Concurrent Radiotherapy Research Articles

Investigation of Gastrointestinal Toxicities Associated with Concurrent Abdominal Radiation Therapy and the Tyrosine Kinase Inhibitor Sunitinib in a Mouse Model.

Tyrosine kinase inhibitors (TKIs) may be combined with radiation therapy (RT) to enhance tumor control; however, increased incidences of gastrointestinal (GI) toxicity have been reported with this combination. We hypothesize that toxicity is due to compromised intestinal healing caused by inhibition of vascular repair and proliferation pathways. This study explores underlying tissue toxicity associated with abdominal RT and concurrent sunitinib in a mouse model. Four groups of CD-1 mice were treated with 12 Gy abdominal RT, oral sunitinib, abdominal RT + sunitinib, or sham treatment. Mice received oral sunitinib or the vehicle via gavage for 14 days. On day 7, mice were irradiated with 12 Gy abdominal RT or sham treated. Mice were euthanized on day 14 and intestinal tract was harvested for semiquantitative histopathologic evaluation and immunohistochemical quantification of proliferation (Ki67) and vascular density (CD31). Non-irradiated groups had stable weights while abdominal irradiation resulted in weight loss, with mice receiving RT + SUN having greater weight loss than mice receiving RT alone. Semiquantitative analysis showed significant increases in inflammation in irradiated groups. The difference in the density of CD31+ cells was significantly increased in RT alone compared to SUN alone. Ki67+ density was not significant. In summary, we identify a lack of angiogenic response in irradiated GI tissues when abdominal RT is combined with a TKI, which may correlate with clinical toxicities seen in canine and human patients receiving combined treatment.

Clinical trials of R-(-)-gossypol (AT-101) in newly diagnosed and recurrent glioblastoma: NABTT 0602 and NABTT 0702.

AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma. In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS). A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM. AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.

Retracted: Clinical Effect of Apatinib Mesylate Tablets Combined with Paclitaxel Concurrent Radiotherapy and Chemotherapy in the First-Line Treatment of Locally Advanced Nasopharyngeal Carcinoma.

[This retracts the article DOI: 10.1155/2022/6293816.].

Treatment-related pneumonitis after thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 monoclonal antibodies in advanced esophageal squamous cell carcinoma.

This study aims to evaluate the risk factors of treatment-related pneumonitis (TRP) following thoracic radiotherapy/chemoradiotherapy combined with anti-PD‑1 monoclonal antibodies (mAbs) in patients with advanced esophageal squamous cell carcinoma (ESCC). We retrospectively reviewed 97patients with advanced ESCC who were treated with thoracic radiotherapy/chemoradiotherapy combined with anti-PD‑1 mAbs. Among them, 56patients received concurrent radiotherapy with anti-PD‑1 mAbs and 41patients received sequential radiotherapy with anti-PD‑1 mAbs. The median prescribed planning target volume (PTV) dose was 59.4 Gy (range from 50.4 to 66 Gy, 1.8-2.2 Gy/fraction). Clinical characteristics, the percentage of lung volume receiving more than 5-50 Gy in increments of 5 Gy (V5-V50, respectively) and the mean lung dose (MLD) were analyzed as potential risk factors for TRP. 46.4% (45/97), 20.6% (20/97), 20.6% (20/97), 4.1% (4/97), and 1.0% (1/97) of the patients developed any grade of TRP, grade1 TRP, grade2 TRP, grade3 TRP, and fatal (grade5) TRP, respectively. Anti-PD‑1 mAbs administered concurrently with radiotherapy, V5, V10, V15, V25, V30, V35, V40 and MLD were associated with the occurrence of grade2 or higher TRP. Concurrent therapy (P = 0.010, OR = 3.990) and V5 (P = 0.001, OR = 1.126) were independent risk factors for grade2 or higher TRP. According to the receiver operating characteristic (ROC) curve analysis, the optimal V5 threshold for predicting grade2 or higher TRP was 55.7%. The combination of thoracic radiotherapy/chemoradiotherapy with anti-PD‑1 mAbs displayed atolerable pulmonary safety profile. Although the incidence of TRP was high, grade1-2 TRP accounted for the majority. Anti-PD‑1 mAbs administered concurrently with radiotherapy and the lung V5 were significantly associated with the occurrence of grade2 or higher TRP. Therefore, it seems safer to control V5 below 55% in clinical, especially for the high-risk populations receiving concurrent therapy.

