Combining Immune Checkpoint Inhibitors with Loco-Regional Treatments in Hepatocellular Carcinoma: Ready for Prime Time?

Hepatocellular carcinoma (HCC) is a disease with a poor prognosis, often diagnosed at an advanced stage. Therapeutic options have developed considerably in recent years, particularly with trans-arterial treatments. Systemic treatments have also evolved significantly, with the rise of immune checkpoint inhibitors (ICI) as first-line treatment for advanced HCC. The combination of loco-regional treatments and ICI is opening up new prospects and is the subject of numerous clinical trials. Recently, two global phase 3 trials investigating ICI-based adjuvant combinations have demonstrated improvements in recurrence-free survival or progression-free survival in patients treated with resection, ablation, or trans-arterial chemoembolization. However, mature data and overall survival results are still awaited but will be difficult to interpret. We are at the start of a new era of combinations of loco-regional treatments and immunotherapy. The identification of the best therapeutic strategies and predictive biomarkers is a crucial issue for future standards in clinical practice.

Salvage prostate intensity modulated radiation therapy after cryotherapy failure.

Cryotherapy is an ablative therapy that can be used to treat localized prostate cancer. In case of recurrence, treatment options are not well-defined, and their outcomes are unknown. We therefore collected all patients treated with radiotherapy after cryotherapy for prostate cancer recurrence in Nantes (France) between 2012 and 2019. We identified ten patients. After a median follow-up of 5 years, two patients presented late grade 3 toxicities; one patient presented a grade 3 rectal hemorrhage, and one had a grade 3 hematuria. Two patients relapsed at 61 and 62 months, and three patients died of other causes. Radiotherapy to treat local prostate cancer recurrence after cryotherapy seems feasible and effective in local control. These results do not allow us to recommend this technique in current practice but are encouraging for the conduct of prospective trials.

Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial.

BACKGROUND: The relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. OBJECTIVE: To evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. INTERVENTION: All patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. RESULTS AND LIMITATIONS: The 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4-90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. CONCLUSIONS: Adding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. PATIENT SUMMARY: Our study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

Extramedullary hematopoiesis causing spinal cord compression in polycythemia vera: A case report and literature review.

Extramedullary hematopoiesis (EMH) is a rare cause of spinal cord compression defined as finding hematopoietic elements outside the physiological location in the bone marrow. We report the case of a 70-year-old man with JAK 2 positive myeloproliferative syndrome type polycythemia vera (PV), initially treated with hydroxyurea. Two years after diagnosis, he presented progression with biological and clinical evolution associating hyperleukocytosis and hepatosplenomegaly with no evidence of acute myeloid leukemia. Treatment with hydroxyurea and ruxolitinib was introduced. Six months later, clinical symptoms suggesting spinal cord compression from the T2 region appeared. Medullary MRI revealed a multistage spinal cord injury from T2 to S1, while brain CT excluded any intracranial location. The biopsy diagnosed extramedullary hematopoiesis with no CD34 + blast cell, corresponding polycythemia vera. Given the lack of consensus and after a review of the literature, irradiation was planned to treat a volume from T1 to S2 with a dose of 18 Gy in 10 sessions of 1.8 Gy. At the end of the radiotherapy, the patient started to recover his motor and sensory functions. Six months later, he walked without assistance and had no significant acute toxicity. Using radiotherapy to treat spinal cord compression caused by EMH is justified with excellent early response and no major side effects. We present here this case and the systematic review of the literature on this matter.

Salvage radiotherapy after initial cryotherapy for localized prostate cancer: A systematic review of the literature.

The treatment of local prostate cancer recurrence after cryotherapy is challenging since the optimal management is unknown. We collected the available evidence to date to better define the risk and benefit of salvage radiotherapy (SRT) after cryotherapy failure for localized prostate cancer. This review confirms the feasibility of SRT in terms of biochemical control and late toxicity rate. However, the absence of comparative trials or prospective studies, coupled with the heterogeneity of patients treated and the variations in treatments delivered across the analyzed studies, highlights the need for cautious consideration when opting for salvage radiotherapy. Therefore, we highly recommend the inclusion of patients in dedicated clinical trials to comprehensively assess the efficacy and safety of this approach.

Cardiologist-Performed Baseline Evaluation with an Assessment of Coronary Status for Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Impact on Newly Diagnosed Coronary Artery Disease.

