Platinum-based Chemoradiotherapy Research Articles

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer.

Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study.

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Dose-response relationships between radiation exposure, bone marrow function as measured by 18F-FLT PET, and lymphocyte counts during chemoradiation for non-small cell lung cancer

Purpose18F-Fluorothymidine(FLT)-PET enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/CT scans before and during chemoradiation (CRT) for non-small cell lung cancer (NSCLC) were repurposed to investigate dose-response effects of radiation on BM proliferation. Methods and materialsTwenty-six NSCLC patients underwent platinum-based CRT to 60Gy in 30 fractions with FLT-PET/CT scans at baseline, week 2 (20Gy) and week 4 (40Gy). FLT uptake in BM was isolated using Medical Image Merge software. Week 2 and week 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (SUVmax and visual parameters) were analyzed using generalized-linear and restricted cubic-spline models. Percentage volumes of total BM without appreciable FLT uptake (“ablated”) on week 2 and week 4 FLT-PET scans were calculated by comparisons with baseline scans. ResultsThoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3Gy by week 2. In all cases BM FLT SUVmax declined rapidly as radiation dose increased. BM proliferation significantly decreased by more than 95% after ≥3-4Gy at 2 weeks and ≥4-5Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. Median percentage of total BM ablated was 13.1% (range 5.6-20.3) at 2 weeks and 15.7% (range 9.2 - 24.1) at 4 weeks. Mean lymphocyte counts fell from baseline of 2.01×109/L to 0.77 week 2, and 0.60 week 4. Lymphocyte decline strongly correlated with percentage of total BM ablated by week 4 (y=-46 -1.64 x, R2adj = 0.34, p=0.001). ConclusionsBM ablation associated with low dose-radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ-at-risk and reducing the BM volume exposed to ≥3Gy may help preserve lymphocytes essential for effective adjuvant immunotherapy.

Small cell cancer of the esophagus, treatment outcomes of a rare histological type

Purpose: To demonstrate treatment outcomes in two patients with small cell esophageal cancer. Cases reports. Patient M. was assigned to receive polychemotherapy (PC H) composed of etoposide 100 mg/ m2 intravenously on days 1–3 + cisplatin 80 mg/m2 on day 1, every 21 days for 6 cycles and lanreotide 120 mg subcutaneously, every 28 days, followed by chemoradiotherapy (CRT). The patient received 1 cycle of PCT , which was well tolerated. Then, the patient received a cycle of 3D-conformal radiation therapy concurrently with 2 cycles of chemotherapy: etoposide 120 mg/m2 + cisplatin 80 mg/m2. Chemoradiotherapy was well tolerated. Dysphagia regression to grade I was observed. Currently, the patient continues to receive treatment (etoposide 100 mg/ m2 intravenously on days 1–3 + cisplatin 80 mg/m2 on day 1, every 21 days for 6 cycles and lanreotide 120 mg subcutaneously, every 28 days) and tolerates it well. Patient A. was assigned to receive PCT with etoposide 120 mg/m2 + cisplatin 80 mg/m2. After 4 cycles of PCT , the follow-up CT images revealed disease progression (enlarged retroperitoneal lymph nodes). The patient underwent external bean radiation therapy to the primary tumor. Radiotherapy was relatively well tolerated. The patient underwent the course of radiation therapy relatively satisfactorily. Due to the progression of the disease, symptomatic treatment was assigned. The patient died 9 months after diagnosis. Conclusion. Small cell carcinoma of the esophagus is a rare histological type with poor prognosis. Concurrent platinum-based chemoradiotherapy allows achievement of stable disease and disease control.

ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC).

