) is a recent alternative however not yet validated as a standard treatment. This review of the literature reports and compares the toxicities and the quality of life, either after exclusive brachytherapy with iodine 125 or after SBRT. The comparison is made with the limitations of the absence of randomized trial comparing the two treatment techniques. Acute toxicity appears to be lower after SBRT compared to brachytherapy (from 10 to 40 % versus 30 to 40 %, respectively). Conversely, acute and late gastrointestinal toxicity (from 0 to 21 % and from 0 to 10 % of grade 2, respectively) appears more frequent with SBRT. Late urinary toxicity seems identical between both techniques (from 20 to 30 % of grade 2), with a possible urinary flare syndrome. Both treatments have an impact on erectile dysfunction, although it is not possible to conclude that a technique is superior because of the limited data on SBRT. SBRT has better bowel and urinary (irritation or obstruction) quality of life scores than brachytherapy; while sexual and urinary incontinence remain the same. The absence of randomized trial comparing SBRT with brachytherapy for prostate cancers does not allow to conclude on the superiority of one technique over another, thus justifying a phase III medicoeconomic evaluation.     

Hypofractionated stereotactic radiotherapy for large brain metastases: Optimizing the dosimetric parameters

PurposeStereotactic radiotherapy plays a major role in the treatment of brain metastases (BM). We aimed to compare the dosimetric results of four plans for hypofractionated stereotactic radiotherapy (HFSRT) for large brain metastases.Material and methodsTen patients treated with upfront NovalisTx® non-coplanar multiple dynamic conformal arcs (DCA) HFSRT for ≥ 25 mm diameter single BM were included. Three other volumetric modulated arc therapy (VMAT) treatment plans were evaluated: with coplanar arcs (Eclipse®, Varian, VMATc_Eclipse®), with coplanar and non-coplanar arcs (VMATnc_Eclipse®), and with non-coplanar arcs (Elements Cranial SRS®, Brainlab, VMATnc_Elements®). The marginal dose prescribed for the PTV was 23.1 Gy (isodose 70%) in three fractions. The mean GTV was 27 mm³.ResultsBetter conformity indices were found with all VMAT techniques compared to DCA (1.05 vs 1.28, P < 0.05). Better gradient indices were found with VMATnc_Elements® and DCA (2.43 vs 3.02, P < 0.001). High-dose delivery in healthy brain was lower with all VMAT techniques compared to DCA (5.6 to 6.3 cc vs 9.4 cc, P < 0.001). Low-dose delivery (V5 Gy) was lower with VMATnc_Eclipse® or VMATnc_Elements® than with DCA (81 or 94 cc vs 110 cc, P = 0.02).ConclusionsNovalisTx® VMAT HFSRT for ≥ 25 mm diameter brain metastases provides the best dosimetric compromise in terms of target coverage, sparing of healthy brain tissue and low-dose delivery compared to DCA.     

Fractionated Stereotactic Radiation Therapy for Pituitary Adenomas: An alternative escalating protocol of hypofractionated stereotactic radiotherapy delivering 35 Gy in 5 fractions

PurposeEvaluate efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for patients treated for pituitary adenoma (PA) with an alternative HSRT escalating protocol delivering 35 Gy in 5 fractions.Material and methodsFrom June 2007 to March 2017, 29 patients with pituitary adenoma were treated in Antoine Lacassagne Cancer Centre with an alternative HSRT protocol. Prescribed dose was 35 Gy in 5 fractions of 7 Gy. Radiographic responses were assessed by annual MRI. Hormone blood samples were evaluated each year after HSRT.ResultsA total of 29 patients aged between 23 and 86 years (median 54 years) were included. Twelve patients received HSRT for recurrent cases and 12 received postoperative adjuvant HSRT, 5 patients did not have surgery. After a median follow-up period of 47 months local control rate was 96%. One patient presented an out-field tumor regrowth 73 months after HSRT. The majority of PA were endocrine-active (18 patients, 62%). After HSRT, 8 patients (44%) presented complete response on initial secretion, 4 patients (23%) presented partial response on initial secretion. Four patients (14%) presented grade 2 or more acute radiation toxicities. One grade 4 visual disorder was observed for one patient.ConclusionsHSRT delivering 35 Gy in 5 fractions represents a feasible treatment and shows promising results to reduce hormonal overproduction and to improve local control in PA.     

