Low-dose Radiotherapy Research Articles

Which Patients With Rhabdomyosarcoma Need Radiotherapy? Analysis of the Radiotherapy Strategies of the CWS-96 and CWS-2002P Studies and SoTiSaR Registry.

To analyze and compare the indications, doses, and application methods of radiotherapy (RT) and their influence on prognosis of patients with localized rhabdomyosarcoma (RMS). One thousand four hundred seventy patients with localized RMS 21 years and younger entered on CWS-96, CWS-2002P, and SoTiSaR were eligible for the analysis. The median follow-up was 6.5 years (IQR, 3.3-9.5). The 5-year event-free survival (EFS) and local control survival (LCS) for 910 (62%) irradiated versus nonirradiated patients were 71% versus 69% and 78% versus 73% (P = .03), respectively. Ninety-five percent of patients in IRS I (90% embryonal RMS [eRMS]) were nonirradiated (EFS, 87%). Irradiated patients with IRS II had improved LCS (91% v 80%; P = .01) and EFS (not significant). In IRS III, EFS and LCS were significantly better for RT patients: 71% versus 56% (P = 3.1e-06) and 76% versus 61% (P = 4.1e-07). Patients with tumors in the head and neck region (orbita, parameningeal, and nonparameningeal) and in other sites had significantly better EFS and LCS and in parameningeal also overall survival (OS). The efficacy of low RT doses of 32 Gy (hyperfractionated, accelerated RT [HART]) and 36 and 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable groups and higher doses of 44.8 Gy (HART) and 50.4 and 55.4 Gy (CFRT) in the unfavorable groups was comparable. Proton RT was used predominantly in head/neck-parameningeal (HN-PM) tumors, with similar EFS and LCS to photon RT. RT can be omitted in patients with IRS I eRMS. RT improves LCS and EFS in IRS II and III. RT improves OS in patients with HN-PM, with proton RT comparable with photon RT. Doses of 32 Gy (HART) or 36 and 41.4 Gy (CFRT) had comparable efficacy in patients with favorable risk profiles and 44.8 Gy (HART) or 50.4 and 55.8 Gy (CFRT) in the unfavorable groups.

Very low-dose radiotherapy for extranodal marginal zone lymphoma of bronchus-associated lymphoid tissue

Extranodal marginal zone lymphoma of bronchus-associated lymphoid tissue (BALT) is a rare cancer for which optimal treatment strategies are undefined. Retrospective analyses suggest excellent outcomes with surgical resection for localized BALT lymphoma; however, the role of radiotherapy remains underexplored. We report the largest-to-date single-center analysis of 13 primary BALT lymphoma patients treated with radiotherapy. Of 15 treated lesions, we report a 100% response rate with complete response (CR) achieved in 67% of lesions. Among 10 lesions treated with very low-dose radiotherapy (VLDRT; 4 Gray [Gy]), 6 (60%) achieved a CR; among 5 lesions treated with full-dose radiotherapy (24–36 Gy), 4 (80%) achieved a CR. There were no local recurrences. Only one patient, treated with 30 Gy, developed an acute grade 3/4 toxic effect. There were no events of radiation-induced secondary malignancies. Our institutional experience indicates that radiotherapy, including VLDRT, is a safe and effective treatment for primary BALT lymphoma.

Matched-pair analysis of the impact of low-dose postoperative radiotherapy on prognosis in patients with advanced hypopharyngeal squamous cell carcinoma without positive surgical margins and extracapsular extension.