BACKGROUND: Given the potential cardiovascular risks of androgen deprivation therapy (ADT), it is essential to identify patients who may be at an increased risk for coronary artery disease (CAD). Despite the recent ESC recommendations, there is no consensus on when to refer a patient to a cardiologist for further evaluation. OBJECTIVE: To report on new diagnoses of CAD in patients with prostate cancer (PCa) requiring ADT who underwent a systematic cardio-onco evaluation with an assessment of their coronary status. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, monocentric study that included patients with PCa who had completed a cardio-onco evaluation with an assessment of their coronary status in the cardio-oncology department at the Western Cancer Institute, Nantes, between January 2019 and August 2022. INTERVENTION: The baseline cardio-onco evaluation included a physical exam, transthoracic echography, and electrocardiogram, followed with a systematic evaluation of their coronary status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to determine the incidence of newly diagnosed CAD. The secondary objective was to evaluate the number of changes in cardiovascular treatment. RESULTS AND LIMITATIONS: Among the 34 patients who underwent cardio-onco evaluation, 7 (20.6%) were diagnosed with CAD, with a median time to diagnosis of 5 months. Most patients were asymptomatic, with one who experienced a myocardial infarction. Of the 27 patients without CAD, 44.4% underwent a therapeutic intervention by the cardiologist, with no cardiac deaths during follow-up. Overall, 55.9% of patients had a therapeutic intervention after the cardio-onco evaluation. CONCLUSIONS: The high incidence of newly diagnosed CAD in asymptomatic patients supports the need for screening for CAD in this population. Further research is needed to determine whether routine screening for CAD in patients receiving ADT would result in significant clinical benefits.

Phase 1 Study of the Combination of Escalated Total Marrow Irradiation Using Helical Tomotherapy and Fixed High-Dose Melphalan (140 mg/m²) Followed by Autologous Stem Cell Transplantation at First Relapse in Multiple Myeloma.

PURPOSE: A second intensification is an option at first relapse in multiple myeloma (MM) after more than 36 months of initial remission. Many conditioning regimens have been tested, with or without total body irradiation (TBI). Recently, it was found that TBI could be replaced by total marrow irradiation (TMI) using helical tomotherapy, with promising results. METHODS AND MATERIALS: This study was a prospective multicenter phase 1 trial that aimed to determine the maximum tolerated dose (MTD) of TMI administered in association with melphalan 140 mg/m², followed by autologous stem cell transplantation as consolidation at first relapse in MM. Four dose levels were explored: 8 Gy, 10 Gy, 12 Gy, and 14 Gy. The dose-limiting toxicity (DLT) was defined as grade 4 neutropenia >15 days, grade 4 thrombopenia >28 days, and all other grade 4 nonhematologic toxic effects except nausea, vomiting, alopecia, mucositis, and reaction to autologous stem cell infusion. RESULTS: Thirteen patients were included; only 1 DLT at the third escalated dose level (12 Gy) was observed, whereas 1 patient was treated at 14 Gy with no adverse events. The MTD was not reached. The rate of acute toxicity was low: 38% of grade 3-4 diarrhea, mucositis, or unexplained fever. Regarding the lungs, the mean dose administered was systematically less than 8 Gy. After a median follow-up of 55 months, 70% of participants were alive. Of these 13 patients, 38.5% were in very good partial response and 30.8% were in complete response. Three of them were progression-free. Six patients were long survivors, still alive after 55 months of follow-up. CONCLUSIONS: Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered to the planning target volume while sparing organs at risk. This technique could be discussed for all regimens before auto- or allo-stem cell rescue when TBI is required.

Randomized phase II trial in prostate cancer with hormone-sensitive OligometaSTatic relapse: Combining stereotactic ablative radiotherapy and durvalumab (POSTCARD GETUG P13): Study protocol.

Background: As in other solid tumors, increasing evidence indicates that patients diagnosed with a limited number of prostate cancer metastases, so-called oligometastases, have a better prognosis than patients with extensive metastatic disease. Stereotactic body radiotherapy (SBRT) is now considered an option in this population.Programmed death-1 (PD-1) and its ligands (PD-L1) are targeted by immune checkpoint inhibitors. Preclinical studies have shown that the tumor immune microenvironment changes when combining radiotherapy with immunotherapy, especially with hypofractionated radiotherapy.The oligometastatic setting appears to be the most relevant clinical situation for evaluating the immune response generated by radiotherapy and immune checkpoint inhibitors in patients with an intact immune system.We hypothesize that durvalumab will enhance the immune response following SBRT targeting oligometastatic lesions. Our purpose is to demonstrate, via a randomized 2:1 phase II trial, that SBRT (3 fractions) with durvalumab in oligometastatic hormone-sensitive prostate cancer patients would improve progression-free survival in patients with prostate cancer with up to 5 metastases compared to patients who exclusively received SBRT. Methods: This is a multicentric randomized phase II study in French academic hospitals. Patients with prostate cancer and up to 5 metastases (lymph node and/or bone) were randomized into a 2:1 ratio between Arm A (experimental group), corresponding to durvalumab and SBRT to the metastases, and Arm B (control group), corresponding to SBRT alone to the metastases. The study aims to accrue a total of 96 patients within 3 years. The primary endpoint is two-year progression-free survival and secondary endpoints include androgen deprivation therapy-free survival, quality of life, toxicity, prostate cancer specific survival, overall survival, and immune response. Discussion: The expected benefit for the patients in the experimental arm is longer life expectancy with acceptable toxicity. We also expect our study to provide data for better understanding the synergy between immunotherapy and radiotherapy in oligometastatic prostate cancer.