LBA5 Background: The standard of care (SoC) for pts with LS-SCLC is concurrent platinum-based chemoradiotherapy (cCRT) ± prophylactic cranial irradiation (PCI). ADRIATIC (NCT03703297), a phase 3, randomized, double-blind, placebo (PBO)-controlled, multicenter, global study, assessed D ± tremelimumab (T) as consolidation tx for pts with LS-SCLC who had not progressed after cCRT. Here we report results for D vs PBO from the first planned interim analysis (IA). Methods: Eligible pts had stage I–III LS-SCLC (stage I/II inoperable) and WHO performance status 0/1, and had not progressed after cCRT. PCI was permitted before randomization. Pts were randomized 1–42 days after cCRT to D 1500 mg + PBO, D 1500 mg + T 75 mg, or PBO + PBO every 4 weeks (Q4W) for 4 cycles, followed by D (D±T arms) or PBO Q4W until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months (mo). The first 600 pts were randomized in a 1:1:1 ratio; subsequent pts were randomly assigned 1:1 to D or PBO. Randomization was stratified by stage (I/II vs III) and receipt of PCI (yes vs no). The dual primary endpoints were OS and PFS (blinded independent central review per RECIST v1.1) for D vs PBO. OS and PFS for D+T vs PBO were alpha-controlled secondary endpoints. Results: 730 pts were randomized, including 264 to D and 266 to PBO. Baseline characteristics and prior tx were well balanced between arms. Radiation schedule in the D vs PBO arms was once daily in 73.9% vs 70.3% of pts and twice daily in 26.1% vs 29.7%; 53.8% of pts in each arm received PCI. At this IA (data cutoff 15Jan2024), median (range) duration of follow-up for OS and PFS in censored pts was 37.2 (0.1–60.9) and 27.6 (0.0–55.8) mo, respectively. OS was significantly improved with D vs PBO (HR 0.73 [95% CI 0.57–0.93]; p=0.0104; median OS 55.9 [95% CI 37.3 – not estimable] vs 33.4 [25.5–39.9] mo; 24-mo OS rate 68.0% vs 58.5%; 36-mo OS rate 56.5% vs 47.6%). PFS was also significantly improved with D vs PBO (HR 0.76 [95% CI 0.61–0.95]; p=0.0161; median PFS 16.6 [95% CI 10.2–28.2] vs 9.2 [7.4–12.9] mo; 18-mo PFS rate 48.8% vs 36.1%; 24-mo PFS rate 46.2% vs 34.2%). Tx benefit was generally consistent across predefined pt subgroups for both OS and PFS. With D vs PBO, maximum grade 3/4 all-cause adverse events (AEs) occurred in 24.3% vs 24.2% of pts; AEs led to tx discontinuation in 16.3% vs 10.6% of pts and to death in 2.7% vs 1.9%. Any-grade pneumonitis/radiation pneumonitis was reported in 38.0% vs 30.2% of pts with D vs PBO (maximum grade 3/4 in 3.0% vs 2.6%). The D+T arm remains blinded until the next planned analysis. Conclusions: D as consolidation tx after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with PBO in pts with LS-SCLC. D was well tolerated and AEs were consistent with the known safety profile, with no new signals observed. These data support consolidation D as a new SoC for pts with LS-SCLC who have not progressed after cCRT. Clinical trial information: NCT03703297 .

Tisotumab vedotin in head and neck squamous cell carcinoma: Updated analysis from innovaTV 207 Part C.

6012 Background: Recurrent or metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) is treated in the first-line with an immunotherapy-based approach, including in combination with platinum-based chemotherapy or as monotherapy, or platinum-based combination plus targeted therapy. Still, most pts experience disease progression, and the efficacy of subsequent line treatment options is limited. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to tissue factor. TV at 1.7 mg/kg IV Q2W has demonstrated encouraging antitumor activity in 2L-4L r/m HNSCC from the innovaTV 207 (NCT03485209) study. Here, we present data from the full cohort, Part C. Methods: innovaTV 207 is an open-label, global, phase 2, multicohort, multicenter study evaluating TV monotherapy or in combination for advanced solid tumors. In Part C, pts with r/m HNSCC received TV monotherapy (1.7 mg/kg IV Q2W). All pts were required to have received a platinum-based regimen, either in the r/m setting, or have persistent disease following platinum-based chemoradiation and a checkpoint inhibitor (CPI), if eligible. Primary endpoint was confirmed objective response rate (cORR) per investigator. Secondary endpoints included duration of response (DOR), time-to-response (TTR), and safety. Results: As of 6 Sept 2023, 40 pts with HNSCC were treated. 39 (97.5%) pts received prior platinum-based therapy. In the r/m setting, 25 (62.5%) pts received ≤2 prior lines of systemic therapy (median: 2; range: 1-3), 40 (100%) pts received prior CPI, 23 (57.5%) pts received prior taxane, and 27 (67.5%) pts received prior cetuximab. The most common subsites at diagnosis were oropharynx (n=16, of which 12 were p16 positive), larynx (n=10), and oral cavity (n=9). In the full cohort, cORR was 32.5% (95% CI, 18.6-49.1), with 1 complete response and 12 partial responses. Median DOR was 5.6 mo (95% CI, 3.0-NR) and median TTR was 1.4 mo. Among pts with ≤2 prior lines (n=25), cORR was 40.0% (95% CI, 21.1-61.3). In this subgroup, DOR is not yet mature (range: 1.2+ to 7.9+ mo), and among the 10 responders, 6 pts remain in response; median TTR was 1.5 mo. In the full cohort, 85.0% of pts had at least 1 treatment-related adverse event (TRAE). Grade ≥3 TRAEs occurred in 25.0% of pts, of which the most common were peripheral neuropathy events (12.5%). Adverse events of special interest were prespecified for ocular, peripheral neuropathy, and bleeding events, and occurred in 21 (52.5%), 19 (47.5%), and 15 (37.5%) pts, respectively. Updated efficacy and safety data are planned. Conclusions: TV demonstrated encouraging antitumor activity in a heavily pretreated r/m HNSCC population with a manageable safety profile consistent with previous TV monotherapy data. The study is ongoing; TV represents a promising treatment option for pts with r/m HNSCC who have progressed after prior platinum-based therapy and immunotherapy. Clinical trial information: NCT03485209 .

