Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer:12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease

The European Organisation for Research and Treatment of Cancer (EORTC) trial 22991 (NCT00021450) showed that 6 months of concomitant and adjuvant androgen suppression (AS) improves event- (EFS, Phoenix) and clinical disease-free survival (DFS) of intermediate- and high-risk localized prostatic carcinoma, treated by external-beam radiotherapy (EBRT) at 70-78 Gy. We report the long-term results in intermediate-risk patients treated with 74 or 78 Gy EBRT, as per current guidelines. Of 819 patients randomly assigned between EBRT or EBRT plus AS started on day 1 of EBRT, 481 entered with intermediate risk (International Union Against Cancer TNM 1997 cT1b-c or T2a with prostate-specific antigen (PSA) ≥ 10 ng/mL or Gleason ≤ 7 and PSA ≤ 20 ng/mL, N0M0) and had EBRT planned at 74 (342 patients, 71.1%) or 78 Gy (139 patients, 28.9%). We report the trial primary end point EFS, DFS, distant metastasis-free survival (DMFS), and overall survival (OS) by intention-to-treat stratified by EBRT dose at two-sided α = 5%. At a median follow-up of 12.2 years, 92 of 245 patients and 132 of 236 had EFS events in the EBRT plus AS and EBRT arm, respectively, mostly PSA relapse (48.7%) or death (45.1%). EBRT plus AS improved EFS and DFS (hazard ratio [HR] = 0.53; CI, 0.41 to 0.70; P < .001 and HR = 0.67; CI, 0.49 to 0.90; P = .008). At 10 years, DMFS was 79.3% (CI, 73.4 to 84.0) with EBRT plus AS and 72.7% (CI, 66.2 to 78.2) with EBRT (HR = 0.74; CI, 0.53 to 1.02; P = .065). With 140 deaths (EBRT plus AS: 64; EBRT: 76), 10-year OS was 80.0% (CI, 74.1 to 84.7) with EBRT plus AS and 74.3% (CI, 67.8 to 79.7) with EBRT, but not statistically significantly different (HR = 0.74; CI, 0.53 to 1.04; P = .082). Six months of concomitant and adjuvant AS statistically significantly improves EFS and DFS in intermediate-risk prostatic carcinoma, treated by irradiation at 74 or 78 Gy. The effects on OS and DMFS did not reach statistical significance

Study of the immunological effects of radiotherapy and its fractionation to optimize its association with chemotherapy and immunotherapy