Safety and efficacy of chemotherapy for patients with unresectable pancreatic cancer concomitant with collagen disease: A multicenter retrospective observational study.

650 Background: In patients with collagen disease, such as rheumatoid arthritis, steroids and immunomodulators are often used for treatment. These treatments increase the risk of adverse events, including infections; thus, cancer patients with collagen disease are often excluded from clinical trials of chemotherapy for cancer. Therefore, evidence is lacking regarding the safety and efficacy of chemotherapy for pancreatic cancer concomitant with collagen diseases. Methods: This was a multicenter, retrospective study in Japan. Patients who started first-line chemotherapy or chemoradiotherapy for unresectable pancreatic cancer between January 2015 and December 2019 and had concurrent collagen diseases were included. We evaluated adverse events (AEs), discontinuation of anticancer treatment due to AEs, progression-free survival (PFS) and overall survival (OS). Results: A total of 52 patients were enrolled from 20 institutions in Japan, and a total of 101 regimens were administered. Concomitant collagen diseases included rheumatoid arthritis (n=35), systemic lupus erythematosus (n=5), Sjögren's syndrome (n=4), vasculitis syndrome (n=3), dermatomyositis/polymyositis (n=2), polymyalgia rheumatica (n=1), systemic sclerosis (n=1), and Behçet’s disease (n=1). The most common regimens for pancreatic cancer were gemcitabine/nab-paclitaxel (GnP, n=40), S-1 monotherapy (n=18), gemcitabine monotherapy (n=15), modified FOLFIRINOX (n=10), S-1 concurrent radiotherapy (n=5), and FOLFOX (n=4). Treatment discontinuation due to AEs occurred in 21 regimens (20.8%). The most common causes of discontinuation were thrombosis in 4 regimens, interstitial lung disease (ILD) in 3 regimens, and fatigue in 3 regimens. Infection as an adverse event was observed in 7 regimens (6.9%). By regimen, GnP had the highest discontinuation rate for adverse events of 37.5% and an incidence of ILD of 15.0%. The median PFS was 5.6 months in first-line therapy, and the median OS was 11.1 months. By regimen, the median PFS (5.8 months) and median OS (13.3 months) for metastatic patients receiving first-line GnP were comparable to those in previous reports on GnP for patients without collagen disease. Conclusions: Patients with pancreatic cancer concomitant with collagen disease have a high discontinuation rate due to AEs, and attention should be given to the occurrence of thrombosis and ILD.

Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review.

Dedifferentiation is a very rare phenomenon in uterine leiomyosarcoma (LMS). The aim of this study was to comprehensively analyze the clinicopathological characteristics of uterine dedifferentiated LMS (DDLMS). We reviewed electronic medical records and pathology slides from five patients with uterine DDLMS and performed immunostaining. The mean age of the patients was 56 years. Two patients presented with abdominal discomfort, while in three cases the uterine tumors were detected on routine medical examination. The mean size of the tumors was 17.0 cm. Four patients underwent hysterectomy. The initial stages were distributed as IB (2/5), IIIC (2/5), and IVC (1/5). Post-operative concurrent chemoradiation therapy, radiation therapy, and chemotherapy were administered in one, one, and two patients, respectively. Despite post-operative treatment, three patients developed metastatic recurrences in the abdominal and pelvic organs. Recurrence-free survival time ranged between 4 and 30 months. Histologically, the differentiated areas demonstrated the classic morphology of malignant smooth muscle differentiation, whereas the dedifferentiated areas resembled undifferentiated pleomorphic sarcoma and were characterized by large pleomorphic tumor cells admixed with haphazardly arranged atypical cells with marked nuclear pleomorphism. All cases also exhibited heterologous components, including chondrosarcoma (CSA; 3/5) and rhabdomyosarcoma (2/5). In two cases, the heterologous components were initially detected in primary tumors. In three cases, the primary tumors did not exhibit any dedifferentiated or heterologous components. Instead, more than half of the recurrent tumors consisted of heterologous components. Three cases showed a sharp demarcation between the LMS and CSA components, while in two cases the dedifferentiated area imperceptibly merged with the differentiated component. Immunostaining revealed that the dedifferentiated components exhibited a lack of desmin immunoreactivity in three of the four examined cases. A subset of uterine LMS represents various amounts and types of dedifferentiation and heterologous components in both primary and recurrent tumors. Routine recognition of DDLMS and distinction from its mimickers are required for accurate diagnosis and further characterization of these rare tumors.