Long-term outcomes of anlotinib and penpulimab combined with chemotherapy in the treatment of patients with metastatic nasopharyngeal carcinoma that failed definitive platinum-based chemoradiotherapy.

6040 Background: The median progression-free survival (mPFS) of anti-PD-1 monoclonal antibody (mAb) plus gemcitabine (G) and cisplatin (C) in the first-line treatment of metastatic nasopharyngeal carcinoma (M NPC) is still limited in about 10 ~12 months. The tolerance is also unfavorable, especially for patients (pts) who had undergone platinum-based chemoradiotherapy (CRT) previously. We performed a phase 2 study to explore the potency of replacing cisplatin with anloinib (A), a multi-kinase inhibitor in combined with penpulimab (P), a novel anti-PD-1 mAb as the first-line treatment of M NPC for pts with prior explosure of platinum-based CRT. Here we report the updated long term outcomes of this study. Methods: This is a prospective, three cohorts, single-arm study. Eligible pts were aged 18 ~ 75 years old, diagnosed with NPC and developed metastasis after platinum-based CRT. Pts who were diagnosed as having M NPC at the first visit or experienced treatment failure within 6 months after definitive CRT or adjuvant therapy were excluded. Pts were randomized to receive G + A + P (cohort GAP), G + C + A + P (cohort GCAP) or G+C+P (cohort GCP). Gemcitabine (1000mg/m2, d1, d8) and cisplatin (80mg/m2, d1) were given intravenously for 4 to 6 cycles, 3 weeks per cycle. Penpulimab (200mg, d1) and anlotinib (10mg, qd, d1-14) were given intravenously and orally respectively until disease progression, or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Results: 21 pts were randomized to three cohorts in lead-in phase while only cohort GAP was selected into expansion phase to enrolled another 7 pts. Finally, totally 28 pts were enrolled and received study treatment. The data cutoff date was December 1, 2023. The median follow-up was 20.2 month (95% CI: 17.0, 23.4). The results were summered in the table below. In cohort GAP, the confirmed ORR was 92.3% (95% CI: 64.0%, 99.8%) and the mPFS was still not reached (95% CI: NE, NE). The most common Grade 3 treatment-related adverse event (TRAE) was neutrophil count decreased (3 pts). Only one patient occurred Grade 4 TRAE (neutrophil count decreased) and no treatment-related death was observed. Conclusions: The long term outcomes of this phase 2 study preliminarily disclosed the advantage of the treatment regimen including gemcitabine, anlotinib and penpulimab as the first-line treatment of M NPC, especially for pts who had exposed to platinum-based chemotherapy. The further study with more sample size is warranted. Clinical trial information: NCT04736810 . [Table: see text]

Immunotherapy in thymic epithelial tumors: tissue predictive biomarkers for immune checkpoint inhibitors.

Thymic epithelial tumors (TETs) are rare malignant neoplasms arising in the thymus gland. Nevertheless, TETs, including thymomas (TMs), thymic carcinomas (TCs), and thymic neuroendocrine neoplasms (TNENs), are the most common mediastinal malignancies overall. A multidisciplinary approach is required for the appropriate diagnostic and therapeutic management of TETs. To date, the main therapeutic strategies are largely depended on the stage of the tumor and they include surgery with or without neoadjuvant or adjuvant therapy, represented by platinum-based chemotherapy, radiotherapy or chemoradiotherapy. Immune checkpoint inhibitors (ICIs) are ongoing under evaluation in the advanced or metastatic diseases despite the challenges related to the very low tumor mutation burden (TMB) and the high incidence of immune-related adverse events in TETs. In this regard, predictive impact of tissue biomarkers expression such as programmed cell death ligand-1 (PD-L1), and other emerging biomarkers, as well as their optimal and shared interpretation are currently under evaluation in order to predict response rates to ICIs in TETs.

