Does IPSS-R downstaging before transplantation improve the prognosis of patients with myelodysplastic neoplasms?

ABSTRACT: In patients with myelodysplastic syndrome (MDS), higher revised International Prognostic Scoring System (IPSS-R) scores at transplant are associated with worse transplant outcome and, thus, lowering IPSS-R scores by therapeutic intervention before transplantation may seem beneficial. However, there is no evidence, to date, to support this approach. In a retrospective analysis, a total of 1482 patients with MDS with sufficient data to calculate IPSS-R score at diagnosis and at time of transplantation were selected from the European Society for Blood and Marrow Transplantation transplant registry and analyzed for transplant outcome in a multivariable Cox model including IPSS-R score at diagnosis, treatment intervention, change in IPSS-R score before transplant, and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R score change in untreated patients and moderately superior in patients treated with chemotherapy with improved IPSS-R score at transplant. Improved IPSS-R score after hypomethylating agents (HMAs) or other therapies showed no beneficial effect. However, when IPSS-R score progressed after chemotherapy, HMAs, or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R score downstaging or reduction of BM blasts after chemotherapy and no benefit for HMAs or other treatments and thus question the role of prior therapy in patients with MDS scheduled for transplantation. The model-based survival estimates should help inform decision-making for both doctors and patients.

Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) were classified in the adverse-risk category in the presence of high-risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1-mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse-risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long-term posttransplant survival.

Outcomes of CMML patients undergoing allo-HCT are significantly worse compared to MDS-a study of the CMWP of the EBMT.

Although CMML since long has been separated from MDS, many studies continue to evaluate the outcomes of both diseases after hematopoietic cell transplantation (allo-HCT) together. Data evaluating outcomes of a large CMML cohort after allo-HCT compared to MDS are limited. We aim to compare outcomes of CMML to MDS patients who underwent allo-HCT between 2010 and 2018. Patients ≥18 years with CMML and MDS undergoing allo-HCT reported to the EBMT registry were analyzed. Progression to AML before allo-HCT was an exclusion criterion. Overall survival (OS), progression/relapse-free survival (PFS), relapse incidence (including progression) (REL), and non-relapse mortality (NRM) were evaluated in univariable and multivariable (MVA) Cox proportional hazard models including interaction terms between disease and confounders. In total, 10832 patients who underwent allo-HCT were included in the study, there were a total of 1466 CMML, and 9366 MDS. The median age at time of allo-HCT in CMML (median 60.5, IQR 54.3-65.2 years) was significantly higher than in the MDS cohort (median 58.8, IQR 50.2-64.5 years; p < .001). A significantly higher percentage of CMML patients were male (69.4%) compared to MDS (61.2%; p < .001). There were no clinically meaningful differences in the distribution of Karnofsky score, Sorror HCT-CI score at allo-HCT, and donor type, between the CMML and MDS patients. RIC platforms were utilized in 63.9% of CMML allo-HCT, and in 61.4% of MDS patients (p = .08). In univariable analyses, we found that OS, PFS, and REL were significantly worse in CMML when compared with MDS (all p < .0001), whereas no significant difference was observed in NRM (p = .77). In multivariable analyses, the HR comparing MDS versus CMML for OS was 0.81 (95% CI, 0.74-0.88, p < .001), PFS 0.76 (95% CI 0.70-0.82, p < .001), relapse 0.66 (95% CI 0.59-0.74, p < .001), and NRM 0.87 (95% CI 0.78-0.98, p = .02), respectively. The association between baseline variables and outcome was found to be similar in MDS and CMML (all interaction p > .05) except for a decreasing trend over time of the risk of relapse in CMML (HR allo-HCT per year later 0.94, 95% CI 0.90-0.98), whereas no such trend was observed in MDS (HR 1.00, 95% CI 0.98-1.02). The poor outcome observed for CMML could be related to variables not measured in this study or to factors inherent to the disease itself. This study demonstrates that outcomes of CMML patients after allo-HCT are significantly worse compared to MDS. The results of this study may contribute to future recommendations for allo-HCT in CMML patients.