We conducted a comparative analysis between low and high-dose postoperative radiotherapy in patients with hypopharyngeal squamous cell carcinoma (HPSCC) in stage III or IV without positive surgical margins and extracapsular extension (ECE). Propensity score matching (PSM) was used to eliminate confounding factors and reduce bias. The matched-pair analysis included 156 patients divided into two groups: the low-dose radiotherapy group (LD-RT 50 Gy, 78 cases) and the high-dose radiotherapy group (HD-RT 60 Gy, 78 cases). Both cohorts were statistically comparable in terms of age, gender, subsite, and TNM classification. The median follow-up time was 49 months (ranging from 5 to 100 months). The overall survival (OS) rate, progression-free survival (PFS) rate, locoregional control rate (87% vs. 85.7%; p = 0.754), distant metastases-free survival (79.2% vs. 76.6%; p = 0.506), and the occurrence of second primary tumors (96.1% vs. 93.5%; p = 0.347) showed no significant differences between the LD-RT group and the HD-RT group. The 3-year OS was 64.9% and 61% in the low-dose and high-dose group, respectively, and 63% in the entire group (p = 0.547). The 3-year PFS was 63.6% and 54.5% (p = 0.250), respectively, and the 3-year PFS of the entire group was 59.1%. Multivariate analyses revealed that pathological T and N classification, and pathological differentiation were associated with 3-year OS, PFS, and LRFS and were independent prognostic factors (p < 0.05). LD-RT was not associated with an increased risk of death and disease progression compared to HD-RT. The results of postoperative low-dose radiotherapy did not show inferiority to those of high-dose radiation for patients with advanced hypopharyngeal cancer without positive surgical margins and ECE in terms of OS, PFS, locoregional control, and metastases-free survival.

Response and local control in patients treated with low-dose radiotherapy for tumoral mycosis fungoides

Low-dose radiotherapy (LDRT), defined in this study as 2 fractions of 4 Gy delivered on consecutive days, is an effective option for local palliation of mycosis fungoides (MF), but its efficacy for tumoral lesions (TL) needs investigation. We assessed response and local control (LC) rates for patients treated with LDRT for MF and compared these outcomes between TL and non-TL. A total of 73 lesions in 18 patients treated with LDRT between 2013-2020 were analyzed. Response was defined as complete response (CR), partial response (PR), or no response (NR). In the non-TL versus TL groups, CR was observed in 16.7% v. 4.0%, PR in 81.2% v. 80.0%, NR in 2.1% v. 16.0%, respectively. 2-year LC was 100% for non-TL and 61% for TLs (p < 0.01). LDRT yields excellent response and lesion control for non-TLs and is associated with lower response rates and LC for TLs.

Inside Cover Picture

Jinjin Shi and co‐workers systematically reviewed the recent progress on high‐Z metal‐based nanomaterials. Tried to introduce the mechanism and developments through three parts: high‐Z metal‐based nanoparticles, high‐Z metal‐based nanoscale metal‐organic frameworks and high‐Z metal‐doping nanomaterials. It can also provide a reference for high‐Z based radiosensitization development and clinical applications in research of low dose radiotherapy. More details are discussed in the article on page 2545—2556.image

Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naive Stage IV PD-L1+ Non-Small-Cell Lung Cancer Patients.

Low-dose radiation therapy (LDRT) may enhance the synergistic anti-tumor effect of combined immunotherapy and stereotactic body radiation therapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC). This prospective phase 1 study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT (30 Gy/3f) to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a PD-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAEs) occurred in 96.6% (28/29) of patients (grade ≥ 3, 20.7% [6/29]); two patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval 3.7-16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging TCR clonotypes were associated with better PFS. The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with PD-L1-positive, driver gene-negative primary metastatic NSCLC.

Low-dose radiotherapy for greater trochanteric pain syndrome—a single-centre analysis

PurposeTo determine predictive factors associated with a good response (GR) to and efficacy of low-dose radiotherapy (LDRT) in patients with greater trochanteric pain syndrome (GTPS).MethodsPatients with GTPS were irradiated on a linear accelerator with 0.5–1.0 Gy per fraction to a total dose of 3.0–4.0 Gy per series. The endpoint was subjective good response (GR) to treatment 2 months after completion of the last LDRT series, defined as complete pain relief or marked improvement assessed using the von Pannewitz score. A positive response to steroid injection (SI) was defined as pain relief of at least 7 days. Patient and treatment-related characteristics were evaluated with respect to LDRT outcomes.ResultsOutcomes were assessed for 71 peritrochanteric spaces (PTSs; 65 patients, 48 females, with mean age of 63 [44–91] years). Prior SI had been given to 55 (77%) PTSs and 40 PTSs received two series of LDRT. Two months after completion of LDRT, GR was reported in 42 PTSs (59%). Two series of LDRT provided a significantly higher rate of GR than one series (72.5 vs. 42% PTSs, p = 0.015). Temporary pain relief after prior SI predicted GR to LDRT compared with PTSs which had not responded to SI (73 vs. 28% PTSs, p = 0.001). A regional structural abnormality, present in 34 PTSs (48%), was associated with a reduction of GR to LDRT (44 vs. 73% PTSs, p = 0.017).ConclusionLDRT is an effective treatment for GTPS. Administration of two LDRT series, prior response to SI, and absence of structural abnormalities may predict significantly better treatment outcomes.