Efficacy and safety of bevacizumab in neoadjuvant and concurrent chemoradiotherapy for refractory cervical cancer patients.

A platinum-based concurrent chemoradiotherapy (CCRT) is the standard treatment for refractory cervical cancer (CC). However, the recurrence of disease and the occurrence of metastasis remain prevalent. We observed the long-term efficacy and safety of bevacizumab combined with neoadjuvant chemotherapy (NACT) and CCRT in refractory CC. A total of 62 patients with refractory CC were enrolled in this study from January 2016 to December 2019. The NACT regimen included bevacizumab (7.5 mg/kg), docetaxel (75 mg/m2), and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. The CCRT regimen included bevacizumab (7.5 mg/kg) and cisplatin (75 mg/m2), administered tri-weekly for 2 cycles. A dose of 45-50 Gy was prescribed for external beam radiotherapy (EBRT), while 30-35 Gy in 4-5 fractions was prescribed for brachytherapy (BT). Among the patients, 21 patients (33.9%) were at stages IIB-IIIB, 8 patients (12.9%) were at stage IIIC1, 19 patients (30.6%) were at stage IIIC2, and 14 patients (22.6%) were at stage IVB. Pelvic, para-aortic, supraclavicular, and inguinal lymph node metastases were discovered in 41 patients (66.1%). The median follow-up was 49.8 months (12.3-82.7 months). The median tumor volumes pre-treatment, after NACT, and before BT were 84.64 ± 53.15 cm3, 1.64 ± 13.15 cm3, and 0 ± 1.5 cm3, respectively. Complete clinical response (cCR) rates after NACT and EBRT were 35.5% and 66.1%, respectively. Four years after the diagnosis, the overall survival (OS) rate was 78.6%, the local region-free survival (LRFS) rate was 91.3%, the disease-free survival (DFS) rate was 70.6%, and the distant metastasis-free survival (DMFS) rate was 81.4%. A total of 29 patients (46.8%) experienced grade 3/4 hematological toxicity, 3 patients (4.8%) experienced grade 3 gastrointestinal toxicities, and none experienced grade 5 adverse events. Bevacizumab combined with NACT and CCRT significantly improved cCR and OS in refractory CC with acceptable toxicity.

Concurrent simultaneous integrated boost radiotherapy and cetuximab in head and neck squamous cell cancer patients: is it feasible in daily clinical practice?

Locally advanced head and neck squamous cell carcinoma (LA-Hnscc) is a true therapeutical challenge in the modern era and the scientific community is trying to face this challenge with new therapeutical strategies, including combinations of monoclonal antibodies and radiation therapy. The aim of this study is to evaluate clinical outcomes in LA-Hnscc patients unfit to receive platinum-based chemotherapy, treated with concurrent simultaneous integrated boost-intensity modulated radiotherapy (Sib-Imrt) + cetuximab (Ctx) in daily clinical practice. LA-Hnscc patients not included in other prospective studies treated in 4 Italian radiotherapy units (2 Messina, 1 Rome, and 1 Lecce) using Sib-Imrt and Ctx were included in this study. Acute and late toxicities and overall survival (OS) have been evaluated. Data regarding 27 patients with squamous tumour were collected and reviewed. The primary tumour sites were oropharynx in 14 patients (51.9%), oral cavity in 7 (25.9%), larynx in 3 (11%) and other sites in 3(11%). There were 20 (74%) patients had stage IV (16 IVa and 4 IVb). Complete remission was observed in 18 patients (66.7%), a partial remission in 4 (14.8%) whilst 4 had a progression disease (14.8%). After 3 year of follow-up 7/27 patients were deaths. The OS was 95.5%, 62.5% and 52.9% respectively at 1,2 and 3 years. Acute toxicities were observed in all treated patients (mucositis, dermatitis and dysphagia) while 66.7% of patients developed late toxicities. All observed toxicities were grade 1 to 3 and just 1 patient developed a G4 toxicity. The concurrent bio-radiotherapy of Sib-Imrt and cetuximab is feasible in real-life daily clinical practice for LA-Hnscc patients unfit for platinum-based chemoradiotherapy.

