Emerging treatment paradigms for brain metastasis in non-small-cell lung cancer: an overview of the current landscape and challenges ahead.

Advances in the last decade in genomic profiling and the identification of druggable targets amenable to biological agents have transformed the management and survival of a subgroup of patients with brain metastasis in non-small-cell lung cancer. In parallel, clinicians have reevaluated the role of whole brain radiotherapy in selected patients with brain metastases to reduce neurocognitive toxicity. Continual progress in this understudied field is required: optimization of the sequence of schedules for therapies in patients with brain metastases of differing genomic profiles, focusing on new strategies to overcome mechanisms of biological resistance and increasing drug penetrability into the central nervous system. This review summarizes the field to date and possible treatment strategies based on current evidence.

Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation.

OBJECTIVE: To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after chemoradiation. METHODS: Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was tend; MR acquisitions performed at tend-2M, tend-4M and tend-6M (respectively 2, 4 and 6 months before tend) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between ∆B from tend-4M to tend-2M and ∆B from tend-6M to tend-4M. The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis. RESULTS: The fraction of hypoperfused tumor volume (F_hPg) was a relevant biomarker. A ratio R(F_hPg) ≥ 0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (≥0.61) was associated with more relapse at tend compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008). CONCLUSION: Iterative analysis of F_hPg from consecutive examinations could provide surrogate markers to predict progression at the next follow-up. KEY POINTS: • Related rCBV biomarkers from DSC were assessed to anticipate GBM progression. • Biomarkers were assessed through their patterns of variation during the follow-up. • The fraction of hypoperfused tumour volume (F_hP g ) seemed to be a relevant biomarker. • An innovative ratio R(F_hP g ) could be an early surrogate marker of relapse. • A significant time gain could be achieved in the management of GBM patients.

Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group.

BACKGROUND: Advanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs. METHODS: Patients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1.5 mg/m(2), q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1). RESULTS: Eleven patients treated with trabectedin for advanced SFT were identified. Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %). The best RECIST response was a partial response (PR) in one patient (9.1 %) and stable disease (SD) in eight patients (72.7 %). Disease-control rate (DCR = PR + SD) was 81.8 %. After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS was 22.3 months (95 % CI = 9.1 months; not reached). The median GMI was 1.49 (range: 0.11-4.12). CONCLUSION: Trabectedin is a very promising treatment for advanced SFTs. Further investigations are needed.

Radiotherapy in the management of synchronous metastatic lung cancer.

Metastatic lung cancer classically portends a poor prognosis. The management of metastatic lung cancer has dramatically changed with the emergence of immune checkpoint inhibitors, targeted therapy and due to a better understanding of the oligometastatic process. In metastatic lung cancers, radiation therapy which was only used with palliative intent for decades, represents today a promising way to treat primary and oligometastatic sites with a curative intent. Herein we present through a literature review the role of radiotherapy in the management of synchronous metastatic lung cancers.

The role of radiation therapy for de novo metastatic bladder and renal cancers.

Metastatic bladder and renal cancers account respectively for 2.1% and 1.8% of cancer deaths worldwide. The advent of immune checkpoint inhibitors has revolutionized the management of metastatic disease, by demonstrating considerable improvements in overall survival. However, despite initial sensitivity to immune checkpoint inhibitors for most patients, both bladder and renal cancer are associated with short progression-free survival and overall survival, raising the need for further strategies to improve their efficacy. Combining systemic therapies with local approaches is a longstanding concept in urological oncology, in clinical settings including both oligometastatic and polymetastatic disease. Radiation therapy has been increasingly studied with either cytoreductive, consolidative, ablative or immune boosting purposes, but the long-term impact of this strategy remains unclear. This review intends to address the impact of radiation therapy with either curative or palliative intent, for synchronous de novo metastatic bladder and renal cancers.

Radiotherapy in the management of lung oligometastases.

In recent years, the development of both medical imaging and new systemic agents (targeted therapy and immunotherapy) have revolutionized the field of oncology, leading to a new entity: oligometastatic disease. Adding local treatment of oligometastases to systemic treatment could lead to prolonged survival with no significant impact on quality of life. Given the high prevalence of lung oligometastases and the new systemic agents coming with increased pulmonary toxicity, this article provides a comprehensive review of the current state-of-art for radiotherapy of lung oligometastases. After reviewing pretreatment workup, the authors define several radiotherapy regimen based on the localization and size of the oligometastases. A comment on the synergistic combination of medical treatment and radiotherapy is also made, projecting on future steps in this specific clinical setting.