Les inhibiteurs de point de contrôle immunitaire (ICI) ont révolutionné te traitement des cancers, mais seuls 20 à 40% des patients présentent une réponse objective. Ainsi, des combinaisons des ICI avec un traitement anticancéreux comme la chimiothérapie (CT) et/ou la radiothérapie (RT) ont été développées pour améliorer les réponses. Afin d'optimiser leur efficacité, ces combinaisons doivent tenir compte de la manière dont les différents traitements modulent le système immunitaire. Nos objectifs étaient de décrire l'impact de la chimioradiothérapie concomitante (RTCT) sur les réponses immunitaires anti-tumorales périphériques et celui du fractionnement de la RT en association avec la CT et/ou les ICI sur la réponse anti tumorale et le microenvironnement tumoral (TME). Nos résultats préliminaires chez 29 patients traités par RTCT à base de sels de platine ont montré une perte des lymphocytes Th1 circulants spécifiques de la télomérase, antigène tumoral surexprimé dans les cancers, après traitement. Cette perte était associée à une augmentation du taux des lymphocytes T régulateurs (Treg) circulants. De plus, la présence d une réponse anti-tumorale spécifique avant le traitement était associée à une meilleure réponse clinique après RTCT. Ensuite, nous avons montré chez des patients atteints d'un cancer du rectum localement avancé une induction de l'expression de PD·L1 dans le TME après RT néoadjuvante indépendamment du fractionnement. Dans un deuxième temps, nous avons voulu cibler les voies immunosuppressives induites par la RT en fonction du fractionnement. Dans un modèle murin de cancer colorectal CT26. le schéma 18x2Gy a induit les MDSC et l'expression de PD-L 1.Nous avons comparé l'efficacité clinique de deux fractionnements, (3x8Gy et 18x2Gy) en association avec une CT par 5-Fluorouracile (SFU) connu pour son action déplétante des MDSC et un anticorps monoclonal ciblant PD·Ll. Nous avons montré que dans le cadre d'une CT avec SFU, la réponse clinique était la même quel que soit le fractionnement. En revanche, lorsqu'on associe la RTCT à l'anti-PD-L 1 la croissance tumorale était plus ralentie avec le schéma normofractionné avec 63% de reponse complète. De plus, cette triple combinaison a induit une expansion de lymphocytes T CD8 cytotoxiques au sein du TME ainsi qu'une protection vis-à-vis d'un nouveau challenge tumoral. En parallèle, nous avons évalué la RT associée à un anti-PD·Ll et un anti-CTLA 4 pour cibler les Ireg induits par le schéma 3x8Gy. D"une manière surprenante. l'association 3x8Gy + anti-CTLA-4 • anti·PD-Ll était moins efficace que l'association 18x2Gy + anti·CTLA-4 + anti-PD·L 1. La déplétion des U CD4 avant un traitement par 3x8Gy + anti-CTLA-4 + anti-PD· ll a entrainé une guérison de toutes les souris, suggérant un rôle immunosupprcsseur d'une sous-population de LT CD4. La déplétion des LT CDS a entrainé une perte du contrôle tumoral quel que soit le fractionnement. Par ailleurs. nous avons constaté après rechallenge tumoral, un rejet chez toutes les souris qui avaient répondu à la combinaison RT + anti·CTLA-4 • anti·PD·Ll. Cette réponse mémoire dépendait des LT CD4 notamment pour le schéma normofractionné. En conclusion, nous avons montré une baisse des réponses immunitaires périphériques anti-tumorales aµprès des RTCT médiée par l'induction de mécanismes irmrnunosuppresseurs. Ces rnécanismes diffèrent selon le fractionnerment de la RT et peuvent être ciblés de manière à rendre les combinaisons synergiques.Immune hcckpoinl inhibitors (ICI) have revolutionized cancer treatment. but only 20 to 40% of patie,ts show an objective response. Thus, combinations of ICI with other cancer treatment such as chernotherapy (CT) and/or radiotherapy (RT) have been developed to irnprove responses. ln order to optimize their etticiency. these combinations must take into accounc the way the different treatments niodulate the immune system. Our aim was to describe the impact of concurrent ch moradiotherapy (CRT) on peripheral anti-tumor immun responses, and that of RT fractionation in combination with CT and/or ICI on tre anti-tumor response ano the turnor microenvironment (TME) in cli ical and preclinical models. Our preliminary results Ï'1 29 patients lreated with platinum-based CRT showed a loss of the peripheral Thl responses to tclomerase. a tumor antigen overexpressed in cancers. This loss wa, associated with an hcrease in circulating regulatory T cells (Treg��). Moreover, the presence of a specitic anti-tumor response at ba,eline was associated with a better clinical respome a��er CRT. ln locally advanced rectal cancer patients treated with neoadjuvant RT, we studied the expression of PD-L; in the TME. We found that norrnofraction led and hypofractionated RT induced signiticanlly PO-L: with no difference between the two treatment modalities. Next, we wanted co targec th immunosuppressive pathways induced by RT ac.cording to fractionation. ln a murine model f cr26 colorectal cancer, normofractionated RT (18x2Gy) lecl lo increased MDSC, and induced PD·Ll on tumor cells. We compared the clinical etticacy of two fractionations (3x8Gy and :l 8x2Gy) in assoc."acion with SFluorouracil (SFU) known for its depleting action on MDSCs. and a monoclonal antibody targetir.g PD-ll. We showed that in the context of SFU-based CRT, the clinical response was the same whatever the fractionation. On the other hand, when CRT was associated with anti·PD­ll therapy, tumor control was signiticantly bettcr with the normofractionated scheme compare<;! to hypofractionation, achieving a 63% complete response rate. Also, SFU-based normofractiorated CRT - anti-PD-Ll indu ed early expansion of functional CDS+ T cells infiltration and provided long-lasting antitumor immunicy. On the other hand, we evaluated RT associated with an anti-PD-Ll and an anti-CTLA-1\ to target Trcgs indi..ced by the 3x8Gy scheme. Surprisingly, the 3x8Gy + anti-C flA-4 ➔ anti·PD·Ll cornbination was less efficient than the 1Bx2Gy • anti-CTLA-4 + anti-PO·L 1 combination. D pletion of CD4 T cells before treatment led to a complete response in ail mice treatcd with 3x8Gy + anti-CTLA-4 + anti-PD-L1, suggesting an immunosuopressive role of a C0<1 T cell subpopulation. The depletion of CDS T cells led to a loss of tumor contrai regardless of the fractionation. ln addition, we observed atter turnor rechallenge a rejection in ail the mice which 11ad responded to the combination RT I anti CTLA-4 - anti-PD-Ll. his rnemory response was dependent of CD4 T cells, particularly for the normofractionated scheme. ln conclusion, we have shown a decrease in anti-tumor peripheral immune responses atter CR r mediated by the induction of immunosuppressiv<i mechanisms. These med1anisms difter depending on the Rl fractionation and can t;c targeted to synergite the lh rapeutic combinations