Platinum-based adjuvant chemoradiotherapy versus adjuvant radiotherapy in patients with head and neck adenoid cystic carcinoma

PurposeThe objective of the study was to assess the effectiveness and toxicity of platinum-based adjuvant chemoradiotherapy (POCRT) in comparison to postoperative radiotherapy (PORT) in patients with head and neck adenoid cystic carcinoma (HNACC).Materials and methodsThis retrospective study analyzed patients diagnosed with HNACC at our center between January 2010 and April 2020. A 1:1 propensity score matching method was used to create a matched cohort.ResultsIn this study, 206 patients were analyzed, with 147 patients (71.4%) receiving postoperative radiotherapy (PORT) and 59 patients (28.6%) receiving POCRT. Twenty-one patients experienced local–regional failure. The 3-, 5-, and 10-yr local–regional control (LRC) rate for the cohort were 92.0%, 90.6%, and 86.9%, respectively. In both the entire cohort and the matched cohort, the POCRT group exhibited superior LRC compared to the PORT group (Gray's test, all P < 0.05*). Multivariate analysis identified adjuvant concurrent chemotherapy as an independent prognostic factor for LRC (Competing risks regression, HR = 0.144, 95% CI 0.026–0.802, P = 0.027*). In addition, the POCRT group had higher incidences of upper gastrointestinal toxicity and hematologic toxicities, including leukopenia, neutropenia, and anemia (all P < 0.05*).ConclusionIn terms of reducing locoregional failures in HNACC patients, POCRT may potentially offer a more effective therapeutic approach than using PORT alone, although it also entails an augmented burden of treatment-related toxicity.

Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma.

Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy. Patients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors. Ten patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available in situ hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%. TP53 mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (p = 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were NF1, KMT2D, PIK3C2B, and TFGBR2. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples. Chemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.

Body composition radiomic features as a predictor of survival in patients with non-small cellular lung carcinoma: A multicenter retrospective study

ObjectivesThis study combined two novel approaches in oncology patient outcome predictions—body composition and radiomic features analysis. The aim of this study was to validate whether automatically extracted muscle and adipose tissue radiomic features could be used as a predictor of survival in patients with non-small cell lung cancer. MethodsThe study included 178 patients with non-small cell lung cancer receiving concurrent platinum-based chemoradiotherapy. Abdominal imaging was conducted as a part of whole-body positron emission tomography/computed tomography performed before therapy. Methods used included automated assessment of the volume of interest using densely connected convolutional network classification model - DenseNet121, automated muscle and adipose tissue segmentation using U-net architecture implemented in nnUnet framework, and radiomic features extraction. Acquired body composition radiomic features and clinical data were used for overall and 1-y survival prediction using machine learning classification algorithms. ResultsThe volume of interest detection model achieved the following metric scores: 0.98 accuracy, 0.89 precision, 0.96 recall, and 0.92 F1 score. Automated segmentation achieved a median dice coefficient >0.99 in all segmented regions. We extracted 330 body composition radiomic features for every patient. For overall survival prediction using clinical and radiomic data, the best-performing feature selection and prediction method achieved areas under the curve–receiver operating characteristic (AUC-ROC) of 0.73 (P < 0.05); for 1-y survival prediction AUC-ROC was 0.74 (P < 0.05). ConclusionAutomatically extracted muscle and adipose tissue radiomic features could be used as a predictor of survival in patients with non-small cell lung cancer.

Polyamine transport inhibition and cisplatin synergistically enhance tumor control through oxidative stress in murine head and neck cancer models

BackgroundSurgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells. MethodsCell proliferation was measured in syngeneic mouse HNSCC cell lines treated with cisplatin ± AMXT-1501. Synergy was determined by administering cisplatin and AMXT-1501 at a ratio of 1:10 to cancer cells in vitro. Cancer cells were transferred onto mouse flanks to test the efficacy of treatments in vivo. Reactive oxygen species (ROS) were measured. Cellular apoptosis was measured with flow cytometry using Annexin V/PI staining. High-performance liquid chromatography (HPLC) was used to quantify polyamines in cell lines. Cell viability and ROS were measured in the presence of exogenous cationic amino acids. ResultsThe combination of cisplatin and AMXT-1501 synergize in vitro on HNSCC cell lines. In vivo combination treatment resulted in tumor growth inhibition greater than either treatment individually. The combination treatment increased ROS production and induced apoptotic cell death. HPLC revealed the synergistic mechanism was independent of intracellular polyamine levels. Supplementation of cationic amino acids partially rescued cancer cell viability and reduced ROS. ConclusionAMXT-1501 enhances the cytotoxic effects of cisplatin in vitro and in vivo in aggressive HNSCC cell lines through a polyamine-independent mechanism.