Quality of life following treatment with intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer

ObjectivesStudies that focus on the feasibility of using erlotinib plus chemoradiation to treat locally advanced head and neck cancer have given hints of improved survival outcomes compared to chemoradiation alone. However, the influence of this treatment regimen on the quality of life of the patients has not been documented. We conducted a study of this triple combination and now have documented follow-up survival data as well as long-term quality of life (QoL) measures.MethodsThree sets of QoL questionnaires were given to patients with a diagnosis of head and neck cancer at two time points, pre- and post-treatment, to assess differences in quality of life after receiving chemotherapy with intra-arterial (IA) cisplatin (150 mg/m2), concomitant radiation (70 Gy), and oral erlotinib (150 mg/day). Additionally, patients were followed for a total of 5 years.ResultsTreatment had a detrimental effect on appearance, taste, and saliva domain scores in their QoL questionnaires. Nonetheless, fewer patients reported pain and anxiety.Significance of resultsThe combination of erlotinib with chemoradiation produced similar adverse effects on the QoL scores of patients with head and neck cancer as compared to chemoradiation alone.

Abstract IA005: PET imaging predictors of response to chemoradiotherapy in cervical cancer

Abstract Although HPV transformed tumors are presumed to be radiation sensitive, approximately one third of locally advanced cervical cancer patients fail the current standard of care (concurrent cisplatin and radiation therapy). Work in our laboratory has combined the results of functional imaging with 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) imaging together with bioinformatic analyses of associated translational correlates to define new predictors of resistance to DNA damaging therapies. Results of this work demonstrate that cervical tumors with increased FDG uptake on pretreatment FDG-PET imaging are characterized by myeloid predominant inflammatory infiltrates, including immature monocytes and macrophages. Co-culture of cervical tumor cells with macrophages is associated with increased glucose uptake and pro-survival signaling in tumor cells mediated through macrophage derived IL-6 and signaling through the JAK-STAT pathway. We are currently using a combination of single cell sequencing and spatially resolved approaches to further define PET associated and chemoradiation induced changes in cervix tumor cell metabolism and the immune tumor microenvironment with the goal of defining new targets for personalized therapies. Importantly, cervical cancers retain and transcribe portions of the HPV genome. At the end of the talk, we will review recent work in our lab that highlights the impact of HPV associated gene expression, including splice variants, on the response to DNA damaging agents. Citation Format: Julie K. Schwarz. PET imaging predictors of response to chemoradiotherapy in cervical cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA005.

Concurrent Olaparib and Radiation Therapy in Older Patients With Newly Diagnosed Glioblastoma: The Phase 1 Dose-Escalation PARADIGM Trial

Background: Patients with glioblastoma who are elderly or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiotherapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. Methods: Phase I of the PARADIGM trial was a 3+3 dose escalation study testing olaparib in combination with radiotherapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 or over (WHO PS 0-1) or aged 18-69 with PS 2. The primary outcome was the recommended phase 2 dose (RP2D) of olaparib. Secondary endpoints included safety and tolerability, overall survival (OS) and progression free survival (PFS). Effects on cognitive function were assessed by mini-mental state examination (MMSE). Results: Of 16 eligible patients (56.25% male, median age 71.5 [range 44-78 years], 75% PS 0-1), one dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the RP2D was determined as 200 mg twice daily. Median OS and PFS were 10.8 months (80% CI: 7.3-11.4) and 5.5 months (80% CI: 3.9-5.9) respectively. MMSE plots indicated that cognitive function was not adversely affected by the olaparib-radiotherapy combination. Conclusions: Olaparib can be safely combined with hypofractionated brain radiotherapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomised phase II study and support future trials of PARP inhibitors in combination with radiotherapy for patients with brain tumors.