Etude des effets immunologiques de la radiothérapie et de son fractionnement pour optimiser son association avec la chimiothérapie et l'immunothérapie

Immune hcckpoinl inhibitors (ICI) have revolutionized cancer treatment. but only 20 to 40% of patie,ts show an objective response. Thus, combinations of ICI with other cancer treatment such as chernotherapy (CT) and/or radiotherapy (RT) have been developed to irnprove responses. ln order to optimize their etticiency. these combinations must take into accounc the way the different treatments niodulate the immune system. Our aim was to describe the impact of concurrent ch moradiotherapy (CRT) on peripheral anti-tumor immun responses, and that of RT fractionation in combination with CT and/or ICI on tre anti-tumor response ano the turnor microenvironment (TME) in cli ical and preclinical models. Our preliminary results Ï'1 29 patients lreated with platinum-based CRT showed a loss of the peripheral Thl responses to tclomerase. a tumor antigen overexpressed in cancers. This loss wa, associated with an hcrease in circulating regulatory T cells (Treg��). Moreover, the presence of a specitic anti-tumor response at ba,eline was associated with a better clinical respome a��er CRT. ln locally advanced rectal cancer patients treated with neoadjuvant RT, we studied the expression of PD-L; in the TME. We found that norrnofraction led and hypofractionated RT induced signiticanlly PO-L: with no difference between the two treatment modalities. Next, we wanted co targec th immunosuppressive pathways induced by RT ac.cording to fractionation. ln a murine model f cr26 colorectal cancer, normofractionated RT (18x2Gy) lecl lo increased MDSC, and induced PD·Ll on tumor cells. We compared the clinical etticacy of two fractionations (3x8Gy and :l 8x2Gy) in assoc."acion with SFluorouracil (SFU) known for its depleting action on MDSCs. and a monoclonal antibody targetir.g PD-ll. We showed that in the context of SFU-based CRT, the clinical response was the same whatever the fractionation. On the other hand, when CRT was associated with anti·PD­ll therapy, tumor control was signiticantly bettcr with the normofractionated scheme compare<;! to hypofractionation, achieving a 63% complete response rate. Also, SFU-based normofractiorated CRT - anti-PD-Ll indu ed early expansion of functional CDS+ T cells infiltration and provided long-lasting antitumor immunicy. On the other hand, we evaluated RT associated with an anti-PD-Ll and an anti-CTLA-1\ to target Trcgs indi..ced by the 3x8Gy scheme. Surprisingly, the 3x8Gy + anti-C flA-4 ➔ anti·PD·Ll cornbination was less efficient than the 1Bx2Gy • anti-CTLA-4 + anti-PO·L 1 combination. D pletion of CD4 T cells before treatment led to a complete response in ail mice treatcd with 3x8Gy + anti-CTLA-4 + anti-PD-L1, suggesting an immunosuopressive role of a C0<1 T cell subpopulation. The depletion of CDS T cells led to a loss of tumor contrai regardless of the fractionation. ln addition, we observed atter turnor rechallenge a rejection in ail the mice which 11ad responded to the combination RT I anti CTLA-4 - anti-PD-Ll. his rnemory response was dependent of CD4 T cells, particularly for the normofractionated scheme. ln conclusion, we have shown a decrease in anti-tumor peripheral immune responses atter CR r mediated by the induction of immunosuppressiv<i mechanisms. These med1anisms difter depending on the Rl fractionation and can t;c targeted to synergite the lh rapeutic