Progression-Free Survival as a Surrogate Endpoint of Overall Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiotherapy: Trial-Level Meta-Analysis and Individual-Level Analysis of NRG/RTOG 0617 and PROCLAIM

Overall Survival (OS) is the gold standard endpoint in randomized clinical trials (RCTs) of Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC). Intermediate endpoints that can be observed at earlier time points and predict OS would improve trial efficiency and expedite the adoption of proven interventions. Atrial-level meta-analysis was conducted using a weighted regression analysis to quantify the correlation between PFS and OS hazard ratios (HRs). Large (n≥ 100) contemporary RCTs in LA-NSCLC that used platinum-based chemoradiation were included. An individual-level surrogacy analysis based on Prentice criteria was performed to evaluate if PFS could reliably predict OS using NRG/RTOG 0617 (NCT00533949), a phase III RCT of dose escalated CRT. The individual-level correlation between PFS and OS was validated using PROCLAIM (NCT00686959) control arm. Nineteen RCTs comprising a total of 5525 patients (pts) were included in the trial-level meta-analysis. A moderately high correlation was observed between PFS HR and OS HR (R2 = 0.68, 95% CI = 0.42-0.94). Individual-level analysis of NRG/RTOG 0617 showed that, as reported, RT dose was associated with OS (HR = 1.28, 95% CI = 1.04-1.58, p = 0.02) and PFS (HR = 1.21, 95% CI = 0.99-1.46, p = 0.06). Progressive disease (PD) was highly associated with OS, where pts having PD within 6mo or 12mo had a significantly higher mortality risk than those not having PD within 6mo or 12 mo, respectively, in landmark analysis (PD within 6mo: HR = 2.56, 95% CI = 1.82-3.59, p<0.0001; PD within 12mo: HR = 3.18, 95% CI = 2.45-4.12, p<0.0001). Accounting for PD moderately reduced RT dose effect on OS (HR = 1.21, 95% CI = 0.98-1.49), suggesting RT dose effect on OS may be mediated partially through PD. The association between OS and PD occurrence within 6mo or 12mo was similar in PROCLAIM control arm (PD within 6mo: HR = 2.06, 95% CI = 1.48-2.86, p<0.0001; PD within 12mo: HR = 2.02, 95% CI = 1.38-2.95, p<0.0001). A moderately high trial-level surrogacy between PFS and OS was identified in trial-level meta-analysis. PD occurrence also reliably predicted OS at the individual patient level in both NRG/RTOG 0617 and PROCLAIM. These results support the use of PFS as a valid endpoint in clinical trials of LA-NSCLC.

Clinical Significance of Arginine Signaling in Patients with Cervical Cancer Receiving Cisplatin Chemoradiation Therapy

Many human malignancies do not produce sustainable amounts of arginine (Arg) because the rate-limiting enzyme, arginosuccinate synthetase 1 (ASS1), in the biosynthesis of Arg has been silenced. We investigated the clinical significance of ASS1 expression on cisplatin chemoradiation therapy for cervical cancer. A total of 118 consecutive patients with FIGO stages IB to IVA cervical cancer who had received platinum-based concurrent chemoradiotherapy were identified and their clinical courses were reviewed. Immunohistochemical studies were performed on their formalin-fixed, paraffin-embedded tissues. The prognostic value of ASS1 was investigated by performing univariate and multivariate analyses on factors affecting patient survival. Median follow-up for all patients was 5.5 years (range: 1 to 23.5 years). Overexpression of ASS1 was an independent prognostic factor. The 5-year disease-free survival for patients with ASS1-positive tumors was 72.3%, compared with 51.6% for patients with ASS1-negative tumors (P = 0.02). Univariate Cox proportional hazards models showed positive ASS1 immunostaining (hazard ratio [HR]: 0.50, 95% CI: 0.28-0.90), FIGO stage (HR: 0.33, 95% CI: 0.18-0.59) and brachytherapy (HR: 0.22, 95% CI: 0.10-0.48) were significant prognostic factors affecting disease-free survival. In multivariate analyses, positive ASS1 remained an independent significant prognostic factor for DFS (HR = 0.45, 95% CI: 0.25-0.83). Overexpression of ASS1 is an independent prognostic factor for cervical cancer patients receiving cisplatin concurrent chemoradiotherapy.

Hypomagnesemia and Survival in Patients with Cervical Cancer Treated with Definitive Chemoradiotherapy