Radiotherapy combination opportunities leveraging immunity for the next oncology practice.

Approximately one-half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy (RT), with the explicit goal of eliminating tumors through direct killing. The current RT dose and schedule regimens have been empirically developed. Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote, nonirradiated tumor deposits-the so-called "abscopal effect"- the underlying mechanisms were poorly understood and were not therapeutically exploited. Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy. In the wake of recent therapeutic breakthroughs in the field of immunotherapy, rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade. Thus, a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations. Here, the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy-RT combinations. Furthermore, a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field. CA Cancer J Clin 2017;67:65-85. © 2016 American Cancer Society.

Validation of MLC leaf open time calculation methods for PSQA in adaptive radiotherapy with tomotherapy units.

BACKGROUND: Treatment delivery safety and accuracy are essential to control the disease and protect healthy tissues in radiation therapy. For usual treatment, a phantom-based patient specific quality assurance (PSQA) is performed to verify the delivery prior to the treatment. The emergence of adaptive radiation therapy (ART) adds new complexities to PSQA. In fact, organ at risks and target volume re-contouring as well as plan re-optimization and treatment delivery are performed with the patient immobilized on the treatment couch, making phantom-based pretreatment PSQA impractical. In this case, phantomless PSQA tools based on multileaf collimator (MLC) leaf open times (LOTs) verifications provide alternative approaches for the Radixact® treatment units. However, their validity is compromised by the lack of independent and reliable methods for calculating the LOT performed by the MLC during deliveries. PURPOSE: To provide independent and reliable methods of LOT calculation for the Radixact® treatment units. METHODS: Two methods for calculating the LOTs performed by the MLC during deliveries have been implemented. The first method uses the signal recorded by the build-in detector and the second method uses the signal recorded by optical sensors mounted on the MLC. To calibrate the methods to the ground truth, in-phantom ionization chamber LOT measurements have been conducted on a Radixact® treatment unit. The methods were validated by comparing LOT calculations with in-phantom ionization chamber LOT measurements performed on two Radixact® treatment units. RESULTS: The study shows a good agreement between the two LOT calculation methods and the in-phantom ionization chamber measurements. There are no notable differences between the two methods and the same results were observed on the different treatment units. CONCLUSIONS: The two implemented methods have the potential to be part of a PSQA solution for ART in tomotherapy.

Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis.

BACKGROUND: The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis. METHODS: For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524. FINDINGS: The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2-13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59-0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69-0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75-1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%). INTERPRETATION: The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma. FUNDING: Institut National du Cancer and Ligue Nationale Contre le Cancer.

A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.

Fludarabine versus cyclophospamide in combination with myeloablative total body irradiation as conditioning for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Total body irradiation (TBI) at a dose of 12 Gy combined with cyclophosphamide (CyTBI12Gy) is one of the standard myeloablative regimens for patients with acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cyclophosphamide may be substituted with fludarabine (FluTBI12Gy) to reduce toxicity. We retrospectively compared outcomes of CyTBI12Gy with FluTBI12Gy for patients with AML treated in complete remission (CR) with allo-HCT from either a matched sibling or unrelated donor. Of 1684 adults who met inclusion criteria, 109 patients in each group were included in a matched-pair analysis. The cumulative incidence of relapse at 2 years was 25% in the FluTBI12Gy compared to 28% in the CyTBI12Gy group (p = .44) while non-relapse mortality (NRM) was 17% versus 19%, (p = .89) respectively. The rates of leukemia-free survival and overall survival were 65% versus 54% (p = .28) and 70% versus 60.5% (p = .17). Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly lower for FluTBI12Gy than CyTBI12Gy (16% vs. 34%, p = .005), while the incidences of grade 3-4 acute GVHD and chronic GVHD did not differ significantly. The probability of GVHD and relapse-free survival was 49% in the FluTBI12Gy and 41% in the CyTBI12Gy group (p = .17). We conclude that for patients with AML treated with allo-HCT in CR, cyclophosphamide may be substituted with fludarabine in a regimen based on TBI at a dose of 12 Gy without negative impact on the efficacy. FluTBI12Gy is associated with reduced risk of grade 2-4 acute GVHD and encouraging survival rates.