[Impact of immunotherapy on the therapeutic strategy for the management of stage I non-small cell lung cancer: The radiation oncologist's point of view]. / Influence de l'immunothérapie sur le choix du traitement des cancers bronchiques non à petites cellules de stade I : point de vue de l'oncologue radiothérapeute.

Surgery is the standard treatment for operable patients with stage I non-small cell lung cancer (NSCLC) (T1-T2aN0M0). Stereotactic body radiotherapy (SBRT) is the treatment of choice for non-operable patients, and its positioning for operable patients remains to be clarified. The pattern of recurrence after management of stage I NSCLC is dominated by the risk of distant recurrence, this constituting the rationale for the adjunction of systemic treatment, and especially check point inhibitor (CPI), in combination with surgery or SBRT for patients with high risk features. While the benefit of postoperative CPI on the micro-metastatic disease is logically considered within the framework of a simply additive effect of both therapeutic modalities, it is reasonable to consider a synergistic effect of both CPI and SBRT. Given the role of tumor draining nodes in the development of an anti-tumor immune response, a "tumor-draining node sparing" strategy enabled by SBRT could therefore be of major interest in combination with CPI. Pending confirmation of the role of CPI in combination with RTS for the management of stage I NSCLC, we thus discuss in this review the theoretical advantages that this therapeutic strategy could have compared to a surgical strategy.

[Stereotactic radiotherapy for operable stage I non-small cell lung cancer]. / Place de la radiothérapie stéréotaxique pour les cancers bronchiques non à petites cellules de stade I opérables.

Standard treatment stage of non-small cell lung cancer is currently surgery. For inoperable patients, stereotactic body radiotherapy is the reference treatment. This non-invasive technique has developed considerably and its excellent results in terms of carcinological control and tolerance raise the question of its indication for operable patients, especially for old patients and/or with comorbidities. This article reviews the available data in the literature of the place of stereotactic body radiotherapy for medically operable patients with stage I non-small cell lung cancer.

[Bladder-sparing trimodal therapy for muscle invasive bladder cancer]. / Stratégie de préservation vésicale basée sur le traitement trimodal : quelle place dans la prise en charge du carcinome infiltrant de la vessie ?

Organ-sparing strategies in the management of local or locally advanced cancers meet a dual objective: tumor control and preservation of the function of the involved organ. Given the morbidity and mortality of cystectomy and its impact on quality of life and bladder function, bladder-sparing strategies have emerged for the management of urothelial muscle invasive bladder cancer, mostly through trimodal treatment, which consists in maximal trans-urethral resection of bladder tumor, followed by chemo-radiotherapy. This review presents the modalities of trimodal treatment, before exposing the advantages and limitations of this strategy compared to cystectomy among operable patients. Despite the absence of comparative data from randomized trials, the two approaches seem to provide similar oncological results among appropriately selected patients. In modern series, the rate of salvage cystectomy is approximately 15% at 5 years; this delayed cystectomy does not seem to be associated with greater morbidity and mortality as compared to upfront cystectomy. Emphasis is placed in the review on quality of life data of these two approaches. In order to optimize the selection of patients eligible to trimodal therapy, the classical predictive factors of response to radio(chemo)therapy are critically analyzed, with the perspective of innovative molecular biomarkers. Finally, a close multidisciplinary collaboration is needed for the choice and the execution of the therapeutic strategy, and the patient should be fully involved in the decision-making process.

Radiotherapy for primary lung cancer.

Herein are presented the recommendations from the Société française de radiothérapie oncologique regarding indications and modalities of lung cancer radiotherapy. The recommendations for delineation of the target volumes and organs at risk are detailed.

Impact of radiotherapy on survival in resected or unresectable anaplastic thyroid carcinomas, a Rare Cancer Network study.

