Outcomes and toxicity in re-irradiation of gynecologic cancer: Systematic review of the Italian association of radiation and clinical oncology (AIRO).

AIMS: The aim of this study was to provide a literature review on the efficacy and safety of reirradiation(re-I) of locoregional recurrences in gynecological malignancies. METHODS: A computerized literature search was performed in 4 electronic databases (1993-2020). Random-effects models and a tendency towards high heterogeneity (Cochran Q chi-square test and the I2 statistic) were used. A meta-analysis technique over single and multi-arm studies was performed to determine the pooled acute and late toxicity rate ≥ G3, locoregional control (LC), and overall survival (OS). RESULTS: Out of 178 articles, only 18 articles accounting for 820 patients (pts) met the inclusion criteria. Outcomes were evaluable for 522 patients. Subgroup analyses highlighted moderate to high heterogeneity among studies. BT (Brachytherapy) showed a 2y OS of 63% (95% CI, 55 to 71 p = 0,36) and 5y OS of 42% (95% CI, 35 to 50, p = 0,43) with 1y-2y-3y LC of 74 (95% CI, 62 to 75, p = 0.04)49% (95% CI, 40 to 58, p = 0.38) and 48% (95% CI, 39 to 58, p = 0,45) respectively. Chemotherapy does not improve SBRT outcomes: BT showed a G3- G4 toxicities rate was of26% (95% CI: 8-49%); studies on SBRT re-I showed a G3-G4 toxicity around of 20% if combined with CHT, and <10 when alone. CONCLUSION: A large heterogeneity among studies was revealed, but showing promising results in terms of safety and feasibility. BT resulted the best kind of radiation therapy delivery in terms of clinical outcome and comparable to the SBRT technique in terms of toxicities.

Modulation of Radiation Doses and Chimeric Antigen Receptor T Cells: A Promising New Weapon in Solid Tumors-A Narrative Review.

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.

Introducing Radiotherapy in Metastatic Merkel Cell Carcinoma Patients with Limited Progression on Avelumab: An Effective Step against Primary and Secondary Immune Resistance?

PURPOSE: To investigate the ability of radiotherapy (RT) to prolong progression-free survival (PFS) and to report treatment-related toxicities among oligoprogressive metastatic Merkel cell carcinoma (mMCC) patients on avelumab. METHODS: We retrospectively collected clinical data on mMCC patients who underwent radiotherapy for limited progression on avelumab. Patients were categorized as primary or secondary immune refractory depending on the time of onset of resistance to immunotherapy (at the first or subsequent follow-up visits after avelumab initiation). Pre- and post-RT PFS were calculated. Overall survival (OS) from the first progression treated with RT was also reported. Radiological responses and toxicities were evaluated according to the irRECIST criteria and RTOG scoring system, respectively. RESULTS: Eight patients, including five females, with a median age of 75 years, met our inclusion criteria. The median gross tumor and clinical target volumes at first progression on avelumab were 29.85 cc and 236.7 cc, respectively. The treatment sites included lymph node, skin, brain, and spine metastases. Four patients received more than one course of RT. Most patients were treated with palliative radiation doses (mainly 30 Gy in 3 Gy/day fractions). Two patients were treated with stereotactic RT. Five/eight patients were primary immune refractory. The objective response rate at the first post-RT assessment was 75%, whereas no local failure was reported. The median pre-RT PFS was 3 months. The pre-RT PFS was 37.5% at 6 months and 12.5% at 1 year. The median post-RT PFS was not reached. The post-RT PFS was 60% at 6 months and 1 year. The post-RT OS was 85.7% at 1 year and 64.3% at 2 years. No relevant treatment-related toxicity was observed. After a median follow-up of 18.5 months, 6/8 patients are still alive and continuing on avelumab therapy. CONCLUSIONS: Adding radiotherapy to mMCC patients with limited progression on avelumab seems to be safe and effective in prolonging the successful use of immunotherapy, regardless of the type of immune refractoriness.

The "Combo" radiotherapy treatment for high-risk grade 2 meningiomas: dose escalation and initial safety and efficacy analysis.

PURPOSE: The subgroup "high-risk" WHO grade 2 (hRG2) meningiomas may benefit from adjuvant radiation therapy (RT), but results are still suboptimal with high rates of local progression. A dose escalation using high-conformal RT techniques needs to be evaluated in terms of efficacy and safety. We report the results of a dose-escalation study, named "Combo-RT", combining Intensity Modulated Radiotherapy (IMRT) or Volumetric Arc Therapy (VMAT) with Hypofractionated Stereotactic Radiotherapy (hSRT) boost. PATIENTS AND METHODS: From November 2015 to January 2019, we prospectively enrolled 16 patients with hRG2. Seven patients had subtotal resection (STR) and 9 patients had a recurrent tumor. All patients received Combo-RT: LINAC-IMRT/ VMAT on the surgical bed and CyberKnife-hSRT boost on residual/recurrent meningioma Toxicity and initial efficacy were evaluated. RESULTS: The median age was 62 years (range, 31-80 years). The median cumulative dose delivered was 46 Gy For IMRT or VMAT and 15 Gy in 3 fractions at a median isodose line of 77% for hSRT. The median cumulative BED and EQD2 were 108.75 Gy and 72.5 Gy respectively. 3-year-PFS was 75% for the whole cohort,100% for patients with STR, and 55.5% for recurrent patients. Negligible toxicities, and stable or improved symptoms during long-term follow-up were observed. Salvage treatment for recurrence was an independent predictor of treatment failure (P = 0.025). CONCLUSIONS: With the limitation of a small series of patients, our results suggest that a dose escalation for hRG2 meningiomas, using a Combo-RT approach, is safe and particularly effective in the subgroup of patients with STR. Further studies are warranted.

Impressive Results after "Metabolism-Guided" Lattice Irradiation in Patients Submitted to Palliative Radiation Therapy: Preliminary Results of LATTICE_01 Multicenter Study.

Purpose: To evaluate feasibility, toxicities, and clinical response in Stage IV patients treated with palliative "metabolism-guided" lattice technique. Patients and Methods: From June 2020 to December 2021, 30 consecutive clinical stage IV patients with 31 bulky lesions were included in this study. All patients received palliative irradiation consisting of a spatially fractionated high radiation dose delivered in spherical deposits (vertices, Vs) within the bulky disease. The Vs were placed at the edges of tumor areas with different metabolisms at the PET exam following a non-geometric arrangement. Precisely, the Vs overlapped the interfaces between the tumor areas of higher 18F-FDG uptake (>75% SUV max) and areas with lower 18F-FDG uptake. A median dose of 15 Gy/1 fraction (range 10−27 Gy in 1/3 fractions) was delivered to the Vs. Within 7 days after the Vs boost, all the gross tumor volume (GTV) was homogeneously treated with hypo-fractionated radiation therapy (RT). Results: The rate of symptomatic response was 100%, and it was observed immediately after lattice RT delivery in 3/30 patients, while 27/30 patients had a symptomatic response within 8 days from the end of GTV irradiation. Radiation-related acute grade ≥1 toxicities were observed in 6/30 (20%) patients. The rate of overall clinical response was 89%, including 23% of complete remission. The 1-year overall survival rate was 86.4%. Conclusions: "Metabolism-guided" lattice radiotherapy is feasible and well-tolerated, being able to yield very impressive results both in terms of symptom relief and overall clinical response rate in stage IV bulky disease patients. These preliminary results seem to indicate that this kind of therapy could emerge as the best therapeutic option for this patient setting.

miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma.

Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.