Outcomes after allogeneic hematopoietic cell transplant in patients diagnosed with blast phase of myeloproliferative neoplasms: A retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) <90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active disease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS ≥90 and in CR at transplant had a better prognosis.

Recurrences of ventricular tachycardia after stereotactic arrhythmia radioablation arise outside the treated volume: analysis of the Swiss cohort.

AIMS: Stereotactic arrhythmia radioablation (STAR) has been recently introduced for the management of therapy-refractory ventricular tachycardia (VT). VT recurrences have been reported after STAR but the mechanisms remain largely unknown. We analysed recurrences in our patients after STAR. METHODS AND RESULTS: From 09.2017 to 01.2020, 20 patients (68 ± 8 y, LVEF 37 ± 15%) suffering from refractory VT were enrolled, 16/20 with a history of at least one electrical storm. Before STAR, an invasive electroanatomical mapping (Carto3) of the VT substrate was performed. A mean dose of 23 ± 2 Gy was delivered to the planning target volume (PTV). The median ablation volume was 26 mL (range 14-115) and involved the interventricular septum in 75% of patients. During the first 6 months after STAR, VT burden decreased by 92% (median value, from 108 to 10 VT/semester). After a median follow-up of 25 months, 12/20 (60%) developed a recurrence and underwent a redo ablation. VT recurrence was located in the proximity of the treated substrate in nine cases, remote from the PTV in three cases and involved a larger substrate over ≥3 LV segments in two cases. No recurrences occurred inside the PTV. Voltage measurements showed a significant decrease in both bipolar and unipolar signal amplitude after STAR. CONCLUSION: STAR is a new tool available for the treatment of VT, allowing for a significant reduction of VT burden. VT recurrences are common during follow-up, but no recurrences were observed inside the PTV. Local efficacy was supported by a significant decrease in both bipolar and unipolar signal amplitude.

Long-term results from a clinical study of xevinapant plus chemoradiotherapy in people with high-risk locally advanced squamous cell carcinoma of the head and neck: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: Squamous cell carcinoma of the head and neck (SCCHN) is the most common type of head and neck cancer. About half of the people with locally advanced (LA) SCCHN will have surgery to remove their cancer. For people who do not have surgery, chemoradiotherapy is the standard treatment, with the aim of fully removing the cancer. However, in many people, this treatment does not completely kill the cancer. This summary presents the main results of a phase 2 study of a medicine called xevinapant, which is under investigation as a potential future medicine for people with this type of cancer. WHAT DID THE RESEARCHERS WANT TO FIND OUT?: In this study, researchers wanted to find out whether xevinapant plus chemoradiotherapy could stop the cancer from growing back or getting worse in the years after treatment completion in people with LA SCCHN. They also looked at whether people with this type of cancer had side effects from taking this medicine. Short-term results were collected 18 months after treatment with chemoradiotherapy ended. These results showed that people who received xevinapant plus chemoradiotherapy were less likely to have their cancer grow back, or get worse in the part of the body where it was first found, than people who received liquid placebo-which looked and tasted the same as the active medicine (in this case, xevinapant), but did not contain any medicine-plus chemoradiotherapy. Researchers then continued to collect information for a longer amount of time (at least 3 years). They wanted to see if treatment with xevinapant plus chemoradiotherapy was stopping the cancer from growing back or getting worse and helping people live longer. After this, people were monitored for a further 2 years to see if they were alive 5 years after treatment. WHAT WERE THE MAIN FINDINGS OF THE STUDY?: The results showed that people with this type of cancer who were treated with xevinapant plus chemoradiotherapy were less likely to die, lived longer on average, and were less likely to have their cancer get worse. A phase 3 study, named TrilynX, in a larger group of people, is currently taking place to confirm the results of this study. Clinical Trial Registration: NCT02022098 (Debio 1143-201 Dose-finding and Efficacy Phase I/II Trial) (ClinicalTrials.gov).