combinations.Les inhibiteurs de point de contrôle immunitaire (ICI) ont révolutionné te traitement des cancers, mais seuls 20 à 40% des patients présentent une réponse objective. Ainsi, des combinaisons des ICI avec un traitement anticancéreux comme la chimiothérapie (CT) et/ou la radiothérapie (RT) ont été développées pour améliorer les réponses. Afin d'optimiser leur efficacité, ces combinaisons doivent tenir compte de la manière dont les différents traitements modulent le système immunitaire. Nos objectifs étaient de décrire l'impact de la chimioradiothérapie concomitante (RTCT) sur les réponses immunitaires anti-tumorales périphériques et celui du fractionnement de la RT en association avec la CT et/ou les ICI sur la réponse anti tumorale et le microenvironnement tumoral (TME). Nos résultats préliminaires chez 29 patients traités par RTCT à base de sels de platine ont montré une perte des lymphocytes Th1 circulants spécifiques de la télomérase, antigène tumoral surexprimé dans les cancers, après traitement. Cette perte était associée à une augmentation du taux des lymphocytes T régulateurs (Treg) circulants. De plus, la présence d une réponse anti-tumorale spécifique avant le traitement était associée à une meilleure réponse clinique après RTCT. Ensuite, nous avons montré chez des patients atteints d'un cancer du rectum localement avancé une induction de l'expression de PD·L1 dans le TME après RT néoadjuvante indépendamment du fractionnement. Dans un deuxième temps, nous avons voulu cibler les voies immunosuppressives induites par la RT en fonction du fractionnement. Dans un modèle murin de cancer colorectal CT26. le schéma 18x2Gy a induit les MDSC et l'expression de PD-L 1.Nous avons comparé l'efficacité clinique de deux fractionnements, (3x8Gy et 18x2Gy) en association avec une CT par 5-Fluorouracile (SFU) connu pour son action déplétante des MDSC et un anticorps monoclonal ciblant PD·Ll. Nous avons montré que dans le cadre d'une CT avec SFU, la réponse clinique était la même quel que soit le fractionnement. En revanche, lorsqu'on associe la RTCT à l'anti-PD-L 1 la croissance tumorale était plus ralentie avec le schéma normofractionné avec 63% de reponse complète. De plus, cette triple combinaison a induit une expansion de lymphocytes T CD8 cytotoxiques au sein du TME ainsi qu'une protection vis-à-vis d'un nouveau challenge tumoral. En parallèle, nous avons évalué la RT associée à un anti-PD·Ll et un anti-CTLA 4 pour cibler les Ireg induits par le schéma 3x8Gy. D"une manière surprenante. l'association 3x8Gy + anti-CTLA-4 • anti·PD-Ll était moins efficace que l'association 18x2Gy + anti·CTLA-4 + anti-PD·L 1. La déplétion des U CD4 avant un traitement par 3x8Gy + anti-CTLA-4 + anti-PD· ll a entrainé une guérison de toutes les souris, suggérant un rôle immunosupprcsseur d'une sous-population de LT CD4. La déplétion des LT CDS a entrainé une perte du contrôle tumoral quel que soit le fractionnement. Par ailleurs. nous avons constaté après rechallenge tumoral, un rejet chez toutes les souris qui avaient répondu à la combinaison RT + anti·CTLA-4 • anti·PD·Ll. Cette réponse mémoire dépendait des LT CD4 notamment pour le schéma normofractionné. En conclusion, nous avons montré une baisse des réponses immunitaires périphériques anti-tumorales aµprès des RTCT médiée par l'induction de mécanismes irmrnunosuppresseurs. Ces rnécanismes diffèrent selon le fractionnerment de la RT et peuvent être ciblés de manière à rendre les combinaisons synergiques