Cytokine release syndrome and tumor lysis syndrome in a multiple myeloma patient treated with palliative radiotherapy: A case report and review of the literature.

We present the case of a 53-year-old woman treated with analgesic radiotherapy for a multiple myeloma bone lesion of the forearm. After a first fraction of 5 Gray (Gy), she presented with an acute respiratory syndrome with fever a few hours after the treatment. The same symptoms occurred after the second fraction 3 days later. The patient recovered quickly thanks to intravenous hydration and suspension of the radiotherapy. Biological tests revealed a tumor lysis syndrome. We concluded that the clinical symptoms could be defined as cytokine release syndrome. This is the second time in the literature that cytokine release syndrome has been described following radiotherapy. First, we synthesize TLS and radiotherapy to determine how radiotherapy could be a trigger associated with other well-known factors. Furthermore, we discuss radiotherapy and cytokine release syndrome. SUMMARY: We present the case of a woman treated with analgesic radiotherapy for a multiple myeloma bone lesion. Following the first and the second treatment fraction, the patient presented with an acute respiratory syndrome with fever and biological tests revealed a tumor lysis syndrome. We concluded that the clinical symptoms could be defined as cytokine release syndrome. Furthermore, we discuss how radiotherapy could be a trigger of cytokine release syndrome and tumor lysis syndrome in association with chemotherapy drugs.

[Oligorecurrent prostate cancer: current management and perspectives]. / Prise en charge des rechutes oligométastatiques des cancers de prostate : actualités et perspectives.

Oligometastatic prostate cancer (PCa) is an intense area of research thanks to the development of novel PET tracers such as 18F-choline or 68Ga-PSMA. Several retrospective studies in patients with hormone-sensitive oligorecurrent PCa (usually up to 5 metastases with a controlled primary tumor) showed PSA response and a low toxicity profile of metastasis-directed therapies (MDT) such as Stereotactic Body Radiation Therapy (SBRT) or salvage lymph node dissection. More recently, randomized phase 2 studies showed that SBRT can delay the introduction of androgen deprivation, decrease biochemical relapses and increase overall survival. Regarding oligoprogressive metastatic castration-resistant PCa, limited data is however available. Based on these studies the European Association of Urology and the American Society of Radiotherapy EAU now recommend using MDT instead of observation. Several studies are undergoing in France and worldwide in order to confirm the exact role of MDT.

Haute Couture or Ready-to-Wear? Tailored Pelvic Radiotherapy for Prostate Cancer Based on Individualized Sentinel Lymph Node Detection.

Prostate cancer (PCa) pelvic radiotherapy fields are defined by guidelines that do not consider individual variations in lymphatic drainage. We examined the feasibility of personalized sentinel lymph node (SLN)-based pelvic irradiation in PCa. Among a SLN study of 202 patients, we retrospectively selected 57 patients with a high risk of lymph node involvement. Each single SLN clinical target volume (CTV) was individually segmented and pelvic CTVs were contoured according to Radiation Therapy Oncology Group (RTOG) guidelines. We simulated a radiotherapy plan delivering 46 Gy and calculated the dose received by each SLN. Among a total of 332 abdominal SLNs, 305 pelvic SLNs (beyond the aortic bifurcation) were contoured (mean 5.4/patient). Based on standard guidelines, CTV missed 67 SLNs (22%), mostly at the common iliac level (40 SLNs). The mean distance between iliac vessels and the SLN was 11mm, and despite a 15mm margin around the iliac vessels, 9% of SLNs were not encompassed by the CTV. Moreover, 42 SLNs (63%) did not receive 95% of the prescribed dose. Despite a consensus on contouring guidelines, a significant proportion of SLNs were not included in the pelvic CTV and did not receive the prescribed dose. A tailored approach based on individual SLN detection would avoid underdosing pelvic lymph nodes that potentially contain tumor cells.

Preoperative Chemoradiotherapy for Rectal Cancer in Patients Aged 75 Years and Older: Acute Toxicity, Compliance with Treatment, and Early Results.