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.

Clinical Management of Patients with Gastric MALT Lymphoma: A Gastroenterologist's Point of View.

Gastric mucosa-associated lymphoid tissue (MALT) lymphomas (GML) are non-Hodgkin lymphomas arising from the marginal zone of the lymphoid tissue of the stomach. They are usually induced by chronic infection with Helicobacter pylori (H. pylori); however, H. pylori-negative GML is of increasing incidence. The diagnosis of GML is based on histological examination of gastric biopsies, but the role of upper endoscopy is crucial since it is the first step in the diagnostic process and, with currently available novel endoscopic techniques, may even allow an in vivo diagnosis of GML per se. The treatment of GML, which is usually localized, always includes the eradication of H. pylori, which should be performed even in H. pylori-negative GML. In the case of GML persistence after eradication of the bacteria, low-dose radiotherapy may be proposed, while systemic treatments (immunochemotherapy) should be reserved for very rare disseminated cases. In GML patients, at diagnosis but even after complete remission, special attention must be paid to an increased risk of gastric adenocarcinoma, especially in the presence of associated gastric precancerous lesions (gastric atrophy and gastric intestinal metaplasia), which requires adequate endoscopic surveillance of these patients.

Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acquired Hypocellular Bone Marrow Failure

Children with acquired hypocellular bone marrow failure of unknown cause (AHBMF) are usually diagnosed either with severe aplastic anemia (SAA) or refractory cytopenia of childhood (RCC). Patients with AHBMF who lack a matched donor and who failed or relapsed after immunosuppressive therapy (IST) need alternative therapies. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) offers a curative treatment for these patients. We report a multicenter Spanish experience with haplo-HSCT in pediatric patients with AHBMF. Eleven pediatric patients (SAA, n=9; RCC, n=2) underwent haplo-HSCT with different lymphodepletion strategies. Most patients (10 of 11) had previously failed to respond or relapsed after IST. The conditioning regimen was reduced intensity in SAA and myeloablative in RCC. Patients with SAA received low-dose radiotherapy as part of their conditioning regimen. All patients engrafted. Viral reactivation was common (8 of 11). Acute GVHD grade ≥II was seen in 5 patients. Chronic GVHD was diagnosed in 4 of the long-term survivors. Transplantation-associated microangiopathy was a frequent complication in SAA patients and was related to worse outcome. Two patients died of transplantation-related complications. Overall survival was 81%, with a median follow-up of 36 months. Haplo-HSCT can be a successful salvage curative treatment for pediatric patients with AHBMF, but with significant toxicities that must be addressed. Transplantation-associated microangiopathy was the most critical complication.

Cu-doped polypyrrole hydrogel with tumor catalyst activity for NIR-II thermo-radiotherapy.

Introduction: Radiotherapy (RT) is one of the key methods for treating breast cancer. However, the effect of single RT is often poor because of insufficient deposition of X-rays in tumor sites and radiation resistance induced by the abnormal tumor microenvironment (overexpression of glutathione (GSH)). The development of multifunctional RT sensitizers and synergetic therapeutic strategies is, therefore, a promising area for enhancing the anticancer effect of RT. Methods: In this study, a multifunctional nanozyme hydrogel based on Cu-doped polypyrrole (CuP) was designed to work concertedly with a second near-infrared thermal RT. The CuP-based hydrogel (CH) reached the tumor site when injected in-situ and achieved long-term storage. Results: Once stimulated with 1064-nm laser irradiation, the heated and softened hydrogel system released CuP nanozyme to provide photothermal therapy, thereby inhibiting the repair of DNA damage caused by RT. In addition, CuP with dual nanozyme activity depleted the intracellular GSH to reduce the antioxidant capacity of the tumor. Moreover, CuP converted H2O2 to produce ·OH to directly kill the tumor cells, thus enhancing the capability of low-dose RT to inhibit tumor growth. In vivo experiments showed that the CH system used in combination with a low-power 1064-nm laser and low-dose RT (4 Gy) exhibited good synergistic anticancer effects and biological safety. Discussion: As a new light-responsive hydrogel system, CH holds immense potential for radio-sensitization.