PURPOSE: Anaplastic thyroid carcinomas (ATC) are a heterogenous group of tumors of overall dismal prognosis. We designed models to identify relevant prognostic factors of survival of irradiated ATC patients including radiotherapy modalities (field size, dose). MATERIAL AND METHODS: Between 2000 and 2017, 166 ATC patients' treatments were divided into surgery and postoperative radiotherapy (poRT) or definitive radiotherapy (RT). Multiple imputation approach was used for missing data. Prognostic factors were identified using Lasso-penalized Cox modelling and predicted risk scores were built. RESULTS: Patients undergoing RT (n=70) had more adverse patient and disease characteristics than those undergoing poRT (n=96). Corresponding median survival rates were 5.4 and 12.1 months, respectively. PoRT patients undergoing poRT more likely received extended-field radiotherapy with prophylactic nodal irradiation, but rather received platinum- vs. adriamycin-based chemoradiotherapy. Radiotherapy was conventionally fractionated, delivered >60Gy in 51.9% and 61.7% and used extended fields in 88.5% and 71.2% of patients with poRT or RT. Radiotherapy interruption rates for toxicity were similar in the two groups. The best poRT-group model identified age>45yo, PS≥1, pathologic tumor stage≥pT4b,>N1 and R2 resection as poor prognostic factors. The best RT-group model (C-index of 0.72) identified PS≥3,>N1 and extended-field radiotherapy with prophylactic nodal irradiation (as opposed to tumour-bed irradiation only) as poor prognostic factors. CONCLUSION: In patients undergoing poRT, radiotherapy parameters had little influence over their survival irrespective of patient, disease characteristics, and quality of resection. In patients undergoing RT, extended-field radiotherapy improved survival in addition to PS and nodal stage.

Recommendations for stereotactic body radiation therapy for spine and non-spine bone metastases. A GETUG (French society of urological radiation oncolgists) consensus using a national two-round modified Delphi survey.

Background and purpose: The relevance of metastasis-directed stereotactic body radiation therapy (SBRT) remains to be demonstrated through phase III trials. Multiple SBRT procedures have been published potentially resulting in a disparity of practices. Therefore, the french society of urological radiation oncolgists (GETUG) recognized the need for joint expert consensus guidelines for metastasis-directed SBRT in order to standardize practice in trials carried out by the group. Materials and methods: After a comprehensive literature review, 97 recommendation statements were created regarding planning and delivery of spine bone (SBM) and non-spine bone metastases (NSBM) SBRT. These statements were then submitted to a national online two-round modified Delphi survey among main GETUG investigators. Consensus was achieved if a statement received ≥ 75 % agreements, a trend to consensus being defined as 65-74 % agreements. Any statement without consensus at round one was re-submitted in round two. Results: Twenty-one out of 29 (72.4%) surveyed experts responded to both rounds. Seventy-five statements achieved consensus at round one leaving 22 statements needing a revote of which 16 achieved consensus and 5 a trend to consensus. The final rate of consensus was 91/97 (93.8%). Statements with no consensus concerned patient selection (3/19), dose and fractionation (1/11), prescription and dose objectives (1/9) and organs at risk delineation (1/15). The voting resulted in the writing of step-by-step consensus guidelines. Conclusion: Consensus guidelines for SBM and NSBM SBRT were agreed upon using a validated modified Delphi approach. These guidelines will be used as per-protocole recommendations in ongoing and further GETUG clinical trials.

[A review of adaptive radiotherapy for bladder cancer]. / Radiothérapie adaptative des cancers de la vessie : état de l'art et perspectives pratiques.