Etude des effets immunologiques de la radiothérapie et de son fractionnement pour optimiser son association avec la chimiothérapie et l'immunothérapie

Immune hcckpoinl inhibitors (ICI) have revolutionized cancer treatment. but only 20 to 40% of patie,ts show an objective response. Thus, combinations of ICI with other cancer treatment such as chernotherapy (CT) and/or radiotherapy (RT) have been developed to irnprove responses. ln order to optimize their etticiency. these combinations must take into accounc the way the different treatments niodulate the immune system. Our aim was to describe the impact of concurrent ch moradiotherapy (CRT) on peripheral anti-tumor immun responses, and that of RT fractionation in combination with CT and/or ICI on tre anti-tumor response ano the turnor microenvironment (TME) in cli ical and preclinical models. Our preliminary results Ï'1 29 patients lreated with platinum-based CRT showed a loss of the peripheral Thl responses to tclomerase. a tumor antigen overexpressed in cancers. This loss wa, associated with an hcrease in circulating regulatory T cells (Treg��). Moreover, the presence of a specitic anti-tumor response at ba,eline was associated with a better clinical respome a��er CRT. ln locally advanced rectal cancer patients treated with neoadjuvant RT, we studied the expression of PD-L; in the TME. We found that norrnofraction led and hypofractionated RT induced signiticanlly PO-L: with no difference between the two treatment modalities. Next, we wanted co targec th immunosuppressive pathways induced by RT ac.cording to fractionation. ln a murine model f cr26 colorectal cancer, normofractionated RT (18x2Gy) lecl lo increased MDSC, and induced PD·Ll on tumor cells. We compared the clinical etticacy of two fractionations (3x8Gy and :l 8x2Gy) in assoc."acion with SFluorouracil (SFU) known for its depleting action on MDSCs. and a monoclonal antibody targetir.g PD-ll. We showed that in the context of SFU-based CRT, the clinical response was the same whatever the fractionation. On the other hand, when CRT was associated with anti·PD­ll therapy, tumor control was signiticantly bettcr with the normofractionated scheme compare<;! to hypofractionation, achieving a 63% complete response rate. Also, SFU-based normofractiorated CRT - anti-PD-Ll indu ed early expansion of functional CDS+ T cells infiltration and provided long-lasting antitumor immunicy. On the other hand, we evaluated RT associated with an anti-PD-Ll and an anti-CTLA-1\ to target Trcgs indi..ced by the 3x8Gy scheme. Surprisingly, the 3x8Gy + anti-C flA-4 ➔ anti·PD·Ll cornbination was less efficient than the 1Bx2Gy • anti-CTLA-4 + anti-PO·L 1 combination. D pletion of CD4 T cells before treatment led to a complete response in ail mice treatcd with 3x8Gy + anti-CTLA-4 + anti-PD-L1, suggesting an immunosuopressive role of a C0<1 T cell subpopulation. The depletion of CDS T cells led to a loss of tumor contrai regardless of the fractionation. ln addition, we observed atter turnor rechallenge a rejection in ail the mice which 11ad responded to the combination RT I anti CTLA-4 - anti-PD-Ll. his rnemory response was dependent of CD4 T cells, particularly for the normofractionated scheme. ln conclusion, we have shown a decrease in anti-tumor peripheral immune responses atter CR r mediated by the induction of immunosuppressiv<i mechanisms. These med1anisms difter depending on the Rl fractionation and can t;c targeted to synergite the lh rapeutic