Nanoparticles Hitchhike on Monocytes for Glioblastoma Treatment after Low-Dose Radiotherapy.

Glioblastomas (GBMs) are aggressive primary brain tumors with fatal outcome. Traditional chemo-radiotherapy has poor therapeutic effect and significant side effects, due to the drug and radiotherapy (RT) resistance, natural blood-brain barrier, and high-dose RT damage. Even more, tumor-associated monocytes (macrophages and microglia, TAMs) constitute up to 30%-50% of the GBM cellular content, and the tumor microenvironment (TME) in GBM is extremely immunosuppressive. Here, we synthesized nanoparticles (D@MLL) that hitchhike on circulating monocytes to target intracranial GBMs with the assistance of low-dose RT. The chemical construction of D@MLL was DOX·HCl loaded MMP-2 peptide-liposome, which could target monocytes by the surface modified lipoteichoic acid. First, low-dose RT at the tumor site increases monocyte chemotaxis and induces M1 type polarization of TAMs. Subsequently, the intravenous injected D@MLL targets circulating monocytes and hitchhikes with them to the central site of the GBM area. DOX·HCl was then released by the MMP-2 response, inducing immunogenic cell death, releasing calreticulin and high-mobility group box 1. This further contributed to TAMs M1-type polarization, dendritic cell maturation, and T cell activation. This study demonstrates the therapeutic advantages of D@MLL delivered by endogenous monocytes to GBM sites after low-dose RT, and it provides a high-precision treatment for GBMs.

The effects of low-dose radiation therapy in patients with mild-to-moderate Alzheimer's dementia: an interim analysis of a pilot study.

We aimed to determine whether low-dose radiotherapy (LDRT) is effective in patients with Alzheimer disease (AD). We included patients according to the following criteria: probable Alzheimer's dementia according to the New Diagnostic Criteria for Alzheimer's Disease; confirmation of amyloid plaque deposits on baseline amyloid positron emission tomography (PET); a Korean Mini-Mental State Examination 2nd edition (K-MMSE-2) score of 13-26; and a Global Clinical Dementia Rating (CDR) score of 0.5-2 points. LDRT was performed six times at 0.5 Gy each. Post-treatment cognitive function tests and PET-CT examinations were performed to evaluate efficacy. The medication for AD treatment was maintained throughout the study period. At 6 months after LDRT, neurological improvement was seen in 20% of patients. Patient #2 showed improvement in all domains of the Seoul Neuropsychological Screening Battery II (SNSB-II). Moreover, the K-MMSE-2 and Geriatric Depression Score-Short Form scores improved from 20 to 23 and from 8 to 2, respectively. For patient #3, the CDR score (sum of box score) improved from 1 (4.0) to 1 (3.5) at 3 months follow-up. Moreover, the Z scores for language and related functions, memory, and frontal executive function improved to -2.56, -1.86, and -1.32, respectively at the 6-month follow-up. Two patients complained of mild nausea and mild hair loss during LDRT, which improved after treatment. One of the five patients with AD treated with LDRT experienced a temporary improvement in SNSB-II. LDRT is tolerable in patients with AD. We are currently under follow-up and will conduct cognitive function tests after 12 months after LDRT. A large-scale randomized controlled trial with a longer follow-up period is warranted to determine the effect of LDRT on patients with AD.

Durable control of metastases in an HLA-A2+ patient with refractory melanoma after low-dose radiotherapy in combination with MAGE-A4 T cell therapy: a case report.