International assessment of interobserver reproducibility of flap delineation in head and neck carcinoma.

Background: Several reports have suggested that radiotherapy after reconstructive surgery for head and neck cancer (HNC), could have deleterious effects on the flaps with respect to functional outcomes. To predict and prevent toxicities, flap delineation should be accurate and reproducible. The objective of the present study was to evaluate the interobserver variability of frequent types of flaps used in HNC, based on the recent GORTEC atlas.Materials and methods: Each member of an international working group (WG) consisting of 14 experts delineated the flaps on a CT set from six patients. Each patient had one of the five most commonly used flaps in HNC: a regional pedicled pectoralis major myocutaneous flap, a local pedicled rotational soft tissue facial artery musculo-mucosal (FAMM) (2 patients), a fasciocutaneous radial forearm free flap, a soft tissue anterolateral thigh (ALT) free flap, or a fibular free flap. The WG's contours were compared to a reference contour, validated by a surgeon and a radiologist specializing in HNC. Contours were considered as reproducible if the median Dice Similarity Coefficient (DSC) was > 0.7.Results: The median volumes of the six flaps delineated by the WG were close to the reference contour value, with approximately 50 cc for the pectoral, fibula, and ALT flaps, 20 cc for the radial forearm, and up to 10 cc for the FAMM. The volumetric ratio was thus close to the optimal value of 100% for all flaps. The median DSC obtained by the WG compared to the reference for the pectoralis flap, the FAMM, the radial forearm flap, ALT flap, and the fibular flap were 0.82, 0.40, 0.76, 0.81, and 0.76, respectively.Conclusions: This study showed that the delineation of four main flaps used for HNC was reproducible. The delineation of the FAMM, however, requires close cooperation between radiologist, surgeon and radiation oncologist because of the poor visibility of this flap on CT and its small size.

Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design.

Xevinapant is a first-in-class antagonist of inhibitor of apoptosis proteins, which enhances cancer cell sensitivity to chemotherapy and radiotherapy. In a phase II randomized study in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), xevinapant plus standard-of-care cisplatin-based chemoradiotherapy (CRT) showed superior efficacy versus placebo plus CRT. Here, we describe the design of TrilynX (NCT04459715), a randomized, double-blind, phase III study. In total, 700 patients with unresected LA SCCHN will be randomized 1:1 to receive xevinapant or placebo plus standard-of-care CRT followed by xevinapant monotherapy or placebo. The primary end point is event-free survival by blinded independent review committee. Secondary end points include progression-free survival, locoregional control, overall survival and safety.

Xevinapant is being developed as a new type of cancer treatment. Xevinapant works by enhancing the effects of chemotherapy and radiotherapy (chemoradiotherapy), which are standard anticancer treatments. Researchers are studying whether adding xevinapant to these treatments could be helpful for people with head and neck cancers that have not spread to other parts of the body and cannot be removed by surgery. In a study of 96 people with this disease, those treated with chemoradiotherapy plus xevinapant on average lived longer than people treated with chemoradiotherapy plus placebo (liquid that looked the same but did not contain any medicine). To confirm the results, researchers have started a larger study, called TrilynX, that will compare the same treatments in around 700 people worldwide. This study will show if adding xevinapant to chemoradiotherapy can help to keep the cancer from progressing, control symptoms better and help people live longer. Clinical trial registration: NCT04459715 (ClinicalTrials.gov).

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.

Here, we highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy⋅s-1). Compared with conventional dose-rate (CONV; 0.07-0.1 Gy⋅s-1) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory. Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

Validation of Monte Carlo dose calculation algorithm for CyberKnife multileaf collimator.