Concurrent chemoradiotherapy versus radiotherapy alone in older patients with stage II nasopharyngeal carcinoma after intensity-modulated radiotherapy: A propensity score-matched cohort study

Background and purposeWhether concurrent chemoradiotherapy (CCRT) benefits the older (age ≥ 60 years) patients with stage II nasopharyngeal carcinoma (NPC) has not been determined. This study aimed to compare the outcomes and toxicities of CCRT with Intensity-Modulated Radiotherapy (IMRT) alone in older patients with stage II NPC. Materials and methodsBetween January 2010 and December 2017, 220 older (age ≥ 60 years) patients with stage II NPC were analyzed. A pair of 53 patients were matched between the CCRT group and RT group by using propensity score matching (PSM) in terms of age, sex, pathological type, T and N stage, ACE-27 scores, CRP, LDH and Hb. Cancer-specific survival (CSS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were analysed by the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to assess the prognostic risk factors by using a Cox’s proportional hazards regression model. Treatment toxicities were clarified and compared between the two groups by using the χ2 test. ResultsThe median follow-up time of the whole cohort was 82.0 months (range, 11–151 months). PSM analysis indicated that compared with the RT group, significantly higher 5-year CSS (98.1 % vs. 83.0 %, P = 0.02), PFS (98.1 % vs. 79.2 %, P = 0.01) and DMFS (100.0 % vs. 92.4 %, P = 0.04) were observed in the CCRT group. Multivariate analysis showed that CCRT was an independent prognostic factor predicting CSS (HR, 0.34; 95 % CI, 0.15–0.79; P = 0.01), PFS (HR, 0.48; 95 % CI, 0.25–0.93; P = 0.03), and LRRFS (HR, 0.36; 95 % CI, 0.14–0.90; P = 0.03), and a higher ACE-27 score predicted a worse CSS. Patients in the CCRT group experienced higher frequencies of the acute toxicities than patients in the RT group. Late complications were comparable between the two groups. ConclusionCCRT significantly improved the survival benefits for the older patients with stage II NPC compared with IMRT alone without adding late complications, whereas increased some of the treatment-associated acute toxicities.

Hemoglobin level and survival in cervical cancer with chemoradiotherapy at high altitude, 2020-2022.

The purpose of this retrospective study was to determine the prognosis of altitude and pre-treatment hemoglobin (Hb) levels with progression-free survival (PFS) among women from the jungle and Andean regions of Peru with cervical cancer (CC) receiving weekly cisplatin and concurrent radiotherapy followed by brachytherapy or teletherapy boost. Patients with advanced clinical stage II-IVA CC were grouped according to Hb level (≥ 12.0, 11.9-10.0, 9.9-9.0 and ≤ 8.9 g/dL). Outcome measures were PFS, overall survival and local PFS. Between 1/2020 and 12/2022, 159 patients contributed demographic, clinical, pre-treatment Hb and outcome data with a median follow-up of 38 months. Kaplan-Meier estimates for survivals according to pre-treatment Hb level were significant when compared to a level of ≤8.9 g/dL, while estimates with altitude did not show statistical significance. Cox regression analysis of PFS demonstrated that pre-treatment Hb levels ≤8.9 g/dL (p = 0.000) were a significant factor. Age (p = 0.023), stage (p = 0.000), tumour size (p = 0.006) and treatment duration (p = 0.000) were also significant in the regression model. There is no difference between altitude and survival, but the difference in pre-treatment Hb level was a prognostic indicator of survival, with a Hb level of ≤8.9 g/dL being the worst prognosis.

A starry sky image result in a patient with active bleeding due to malignancy cause.