There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can enhance intratumoral T cell infiltration and efficacy. This case report describes a 71-year-old female patient with rectal mucosal melanoma that had developed metastases to liver, lung, mediastinum, axillary nodes, and brain. After systemic therapies had failed, she enrolled in the radiation sub-study of our phase-I clinical trial exploring the safety and efficacy of afamitresgene autoleucel (afami-cel), genetically engineered T cells with a T cell receptor (TCR) targeting the MAGE-A4 tumor antigen in patients with advanced malignancies (NCT03132922). Prior to the infusion of afami-cel, she received concurrent lymphodepleting chemotherapy and LDRT at 5.6 Gy/4 fractions to the liver. Time to partial response was 10 weeks, and duration of overall response was 18.4 weeks. Although the patient progressed at 28 weeks, the disease was well controlled after high-dose radiotherapy to liver metastases and checkpoint inhibitors. As of the last follow-up, she remains alive over two years after LDRT and afami-cel therapy. This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.

DIPG-15. CONCURRENT GB-13 (IL13.E13K-PE4E) IMPROVES THE EFFICACY OF RADIATION THERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA

Abstract Diffuse midline glioma with H3 K27 alterations (DMG) is the most aggressive primary malignant brain tumor in the pediatric population. Radiation therapy (RT) is the standard-of-care; however, it has not demonstrated a significant improvement in overall survival or stalled disease progression, and children usually succumb to disease within 12-15 months of diagnosis. Consequently, finding efficient treatments for DMG remains one of the most critical unmet needs in modern neuro-oncology. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface receptor upregulated in ~80% of DMG versus normal brain, posing a potentially promising therapeutic target. Immunotherapies harnessing IL-13Rα2 to selectively delivery cytotoxic payloads, such as pseudomonas exotoxin A (PE), to tumor cells have been previously demonstrated to be safe in DMG patients and efficacious in preclinical models of DMG with high IL-13Rα2 expression using convection-enhanced delivery (CED). Furthermore, there is evidence that PE-based therapies can sensitize cells to RT. In this study, we utilized in vitro and in vivo models of DMG to evaluate clinically-relevant combination treatments of RT and the IL-13/PE immunotoxin GB-13 (IL13.E13K-PE4E). GB-13 improved the effectiveness of low-dose RT in multiple DMG cell lines by promoting caspase activation, which boosted apoptotic cell death. Intratumoral administration of GB-13 via chronic CED decreased tumor burden and prolonged survival in both DMG patient-derived orthotopic xenograft and genetically engineered mouse models. When GB-13 and RT were administered concurrently, this impact became even more prominent, informing future preclinical and clinical investigation of a potentially efficacious therapeutic approach in a subset of DMG.

PRIMARY HEPATIC LYMPHOMA: ROLE OF LOW‐DOSE RADIOTHERAPY AND PAIRED LITERATURE REVIEW

Introduction: Primary hepatic lymphomas (PHL) are a rare form of non-Hodgkin lymphoma for which there are no established treatment guidelines. Available literature is largely comprised of small case reports and there are no reports on low-dose radiotherapy (RT) for indolent PHL. We report our institutional experience treating PHL within the context of existing literature to better understand the role of RT. We hypothesize that low-dose RT offers comparable outcomes to observation (obs), surgery and systemic therapy (ST) in select patients. Methods: We conducted a single-institution retrospective analysis of all biopsy-proven PHL patients (pts) diagnosed from 2000-2021 without other lymphomatous solid organ involvement. Subgroup analysis was performed for diffuse large B-cell lymphoma (DLBCL) and indolent lymphoma (IL). Univariable (UVA) and multivariable analysis (MVA) for overall survival (OS) was performed using the Cox proportional hazards model. Literature review was conducted using key words including “liver”, “lymphoma”, and “treatment” to identify all available reported cases of PHL. Results: We identified 30 PHL pts within our institution and 192 pts from literature review, with subgroup analysis of DLBCL and IL pts in the institutional cohort (n = 15, 9) and literature review (n = 78, 76), respectively (Table 1). Among the IL institutional cohort (n = 9), 3 pts underwent obs and 2 each received RT, ST and surgery. There were no recurrences among pts treated with RT, surgery or obs with median OS of 12.4 years, whereas both ST pts experienced either transformation to DLBCL or recurrence. Both RT patients received low-dose RT of 4Gy in 2 fractions. Literature review identified only 1 case report of RT use for IL with a dose of 41.4Gy. Conclusions: There is limited literature regarding use of RT in indolent PHLs. We present the first report of low-dose RT for indolent PHL with comparable outcomes to alternative modalities. PHL DLBCL is predominantly treated with ST in both our institutional experience and in the literature. Although our data is limited by the small cohort size reflective of the rarity of disease, our results are encouraging for the consideration of low-dose RT as a management option for appropriate patients with indolent PHL. Keywords: extranodal non-Hodgkin lymphoma, radiation therapy No conflicts of interests pertinent to the abstract.