Hypomagnesemia is a common side effect of platinum-based chemotherapy regimens. Although there are data reporting that hypomagnesemia is associated with worse survival in patients receiving platinum-based chemotherapy or chemoradiotherapy (CRT), this has not been documented in patients with cervical cancer treated with definitive CRT. We hypothesized that in patients with cervical cancer undergoing definitive CRT, on-treatment hypomagnesemia would be associated with longer treatment duration and worse cancer-specific survival (CSS). Patients with cervical cancer treated with definitive CRT from 1999 to 2015 were identified from a single cancer center's clinicopathologic database. Lowest on-treatment magnesium value was recorded and categorized as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading (grade 1: <0.7 - 0.5 mmol/L, grade 2: <0.5 - 0.4 mmol/L, grade 3: <0.4-0.3 mmol/L, and grade 4 <0.3 mmol/L). Grade 0 was defined as ≥ 0.7 mmol/L. Treatment duration was defined as the number of days between the first day of radiotherapy until the last day of pelvic treatment (either brachytherapy or pelvic external beam radiotherapy boost). Prolonged treatment was considered as any treatment duration greater than 63 days. CSS for patients with either grade 0-1 or grade ≥ 2 CTCAE v5.0 magnesium toxicity was estimated using the Kaplan-Meier method, and the Peto & Peto modification to the generalized Gehan-Wilcoxon was used to determine statistical significance between groups. Associations with prolonged treatment duration was explored using logistic regression. P-values of <0.05 were considered statistically significant. A total of 186 patients were identified; median follow-up was 7 (IQR 2-11) years. 125 (67%) had stage I-II disease and 61 (33%) stage III-IV. Median treatment duration was 51 (IQR 48-57) days. All patients received concurrent weekly cisplatin-based chemotherapy with RT: the majority (n = 133; 72%) received 5 or 6 cycles. 147 (79%) patients received routine IV magnesium infusion with their chemotherapy and 173 (93%) received routine IV mannitol. During treatment the highest CTCAE v5.0 magnesium toxicity score was grade 0-1 in 158 (85%) and grade ≥ 2 in 28 (15%). Magnesium grade ≥ 2 was associated with worse 5-year CSS [grade 0-1: 5yr CSS 67.2%, (95% CI 60.1-75.1); grade ≥ 2: 5yr CSS 50%, (95% CI 34.5-72.4); p = 0.039]. Magnesium status was not associated with an increase in treatment duration [OR 1.465 (95% CI 0.3177 - 6.753); p = 0.625]. On-treatment hypomagnesemia ≥ grade 2 (CTCAE v5.0) was associated with worse CSS but did not predict longer treatment duration. This is the first study that shows a detrimental survival impact of on-treatment hypomagnesemia in this patient population. These findings highlight the need to ensure adequate monitoring, support and correction of magnesium during definitive CRT.

Adjuvant Radiation Therapy Improves Local Control in the Treatment of Adnexal Carcinoma

Adnexal carcinoma (AC) is a rare subset of cutaneous malignancies derived from skin adnexa. There are limited data on the role of adjuvant radiation therapy (RT). This study investigates outcomes associated with adjuvant RT at our high-volume referral center. Using an institutional pathology database we identified 45 patients with locoregionally-confined AC treated between 2001-2020 with curative intent surgery and RT at initial diagnosis or at the time of locoregionally-confined recurrence. Clinicopathologic variables were described and time to relapse events were assessed by the Kaplan-Meier method. Median age was 64 yrs (IQR 57-71). Primary tumors were in the head and neck (H&N, n = 36, 80%), trunk/extremities (n = 8, 18%) or unknown (n = 1). The most common histologic subtypes were: sebaceous-14 (31%), microcystic adnexal carcinoma-9 (20%), eccrine-6 (13%), and trichilemmal-5 (11%). Twenty-two (50% of known primaries) had PNI. All patients had primary tumor excision. Six had clinically evident lymphadenopathy (13%), all of whom had lymph node dissection (LND). Five patients without evidence of nodal disease (13%) had sentinel lymph node biopsy (SLNB) with one having SLN+ disease. Thirty patients (67%) received adjuvant locoregional RT at initial diagnosis with the following targets: 21 (30%) primary only, 4 (13%) nodal only, and 5 (17%) both. Of those receiving nodal RT, 7 (78%) had LN+ LND with 2 of those receiving concurrent platinum-based chemoradiation. Sixteen were treated at recurrence with the following targets: 4 (25%) primary only (1 having had prior adjuvant nodal RT), 4 (25%) nodal only, and 8 (50%) both. Across the full cohort, median RT dose was 60 Gy in 30 fractions. Median follow-up from initial surgical resection was 60 months (IQR 30-160). 5-year LC, NC, DFS and DSS were 71%, 86%, 66%, and 91% respectively. The only evaluated factor associated with better outcome was adjuvant primary site RT (5-yr LC 83% vs. 56%, p = 0.01 and 5-yr DFS 83% vs. 46%, p = 0.0003). All 15 patients with local recurrence (LR) had salvage surgery with median subsequent follow-up of 75 months (IQR 2-94). Overall, 5 patients receiving adjuvant primary site RT at any time (initial or salvage) developed subsequent local recurrence (13%). Of the 8 patients who developed nodal recurrence (NR) during follow-up, 1 received adjuvant nodal RT at initial diagnosis. Six of 7 who did not receive prior RT then received adjuvant nodal RT after LND and only 1 developed subsequent NR. AC is a rare skin cancer with a primarily locoregional recurrence pattern. In our experience, adjuvant RT was associated with improved LC which, depending on the tumor location, may help prevent morbid or cosmetically-impactful salvage surgery. Patients with AC would benefit from radiation oncology referral to discuss adjuvant treatment.