Hemostatic powders (HP) are increasingly used to address limitations in conventional endoscopic techniques for gastrointestinal bleeding. HP is a relatively recent addition to the arsenal of hemostatic endoscopic procedures (HEPs) for gastrointestinal bleeding (GIB) due to benign and malignant lesions, which all life-threatening conditions. HP acts as a mechanical barrier and/or promotes platelet activation and coagulation cascade. Malignancy causes comprise 1-5% of all non-variceal upper gastrointestinal bleeding (NVUGIB). UI-EWD (NexPowder) is composed of oxidized dextran and succinic anhydride, which is converted to an adhesive hydrogel upon contact with moisture. The resulting hydrogel cross-links within itself and with adjacent tissue to create a mechanical barrier to promote hemostasis. As it does not require clot formation to achieve hemostasis, UI-EWD does not require active bleeding. This provides it a potential role in prophylaxis, such as post-procedure or following primary hemostasis achieved with conventional endoscopic techniques. While UI-EWD is the newest development in hemostatic powders for clinical use, initial results are promising. We report the case of a 51-year-old male with epidermoid esophageal stenosing carcinoma recently diagnosed and locally advanced. Started treatment concurrent chemotherapy and radiotherapy, being necessary a nasogastric tube for parenteral nutrition. Our patient came to the emergency unit due to hematemesis which came from a pressure ulcer with active bleeding shown in gastroscopy exploration, withdrawing the tube and spraying onto the surface of the bleeding site UI-EWD until the bleeding lesion was completely covered with the powder, doing successful hemostasis confirmed by hemostasis until 5 minutes after the endoscopic treatment. HP is highly effective in patients with NVUGIB when used either in combination with or as rescue therapy. Rapid development of hemostatic powders and growing clinical expertise has established these agents as a valuable strategy in gastrointestinal bleeding.

'Immunotherapeutic Strategies for Intra-cranial Metastatic Melanoma - a Meta-analysis and Systematic Review'.

Immune-activating anti-CTLA4 and anti-PD1 monoclonal antibodies (alone or in combination) are being used to treat advanced melanoma patients and can lead to durable remissions, and long-term overall survival may be achieved in between 50-60% of patients. Although intracranial metastases are very common in melanoma (about 50-75% of all patients with advanced disease), most of the pivotal prospective clinical trials exclude patients with intra-cranial metastases, certainly if their lesions are symptomatic and steroid-requiring and the degree of sensitivity of intra-cranial melanoma to immunotherapy remains uncertain, and requires further investigation especially in view of the demonstrable activity of RAF-MEK inhibitors in this clinical setting and the emergence of stereotactic radiotherapy. Our study aimed to evaluate the efficacy and toxicity of immunotherapy against advanced melanoma patients with brain metastases. In terms of comparative studies, only retrospective analyses could be identified. Based on 3 retrospective studies, treatment of patients with melanoma brain metastases with immunotherapeutic approaches improves overall survival substantially compared with supportive measures alone (no active anticancer treatment). The efficacy of targeted therapy appeared to be comparable to that of immune therapy in terms of overall survival, based on a small number of patients. The combination of concurrent radiation therapy to the brain and systemic immunotherapy led to improved overall survival compared to radiotherapy alone, suggesting potential synergism between the approaches, and combination treatment could be delivered safely. Our review supports the use of immunotherapeutic strategies for these patients although treatment efficacy appears to be lower for symptomatic lesions. In view of the extremely high efficacy of stereotactic radiotherapy approaches in the brain, understanding the interaction between radiotherapy and immunotherapy is vital and should be an area of active investigation.

Efficacy and safety of cisplatin combined with paclitaxel concurrent radiotherapy in patients with locally advanced cervical squamous cell carcinoma

Efficacy and safety of cisplatin combined with paclitaxel concurrent radiotherapy in patients with locally advanced cervical squamous cell carcinoma

The Distant Molecular Effects on the Brain by Cancer Treatment.

Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.

Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study

Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n= 21; Vp3, n= 23; Vp4, n= 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. NCT04611165.

Advanced hepatocellular carcinoma with major portal vein invasion: Therapeutic outcomes of hepatic arterial infusion chemotherapy vs concurrent radiotherapy.