HIGH RATE OF METABOLIC COMPLETE RESPONSE AFTER LOW DOSE RADIOTHERAPY AND OBINUTUZUMAB IN EARLY STAGE FOLLICULAR LYMPHOMA: INITIAL RESULTS OF THE GAZAI STUDY (GLA 2018‐3)

Introduction: The FORT trial demonstrated a higher complete remission (CR) rate using 12 × 2 Gy compared to 2 × 2 Gy in Follicular Lymphoma (FL) (67% vs. 47%). This benefit resulted also in an improved progression free survival (PFS). The TROG 99.03 trial and the MIR study showed an improved PFS with the addition of Rituximab to radiation therapy of 30–40 Gy in early stage FL. Preclinical data suggest that the anti-CD20 antibody may act synergistic with radiation therapy and therefore enhance the radiation effect of low dose radiotherapy. The prospective, multicentric phase II GAZAI study of the German Lymphoma Alliance (GLA) investigated the efficacy of low dose radiation therapy (2 × 2 Gy) in combination with the anti-CD20 antibody Obinutuzumab in early stage nodal FL. The primary endpoint was the metabolic complete remission at the end of therapy. Methods: Patients with early stage FL grade 1/2 were recruited in 11 German centers. Ann Arbor stage I or II was confirmed by FDG-PET/CT. Patients received 1000 mg Obinutuzumab flat dose intravenously in weeks 1, 2, 3, 4, 8, 12 and 16. An interim CT scan was performed in week 7 for response evaluation and subsequent treatment planning. Radiation therapy was applied to the initial involved sites (site of diagnostic surgical intervention and PET positive sites) in week 9. The radiation dose was 2 x 2 Gy on two succeeding days. A FDG-PET/CT was performed at the end of therapy in week 18 for evaluation of the metabolic and morphologic response. Minimal detectable/residual disease (MRD) in peripheral blood was monitored at baseline and at week 18 by allel-specific RQ PCR targeting t(14;18) translocations and clonal immunoglobulin heavy chain (IGH) rearrangements. Results: Of 89 patients included in the study, 54 entered the treatment phase showing FDG-PET-positive lymph nodes qualifying for the primary endpoint. At week 18, metabolic CR (Deauville score (DS) <3) was seen in 46/53 patients (87%; one patient only had a CT without FDG-PET). Partial metabolic remission with a DS 3 was seen in 3 patients (6%) and 3 patients showed a DS 4. Morphologic (CT based) CR/CRu according to Cheson 1999 criteria was seen in 21/54 patients (39%) at week 7 and in 49/54 patients (91%) at week 18. Morphologic PR was seen in 17 patients (32%) at week 7 and in 4 patients (7%) at week 18; one patient (2%) showed progressive disease (metabolic and morphologic) outside of the radiation field. 13/54 patients (24%) were initially MRD positive. All but one patient converted to MRD negativity at week 18. Conclusions: Low dose radiation therapy using 2 × 2 Gy in combination with Obinutuzumab is highly effective in early stage FL. Longer follow-up is necessary to investigate if this effectivity also results in a prolonged PFS. Currently, the FORTplus trial is looking for non-inferiority of this regimen in comparison to a conventional radiation dose (12 × 2 Gy) combined with Rituximab. The research was funded by: Roche Pharma Keywords: combination therapies, indolent non-Hodgkin lymphoma, radiation therapy Conflicts of interests pertinent to the abstract K. Herfarth Research funding: Roche Pharma Educational grants: Roche Pharma C. W. Scholz Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma K. Hübel Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speaker Honoraria Roche Pharma Research funding: Roche Pharma C. Buske Consultant or advisory role: Roche Pharma Honoraria: Roche Pharma Research funding: Roche Pharma J. Dürig Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma G. Lenz Consultant or advisory role: Advisory board Roche Pharma Honoraria: Speakers honoraria Roche Pharma Research funding: Roche Pharma C. Pott Research funding: Roche Pharma M. Dreyling Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Research funding: Roche Pharma

Final results of pilot trial to evaluate anti-PD1 and 8 Gy in 1 fx for relapsed refractory multiple myeloma.