PURPOSE: Treatment of locally advanced rectal cancer (T3-T4 or N+) is based on short-course radiotherapy (RT) or chemoradiotherapy (CRT) followed by surgery. It is estimated that 30-40 % of rectal cancer occurs in patients aged 75 years or more. Data on adherence to neoadjuvant CRT and its safety remain poor owing to the under-representation of older patients in randomized clinical trials and the discordance in the results from retrospective studies. The aim of this study was to assess adherence with preoperative CRT and tolerability in older patients with a stage II/III unresectable rectal cancer. METHODS: Patients aged 75 years or more with stage II/III rectal cancer treated with preoperative CRT at the University Hospital of Besancon from 1993 to 2011 were included. Feasibility, toxicities, overall survival, and local recurrence rates were studied. RESULTS: Fifty-six patients with a Charlson score from 2 to 6 were included. The mean age was 78 years. The compliance rates for RT and chemotherapy were 91 and 41.1 %, respectively. Two patients stopped CRT; one for hemostatic surgery, and one for severe sepsis. For CRT, the rate of grade ≥3 toxicity was 14.29 %, mainly the digestive type. Fifty-two patients underwent tumor resection, including 76.79 % total mesorectal excision resection with 84.6 % complete resection, and a rate of postoperative complications of 39.6 %. At 2 years, the overall survival and local recurrences rates were 87.3 and 7.8 %, respectively. CONCLUSION: In older patients, selected preoperative CRT, with an adapted chemotherapy dose, is well tolerated. The main toxicity was gastrointestinal. Adherence to RT is comparable to that of younger patients.

Focal or whole-gland salvage prostate brachytherapy with iodine seeds with or without a rectal spacer for postradiotherapy local failure: How best to spare the rectum?

PURPOSE: Salvage prostate permanent implant (sPPI) for postradiation local failure provides high rates of biochemical control. The cumulative dose delivered to the prostate and the rectum is still unknown. METHODS AND MATERIALS: We reviewed the postimplant CT-based dosimetry of 18 selected patients who underwent sPPI with (125)I seeds for isolated biopsy-proven local failure several years after external beam radiation therapy. Ten patients had whole-prostate sPPI, and 8 patients had multiparametric MRI-based focal sPPI. In 8 patients, hyaluronic acid (HA) gel was injected into the prostate-rectum space. RESULTS: The median cumulative biological effective dose after EBRT + sPPI for the prostate and the rectum was higher in patients treated with whole-gland sPPI than in patients treated with focal sPPI (313.5 Gy2 vs. 174.4 Gy2; p = 0.06 and 258.1 Gy3 vs. 172.6 Gy3; p < 0.01, respectively). The median D0.1cc for the rectum was significantly lower in patients who had HA gel: 63.3 Gy (29.0-78.3) vs. 83.9 Gy (34.9-180.0) (p = 0.04). CONCLUSIONS: Cumulative prostate and rectum biological effective doses were lower with focal sPPI. D0.1cc delivered to the rectum was significantly lower with HA gel, while there was no difference between focal or whole-gland plans.

Phase II Study of a Platinum-Based Adapted Chemotherapy Regimen Combined with Radiotherapy in Patients 75 Years and Older with Esophageal Cancer.

BACKGROUND AND OBJECTIVE: The management of elderly patients with cancer is a therapeutic challenge and a public health problem. The aim of this phase II single-arm study was to evaluate the acute toxicities and efficacy of chemoradiotherapy (CRT) comprising a single platinum-based agent combined with radiotherapy in elderly patients with esophageal cancer. METHODS: Between March 2000 and October 2011, patients aged 75 years and older were prospectively treated with external beam radiotherapy combined with cisplatin or oxaliplatin. Other selection criteria included Eastern Cooperative Oncology Group status 0-2, disease stage II-III, squamous cell carcinoma or adenocarcinoma, and an adequate biological profile. The radiotherapy dose was 50 Gy administered over 5 weeks to the primary tumor and involved lymph nodes. Cisplatin was planned at a dose of 75 mg/m(2) on days 1 and 21 and oxaliplatin at 85 mg/m(2) on days 1, 15, and 29. Treatment was delivered an outpatient setting. RESULTS: Thirty patients with a mean age of 85.2 (range 79.4-92.0) years were included; 28 completed the treatment. Dysphagia was the only grade 4 toxicity to occur during the study; no grade 5 toxicities were observed. Six weeks after the completion of treatment, 16 patients (53.3%) were in complete response. Two patients in complete response died from pneumonitis 5 and 7 months after CRT. With a 36-month median follow-up, 18 patients died from cancer (nine from local failure, nine from metastasis). Seven patients died from other causes and two patients were alive 40.3 and 56 months after the end of their treatment. Three-year overall survival was 22.2%. CONCLUSIONS: Selected elderly patients with esophageal cancer and adequate functional status should not be excluded from CRT and may be able to tolerate the treatment with acceptable acute toxicities. However, mid-term efficacy is mediocre. Our data also suggest that the therapeutic ratio or locoregional control might be improved by increasing the radiotherapy dose or by testing new radiosensitizer agents since half of the failures were within the treated volume. TRIAL REGISTRATION: EudraCT no. 2009-010113-76.