Application of a multi-institutional nomogram predicting salvage whole brain radiation-free survival to patients treated with postoperative stereotactic radiotherapy for brain metastases

PurposeThe ultimate goal of stereotactic radiotherapy (SRT) of brain metastases (BM) is to avoid or postpone whole brain radiotherapy (WBRT). A nomogram based on multi-institutional data was developed by Gorovets, et al. to estimate the 6 and 12-months WBRT-free survival (WFS). The aim of the current retrospective study was to validate the nomogram in a cohort of postoperative BM patients treated with adjuvant SRT.Material and methodsWe reviewed the data of 68 patients treated between 2008–2017 with postoperative SRT for BM. The primary endpoint was the WFS. The receiver operating characteristic curve and area under the curve (AUC) were calculated for both 6- and 12-months time points.ResultsAfter a median follow-up of 64 months, the 1-year cumulative incidence of local and distant brain relapse rates were 15% [95% CI = 8–26%] and 34% [95% CI = 24–48%], respectively. At recurrence, repeated SRT or salvage WBRT were applied in 33% and 57% cases, respectively. The WFS rates at 6 and 12 months were 88% [95% CI = 81–97%] and 67% [95% CI = 56–81%], respectively. Using the Gorovets nomogram, the 6 months rates were overestimated while they were accurate at 12 months. AUC values were 0.47 and 0.62 for the 6- and 12-months respectively. Overall, Harrell's concordance index was 0.54.ConclusionThis nomogram-predicted well the 12 months WFS but its discriminative power was quite low. This underlines the limits of this kind of predictive tool and leads us to consider the use of big data analysis in the future.     

Hypofractionated radiotherapy for non-metastatic bone and soft tissue sarcomas

PurposeTo evaluate the efficacy and toxicity of hypofractionated radiotherapy in non-metastatic soft tissue and bone sarcomas.Patients and methodsThirty patients underwent hypofractionated radiotherapy between 2007 and 2015. Overall, 17 patients underwent primary hypofractionated radiotherapy, nine underwent hypofractionated radiotherapy for reirradiation, and four received a boost dose via hypofractionated radiotherapy after external beam radiotherapy. Most common disease sites were head and neck and retroperitoneum. Hypofractionated radiotherapy was administered with a definitive, adjuvant, or neoadjuvant intent.ResultsMedian age was 37 years (range: 11–82 years). Median hypofractionated radiotherapy dose was 35 Gy (range: 20–50 Gy) in three to five fractions. Median follow-up was 21 months (range: 1–108 months). One- and 2-year overall survival rate was 75% and 52%, respectively. One- and 2-year local recurrence-free survival rate was 59% and 48%, with local recurrence rates of 16% and 33% in 1 and 2 years, respectively. Univariate analysis revealed tumour size (P = 0.04), hypofractionated radiotherapy intent (P = 0.016) and reirradiation (P = 0.001) as prognostic factors for local recurrence-free survival. Severe late toxicity was observed in one patient as grade 3 trismus.ConclusionHypofractionated radiotherapy as the primary treatment or for reirradiation has been shown to be safe in the treatment of bone and soft tissue sarcomas. It can provide relatively good local control and survival rates.     

Radiothérapie des oligométastases : principaux essais en cours et à venir en France

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.     

Effets de l’irradiation à haute dose sur la vascularisation : physiopathologie et conséquences cliniques

A review of the literature has been conducted to better understand the effect of stereotactic radiotherapy on tumour vascularization and their consequences. High irradiation doses cause the death of endothelial cells by apoptosis through the ceramide pathway. Vascular consequences are multiple: increased permeability, decreased blood flow, increased hypoxia and tumoral necrosis. This necrosis causes an indirect death of the cancer cells in the days following the irradiation. The importance of indirect cell death in tumour control remains controversial, but it can explain the good clinical results of stereotactic radiotherapy. Stereotactic radiotherapy is a treatment of the tumour microenvironment. Tumour recurrence in this hypoxic environment is slower through disturbance of revascularization mechanisms but also more aggressive, with increased resistance to treatment and a higher risk of metastasis. In a longer time, vascular damage leads to chronic inflammation and a dysfunctional healing process resulting in vascular occlusion. This phenomenon is used in the treatment of arteriovenous malformations but is also responsible for damage to healthy tissues responsible for chronic complications. This is why high-dose irradiation can only be delivered using stereotactic radiotherapy, which reduces the irradiated volume.     