8017 Background: Single agent Immune-Checkpoints, such as Anti-PD1, have not be successful. A pilot phase 1, 2 trial (NCT03267888) was conducted to see if radiotherapy (RT) and anti-PD1 (Pembrolizumab) could provide early signals of safety and response. Methods: Inclusion criteria included patients &gt; 18 years of age, ECOG 0-1, able to give informed consent, have relapsed/refractory myeloma, and have ≥1 osseous and/or extra-osseous lesion that could undergo RT. Patients had to be candidates for anti-PD1 based on organ function testing, have measurable disease per International Myeloma Working Group Criteria (IMWG), and/or have progressive disease on serial staging PET/CT. IRB approval was obtained. RT (8 Gy in 1 fx) was given on day 0, cycle 1 followed by pembrolizumab (200 mg/kg iv on day 2 or 3, then every 3 weeks +/- 7 days) for 2 years or until progression. Primary endpoint was toxicity. Secondary endpoints were IMWG response, abscopal response, overall survival (OS), and immunological changes on serial blood collections. Patients were assessed at 3, 6, and 12 months for progression free survival (PFS) using IMWG and serial PET/CT scans. Patients with stable disease were continued on the trial. Patients that progressed were censored. Standard statistical analysis was performed, and included Kaplan-Meier to estimate OS and PFS. Results: From June, 2018 until October, 2021, 32 patients were screened and 25 were enrolled. Of the enrolled patients, 76% were Caucasian, 64% had ECOG 1, and the mean age was 60 years. Prior to enrollment, the median number of prior lines of therapy that a patient had filed was 5.0 (range: 2 – 11). There was no grade 2 or higher radiation related toxicity within the irradiated volume using CTCAE 4.0. Only one case of ≥ grade 3 (fevers) pembrolizumab-related toxicity was noted. Abscopal response, defined as improvement of a non-targeted lesion, was noted in 5 of 25 patients (20%). IMWG showed robust reduction in the paraproteins and other myeloma labs, suggesting response to radiotherapy and anti-PD1. A total of 8 patients showed response. Of those responding patients, 5 were post CarT cell patients, suggesting that the most benefit may be in post CarT cell patients. None of the post CarT cell patients were noted to have cytokine release syndrome and/or neurotoxicity. Of the responding patients, some of these were associated to have a robust CD 8 T cell activation. The 6 and 12 month PFS for the entire cohort was 31.8% and 22.7%, respectively. The 6 and 12-month OS for the entire cohort was 68% and 64%, respectively. Those that were post CarT, there was a higher 6 month PFS (50%) and OS (71.4%). Conclusions: Combination therapy of single-fraction, low-dose radiation therapy with pembrolizumab appears to be safe and shows early promise of efficacy in MM pts progressing following CarT therapy. Larger trials are warranted in the relapsed/refractory myeloma patients. Clinical trial information: NCT03267888 .

Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoRTPC02): The first-stage result from an open label, single-arm, two stage, phase II clinical trial.