PURPOSE: To commission and evaluate the Monte Carlo (MC) dose calculation algorithm for the CyberKnife equipped with a multileaf collimator (MLC). METHODS: We created a MC model for the MLC using an integrated module of the CyberKnife treatment planning software (TPS). Two parameters could be optimized: the maximum energy and the source full width at half-maximum (FWHM). The optimization was performed by minimizing the differences between the measured and the MC calculated tissue phantom ratios and profiles. MLC plans were calculated in the TPS with the MC algorithm and irradiated on different phantoms. The dose was measured using an A1SL ionization chamber and EBT3 Gafchromic films, and then compared to the TPS dose to obtain dose differences (ΔD). Finally, patient-specific quality assurances (QA) were performed with global gamma index criteria of 3%/1 mm. RESULTS: The maximum energy and source FWHM showing the best agreement with measurements were 6.4 MeV and 1.8 mm. The output factors calculated with these parameters gave an agreement within ±1% with measurements. The ΔD showed that MC model systematically underestimated the dose with an average of -1.5% over all configurations tested. For depths deeper than 12 cm, the ΔD increased, up to -3.0% (maximum at 15.5 cm depth). CONCLUSIONS: The MC model for MLC of CyberKnife is clinically acceptable but underestimates the delivered dose by an average of -1.5%. Therefore, we recommend using the MC algorithm with the MLC only in heterogeneous regions and for shallow-seated tumors.

Commissioning and validation of RayStation treatment planning system for CyberKnife M6.

BACKGROUND: RaySearch (AB, Stockholm) has released a module for CyberKnife (CK) planning within its RayStation (RS) treatment planning system (TPS). PURPOSE: To create and validate beam models of fixed, Iris, and multileaf collimators (MLC) of the CK M6 for Monte Carlo (MC) and collapsed cone (CC) algorithms in the RS TPS. METHODS: Measurements needed for the creation of the beam models were performed in a water tank with a stereotactic PTW 60018 diode. Both CC and MC models were optimized in RS by minimizing the differences between the measured and computed profiles and percentage depth doses. The models were then validated by comparing dose from the plans created in RS with both single and multiple beams in different phantom conditions with the corresponding measured dose. Irregular field shapes and off-axis beams were also tested for the MLC. Validation measurements were performed using an A1SL ionization chamber, EBT3 Gafchromic films, and a PTW 1000 SRS detector. Finally, patient-specific QAs with gamma criteria of 3%/1 mm were performed for each model. RESULTS: The models were created in a straightforward manner with efficient tools available in RS. The differences between computed and measured doses were within ±1% for most of the configurations tested and reached a maximum of 3.2% for measurements at a depth of 19.5-cm. With respect to all collimators and algorithms, the maximum averaged dose difference was 0.8% when considering absolute dose measurements on the central axis. The patient-specific QAs led to a mean result of 98% of points fulfilling gamma criteria. CONCLUSIONS: We created both CC and MC models for fixed, Iris, and MLC collimators in RS. The dose differences for all collimators and algorithms were within ±1%, except for depths larger than 9 cm. This allowed us to validate both models for clinical use.

[Place of stereotactic radiotherapy in oligoprogressive non-small cell lung cancer]. / Place de la radiothérapie stéréotaxique dans le cancer du poumon non à petites cellules en oligoprogression.

This review of the literature provides an overview of the combination of stereotactic radiotherapy (SBRT) with immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) in oligo-progressive non-small cell lung neoplasia. This combination showed local control of 76-100% and distant response rates of 8-60%. They reported progression-free survival of 2.7-24 months and overall survival of 13.4-41.2 months. All-grade toxicity rates ranged from 0% to 42%, with grade≥3 toxicity ranging from 0% to 14%. The combination of SBRT with ICI or TKIs exhibits a safe profile with high rates of local control with this combination. This could delay the use of a new line of systemic therapy in these patients with often limited therapeutic resources.