Hepatocellular carcinoma (HCC) with major portal vein invasion (MPVI) presents very poor outcomes. Hepatic artery infusion chemotherapy (HAIC) and radiation therapy (RT) have both been found to be effective for advanced HCC. In this retrospective study, we compared the therapeutic outcomes of our "new" HAIC regimen with and without concurrent RT, before and after propensity score matching (PSM) in treating HCC patients with MPVI. One hundred forty patients with MPVI received HAIC alone and 35 patients underwent concurrent HAIC and RT during a 16-year period. The left subclavian artery was adopted as the entry site for a temporary catheter placement for a 5-day chemoinfusion. The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was adopted to assess the objective response rate (ORR). The Kaplan-Meier curve was used to calculate progression-free survival (PFS) and overall survival (OS) between the two groups. Univariate and multivariate analyses by Cox regression model were used to assess hazard ratios. Of the 140 patients with Child-Pugh A liver function, the median OS was 17.0 months. In the initial cohort, higher ORR and PFS were found in the concurrent RT group than in the HAIC alone group (80% vs 66.4% and 9 vs 8 months, respectively) but shorter OS (10.5 vs 14.5 months, p = 0.039) was observed. After PSM, the OS was 10 and 15 months ( p = 0.012), respectively. Multivariable Cox regression analysis revealed that the significant factors for adjusting hazard ratios for OS were Child-Pugh classification, alpha fetal protein (AFP) level, and hepatic vein invasion. HAIC is an effective treatment for advanced HCC patients with MPVI. Concurrent HAIC and full-dose RT were associated with worse clinical outcomes.

Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients.

Standard-of-care first-line therapy for patients with newly diagnosed glioblastoma (ndGBM) is maximal safe surgical resection, then concurrent radiotherapy and temozolomide, followed by maintenance temozolomide. IGV-001, the first product of the Goldspire™ platform, is a first-in-class autologous immunotherapeutic product that combines personalized whole tumor-derived cells with an antisense oligonucleotide (IMV-001) in implantable biodiffusion chambers, with the intent to induce a tumor-specific immune response in patients with ndGBM. Here, we describe the design and rationale of a randomized, double-blind, phase IIb trial evaluating IGV-001 compared with placebo, both followed by standard-of-care treatment in patients with ndGBM. The primary end point is progression-free survival, and key secondary end points include overall survival and safety.

Effect of Neoadjuvant Concurrent Chemoradiation on Operability and Survival in Locally Advanced Inoperable Breast Cancer

PurposeInoperable locally advanced breast cancers (LABC) are treated with neoadjuvant chemotherapy (NACT). We studied the use of neoadjuvant concurrent chemoradiation (NACCRT) in patients with inoperable LABC. Patients and MethodsFrom May 2017 to Dec 2021, the study recruited patients with Stage III inoperable LABC. The treatment included 4 cycles of Adriamycin and Cyclophosphamide and 4 cycles of Paclitaxel, along with concurrent radiotherapy to a total dose of 46 Gy. Thereafter, all patients were evaluated for surgery, and additional treatments were given based on receptor status. The effects of NACCRT on the pathological complete response (pCR), operability, and survival were analyzed. ResultsThe study involved 202 female patients with a median age of 52 years. Of these, 23.7% had IIIA, 65.3% had IIIB, and 10.8% had IIIC disease. Hormone-receptor (HR) positive disease was observed in 44.6% of patients, triple-negative breast cancer (TNBC) in 24.8%, and HER2-positive disease in 30.7%. Modified radical mastectomy (MRM) was performed in 88.1% of patients, 8.5% remained inoperable, and 3.4% declined surgery. Among the patients who underwent MRM, 36.5% of patients had a pCR. Patients who were operable and underwent MRM had complete resections and had negative margins. pCR was observed in 16% with HR-positive disease, 45.6% with TNBC, and 60.7% with HER2-positive disease. Grade 3 skin reactions were observed in 19.3%. Postoperative wound morbidity requiring hospitalization was observed in 10.6% of patients.After a median follow-up of 42 months, the 4-year EFS and OS were 63.4% and 71.5%, respectively. HER2-positive patients who achieved pCR had significantly improved EFS and OS. ConclusionsOur study shows that using NACCRT can improve operability and survival outcomes in patients with inoperable LABC.