6078 Background: Neoadjuvant immunotherapy and chemotherapy has been explored in phase I/II clinical studies in head and neck squamous cell carcinoma (HNSCC), confirming its safety and efficacy. However, the pathological complete response (pCR) / major pathological response (MPR) rate still needed for improvement. Recent studies revealed that low dose radiotherapy can overcome immunosuppressive tumors by reversing immune desertification when combining immunotherapy. Here, we conducted this clinical trial to explore the efficacy and safety of neoadjuvant low-dose radiotherapy, PD-1 inhibitor, combined with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma. Methods: This was an open-label, single-arm, phase II clinical trial. Patients with untreated, histologically confirmed HNSCC staging III-IVB were included. The eligible patients were scheduled to be administrated neoadjuvant low-dose radiotherapy (1GY/1F, D1, D2, D8, D15, Q3W), PD-1 inhibitor tislelizumab (200 mg D1, Q3W), combined with albumin-bound paclitaxel (100mg/m2, D1, D8, D15, Q3W) and cisplatin (25mg/m2, D1, D8, D15, Q3W) for two cycles. Radically surgical resection was planned to conduct 3-4 weeks after neoadjuvant therapy. The primary endpoint was pCR rate. The second endpoints consisted of MPR rate, objective response rate (ORR), R0 resection rate, safety, non-surgery-delay rate and quality of life. 25 patients will finally be enrolled in this study. Simon's two-stage design was adopted, and 10 patients should be included in the first stage. If 2 or more of the first 10 patients reached pCR, the second stage would be successfully entered. Results: By Jan 10, 2023, 10 patients were enrolled. 7 out of 10 patients successfully received the study regimen and finished the operation on schedule. Our primary endpoint of first stage was met. 4/7 (57%) patients achieved pCR at the primary site , 3/7 (43%) patients achieved MPR. The pCR/MPR rate was 100%. R0 resection rate was 100%. Totally 9 patients underwent MRI scan pre and post neoadjuvant therapy, and the assessment per RESCIST criteria were as follow: 0/9 (0%) CR, 6/9 (66%) PR, 3/9 (33%) SD. The treatment-related adverse events (TRAEs) were manageable. The most shared adverse events of grade 1/2 were anorexia (89%), anemia (89%) and nausea (66%). No surgical delay was observed. Conclusions: Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin contributed to an outstanding pCR/MPR rate of 100% (pCR rate of 57% and MPR rate of 43%) at present, and was generally tolerated in locally advanced HNSCC. The second stage is ongoing. Clinical trial information: NCT05343325 . Research Sponsor: BeiGene Co., Ltd. and CSPC Co., Ltd.

Effect of hypofractionated radiotherapy, PD-1 immunotherapy, and anti-angiogenic therapy on abscopal responses and the tumor microenvironment.

e14609 Background: Hypofractionated radiotherapy (HFRT) of the primary tumor can induce abscopal effects in metastatic cancer, which could be enhanced by adding PD-1 immunotherapy (IO) and low-dose radiotherapy (LDRT) of distant disease. However, this strategy remains with suboptimal efficacy. Translational research has shown that LDRT primarily modulates the immune microenvironment of tumors in the irradiated area, a mechanism shared by anti-angiogenic therapy (AAT). Therefore, this study aimed to compare the efficacy (abscopal responses and cytokine levels in the tumor microenvironment) between HFRT+IO+AAT and HFRT+IO+LDRT. Methods: Bilateral mouse tumor models were divided into seven groups for various treatments (Table 1). After treatment, blood and tumor samples of mice were collected for analysis. We evaluated clinical effects of HFRT+IO+AAT in 4 patients with unirradiated lung metastases in a currently-accruing phase Ib study of stereotactic body radiotherapy (SBRT) plus anlotinib (AAT) with or without toripalimab (PD-1 IO) in driver mutation-negative non-small cell lung cancer (NCT05021328). Results: The results of animal studies are shown in Table 1. HFRT to the primary tumor combined with AAT and IO enhanced the abscopal response in secondary tumor compared to HFRT, HFRT+IO, HFRT+AAT, IO+AAT, as well as HFRT+LDRT+IO. The most noteworthy secondary tumor control was observed in mice receiving HFRT+IO+AAT. The enhanced abscopal responses were associated with increased infiltration of CD8+ effector T cells, increased expression of IFN-γ and levels of TNF-α. From the prospective trial population, 4 unirradiated lung lesions in the HFRT+IO+AAT cohort decreased by an average of 48% in size (n=3 partial response, n=1 stable disease). No grade 3 treatment-related toxicity was observed. Conclusions: HFRT+IO+AAT is a promising therapeutic combination that may optimize abscopal responses, potentially even further than HFRT+LDRT+IO. This new “triple therapy” was safe and efficacious in patients and deserves further study. [Table: see text]