Cette revue de la littérature réalise un état des lieux de l'association de la radiothérapie stéréotaxique (SBRT) aux inhibiteurs de points de contrôle immunitaire (IPCI) et inhibiteurs de la tyrosine kinase (ITK) dans les néoplasies pulmonaires non à petites cellules en oligoprogression. Cette association montrait un contrôle local entre 76 et 100 % et un taux de réponse à distance entre 8 et 60 %. Elle était associée à une survie sans progression de 2,7 à 24 mois et une survie globale de 13,4 à 41,2 mois. Les taux de toxicité tous grades confondus étaient de 0 à 42 %, dont ceux de grade ≥ 3 entre 0 et 14 %. L'association de la SBRT aux IPCI ou ITK arbore un profil de sécurité avec des taux élevés de contrôle local avec cette combinaison. Cela pourrait retarder le recours à une nouvelle ligne de traitement systémique chez ces patients aux ressources thérapeutiques souvent limitées.

[Management of brain metastases in 2022]. / Prise en charge des métastases cérébrales en 2022.

Brain metastases (BM) are a common occurrence of systemic cancers. Technical improvements in neuroimaging offer additional tools for an early detection of BM, to target them precisely and differentiate these lesions from other cerebral pathologies. The therapeutic tools have also evolved from neurosurgery and whole brain therapy to include stereotactic radiosurgery, targeted and immune therapies. Given the numerous treatment options available, a multidisciplinary approach is essential to offer the patient a personalized approach to optimize the sequence and combination of treatments to offer the best outcome possible. This article aims to review key elements of diagnosis, risk stratification and modern treatment paradigms in the diagnosis and management of BM.

Les métastases cérébrales (MC) sont une manifestation fréquente des cancers systémiques. Les améliorations des techniques de radiologie offrent des options supplémentaires pour détecter de manière précoce les MC, les cibler avec précision et les différencier d'autres pathologies. Les outils thérapeutiques se sont également élargis pour inclure des techniques de radiothérapie stéréotaxiques, des thérapies ciblées et des immunothérapies. Au vu des nombreuses options de traitement pour les patients souffrant de MC, une approche multidisciplinaire doit impérativement être favorisée pour personnaliser le traitement de chaque patient et améliorer le pronostic. Cet article décrit les éléments clés du diagnostic, de la stratification du risque et les paradigmes modernes de la prise en charge et des traitements des patients avec MC.

Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

Cetuximab, docetaxel, and cisplatin versus platinum, fluorouracil, and cetuximab as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (GORTEC 2014-01 TPExtreme): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel-platinum-cetuximab) showed promising results, with a median overall survival of 14·0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum-fluorouracil-cetuximab) in this setting. METHODS: This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18-70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m2 and cisplatin 75 mg/m2, both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m2 was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m2 on day 1-4, cisplatin 100 mg/m2 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on day 1 of cycle 1 and 250 mg/m2 weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m2 cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at ClinicalTrials.gov, NCT02268695. FINDINGS: Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34·4 months (IQR 26·6-44·8) in the TPEx group and 30·2 months (25·5-45·3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14·5 months [95% CI 12·5-15·7] in the TPEx group and 13·4 months [12·2-15·4] in the EXTREME group; hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p<0·0001). In the TPEx group, 118 (45%) of 263 patients had at least one serious adverse event versus 143 (54%) of 265 patients in the EXTREME group. 16 patients in the TPEx group and 21 in the EXTREME group died in association with adverse events, including seven patients in each group who had fatal infections (including febrile neutropenia). Eight deaths in the TPEx group and 11 deaths in the EXTREME group were assessed as treatment related, most frequently sepsis or septic shock (four in each treatment group). INTERPRETATION: Although the trial did not meet its primary endpoint, with no significant improvement in overall survival with TPEx versus EXTREME, the TPEx regimen had a favourable safety profile. The TPEx regimen could provide an alternative to standard of care with the EXTREME regimen in the first-line treatment of patients with recurrent or metastatic HNSCC, especially for those who might not be good candidates for up-front pembrolizumab treatment. FUNDING: Merck Santé and Chugai Pharma.