The Sensitization of Murine Hematopoietic Progenitors and Stem Cells to DNA Damaging Agents By Quizartinib Is Associated with the Transcriptional Downregulation of DNA Damage Repair Genes

Background: The FLT3 inhibitor quizartinib induces quiescence of murine hematopoietic progenitors, and this affords their protection from S phase specific chemotherapies. In this study we investigated whether quizartinib can also protect hematopoietic progenitors from the cytotoxic effects of DNA damaging chemotherapies and radiation. Methods: C57BL/6 mice were primed with 30 mg/kg of quizartinib or vehicle (5% cyclodextrin) by oral gavage, and treated with DNA damaging chemotherapies, either cyclophosphamide, carboplatin, cisplatin, temozolomide or mitoxantrone 6 hours later, or 5.5Gy total body irradiation (TBI) after 9 hours. This TBI dose represents half the 11 Gy split dose used for bone marrow conditioning of C57BL/6 mice prior to HSC transplantation. Bone marrow cells were analyzed by flow cytometry after 3 to 6 days to identify progenitor and stem cell populations. Results: In contrast to quizartinib's protection against the cytotoxic effects of 5-FU and gemcitabine, all 5 DNA-damaging chemotherapies caused an increased loss of total bone marrow cellularity when mice were primed with quizartinib compared to vehicle primed controls. Flow cytometry analysis revealed that the numbers of myeloid and multipotent progenitors, and short-term and long-term hematopoietic stem cells (HSCs), were markedly lower in the quizartinib-treated mice. DNA damage and the resultant cell death caused by ionizing radiation is cell cycle specific, particularly for cells traversing from G 1 to S phases of the cell cycle. The ability of quizartinib to induce quiescence in myeloid and multipotent progenitors suggested that quizartinib may protect these cells from radiation. To test this, mice were dosed with vehicle or 30 mg/kg of quizartinib and 9 hours later exposed mice to 5.5 Gy of TBI. Analysis of bone marrow cells at day 6 revealed that total bone marrow cellularity and the numbers of progenitor and stem cells were markedly reduced in quizartinib-dosed mice compared to vehicle controls. For subsequent experiments mice were treated with 3 Gy TBI because the combination of quizartinib and 5.5 Gy caused severe myeloablation. As part of a series of experiments examining the kinetics of quizartinib's sensitization of bone marrow cells we tested whether the sensitization was maintained when mice were dosed with quizartinib 24 hours prior to 3 Gy TBI. Analysis of bone marrow cells 6 days later revealed that quizartinib dosed mice showed a significantly greater loss of total bone marrow cells, progenitor cells and stem cells compared to vehicle dosed mice (Figure 1). To identify possible mechanisms by which quizartinib sensitizes hematopoietic progenitors to DNA damaging agents we investigated quantitative gene expression profiling of the HPC7 hematopoietic progenitor cell line. These cells provide a suitable in vitro model since quizartinib induces their quiescence and provides protection against 5-FU. HPC7 cells were treated with 100 µM quizartinib, or vehicle, for 18 hr before RNA was harvested and sent for Next-generation sequencing. We found that quiescence induction in HPC7 cells by quizartinib correlated with the transcriptional downregulation of a wide range of genes involved in DNA damage repair pathways (including Brca1/2, Rad51, Palb2, Chek1 and Nbn), thus providing a possible mechanism for the enhanced cytotoxic effects of DNA damaging agents. Conclusions: Quizartinib sensitizes hematopoietic progenitors and stem cells to DNA-damaging agents, an effect that correlates with the transcriptional downregulation of many DNA damage repair genes. The enhanced depletion of hematopoietic progenitors and stem cells by DNA damaging agents in the presence of quizartinib has important clinical implications. Administering concurrent DNA damaging chemotherapy or radiotherapy with quizartinib treatment should be avoided. However, this interaction could facilitate a reduction in radiation/chemotherapy doses administered for bone marrow conditioning prior to HSC transplantation. By reducing these doses, but not compromising the conditioning process, non-hematopoietic side effects could be minimized and may allow currently excluded patients to be considered for HSC transplantation. Disclosure: This study was partly funded by Daiichi Sankyo.