Comorbidity in limited disease small-cell lung cancer: Age-adjusted Charlson comorbidity index and its association with overall survival following chemoradiotherapy.

Combined, platinum-based thoracic chemoradiotherapy (TCR) is the current state-of-the-art treatment for patients with limited disease (LD) small-cell lung cancer (SCLC). There is only limited data available regarding the effect of comorbidities on survival following TRC. The purpose of this study is to assess the age-adjusted Charlson comorbidity index (ACCI) as a predictor of overall survival in LD-SCLC patients undergoing TCR. We retrospectively analyzed 367 SCLC patients diagnosed with LD-SCLC who received TCR between 2003 and 2017. We evaluated the ACCI (n=348) as a predictor of overall survival (OS). In this cohort, 322 patients (88%) received platinum-based TCR (either cisplatin or carboplatin), and 37 (10%) patients received vincristine based TCR. Median radiation dose was 60Gy (range 24-66Gy). Additionally, 83% of patients (n=303) received prophylactic cranial irradiation (PCI, 30Gy in 2Gy fractions). Kaplan-Meier survival analysis was performed for OS. For comparison of survival curves, Log-rank (Mantel-Cox) test was used. Univariate and multivariate Cox proportional-hazards ratios (HRs) were used to assess the influence of cofactors on OS. Patients with an ACCI>6 had a significantly shorter OS compared with patients with an ACCI≤6 (median 11 vs. 20months; p=0.005). Univariate analysis for OS revealed a statistically significant effect for ACCI>6 (HR 1.7; 95% CI 1.2-2.4; p=0.003), PCI (HR 0.5; 95% CI 0.3-0.7; p<0.001), and Karnofsky performance status≤70% (KPS) (HR 1.4; 95% CI 1.1-1.90; p=0.015). In multivariate analysis, OS was significantly associated with PCI (HR 0.6; 95% CI 0.4-0.9; p=0.022) and ACCI>6 (HR 1.5; 95% CI 1.0-2.1; p=0.049). Comorbidity is significantly associated with survival in patients with LD-SCLC undergoing TCR. The ACCI may be a valuable tool to identify patients with a shorter survival and thus might be used for risk stratification and oncological decision making.

Efficacy of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine for the prevention of mucositis induced by platinum-based chemoradiation in head and neck cancer: A phase II study

The current standard treatment modality for advanced head and neck squamous cell carcinoma (HNSCC), namely platinum-based (PB) concurrent chemoradiotherapy (CRT), is associated with frequent severe mucositis which is responsible for the multiple acute and late adverse events. So far, effective preventive methods for this CRT-induced mucositis are not identified. In the current study, we examined the prophylactic effects of beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) (HMB/Arg/Gln) mixture. Patients with HNSCC who were subject to PBCRT were randomly assigned to HMB/Arg/Gln intervention (Group I) and non-intervention (Group NI) cohort. The incidences of ≧ grade 3 mucositis (primary endpoint), ≧ grade 2 mucositis, and opioid usage and the degree of body weight loss (secondary endpoints) were compared between Group I and Group NI. A total of 75 patients were enrolled to this study and 38 patients were assigned to Group I, while 37 patients were to Group NI. After excluding patients who failed to complete CRT (3 in Group I and 2 in Group NI) or withdrew consents (11 in Group I and 1 in Group NI), 24 patients in Group I and 34 patients in Group NI were evaluated. HMB/Arg/Gln failed to reduce the incidences of ≧ grade 2 mucositis, but significantly (p=0.0003) inhibited grade 3 mucositis in the late phase CRT, reducing the incidence from 64.6% (Group NI) to 25% (Group I) at 70Gy. The degree of body weight loss was significantly (p=0.0038) lower in Group I (5.6%) compared to Group NI (8.9%), preventing the progression of PBCRT-induced cachexia. HMB/Arg/Gln administration demonstrated inhibitory effects on the progression of grade 3 mucositis and cancer cachexia in HNSCC patients treated with PBCRT. A larger scale phase III study is encouraged. This study is registered to the UMIN Clinical Trial Registry: UMIN000050011.