PURPOSE: Radiation therapy (RT) for muscle invasive bladder cancer (MIBC) is challenging, with observed variations in bladder shape and size resulting in inappropriate coverage of the target volumes (CTV). Large margins were historically applied around the CTV, increasing the dose delivered to organs at risk (OAR). With repositioning imaging and visualization of soft tissues during image guided RT, an opportunity to consider these movements and deformations appeared possible with an adaptive RT approach (ART). MATERIALS AND METHODS: A bibliographic search on the PubMed database has been done in January 2019. Studies focusing on patients with MIBC, treating on ART, with the objectives of feasibility, clinical and/or dosimetric evaluation and comparison with a standard irradiation technique were eligible. The purpose of this review was to define the different ART techniques used in clinical practice, to discuss their advantages compared to conventional RT in terms of target volume's coverage and OAR dose and to describe their feasibility in clinical practice. RESULTS: A total of 30 studies were selected. The strategies known as "composite offline", "plan of the day" not individualized or individualized, and "re-optimization" have been identified. All the studies have shown a significant benefit of ART in target coverage and dose of OAR, especially the rectum and small bowel. All ART plans produced are not used during RT sessions. Inter-observer variability for the selection of these plans can be observed. The practical implementation within a department required staff education and training, and increases the duration of treatment preparation. The "A-POLO" approach seems to be the most suitable for practice. CONCLUSION: ART is the technique of choice for bladder cancer RT. The "plan of the day" approach, individualized according to the A-POLO methodology, seems to be the most effective. The emergence of daily re-optimization, especially using MRI-Linac, is promising. The correlation between dosimetric benefits and clinical efficacy and safety results should be demonstrated into future trials.

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.

RADIORYTHMIC: Phase III, Opened, Randomized Study of Postoperative Radiotherapy Versus Surveillance in Stage IIb/III of Masaoka Koga Thymoma after Complete Surgical Resection.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that may be aggressive and difficult to treat. Knowledge and level of evidence for treatment strategies are mainly based on retrospective studies or expert opinion. Currently there is no strong evidence that postoperative radiotherapy after complete resection of localized thymoma is associated with survival benefit in patients. RADIORYTHMIC is a phase III, randomized trial aiming at comparing postoperative radiotherapy versus surveillance after complete resection of Masaoka-Koga stage IIb/III thymoma. Systematic central pathologic review will be performed before patient enrollment as per the RYTHMIC network pathway. PATIENTS AND METHODS: Three hundred fourteen patients will be included; randomization 1:1 will attribute either postoperative radiotherapy (50-54 Gy to the mediastinum using intensity-modulated radiation therapy or proton beam therapy) or surveillance. Stratification criteria include histologic grading (thymoma type A, AB, B1 vs B2, B3), stage, and delivery of preoperative chemotherapy. Patient recruitment will be mainly made through the French RYTHMIC network of 15 expert centers participating in a nationwide multidisciplinary tumor board. Follow-up will last 7 years. The primary endpoint is recurrence-free survival. Secondary objectives include overall survival, assessment of acute and late toxicities, and analysis of prognostic and predictive biomarkers. RESULTS: The first patient will be enrolled in January 2021, with results expected in 2028.

Gene therapy and cell therapy for the management of radiation damages to healthy tissues: Rationale and early results.

Nowadays, ionizing radiations have numerous applications, especially in medicine for diagnosis and therapy. Pharmacological radioprotection aims at increasing detoxification of free radicals. Radiomitigation aims at improving survival and proliferation of damaged cells. Both strategies are essential research area, as non-contained radiation can lead to harmful effects. Some advances allowing the comprehension of normal tissue injury mechanisms, and the discovery of related predictive biomarkers, have led to developing several highly promising radioprotector or radiomitigator drugs. Next to these drugs, a growing interest does exist for biotherapy in this field, including gene therapy and cell therapy through mesenchymal stem cells. In this review article, we provide an overview of the management of radiation damages to healthy tissues via gene or cell therapy in the context of radiotherapy. The early management aims at preventing the occurrence of these damages before exposure or just after exposure. The late management offers promises in the reversion of constituted late damages following irradiation.

[Image-guided radiotherapy in lung cancer]. / Radiothérapie guidée par l'image dans le cancer du poumon.

Image-guided radiotherapy takes place at every step of the treatment in lung cancer, from treatment planning, with fusion imaging, to daily in-room repositioning. Managing tumoral and surrounding thoracic structures motion has been allowed since the routine use of 4D computed tomography (4DCT). The integration of respiratory motion has been made with "passive" techniques based on reconstruction images from 4DCT planning, or "active" techniques adapted to the patient's breathing. Daily repositioning is based on regular images, weekly or daily, low (kV) or high (MV) energy. MRI and functional imaging also play an important part in lung cancer radiation and open the way for adaptative radiotherapy.

Subventricular zones: new key targets for glioblastoma treatment.

BACKGROUND: We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma. METHODS: Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS). RESULTS: Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively). CONCLUSION: Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.