Meningioma of the skull base: Long-term outcome after image-guided stereotactic radiotherapy

PurposeThe purpose of this study was to analyse the feasibility, safety, and long-term efficacy of linear accelerator-based fractionated stereotactic radiotherapy for meningiomas of the skull base. We evaluated the long-term clinical outcome of patients and identified prognostic factors after fractionated stereotactic radiotherapy.Patients and methodsBetween 10/1995 and 03/2009, 136 patients with a median age of 57 years with skull base meningioma received fractionated stereotactic radiotherapy. A total of 34 patients had a grade I meningioma, in 102 cases no histology was obtained (grade 0). Fractionated stereotactic radiotherapy was delivered as primary treatment for 57 patients and postoperatively for 79. The patients received a mean total dose of 56.95 (min/max 32.4/63) Gy.ResultsMedian follow-up was 44.9 months. Overall progression-free survival was 96.9% after 3 years, 93.8% after 5 years, and 91.5% after 10 years. Patients with unknown histology showed progression-free survival rates of 100%, 98.7%, and 93.5% at 3, 5, and 10 years and patients with biopsy-proven grade I meningioma showed rates of 100% after 3 years, 91.7% after 5 years and 85.9% after 10 years. Patients with adjuvant radiotherapy showed significantly worse progression-free survival rates than patients who had been treated with primary radiotherapy (P = 0.043), progression-free survival rates were independent of tumour size. The most common acute grade I symptoms were headache, fatigue, and local alopecia. The most common chronic grade I symptoms were fatigue and headache.ConclusionsThis large study showed that fractionated stereotactic radiotherapy is an effective and safe treatment modality with high progression-free survival rates for intracranial meningioma. We identified “prior surgery” as significant poor prognostic factor.     

Brachytherapy boost (BT-boost) or stereotactic body radiation therapy boost (SBRT-boost) for high-risk prostate cancer (HR-PCa)

Systematic review for the treatment of high-risk prostate cancer (HR-PCa, D’Amico classification risk system) with external body radiation therapy (EBRT) + brachytherapy-boost (BT-boost) or with EBRT + stereotactic body RT-boost (SBRT-boost). In March 2020, 391 English citations on PubMed matched with search terms “high risk prostate cancer boost”. Respectively 9 and 48 prospective and retrospective studies were on BT-boost and 7 retrospective studies were on SBRT-boost. Two SBRT-boost trials were prospective. Only one study (ASCENDE-RT) directly compared the gold standard treatment [dose-escalation (DE)-EBRT + androgen deprivation treatment (ADT)] versus EBRT + ADT + BT-boost. Biochemical control rates at 9 years were 83% in the experimental arm versus 63% in the standard arm. Cumulative incidence of late grade 3 urinary toxicity in the experimental arm and in the standard arm was respectively 18% and 5%. Two recent studies with HR-PCa (National Cancer Database) demonstrated better overall survival with BT-boost (low dose rate LDR or high dose rate HDR) compared with DE–EBRT. These recent findings demonstrate the superiority of EBRT + BT-boost + ADT versus DE–EBRT + ADT for HR-PCa. It seems that EBRT + BT-boost + ADT could now be considered as a gold standard treatment for HR-PCa. HDR or LDR are options. SBRT-boost represents an attractive alternative, but the absence of randomised trials does not allow us to conclude for HR-PCa. Prospective randomised international phase III trials or meta-analyses could improve the level of evidence of SBRT-boost for HR-PCa.     

Lung stereotactic radiation therapy: Intercomparison of irradiation devices in terms of outcome and predictive factors

PurposeTo compare three different radiotherapy devices able to perform pulmonary stereotactic radiotherapy: CyberKnife® (CK), Helical Tomotherapy® (HT), and volumetric modulated arc therapy (VMAT). This study aims to define the patients’ outcome in terms of SBRT efficacy and toxicities depending of the device choice.Materials and methodsWe retrospectively analyzed the clinical, radiological, and dosimetric data of patients treated with lung SBRT between 2016 and 2020 at Lausanne University Hospital, using the Chi² test for proportions, the t-test for means comparisons, the Kaplan-Meier method for survival, and the Log-rank test and Cox-regression for intergroups comparisons.ResultsWe identified 111 patients treated by either CK (59.9%), VMAT (38.0%), or HT (2.1%). Compared to other techniques, CK treated comparable gross tumor volume (GTV; 2.1 vs. 1.4 cm³, P = 0.84) with smaller planning treatment volume (PTV; 12.3 vs. 21.9 cm³, P = 0.013) and lower V5 (13.5 vs. 19.9 cm³, P = 0.002). Local control rates at 2 years were not different whatever the irradiation device, respectively of 96.2% (range, 90.8–100) and 98.1% (range, 94.4–100), P = 0.68. Toxicity incidence significantly increased with V5 value > 17.2% (56.0 vs. 77.4%, P = 0.021).ConclusionCompared to other SBRT techniques, CK treatments permitted to treat comparable GTV with reduced PTV and V5. Toxicity incidence was less frequent when reducing the V5. CK is particularly attractive in case of multiple courses of lung SBRT or lung reirradiation.     