combinations.Les inhibiteurs de point de contrôle immunitaire (ICI) ont révolutionné te traitement des cancers, mais seuls 20 à 40% des patients présentent une réponse objective. Ainsi, des combinaisons des ICI avec un traitement anticancéreux comme la chimiothérapie (CT) et/ou la radiothérapie (RT) ont été développées pour améliorer les réponses. Afin d'optimiser leur efficacité, ces combinaisons doivent tenir compte de la manière dont les différents traitements modulent le système immunitaire. Nos objectifs étaient de décrire l'impact de la chimioradiothérapie concomitante (RTCT) sur les réponses immunitaires anti-tumorales périphériques et celui du fractionnement de la RT en association avec la CT et/ou les ICI sur la réponse anti tumorale et le microenvironnement tumoral (TME). Nos résultats préliminaires chez 29 patients traités par RTCT à base de sels de platine ont montré une perte des lymphocytes Th1 circulants spécifiques de la télomérase, antigène tumoral surexprimé dans les cancers, après traitement. Cette perte était associée à une augmentation du taux des lymphocytes T régulateurs (Treg) circulants. De plus, la présence d une réponse anti-tumorale spécifique avant le traitement était associée à une meilleure réponse clinique après RTCT. Ensuite, nous avons montré chez des patients atteints d'un cancer du rectum localement avancé une induction de l'expression de PD·L1 dans le TME après RT néoadjuvante indépendamment du fractionnement. Dans un deuxième temps, nous avons voulu cibler les voies immunosuppressives induites par la RT en fonction du fractionnement. Dans un modèle murin de cancer colorectal CT26. le schéma 18x2Gy a induit les MDSC et l'expression de PD-L 1.Nous avons comparé l'efficacité clinique de deux fractionnements, (3x8Gy et 18x2Gy) en association avec une CT par 5-Fluorouracile (SFU) connu pour son action déplétante des MDSC et un anticorps monoclonal ciblant PD·Ll. Nous avons montré que dans le cadre d'une CT avec SFU, la réponse clinique était la même quel que soit le fractionnement. En revanche, lorsqu'on associe la RTCT à l'anti-PD-L 1 la croissance tumorale était plus ralentie avec le schéma normofractionné avec 63% de reponse complète. De plus, cette triple combinaison a induit une expansion de lymphocytes T CD8 cytotoxiques au sein du TME ainsi qu'une protection vis-à-vis d'un nouveau challenge tumoral. En parallèle, nous avons évalué la RT associée à un anti-PD·Ll et un anti-CTLA 4 pour cibler les Ireg induits par le schéma 3x8Gy. D"une manière surprenante. l'association 3x8Gy + anti-CTLA-4 • anti·PD-Ll était moins efficace que l'association 18x2Gy + anti·CTLA-4 + anti-PD·L 1. La déplétion des U CD4 avant un traitement par 3x8Gy + anti-CTLA-4 + anti-PD· ll a entrainé une guérison de toutes les souris, suggérant un rôle immunosupprcsseur d'une sous-population de LT CD4. La déplétion des LT CDS a entrainé une perte du contrôle tumoral quel que soit le fractionnement. Par ailleurs. nous avons constaté après rechallenge tumoral, un rejet chez toutes les souris qui avaient répondu à la combinaison RT + anti·CTLA-4 • anti·PD·Ll. Cette réponse mémoire dépendait des LT CD4 notamment pour le schéma normofractionné. En conclusion, nous avons montré une baisse des réponses immunitaires périphériques anti-tumorales aµprès des RTCT médiée par l'induction de mécanismes irmrnunosuppresseurs. Ces rnécanismes diffèrent selon le fractionnerment de la RT et peuvent être ciblés de manière à rendre les combinaisons synergiques