Rôle de la radiothérapie ablative des métastases chez les patients atteints de cancer de la prostate oligométastatique hormonosensible : un essai du Groupe d’étude des tumeurs urogénitales et de l’Association française d’urologie

The goal of treatment of metastatic prostate cancer remains palliation. The oligometastatic state could be the right time to intensify therapy by introducing metastases directed treatments. The aim of this trial was to evaluate the benefit of radiotherapy to all macroscopic metastatic sites and to the primary disease in patients with hormone sensitive oligometastatic prostate cancer.     

Robotic stereotactic treatment for malignant metastasis of solid tumour in the pancreas: A multiple case report and review of literature

Metastatic involvement of the pancreas occurs in 5% of patients affected by advanced malignancies. Surgical resection has been reported by number of authors as a valuable option to improve disease control, in particular in patients with limited disease burden and favourable histotypes; however, the benefit of this procedure has been questioned due to patient selection, technical challenges and relevant risk of perioperative mortality and severe complications. In the present study, a cohort of surgically unfit patients affected by a solitary metastasis in the pancreas from various primary tumours received stereotactic radiotherapy with an ablative dose schedule, obtaining promising local and distant disease progression-free delay with minor toxicity. This is the first report to our knowledge on the use of ablative stereotactic radiotherapy of metastasis in the pancreatic gland.     

Bronchiolitis obliterans organizing pneumonia after stereotactic ablative radiation therapy for lung cancer: A case report

Bronchiolitis obliterans organizing pneumonia is an interstitial lung disease rarely occurring after radiotherapy probably due to an activation of autoimmune processes. Most cases have been described after postoperative radiotherapy for breast cancer. Corticosteroids represent the main treatment, prognosis is generally favorable. We described a case of bronchiolitis obliterans organizing pneumonia after stereotactic ablative radiation therapy for a recurrent lung cancer. Antibiotics and steroids were administered to solve the clinical picture. After three years, a new lesion at the right lung was found and treated with stereotactic ablative radiation therapy and concomitant long course of steroids with no recurrence of bronchiolitis obliterans organizing pneumonia. Bronchiolitis obliterans organizing pneumonia is a rare event after radiotherapy with undefined risk factors. In our case, steroids played an important role in management and, maybe, in preventing bronchiolitis obliterans organizing pneumonia recurrence after second course of stereotactic ablative radiation therapy.     

What effective technique to differentiate radiation brain necrosis from a tumor progression in patients treated with radiation: A monocentric retrospective study combining the MRI TRAMs technique and the (18F)-dopa PET/CT

PurposeBrain necrosis after radiotherapy is a challenging diagnosis, since it has similar radiological appearance on standard MRI to tumor progression. Consequences on treatment decisions can be important. We compare recent imaging techniques in order to adopt a reliable diagnostic protocol in doubtful situations.Patients and methodThis is a retrospective study comparing the performance of three imaging techniques after radiotherapy of brain metastasis: Perfusion-MRI, TRAMs technique and F-dopa PET-CT. The evolution of the treated metastasis volume was also analyzed by contouring all patients MRIs. All included patients were suspected of relapse and had the three exams once the volume of treated metastasis increased.ResultsThe majority of our patients were treated by stereotactic radiotherapy. Suspicion of relapse was on average around 17 months after treatment. Four cases of radionecrosis were diagnosed and six cases of real tumor progression. Neurological symptoms were less present in radionecrosis cases. All of our radionecrosis cases had relative cerebral blood volume below 1. F-dopa PET-CT succeeded to set the good diagnosis in eight cases, although we found one false positive and one false negative exam. The TRAMs technique failed in one case of false negative exam.ConclusionsPerfusion-MRI showed high performance in the diagnosis of radionecrosis, especially when calculating relative cerebral blood volume rate. The TRAMs technique showed interesting results and deserves application in daily routine combined with the perfusion-MRI. F-dopa CT might induce false results because of different metabolic uptake according to tumor type, medication and brain blood barrier leak.