The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to modify the tumor micro environment (TME) and to induce a local and systemic (abscopal effect) immune response. Conversely, RT is able to increase some immunosuppressive barriers, which can lead to tumor radioresistance. Fractionation and dose can affect the immunomodulatory properties of RT. Here, we review how fractionation, dose and timing shape the RT-induced anti-tumor immune response and the therapeutic effect of RT. We discuss how immunomodulators targeting immune checkpoint inhibitors and the cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway can be successfully combined with RT. We then review current trials evaluating the RT/Immunotherapy combination efficacy and suggest new innovative associations of RT with immunotherapies currently used in clinic or in development with strategic schedule administration (fractionation, dose, and timing) to reverse immune-related radioresistance. Overall, our work will present the existing evidence supporting the claim that the reactivation of the anti-tumor immune response can be regarded as the 6th R of Radiobiology

Present and Future Research on Anal Squamous Cell Carcinoma

Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no substantial advances in disease knowledge and treatment, it is finally gaining momentum with the arrival of a taxane-based chemotherapy and immunotherapy. Currently, about 20 combination clinical trials with an anti-PD1/L1 are ongoing in localized and advanced stages, in association with radiotherapy, chemotherapy, tumor vaccines, anti-CTLA4, anti-EGFR, or antiangiogenic molecules. Moreover, a new biomarker with high sensitivity and specificity such as HPV circulating tumor DNA (HPV ctDNA) by liquid biopsy, is improving not only the prognostic measurement but also the treatment strategy guidance for this disease. Finally, better understanding of potential targets is reshaping the present and future clinical research in this unique, HPV genotype-16-related disease in the great majority of patients

Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials

Quality Assurance of Dose-Escalated Radiation Therapy in a Randomized Trial for Locally Advanced Oesophageal cancer

International audienc

Cisplatin-based chemoradiation decreases telomerase-specific CD4 TH1 response but increases immune suppressive cells in peripheral blood

International audienceBackground: The synergistic effect of chemoradiation (CRT) has been previously demonstrated in several cancer types. Here, we investigated the systemic immune effects of CRT in patients with lung or head and neck cancer. Materials and methods: Peripheral blood mononuclear cells were collected at baseline and 1 month after treatment from blood samples of 29 patients treated with cisplatin-based chemoradiotherapy for lung or head and neck cancer. Circulating anti-tumor Th1 response was assessed by the ELISpot assay using a mixture of human leucocyte antigen (HLA) class II restricted peptides derived from telomerase (TERT). Phenotyping of circulating immunosuppressive cells (Treg and MDSC) was performed by flow cytometry. Results: A significant increase of circulating Treg was observed in 60% of patients after CRT The mean rate of Treg was 3.1% versus 4.9% at baseline and after CRT respectively, p = 0.0015). However, there was a no significant increase of MDSC rate after CRT. In contrast, a decrease of tumor-specific Th1 response was documented in 7 out of 10 evaluated patients. We found high frequency of pre-existing tumor-specific Th1 response among patients with objective response after CRT compared to non-responders. Conclusion: Cisplatin-based CRT promotes expansion of Treg and decrease of circulating anti-tumor Th1 response in peripheral blood. The balance towards a sustained specific anti-tumor T-cell response appears to be associated with response to CRT

Managing postoperative biochemical relapse in prostate cancer, from the perspective of the Francophone group of Urological radiotherapy (GFRU).

Up to 50% of patients treated with radical surgery for localized prostate cancer may experience biochemical recurrence that requires appropriate management. Definitions of biochemical relapse may vary, but, in all cases, consist of an increase in a PSA without clinical or radiological signs of disease. Molecular imaging through to positron emission tomography has taken a preponderant place in relapse diagnosis, progressively replacing bone scan and CT-scan. Prostate bed radiotherapy is currently a key treatment, the action of which should be potentiated by androgen deprivation therapy. Nowadays perspectives consist in determining the best combination therapies, particularly thanks to next-generation hormone therapies, but not exclusively. Several trials are ongoing and should address these issues. We present here a literature review aiming to discuss the current management of biochemical relapse in prostate cancer after radical surgery, in lights of recent findings, as well as future perspectives